KR20220162364A - 신규 스퀘어아마이드 유도체 및 이의 용도 - Google Patents
신규 스퀘어아마이드 유도체 및 이의 용도 Download PDFInfo
- Publication number
- KR20220162364A KR20220162364A KR1020210070727A KR20210070727A KR20220162364A KR 20220162364 A KR20220162364 A KR 20220162364A KR 1020210070727 A KR1020210070727 A KR 1020210070727A KR 20210070727 A KR20210070727 A KR 20210070727A KR 20220162364 A KR20220162364 A KR 20220162364A
- Authority
- KR
- South Korea
- Prior art keywords
- amino
- trans
- cyclohexyl
- cyclobut
- dione
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 101100072149 Drosophila melanogaster eIF2alpha gene Proteins 0.000 claims abstract description 20
- 230000026731 phosphorylation Effects 0.000 claims abstract description 18
- 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 18
- 230000002503 metabolic effect Effects 0.000 claims abstract description 8
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 460
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 408
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 269
- RGBVWCQARBEPPW-UHFFFAOYSA-N cyclobut-3-ene-1,2-dione Chemical compound O=C1C=CC1=O RGBVWCQARBEPPW-UHFFFAOYSA-N 0.000 claims description 225
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 49
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
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- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 7
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- 102000005877 Peptide Initiation Factors Human genes 0.000 claims description 6
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
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- -1 phenoxy-cyclohexyl structure Chemical group 0.000 abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 6
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 4
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- 125000003277 amino group Chemical group 0.000 abstract description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract description 2
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- PWEBUXCTKOWPCW-UHFFFAOYSA-L squarate Chemical group [O-]C1=C([O-])C(=O)C1=O PWEBUXCTKOWPCW-UHFFFAOYSA-L 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
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- DOQJUPYDMNCIIJ-UHFFFAOYSA-N 3-(3-chloroanilino)-4-methoxycyclobut-3-ene-1,2-dione Chemical compound O=C1C(=O)C(OC)=C1NC1=CC=CC(Cl)=C1 DOQJUPYDMNCIIJ-UHFFFAOYSA-N 0.000 description 4
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- GSXABZZESQXKFW-UHFFFAOYSA-N 3-(4-tert-butylanilino)-4-methoxycyclobut-3-ene-1,2-dione Chemical compound O=C1C(=O)C(OC)=C1NC1=CC=C(C(C)(C)C)C=C1 GSXABZZESQXKFW-UHFFFAOYSA-N 0.000 description 4
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Abstract
본 발명은 신규 스퀘어아마이드 유도체 및 이의 용도에 관한 것으로, 유레아 모핵의 화합물을 생물학적 동등체(bioisostere)인 스퀘어아마이드로 치환하는 전략으로 eIF2α 인산화 효능을 통한 항암 활성을 나타내는 신규 유도체를 제공한다. 스퀘어아마이드는 카보닐 기에 연결된 이중 결합을 지닌 특이적인 구조를 포함한다. 사각 고리의 스쿼레이트 환에 아민기를 지닌 전구체를 컨쥬게이트 첨가 반응으로 매개하여 스퀘어아마이드 구조를 만들 수 있다. 본 발명은 다양한 치환기를 지닌 아닐린 환을 스퀘어아마이드에 도입한 핵심 중간체를 효율적으로 구축하고, 이를 활용하여 반대편 질소에 페녹시사이클로헥실 구조를 도입한 유도체를 제공한다. 합성된 신규 유도체는 eIF2α 인산화 효과 및 인 비트로(in vitro)에서 암세포 증식 저해 활성을 보이므로, 대사항암제로서 활용될 수 있다.
Description
본 발명은 신규 스퀘어아마이드 유도체 및 이의 용도에 관한 것이다.
세포는 다양한 스트레스 상황에 직면하게 될 때 통합 스트레스 반응 (integrated stress response) 경로를 활성화하여 세포 내 변화에 대응하기 위해 단백질의 합성을 조절한다. 진핵생물에서 통합 스트레스 반응은 진핵생물 번역 개시 인자(eukaryotic translation initiation factor 2α; eIF2α)의 인산화로 수렴되며, 이는 스트레스를 감지하는 4종의 eIF2α 카이네이즈(HRI, PERK, GCN2, PKR)의 활성화로 인해 매개된다. eIF2α의 인산화가 일어나면 전반적인 단백질 합성은 저해되고, 역설적으로 스트레스에 대처하는 인자인 ATF4 등은 발현이 증가하여 결과적으로 세포의 정상 상태로의 회복을 촉진한다. eIF2α는 세포의 암화 과정에서 과발현 되는 특성을 지니며, 하부 신호전달을 통해 세포 내 단백질의 합성을 조절하므로, eIF2α의 인산화를 암세포 특이적인 대사 조절 표적으로 간주할 수 있다. 최근의 연구로부터 eIF2α의 인산화를 촉진하여 항암 효과를 유도할 수 있음이 보고되었으며, Halperin 연구팀이 개발한 유레아 모핵을 지닌 화합물의 eIF2α 인산화 효능 및 항암 활성이 우수함을 확인하였다 (J. Med. Chem. 2013, 56, 9457). 하지만, 현재까지 임상시험 단계로 진입한 eIF2α 인산화 효능이 있는 저분자 후보물질은 보고된 바가 없다. 따라서, 추가 연구의 필요성이 충분하며, 이 기전을 이용한 대사항암제를 개발할 수 있을 것으로 기대된다. 현재 대사항암제는 백혈병에서 효력이 좋음이 가장 잘 알려져 있으며, 그 이외에도 유방암, 뇌종양, 육종 등의 희귀암에서도 좋은 효과를 나타낸다는 연구 결과가 보고되었다. eIF2α 인산화 조절을 통한 대사항암제가 개발된다면, 앞서 언급한 여러 암 이외에도 eIF2α의 상위 신호전달 인자인 HRI, PERK, GCN2, PKR의 이상 발현과 관련이 있는 희귀암의 치료에도 이용할 수 있을 것이다.
본 발명의 목적은 신규 스퀘어아마이드 유도체 화합물을 제공하는 데에 있다.
본 발명의 다른 목적은 상기 신규 스퀘어아마이드 유도체 화합물을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공하는 데에 있다.
본 발명의 또 다른 목적은 상기 신규 스퀘어아마이드 유도체 화합물을 유효성분으로 함유하는 암 예방 또는 개선용 건강기능식품 조성물을 제공하는 데에 있다.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 스퀘어아마이드 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물을 제공한다.
[화학식 1]
상기 화학식 1에서,
R1, R2 및 R4는 각각 동일하거나 다를 수 있고, 수소(H), 하이드록시(OH), 할로겐, 트리플루오로메틸(CF3), (C1~C4)알킬, (C1~C4)알콕시 및 아세테이트(COOMe)로 이루어진 군에서 선택되고,
R3은 수소(H) 및 시아노(CN)로 이루어진 군에서 선택되며,
R5는 트리플루오로메틸기(CF3), 시아노(CN), 나이트리트(NO2), (C1~C4)알킬술포닐(SO2Me) 및 아미노술포닐(SO2NH2)로 이루어진 군에서 선택된다.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공한다.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 대사항암제용 약학조성물을 제공한다.
또한, 본 발명은 상기 화합물을 투여하는 단계를 포함하는 암세포 대사 억제방법을 제공한다.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 개선용 건강기능식품 조성물을 제공한다.
본 발명은 신규 스퀘어아마이드 유도체 및 이의 용도에 관한 것으로, 유레아 모핵의 화합물을 생물학적 동등체(bioisostere)인 스퀘어아마이드로 치환하는 전략으로 eIF2α 인산화 효능을 통한 항암 활성을 나타내는 신규 유도체를 제공한다. 스퀘어아마이드는 카보닐 기에 연결된 이중 결합을 지닌 특이적인 구조를 포함한다. 사각 고리의 스쿼레이트 환에 아민기를 지닌 전구체를 컨쥬게이트 첨가 반응으로 매개하여 스퀘어아마이드 구조를 만들 수 있다. 본 발명은 다양한 치환기를 지닌 아닐린 환을 스퀘어아마이드에 도입한 핵심 중간체를 효율적으로 구축하고, 이를 활용하여 반대편 질소에 페녹시사이클로헥실 구조를 도입한 유도체를 제공한다. 합성된 신규 유도체는 eIF2α 인산화 효과 및 인 비트로(in vitro)에서 암세포 증식 저해 활성을 보이므로, 대사항암제로서 활용될 수 있다.
도 1은 N,N'-스퀘어아마이드 유도체들의 설계 전략을 나타낸다.
도 2는 스퀘어아마이드 유도체의 중간체 7a-r의 합성 과정을 나타낸다.
도 3은 스퀘어아마이드 유도체 8-86의 합성 과정을 나타낸다.
도 2는 스퀘어아마이드 유도체의 중간체 7a-r의 합성 과정을 나타낸다.
도 3은 스퀘어아마이드 유도체 8-86의 합성 과정을 나타낸다.
이하, 본 발명을 보다 상세하게 설명한다.
단백질 합성의 개시에서 중요한 단계로 eIF2, GTP, 그리고 Met-tRNAi로 구성되는 복합체의 형성이 있다. 이 복합체는 정상적인 세포 기능을 수행하는데 중요한 역할을 하며, 그 조절에 이상이 있을 경우 여러 가지 질병을 유발하는 것으로 알려져 새로운 치료제 개발의 타겟으로 주목받고 있는데, 본 발명자들은 다양한 치환기를 지닌 아닐린 환을 스퀘어아마이드에 도입한 핵심 중간체를 효율적으로 구축하고, 이를 활용하여 반대편 질소에 페녹시사이클로헥실 구조를 도입한 유도체를 합성하였으며, 이렇게 합성된 신규 유도체는 eIF2α 인산화 효과 및 인 비트로(in vitro)에서 암세포 증식 저해 활성을 보이는 것을 확인하고, 본 발명을 완성하였다.
본 발명은 하기 화학식 1로 표시되는 스퀘어아마이드 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물을 제공한다.
[화학식 1]
상기 화학식 1에서,
R1, R2 및 R4는 각각 동일하거나 다를 수 있고, 수소(H), 하이드록시(OH), 할로겐, 트리플루오로메틸(CF3), (C1~C4)알킬, (C1~C4)알콕시 및 아세테이트(COOMe)로 이루어진 군에서 선택되고,
R3은 수소(H) 및 시아노(CN)로 이루어진 군에서 선택되며,
R5는 트리플루오로메틸기(CF3), 시아노(CN), 나이트리트(NO2), (C1~C4)알킬술포닐(SO2Me) 및 아미노술포닐(SO2NH2)로 이루어진 군에서 선택될 수 있다.
바람직하게는, 상기 스퀘어아마이드 유도체 화합물은 화학식 1에서 R1은 수소(H), 플루오린(F), 염소(Cl), (C1~C2)알콕시, 트리플루오로메틸(CF3) 및 (C3~C4)알킬로 이루어진 군에서 선택되며, R2는 수소(H), 플루오린(F), 염소(Cl), 트리플루오로메틸(CF3), (C3~C4)알킬, (C1~C2)알콕시 및 아세테이트(COOMe)로 이루어진 군에서 선택되며, R3은 수소(H) 및 시아노(CN)로 이루어진 군에서 선택되며, R4는 수소(H), 플루오린(F), 염소(Cl), (C1~C2)알콕시, 트리플루오로메틸(CF3) 및 (C3~C4)알킬로 이루어진 군에서 선택되며, R5는 트리플루오로메틸기(CF3), 시아노(CN), 나이트리트(NO2), (C1~C2)술포닐(SO2Me) 및 아미노술포닐(SO2NH2)로 이루어진 군에서 선택될 수 있다.
보다 바람직하게는, 상기 스퀘어아마이드 유도체 화합물은 화학식 1에서 R1은 수소(H), 플루오린(F), 염소(Cl), 메톡시(OMe), 트리플루오로메틸(CF3) 및 t-부틸(t-Bu)로 이루어진 군에서 선택되며, R2는 수소(H), 플루오린(F), 염소(Cl), 트리플루오로메틸(CF3), t-부틸(t-Bu), 메톡시(OMe) 및 아세테이트(COOMe)로 이루어진 군에서 선택되며, R3은 수소(H) 및 시아노(CN)로 이루어진 군에서 선택되며, R4는 수소(H), 플루오린(F), 염소(Cl), 메톡시(OMe), 트리플루오로메틸(CF3) 및 t-부틸(t-Bu)로 이루어진 군에서 선택되며, R5는 트리플루오로메틸기(CF3), 시아노(CN), 나이트리트(NO2), 메틸술포닐(SO2Me) 및 아미노술포닐(SO2NH2)로 이루어진 군에서 선택될 수 있다.
