KR20220129447A - Novel compounds as Transglutaminase 2 inhibitors and composition for preventing or treating cancer containing the compounds - Google Patents
Novel compounds as Transglutaminase 2 inhibitors and composition for preventing or treating cancer containing the compounds Download PDFInfo
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- KR20220129447A KR20220129447A KR1020210136433A KR20210136433A KR20220129447A KR 20220129447 A KR20220129447 A KR 20220129447A KR 1020210136433 A KR1020210136433 A KR 1020210136433A KR 20210136433 A KR20210136433 A KR 20210136433A KR 20220129447 A KR20220129447 A KR 20220129447A
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- cancer
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- transglutaminase
- disease
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Description
본 발명은 트랜스글루타미나제-2 활성 억제용 신규 화합물 및 이를 함유하는 암 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a novel compound for inhibiting transglutaminase-2 activity and a composition for preventing or treating cancer containing the same.
트랜스글루타미나제(Transglutaminase; TGase; TG)는 특이 펩티드에 결합된 글루타민 잔기의 γ-카르복사미드기와 다양한 아민들 사이의 결합을 촉진하는 효소로, 자유 아민기(예컨데, 단백질 또는 펩티드-결합 라이신) 특히 라이신의 ε-아미노기와 단백질 또는 펩티드-결합 글루타민의 γ-카르복사미드기 사이에 공유결합 형성을 촉진하는 효소이다. 이 중 제2형 TGase(TGase2; TG2)는 일차적으로는 손상의 예방과 방어 및 복구를 촉진하는 데 있어서 주요한 역할을 하는 것으로 여겨졌으나, 최근의 연구들에 의하면 비정상적으로 과도하게 유발될 경우에는 신경퇴행성 질환(neurodegenerative diseases), 죽상동맥경화증(atherosclerosis), 염증성 질환(inflammatory diseases) 및 자가면역 질환(autoimmune diseases) 등과 같은 질병의 발생에 주요한 역할을 하는 것으로 보고되고 있다. 또한 콜라겐, 섬유결합소(fibronectin), 라미니아(laminia), 니도겐(nidogen) 및 프로테오글리칸(proteoglycan) 등의 기질단백질(matrix protein)들과 비가역적으로 결합하거나, 세포 외 기질의 단백질분해효소(proteolytic enzyme)에 대한 저항성을 증가시켜, 심한 세포 외 기질의 침착을 유도하여 조직의 섬유화에 관여하는 것으로 제시되고 있다. 실제로 실험적인 신장 및 간 섬유화에 있어서 TG2가 주요한 역할을 하고, 억제제를 이용하여, 그 활성을 억제하였을 경우, 섬유화의 정도가 감소하는 것으로 보고된 바 있다. TG2는 콜라겐 합성 및 상피-중간엽 전이(epithelial-mesenchymal transition)의 증가에 있어서 주요한 매개체인 TGF(transforming growth factor)-β1과 밀접한 연관관계가 있어, 비활성화 상태의 TGF-β1을 활성화시키는 데 있어서 주요한 역할을 하고, TGF-β1은 TG2의 주요한 유도인자인 것으로 보고되고 있어, TGF-β1와 TG2가 조직 섬유화과정에서 상호 긴밀한 기능을 하는 것으로 판단된다.Transglutaminase (TGase; TG) is an enzyme that promotes binding between the γ-carboxamide group of a glutamine residue bound to a specific peptide and various amines, and a free amine group (e.g., protein or peptide-binding Lysine), in particular, is an enzyme that promotes the formation of a covalent bond between the ε-amino group of lysine and the γ-carboxamide group of protein or peptide-bound glutamine. Among them, type 2 TGase (TGase2; TG2) was primarily considered to play a major role in promoting injury prevention, defense, and repair. It is reported to play a major role in the development of diseases such as neurodegenerative diseases, atherosclerosis, inflammatory diseases and autoimmune diseases. In addition, it irreversibly binds to matrix proteins such as collagen, fibronectin, laminia, nidogen and proteoglycan, or extracellular matrix proteolytic enzymes ( It has been suggested that it is involved in tissue fibrosis by increasing resistance to proteolytic enzymes, inducing severe extracellular matrix deposition. In fact, it has been reported that TG2 plays a major role in experimental renal and liver fibrosis, and when its activity is inhibited using an inhibitor, the degree of fibrosis is reduced. TG2 is closely related to transforming growth factor (TGF)-β1, which is a major mediator in the increase of collagen synthesis and epithelial-mesenchymal transition. It has been reported that TGF-β1 is a major inducer of TG2, suggesting that TGF-β1 and TG2 have a close function in the tissue fibrosis process.
이에, 트랜스글루타미나제-2 발현 이상으로 인한 질병을 치료하기 위한 신약 개발 차원에서 안전하고 효과적인 트랜스글루타미나제-2 억제제에 대한 연구가 요구되고 있으나, 아직은 미미한 실정이다.Accordingly, research on safe and effective transglutaminase-2 inhibitors is required for the development of new drugs for treating diseases caused by abnormal transglutaminase-2 expression, but the situation is still insignificant.
본 발명의 목적은 트랜스글루타미나제-2 활성 억제용 신규 화합물 또는 이의 약학적으로 허용가능한 염 및 이를 함유하는 암 예방 또는 치료용 조성물을 제공하는 데에 있다. An object of the present invention is to provide a novel compound for inhibiting transglutaminase-2 activity, or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating cancer containing the same.
본 발명의 일 양태에 따르면, 하기 화학식 1로 표시되는 신규 화합물 또는 이의 약학적으로 허용가능한 염이 제공된다.According to one aspect of the present invention, there is provided a novel compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서 R1, R2, R3, R4 및 R5는 각각 독립적으로 수소, 할로겐 또는 트리플루오로메틸이다. 상기 할로겐은 F, Cl, Br 또는 I에서 선택된다. In Formula 1, R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen or trifluoromethyl. The halogen is selected from F, Cl, Br or I.
상기 화학식 1에서 R6는 , , , , , , , , , , 또는 에서 독립적으로 선택된다. In Formula 1, R 6 is , , , , , , , , , , or independently selected from
본 발명의 상기 화학식 1로 표시되는 화합물은 하기 42종의 화합물 중에서 선택될 수 있다. The compound represented by Formula 1 of the present invention may be selected from the following 42 types of compounds.
본 발명에 따른 화학식 1의 화합물은 약학적으로 허용 가능한 염의 형태로 사용될 수 있다. 상기"약학적으로 허용 가능한 염"은 모 화합물의 약물학적 활성을 유지하는 화합물 염을 의미하는 것으로서, 예를 들어 (i) 염산, 브롬화수소산, 황산, 질산, 및 인산과 같은 무기산과 형성된 염; (ii) 아세트산, 프로피온산, 이소부티르산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 타르타르산, 시트르산, 아스코르빈산, 팔미트산, 말레인산, 하이드록시말레인산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 벤젠설폰산 및 톨루엔설폰산과 같은 유기산과 형성되는 염; (iii) 모 화합물에 존재하는 산성 프로톤이 금속 이온, 예를 들어 알칼리 금속 이온, 알칼리 토금속 이온, 또는 알루미늄 이온에 의해 교체될 때 형성되는 염; (iv) 에탄올아민, 디에탄올아민, 트리에탄올아민, N-메틸글루카민과 같은 유기 염기와의 배위체; 또는 (v) 알기네이트와 같은 아미노산의 염일 수 있다.The compound of Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt. The "pharmaceutically acceptable salt" refers to a compound salt that retains the pharmacological activity of the parent compound, for example, (i) a salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; (ii) acetic acid, propionic acid, isobutyric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid , salts formed with organic acids such as hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; (iii) salts formed when acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions; (iv) coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine; or (v) a salt of an amino acid such as alginate.
본 발명의 다른 일 양태에 따르면, 전술한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는, 트랜스글루타미나제-2 활성 억제제가 제공된다.According to another aspect of the present invention, there is provided a transglutaminase-2 activity inhibitor containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
본 발명의 다른 일 양태에 따르면, 전술한 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 트랜스글루타미나제-2 활성 증가에 의해 발병되는 질환의 예방 또는 치료용 약제학적 조성물이 제공된다.According to another aspect of the present invention, a pharmaceutical composition for preventing or treating a disease caused by an increase in transglutaminase-2 activity containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. this is provided
본 발명의 "트랜스글루타미나제2 활성증가에 의해 발병되는 질환"은 트랜스글루타미나제2가 과발현되는 등 그 활성이 증가되어 초래되는 모든 질병을 포함하며, 구체적으로는 신경계질환과 암을 포함한다.The "disease caused by increased transglutaminase 2 activity" of the present invention includes all diseases caused by increased transglutaminase 2 activity, such as overexpression, specifically, neurological diseases and cancer. include
신경계질환의 경우, 신경 세포의 사망 또는 손상과 관련되는 질환으로, 특히 알츠하이머 질환, 다경색 치매, 알츠하이머 질환과 다경색 치매의 혼합형, 파킨슨씨 질환, 저갑상선증, 알코올성 치매 알츠하이머, 헌팅턴 병 등의 중추신경계 세포의 손상 및 사망에 따른 중추신경계 질환이 대표적이다.Neurological diseases are diseases related to the death or damage of nerve cells, especially Alzheimer's disease, multi-infarct dementia, a mixed type of Alzheimer's disease and multi-infarct dementia, Parkinson's disease, hypothyroidism, alcoholic dementia, Alzheimer's disease, Huntington's disease, etc. Central nervous system diseases caused by damage and death of central nervous system cells are representative.
암의 경우, 대장암, 소장암, 직장암, 항문암, 식도암, 췌장암, 위암, 신장암, 자궁암, 유방암, 폐암, 임파선암, 갑상선암, 전립선암, 백혈병, 피부암, 결장암, 뇌종양, 방광암, 난소암, 담낭암 등을 포함하고, 바람직하게는 신장암을 포함하나, 이에 제한되는 것은 아니다. 상기 신장암은 투명신세포암(clear cell RCC), 유두신세포암(papillary RCC), 혐색소신세포암(chromophobe RCC), 집합관신세포암(collecting tuve RCC) 및 요로상피암(urothelial cancer, transitional cell carcinoma, TCC)으로 구성되는 군으로부터 선택되는 것을 특징으로 하나, 이에 제한되는 것은 아니다.In the case of cancer, colorectal cancer, small intestine cancer, rectal cancer, anal cancer, esophageal cancer, pancreatic cancer, stomach cancer, kidney cancer, uterine cancer, breast cancer, lung cancer, lymph gland cancer, thyroid cancer, prostate cancer, leukemia, skin cancer, colon cancer, brain tumor, bladder cancer, ovarian cancer , gallbladder cancer, and the like, and preferably kidney cancer, but is not limited thereto. The kidney cancer is clear cell RCC, papillary RCC, chromophobe RCC, collecting tube RCC, and urothelial cancer, transitional It is characterized in that it is selected from the group consisting of cell carcinoma, TCC), but is not limited thereto.
본 발명의 약제학적 조성물은 화학식 1의 화합물을 약학적으로 허용 가능한 염의 형태로 함유할 수 있다. 상기"약학적으로 허용 가능한 염"은 앞서 정의한 바와 같다.The pharmaceutical composition of the present invention may contain the compound of Formula 1 in the form of a pharmaceutically acceptable salt. The "pharmaceutically acceptable salt" is as defined above.
