KR102230832B1 - N-substituted thiourea or urea derivatives and pharmaceutical composition for use in preventing or treating glutaminyl cyclase activity related diseases containing the same as an active ingredient - Google Patents

N-substituted thiourea or urea derivatives and pharmaceutical composition for use in preventing or treating glutaminyl cyclase activity related diseases containing the same as an active ingredient Download PDF

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KR102230832B1
KR102230832B1 KR1020190071534A KR20190071534A KR102230832B1 KR 102230832 B1 KR102230832 B1 KR 102230832B1 KR 1020190071534 A KR1020190071534 A KR 1020190071534A KR 20190071534 A KR20190071534 A KR 20190071534A KR 102230832 B1 KR102230832 B1 KR 102230832B1
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methyl
dimethoxyphenyl
propyl
imidazol
urea
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김영호
김희
하희진
최광현
유영동
이지우
안지혜
홍반하이
고티홍반
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(주) 메디프론디비티
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Abstract

본 발명은 N-치환된 티오우레아 또는 우레아 유도체 및 이를 유효성분으로 함유하는 글루타미닐 사이클레이즈(QC) 활성 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명에 따른 페닐티오우레아 유도체는 시험관 내(in vitro)에서 QC(glutaminyl cyclase)와 결합하여 50 nM 이하의 낮은 IC50 값으로 QC를 저해하며, BBB(blood-brain barrier)를 통과하여 뇌 내부의 QC를 저해할 수 있고, 생체 내(in vivo)에서 뇌에서의 AβN3pE-40, AβN3pE-42, Aβ1-40, 및 Aβ1-42의 농도를 현저하게 감소시킬 뿐만 아니라, 세포 독성이 없어 부작용의 우려가 적으므로, QC 활성 관련 질환인 알츠하이머병, 뇌혈관성 치매증, 두부 손상에 의한 치매, 다경색 치매, 알츠하이머병과 다경색 치매의 혼합형 또는 알코올성 치매 등을 포함하는 치매, 픽(pick)병, 크루츠-야콥(Creutzfeldt-Jakob)병, 두부손상에 의한 파킨슨(Parkinson)병, 헌팅턴(Huntington)병 등의 예방 또는 치료에 유용하게 사용될 수 있다.The present invention relates to an N-substituted thiourea or urea derivative and a pharmaceutical composition for preventing or treating diseases related to glutaminyl cyclase (QC) activity containing the same as an active ingredient. The phenylthiourea derivative according to the present invention binds with QC (glutaminyl cyclase) in vitro and inhibits QC with a low IC 50 value of 50 nM or less, and passes through the blood-brain barrier (BBB) to the inside of the brain. It can inhibit the QC of Aβ N3pE-40 in the brain in vivo, Aβ N3pE-42 , Aβ 1-40 , and Not only does it significantly reduce the concentration of Aβ 1-42 , but also has no cytotoxicity, so there is little risk of side effects.Therefore, it is different from Alzheimer's disease, cerebrovascular dementia, dementia due to head injury, multi-infarct dementia, and Alzheimer's disease. Prevention or treatment of dementia, including mixed type of infarct dementia or alcoholic dementia, pick's disease, Creutzfeldt-Jakob's disease, Parkinson's disease, and Huntington's disease due to head injury It can be used usefully.

Description

N-치환된 티오우레아 또는 우레아 유도체 및 이를 유효성분으로 함유하는 글루타미닐 사이클레이즈 활성 관련 질환의 예방 또는 치료용 약학적 조성물{N-substituted thiourea or urea derivatives and pharmaceutical composition for use in preventing or treating glutaminyl cyclase activity related diseases containing the same as an active ingredient}N-substituted thiourea or urea derivatives and pharmaceutical composition for preventing or treating diseases related to glutaminyl cyclase activity containing the same as an active ingredient {N-substituted thiourea or urea derivatives and pharmaceutical composition for use in preventing or treating glutaminyl cyclase activity related diseases containing the same as an active ingredient}

본 발명은 N-치환된 티오우레아 또는 우레아 유도체 및 이를 유효성분으로 포함하는 글루타미닐 사이클레이즈 활성 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to an N-substituted thiourea or urea derivative and a pharmaceutical composition for preventing or treating diseases related to glutaminyl cyclase activity comprising the same as an active ingredient.