일 실시예로는, 상기 스퀘어아마이드 유도체 화합물은 3-(페닐아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-(Phenylamino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-(페닐아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((3,4-Dioxo-2-(phenylamino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-4-(페닐아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-(phenylamino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(메틸설포닐)페녹시)시클로헥실)아미노)-4-(페닐아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-(phenylamino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-(페닐아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((3,4-Dioxo-2-(phenylamino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔[3-((3-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene], 4-(((1,4-트랜스)-4-((2-((3-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((3-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((3-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((3-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸설포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((3-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-클로로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((3-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((3-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((3-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸설포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-클로로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((3-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)-4-((3-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((3-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((3,4-Dioxo-2-((3-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-4-((3-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-4-((3-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((3-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((3,4-Dioxo-2-((3-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((3-(tert-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((3-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((3-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((3-(tert-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((3-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((3-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((3-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((3-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((4-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((4-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((4-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((4-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-(2-((4-클로로페닐)아미노-3,4-디옥소시클로부트-1-엔-1-닐)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((4-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((4-클로로페닐)아미노-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-클로로페닐)아미노-4-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)-4-(4-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((4-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-닐)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((3,4-Dioxo-2-((4-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노-4-((4-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-4-((4-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-(터트-부틸)페닐)아미노)-4-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((4-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((4-(tert-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((4-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((4-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((4-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((4-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 메틸 4-((3,4-디옥소-2-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((3,4-dioxo-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-1-en-1-yl)amino)benzoate], 메틸 4-((2-(((1,4-트랜스)-4-(4-시아노페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((2-(((1,4-trans)-4-(4-cyanophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate], 메틸 4-((2-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate], 메틸 4-((2-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate], 3-((2-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((2-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((2-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-클로로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((2-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((2-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)-4-((2-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)amino)-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((2-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((3,4-Dioxo-2-((2-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-4-((2-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-4-((2-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((2-(tert-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((2-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((2-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((2-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((2-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3,4-디옥소-2-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((3,4-Dioxo-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile], 3-((2-(((1,4-트랜스)-4-(4-시아노페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((2-(((1,4-trans)-4-(4-Cyanophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile], 3-((2-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((2-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile] 및 3-((2-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((2-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile]로 이루어진 군에서 선택될 수 있으나, 이에 한정되는 것은 아니다.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공한다.
바람직하게는, 본 발명에 따른 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α, eIF2α)의 인산화를 촉진할 수 있다.
바람직하게는, 상기 암은 혈액암, 유방암, 육종암 또는 뇌암일 수 있으나, 이에 한정되는 것은 아니다.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 대사항암제용 약학조성물을 제공한다.
또한, 본 발명은 상기 화합물을 투여하는 단계를 포함하는 암세포 대사 억제방법을 제공한다.
상기 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α; eIF2α)의 인산화를 촉진하여 암세포의 대사를 차단하여 사멸할 수 있다.
상기 대사항암제는 화학항암제, 표적항암제 및 면역항암제의 뒤를 잇는 4세대 항암제로 불리며, 정상세포에 비해 활발하게 세포 분열을 일으키는 암세포 대사 활동을 차단하는 방식으로, 기존 항암 치료제와 달리 암세포 대사과정을 차단하여 암세포만 골라 죽이는 항암제이며, 특히 암세포 대사량을 50% 이상 낮추고, 암세포 성장을 억제하는 과정에서 정상세포에 대한 피해가 거의 없다는 것이 특징이다.
본 발명에서, 상기 약학적으로 허용가능한 염은 나트륨염, 칼륨염, 칼슘염, 리튬염, 마그네슘염, 세슘염, 아미늄(aminium)염, 암모늄염, 트리에칠아미늄염 및 피리디늄염으로 이루어진 군에서 선택된 하나 이상의 염기성 염일 수 있으나, 이에 제한되는 것은 아님을 명시한다.
또한, 상기 약학적으로 허용가능한 염은 염산, 브롬산, 황산, 아황산, 인산, 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 벤젠설폰산, 캠퍼설폰산, 옥살산, 말론산, 글루타릭산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산 및 아스파르탄산으로 이루어진 군에서 선택된 하나 이상의 산성 염일 수 있으나, 이에 제한되는 것은 아님을 명시한다.
본 발명의 약학 조성물은 투여를 위하여, 상기 기재한 성분 이외에 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.
본 발명의 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용할 수 있다. 상세하게는 제형화할 경우 통상 사용하는 충진제, 중량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형 제제로는 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하나, 이에 한정되는 것은 아니다. 이러한 고형 제제는 상기 유효성분 외에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘 카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등을 첨가하여 조제될 수 있다. 비경구 투여를 위한 제제는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제 및 과제를 포함한다. 비수성 용제 및 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 오일, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로솔, 트윈 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.
본 발명의 약학 조성물은 경구형 또는 비경구형 제제로 제조할 수 있으며, 경구, 정맥, 뇌실내, 진피내, 근육내, 복막내, 비강 또는 경막외(eidural) 경로로 투여할 수 있으나, 이에 제한되는 것은 아님을 명시한다.
본 발명의 약학 조성물의 적합한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있는 바, 상기 조성물의 일일 투여량은 바람직하게는 0.01 mg/kg 내지 100 mg/kg이며, 필요에 따라 일일 1회 내지 수회로 나누어 투여할 수 있다.
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 암 예방 또는 개선용 건강기능식품 조성물을 제공한다.
상기 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일 주스, 합성 과일 주스 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 또한, 건강기능식품 조성물은 육류, 소세지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 껌류, 아이스크림류, 스프, 음료수, 차, 기능수, 드링크제, 알코올 및 비타민 복합제 중 어느 하나의 형태일 수 있다.
또한, 상기 건강기능식품 조성물은 식품첨가물을 추가로 포함할 수 있으며, 식품첨가물로서의 적합 여부는 다른 규정이 없는 한 식품의약품안전처에 승인된 식품첨가물공전의 총칙 및 일반 시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.
상기 식품첨가물공전에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산 칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀룰로오스, 고랭색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류 첨가 알칼리제, 보존료제제, 타르색소 제제 등의 혼합 제제류 등을 들 수 있다.
이때, 건강기능식품 조성물을 제조하는 과정에서 식품에 첨가되는 본 발명에 따른 조성물은 필요에 따라 그 함량을 적절히 가감할 수 있다.
이하에서는 실시예 및 실험예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예 및 실험예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예 및 실험예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
<합성예>
1. 3-(페닐아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-(Phenylamino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 8)
실온에서 3-methoxy-4-(phenylamino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.30 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (115.0 mg, 0.44 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 8 (101 mg, 95%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.58 (s, 1H), 7.77 (s, 1H), 7.63 (d, 2H, J = 8.3 Hz), 7.46 (d, 2H, J = 7.1 Hz), 7.34 (t, 2H, J = 7.5 Hz), 7.15 (d, 2H, J = 8.3 Hz), 7.02 (t, 1H, J = 7.2 Hz), 4.52 (m, 1H), 3.95 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.6, 180.1, 168.6, 163.7, 160.3, 139.0, 129.4, 128.6, 127.0, 127.0, 126.9, 126.9, 125.9, 123.2, 122.6, 121.4, 121.1, 120.8, 120.5, 120.4, 117.9, 115.9, 74.0, 51.8, 30.8, 29.2.
2. 4-(((1,4-트랜스)-4-((3,4-디옥소-2-(페닐아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((3,4-Dioxo-2-(phenylamino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 9)
실온에서 3-methoxy-4-(phenylamino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.30 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (95.8 mg, 0.44 mmol)를 Argon대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 9 (101 mg, 89%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.74 (d, 2H, J = 8.5 Hz), 7.44 (d, 2H, J = 7.1 Hz), 7.34 (t, 2H, J = 7.5 Hz), 7.14 (d, 2H, J = 8.4 Hz), 7.03 (t, 1H, J = 7.2 Hz), 4.54 (m, 1H), 3.94 (m, 1H), 2.08 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.7, 180.2, 168.7, 163.9, 161.1, 139.1, 134.4, 129.5, 122.9, 119.3, 118.1, 116.5, 102.7, 74.3, 51.9, 30.9, 29.3.
3. 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-4-(페닐아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-(phenylamino)cyclobut-3-ene-1,2-dione](화합물 10)
실온에서 3-methoxy-4-(phenylamino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.30 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (105.0 mg, 0.44 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 10 (115 mg, 95%)을 밝은 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.18 (d, 2H, J = 9.3 Hz), 7.78 (s, 1H), 7.46 (d, 2H, J = 7.8 Hz), 7.34 (t, 2H, J = 7.9 Hz), 7.19 (d, 2H, J = 9.3 Hz), 7.02 (t, 2H, J = 7.4 Hz), 4.61 (m, 1H), 3.95 (m, 1H), 2.10 (m, 4H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.6, 180.1, 168.6, 163.8, 162.9, 140.6, 139.1, 129.4, 126.0, 122.7, 118.0, 115.8, 74.8, 51.7, 30.8, 29.2.
4. 3-(((1,4-트랜스)-4-(4-(메틸설포닐)페녹시)시클로헥실)아미노)-4-(페닐아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-(phenylamino)cyclobut-3-ene-1,2-dione](화합물 11)
실온에서 3-methoxy-4-(phenylamino)cyclobut-3-ene-1,2-dione (50.0 mg, 0.25 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (99.4 mg, 0.37 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 11 (53 mg, 49%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 10.89 (s, 1H), 8.97 (d, 1H, J = 7.6 Hz), 7.79 (d, 2H, J = 8.9 Hz), 7.54 (d, 2H, J = 8.0 Hz), 7.29 (t, 2H, J = 7.9 Hz), 7.18 (d, 2H, J = 8.9 Hz), 6.97 (t, 1H, J = 7.4 Hz), 4.56 (m, 1H), 3.98 (m, 1H), 3.13 (s, 3H), 2.13 (m, 2H), 2.03 (m, 2H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.4, 179.8, 168.8, 164.0, 161.3, 139.5, 132.3, 129.3, 129.2, 122.3, 117.8, 115.9, 74.0, 51.5, 44.0, 30.3, 28.6.
5. 4-(((1,4-트랜스)-4-((3,4-디옥소-2-(페닐아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-
trans
)-4-((3,4-Dioxo-2-(phenylamino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide](화합물 12)
실온에서 3-methoxy-4-(phenylamino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.20 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (79.8 mg, 0.30 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 12 (102 mg, 99%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.57 (s, 1H), 7.74 (d, 2H, J = 8.5 Hz), 7.74 (m, 1H), 7.46 (d, 2H, J = 7.1 Hz), 7.34 (t, 2H, J = 7.7 Hz), 7.20 (s, 2H), 7.12 (d, 2H, J = 8.6 Hz), 7.03 (t, 1H, J = 7.2 Hz), 4.52 (m, 1H), 3.95 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.6, 180.1, 168.6, 163.7, 159.8, 139.0, 136.0, 129.4, 127.8, 122.7, 118.0, 115.4, 74.0, 51.8, 30.9, 29.2.
6. 3-((3-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔[3-((3-Fluorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene](화합물 13)
실온에서 3-((3-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.27 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (106.0 mg, 0.41 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 13 (90 mg, 74%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 9.72 (s, 1H), 7.80 (d, 1H, J = 6.8 Hz), 7.62 (d, 2H, J = 7.6 Hz), 7.53 (d, 1H, J = 10.2 Hz), 7.36 (ddd, 1H, J = 14.9, 8.2, 1.8 Hz), 7.15 (d, 2H, J = 7.8 Hz), 7.12 (m, 1H), 6.82 (t, 1H, J = 8.5 Hz), 4.52 (m, 1H), 3.94 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.8, 180.1, 168.7, 163.8, 163.3, 161.9, 160.3, 141.0, 140.9, 131.2, 131.1, 127.9, 127.0, 127.0, 125.7, 123.6, 121.4, 121.3, 121.1, 120.8, 120.6, 115.9, 113.8, 109.0, 108.9, 105.2, 105.0, 74.0, 51.9, 30.8, 29.2.
7. 4-(((1,4-트랜스)-4-((2-((3-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((3-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 14)
실온에서 3-((3-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.27 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (88.0 mg, 0.41 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 14 (111 mg, 99%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.63 (s, 1H), 7.76 (m, 1H), 7.75 (d, 2H, J = 8.3 Hz), 7.52 (d, 1H, J = 10.1 Hz), 7.36 (dd, 1H, J = 14.9, 7.5 Hz), 7.14 (d, 2H, J = 8.7 Hz), 7.12 (m, 1H), 6.83 (t, 1H, J = 7.9 Hz), 4.55 (m, 1H), 3.94 (m, 1H), 2.08 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.8, 180.1, 168.7, 163.8, 163.3, 161.9, 161.0, 141.0, 140.9, 134.3, 131.3, 131.1, 119.3, 116.4, 113.8, 109.1, 108.9, 105.2, 105.0, 102.6, 74.1, 51.9, 30.8, 29.2.