또한, 본 발명의 약제학적 조성물은 본 발명의 상기 화학식 1의 화합물의 이성질체, 용매화물, 또는 프로드러그(prodrug)을 함유할 수 있다. 여기서 "이성질체"는 디아스테레오머 및 에난티오머를 비롯한 모든 가능한 입체화학적 이성질체를 포함한다. 본 발명의 화합물은 모든 가능한 입체화학적 이성질체 형태의 혼합물을 지칭하는 것으로 이해할 수 있다. 또한, 용어"용매화물"은 용질 (예를 들어 화학식 1의 화합물)과 용매의 복합체를 가리키는 것으로서, 용매가 물인 경우 상기 용매화물은 수화물로 지칭될 수 있다. 용어 "프로드러그"는 생체내에 투여된 후에 생체 흡수 및 대사에 의하여 약효를 갖는 활성 화합물로 변환되는 화합물을 가리킨다. 상기 프로드러그는 그 자체로 비활성이거나 활성 화합물보다 활성이 덜한 화합물이며, 다만, 취급, 투여, 또는 대사에 유리한 특성을 제공할 수 있다. 상기 프로드러그는 활성 화합물의 에스테르 형태 (예를 들어, 생리학적으로 허용 가능한 대사적으로 불안정한 에스테르)이거나 당 유도체의 형태, 또는 아미노산 에스테르 유도체의 형태일 수 있다.In addition, the pharmaceutical composition of the present invention may contain an isomer, solvate, or prodrug of the compound of Formula 1 of the present invention. "Isomer" herein includes all possible stereochemically isomers, including diastereomers and enantiomers. It can be understood that the compounds of the present invention refer to mixtures of all possible stereochemically isomeric forms. In addition, the term "solvate" refers to a complex of a solute (eg, a compound of Formula 1) and a solvent, and when the solvent is water, the solvate may be referred to as a hydrate. The term "prodrug" refers to a compound that is converted into an active compound having a medicinal effect by bioabsorption and metabolism after administration in vivo. The prodrug is a compound that is itself inactive or less active than the active compound, provided that it may provide advantageous properties for handling, administration, or metabolism. The prodrug may be in the form of an ester of the active compound (eg, a physiologically acceptable metabolically labile ester), a sugar derivative, or an amino acid ester derivative.
본 발명의 약제학적 조성물은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염에 추가하여 약학적으로 허용 가능한 담체를 추가로 더 포함할 수도 있다. 상기 약학적으로 허용 가능한 담체는 약제학 분야에서 통상적으로 사용되는 것일 수 있으며, 부형제 (예를 들어, 전분, 칼슘 카보네이트, 수크로스, 락토스, 소르비톨, 만니톨, 셀룰로오스 등) 또는 희석제 (예를 들어, 생리식염수, 정제수 등)일 수 있다. The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable carrier may be one commonly used in the pharmaceutical field, and an excipient (eg, starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, etc.) or a diluent (eg, physiological saline, purified water, etc.).
또한, 필요에 따라, 본 발명의 약제학적 조성물은 상기 약학적으로 허용 가능한 담체 이외의 약학적으로 허용 가능한 첨가제, 예를 들어, 결합제, 붕해제, 활택제, 제피제, 필름 코팅 기제, 장용성 필름 코팅 기제, 연질 캡슐 기제, 용해보조제, 유화제, 현탁화제, 안정화제, 완충제, 항산화제, 계면활성제, 감미제, 교미제, 보존제, 점증제, 방향제, 또는 착색제를 더 포함할 수도 있다.In addition, if necessary, the pharmaceutical composition of the present invention may contain pharmaceutically acceptable additives other than the pharmaceutically acceptable carrier, for example, a binder, a disintegrant, a lubricant, a coating agent, a film coating base, an enteric film. It may further include a coating base, a soft capsule base, a solubilizing agent, an emulsifier, a suspending agent, a stabilizer, a buffer, an antioxidant, a surfactant, a sweetening agent, a flavoring agent, a preservative, a thickening agent, a flavoring agent, or a coloring agent.
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있다. 비경구의 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 내피 투여, 국소 투여, 비강내 투여, 폐내 투여, 및 직장내 투여 등으로 투여할 수 있다. 경구 투여시, 본 발명의 조성물은 고체 또는 액제 제형의 형태로 제형화될 수 있다. 고체 제형은 예를 들어, 정제, 캡슐제(연질 & 경질 캡슐제), 산제, 과립제, 환제, 트로키제 등일 수 있으며, 액체 제형은 예를 들어, 엘릭서, 현탁액제, 유액제, 용액제, 시럽제, 리모나아데제 등의 형태일 수 있다. The pharmaceutical composition of the present invention may be administered orally or parenterally. In the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration may be used. For oral administration, the composition of the present invention may be formulated in the form of a solid or liquid dosage form. Solid dosage forms can be, for example, tablets, capsules (soft & hard capsules), powders, granules, pills, troches, and the like, and liquid dosage forms can be, for example, elixirs, suspensions, emulsions, solutions, syrups, etc. , and may be in the form of limonaadese.
본 발명의 약제학적 조성물의 투여량은 투여방법, 복용자의 연령, 성별, 환자의 중증도, 상태, 불활성율, 및 병용되는 약물을 고려하여 결정할 수 있으며, 1회 또는 수회로 나누어 투여할 수 있다. The dosage of the pharmaceutical composition of the present invention may be determined in consideration of the administration method, the age, sex, the severity of the patient, the condition, the inactivation rate, and the drug used in combination, and may be administered once or divided into several doses.
본 발명은 트랜스글루타미나제-2 활성 억제용 신규 화합물 또는 이의 약학적으로 허용가능한 염 및 이를 함유하는 암 예방 또는 치료용 조성물에 관한 것으로서, 이에 따른 화학식 1의 화합물은 트랜스글루타미나제-2의 활성을 유의적으로 억제하고, 암세포의 사멸효과가 우수한 바, 트랜스글루타미나제-2의 활성 증가에 의해 초래될 수 있는 되는 신장 질환을 비롯한, 다양한 질환, 특히 각종 암 질환의 예방, 개선 또는 치료를 위한 조성물의 유효성분으로 이용될 수 있다.The present invention relates to a novel compound for inhibiting transglutaminase-2 activity or a pharmaceutically acceptable salt thereof and a composition for preventing or treating cancer containing the same, wherein the compound of Formula 1 is transglutaminase- 2 significantly inhibits the activity of, and has excellent apoptosis effect on cancer cells, prevention of various diseases, particularly various cancer diseases, including kidney disease, which may be caused by increased activity of transglutaminase-2; It can be used as an active ingredient of a composition for improvement or treatment.
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나, 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지도록, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided so that this disclosure will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.
본 발명의 화합물은 예를 들어 하기의 [반응식 1]에 따라 제조될 수 있다:The compound of the present invention can be prepared, for example, according to the following [Scheme 1]:
[반응식 1][Scheme 1]
상기 화학식 1에서 R1, R2, R3, R4 및 R5는 각각 독립적으로 수소, 할로겐 또는 트리플루오로메틸이다. 상기 할로겐은 F, Cl, Br 또는 I에서 선택된다. 상기 화학식 1에서 R6는 , , , , , , , , , , 또는 에서 독립적으로 선택된다. In Formula 1, R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen or trifluoromethyl. The halogen is selected from F, Cl, Br or I. In Formula 1, R 6 is , , , , , , , , , , or independently selected from
상기 반응식 1에의 조건은 다음과 같다: (a) HNO3, 0℃, 실온(RT), 100℃; (b) Pd/C, H2, Methanol, RT, 24hr; (c) Toluene, Reflux, 6hr; (d) HNO3, HCl, 80℃, RTConditions in Scheme 1 are as follows: (a) HNO 3 , 0° C., room temperature (RT), 100° C.; (b) Pd/C, H 2 , Methanol, RT, 24 hr; (c) Toluene, Reflux, 6 hr; (d) HNO 3 , HCl, 80° C., RT
상기 반응식 1은 1,4-디메톡시벤젠을 출발물질로 하여 합성을 시작한다. 예를 들어, 1,4-디메톡시벤젠 (1)을 HNO3을 이용한 니트로화 반응 (nitration) 을 수행하여 화합물 (2)를 제조하고, Pd/c 촉매 하에서 H2를 이용한 환원반응 (reduction) 을 수행하여 니트로기를 아민기로 환원시켜 화합물 (3)을 제조한다. 화합물 (3)의 1,2-디아민기를 적합한 알데하이드 물질과 반응시켜 환류 조건하에서 고리화 반응 (cyclization)을 통하여 벤조이미다졸 환의 합성이 달성된다. 최종적으로, 화합물 4a-4l을 HNO3, HCl 의 존재 하에 탈메틸화 반응(demethylation) 및 염소화 반응(chlorination)을 수행하여 화합물 5a-5l을 제조하고, 다시 이를 이용하여 화합물 6(6-1 내지 6-42)을 제조한다.Scheme 1 starts the synthesis using 1,4-dimethoxybenzene as a starting material. For example, 1,4-dimethoxybenzene (1) is subjected to a nitration reaction using HNO 3 to prepare compound (2), and a reduction reaction using H 2 under a Pd/c catalyst (reduction) to reduce the nitro group to an amine group to prepare compound (3). The synthesis of a benzimidazole ring is achieved through cyclization under reflux conditions by reacting the 1,2-diamine group of compound (3) with a suitable aldehyde material. Finally, compound 4a-4l was subjected to demethylation and chlorination in the presence of HNO 3 and HCl to prepare compound 5a-5l, and again using this compound 6 (6-1 to 6) -42) is prepared.
이하, 본 발명의 이해를 돕기 위하여 본 발명의 대표 화합물을 들어 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, examples are given by giving representative compounds of the present invention in order to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.
<실시예 1 : 중간체 화합물의 제조> <Example 1: Preparation of intermediate compound>
실시예 1-1 : 1,4-디메톡시-2,3-디니트로벤젠 중간체의 제조 (화합물 2)Example 1-1: Preparation of 1,4-dimethoxy-2,3-dinitrobenzene intermediate (Compound 2)
5g (36.19mmol) 화합물 1,4-디메톡시벤젠에 질산 15mL 을 첨가하여 0℃에서 1시간, 상온에서 1시간, 100℃에서 1시간 동안 교반 하였다. 상온에서 냉각 후, 0℃에서 혼합물을 1N NaOH 용액으로 중화시키고, 감압 필터 하여 고체 화합물을 얻는다. 실리카겔 컬럼크로마토그래피법을 수행하여 (전개용매: n-hexanes/ethyl acetate = 4:1) 하기 중간체인 화합물 2를 제조하였다.To 5 g (36.19 mmol) compound 1,4-dimethoxybenzene, 15 mL of nitric acid was added and stirred at 0° C. for 1 hour, at room temperature for 1 hour, and at 100° C. for 1 hour. After cooling to room temperature, the mixture is neutralized with 1N NaOH solution at 0°C, and filtered under reduced pressure to obtain a solid compound. By performing silica gel column chromatography (eluent: n-hexanes/ethyl acetate = 4:1), the following intermediate compound 2 was prepared.