알츠하이머 병(Alzheimer's disease, AD)은 행동 장애와 연관된 진행성 신경 퇴행성 장애로, 결국은 심한 치매를 유발하게 된다. 다양한 치료법이 알츠하이머 병의 증상 완화를 위해 개발되었지만, 알츠하이머병의 원인과 병인이 완전히 밝혀지지 않았기 때문에 아직 치료법은 개발되지 않았다. 알츠하이머병 발병의 주요 가설 중 하나가 "아밀로이드 가설(amyloid hypothesis)”인데, 임상 시험에서 그 사실을 확인하지 못했기 때문에 의문의 여지가 남아있는 가설이다. 테스트된 약물의 대부분은 Aβ 생성 효소와 Aβ 응집(aggregate)을 타겟으로 하는 저분자(small molecules)과 항체인데, 대부분은 거의 효과를 보이지 않거나 허용되지 않는 정도의 독성을 보인다. 그럼에도, Aβ 펩타이드의 축적이 증상이 나타나기 수십년 전에 시작된다는 점을 감안할 때, 항 아밀로이드 요법이 여전히 초기 환자에게 실행 가능한 접근법이라는 것은 일반적으로 동의하는 바이다. 또한, Aβ 소섬유와 올리고머에는 신경독성(neurotoxic)이거나 신경보호작용(neuroprotective)을 하는 많은 타입들이 있다. 따라서, Aβ 종의 구체적인 형태를 타겟하는 것은 다른 잠재적인 대안에 대하여 효과적인 치료 옵션을 제공할 수 있다.Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with behavioral disorders that eventually leads to severe dementia. Various treatments have been developed to relieve symptoms of Alzheimer's disease, but the cause and etiology of Alzheimer's disease has not been fully identified, so no treatment has yet been developed. One of the main hypotheses for the onset of Alzheimer's disease is the “amyloid hypothesis”, a hypothesis that remains questionable because clinical trials have not confirmed it. Most of the drugs tested are Aβ-producing enzymes and Aβ aggregation. These are small molecules and antibodies targeting aggregates, most of which have little or no effect or show an unacceptable degree of toxicity, but considering that the accumulation of Aβ peptides begins decades before symptoms appear. At the time, it is generally agreed that antiamyloid therapy is still a viable approach for early patients In addition, there are many types of Aβ fibrils and oligomers that are either neurotoxic or neuroprotective. Targeting specific forms of Aβ species can provide effective treatment options over other potential alternatives.

Aβ의 N-말단 가수분해로부터 생성된 N-절사(truncated) Aβ 펩타이드는 Aβn-40/42로 표시되는 아밀로이드 플라크(amyloid plaques)의 주 구성 성분이며, 여기서 n은 2 내지 11이다. 흥미롭게도, 알츠하이머병 뇌의 전체 Aβ 플라크의 50% 이상은 Aβ 안의 N-말단 글루타메이트(E), E3, E11의 고리화에 의해 생성되는 피로글루타메이트(pyroglutamate) Aβ(pE- Aβ), AβN3pE3-40/42, AβN3pE11-40/42으로 구성되어 있다. pE- Aβs는 정상 뇌가 아닌 알츠하이머병 뇌에만 존재하는 것으로 보이며, 용해성 독성 올리고머로 빠르고 비가역적으로 응집되어 장기간에 걸쳐 비활성 무정형 소섬유를 형성한다. 게다가, pE- Aβs는 Aβ1-40/42과 타우(tau)의 응집의 종자 역할을 하여 알츠하이머 발병의 중요한 개시제 기능을 하는데, 이는 pE- Aβs는 현재 항-아밀로이드 전략을 보강할 수 있는 잠재적 타겟이 될수 있음을 말한다.The resulting N-terminal from the hydrolysis - - N of Aβ truncated (truncated) Aβ-peptide is the main constituent of amyloid plaques (amyloid plaques) are represented by Aβ n-40/42, where n is 2 to 11. Interestingly, more than 50% of the total Aβ plaques in the Alzheimer's brain are produced by the cyclization of the N-terminal glutamate (E), E3, and E11 in Aβ . 40/42 and Aβ N3pE11-40/42 . pE-Aβs appear to be present only in the Alzheimer's brain, not the normal brain, and are soluble toxic oligomers that rapidly and irreversibly aggregate to form inactive amorphous fibrils over a long period of time. In addition, pE-Aβs act as an important initiator of Alzheimer's pathogenesis by serving as a seed for aggregation of Aβ 1-40/42 and tau, which pE-Aβs are potential targets that can augment current anti-amyloid strategies. It says that it can be.