8. 3-((3-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Fluorophenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 15)
실온에서 3-((3-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.27 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (96.1 mg, 0.41 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 15 (88 mg, 76%)을 밝은 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.19 (d, 2H, J = 9.3 Hz), 7.83 (s, 1H), 7.53 (d, 1H, J = 11.1 Hz), 7.36 (dd, 1H, J = 15.0, 8.1 Hz), 7.19 (d, 2H, J = 9.3 Hz), 7.13 (dd, 1H, J = 8.1, 1.6 Hz), 6.83 (td, 1H, J = 8.5, 2.2 Hz), 4.62 (m, 1H), 3.95 (m, 1H), 2.13 (m, 2H), 2.07 (m, 2H), 1.57 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.8, 180.1, 168.7, 163.8, 163.3, 162.9, 161.9, 141.0, 141.0, 140.6, 131.2, 131.1, 126.0, 115.8, 113.8, 109.1, 108.9, 105.2, 105.0, 74.7, 51.8, 30.8, 29.2.
9. 3-((3-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸설포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Fluorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 16)
실온에서 3-((3-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (73.1 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 16 (83 mg, 99%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.82 (d, 2H, J = 8.7 Hz), 7.52 (d, 1H, J = 10.5), 7.36 (dd, 1H, J = 15.1, 7.9 Hz), 7.19 (d, 2H, J = 8.8 Hz), 7.14 (d, 1H, J = 7.8 Hz), 6.83 (t, 1H, J = 7.6 Hz), 4.56 (m, 1H), 3.96 (m, 1H), 3.15 (s, 3H), 2.12 (m, 2H), 2.07 (m, 2H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.8, 180.1, 186.8, 163.8, 163.3, 161.9, 161.3, 141.1, 141.0, 132.4, 131.2, 131.1, 129.3, 115.8, 113.9, 109.1, 108.9, 105.2, 105.0, 74.2, 51.9, 44.0, 30.8, 29.2.
10. 4-(((1,4-트랜스)-4-((2-((3-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-
trans
)-4-((2-((3-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide](화합물 17)
실온에서 3-((3-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (73.3 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 17 (73 mg, 88%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.79 (s, 1H), 7.74 (d, 2H, J = 8.5 Hz), 7.52 (d, 1H, J = 10.0), 7.36 (dd, 1H, J = 14.9, 7.6 Hz), 7.20 (s, 2H), 7.12 (d, 2H, J = 8.2 Hz), 6.83 (t, 1H, J = 7.7 Hz), 4.52 (m, 1H), 3.94 (m, 1H), 2.09 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.8, 180.1, 168.8, 163.8, 163.3, 161.9, 159.8, 141.0, 141.0, 136.0, 131.2, 131.1, 127.8, 115.4, 113.8, 109.1, 108.9, 105.2, 105.0, 74.0, 51.9, 30.9, 29.2.
11. 3-((3-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Chlorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 18)
실온에서 3-((3-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.25 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (98.3 mg, 0.38 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 18 (109 mg, 93%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 9.71 (s, 1H), 7.79 (m, 1H), 7.70 (s, 1H), 7.63 (d, 2H, J = 7.6 Hz), 7.34 (td, 1H, J = 7.9, 1.7 Hz), 7.27 (d, 1H, 8.2 Hz), 7.15 (d, 2H, J = 7.6 Hz), 7.05 (d, 1H, J = 7.7 Hz), 4.52 (m, 1H), 3.94 (m, 1H), 2.09 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.8, 180.1, 168.8, 163.2, 160.2, 140.6, 133.8, 130.9, 128.6, 126.9, 126.9, 125.9, 123.2, 122.1, 121.4, 121.1, 120.8, 120.5, 120.4, 117.6, 116.4, 115.8, 74.0, 51.9, 30.8, 29.2.
12. 4-(((1,4-트랜스)-4-((2-((3-클로로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((3-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 19)
실온에서 3-((3-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.25 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (81.9 mg, 0.40 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 19 (99 mg, 86%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 7.75 (dd, 2H, J = 8.6, 1.4 Hz), 7.69 (s, 1H), 7.35 (td, 1H, J = 8.0, 1.2 Hz), 7.27 (d, 1H, J = 7.8 Hz), 7.14 (dd, 2H, J = 8.5, 1.3 Hz), 7.05 (d, 1H, J = 8.0 Hz), 4.54 (m, 1H), 3.94 (m, 1H), 2.08 (m, 4H), 1.51 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.8, 180.1, 168.8, 163.2, 160.9, 140.6, 134.2, 133.8, 131.0, 122.1, 119.2, 117.7, 116.4, 116.4, 102.6, 74.1, 51.8, 30.8, 29.2.
13. 3-((3-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Chlorophenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 20)
실온에서 3-((3-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.9 mg, 0.26 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (90.8 mg, 0.38 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 20 (78 mg, 69%)을 밝은 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 9.57 (s, 1H), 8.18 (dd, 2H, J = 9.1, 1.8 Hz), 7.80 (s, 1H), 7.69 (s, 1H), 7.34 (td, 1H, J = 8.0, 1.4 Hz), 7.26 (d, 1H, J = 8.0 Hz), 7.18 (dd, 2H, J = 9.1, 1.8 Hz), 7.04 (d, 1H, J = 7.8 Hz), 4.61 (m, 1H), 3.94 (m, 1H), 2.09 (m, 4H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.8, 180.1, 168.7, 163.2, 162.8, 140.6, 133.8, 131.0, 125.9, 122.1, 117.6, 116.4, 115.7, 115.4, 74.7, 51.8, 30.7, 29.1.
14. 3-((3-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸설포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Chlorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 21)
실온에서 3-((3-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (68.0 mg, 0.25 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 21 (71 mg, 88%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 7.83 (d, 2H, J = 8.0 Hz), 7.70 (s, 1H), 7.34 (t, 1H, J = 7.9 Hz), 7.27 (d, 1H, J = 7.8 Hz), 7.19 (d, 2H, J = 8.2 Hz), 7.05 (d, 1H, J = 7.5 Hz), 4.56 (m, 1H), 3.95 (m, 1H), 3.16 (s, 3H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.8, 180.1, 168.8, 163.2, 161.2, 140.6, 133.8, 132.4, 130.9, 129.2, 122.1, 117.6, 116.4, 115.8, 74.2, 51.8, 44.0, 30.7, 29.1.
15. 4-(((1,4-트랜스)-4-((2-((3-클로로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-
trans
)-4-((2-((3-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide](화합물 22)
실온에서 3-((3-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (68.0 mg, 0.25 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 22 (90 mg, 99%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.71 (s, 1H), 7.79 (d, 1H, J = 7.2 Hz), 7.73 (d, 2H, J = 8.7 Hz), 7.70 (s, 1H), 7.35 (t, 1H, J = 8.2 Hz), 7.27 (d, 1H, J = 8.3 Hz), 7.22 (s, 2H), 7.12 (d, 2H, J = 8.7 Hz), 7.06 (d, 1H, J = 7.9 Hz), 4.52 (m, 1H), 3.95 (m, 1H), 2.09 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.9, 180.1, 168.8, 163.2, 159.8, 140.5, 136.0, 133.8, 131.0, 127.7, 122.1, 117.7, 116.4, 115.4, 74.0, 51.9, 30.8, 29.2.
16. 3-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)-4-((3-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione](화합물 23)
실온에서 3-methoxy-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.22 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (86.0 mg, 0.33 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 23 (67 mg, 61%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.93 (s, 1H), 7.79 (s, 1H), 7.63 (d, 2H, J = 8.6 Hz), 7.60 (m, 1H), 7.56 (t, 1H, J = 7.7 Hz), 7.34 (d, 1H, J = 7.2 Hz), 7.15 (d, 2H, J = 8.3 Hz), 4.53 (m, 1H), 3.96 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.0, 180.2, 168.9, 163.2, 160.3, 139.9, 130.6, 130.4, 130.1, 129.9, 127.9, 127.3, 127.1, 127.0, 127.0, 127.0, 125.7, 125.2, 123.6, 123.0, 121.6, 121.4, 121.3, 121.1, 120.8, 120.6, 118.7, 118.7, 115.9, 114.3, 74.0, 52.0, 30.8, 29.2.
17. 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((3-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((3,4-Dioxo-2-((3-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 24)
실온에서 3-methoxy-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.22 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (71.8 mg, 0.33 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 24 (63 mg, 63%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.83 (s, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.75 (d, 2H, J = 8.6 Hz), 7.60 (d, 1H, J = 8.1 Hz), 7.56 (t, 1H, J = 7.8 Hz), 7.35 (d, 1H, J = 7.3 Hz), 7.15 (d, 2H, J = 8.7 Hz), 4.55 (m, 1H), 3.95 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.0, 180.2, 168.8, 163.2, 161.0, 139.9, 134.3, 130.6, 130.4, 130.1, 129.9, 127.3, 125.1, 123.0, 121.6, 120.8, 119.2, 118.8, 118.7, 118.7, 118.7, 116.4, 114.3, 102.6, 74.1, 51.9, 30.8, 29.2.
18. 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-4-((3-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione](화합물 25)
실온에서 3-methoxy-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.22 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (78.4 mg, 0.33 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 25 (85 mg, 81%)을 황토색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.19 (d, 2H, J = 9.1 Hz), 7.92 (s, 1H), 7.61 (d, 1H, J = 8.0 Hz), 7.56 (t, 1H, J = 7.8 Hz), 7.35 (d, 1H, J = 7.4 Hz), 7.19 (d, 2H, J = 9.1 Hz), 4.62 (m, 1H), 3.97 (m, 1H), 2.14 (m, 2H), 2.08 (m, 2H), 1.58 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.0, 180.3, 168.9, 163.3, 162.9, 140.6, 140.0, 130.6, 130.4, 130.1, 129.9, 127.3, 126.0, 125.2, 123.0, 121.6, 120.8, 118.7, 115.8, 114.4, 74.7, 51.9, 30.8, 29.2.
19. 3-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-4-((3-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione](화합물 26)
실온에서 3-methoxy-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (59.6 mg, 0.22 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 26 (36 mg, 48%)을 황토색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.93 (s, 1H) 7.83 (d, 2H, J = 8.5 Hz), 7.81 (m, 1H), 7.60 (d, 1H, J = 7.8 Hz), 7.56 (t, 1H, J = 7.7 Hz), 7.34 (d, 1H, J = 7.2 Hz), 7.20 (d, 2H, J = 8.6 Hz), 4.57 (m, 1H), 3.96 (m, 1H), 3.16 (s, 3H), 2.12 (m, 2H), 2.07 (m, 2H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.0, 180.2, 168.9, 163.2, 161.3, 140.0, 132.4, 130.6, 130.4, 130.1, 129.9, 129.3, 127.3, 125.2, 123.0, 121.6, 120.8, 118.7, 118.7, 115.8, 114.4, 74.2, 51.9, 44.0, 30.8, 29.2.
20. 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((3-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-
trans
)-4-((3,4-Dioxo-2-((3-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide](화합물 27)
실온에서 3-methoxy-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (60.8 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 27 (18 mg, 23%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.84 (s, 1H), 7.93 (s, 1H) 7.73 (d, 2H, J = 8.8 Hz), 7.60 (d, 1H, J = 8.2 Hz), 7.56 (t, 1H, J = 7.8 Hz), 7.35 (d, 1H, J = 7.4 Hz), 7.12 (d, 2H, J = 8.9 Hz), 4.52 (m, 1H), 3.96 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.0, 180.2, 168.9, 163.2, 159.8, 139.9, 136.0, 130.6, 130.4, 130.1, 129.9, 127.8, 127.3, 125.1, 123.0, 121.5, 120.8, 118.7, 118.7, 115.4, 114.3, 74.0, 51.9, 30.8, 29.2.
21. 3-((3-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-(
tert
-Butyl)phenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 28)
실온에서 3-((3-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (59.9 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 28 (50 mg, 67%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.54 (s, 1H), 7.69 (d, 1H, J = 3.1 Hz), 7.63 (d, 2H, J = 8.6 Hz), 7.53 (s, 1H), 7.26 (t, 1H, J = 7.7 Hz), 7.22 (d, 1H, J = 7.3 Hz), 7.16 (d, 2H, 8.5 Hz), 7.05 (d, 1H, J = 7.3 Hz), 4.53 (m, 1H), 3.95 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H), 1.28 (s, 9H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.5, 180.2, 168.5, 163.9, 160.3, 152.2, 138.7, 129.1, 127.9, 127.1, 127.0, 127.0, 127.0, 125.7, 123.6, 121.4, 121.3, 121.1, 120.8, 120.5, 119.7, 115.9, 115.3, 115.2, 74.0, 51.8, 34.6, 31.1, 30.9, 29.2.
22. 4-(((1,4-트랜스)-4-((2-((3-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((3-(
tert
-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 29)
실온에서 3-((3-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (50.0 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 29 (65 mg, 95%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.53 (s, 1H), 7.75 (d, 2H, J = 8.1 Hz), 7.70 (s, 1H), 7.53 (s, 1H), 7.26 (t, 1H, J = 7.7 Hz), 7.15 (d, 2H, J = 8.1 Hz), 7.05 (d, 1H, J = 7.3 Hz), 4.55 (m, 1H), 3.94 (m, 1H), 2.08 (m, 4H), 1.54 (m, 4H), 1.28 (s, 9H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.5, 180.2, 168.5, 163.9, 161.0, 152.2, 138.7, 134.3, 129.1, 120.0, 119.3, 116.4, 115.2, 115.2, 102.6, 74.1, 51.7, 34.6, 31.1, 30.9, 29.2.