[반응식 2][Scheme 2]
수율: 79%Yield: 79%
1H NMR (CDCl3) δ 3.93(6H, CH3), 7.21(2H, CH) 1 H NMR (CDCl 3 ) δ 3.93 (6H, CH 3 ), 7.21 (2H, CH)
MS (ESI): m/z = 228.68 (M++1)MS (ESI): m/z = 228.68 (M + +1)
실시예 1-2 : 3,6-디메톡시벤젠-1,2-디아민 중간체의 제조 (화합물 3)Example 1-2: Preparation of 3,6-dimethoxybenzene-1,2-diamine intermediate (Compound 3)
상기에서 제조한 1,4-디메톡시-2,3-디니트로벤젠 중간체 2g (8.76mmol) 을 10mL 메탄올에 용해시키고 Pd/C 촉매 100mg 을 첨가한다. 내부를 수소 가스로 치환하고 상온에서 24hr 동안 교반하였다. 혼합물을 감압 필터 하여 얻어진 여액을 감압농축하고 실리카겔 컬럼크로마토그래피법을 수행하여 (전개용매: n-hexanes/ethyl acetate = 4:1) 하기 중간체인 화합물 3을 제조하였다.2 g (8.76 mmol) of the 1,4-dimethoxy-2,3-dinitrobenzene intermediate prepared above was dissolved in 10 mL methanol, and 100 mg of a Pd/C catalyst was added. The inside was replaced with hydrogen gas and stirred at room temperature for 24 hr. The mixture was filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (eluent: n-hexanes/ethyl acetate = 4:1) to prepare compound 3 as the following intermediate.
[반응식 3][Scheme 3]
수율: 85%Yield: 85%
1H NMR (CDCl3) δ 3.51(4H, NH2), 6.31(2H, CH), 3.81(6H, CH3) 1 H NMR (CDCl 3 ) δ 3.51 (4H, NH 2 ), 6.31 (2H, CH), 3.81 (6H, CH 3 )
MS (ESI): m/z = 168.73 (M++1)MS (ESI): m/z = 168.73 (M + +1)
<실시예 2 : 4,7-디메톡시-1H-벤조이미다졸 중간체의 제조 (화합물 4a-4l)><Example 2: Preparation of 4,7-dimethoxy-1H-benzoimidazole intermediate (Compound 4a-4l)>
상기에서 제조한 3,6-디메톡시벤젠-1,2-디아민 중간체 1g (5.94mmol) 을 15mL 톨루엔에 용해시키고 3-fluoro-4-(trifluoromethyl)benzaldehyde, 4-fluoro-3-(trifluoromethyl)benzaldehyde, 4-(trifluoromethyl)benzaldehyde, 3-(trifluoromethyl)benzaldehyde, 4-bromo-3-(trifluoromethyl)benzaldehyde, benzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde, 4-bromo-3-fluorobenzaldehyde, 3,4,5-trifluorobenzaldehyde, 4-bromo-3,5-difluorobenzaldehyde, 3,4-difluorobenzaldehyde 를 각각 11.88 mmol 을 첨가하여 6시간 동안 환류 반응하였다. 상온에서 냉각시킨 후, 에틸아세테이트로 추출하였다. 유기층을 무수 황산 나트륨으로 건조하고 감압농축 하였다. 에틸에테르를 첨가한 후 감압 필터 하여 고체 형태의 화합물인 하기 중간체들인 화합물 4a 내지 4l을 제조하였다.1 g (5.94 mmol) of the 3,6-dimethoxybenzene-1,2-diamine intermediate prepared above was dissolved in 15 mL toluene, and 3-fluoro-4-(trifluoromethyl)benzaldehyde, 4-fluoro-3-(trifluoromethyl)benzaldehyde , 4-(trifluoromethyl)benzaldehyde, 3-(trifluoromethyl)benzaldehyde, 4-bromo-3-(trifluoromethyl)benzaldehyde, benzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde, 4-bromo-3-fluorobenzaldehyde, 3,4,5- 11.88 mmol of trifluorobenzaldehyde, 4-bromo-3,5-difluorobenzaldehyde, and 3,4-difluorobenzaldehyde were each added and refluxed for 6 hours. After cooling to room temperature, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After adding ethyl ether, it was filtered under reduced pressure to prepare the following intermediates, compounds 4a to 4l, which are solid compounds.
실시예 2-1 : 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (화합물 4a) Example 2-1: 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4a)
수율: 78%Yield: 78%
1H NMR (CDCl3) δ 4.21(1H, NH), 8.32(1H, CH), 7.65(1H, CH), 7.25(1H, CH), 6.79(2H, CH), 3.81(6H, CH3) 1 H NMR (CDCl 3 ) δ 4.21 (1H, NH), 8.32 (1H, CH), 7.65 (1H, CH), 7.25 (1H, CH), 6.79 (2H, CH), 3.81 (6H, CH 3 )
MS (ESI): m/z = 340.11 (M++1)MS (ESI): m/z = 340.11 (M + +1)
실시예 2-2 : 2-(4-fluoro-3-(trifluoromethyl)phenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (화합물 4b) Example 2-2: 2-(4-fluoro-3-(trifluoromethyl)phenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4b)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 5.24(1H, NH), 8.12(1H, CH), 7.74(1H, CH), 7.25(1H, CH), 6.85(2H, CH), 3.86(6H, CH3) 1 H NMR (CDCl 3 ) δ 5.24 (1H, NH), 8.12 (1H, CH), 7.74 (1H, CH), 7.25 (1H, CH), 6.85 (2H, CH), 3.86 (6H, CH 3 )
MS (ESI): m/z = 340.03 (M++1)MS (ESI): m/z = 340.03 (M + +1)
실시예 2-3 : 4,7-dimethoxy-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (화합물 4c)Example 2-3: 4,7-dimethoxy-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (Compound 4c)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 4.53(1H, NH), 8.54(2H, CH), 7.64(2H, CH), 6.83(2H, CH), 3.82(6H, CH3) 1 H NMR (CDCl 3 ) δ 4.53 (1H, NH), 8.54 (2H, CH), 7.64 (2H, CH), 6.83 (2H, CH), 3.82 (6H, CH 3 )
MS (ESI): m/z = 322.12 (M++1)MS (ESI): m/z = 322.12 (M + +1)
실시예 2-4 : 4,7-dimethoxy-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (화합물 4d)Example 2-4: 4,7-dimethoxy-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole (Compound 4d)
수율: 77%Yield: 77%
1H NMR (CDCl3) δ 4.13(1H, NH), 8.63(1H, CH), 8.25(1H, CH), 7.56(1H, CH), 7.42(1H, CH), 6.83(2H, CH), 3.81(6H, CH3) 1 H NMR (CDCl 3 ) δ 4.13 (1H, NH), 8.63 (1H, CH), 8.25 (1H, CH), 7.56 (1H, CH), 7.42 (1H, CH), 6.83 (2H, CH), 3.81 (6H, CH 3 )
MS (ESI): m/z = 322.12 (M++1)MS (ESI): m/z = 322.12 (M + +1)
실시예 2-5 : 2-(4-bromo-3-(trifluoromethyl)phenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (화합물 4e)Example 2-5: 2-(4-bromo-3-(trifluoromethyl)phenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4e)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 4.83(1H, NH), 8.05(1H, CH), 7.65(1H, CH), 7.54(1H, CH), 6.83(2H, CH), 3.81(6H, CH3) 1 H NMR (CDCl 3 ) δ 4.83 (1H, NH), 8.05 (1H, CH), 7.65 (1H, CH), 7.54 (1H, CH), 6.83 (2H, CH), 3.81 (6H, CH 3 )
MS (ESI): m/z = 400.23 (M++1)MS (ESI): m/z = 400.23 (M + +1)
실시예 2-6 : 4,7-dimethoxy-2-phenyl-1H-benzo[d]imidazole (화합물 4f)Example 2-6: 4,7-dimethoxy-2-phenyl-1H-benzo[d]imidazole (Compound 4f)
수율: 86%Yield: 86%
1H NMR (CDCl3) δ 5.43(1H, NH), 8.29(2H, CH), 7.52(2H, CH), 7.42(1H, CH), 6.81(2H, CH), 3.82(6H, CH3) 1 H NMR (CDCl 3 ) δ 5.43 (1H, NH), 8.29 (2H, CH), 7.52 (2H, CH), 7.42 (1H, CH), 6.81 (2H, CH), 3.82 (6H, CH 3 )
MS (ESI): m/z = 254.34 (M++1)MS (ESI): m/z = 254.34 (M + +1)
실시예 2-7 : 2-(3-fluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (화합물 4g)Example 2-7: 2-(3-fluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (compound 4g)
수율: 83%Yield: 83%
1H NMR (CDCl3) δ 4.83(1H, NH), 8.04(1H, CH), 7.51-7.48(2H, CH), 7.22(1H, CH), 6.81(2H, CH), 3.82(6H, CH3) 1 H NMR (CDCl 3 ) δ 4.83 (1H, NH), 8.04 (1H, CH), 7.51-7.48 (2H, CH), 7.22 (1H, CH), 6.81 (2H, CH), 3.82 (6H, CH) 3 )
MS (ESI): m/z = 272.15 (M++1)MS (ESI): m/z = 272.15 (M + +1)
실시예 2-8 : 2-(4-fluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (화합물 4h)Example 2-8: 2-(4-fluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4h)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 5.23(1H, NH), 7.78(2H, CH), 7.31(2H, CH), 6.84(2H, CH), 3.82(6H, CH3) 1 H NMR (CDCl 3 ) δ 5.23 (1H, NH), 7.78 (2H, CH), 7.31 (2H, CH), 6.84 (2H, CH), 3.82 (6H, CH 3 )
MS (ESI): m/z = 272.21 (M++1)MS (ESI): m/z = 272.21 (M + +1)
실시예 2-9 : 2-(4-bromo-3-fluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (화합물 4i)Example 2-9: 2-(4-bromo-3-fluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4i)
수율: 86%Yield: 86%
1H NMR (CDCl3) δ 5.34(1H, NH), 7.62(1H, CH), 7.43-7.42(2H, CH), 6.81(2H, CH), 3.82(6H, CH3) 1 H NMR (CDCl 3 ) δ 5.34 (1H, NH), 7.62 (1H, CH), 7.43-7.42 (2H, CH), 6.81 (2H, CH), 3.82 (6H, CH 3 )
MS (ESI): m/z = 350.13 (M++1)MS (ESI): m/z = 350.13 (M + +1)
실시예 2-10 : 4,7-dimethoxy-2-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole (화합물 4j)Example 2-10: 4,7-dimethoxy-2-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole (Compound 4j)
수율: 89%Yield: 89%
1H NMR (CDCl3) δ 5.12(1H, NH), 7.24(2H, CH), 6.81(2H, CH), 3.80(6H, CH3) 1 H NMR (CDCl 3 ) δ 5.12 (1H, NH), 7.24 (2H, CH), 6.81 (2H, CH), 3.80 (6H, CH 3 )
MS (ESI): m/z = 308.12 (M++1)MS (ESI): m/z = 308.12 (M + +1)
실시예 2-11 : 2-(4-bromo-3,5-difluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (화합물 4k)Example 2-11: 2-(4-bromo-3,5-difluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4k)
수율: 88%Yield: 88%
1H NMR (CDCl3) δ 5.34(1H, NH), 7.17(2H, CH), 6.81(2H, CH), 3.80(6H, CH3) 1 H NMR (CDCl 3 ) δ 5.34 (1H, NH), 7.17 (2H, CH), 6.81 (2H, CH), 3.80 (6H, CH 3 )
MS (ESI): m/z = 368.23 (M++1)MS (ESI): m/z = 368.23 (M + +1)
실시예 2-12 : 2-(3,4-difluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (화합물 4l)Example 2-12: 2-(3,4-difluorophenyl)-4,7-dimethoxy-1H-benzo[d]imidazole (Compound 4l)
수율: 75%Yield: 75%
1H NMR (CDCl3) δ 5.12(1H, NH), 7.53-7.51(2H, CH), 7.26(1H, CH), 6.81(2H, CH), 3.82(6H, CH3) 1 H NMR (CDCl 3 ) δ 5.12 (1H, NH), 7.53-7.51 (2H, CH), 7.26 (1H, CH), 6.81 (2H, CH), 3.82 (6H, CH 3 )
MS (ESI): m/z = 290.12 (M++1)MS (ESI): m/z = 290.12 (M + +1)
<실시예 3 : 화합물 5a-5l의 제조><Example 3: Preparation of compound 5a-5l>
실시예 2에서 제조한 각각의 중간체 2.00mmol 에 염산 9mL 과 질산 3mL 을 천천히 첨가하고 이 혼합물을 80℃에서 1시간 및 상온에서 1시간 동안 교반 하였다. 혼합물을 탄산수소나트륨으로 중화시키고 에틸아세테이트로 추출하였다. 유기층을 무수 황산 나트륨으로 건조하고 감압농축 하였다. 에틸에테르를 첨가한 후 감압 필터 하여 고체 형태의 화합물인 하기 화합물들을 제조하였다.9 mL of hydrochloric acid and 3 mL of nitric acid were slowly added to 2.00 mmol of each intermediate prepared in Example 2, and the mixture was stirred at 80° C. for 1 hour and at room temperature for 1 hour. The mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After addition of ethyl ether, it was filtered under reduced pressure to prepare the following compounds, which are solid compounds.