pE- Aβs 펩타이드는 주로 포유 동물의 뇌의 해마 및 피질에서 발견되는 글루타미닐 사이클레이즈(glutaminyl cyclase, QC)에 의해 생성된다. 중요한 것은, QC는 알츠하이머병 환자와 동물 모델의 뇌에서 과발현되며, QC를 넉아웃(knock-out)시킨 알츠하이머병 모델 쥐에서 인지기능이 회복됨이 확인되었다. 저분자 QC 저해제는 알츠하이머병 쥐에서 뇌의 pE- Aβ 및 Aβ 플라크 수준을 효과적으로 감소시키고, 기억력 결핍을 회복시킴이 보고되었다. 이런 연구는 뇌의 QC 활성 저해는 알츠하이머병 환자에 유의미한 효과를 가져올 수 있음을 제안한다. 몇 연구 그룹들은 이미다졸(imidazole)과 벤즈이미다졸(benzimidazole) 중심 구조에 기초한 QC 저해제를 개발했다(도 1). 가장 저명한 물질은 Probiodrug에서 발견한 PQ912이다. PQ912는 임상 시험에서 심한 독성 없이 알츠하이머병 환자의 시냅스(synaptic)와 신경학 기능의 향상을 보였다. 최근 Rubinstein과 그의 동료들은 N-메틸트리아졸-기반의 저해제를 도입했는데, 3D-약물특이분자단(pharmacophore) 기반의 in silico 방법으로 발견되었다(도1(3)). 또 Wu와 그의 동료들은 다이페닐그룹이 컨쥬게이트된 이미다졸 저해제에 대해 보고하였는데, 세포 모델에서 pE-Aβ3-42 양의 큰 감소와 알츠하이머병 모델 쥐의 행동 개선을 보였다. 그 후로도 구성요소 기반의 접근에 의한 저분자 저해제 발견이 보고되고 있고, in vitro 활성을 보이고 있다.The pE-Aβs peptide is mainly produced by glutaminyl cyclase (QC), which is found in the hippocampus and cortex of the mammalian brain. Importantly, it was confirmed that QC is overexpressed in the brains of Alzheimer's disease patients and animal models, and cognitive function is restored in Alzheimer's disease model mice that knock-out QC. Small molecule QC inhibitors have been reported to effectively reduce brain pE-Aβ and Aβ plaque levels and restore memory deficit in Alzheimer's disease mice. These studies suggest that inhibition of brain QC activity may have a significant effect in patients with Alzheimer's disease. Several research groups have developed QC inhibitors based on the central structure of imidazole and benzimidazole (Fig. 1). The most prominent substance is PQ912, found in Probiodrug. PQ912 has been shown to improve synaptic and neurological function in patients with Alzheimer's disease without severe toxicity in clinical trials. Recently, Rubinstein and his colleagues introduced an N-methyltriazole-based inhibitor, which was discovered by a 3D-pharmacophore-based in silico method (Fig. 1(3)). In addition, Wu and his colleagues reported on an imidazole inhibitor conjugated with a diphenyl group, which showed a large decrease in the amount of pE-Aβ 3-42 in a cell model and improved behavior in Alzheimer's disease model mice. Since then, the discovery of small molecule inhibitors by a component-based approach has been reported and shows in vitro activity.