23. 3-((3-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-(
tert
-Butyl)phenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 30)
실온에서 3-((3-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (50.0 mg, 0.19 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (68.3 mg, 0.29 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 30 (71 mg, 78%)을 밝은 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.55 (s, 1H), 8.19 (d, 2H, J = 9.2 Hz), 7.71 (s, 1H), 7.53 (s, 1H), 7.26 (t, 1H, J = 7.7 Hz), 7.19 (d, 2H, J = 9.3 Hz), 7.06 (d, 1H, J = 7.4 Hz), 4.62 (m, 1H), 3.96 (m, 1H), 2.13 (m, 2H), 2.08 (m, 2H), 1.57 (m, 4H), 1.28 (s, 9H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.5, 180.2, 168.5, 163.9, 162.9, 152.2, 140.6, 138.7, 129.0, 125.9, 119.6, 115.7, 115.2, 115.1, 74.7, 51.7, 34.6, 31.0, 30.8, 29.1.
24. 3-((3-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-(
tert
-Butyl)phenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 31)
실온에서 3-((3-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (62.2 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 31 (63 mg, 82%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 7.83 (d, 2H, J = 8.5 Hz), 7.74 (s, 1H), 7.53 (s, 1H), 7.26 (t, 1H, J = 7.6 Hz), 7.22 (m, 1H), 7.20 (d, 2H, J = 8.6 Hz), 7.06 (d, 1H, J = 7.0 Hz), 4.57 (m, 1H), 3.96 (m, 1H), 3.16 (s, 3H), 2.10 (m, 4H), 1.56 (m, 4H), 1.28 (s, 9H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.5, 180.2, 168.5, 163.9, 161.2, 152.2, 138.7, 132.4, 129.2, 129.0, 119.6, 115.8, 115.2, 115.1, 74.2, 51.7, 44.0, 34.6, 31.1, 30.8, 29.1.
25. 4-(((1,4-트랜스)-4-((2-((3-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-
trans
)-4-((2-((3-(
tert
-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide](화합물 32)
실온에서 3-((3-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (50.0 mg, 0.19 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (77.8 mg, 0.29 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 32 (25 mg, 26%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.55 (s, 1H), 7.74 (d, 2H, J = 8.8 Hz), 7.70 (s, 1H), 7.53 (s, 1H), 7.26 (t, 1H, J = 7.7 Hz), 7.22 (d, 1H, J = 8.4 Hz), 7.20 (s, 2H), 7.12 (d, 2H, J = 8.8 Hz), 7.06 (d, 1H, J = 7.4 Hz), 4.52 (m, 1H), 3.95 (m, 1H), 2.09 (m, 4H), 1.54 (m, 4H), 1.28 (s, 9H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.5, 180.2, 168.5, 163.8, 159.7, 152.1, 138.7, 136.0, 128.9, 127.7, 119.6, 115.4, 115.2, 115.1, 74.0, 51.7, 34.5, 31.0, 30.7, 29.1.
26. 3-((3-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Methoxyphenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 33)
실온에서 3-methoxy-4-((3-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.26 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (100.0 mg, 0.39 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 33 (95 mg, 80%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.59 (s, 1H), 7.76 (s, 1H), 7.63 (d, 2H, J = 8.7 Hz), 7.25 (m, 1H), 7.23 (t, 1H, J = 8.0 Hz), 7.15 (d, 2H, J = 8.6 Hz), 6.92 (d, 1H, J = 8.4 Hz), 6.60 (dd, 1H, 8.2, 2.1 Hz), 4.52 (m, 1H), 3.95 (m, 1H), 3.75 (s, 3H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.6, 180.1, 168.5, 163.6, 160.2, 140.2, 130.2, 128.6, 127.0, 127.0, 126.9, 126.9, 125.9, 123.2, 121.4, 121.1, 120.7, 120.5, 120.4, 115.9, 110.1, 108.4, 103.7, 74.0, 55.1, 51.8, 30.8, 29.2.
27. 4-(((1,4-트랜스)-4-((2-((3-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((3-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 34)
실온에서 3-methoxy-4-((3-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.26 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (83.5 mg, 0.36 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 34 (101 mg, 94%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.55 (s, 1H), 7.75 (d, 2H, J = 8.5 Hz), 7.24 (m, 1H), 7.23 (t, 1H, J = 7.9 Hz), 7.14 (d, 2H, J = 8.6), 6.91 (d, 1H, J = 7.9 Hz), 6.60 (d, 1H, J = 8.2 Hz), 4.55 (m, 1H), 3.94 (m, 1H), 3.75 (s, 3H), 2.08 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.6, 180.1, 168.6, 163.7, 161.0, 160.3, 140.3, 134.3, 130.3, 119.3, 116.4, 110.1, 109.4, 103.7, 102.6, 74.1, 55.1, 51.8, 30.9, 29.2.
28. 3-((3-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Methoxyphenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 35)
실온에서 3-methoxy-4-((3-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.26 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (91.2 mg, 0.39 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 35 (99 mg, 88%)을 밝은 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.19 (d, 2H, J = 9.3 Hz), 7.79 (s, 1H), 7.24 (m, 1H), 7.23 (t, 1H, J = 8.1 Hz), 7.19 (d, 2H, J = 9.3 Hz), 6.92 (dd, 1H, J = 7.9, 1.8 Hz), 6.60 (dd, 1H, J = 8.3, 2.4 Hz), 4.62 (m, 1H), 3.96 (m, 1H), 3.76 (s, 3H), 2.13 (m, 2H), 2.08 (m, 2H), 1.57 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.5, 180.1, 168.5, 163.6, 162.9, 160.2, 140.6, 140.2, 130.2, 125.9, 115.7, 110.1, 108.4, 103.7, 74.7, 55.1, 51.7, 30.8, 29.1.
29. 3-((3-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Methoxyphenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 36)
실온에서 3-methoxy-4-((3-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (69.3 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 36 (74 mg, 91%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.82 (d, 2H, J = 8.7 Hz), 7.75 (s, 1H), 7.25 (m, 1H), 7.23 (m, 1H), 7.19 (d, 2H, J = 8.7 Hz), 6.92 (d, 1H, J = 7.8 Hz), 6.60 (d, 1H, J = 8.2 Hz), 4.56 (m, 1H), 3.95 (m, 1H), 3.75 (s, 3H), 3.15 (s, 3H), 2.10 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.6, 180.1, 168.6, 163.7, 161.3, 160.3, 140.3, 132.4, 130.3, 129.3, 115.8, 110.1, 108.4, 103.7, 74.2, 55.1, 51.8, 44.0, 30.8, 29.2.
30. 4-(((1,4-트랜스)-4-((2-((3-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-
trans
)-4-((2-((3-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide](화합물 37)
실온에서 3-methoxy-4-((3-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (69.6 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 37 (60 mg, 74%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 9.59 (s, 1H), 7.74 (d, 2H, J = 8.8 Hz), 7.23 (m, 4H), 7.12 (d, 2H, J = 8.8 Hz), 6.91 (dd, 1H, J = 8.0, 1.6 Hz), 6.60 (dd, 1H, J = 8.2, 2.2 Hz), 4.51 (m, 1H), 3.93 (m, 1H), 3.75 (s, 3H), 2.09 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.6, 180.1, 168.6, 163.7, 160.3, 159.8, 140.3, 136.0, 130.3, 127.8, 115.4, 110.1, 108.4, 103.7, 74.0, 55.1, 51.8, 30.8, 29.2.
31. 3-((4-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Fluorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 38)
실온에서 3-((4-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (70.3 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 38 (68 mg, 84%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 7.74 (s, 1H), 7.62 (d, 2H, J = 8.6 Hz), 7.46 (dd, 2H, J = 7.9, 4.1 Hz), 7.18 (m, 2H), 7.15 (d, 2H, J = 9.0 Hz), 4.52 (m, 1H), 3.94 (m, 1H), 2.08 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.4, 180.2, 168.5, 163.6, 160.3, 159.3, 156.9, 135.5, 135.5, 128.6, 127.0, 127.0, 126.9, 126.9, 125.9, 123.2, 121.4, 121.1, 120.8, 120.5, 120.4, 119.8, 119.7, 116.1, 115.9, 74.0, 51.8, 30.8, 29.2.
32. 4-(((1,4-트랜스)-4-((2-((4-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((4-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 39)
실온에서 3-((4-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (58.7 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 39 (64 mg, 87%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.59 (s, 1H), 7.76 (d, 2H, J = 8.8 Hz), 7.72 (s, 1H), 7.45 (m, 2H), 7.15 (d, 2H, J = 8.9 Hz), 4.55 (m, 1H), 3.94 (m, 1H), 2.08 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.4, 180.2, 168.5, 163.6, 161.0, 159.1, 157.2, 135.5, 135.5, 134.3, 119.8, 119.7, 119.2, 116.4, 116.1, 116.0, 102.6, 74.1, 51.8, 30.9, 29.2.
33. 3-((4-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Fluorophenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 40)
실온에서 3-((4-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (64.0 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 40 (73 mg, 94%)을 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.62 (s, 1H), 8.19 (d, 2H, J = 9.2 Hz), 7.75 (s, 1H), 7.45 (m, 2H), 7.19 (d, 2H, J = 9.1 Hz), 7.19 (m, 2H), 4.61 (m, 1H), 3.95 (m, 1H), 2.12 (m, 2H), 2.07 (m, 2H), 1.57 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.4, 180.2, 168.5, 163.6, 162.9, 159.1, 157.2, 140.6, 135.5, 126.0, 119.8, 119.8, 116.1, 116.0, 115.8, 74.8, 51.7, 30.8, 29.2.
34. 3-((4-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Fluorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 41)
실온에서 3-((4-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (73.1 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 41 (75 mg, 91%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.83 (d, 2H, J = 8.7 Hz), 7.74 (s, 1H), 7.45 (m, 2H), 7.20 (d, 2H, J = 8.7 Hz), 7.17 (m, 2H), 4.56 (m, 1H), 3.95 (m, 1H), 3.16 (s, 3H), 2.12 (m, 2H), 2.07 (m, 2H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.4, 180.2, 168.5, 163.6, 161.3, 159.1, 157.2, 135.6, 132.4, 129.3, 119.8, 119.8, 116.2, 116.0, 115.8, 74.2, 51.8, 44.0, 30.9, 29.2.
35. 3-((4-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Chlorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 42)
실온에서 3-((4-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.25 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (98.2 mg, 0.38 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 42 (85 mg, 72%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.67 (s, 1H), 7.79 (s, 1H), 7.62 (d, 2H, J = 8.3 Hz), 7.47 (d, 2H, J = 7.6 Hz), 7.37 (d, 2H, J = 8.5 Hz), 7.14 (d, 2H, J = 8.3 Hz), 4.51 (m, 1H), 3.95 (m, 1H), 2.08 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.7, 180.1, 168.7, 163.4, 160.3, 138.1, 129.3, 127.9, 127.1, 127.0, 127.0, 127.0, 126.5, 125.7, 123.6, 121.4, 121.3, 121.1, 120.8, 120.6, 119.6, 115.9, 74.0, 51.9, 30.9, 29.2.
36. 4-(((1,4-트랜스)-4-(2-((4-클로로페닐)아미노-3,4-디옥소시클로부트-1-엔-1-닐)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((4-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 43)
실온에서 3-((4-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.25 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (82.0 mg, 0.38 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 43 (98 mg, 92%)을 연한 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.75 (d, 2H, J = 8.0 Hz), 7.46 (d, 2H, J = 6.6 Hz), 7.38 (d, 2H, J = 7.2 Hz), 7.15 (d, 2H, J = 8.0 Hz), 4.55 (m, 1H), 3.94 (m, 1H), 2.08 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 150 MHz) δ 183.7, 180.1, 168.6, 163.3, 160.9, 138.0, 134.2, 129.2, 126.5, 119.6, 119.2, 116.3, 102.6, 74.1, 51.8, 30.8, 29.1.
37. 3-((4-클로로페닐)아미노-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Chlorophenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 44)
실온에서 3-((4-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (50.0 mg, 0.21 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (74.6 mg, 0.32 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 44 (69 mg, 74%)을 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 10.93 (s, 1H), 8.88 (d, 1H, J = 7.5 Hz), 8.18 (d, 2H, J = 9.2 Hz), 7.57 (d, 2H, J = 8.5 Hz), 7.36 (d, 2H, J = 8.8 Hz), 7.20 (d. 2H, J = 9.3 Hz), 4.63 (m, 1H), 3.99 (m, 1H), 2.10 (m, 2H), 2.05 (m, 2H), 1.58 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.5, 179.8, 168.9, 163.6, 162.9, 140.5, 138.6, 129.1, 126.2, 125.9, 119.3, 115.8, 74.5, 51.5, 30.3, 28.6.