실시예 3-1 : 5,6-dichloro-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 5a)Example 3-1: 5,6-dichloro-2-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5a)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 13.13(1H, NH), 8.32(1H, CH), 7.64(1H, CH), 7.42(1H, CH) 1 H NMR (CDCl 3 ) δ 13.13 (1H, NH), 8.32 (1H, CH), 7.64 (1H, CH), 7.42 (1H, CH)
MS (ESI): m/z = 377.87 (M++1)MS (ESI): m/z = 377.87 (M + +1)
실시예 3-2 : 5,6-dichloro-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 5b)Example 3-2: 5,6-dichloro-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5b)
수율: 85%Yield: 85%
1H NMR (CDCl3) δ 13.62(1H, NH), 8.12(1H, CH), 7.75(1H, CH), 7.22(1H, CH) 1 H NMR (CDCl 3 ) δ 13.62(1H, NH), 8.12(1H, CH), 7.75(1H, CH), 7.22(1H, CH)
MS (ESI): m/z = 377.81 (M++1)MS (ESI): m/z = 377.81 (M + +1)
실시예 3-3 : 5,6-dichloro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 5c)Example 3-3: 5,6-dichloro-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5c)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 13.42(1H, NH), 8.53(2H, CH), 7.62(2H, CH) 1 H NMR (CDCl 3 ) δ 13.42 (1H, NH), 8.53 (2H, CH), 7.62 (2H, CH)
MS (ESI): m/z = 359.82 (M++1)MS (ESI): m/z = 359.82 (M + +1)
실시예 3-4 : 5,6-dichloro-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 5d)Example 3-4: 5,6-dichloro-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5d)
수율: 89%Yield: 89%
1H NMR (CDCl3) δ 12.92(1H, NH), 8.62(1H, CH), 8.22(1H, CH), 7.54(1H, CH), 7.42(1H, CH) 1 H NMR (CDCl 3 ) δ 12.92(1H, NH), 8.62(1H, CH), 8.22(1H, CH), 7.54(1H, CH), 7.42(1H, CH)
MS (ESI): m/z = 359.89 (M++1)MS (ESI): m/z = 359.89 (M + +1)
실시예 3-5 : 2-(4-bromo-3-(trifluoromethyl)phenyl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione (화합물 5e)Example 3-5: 2-(4-bromo-3-(trifluoromethyl)phenyl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione (Compound 5e)
수율: 86%Yield: 86%
1H NMR (CDCl3) δ 13.22(1H, NH), 8.05(1H, CH), 7.67-7.61(2H, CH) 1 H NMR (CDCl 3 ) δ 13.22 (1H, NH), 8.05 (1H, CH), 7.67-7.61 (2H, CH)
MS (ESI): m/z = 439.75 (M++1)MS (ESI): m/z = 439.75 (M + +1)
실시예 3-6 : 5,6-dichloro-2-phenyl-1H-benzo[d]imidazole-4,7-dione (화합물 5f)Example 3-6: 5,6-dichloro-2-phenyl-1H-benzo[d]imidazole-4,7-dione (Compound 5f)
수율: 79%Yield: 79%
1H NMR (CDCl3) δ 13.33(1H, NH), 8.31(2H, CH), 7.52-7.44(3H, CH) 1 H NMR (CDCl 3 ) δ 13.33 (1H, NH), 8.31 (2H, CH), 7.52-7.44 (3H, CH)
MS (ESI): m/z = 291.84 (M++1)MS (ESI): m/z = 291.84 (M + +1)
실시예 3-7 : 5,6-dichloro-2-(3-fluorophenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 5g)Example 3-7: 5,6-dichloro-2-(3-fluorophenyl)-1H-benzo[d]imidazole-4,7-dione (compound 5g)
수율: 78%Yield: 78%
1H NMR (CDCl3) δ 13.22(1H, NH), 8.03(1H, CH), 7.51-7.42(1H, CH), 7.23(1H, CH) 1 H NMR (CDCl 3 ) δ 13.22 (1H, NH), 8.03 (1H, CH), 7.51-7.42 (1H, CH), 7.23 (1H, CH)
MS (ESI): m/z = 309.82 (M++1)MS (ESI): m/z = 309.82 (M + +1)
실시예 3-8 : 5,6-dichloro-2-(4-fluorophenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 5h)Example 3-8: 5,6-dichloro-2-(4-fluorophenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5h)
수율: 85%Yield: 85%
1H NMR (CDCl3) δ 13.22(1H, NH), 7.76(2H, CH), 7.32(2H, CH) 1 H NMR (CDCl 3 ) δ 13.22 (1H, NH), 7.76 (2H, CH), 7.32 (2H, CH)
MS (ESI): m/z = 309.92 (M++1)MS (ESI): m/z = 309.92 (M + +1)
실시예 3-9 : 2-(4-bromo-3-fluorophenyl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione (화합물 5i)Example 3-9: 2-(4-bromo-3-fluorophenyl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione (Compound 5i)
수율: 84%Yield: 84%
1H NMR (CDCl3) δ 13.14(1H, NH), 7.63(1H, CH), 7.43-7.42(2H, CH) 1 H NMR (CDCl 3 ) δ 13.14 (1H, NH), 7.63 (1H, CH), 7.43-7.42 (2H, CH)
MS (ESI): m/z = 389.81 (M++1)MS (ESI): m/z = 389.81 (M + +1)
실시예 3-10 : 5,6-dichloro-2-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 5j)Example 3-10: 5,6-dichloro-2-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 5j)
수율: 80%Yield: 80%
1H NMR (CDCl3) δ 13.13(1H, NH), 7.25(2H, CH) 1 H NMR (CDCl 3 ) δ 13.13 (1H, NH), 7.25 (2H, CH)
MS (ESI): m/z = 345.89 (M++1)MS (ESI): m/z = 345.89 (M + +1)
실시예 3-11 : 2-(4-bromo-3,5-difluorophenyl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione (화합물 5k)Example 3-11: 2-(4-bromo-3,5-difluorophenyl)-5,6-dichloro-1H-benzo[d]imidazole-4,7-dione (Compound 5k)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 13.22(1H, NH), 7.16(2H, CH) 1 H NMR (CDCl 3 ) δ 13.22 (1H, NH), 7.16 (2H, CH)
MS (ESI): m/z = 407.72 (M++1)MS (ESI): m/z = 407.72 (M + +1)
실시예 3-12 : 5,6-dichloro-2-(3,4-difluorophenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 5l)Example 3-12: 5,6-dichloro-2- (3,4-difluorophenyl) -1H-benzo [d] imidazole-4,7-dione (Compound 5l)
수율: 88%Yield: 88%
1H NMR (CDCl3) δ 12.22(1H, NH), 7.55- 7.51(2H, CH), 7.26(1H, CH) 1 H NMR (CDCl 3 ) δ 12.22 (1H, NH), 7.55-7.51 (2H, CH), 7.26 (1H, CH)
MS (ESI): m/z = 327.83 (M++1)MS (ESI): m/z = 327.83 (M + +1)
<실시예 4 : 화합물 6의 제조><Example 4: Preparation of compound 6>
화합물 5a-5l을 이용하여 하기와 같은 반응식들을 통해 화합물 6-1 내지 6-42의 총 42개의 화합물을 합성하였다. A total of 42 compounds of compounds 6-1 to 6-42 were synthesized through the following schemes using compounds 5a-5l.
실시예 4-1. (S)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-2-phenyl-1H-benzo[d]imidazole-4,7-dione (화합물 6-1)Example 4-1. (S)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-2-phenyl-1H-benzo[d]imidazole-4,7-dione (Compound 6-1)
화합물 5f와 (S)-3-aminopiperidin-2-one를 상온에서 CH2Cl2 용매 하에 동일 몰 비로 혼합하고, HCl을 소량 적정하였다. 반응산물로서 최종적으로 화합물 6-1을 수득하였다. Compound 5f and (S)-3-aminopiperidin-2-one were mixed in the same molar ratio in a CH 2 Cl 2 solvent at room temperature, and a small amount of HCl was titrated. Finally, compound 6-1 was obtained as a reaction product.
수율: 85%Yield: 85%
1H NMR (CDCl3) δ 13.24(1H, NH), 7.52(1H, NH), 2.35(1H, NH), 8.24(2H, CH), 7.53(2H, CH), 7.42(1H, CH), 3.21-3.18(2H, CH2), 3.01(2H, CH), 2.02-1.67(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.24(1H, NH), 7.52(1H, NH), 2.35(1H, NH), 8.24(2H, CH), 7.53(2H, CH), 7.42(1H, CH), 3.21-3.18 (2H, CH 2 ), 3.01 (2H, CH), 2.02-1.67 (4H, CH 2 )
MS (ESI): m/z = 370.12 (M++1)MS (ESI): m/z = 370.12 (M + +1)
이 후, 각 반응식에 따라 제조방법은 동일하게 하되, 화합물 5f와 (S)-3-aminopiperidin-2-one 대신 적절하게 반응과정을 다르게 하여 화합물 6-2 내지 6-42를 제조하였다. 필요에 따라 HCl 대신 HBr을 적정하거나 이 과정은 생략하였다. Thereafter, the preparation method was the same according to each reaction scheme, but compounds 6-2 to 6-42 were prepared by appropriately changing the reaction process instead of compound 5f and (S)-3-aminopiperidin-2-one. If necessary, HBr instead of HCl was titrated or this process was omitted.