KRKR 10-190908910-1909089 B1B1

Panza, F. Nat. Rev. Neurol. 2019, 15, 73-88. Panza, F. Nat. Rev. Neurol. 2019, 15, 73-88. Larner, A. Neurobiol. Aging. 1999, 20, 65-69. Larner, A. Neurobiol. Aging. 1999, 20, 65-69. Bayer, T. Acta Neuropathol. 2014, 127, 787-801. Bayer, T. Acta Neuropathol. 2014, 127, 787-801.

본 발명의 일 측면에서의 목적은 N-치환된 티오우레아 또는 우레아 유도체, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.An object of the present invention is to provide an N-substituted thiourea or urea derivative, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

본 발명의 또 다른 일 측면에서의 목적은 상기 N-치환된 티오우레아 또는 우레아 유도체, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 글루타미닐 사이클레이즈 활성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is a disease related to glutaminyl cyclase activity containing the N-substituted thiourea or urea derivative, its stereoisomer, its hydrate or its pharmaceutically acceptable salt as an active ingredient. It is to provide a pharmaceutical composition for the prevention or treatment of.

본 발명의 또 다른 일 측면에서의 목적은 상기 N-치환된 티오우레아 또는 우레아 유도체, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 글루타미닐 사이클레이즈 활설 관련 질환의 예방 또는 개선용 건강기능식품용 조성물을 제공하는 것이다.Another object of the present invention is a disease related to glutaminyl cyclase activity containing the N-substituted thiourea or urea derivative, its stereoisomer, its hydrate or its pharmaceutically acceptable salt as an active ingredient. It is to provide a composition for the prevention or improvement of health functional food.

본 발명의 다른 일 측면에서의 목적은 상기 N-치환된 티오우레아 또는 우레아 유도체, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염을, 이를 필요로 하는 개체나 대상에 투여하는 단계를 포함하는, 글루타미닐 사이클레이즈 활성 관련 질환의 치료방법을 제공하는 것이다.Another object of the present invention is to administer the N-substituted thiourea or urea derivative, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to a subject or subject in need thereof. To provide a method for treating diseases related to glutaminyl cyclase activity.

본 발명의 또 다른 일 측면에서의 목적은 글루타미닐 사이클레이즈 활성 관련 질환의 치료에 사용하기 위한 상기 N-치환된 티오우레아 또는 우레아 유도체, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.Another object of the present invention is the N-substituted thiourea or urea derivative, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of diseases related to glutaminyl cyclase activity. Is to provide.

본 발명의 또 다른 일 측면에서의 목적은 글루타미닐 사이클레이즈 활성 관련 질환 치료용 약제의 제조에 사용하기 위한 상기 N-치환된 티오우레아 또는 우레아 유도체, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공하는 것이다.In another aspect of the present invention, the N-substituted thiourea or urea derivative, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically thereof for use in the manufacture of a drug for the treatment of diseases related to glutaminyl cyclase activity It is to provide an acceptable use of the salt.

상기 목적을 달성하기 위하여,To achieve the above object,

본 발명의 일 측면은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염을 제공한다.One aspect of the present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure 112019061617410-pat00001
Figure 112019061617410-pat00001

(상기 화학식 1에서,(In Chemical Formula 1,

상기 X는 S 또는 O이고;X is S or O;

상기 L1은 -(CH2)p-이고, p는 0 내지 5이고; L 1 is -(CH 2 ) p -, and p is 0 to 5;

상기 L2는 -(CH2)q-이고, q는 0 내지 5이고;L 2 is -(CH 2 ) q -, and q is 0 to 5;

상기 L3은 -(CH2)r-이고, r은 0 내지 5이고;L 3 is -(CH 2 ) r -, and r is 0 to 5;

상기 Y는 C 또는 N이고;Y is C or N;