38. 3-((4-클로로페닐)아미노-4-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Chlorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 45)
실온에서 3-((4-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (68.0 mg, 0.25 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 45 (70 mg, 88%)을 연한 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.82 (d, 2H, J = 8.5 Hz), 7.46 (d, 2H, J = 7.7 Hz), 7.38 (d, 2H, J = 8.2 Hz), 7.19 (d, 2H, J = 8.4 Hz), 4.56 (m, 1H), 3.95 (m, 1H), 3.15 (s, 3H), 2.12 (m, 2H), 2.07 (m, 2H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.7, 180.1, 168.7, 163.4, 161.3, 138.1, 132.4, 129.3, 129.3, 126.5, 119.6, 115.8, 74.2, 51.8, 44.0, 30.8, 29.2.
39. 3-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)-4-(4-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione](화합물 46)
실온에서 3-methoxy-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (50.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (71.7 mg, 0.28 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 46 (63 mg, 68%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.87 (s, 1H), 7.84 (d, 2H, J = 6.4 Hz), 7.68 (d, 2H, J = 8.6 Hz), 7.62 (m, 4H), 7.15 (d, 2H, J = 8.6 Hz), 4.52 (m, 1H), 3.96 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.3, 180.0, 169.1, 163.1, 160.3, 142.6, 127.8, 127.7, 127.0, 127.0, 127.0, 126.9, 126.7, 126.7, 125.7, 125.6, 123.5, 123.4, 122.8, 122.5, 122.3, 122.0, 121.4, 121.3, 121.3, 121.1, 120.8, 120.6, 117.9, 115.9, 74.0, 51.9, 30.8, 29.2.
40. 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((4-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-닐)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((3,4-Dioxo-2-((4-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 47)
실온에서 3-methoxy-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (50.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (59.8 mg, 0.28 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 47 (78 mg, 93%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.83 (s, 1H), 7.75 (d, 2H, J = 8.7 Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.62 (d, 2H, J = 8.0 Hz), 7.14 (d, 2H, J = 8.8 Hz), 4.55 (m, 1H), 3.95 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.3, 180.0, 169.0, 163.1, 160.9, 142.6, 134.2, 127.7, 126.7, 126.7, 125.6, 123.4, 122.7, 122.5, 122.2, 122.0, 121.3, 119.2, 117.9, 116.3, 102.6, 74.1, 51.9, 30.8, 29.2.
41. 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노-4-((4-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione](화합물 48)
실온에서 3-methoxy-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (50.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (65.3 mg, 0.28 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 48 (71 mg, 82%)을 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.88 (s, 1H), 8.20 (d, 2H, J = 8.8 Hz), 7.86 (s, 1H), 7.69 (d, 2H, J = 8.2 Hz), 7.62 (d, 2H, J = 6.8 Hz), 7.19 (d, 2H, J = 8.9 Hz), 4.62 (m, 1H), 3.97 (m, 1H), 2.14 (m, 2H), 2.08 (m, 2H), 1.58 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.3, 180.0, 169.1, 163.1, 162.9, 142.6, 140.6, 127.7, 126.7, 126.0, 125.6, 123.4, 122.8, 122.5, 122.2, 122.0, 121.3, 118.0, 115.8, 74.7, 51.9, 30.7, 29.1.
42. 3-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-4-((4-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione](화합물 49)
실온에서 3-methoxy-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (60.0 mg, 0.22 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 49 (60 mg, 79%)을 연한 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.88 (s, 1H), 7.83 (d, 2H, J = 8.8 Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.62 (d, 2H, J = 7.9 Hz), 7.20 (d, 2H, J = 8.8 Hz), 4.57 (m, 1H), 3.96 (m, 1H), 3.16 (s, 3H), 2.12 (m, 2H), 2.07 (m, 2H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.3, 180.1, 169.1, 163.1, 161.3, 142.7, 132.4, 129.3, 127.8, 126.8, 126.7, 125.6, 123.5, 122.7, 122.5, 122.2, 122.0, 121.3, 118.0, 115.8, 74.2, 51.9, 44.0, 30.8, 29.2.
43. 3-((4-(터트-부틸)페닐)아미노)-4-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-(
tert
-Butyl)phenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 50)
실온에서 3-((4-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (59.9 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 50 (65 mg, 87%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.54 (s, 1H), 7.72 (s, 1H), 7.63 (d, 2H, J = 8.3 Hz), 7.36 (m, 4H), 7.15 (d, 2H, J = 8.2 Hz), 4.52 (m, 1H), 3.94 (m, 1H), 2.09 (m, 4H), 1.54 (m, 4H), 1.26 (s, 9H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.4, 180.1, 168.4, 163.8, 160.3, 145.1, 136.5, 127.9, 127.1, 127.1, 127.0, 127.0, 126.1, 125.7, 123.6, 121.4, 121.3, 121.0, 120.8, 120.5, 117.8, 115.9, 74.0, 51.8, 34.1, 31.2, 30.9, 29.2.
44. 4-(((1,4-트랜스)-4-((2-((4-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((4-(
tert
-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 51)
실온에서 3-((4-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (50.0 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 51 (60 mg, 88%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.54 (s, 1H), 7.76 (d, 2H, J = 8.7 Hz), 7.72 (s, 1H), 7.36 (m, 4H), 7.15 (d, 2H, J = 8.8 Hz), 4.55 (m, 1H), 3.93 (m, 1H), 2.08 (m, 4H), 1.54 (m, 4H), 1.26 (s, 9H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.3, 180.1, 168.3, 163.8, 160.9, 145.1, 136.4, 134.2, 126.0, 119.2, 117.8, 116.3, 102.6, 74.1, 51.7, 34.0, 31.2, 30.8, 29.2.
45. 3-((4-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-(
tert
-Butyl)phenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 52)
실온에서 3-((4-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (54.7 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 52 (62 mg, 87%)을 연한 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.54 (s, 1H), 8.19 (d, 2H, J = 9.2 Hz), 7.73 (s, 1H), 7.36 (m, 4H), 7.19 (d, 2H, J = 9.2 Hz), 4.62 (m, 1H), 3.95 (m, 1H), 2.10 (m, 4H), 1.57 (m, 4H), 1.26 (s, 9H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.3, 180.1, 168.4, 163.8, 162.9, 145.1, 140.6, 136.5, 126.1, 126.0, 117.8, 115.8, 74.8, 51.7, 34.0, 31.2, 30.8, 29.2.
46. 3-((4-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-(
tert
-Butyl)phenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 53)
실온에서 3-((4-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (62.3 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 53 (57 mg, 74%)을 연한 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.55 (s, 1H), 7.82 (d, 2H, J = 8.6 Hz), 7.73 (d, 1H, J = 4.0 Hz), 7.36 (m, 4H), 7.19 (d, 2H, J = 8.7 Hz), 4.56 (m, 1H), 3.94 (m, 1H), 3.35 (s, 3H), 2.09 (m, 4H), 1.55 (m, 4H), 1.26 (s, 9H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.4, 180.1, 168.4, 163.8, 161.3, 145.1, 136.5, 132.4, 129.3, 126.1, 117.8, 115.8, 74.2, 51.7, 44.0, 34.0, 31.2, 30.8, 29.2.
47. 3-((4-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Methoxyphenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 54)
실온에서 3-methoxy-4-((4-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (66.6 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 54 (72 mg, 91%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.45 (s, 1H), 7.63 (d, 2H, J = 8.7 Hz), 7.37 (d, 2H, J = 8.6 Hz), 7.15 (d, 2H, J = 8.7 Hz), 6.92 (d, 2H, J = 9.1 Hz), 4.52 (m, 1H), 3.93 (m, 1H), 2.09 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.0, 180.3, 168.2, 163.8, 160.3, 155.3, 132.3, 127.9, 127.1, 127.0, 127.0, 127.0, 125.7, 123.6, 121.4, 121.3, 121.1, 120.8, 120.5, 119.6, 115.9, 114.6, 74.0, 55.3, 51.7, 30.9, 29.2.
48. 4-(((1,4-트랜스)-4-((2-((4-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((4-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 55)
실온에서 3-methoxy-4-((4-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (55.6 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 55 (62 mg, 86%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 9.46 (s, 1H), 7.75 (d, 2H, J = 7.6 Hz), 7.66 (s, 1H), 7.36 (d, 2H, J = 8.0 Hz), 7.14 (d, 2H, J = 7.7 Hz), 6.92 (d, 2H, J = 7.6 Hz), 4.54 (m, 1H), 3.93 (m, 1H), 3.73 (s, 3H), 2.08 (m, 4H), 1.53 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 180.2, 168.1, 163.8, 160.9, 155.2, 134.3, 132.2, 119.6, 119.2, 116.4, 114.6, 114.3, 102.6, 74.2, 55.3, 51.7, 30.8, 29.2.
49. 3-((4-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Methoxyphenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 56)
실온에서 3-methoxy-4-((4-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (60.8 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 56 (65 mg, 88%)을 연한 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 9.47 (s, 1H), 8.18 (d, 2H, J = 9.2 Hz), 7.65 (s, 1H), 7.37 (d, 2H, J = 8.7 Hz), 7.18 (d, 2H, J = 9.2 Hz), 6.92 (d, 2H, J = 8.9 Hz), 4.61 (m, 1H), 3.94 (m, 1H), 3.72 (s, 3H), 2.10 (m, 4H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 183.0, 180.3, 168.1, 163.8, 162.9, 155.2, 140.6, 132.2, 125.9, 119.5, 115.7, 114.6, 74.8, 55.3, 51.6, 30.8, 29.1.
50. 3-((4-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Methoxyphenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 57)
실온에서 3-methoxy-4-((4-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (69.3 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 57 (71 mg, 88%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.46 (s, 1H), 7.82 (d, 2H, J = 8.8 Hz), 7.65 (s, 1H), 7.37 (d, 2H, J =7.9 Hz), 7.19 (d, 2H, J = 8.5 Hz), 6.92 (d, 2H, J = 8.8 Hz), 4.56 (m, 1H), 3.94 (m, 1H), 3.73 (s, 3H), 3.15 (s, 3H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 183.0, 180.3, 168.2, 163.8, 161.3, 155.3, 132.4, 132.2, 129.3, 119.6, 115.8, 114.6, 74.2, 55.3, 51.7, 44.0, 30.9, 29.2.
51. 메틸 4-((3,4-디옥소-2-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((3,4-dioxo-2-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-1-en-1-yl)amino)benzoate](화합물 58)
실온에서 methyl 4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (59.5 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 58 (50 mg, 66%)을 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 600 MHz) δ 9.90 (s, 1H), 7.92 (d, 2H, J = 8.8 Hz), 7.86 (m, 1H), 7.63 (d, 2H, J =8.7 Hz), 7.56 (d, 2H, J = 8.2 Hz), 7.15 (d, 2H, J = 8.6 Hz), 4.52 (m, 1H), 3.96 (m, 1H), 3.82 (s, 3H), 2.12 (m, 2H), 2.07 (m, 2H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 150 MHz) δ 184.3, 180.0, 169.1, 165.8, 163.0, 160.2, 143.4, 130.8, 127.3, 126.9, 125.5, 123.7, 123.0, 121.9, 121.2, 121.0, 120.8, 120.6, 117.4, 115.9, 74.0, 51.9, 51.9, 30.8, 29.2.
52. 메틸 4-((2-(((1,4-트랜스)-4-(4-시아노페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((2-(((1,4-
trans
)-4-(4-cyanophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate](화합물 59)
실온에서 methyl 4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (49.7 mg, 0.30 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 59 (53 mg, 77%)을 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 600 MHz) δ 9.85 (s, 1H), 7.92 (d, 2H, J = 8.7 Hz), 7.82 (d, 1H, J = 7.0 Hz), 7.75 (d, 2H, J = 8.8 Hz), 7.55 (d, 2H, J = 8.2 Hz), 7.15 (d, 2H, J = 8.8 Hz), 4.55 (m, 1H), 3.95 (m, 1H), 3.82 (s, 3H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 150 MHz) δ 184.3, 180.0, 169.1, 165.8, 162.9, 160.9, 143.4, 134.2, 130.8, 123.0, 119.2, 117.4, 116.3, 102.6, 74.1, 51.9, 30.8, 29.1.
53. 메틸 4-((2-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((2-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate](화합물 60)
실온에서 methyl 4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (54.2 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 60 (61 mg, 86%)을 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.19 (d, 2H, J = 9.1 Hz), 7.92 (d, 2H, J = 8.5 Hz), 7.86 (m, 1H), 7.55 (d, 2H, J = 7.6 Hz), 7.19 (d, 2H, J = 9.1 Hz), 4.62 (m, 1H), 3.97 (m, 1H), 3.82 (s, 3H), 2.13 (m, 2H), 2.08 (m, 2H), 1.58 (m, 4H); 13C NMR (DMSO-d 6 , 150 MHz) δ 184.3, 180.0, 169.1, 165.8, 163.0, 162.8, 143.4, 140.6, 130.8, 125.9, 123.0, 117.4, 115.7, 74.7, 51.9, 51.8, 30.7, 29.1.