실시예 4-2. (S)-2-(4-bromo-3-fluorophenyl)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-2)Example 4-2. (S)-2-(4-bromo-3-fluorophenyl)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (compound 6-2)
수율: 83%Yield: 83%
1H NMR (CDCl3) δ 12.84(1H, NH), 8.25(1H, NH), 2.15(1H, NH), 7.63(1H, CH), 7.44-7.42(2H, CH), 3.21-3.18(2H, CH2), 3.01(H, CH), 2.03-1.64(4H, CH2) 1 H NMR (CDCl 3 ) δ 12.84 (1H, NH), 8.25 (1H, NH), 2.15 (1H, NH), 7.63 (1H, CH), 7.44-7.42 (2H, CH), 3.21-3.18 (2H) , CH 2 ), 3.01 (H, CH), 2.03-1.64 (4H, CH 2 )
MS (ESI): m/z = 467.85 (M++1)MS (ESI): m/z = 467.85 (M + +1)
실시예 4-3. (S)-6-chloro-2-(3,4-difluorophenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-3)Example 4-3. (S)-6-chloro-2-(3,4-difluorophenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (compound 6- 3)
수율: 91%Yield: 91%
1H NMR (CDCl3) δ 13.23(1H, NH), 8.12(1H, NH), 2.41(1H, NH), 7.53-7.51(2H, CH), 7.27(1H, CH), 3.21-3.18(2H, CH2), 3.03(H, CH), 2.02-1.70(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.23 (1H, NH), 8.12 (1H, NH), 2.41 (1H, NH), 7.53-7.51 (2H, CH), 7.27 (1H, CH), 3.21-3.18 (2H) , CH 2 ), 3.03 (H, CH), 2.02-1.70 (4H, CH 2 )
MS (ESI): m/z = 406.02 (M++1)MS (ESI): m/z = 406.02 (M + +1)
실시예 4-4. (S)-6-chloro-2-(4-fluorophenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-4)Example 4-4. (S)-6-chloro-2-(4-fluorophenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (Compound 6-4)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 13.13(1H, NH), 8.15(1H, NH), 1.61(1H, NH), 7.74(2H, CH), 7.31(2H, CH), 3.21-3.18(2H, CH2), 3.03(H, CH), 2.02-1.68(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.13 (1H, NH), 8.15 (1H, NH), 1.61 (1H, NH), 7.74 (2H, CH), 7.31 (2H, CH), 3.21-3.18 (2H, CH) 2 ), 3.03 (H, CH), 2.02-1.68 (4H, CH 2 )
MS (ESI): m/z = 388.12 (M++1)MS (ESI): m/z = 388.12 (M + +1)
실시예 4-5. (S)-6-chloro-2-(3-fluorophenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-5)Example 4-5. (S)-6-chloro-2-(3-fluorophenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (Compound 6-5)
수율: 88%Yield: 88%
1H NMR (CDCl3) δ 12.83(1H, NH), 8.13(1H, NH), 1.63(1H, NH), 8.03(1H, CH), 7.51-7.46(2H, CH), 7.21(1H, CH), 3.20-3.14(2H, CH2), 3.08(H, CH), 2.02-1.62(4H, CH2) 1 H NMR (CDCl 3 ) δ 12.83 (1H, NH), 8.13 (1H, NH), 1.63 (1H, NH), 8.03 (1H, CH), 7.51-7.46 (2H, CH), 7.21 (1H, CH) ), 3.20-3.14 (2H, CH 2 ), 3.08 (H, CH), 2.02-1.62 (4H, CH 2 )
MS (ESI): m/z = 388.23 (M++1)MS (ESI): m/z = 388.23 (M + +1)
실시예 4-6. (S)-6-chloro-2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-6)Example 4-6. (S)-6-chloro-2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7- dione (compound 6-6)
수율: 86%Yield: 86%
1H NMR (CDCl3) δ 13.12(1H, NH), 7.4(1H, NH), 2.5(1H, NH), 8.32(1H, CH), 7.64(1H, CH), 7.42(1H, CH), 3.24-3.17(2H, CH2), 3.01(H, CH), 1.99-1.62(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.12 (1H, NH), 7.4 (1H, NH), 2.5 (1H, NH), 8.32 (1H, CH), 7.64 (1H, CH), 7.42 (1H, CH), 3.24-3.17 (2H, CH 2 ), 3.01 (H, CH), 1.99-1.62 (4H, CH 2 )
MS (ESI): m/z = 456.21 (M++1)MS (ESI): m/z = 456.21 (M + +1)
실시예 4-7. (S)-6-chloro-2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-7)Example 4-7. (S)-6-chloro-2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7- dione (compound 6-7)
수율: 85%Yield: 85%
1H NMR (CDCl3) δ 12.89(1H, NH), 7.03(1H, NH), 2.42(1H, NH), 8.13(1H, CH), 7.75(1H, CH), 7.21(1H, CH), 3.21-3.18(2H, CH2), 3.01(H, CH), 2.03-1.68(4H, CH2) 1 H NMR (CDCl 3 ) δ 12.89 (1H, NH), 7.03 (1H, NH), 2.42 (1H, NH), 8.13 (1H, CH), 7.75 (1H, CH), 7.21 (1H, CH), 3.21-3.18 (2H, CH 2 ), 3.01 (H, CH), 2.03-1.68 (4H, CH 2 )
MS (ESI): m/z = 456.01 (M++1)MS (ESI): m/z = 456.01 (M + +1)
실시예 4-8. (S)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-8)Examples 4-8. (S)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (compound 6 -8)
수율: 89%Yield: 89%
1H NMR (CDCl3) δ 13.24(1H, NH), 8.34(1H, NH), 2.22(1H, NH), 8.54(2H, CH), 7.66(2H, CH), 3.21-3.17(2H, CH2), 3.01(H, CH), 2.02-1.61(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.24 (1H, NH), 8.34 (1H, NH), 2.22 (1H, NH), 8.54 (2H, CH), 7.66 (2H, CH), 3.21-3.17 (2H, CH) 2 ), 3.01 (H, CH), 2.02-1.61 (4H, CH 2 )
MS (ESI): m/z = 438.17 (M++1)MS (ESI): m/z = 438.17 (M + +1)
실시예 4-9. (S)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-9)Examples 4-9. (S)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (compound 6 -9)
수율: 75%Yield: 75%
1H NMR (CDCl3) δ 13.24(1H, NH), 8.23(1H, NH), 2.31(1H, NH), 8.62(1H, CH), 8.27(1H, CH), 7.55(1H, CH), 7.42(1H, CH), 3.24-3.18(2H, CH2), 3.04(H, CH), 2.02-1.65(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.24 (1H, NH), 8.23 (1H, NH), 2.31 (1H, NH), 8.62 (1H, CH), 8.27 (1H, CH), 7.55 (1H, CH), 7.42 (1H, CH), 3.24-3.18 (2H, CH 2 ), 3.04 (H, CH), 2.02-1.65 (4H, CH 2 )
MS (ESI): m/z = 438.12 (M++1)MS (ESI): m/z = 438.12 (M + +1)
실시예 4-10. (S)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-2-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-10)Examples 4-10. (S)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-2-(3,4,5-trifluorophenyl)-1H-benzo[d]imidazole-4,7-dione (compound 6-10)
수율: 78%Yield: 78%
1H NMR (CDCl3) δ 13.53(1H, NH), 8.04(1H, NH), 2.10(1H, NH), 7.26(2H, CH), 3.01(H, CH), 3.21-3.18(2H, CH2), 2.04-1.68(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.53 (1H, NH), 8.04 (1H, NH), 2.10 (1H, NH), 7.26 (2H, CH), 3.01 (H, CH), 3.21-3.18 (2H, CH) 2 ), 2.04-1.68 (4H, CH 2 )
MS (ESI): m/z = 424.12 (M++1)MS (ESI): m/z = 424.12 (M + +1)
실시예 4-11. (S)-2-(4-bromo-3,5-difluorophenyl)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-11)Examples 4-11. (S)-2-(4-bromo-3,5-difluorophenyl)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (Compound 6-11)
수율: 88%Yield: 88%
1H NMR (CDCl3) δ 13.23(1H, NH), 8.14(1H, NH), 1.63(1H, NH), 7.13(2H, CH), 3.20-3.15(2H, CH2), 3.03(H, CH), 2.02-1.63(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.23 (1H, NH), 8.14 (1H, NH), 1.63 (1H, NH), 7.13 (2H, CH), 3.20-3.15 (2H, CH 2 ), 3.03 (H, CH), 2.02-1.63 (4H, CH 2 )
MS (ESI): m/z = 485.83 (M++1)MS (ESI): m/z = 485.83 (M + +1)
실시예 4-12. (S)-2-(4-bromo-3-(trifluoromethyl)phenyl)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-12)Examples 4-12. (S)-2-(4-bromo-3-(trifluoromethyl)phenyl)-6-chloro-5-((2-oxopiperidin-3-yl)amino)-1H-benzo[d]imidazole-4,7- dione (compound 6-12)
수율: 84%Yield: 84%
1H NMR (CDCl3) δ 12.45(1H, NH), 7.52(1H, NH), 1.63(1H, NH), 8.03(1H, CH), 7.65-7.55(2H, CH), 3.21-3.18(2H, CH2), 3.01(H, CH), 2.03-1.64(4H, CH2) 1 H NMR (CDCl 3 ) δ 12.45 (1H, NH), 7.52 (1H, NH), 1.63 (1H, NH), 8.03 (1H, CH), 7.65-7.55 (2H, CH), 3.21-3.18 (2H) , CH 2 ), 3.01 (H, CH), 2.03-1.64 (4H, CH 2 )
MS (ESI): m/z = 517.85 (M++1)MS (ESI): m/z = 517.85 (M + +1)
실시예 4-13. 6-chloro-5-(2-oxooxazolidin-3-yl)-2-phenyl-1H-benzo[d]imidazole-4,7-dione (화합물 6-13)Examples 4-13. 6-chloro-5-(2-oxooxazolidin-3-yl)-2-phenyl-1H-benzo[d]imidazole-4,7-dione (Compound 6-13)
수율: 86%Yield: 86%
1H NMR (CDCl3) δ 13.2(1H, NH), 8.25(2H, CH), 7.51-7.43(2H, CH), 4.41(2H, CH2), 3.54(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.2 (1H, NH), 8.25 (2H, CH), 7.51-7.43 (2H, CH), 4.41 (2H, CH 2 ), 3.54 (2H, CH 2 )
MS (ESI): m/z = 343.21 (M++1)MS (ESI): m/z = 343.21 (M + +1)
실시예 4-14. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-14)Examples 4-14. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-14)
수율: 89%Yield: 89%
1H NMR (CDCl3) δ 13.23(1H, NH), 7.62(1H, CH), 7.44-7.42(2H, CH), 4.42(2H, CH2), 3.52(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.23(1H, NH), 7.62(1H, CH), 7.44-7.42(2H, CH), 4.42(2H, CH 2 ), 3.52(2H, CH 2 )
MS (ESI): m/z = 438.75 (M++1)MS (ESI): m/z = 438.75 (M + +1)
실시예 4-15. 6-chloro-2-(3,4-difluorophenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-15)Examples 4-15. 6-chloro-2-(3,4-difluorophenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-15)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 12.56(1H, NH), 7.53-7.51(2H, CH), 7.27(1H, CH), 4.41-3.54(4H, CH2) 1 H NMR (CDCl 3 ) δ 12.56 (1H, NH), 7.53-7.51 (2H, CH), 7.27 (1H, CH), 4.41-3.54 (4H, CH 2 )
MS (ESI): m/z = 379.13 (M++1)MS (ESI): m/z = 379.13 (M + +1)