상기 R1은 -H, C1-10의 직쇄 또는 분지쇄 알킬, C3-8의 사이클로알킬, C3-8의 사이클로알킬 C1-5의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 6 원자의 헤테로사이클로알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6 원자의 헤테로사이클로알킬 C1-5의 직쇄 또는 분지쇄 알킬, 비치환 또는 치환된 C6-10의 아릴, 비치환 또는 치환된 C6-10의 아릴 C1-5의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴 C1-10의 직쇄 또는 분지쇄 알킬이고,R 1 is -H, C 1-10 straight or branched chain alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-5 straight or branched chain alkyl, N, O and S An unsubstituted or substituted 5 to 6 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of, a 5 to 6 membered hetero containing at least one heteroatom selected from the group consisting of N, O and S Cycloalkyl C 1-5 straight or branched chain alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted C 6-10 aryl C 1-5 straight or branched chain alkyl, N, O And unsubstituted or substituted 5 to 10 membered heteroaryl containing at least one heteroatom selected from the group consisting of S, and unsubstituted or containing at least one heteroatom selected from the group consisting of N, O and S Substituted 5 to 10 membered heteroaryl C 1-10 straight or branched chain alkyl,

상기 치환된 5 내지 6 원자의 헤테로사이클로알킬은 C1-5의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알킬카보닐, 비치환 또는 치환된 C6의 아릴, 비치환 또는 치환된 C6의 아릴 C1-5의 직쇄 또는 분지쇄 알킬, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴 C1-10의 직쇄 또는 분지쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 5 내지 6 원자의 헤테로사이클로알킬이고,The substituted 5 to 6 membered heterocycloalkyl is C 1-5 straight or branched chain alkyl, C 1-5 straight or branched chain alkylcarbonyl, unsubstituted or substituted C 6 aryl, unsubstituted or substituted C 6 aryl C 1-5 straight chain or branched chain alkyl, and 5 to 6 membered heteroaryl C 1-10 including one or more heteroatoms selected from the group consisting of N, O and S straight chain or branched 5 to 6 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of chain alkyl,

상기 치환된 C6의 아릴은 하나 이상의 할로겐이 치환된 C6의 아릴이고,Aryl of the aryl-substituted C 6 is at least one halogen-substituted C 6,

상기 치환된 C6-10의 아릴 및 5 내지 10 원자의 헤테로아릴은 독립적으로 할로겐, -NH2 및 -NHR4NH2로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C6-10의 아릴 또는 5 내지 10 원자의 헤테로아릴이고,The substituted C 6-10 aryl and 5 to 10 membered heteroaryl are independently halogen, -NH 2 and -NHR 4 NH 2 wherein at least one substituent selected from the group consisting of substituted C 6-10 aryl Or 5 to 10 membered heteroaryl,

상기 R4는 C1-4의 직쇄 또는 분지쇄 알킬이고;R 4 is C 1-4 straight or branched chain alkyl;

상기 R2는,R 2 is,

상기 Y가 N일 경우, 부재이고; 및When Y is N, it is absent; And

상기 Y가 C일 경우, -H, C1-5의 직쇄 또는 분지쇄 알킬이거나, 상기 R1과 함께 연결되어 C3-8의 사이클로알킬을 형성한다).When Y is C, it is -H, C 1-5 straight or branched chain alkyl, or is linked together with R 1 to form C 3-8 cycloalkyl).

본 발명의 다른 일 측면은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 치매, 픽(pick)병, 크루츠-야콥(Creutzfeldt-Jakob) 병, 두부손상에 의한 파킨슨(Parkinson) 병 및 헌팅턴(Huntington) 병으로 이루어지는 군으로부터 선택되는 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention is to treat dementia, pick disease, Creutzfeldt-Jakob disease, and head injury containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of a disease selected from the group consisting of Parkinson's disease and Huntington's disease.

본 발명의 또 다른 일 측면은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 치매, 픽(pick)병, 크루츠-야콥(Creutzfeldt-Jakob) 병, 두부손상에 의한 파킨슨(Parkinson) 병 및 헌팅턴(Huntington) 병으로 이루어지는 군으로부터 선택되는 질환의 예방 또는 개선용 건강식품 조성물을 제공한다.Another aspect of the present invention is dementia containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, pick disease, Creutzfeldt-Jakob disease, head injury It provides a health food composition for preventing or improving diseases selected from the group consisting of Parkinson's disease and Huntington's disease by.