54. 메틸 4-((2-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((2-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate](화합물 61)
실온에서 methyl 4-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (62.0 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 61 (66 mg, 86%)을 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 7.92 (d, 2H, J = 8.4 Hz), 7.82 (m, 1H), 7.82 (d, 2H, J = 8.6 Hz), 7.55 (d, 2H, J = 7.5 Hz), 7.19 (d, 2H, J = 8.4 Hz), 4.57 (m, 1H), 3.96 (m, 1H), 3.82 (s, 3H), 3.15 (s, 3H), 2.12 (m, 2H), 2.07 (m, 2H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 150 MHz) δ 184.3, 180.0, 169.1, 165.8, 163.0, 161.2, 143.4, 132.4, 130.8, 129.2, 123.0, 117.4, 115.8, 74.1, 51.9, 44.0, 43.9, 30.7, 29.1.
55. 3-((2-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Fluorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 62)
실온에서 3-((2-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (70.3 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 62 (44 mg, 55%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.45 (s, 1H), 8.16 (s, 1H), 7.99 (t, 1H, J = 7.2 Hz), 7.63 (d, 2H, J = 8.2 Hz), 7.27 (m, 1H), 7.18 (m, 1H), 7.16 (d, 2H, J = 8.2 Hz), 7.05 (m, 1H), 4.54 (m, 1H), 3.97 (m, 1H), 2.10 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.4, 179.9, 169.0, 163.1, 160.3, 153.1, 151.2, 127.9, 127.1, 127.1, 127.1, 127.0, 127.0, 125.7, 125.0, 125.0, 123.7, 123.6, 123.6, 121.4, 121.3, 121.1, 120.8, 120.5, 115.9, 115.7, 115.5, 74.0, 51.8, 30.9, 29.2.
56. 4-(((1,4-트랜스)-4-((2-((2-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((2-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 63)
실온에서 3-((2-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (58.7 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 63 (44 mg, 60%)을 밝은 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.19 (s, 1H), 7.98 (t, 1H, J = 8.1 Hz), 7.75 (d, 1H, J = 8.7 Hz), 7.27 (dd, 1H, J = 11.4, 8.4 Hz), 7.17 (m, 1H), 7.15 (d, 2H, J = 8.7 Hz), 7.05 (m, 1H), 4.56 (m, 1H), 3.97 (m, 1H), 2.09 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.4, 180.0, 169.0, 163.2, 161.0, 153.2, 151.2, 134.3, 127.1, 127.0, 125.0, 123.7, 123.7, 121.1, 119.3, 116.4, 115.7, 115.5, 102.6, 74.1, 51.8, 30.9, 29.2.
57. 3-((2-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Fluorophenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 64)
실온에서 3-((2-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (64.1 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 64 (53 mg, 69%)을 밝은 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.19 (d, 2H, J = 8.8 Hz), 7.99 (m, 1H), 7.27 (m, 1H), 7.19 (d, 2H, J = 8.7 Hz), 7.17 (m, 1H), 7.05 (m, 1H), 4.63 (m, 1H), 3.98 (m, 1H), 2.11 (m, 4H), 1.59 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.3, 180.0, 169.0, 163.2, 163.0, 153.2, 151.2, 140.6, 127.1, 127.1, 126.0, 125.0, 125.0, 123.7, 123.6, 121.1, 115.8, 115.7, 115.5, 74.7, 51.7, 30.8, 29.2.
58. 3-((2-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Fluorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 65)
실온에서 3-((2-fluorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.18 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (73.1 mg, 0.27 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 65 (20 mg, 24%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.17 (s, 1H), 7.98 (t, 1H, J = 7.6 Hz), 7.83 (d, 2H, J = 8.8 Hz), 7.27 (dd, 1H, J = 11.1, 8.7 Hz), 7.20 (d, 2H, J = 8.8 Hz), 7.18 (m, 1H), 7.05 (dd, 1H, J = 12.3, 6.9 Hz), 4.58 (m, 1H), 3.98 (m, 1H), 3.16 (s, 3H), 2.10 (m, 4H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.3, 179.9, 169.0, 163.2, 161.3, 153.1, 151.2, 132.4, 129.3, 127.1, 127.0, 125.0, 124.9, 123.7, 123.6, 121.1, 115.8, 115.6, 115.5, 74.2, 51.7, 44.0, 30.8, 29.1.
59. 3-((2-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Chlorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 66)
실온에서 3-((2-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.25 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (98.2 mg, 0.38 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 66 (99 mg, 84%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.18 (s, 1H), 8.30 (s, 1H), 7.66 (m, 1H), 7.63 (d, 2H, J = 8.7 Hz), 7.47 (d, 1H, J = 7.9 Hz), 7.33 (t, 1H, J = 7.7 Hz), 7.15 (d, 2H, J = 8.5 Hz), 7.09 (t, 1H, 7.5 Hz), 4.53 (m, 1H), 3.99 (m, 1H), 2.11 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.9, 179.9, 169.0, 163.2, 160.3, 135.1, 129.6, 127.8, 127.0, 127.0, 127.0, 126.9, 125.7, 124.5, 123.5, 122.5, 122.3, 121.4, 121.3, 121.1, 120.8, 120.6, 115.9, 74.0, 51.9, 30.9, 29.3.
60. 4-(((1,4-트랜스)-4-((2-((2-클로로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((2-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 67)
실온에서 3-((2-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.25 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (82.0 mg, 0.38 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 67 (97 mg, 91%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.21 (s, 1H), 8.32 (s, 1H), 7.75 (d, 2H, J = 8.7 Hz), 7.64 (d, 1H, J = 8.0 Hz), 7.48 (d, 1H, J = 8.0 Hz), 7.33 (t, 1H, J = 7.8 Hz), 7.15 (d, 2H, J = 8.6 Hz), 7.09 (t, 1H, J = 7.6 Hz), 4.55 (m, 1H), 3.98 (m, 1H), 2.10 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.9, 179.9, 169.0, 163.2, 161.0, 135.1, 134.3, 129.6, 127.9, 124.5, 122.5, 122.3, 119.2, 116.4, 102.6, 74.2, 51.8, 30.9, 29.3.
61. 3-((2-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Chlorophenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 68)
실온에서 3-((2-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.25 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (89.5 mg, 0.38 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 68 (100 mg, 90%)을 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.32 (s, 1H), 8.19 (d, 2H, J = 9.0 Hz), 7.64 (d, 1H, J = 7.8 Hz), 7.48 (d, 1H, J = 8.0 Hz), 7.33 (t, 1H, J = 7.7 Hz), 7.19 (d, 2H, J = 9.0 Hz), 7.09 (t, 1H, J = 7.6 Hz), 4.62 (m, 1H), 3.99 (m, 1H), 2.12 (m, 4H), 1.57 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.9, 179.9, 169.1, 163.2, 162.9, 140.6, 135.2, 129.6, 127.9, 126.0, 124.5, 122.5, 122.3, 115.8, 74.8, 51.8, 30.9, 29.3.
62. 3-((2-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Chlorophenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 69)
실온에서 3-((2-chlorophenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.25 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (102.0 mg, 0.38 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 69 (48 mg, 40%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.24 (s, 1H), 8.32 (d, 1H, J = 7.9 Hz), 7.83 (d, 2H, J = 8.9 Hz), 7.63 (d, 1H, J = 8.1 Hz), 7.48 (d, 1H, J = 7.8 Hz), 7.33 (t, 1H, J = 7.7 Hz), 7.20 (d, 2H, J = 8.9 Hz), 7.09 (t, 1H, J = 7.7 Hz), 4.58 (m, 1H), 3.99 (m, 1H), 3.16 (s, 3H), 2.11 (m, 4H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 184.9, 179.9, 169.1, 163.2, 161.3, 135.1, 132.4, 129.6, 129.3, 127.9, 124.6, 122.5, 122.3, 115.8, 74.3, 51.9, 44.0, 30.9, 29.3.
63. 3-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)-4-((2-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)amino)-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione](화합물 70)
실온에서 3-methoxy-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.22 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (86.1 mg, 0.33 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 70 (62 mg, 56%)을 흰색 고체로써 얻었다.
1H NMR (CDCl3, 500 MHz) δ 8.49 (s, 1H), 8.25 (s, 1H), 7.51 (d, 2H, J = 8.5 Hz), 7.39 (d, 1H, J = 7.8 Hz), 7.32 (t, 1H, J = 7.6 Hz), 7.24 (d, 1H, J = 7.9 Hz), 6.99 (t, 1H, J = 7.4 Hz), 6.92 (d, 1H, J = 8.5 Hz), 4.27 (m, 1H), 4.11 (m, 1H), 2.09 (m, 4H), 1.53 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 183.3, 181.4, 170.8, 162.8, 160.1, 134.9, 132.3, 127.8, 127.1, 127.1, 127.0, 127.0 ,126.9, 126.3, 126.3, 126.2, 125.6, 125.0 ,124.9, 124.7, 123.4, 123.3, 123.1, 122.8, 122.5, 122.5, 121.8, 121.6, 121.3, 121.3, 121.1, 120.3, 115.7, 74.2, 52.9, 31.1, 29.4.
64. 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((2-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((3,4-Dioxo-2-((2-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 71)
실온에서 3-methoxy-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.22 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (71.8 mg, 0.33 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 71 (79 mg, 78%)을 아이보리색 고체로써 얻었다.
1H NMR (CDCl3, 500 MHz) δ 8.33 (s, 1H), 7.55 (d, 2H, J = 8.3 Hz), 7.38 (d, 1H, J = 7.3 Hz), 7.31 (t, 1H, J = 6.9 Hz), 7.25 (m, 1H), 6.98 (t, 1H, J = 6.8 Hz), 6.91 (d, 2H, J = 8.3 Hz), 4.29 (m, 1H), 4.11 (m, 1H), 2.08 (m, 4H), 1.54 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 183.3, 181.3, 170.8, 162.8, 161.1, 134.9, 134.2, 132.3, 126.8, 126.2, 126.2, 125.0, 124.9, 124.7, 122.5, 121.7, 121.5, 121.2, 121.0, 120.3, 119.4, 116.2, 103.7, 74.4, 52.7, 31.0, 29.4.
65. 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-4-((2-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione](화합물 72)
실온에서 3-methoxy-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.22 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (78.4 mg, 0.33 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 72 (55 mg, 52%)을 연한 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.00 (s, 1H), 8.20 (m, 1H), 8.19 (d, 2H, J = 8.9 Hz), 7.71 (d, 1H, J = 7.6 Hz), 7.66 (t, 1H, J = 7.5 Hz), 7.39 (d, 1H, J = 7.6 Hz), 7.33 (t, 1H, J = 7.1 Hz), 7.19 (d, 2H, J = 9.0 Hz), 4.62 (m, 1H), 3.99 (m, 1H), 2.12 (m, 4H), 1.58 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 185.5, 180.1, 169.2, 163.9, 162.9, 140.6, 135.2, 133.3, 127.2, 126.2, 126.2, 126.0, 125.7, 125.1, 124.6, 122.9, 120.7, 119.9, 119.7, 119.5, 119.2, 115.8, 74.9, 51.8, 31.0, 29.4.
66. 3-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-4-((2-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-
trans
)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione](화합물 73)
실온에서 3-methoxy-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione (60.0 mg, 0.22 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (89.4 mg, 0.33 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 73 (34 mg, 31%)을 아이보리색 고체로써 얻었다.
1H NMR (CDCl3, 500 MHz) δ 7.93 (s, 1H), 7.83 (d, 2H, J = 8.6 Hz), 7.43 (d, 1H, J = 7.8 Hz), 7.38 (t, 1H, J = 7.6 Hz), 7.28 (d, 1H, J = 8.5 Hz), 7.04 (t, 1H, J = 7.4 Hz), 6.98 (d, 2H, J = 8.7 Hz), 4.28 (m, 1H), 4.11 (m, 1H), 3.03 (s, 3H), 2.09 (m, 4H), 1.52 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 185.4, 180.1, 169.1, 163.9, 161.3, 135.1, 133.2, 132.4, 129.3, 127.2, 126.3, 126.2, 126.2, 126.1, 125.7, 125.0, 124.6, 122.9, 120.7, 120.0, 119.7, 119.5, 119.3, 115.8, 74.3, 51.8, 44.0, 31.0, 29.4.
67. 3-((2-터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-(
tert
-Butyl)phenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 74)
실온에서 3-((2-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (50.0 mg, 0.19 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (75.0 mg, 0.29 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 74 (63 mg, 67%)을 아이보리색 고체로써 얻었다.