실시예 4-16. 6-chloro-2-(4-fluorophenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-16)Examples 4-16. 6-chloro-2-(4-fluorophenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-16)
수율: 84%Yield: 84%
1H NMR (CDCl3) δ 13.24(1H, NH), 7.75(2H, CH), 7.31(2H, CH), 4.41(2H, CH2), 3.52(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.24 (1H, NH), 7.75 (2H, CH), 7.31 (2H, CH), 4.41 (2H, CH 2 ), 3.52 (2H, CH 2 )
MS (ESI): m/z = 361.12 (M++1)MS (ESI): m/z = 361.12 (M + +1)
실시예 4-17. 6-chloro-2-(3-fluorophenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-17)Examples 4-17. 6-chloro-2-(3-fluorophenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-17)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 13.24(1H, NH), 8.07(1H, CH), 7.51-7.47(2H, CH), 7.21(1H, CH), 4.41(2H, CH2), 3.52(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.24 (1H, NH), 8.07 (1H, CH), 7.51-7.47 (2H, CH), 7.21 (1H, CH), 4.41 (2H, CH 2 ), 3.52 (2H, CH 2 )
MS (ESI): m/z = 361.12 (M++1)MS (ESI): m/z = 361.12 (M + +1)
실시예 4-18. 6-chloro-2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-18)Example 4-18. 6-chloro-2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-18)
수율: 84%Yield: 84%
1H NMR (CDCl3) δ 13.21(1H, NH), 8.32(1H, CH), 7.65(1H, CH), 7.42(1H, CH), 4.42(2H, CH2), 3.53(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.21 (1H, NH), 8.32 (1H, CH), 7.65 (1H, CH), 7.42 (1H, CH), 4.42 (2H, CH 2 ), 3.53 (2H, CH 2 ) )
MS (ESI): m/z = 429.12 (M++1)MS (ESI): m/z = 429.12 (M + +1)
실시예 4-19. 6-chloro-2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-19)Example 4-19. 6-chloro-2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-oxooxazolidin-3-yl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-19)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 13.25(1H, NH), 8.15(1H, CH), 7.75(1H, CH), 7.21(1H, CH), 4.41(2H, CH2), 3.52(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.25 (1H, NH), 8.15 (1H, CH), 7.75 (1H, CH), 7.21 (1H, CH), 4.41 (2H, CH 2 ), 3.52 (2H, CH 2 ) )
MS (ESI): m/z = 429.13 (M++1)MS (ESI): m/z = 429.13 (M + +1)
실시예 4-20. 6-chloro-5-(2-oxooxazolidin-3-yl)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-20)Examples 4-20. 6-chloro-5-(2-oxooxazolidin-3-yl)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-20)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 12.45(1H, NH), 8.56(2H, CH), 7.65(2H, CH), 4.41(2H, CH2), 3.51(2H, CH2) 1 H NMR (CDCl 3 ) δ 12.45 (1H, NH), 8.56 (2H, CH), 7.65 (2H, CH), 4.41 (2H, CH 2 ), 3.51 (2H, CH 2 )
MS (ESI): m/z = 411.08 (M++1)MS (ESI): m/z = 411.08 (M + +1)
실시예 4-21. 6-chloro-5-(2-oxooxazolidin-3-yl)-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-21)Example 4-21. 6-chloro-5-(2-oxooxazolidin-3-yl)-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-21)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 13.13(1H, NH), 8.62(1H, CH), 8.26(1H, CH), 7.55-7.43(2H, CH), 4.41(2H, CH2), 3.52(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.13 (1H, NH), 8.62 (1H, CH), 8.26 (1H, CH), 7.55-7.43 (2H, CH), 4.41 (2H, CH 2 ), 3.52 (2H, CH 2 )
MS (ESI): m/z = 411.09 (M++1)MS (ESI): m/z = 411.09 (M + +1)
실시예 4-22. (S)-6-chloro-5-((2-oxotetrahydrofuran-3-yl)amino)-2-phenyl-1H-benzo[d]imidazole-4,7-dione (화합물 6-22)Example 4-22. (S)-6-chloro-5-((2-oxotetrahydrofuran-3-yl)amino)-2-phenyl-1H-benzo[d]imidazole-4,7-dione (Compound 6-22)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 12.91(1H, NH), 2.34(1H, NH), 8.27(2H, CH), 7.52-7.41(3H, CH), 4.32-4.23(2H, CH2), 3.41(H, CH), 2.43-2.17(2H, CH2) 1 H NMR (CDCl 3 ) δ 12.91 (1H, NH), 2.34 (1H, NH), 8.27 (2H, CH), 7.52-7.41 (3H, CH), 4.32-4.23 (2H, CH 2 ), 3.41 ( H, CH), 2.43-2.17 (2H, CH 2 )
MS (ESI): m/z = 357.12 (M++1)MS (ESI): m/z = 357.12 (M + +1)
실시예 4-23. (S)-2-(4-bromo-3-fluorophenyl)-6-chloro-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-23)Example 4-23. (S)-2-(4-bromo-3-fluorophenyl)-6-chloro-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (compound 6-23)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 13.12(1H, NH), 1.63(1H, NH), 7.63(1H, CH), 7.43-7.42(2H, CH), 4.34-4.26(2H, CH2), 3.42(H, CH), 2.42-2.21(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.12 (1H, NH), 1.63 (1H, NH), 7.63 (1H, CH), 7.43-7.42 (2H, CH), 4.34-4.26 (2H, CH 2 ), 3.42 ( H, CH), 2.42-2.21 (2H, CH 2 )
MS (ESI): m/z = 454.84 (M++1)MS (ESI): m/z = 454.84 (M + +1)
실시예 4-24. (S)-6-chloro-2-(3,4-difluorophenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-24)Example 4-24. (S)-6-chloro-2-(3,4-difluorophenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (compound 6- 24)
수율: 87%Yield: 87%
1H NMR (CDCl3) δ 13.14(1H, NH), 2.12(1H, NH), 7.53-7.52(2H, CH), 7.26(1H, CH), 4.33-4.27(2H, CH2), 3.44(H, CH), 2.43-2.19(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.14 (1H, NH), 2.12 (1H, NH), 7.53-7.52 (2H, CH), 7.26 (1H, CH), 4.33-4.27 (2H, CH 2 ), 3.44 ( H, CH), 2.43-2.19 (2H, CH 2 )
MS (ESI): m/z = 393.12 (M++1)MS (ESI): m/z = 393.12 (M + +1)
실시예 4-25. (S)-6-chloro-2-(4-fluorophenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-25)Examples 4-25. (S)-6-chloro-2-(4-fluorophenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (Compound 6-25)
수율: 89%Yield: 89%
1H NMR (CDCl3) δ 13.43(1H, NH), 2.52(1H, NH), 7.74(2H, CH), 7.31(2H, CH), 4.37-4.27(2H, CH2), 3.41(H, CH), 2.42-2.17(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.43 (1H, NH), 2.52 (1H, NH), 7.74 (2H, CH), 7.31 (2H, CH), 4.37-4.27 (2H, CH 2 ), 3.41 (H, CH), 2.42-2.17 (2H, CH 2 )
MS (ESI): m/z = 375.12 (M++1)MS (ESI): m/z = 375.12 (M + +1)
실시예 4-26. (S)-6-chloro-2-(3-fluorophenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-26)Example 4-26. (S)-6-chloro-2-(3-fluorophenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (Compound 6-26)
수율: 79%Yield: 79%
1H NMR (CDCl3) δ 13.14(1H, NH), 2.12(1H, NH), 8.03(1H, CH), 7.51-7.48(2H, CH), 7.21(1H, CH), 4.35-4.23(2H, CH2), 3.42(H, CH), 2.46-2.21(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.14 (1H, NH), 2.12 (1H, NH), 8.03 (1H, CH), 7.51-7.48 (2H, CH), 7.21 (1H, CH), 4.35-4.23 (2H) , CH 2 ), 3.42 (H, CH), 2.46-2.21 (2H, CH 2 )
MS (ESI): m/z = 375.12 (M++1)MS (ESI): m/z = 375.12 (M + +1)
실시예 4-27. (S)-6-chloro-2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물6-27)Example 4-27. (S)-6-chloro-2-(3-fluoro-4-(trifluoromethyl)phenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7- dione (compound 6-27)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 13.23(1H, NH), 2.12(1H, NH), 8.32(1H, CH), 7.64(1H, CH), 7.43(1H, CH), 4.34-4.25(2H, CH2), 3.42(H, CH), 2.43-2.18(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.23(1H, NH), 2.12(1H, NH), 8.32(1H, CH), 7.64(1H, CH), 7.43(1H, CH), 4.34-4.25(2H, CH) 2 ), 3.42 (H, CH), 2.43-2.18 (2H, CH 2 )
MS (ESI): m/z = 443.18 (M++1)MS (ESI): m/z = 443.18 (M + +1)
실시예 4-28. (S)-6-chloro-2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물6-28)Example 4-28. (S)-6-chloro-2-(4-fluoro-3-(trifluoromethyl)phenyl)-5-((2-oxotetrahydrofuran-3-yl)amino)-1H-benzo[d]imidazole-4,7- dione (compound 6-28)
수율: 83%Yield: 83%
1H NMR (CDCl3) δ 13.44(1H, NH), 2.51(1H, NH), 8.15(1H, CH), 7.76(1H, CH), 7.22(1H, CH), 4.34-4.23(2H, CH2), 3.41(H, CH), 2.43-2.18(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.44 (1H, NH), 2.51 (1H, NH), 8.15 (1H, CH), 7.76 (1H, CH), 7.22 (1H, CH), 4.34-4.23 (2H, CH) 2 ), 3.41 (H, CH), 2.43-2.18 (2H, CH 2 )
MS (ESI): m/z = 443.12 (M++1)MS (ESI): m/z = 443.12 (M + +1)
실시예 4-29. (S)-6-chloro-5-((2-oxotetrahydrofuran-3-yl)amino)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-29)Example 4-29. (S)-6-chloro-5-((2-oxotetrahydrofuran-3-yl)amino)-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 6 -29)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 12.63(1H, NH), 1.83(1H, NH), 8.56(2H, CH), 7.69(2H, CH), 4.34-4.23(2H, CH2), 3.42(H, CH), 2.45-2.17(2H, CH2) 1 H NMR (CDCl 3 ) δ 12.63 (1H, NH), 1.83 (1H, NH), 8.56 (2H, CH), 7.69 (2H, CH), 4.34-4.23 (2H, CH 2 ), 3.42 (H, CH), 2.45-2.17 (2H, CH 2 )
MS (ESI): m/z = 425.12 (M++1)MS (ESI): m/z = 425.12 (M + +1)