본 발명에 따른 N-치환된 티오우레아 또는 우레아 유도체는 시험관 내(in vitro)에서 QC(glutaminyl cyclase)와 결합하여 50 nM 이하의 낮은 IC50 값으로 QC를 저해하며, BBB(blood-brain barrier)를 통과하여 뇌 내부의 QC를 저해할 수 있고, 생체 내 (in vivo)에서 뇌에서의 AβN3pE-40, AβN3pE-42, Aβ1-40, 및 Aβ1-42의 농도를 현저하게 감소시킬 뿐만 아니라, 세포 독성이 없어 부작용의 우려가 적으므로, QC 활성 관련 질환인 알츠하이머병, 뇌혈관성 치매증, 두부 손상에 의한 치매, 다경색 치매, 알츠하이머병과 다경색 치매의 혼합형 또는 알코올성 치매 등을 포함하는 치매, 픽(pick)병, 크루츠-야콥(Creutzfeldt-Jakob)병, 두부손상에 의한 파킨슨(Parkinson)병, 헌팅턴(Huntington)병 등의 예방 또는 치료에 유용하게 사용될 수 있다.The N-substituted thiourea or urea derivative according to the present invention binds to QC (glutaminyl cyclase) in vitro and inhibits QC with a low IC 50 value of 50 nM or less, and blood-brain barrier (BBB) It can inhibit QC inside the brain by passing through Aβ N3pE-40 in the brain in vivo, Aβ N3pE-42 , Aβ 1-40 , and Not only does it significantly reduce the concentration of Aβ 1-42 , but also has no cytotoxicity, so there is little risk of side effects.Therefore, it is different from Alzheimer's disease, cerebrovascular dementia, dementia due to head injury, multi-infarct dementia, and Alzheimer's disease. Prevention or treatment of dementia, including mixed type of infarct dementia or alcoholic dementia, pick's disease, Creutzfeldt-Jakob's disease, Parkinson's disease, and Huntington's disease due to head injury It can be used usefully.

도 1은 종래 보고된 글루타미닐 사이클레이즈(QC) 저해제들을 나타내는 도면이다.
도 2는 본 발명에 따른 실시예 화합물의 5XFAD 쥐의 인간 AβNpE-40/42 및 Aβ1-40/42 형성 저해율을 나타내는 도면이다.1 is a diagram showing conventionally reported glutaminyl cyclase (QC) inhibitors.
Figure 2 is a diagram showing the inhibition rate of the formation of human Aβ NpE-40/42 and Aβ 1-40/42 in 5XFAD mice of an Example compound according to the present invention.

본 발명은 2014년-2017년 미래창조과학부 원천기술개발사업 (2014M3A9D9069725) 종료 후 후속연구 결과로 도출된 것이다.The present invention was derived as a result of follow-up research after the end of the original technology development project (2014M3A9D9069725) of the Ministry of Science, ICT and Future Planning in 2014-2017.

이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.

한편, 본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.On the other hand, embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided in order to more completely explain the present invention to those with average knowledge in the art. Furthermore, "including" a certain element throughout the specification means that other elements may be further included rather than excluding other elements unless specifically stated to the contrary.

전술한 바와 같이, 알츠하이머 병에 대해 다양한 치료법이 병의 증상 완화를 위해 개발되었지만, 알츠하이머병의 원인과 병인이 완전히 밝혀지지 않아 아직 치료법이 개발되지 않은 실정이다. 본 발명의 일 측면은 알츠하이머병의 주요 가설 중 하나인 아밀로이드 가설을 뒷받침할 글루타미닐 사이클레이즈(Glutaminyl cyclase) 저해제를 제공하여 향후 글루타미닐 사이클레이즈 활성 관련 질병의 예방 및 치료에 큰 기여를 할 수 있다As described above, various treatments for Alzheimer's disease have been developed to relieve symptoms of the disease, but the cause and etiology of Alzheimer's disease have not been fully identified, and thus treatments have not yet been developed. One aspect of the present invention provides a glutaminyl cyclase inhibitor that will support the amyloid hypothesis, which is one of the major hypotheses of Alzheimer's disease, and will contribute greatly to the prevention and treatment of diseases related to glutaminyl cyclase activity in the future. Can be

본 발명의 일 측면은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염을 제공한다.One aspect of the present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure 112019061617410-pat00002
Figure 112019061617410-pat00002