1H NMR (CDCl3, 500 MHz) δ 7.94 (s, 1H), 7.50 (d, 2H, J = 8.6 Hz), 7.39 (d, 1H, J = 7.4 Hz), 7.13 (m, 2H), 6.97 (d, 1H, J = 7.3 Hz), 6.90 (d, 2H, J = 8.6 Hz), 4.22 (m, 1H), 4.02 (m, 1H), 2.03 (m, 4H), 1.50 (m, 2H), 1.40 (m, 2H), 1.31(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 183.6, 183.2, 168.5, 165.1, 160.2, 145.4, 135.5, 128.6, 127.8, 127.8, 127.6, 127.1, 127.1, 127.0, 127.0, 126.8, 125.9, 123.6, 123.3, 123.2, 122.9, 122.6, 120.5, 115.8, 74.4, 52.5, 35.3, 31.4, 30.8, 29.5.
68. 4-(((1,4-트랜스)-4-((2-((2-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((2-(
tert
-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 75)
실온에서 3-((2-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (60.0 mg, 0.23 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (75.0 mg, 0.34 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 75 (61 mg, 59%)을 아이보리색 고체로써 얻었다.
1H NMR (CDCl3, 500 MHz) δ 7.54 (d, 2H, J = 8.4 Hz), 7.39 (d, 1H, J = 7.3 Hz), 7.14 (m, 2H), 6.97 (d, 1H, J = 7.4 Hz), 6.89 (d, 2H, J = 8.5 Hz), 4.24 (m, 1H), 4.02 (m, 1H), 2.03 (m, 4H), 1.51 (m, 2H), 1.41 (m, 2H), 1.32 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 183.3, 182.8, 168.6, 165.0, 161.1, 145.1, 135.4, 134.2, 127.8, 127.7, 127.4, 126.7, 119.4, 116.2, 103.9, 74.5, 52.4, 35.2, 31.3, 30.8, 29.5.
69. 3-((2-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-(
tert
-Butyl)phenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 76)
실온에서 3-((2-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (50.0 mg, 0.19 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (68.0 mg, 0.28 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 76 (29 mg, 32%)을 연한 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.19 (d, 2H, J = 9.2 Hz), 7.76 (s, 1H), 7.40 (m, 1H), 7.22 (m, 2H), 7.19 (d, 2H, J = 9.2 Hz), 7.08 (m, 1H), 4.60 (m, 1H), 3.95 (m, 1H), 2.11 (m, 4H), 1.57 (m, 4H), 1.37 (s, 9H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.2, 180.8, 168.3, 166.0, 162.8, 143.8, 140.6, 135.9, 128.8, 126.4, 126.4, 125.9, 115.7, 115.4, 74.9, 51.5, 34.7, 30.9, 30.6, 29.3.
70. 3-((2-터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-(
tert
-Butyl)phenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 77)
실온에서 3-((2-(tert-butyl)phenyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (62.3 mg, 0.23 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 77 (18 mg, 23%)을 흰색 고체로써 얻었다.
1H NMR (CDCl3, 500 MHz) δ 7.82 (d, 2H, J = 8.7 Hz), 7.43 (d, 1H, J = 7.3 Hz), 7.21 (m, 2H), 6.98 (m, 1H), 6.95 (d, 2H, J = 8.7 Hz), 4.26 (m, 1H), 4.03 (m, 1H), 3.02 (s, 3H), 2.04 (m, 4H), 1.54 (m, 2H), 1.37 (m, 2H), 1.36 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 183.3, 182.7, 168.6, 165.0, 161.9, 145.1, 135.4, 132.1, 129.7, 127.9, 127.7, 127.4, 126.7, 115.9, 74.6, 52.4, 45.0, 35.1, 31.3, 30.8, 29.4.
71. 3-((2-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Methoxyphenyl)amino)-4-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 78)
실온에서 3-methoxy-4-((2-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.15 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (66.7 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 78 (71 mg, 90%)을 흰색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.18 (s, 1H), 8.31 (s, 1H), 7.77 (d, 1H, J = 7.6 Hz), 7.63 (d, 2H, J = 8.2 Hz), 7.16 (d, 2H, J = 8.2 Hz), 7.06 (d, 1H, J = 7.8 Hz), 7.03 (m, 1H), 6.93 (t, 1H, J = 7.3 Hz), 4.53 (m, 1H), 3.98 (m, 1H), 3.91 (s, 3H), 2.10 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.0, 180.0, 168.7, 163.5, 160.3, 148.6, 127.9, 127.7, 127.1, 127.0, 127.0, 127.0, 125.7, 123.7, 123.6, 121.4, 121.3, 121.1, 120.8, 120.7, 120.5, 120.0, 115.9, 111.3, 74.0, 55.9, 51.8, 30.9, 29.3.
72. 4-(((1,4-트랜스)-4-((2-((2-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-
trans
)-4-((2-((2-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile](화합물 79)
실온에서 3-methoxy-4-((2-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (55.6 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 79 (61 mg, 85%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.18 (s, 1H), 8.32 (d, 1H, J = 6.2 Hz), 7.76 (m, 1H), 7.75 (d, 2H, J = 8.6 Hz), 7.15 (d, 2H, J = 8.7 Hz), 7.05 (m, 1H), 7.03 (m, 1H), 6.92 (m, 1H), 4.55 (m, 1H), 3.97 (m, 1H), 3.90 (s, 3H), 2.09 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.1, 180.0, 168.7, 163.6, 161.0, 148.6, 134.3, 127.7, 123.7, 120.8, 120.0, 119.3, 116.4, 111.3, 102.6, 74.2, 55.9, 51.7, 30.9, 29.2.
73. 3-((2-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Methoxyphenyl)amino)-4-(((1,4-
trans
)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 80)
실온에서 3-methoxy-4-((2-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (60.8 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 80 (61 mg, 81%)을 연한 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.18 (s, 1H), 8.33 (s, 1H), 8.19 (d, 2H, J = 9.1 Hz), 7.77 (d, 1H, J = 7.7 Hz), 7.19 (d, 2H, J = 9.1 Hz), 7.06 (d, 1H, J = 8.1 Hz), 7.03 (m, 1H), 6.92 (t, 1H, J = 7.5 Hz), 4.62 (m, 1H), 3.99 (m, 1H), 3.91 (s, 3H), 2.13 (m, 2H), 2.08 (m, 2H), 1.57 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.0, 180.0, 168.7, 163.5, 162.9, 148.6, 140.6, 127.7, 126.0, 123.7, 120.7, 119.9, 115.8, 111.3, 74.8, 55.9, 51.7, 30.9, 29.2.
74. 3-((2-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Methoxyphenyl)amino)-4-(((1,4-
trans
)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione](화합물 81)
실온에서 3-methoxy-4-((2-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (69.3 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 81 (72 mg, 89%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 400 MHz) δ 8.34 (d, 1H, J = 6.2 Hz), 7.83 (d, 2H, J = 8.9 Hz), 7.77 (d, 1H, J = 7.9 Hz), 7.20 (d, 2H, J = 8.9 Hz), 7.05 (m, 1H), 7.04 (m, 1H), 6.92 (m, 1H), 4.57 (m, 1H), 3.98 (m, 1H), 3.90 (s, 3H), 3.16 (s, 3H), 2.10 (m, 4H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 100 MHz) δ 184.0, 180.0, 168.7, 163.5, 161.3, 148.6, 132.4, 129.3, 127.7, 123.7, 120.7, 119.9, 115.8, 111.3, 74.2, 55.9, 51.7, 44.0, 30.8, 29.2.
75. 4-(((1,4-트랜스)-4-((2-((2-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-
trans
)-4-((2-((2-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide](화합물 82)
실온에서 3-methoxy-4-((2-methoxyphenyl)amino)cyclobut-3-ene-1,2-dione (40.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (69.3 mg, 0.26 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 82 (72 mg, 89%)을 아이보리색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 9.18 (s, 1H), 8.31 (d, 1H, J = 7.7 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.74 (d, 2H, J = 8.8 Hz), 7.20 (s, 2H), 7.13 (d, 2H, J = 8.9 Hz), 7.06 (dd, 1H, J = 8.3, 1.5 Hz), 7.03 (m, 1H), 6.93 (m, 1H), 4.52 (m, 1H), 3.98 (m. 1H), 3.91 (s, 3H), 2.10 (m, 4H), 1.54 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.0, 180.0, 168.7, 163.5, 159.8, 148.6, 136.0, 127.7, 127.7, 123.7, 120.7, 119.9, 115.4, 111.3, 74.0, 55.9, 51.7, 30.9, 29.2.
76. 3-((3,4-디옥소-2-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((3,4-Dioxo-2-(((1,4-
trans
)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile](화합물 83)
실온에서 3-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile (50.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (66.0 mg, 0.25 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 83 (56 mg, 64%)을 연한 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 10.09 (s, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.62 (d, 2H, J = 8.6 Hz), 7.15 (d, 2H, J = 8.6 Hz), 4.52 (m, 1H), 3.97 (m. 1H), 2.12 (m, 2H), 2.06 (m, 2H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.5, 180.4, 169.2, 162.5, 160.3, 140.9, 131.8, 131.5, 131.3, 131.0, 127.9, 127.1, 127.0, 127.0, 127.0, 126.3, 125.7, 124.6, 124.1, 123.6, 122.0, 122.0, 121.9, 121.4, 121.4, 121.1, 120.9, 120.6, 119.8, 118.9, 117.5, 115.9, 113.6. 74.0, 52.1, 30.8, 29.2.
77. 3-((2-(((1,4-트랜스)-4-(4-시아노페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((2-(((1,4-
trans
)-4-(4-Cyanophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile](화합물 84)
실온에서 3-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile (50.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (55.0 mg, 0.25 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 84 (56 mg, 68%)을 연한 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.74 (d, 2H, J = 8.7 Hz), 7.14 (d, 2H, J = 8.8 Hz), 4.54 (m, 1H), 3.96 (m, 1H), 2.10 (m, 2H), 2.05 (m, 2H), 1.55 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.5, 180.4, 169.2, 162.5, 161.0, 140.9, 134.3, 131.8, 131.6, 131.3, 131.0, 126.3, 124.7, 124.1, 122.0, 122.0, 121.9, 119.8, 119.3, 118.9, 118.9, 117.5, 116.4, 113.6, 102.6, 74.2, 52.1, 30.8, 29.2.
78. 3-((2-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((2-(((1,4-
trans
)-4-(4-Nitrophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile](화합물 85)
실온에서 3-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile (50.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (60.0 mg, 0.25 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 85 (49 mg, 57%)을 갈색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 10.07 (s, 1H), 8.18 (d, 2H, J = 9.2 Hz), 8.08 (s, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.18 (d, 2H, J = 9.2 Hz), 4.61 (m, 1H), 3.98 (m, 1H), 2.13 (m, 2H), 2.07 (m, 2H), 1.58 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.5, 180.4, 169.1, 162.9, 162.5, 140.9, 140.6, 131.8, 131.5, 131.3, 131.0, 126.3, 126.0, 124.7, 124.1, 122.0, 122.0, 121.9, 119.8, 118.9, 118.9, 118.9, 117.5, 115.8, 113.6, 74.7, 52.0, 30.7, 29.2.
79. 3-((2-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((2-(((1,4-
trans
)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile](화합물 86)
실온에서 3-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile (50.0 mg, 0.17 mmol)의 EtOH (1 mL) 용액을 교반하면서 (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (68.0 mg, 0.25 mmol)를 Argon 대기 하에서 첨가하고, 반응 혼합물을 밤새 교반하였다. 생성된 고체를 여과시키고, MeOH와 EtOAc로 세척하여 화합물 86 (61 mg, 68%)을 밝은 노란색 고체로써 얻었다.
1H NMR (DMSO-d 6 , 500 MHz) δ 8.08 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.82 (d, 2H, J = 8.8 Hz), 7.20 (d, 2H, J = 8.9 Hz), 4.56 (m, 1H), 3.98 (m, 1H), 3.15 (s, 3H), 2.13 (m, 2H), 2.06 (m, 2H), 1.56 (m, 4H); 13C NMR (DMSO-d 6 , 125 MHz) δ 184.5, 180.4, 169.2, 162.5, 161.3, 140.9, 132.4, 131.8, 131.5, 131.3, 131.0, 129.3, 126.3, 124.7, 124.1, 122.0, 122.0, 121.9, 119.8, 118.9, 118.9, 118.8, 117.5, 115.9, 113.6, 74.2, 52.1, 44.0, 30.7, 29.2.
실시예 1:
N
,
N
'-스퀘어아마이드 유도체들에 대한 eIF2α 인산화의 배수 변화 분석
Cell signaling 사의 Pathscan Phospho-eIF2α (Ser51) Sandwich ELISA Kit #7286를 사용하였다. K562 세포주를 37℃ 및 5% CO2에서 serum-free RPMI 배지에서 배양하였다. 세포에 10 μM의 농도로 시험 화합물을 처리하였다. 화합물 처리 후 6시간 뒤에 키트에 동봉된 lysis buffer로 세포를 lysis하여 50 μg의 단백질을 정량하여 얻었다. 그 이후 manufacturer's protocol에 따라 ELISA assay를 진행하여 흡광도를 얻었다. 얻어진 각각의 화합물에 대한 흡광도는 control (DMSO-treated)을 1로 둔 값에 표준화되었다.