실시예 4-30. (S)-6-chloro-5-((2-oxotetrahydrofuran-3-yl)amino)-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-30)Examples 4-30. (S)-6-chloro-5-((2-oxotetrahydrofuran-3-yl)amino)-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4,7-dione (Compound 6 -30)
수율: 83%Yield: 83%
1H NMR (CDCl3) δ 12.45(1H, NH), 1.83(1H, NH), 8.62(1H, CH), 8.29(1H, CH), 7.59(1H, CH), 7.45(1H, CH), 4.34-4.24(2H, CH2), 3.42(H, CH), 2.43-2.18(2H, CH2) 1 H NMR (CDCl 3 ) δ 12.45 (1H, NH), 1.83 (1H, NH), 8.62 (1H, CH), 8.29 (1H, CH), 7.59 (1H, CH), 7.45 (1H, CH), 4.34-4.24 (2H, CH 2 ), 3.42 (H, CH), 2.43-2.18 (2H, CH 2 )
MS (ESI): m/z = 425.11 (M++1)MS (ESI): m/z = 425.11 (M + +1)
실시예 4-31. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-(p-tolylamino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-31)Example 4-31. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-(p-tolylamino)-1H-benzo[d]imidazole-4,7-dione (Compound 6-31)
수율: 89%Yield: 89%
1H NMR (CDCl3) δ 13.13(1H, NH), 4.23(1H, NH), 7.63(1H, CH), 7.44-7.42(2H, CH), 6.96(2H, CH), 6.32(2H, CH), 2.32(3H, CH3) 1 H NMR (CDCl 3 ) δ 13.13 (1H, NH), 4.23 (1H, NH), 7.63 (1H, CH), 7.44-7.42 (2H, CH), 6.96 (2H, CH), 6.32 (2H, CH) ), 2.32(3H, CH 3 )
MS (ESI): m/z = 460.89 (M++1)MS (ESI): m/z = 460.89 (M + +1)
실시예 4-32. 2-(4-bromo-3-fluorophenyl)-5-((4-bromophenyl)amino)-6-chloro-1H-benzo[d]imidazole-4,7-dione (화합물 6-32)Example 4-32. 2-(4-bromo-3-fluorophenyl)-5-((4-bromophenyl)amino)-6-chloro-1H-benzo[d]imidazole-4,7-dione (Compound 6-32)
수율: 87%Yield: 87%
1H NMR (CDCl3) δ 13.14(1H, NH), 3.89(1H, NH), 7.63(1H, CH), 7.44-7.43(2H, CH), 6.97(2H, CH), 6.37(2H, CH), 2.32(3H, CH3) 1 H NMR (CDCl 3 ) δ 13.14 (1H, NH), 3.89 (1H, NH), 7.63 (1H, CH), 7.44-7.43 (2H, CH), 6.97 (2H, CH), 6.37 (2H, CH) ), 2.32(3H, CH 3 )
MS (ESI): m/z = 524.83 (M++1)MS (ESI): m/z = 524.83 (M + +1)
실시예 4-33. 2-(4-bromo-3-fluorophenyl)-5-((3-bromophenyl)amino)-6-chloro-1H-benzo[d]imidazole-4,7-dione (화합물 6-33)Example 4-33. 2-(4-bromo-3-fluorophenyl)-5-((3-bromophenyl)amino)-6-chloro-1H-benzo[d]imidazole-4,7-dione (compound 6-33)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 13.34(1H, NH), 4.24(1H, NH), 7.63(1H, CH), 7.44-7.41(2H, CH), 6.96-6.94(2H, CH), 6.68(H, CH), 6.36(H, CH) 1 H NMR (CDCl 3 ) δ 13.34 (1H, NH), 4.24 (1H, NH), 7.63 (1H, CH), 7.44-7.41 (2H, CH), 6.96-6.94 (2H, CH), 6.68 (H) , CH), 6.36 (H, CH)
MS (ESI): m/z = 524.88 (M++1)MS (ESI): m/z = 524.88 (M + +1)
실시예 4-34. N-(2-(4-bromo-3-fluorophenyl)-6-chloro-4,7-dioxo-4,7-dihydro-1H-benzo[d]imidazol-5-yl)acetamide (화합물 6-34)Example 4-34. N-(2-(4-bromo-3-fluorophenyl)-6-chloro-4,7-dioxo-4,7-dihydro-1H-benzo[d]imidazol-5-yl)acetamide (compound 6-34)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 13.12(1H, NH), 8.23(1H, NH), 7.63(1H, CH), 7.44-7.42(2H, CH), 1.87(1H, CH3) 1 H NMR (CDCl 3 ) δ 13.12 (1H, NH), 8.23 (1H, NH), 7.63 (1H, CH), 7.44-7.42 (2H, CH), 1.87 (1H, CH 3 )
MS (ESI): m/z = 412.82 (M++1)MS (ESI): m/z = 412.82 (M + +1)
실시예 4-35. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazole-4,7-dione (화합물 6-35)Example 4-35. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-((1-methylpiperidin-4-yl)amino)-1H-benzo[d]imidazole-4,7-dione (Compound 6-35)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 13.21(1H, NH), 2.32(1H, NH), 7.62(1H, CH), 7.43-7.42(2H, CH), 2.62(1H, CH), 2.52-2.41(4H, CH2), 2.27(3H, CH3), 1.84-1.62(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.21 (1H, NH), 2.32 (1H, NH), 7.62 (1H, CH), 7.43-7.42 (2H, CH), 2.62 (1H, CH), 2.52-2.41 (4H) , CH 2 ), 2.27(3H, CH 3 ), 1.84-1.62(2H, CH 2 )
MS (ESI): m/z = 468.01 (M++1)MS (ESI): m/z = 468.01 (M + +1)
실시예 4-36. 5-amino-2-(4-bromo-3-fluorophenyl)-6-chloro-1H-benzo[d]imidazole-4,7-dione (화합물 6-36)Example 4-36. 5-amino-2-(4-bromo-3-fluorophenyl)-6-chloro-1H-benzo[d]imidazole-4,7-dione (compound 6-36)
수율: 85%Yield: 85%
1H NMR (CDCl3) δ 13.24(1H, NH), 8.54(1H, NH), 7.63(1H, CH), 7.43-7.41(2H, CH) 1 H NMR (CDCl 3 ) δ 13.24 (1H, NH), 8.54 (1H, NH), 7.63 (1H, CH), 7.43-7.41 (2H, CH)
MS (ESI): m/z = 370.82 (M++1)MS (ESI): m/z = 370.82 (M + +1)
실시예 4-37. (S)-methyl 1-(2-(4-bromo-3-fluorophenyl)-6-chloro-4,7-dioxo-4,7-dihydro-1H-benzo[d]imidazol-5-yl)pyrrolidine-2-carboxylate (화합물 6-37)Example 4-37. (S)-methyl 1-(2-(4-bromo-3-fluorophenyl)-6-chloro-4,7-dioxo-4,7-dihydro-1H-benzo[d]imidazol-5-yl)pyrrolidine- 2-carboxylate (compound 6-37)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 13.33(1H, NH), 7.62(1H, CH), 7.42-7.40(2H, CH), 3.61(3H, CH3), 3.52(1H, CH), 2.75-2.63(2H, CH2), 2.06-1.81(2H, CH2), 1.63-1.52(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.33 (1H, NH), 7.62 (1H, CH), 7.42-7.40 (2H, CH), 3.61 (3H, CH 3 ), 3.52 (1H, CH), 2.75-2.63 ( 2H, CH 2 ), 2.06-1.81 (2H, CH 2 ), 1.63-1.52 (2H, CH 2 )
MS (ESI): m/z = 482.95 (M++1)MS (ESI): m/z = 482.95 (M + +1)
실시예 4-38. (S)-2-(4-bromo-3-fluorophenyl)-6-chloro-5-(3-hydroxypyrrolidin-1-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-38)Example 4-38. (S)-2-(4-bromo-3-fluorophenyl)-6-chloro-5-(3-hydroxypyrrolidin-1-yl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-38 )
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 13.05(1H, NH), 3.62(1H, OH), 7.65(1H, CH), 7.46-7.42(2H, CH), 3.33(1H, CH), 3.01-2.69(4H, CH2), 1.85-1.63(2H, CH2) 1 H NMR (CDCl 3 ) δ 13.05 (1H, NH), 3.62 (1H, OH), 7.65 (1H, CH), 7.46-7.42 (2H, CH), 3.33 (1H, CH), 3.01-2.69 (4H) , CH 2 ), 1.85-1.63(2H, CH 2 )
MS (ESI): m/z = 440.83 (M++1)MS (ESI): m/z = 440.83 (M + +1)
실시예 4-39. (S)-1-(2-(4-bromo-3-fluorophenyl)-6-chloro-4,7-dioxo-4,7-dihydro-1H-benzo[d]imidazol-5-yl)pyrrolidine-2-carboxylic acid (화합물 6-39)Example 4-39. (S)-1-(2-(4-bromo-3-fluorophenyl)-6-chloro-4,7-dioxo-4,7-dihydro-1H-benzo[d]imidazol-5-yl)pyrrolidine-2 -carboxylic acid (compound 6-39)
수율: 80%Yield: 80%
1H NMR (CDCl3) δ 12.92(1H, NH), 11.63(1H, OH), 7.62(1H, CH), 7.45-7.43(2H, CH), 3.64(1H, CH), 2.73-2.71(2H, CH2), 1.96-1.71(2H, CH2), 1.64-1.52(2H, CH2) 1 H NMR (CDCl 3 ) δ 12.92(1H, NH), 11.63(1H, OH), 7.62(1H, CH), 7.45-7.43(2H, CH), 3.64(1H, CH), 2.73-2.71(2H) , CH 2 ), 1.96-1.71 (2H, CH 2 ), 1.64 1.52 (2H, CH 2 )
MS (ESI): m/z = 468.85 (M++1)MS (ESI): m/z = 468.85 (M + +1)
실시예 4-40. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-(pyrrolidin-1-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-40)Examples 4-40. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-(pyrrolidin-1-yl)-1H-benzo[d]imidazole-4,7-dione (Compound 6-40)
수율: 84%Yield: 84%
1H NMR (CDCl3) δ 13.29(1H, NH), 7.66(1H, CH), 7.44-7.43(2H, CH), 2.64(4H, CH2), 1.74(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.29 (1H, NH), 7.66 (1H, CH), 7.44-7.43 (2H, CH), 2.64 (4H, CH 2 ), 1.74 (4H, CH 2 )
MS (ESI): m/z = 424.83 (M++1)MS (ESI): m/z = 424.83 (M + +1)
실시예 4-41. (S)-2-(4-bromo-3-fluorophenyl)-6-chloro-5-(3-(dimethylamino)pyrrolidin-1-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-41)Example 4-41. (S)-2-(4-bromo-3-fluorophenyl)-6-chloro-5-(3-(dimethylamino)pyrrolidin-1-yl)-1H-benzo[d]imidazole-4,7-dione (compound 6-41)
수율: 81%Yield: 81%
1H NMR (CDCl3) δ 12.84(1H, NH), 7.63(1H, CH), 7.44-7.42(2H, CH), 2.93-2.81(4H, CH2), 2.71(1H, CH), 2.23(6H, CH3), 1.74-1.53(2H, CH2) 1 H NMR (CDCl 3 ) δ 12.84 (1H, NH), 7.63 (1H, CH), 7.44-7.42 (2H, CH), 2.93-2.81 (4H, CH 2 ), 2.71 (1H, CH), 2.23 ( 6H, CH 3 ), 1.74-1.53 (2H, CH 2 )
MS (ESI): m/z = 468.12 (M++1)MS (ESI): m/z = 468.12 (M + +1)
실시예 4-42. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-1H-benzo[d]imidazole-4,7-dione (화합물 6-42)Example 4-42. 2-(4-bromo-3-fluorophenyl)-6-chloro-5-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-1H-benzo[d]imidazole-4,7-dione ( compound 6-42)
수율: 82%Yield: 82%
1H NMR (CDCl3) δ 13.12(1H, NH), 3.59(2H, OH), 7.64(1H, CH), 7.44-7.41(2H, CH), 3.42(2H, CH), 3.04-2.83(4H, CH2) 1 H NMR (CDCl 3 ) δ 13.12 (1H, NH), 3.59 (2H, OH), 7.64 (1H, CH), 7.44-7.41 (2H, CH), 3.42 (2H, CH), 3.04-2.83 (4H) , CH 2 )
MS (ESI): m/z = 456.94 (M++1)MS (ESI): m/z = 456.94 (M + +1)
<실험예 1: <Experimental Example 1: in vitroin vitro 트랜스글루타미나제 2 어세이> Transglutaminase 2 Assay>
숙시닐화한 카세인(succinylated casein)에 대한 [1,4-14C] 퓨트레신(putrescine)의 결합(incorporation)을 측정하여 트랜스글루타미나제 2(transglutaminase 2; TGase 2) 활성에 대한 각 화합물의 억제 효과를 결정하였다. 1 mU의 기니아 피그 간 유래의 TGase 2(Sigma, St. Louis,MO, USA)를 10 mM CaCl2을 포함 또는 불포함하는 0.1 mL 반응 완충액에 준비한 다양한 농도의 GK13 또는 GK921와 10분 동안 선-인큐베이션(preincubation)하고, 2% 숙시닐화한 카세인 및 100 nCi의 [1,4-14C] 퓨트레신을 함유하는 0.4 mL의 기질 용액을 첨가하였다. 37℃에서 1시간 동안 인큐베이션한 후, 4 mL의 차가운(4℃) 7.5% (w/v) 트리클로로아세트산(trichloroacetic acid; TCA)을 첨가하여 상기 반응을 종료하였다. TCA-불용성 침전물을 GF/A-등급(grade) 유리 필터(Millipore, Billerica,MA, USA)로 회수하고, 차가운 5% (w/v) TCA로 세척하여, 건조시키고, 섬광 계수기(scintillation counter, Beckman Coulter, Brea, CA, USA)를 이용하여 방사성표지(radiolabel)의 결합을 평가하였다. 완충액과만 선-인큐베이션한 TGase 2를 양성대조군으로 사용하였다. 섬광 수(scintillation counts)를 양성대조군의 것과 비교하고, 로지스틱 선형 회귀법(logistic linear regression method)을 이용하여 각 화합물의 IC50 값을 결정하였다. 데이터는 3회 독립적 실험에 대한 평균으로 나타내었다. By measuring the binding (incorporation) of [1,4-14C] putrescine to succinylated casein, transglutaminase 2 (TGase 2) activity of each compound The inhibitory effect was determined. 1 mU of guinea pig liver-derived TGase 2 (Sigma, St. Louis, MO, USA) was pre-incubated with various concentrations of GK13 or GK921 in 0.1 mL reaction buffer with or without 10 mM CaCl 2 for 10 min. After preincubation, 0.4 mL of a substrate solution containing 2% succinylated casein and 100 nCi of [1,4-14C] putrescine was added. After incubation at 37° C. for 1 hour, 4 mL of cold (4° C.) 7.5% (w/v) trichloroacetic acid (TCA) was added to terminate the reaction. The TCA-insoluble precipitate was recovered with a GF/A-grade glass filter (Millipore, Billerica, MA, USA), washed with cold 5% (w/v) TCA, dried, and scintillated by a scintillation counter. Beckman Coulter, Brea, CA, USA) was used to evaluate the binding of the radiolabel. TGase 2 pre-incubated with buffer only was used as a positive control. The scintillation counts were compared with that of the positive control group, and the IC 50 value of each compound was determined using a logistic linear regression method. Data are presented as the average of three independent experiments.
상기 표 1에 나타난 바와 같이, 본 발명에서 제조한 모든 화합물이 nM 단위의 IC50(The half maximal inhibitory concentration)를 갖는 것으로 확인되어, TGase2 효소 활성 저해 효과를 나타냄을 확인하였다.As shown in Table 1, all the compounds prepared in the present invention were confirmed to have an IC 50 (The half maximal inhibitory concentration) of nM unit, thereby confirming that they exhibit an inhibitory effect on TGase2 enzyme activity.
<실험예 2: SRB(Sulforhodamine B) 어세이><Experimental Example 2: SRB (Sulforhodamine B) assay>
ACHN 및 CAKI-1 세포(10,000 세포/웰 농도, 100 μL)를 각각 개별로 96-웰 마이크로타이터 플레이트(microtiter plates)에 배양하였다. 24시간 후, 각 웰에 약물(100 μL)을 첨가하고, 배양물을 37℃에서 48시간 동안 추가로 인큐베이션하였다. 이후 상기 세포를 TCA(웰 당 50 μL)에서 고정하였다. 상기 플레이트를 최소 1시간 또는 최대 3시간 동안 4℃에서 인큐베이션하였다. 상기 플레이트로부터 액체를 제거하고, 물로 5회 세척한 후 실온(room temperature; RT)에서 약 12 내지 24시간 동안 건조되도록 두었다. 상기 고정된 세포를 100 μL SRB로 실온에서 5분 동안 염색하였다. 염색 후, 플레이트를 1% 빙초산(glacial acetic acid)으로 3회 세척하고, 실온에서 약 12 내지 24시간 동안 건조시켰다. 이후 SRB를 10 mM 트리즈마 염기(Trizma base)에 용해시키고, 515 nm에서 흡광도를 측정하였다. 상기 약물의 효과를 GI50(50% 성장 저해)으로 표현하였다.ACHN and CAKI-1 cells (10,000 cells/well concentration, 100 μL) were each individually cultured in 96-well microtiter plates. After 24 h, drug (100 μL) was added to each well and the culture was further incubated at 37° C. for 48 h. The cells were then fixed in TCA (50 μL per well). The plates were incubated at 4° C. for a minimum of 1 hour or a maximum of 3 hours. The liquid was removed from the plate, washed with water 5 times and then left to dry at room temperature (RT) for about 12 to 24 hours. The fixed cells were stained with 100 μL SRB for 5 min at room temperature. After staining, the plates were washed 3 times with 1% glacial acetic acid and dried at room temperature for about 12 to 24 hours. Then, SRB was dissolved in 10 mM Trizma base, and absorbance was measured at 515 nm. The effect of the drug was expressed as GI 50 (50% growth inhibition).
구체적으로, 화합물 6-1 내지 6-42의 화합물을 각각 10-9, 10-8, 10-7, 10-6, 10-5 M의 농도 단위로 실험하였으며, ACHN, CAKI-1 암세포군을 사용하여, SRB의 대조군 값의 백분율 감소량을 측정하였다. Specifically, the compounds of Compounds 6-1 to 6-42 were tested at concentrations of 10 -9 , 10 -8 , 10 -7 , 10 -6 , and 10 -5 M, respectively, and ACHN and CAKI-1 cancer cell groups were was used to determine the percentage reduction in the control value of SRB.
상기 표 2에 개시된 바와 같이, 상기 42종 화합물 모두 우수한 GI50 값을 나타내어 항암효과가 탁월함을 확인할 수 있다. As disclosed in Table 2, all of the 42 compounds showed excellent GI 50 values, confirming that the anticancer effect was excellent.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해되어야 한다.The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.
Claims (9)
[화학식 1]
상기 화학식 1에서 R1, R2, R3, R4 및 R5는 각각 독립적으로 수소, 할로겐 또는 트리플루오로메틸이다. 상기 할로겐은 F, Cl, Br 또는 I에서 선택되고,
R6는 , , , , , , , , , , 또는 에서 독립적으로 선택된다. A novel compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[Formula 1]
In Formula 1, R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen or trifluoromethyl. The halogen is selected from F, Cl, Br or I,
R 6 is , , , , , , , , , , or independently selected from
상기 할로겐은 F, Cl, Br 또는 I에서 선택되는 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.According to claim 1,
The halogen is a compound or a pharmaceutically acceptable salt thereof, characterized in that selected from F, Cl, Br or I.
상기 화학식 1로 표시되는 화합물은 하기 42종의 화합물로 이루어진 군 중에서 선택되는 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.
According to claim 1,
The compound represented by Formula 1 is a compound or a pharmaceutically acceptable salt thereof, characterized in that selected from the group consisting of the following 42 compounds.
상기 질환은 신경계 질환 또는 암인 것을 특징으로 하는 트랜스글루타미나제-2 활성 증가에 의한 발병되는 질환의 예방 또는 치료용 약학적 조성물.6. The method of claim 5,
The disease is a neurological disease or a pharmaceutical composition for the prevention or treatment of a disease caused by an increase in transglutaminase-2 activity, characterized in that the cancer.
상기 신경계 질환은 알츠하이머 질환, 다경색 치매, 알츠하이머 질환과 다경색 치매의 혼합형, 파킨슨씨 질환, 저갑상선증, 알코올성 치매 알츠하이머 및 헌팅턴병으로 이루어진 군 중에서 선택되는 것을 특징으로 하는 트랜스글루타미나제-2 활성 증가에 의한 발병되는 질환의 예방 또는 치료용 약학적 조성물.7. The method of claim 6,
The nervous system disease is Alzheimer's disease, multi-infarct dementia, a mixed type of Alzheimer's disease and multi-infarct dementia, Parkinson's disease, hypothyroidism, alcoholic dementia Transglutaminase-2, characterized in that selected from the group consisting of Alzheimer's disease and Huntington's disease A pharmaceutical composition for preventing or treating diseases caused by increased activity.
상기 암은 대장암, 소장암, 직장암, 항문암, 식도암, 췌장암, 위암, 신장암, 자궁암, 유방암, 폐암, 임파선암, 갑상선암, 전립선암, 백혈병, 피부암, 결장암, 뇌종양, 방광암, 난소암 및 담낭암으로 이루어진 군 중에서 선택되는 것을 특징으로 하는 트랜스글루타미나제-2 활성 증가에 의한 발병되는 질환의 예방 또는 치료용 약학적 조성물.7. The method of claim 6,
The cancer is colon cancer, small intestine cancer, rectal cancer, anal cancer, esophageal cancer, pancreatic cancer, stomach cancer, kidney cancer, uterine cancer, breast cancer, lung cancer, lymph gland cancer, thyroid cancer, prostate cancer, leukemia, skin cancer, colon cancer, brain tumor, bladder cancer, ovarian cancer and A pharmaceutical composition for preventing or treating diseases caused by increased transglutaminase-2 activity, characterized in that it is selected from the group consisting of gallbladder cancer.
상기 신장암은 투명신세포암(clear cell RCC), 유두신세포암(papillary RCC), 혐색소신세포암(chromophobe RCC), 집합관신세포암(collecting tuve RCC) 및 요로상피암(urothelial cancer, transitional cell carcinoma, TCC)으로 이루어지는 군 군 중에서 선택되는 것을 특징으로 하는 트랜스글루타미나제-2 활성 증가에 의한 발병되는 질환의 예방 또는 치료용 약학적 조성물.9. The method of claim 8,
The kidney cancer is clear cell RCC, papillary RCC, chromophobe RCC, collecting tube RCC, and urothelial cancer, transitional A pharmaceutical composition for preventing or treating diseases caused by increased transglutaminase-2 activity, characterized in that it is selected from the group consisting of cell carcinoma, TCC).
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KR20220129449A (en) | 2022-09-23 |
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