No. | at 10 μM | No. | at 10 μM | No. | at 10 μM |
8 | 0.95 | 35 | 1.05 | 62 | 1.82 |
9 | 0.88 | 36 | 0.60 | 63 | 0.75 |
10 | 0.84 | 37 | 0.67 | 64 | 1.33 |
11 | 0.94 | 38 | 0.65 | 65 | 1.07 |
12 | 0.81 | 39 | 0.83 | 66 | 1.59 |
13 | 0.84 | 40 | 0.82 | 67 | 1.99 |
14 | 0.90 | 41 | 0.62 | 68 | 2.09 |
15 | 0.81 | 42 | 0.93 | 69 | 1.01 |
16 | 0.84 | 43 | 0.87 | 70 | 1.94 |
17 | 0.86 | 44 | 1.47 | 71 | 1.80 |
18 | 0.71 | 45 | 0.79 | 72 | 1.49 |
19 | 1.11 | 46 | 0.71 | 73 | 0.84 |
20 | 1.90 | 47 | 0.51 | 74 | 1.69 |
21 | 0.77 | 48 | 0.91 | 75 | 1.62 |
22 | 2.19 | 49 | 1.02 | 76 | 1.39 |
23 | 2.01 | 50 | 2.04 | 77 | 1.70 |
24 | 1.95 | 51 | 1.82 | 78 | 2.13 |
25 | 1.40 | 52 | 0.77 | 79 | 2.38 |
26 | 1.33 | 53 | 1.33 | 80 | 1.33 |
27 | 1.08 | 54 | 1.82 | 81 | 1.52 |
28 | 1.92 | 55 | 0.84 | 82 | 1.36 |
29 | 1.76 | 56 | 2.27 | 83 | 1.84 |
30 | 1.12 | 57 | 2.11 | 84 | 1.43 |
31 | 1.50 | 58 | 0.97 | 85 | 1.16 |
32 | 1.49 | 59 | 0.83 | 86 | 1.68 |
33 | 0.83 | 60 | 0.97 | ||
34 | 0.83 | 61 | 1.48 |
실시예 2: K562에 대한
N
,
N
'-스퀘어아마이드 유도체들의 항-증식 활성 분석
CCK-8 assay (cell counting kit-8 assay, Dojindo, Kumamoto, Japan)을 수행하였다. K562 세포주를 37℃ 및 5% CO2에서 10% FBS와 1% ABAM이 첨가된 RPMI 배지에서 배양하였다. 세포에 각각 0 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, 20 μM 농도의 시험 화합물을 처리하였다. 3일 동안 배양한 후, 10 μL의 CCK-8 solution을 처리한 후, 4시간 배양하였다. 그 후, 450 nm에서의 흡광도를 측정하여 각각의 화합물의 IC50 value를 구하였다.
IC50 (μM) | |
19 | >20.00 |
20 | 16.09 |
23 | 3.96 |
24 | 5.94 |
25 | 12.25 |
26 | >20.00 |
28 | 6.80 |
29 | 4.09 |
30 | 5.09 |
31 | 5.69 |
35 | >20.00 |
49 | >20.00 |
70 | >20.00 |
71 | >20.00 |
72 | >20.00 |
83 | 4.00 |
84 | 10.07 |
85 | >20.00 |
86 | 14.23 |
실시예 3: K562 및 PBMC 세포주에 대한 선택성 지수(Selectivity index; SI) 분석
K562 세포주에 대한 실험값은 생물학적 실시예 2와 동일하다.
PBMC (정상공여자로부터 분리한 말초혈액 단핵구세포) 세포주를 37℃ 및 5% CO2에서 10% FBS와 1% ABAM이 첨가된 RPMI 배지에 분주한 후, 각각 0 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, 20 μM 농도의 시험 화합물을 처리하였다. 3일 동안 배양한 후, 10 μL의 CCK-8 solution을 처리한 후, 4시간 배양하였다. 그 후, 450 nm에서의 흡광도를 측정하여 각각의 화합물의 IC50 value를 구하였다.
정상세포인 PBMC 대비 K562 세포에서의 SI 측정 결과는 표 3과 같다.
comp | IC50 | ||
K562 | PBMC | SI | |
20 | 16.09 | 19.98 | 1.40 |
23 | 3.96 | 10.82 | 2.77 |
24 | 5.94 | 22.46 | 3.82 |
25 | 12.25 | 16.00 | 1.27 |
28 | 6.80 | 19.37 | 2.86 |
29 | 4.09 | 17.02 | 3.82 |
30 | 5.09 | 12.79 | 2.61 |
31 | 5.69 | 35.05 | 6.10 |
83 | 4.00 | 19.30 | 4.46 |
84 | 10.07 | 29.37 | 2.26 |
86 | 14.23 | 21.03 | 1.31 |
이상으로 본 발명의 특정한 부분을 상세히 기술한 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.
Claims (12)
- 하기 화학식 1로 표시되는 스퀘어아마이드 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물:
[화학식 1]
상기 화학식 1에서,
R1, R2 및 R4는 각각 동일하거나 다를 수 있고, 수소(H), 하이드록시(OH), 할로겐, 트리플루오로메틸(CF3), (C1~C4)알킬, (C1~C4)알콕시 및 아세테이트(COOMe)로 이루어진 군에서 선택되고,
R3은 수소(H) 및 시아노(CN)로 이루어진 군에서 선택되며,
R5는 트리플루오로메틸기(CF3), 시아노(CN), 나이트리트(NO2), (C1~C4)알킬술포닐(SO2Me) 및 아미노술포닐(SO2NH2)로 이루어진 군에서 선택됨. - 제1항에 있어서, 상기 스퀘어아마이드 유도체 화합물은 화학식 1에서 R1은 수소(H), 플루오린(F), 염소(Cl), (C1~C2)알콕시, 트리플루오로메틸(CF3) 및 (C3~C4)알킬로 이루어진 군에서 선택되며, R2는 수소(H), 플루오린(F), 염소(Cl), 트리플루오로메틸(CF3), (C3~C4)알킬, (C1~C2)알콕시 및 아세테이트(COOMe)로 이루어진 군에서 선택되며, R3은 수소(H) 및 시아노(CN)로 이루어진 군에서 선택되며, R4는 수소(H), 플루오린(F), 염소(Cl), (C1~C2)알콕시, 트리플루오로메틸(CF3) 및 (C3~C4)알킬로 이루어진 군에서 선택되며, R5는 트리플루오로메틸기(CF3), 시아노(CN), 나이트리트(NO2), (C1~C2)술포닐(SO2Me) 및 아미노술포닐(SO2NH2)로 이루어진 군에서 선택되는 것을 특징으로 하는 스퀘어아마이드 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물.
- 제1항에 있어서, 상기 스퀘어아마이드 유도체 화합물은 화학식 1에서 R1은 수소(H), 플루오린(F), 염소(Cl), 메톡시(OMe), 트리플루오로메틸(CF3) 및 t-부틸(t-Bu)로 이루어진 군에서 선택되며, R2는 수소(H), 플루오린(F), 염소(Cl), 트리플루오로메틸(CF3), t-부틸(t-Bu), 메톡시(OMe) 및 아세테이트(COOMe)로 이루어진 군에서 선택되며, R3은 수소(H) 및 시아노(CN)로 이루어진 군에서 선택되며, R4는 수소(H), 플루오린(F), 염소(Cl), 메톡시(OMe), 트리플루오로메틸(CF3) 및 t-부틸(t-Bu)로 이루어진 군에서 선택되며, R5는 트리플루오로메틸기(CF3), 시아노(CN), 나이트리트(NO2), 메틸술포닐(SO2Me) 및 아미노술포닐(SO2NH2)로 이루어진 군에서 선택되는 것을 특징으로 하는 스퀘어아마이드 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물.
- 제1항에 있어서, 상기 스퀘어아마이드 유도체 화합물은 3-(페닐아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-(Phenylamino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-(페닐아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((3,4-Dioxo-2-(phenylamino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-4-(페닐아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-(phenylamino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(메틸설포닐)페녹시)시클로헥실)아미노)-4-(페닐아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-(phenylamino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-(페닐아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((3,4-Dioxo-2-(phenylamino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔[3-((3-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene], 4-(((1,4-트랜스)-4-((2-((3-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((3-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((3-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((3-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸설포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((3-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-클로로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((3-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((3-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((3-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸설포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-클로로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((3-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)-4-((3-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((3-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((3,4-Dioxo-2-((3-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-4-((3-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-4-((3-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-((3-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((3-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((3,4-Dioxo-2-((3-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((3-(tert-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((3-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((3-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((3-(tert-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((3-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((3-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((3-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((3-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((3-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((3-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((4-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((4-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((4-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((4-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-(2-((4-클로로페닐)아미노-3,4-디옥소시클로부트-1-엔-1-닐)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((4-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((4-클로로페닐)아미노-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-클로로페닐)아미노-4-((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)-4-(4-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((4-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-닐)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((3,4-Dioxo-2-((4-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노-4-((4-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-4-((4-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-((4-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-(터트-부틸)페닐)아미노)-4-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((4-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((4-(tert-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((4-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((4-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((4-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((4-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((4-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((4-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 메틸 4-((3,4-디옥소-2-((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((3,4-dioxo-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-1-en-1-yl)amino)benzoate], 메틸 4-((2-(((1,4-트랜스)-4-(4-시아노페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((2-(((1,4-trans)-4-(4-cyanophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate], 메틸 4-((2-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate], 메틸 4-((2-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)벤조에이트[Methyl 4-((2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)benzoate], 3-((2-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-플루오로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((2-Fluorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((2-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-플루오로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Fluorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-클로로페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((2-Chlorophenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((2-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-클로로페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Chlorophenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)-4-((2-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)amino)-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((3,4-디옥소-2-((2-(트리플루오로메틸)페닐)아미노)시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((3,4-Dioxo-2-((2-(trifluoromethyl)phenyl)amino)cyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-4-((2-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-4-((2-(트리플루오로메틸)페닐)아미노)시클로부트-3-엔-1,2-디온[3-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-4-((2-(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-(터트-부틸)페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((2-(tert-Butyl)phenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((2-(터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-터트-부틸)페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-(tert-Butyl)phenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤조니트릴[4-(((1,4-trans)-4-((2-((2-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzonitrile], 3-((2-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 3-((2-메톡시페닐)아미노)-4-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)시클로부트-3-엔-1,2-디온[3-((2-Methoxyphenyl)amino)-4-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)cyclobut-3-ene-1,2-dione], 4-(((1,4-트랜스)-4-((2-((2-메톡시페닐)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)시클로헥실)옥시)벤젠술폰아미드[4-(((1,4-trans)-4-((2-((2-Methoxyphenyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)cyclohexyl)oxy)benzenesulfonamide], 3-((3,4-디옥소-2-(((1,4-트랜스)-4-(4-(트리플루오로메틸)페녹시)시클로헥실)아미노)시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((3,4-Dioxo-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)cyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile], 3-((2-(((1,4-트랜스)-4-(4-시아노페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((2-(((1,4-trans)-4-(4-Cyanophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile], 3-((2-(((1,4-트랜스)-4-(4-니트로페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((2-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile] 및 3-((2-(((1,4-트랜스)-4-(4-(메틸술포닐)페녹시)시클로헥실)아미노)-3,4-디옥소시클로부트-1-엔-1-일)아미노)-5-(트리플루오로메틸)벤조니트릴[3-((2-(((1,4-trans)-4-(4-(Methylsulfonyl)phenoxy)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzonitrile]로 이루어진 군에서 선택된 것을 특징으로 하는 스퀘어아마이드 유도체 화합물, 이의 약학적으로 허용가능한 염, 이의 용매화물 또는 이의 입체이성질체에서 선택된 화합물.
- 제1항 내지 제4항 중 어느 한 항에 따른 화합물을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물.
- 제5항에 있어서, 상기 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α; eIF2α)의 인산화를 촉진하는 것을 특징으로 하는 암 예방 또는 치료용 약학조성물.
- 제5항에 있어서, 상기 암은 혈액암, 유방암, 육종암 또는 뇌암인 것을 특징으로 하는 암 예방 또는 치료용 약학조성물.
- 제1항 내지 제4항 중 어느 한 항에 따른 화합물을 유효성분으로 함유하는 대사항암제용 약학조성물.
- 제8항에 있어서, 상기 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α; eIF2α)의 인산화를 촉진하여 암세포의 대사를 차단하는 것을 특징으로 하는 대사항암제용 약학조성물.
- 제1항 내지 제4항 중 어느 한 항에 따른 화합물을 투여하는 단계를 포함하는 암세포 대사 억제방법.
- 제10항에 있어서, 상기 화합물은 진핵생물 번역 개시 인자 2α(eukaryotic translation initiation factor 2α; eIF2α)의 인산화를 촉진하여 암세포의 대사를 차단하는 것을 특징으로 하는 암세포 대사 억제방법.
- 제1항 내지 제4항 중 어느 한 항에 따른 화합물을 유효성분으로 함유하는 암 예방 또는 개선용 건강기능식품 조성물.
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