(상기 화학식 1에서,(In Chemical Formula 1,

상기 X는 S 또는 O이고;X is S or O;

상기 L1은 -(CH2)p-이고, p는 0 내지 5이고; L 1 is -(CH 2 ) p -, and p is 0 to 5;

상기 L2는 -(CH2)q-이고, q는 0 내지 5이고;L 2 is -(CH 2 ) q -, and q is 0 to 5;

상기 L3은 -(CH2)r-이고, r은 0 내지 5이고;L 3 is -(CH 2 ) r -, and r is 0 to 5;

상기 Y는 C 또는 N이고;Y is C or N;

상기 R1은 -H, C1-10의 직쇄 또는 분지쇄 알킬, C3-8의 사이클로알킬, C3-8의 사이클로알킬 C1-5의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 6 원자의 헤테로사이클로알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6 원자의 헤테로사이클로알킬 C1-5의 직쇄 또는 분지쇄 알킬, 비치환 또는 치환된 C6-10의 아릴, 비치환 또는 치환된 C6-10의 아릴 C1-5의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴 C1-10의 직쇄 또는 분지쇄 알킬이고,R 1 is -H, C 1-10 straight or branched chain alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-5 straight or branched chain alkyl, N, O and S An unsubstituted or substituted 5 to 6 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of, a 5 to 6 membered hetero containing at least one heteroatom selected from the group consisting of N, O and S Cycloalkyl C 1-5 straight or branched chain alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted C 6-10 aryl C 1-5 straight or branched chain alkyl, N, O And unsubstituted or substituted 5 to 10 membered heteroaryl containing at least one heteroatom selected from the group consisting of S, and unsubstituted or containing at least one heteroatom selected from the group consisting of N, O and S Substituted 5 to 10 membered heteroaryl C 1-10 straight or branched chain alkyl,

상기 치환된 5 내지 6 원자의 헤테로사이클로알킬은 C1-5의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알킬카보닐, 비치환 또는 치환된 C6의 아릴, 비치환 또는 치환된 C6의 아릴 C1-5의 직쇄 또는 분지쇄 알킬, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴 C1-10의 직쇄 또는 분지쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 5 내지 6 원자의 헤테로사이클로알킬이고,The substituted 5 to 6 membered heterocycloalkyl is C 1-5 straight or branched chain alkyl, C 1-5 straight or branched chain alkylcarbonyl, unsubstituted or substituted C 6 aryl, unsubstituted or substituted C 6 aryl C 1-5 straight chain or branched chain alkyl, and 5 to 6 membered heteroaryl C 1-10 including one or more heteroatoms selected from the group consisting of N, O and S straight chain or branched 5 to 6 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of chain alkyl,

상기 치환된 C6의 아릴은 하나 이상의 할로겐이 치환된 C6의 아릴이고,Aryl of the aryl-substituted C 6 is at least one halogen-substituted C 6,

상기 치환된 C6-10의 아릴 및 5 내지 10 원자의 헤테로아릴은 독립적으로 할로겐, -NH2 및 -NHR4NH2로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C6-10의 아릴 또는 5 내지 10 원자의 헤테로아릴이고,The substituted C 6-10 aryl and 5 to 10 membered heteroaryl are independently halogen, -NH 2 and -NHR 4 NH 2 wherein at least one substituent selected from the group consisting of substituted C 6-10 aryl Or 5 to 10 membered heteroaryl,

상기 R4는 C1-4의 직쇄 또는 분지쇄 알킬이고;R 4 is C 1-4 straight or branched chain alkyl;

상기 R2는,R 2 is,

상기 Y가 N일 경우, 부재이고; 및When Y is N, it is absent; And

상기 Y가 C일 경우, -H, C1-5의 직쇄 또는 분지쇄 알킬이거나, 상기 R1과 함께 연결되어 C3-8의 사이클로알킬을 형성한다.When Y is C, -H, C 1-5 straight or branched chain alkyl, or is linked together with R 1 to form C 3-8 cycloalkyl.

다른 측면에서,On the other side,

상기 상기 X는 S 또는 O이고;The X is S or O;

상기 L1은 -(CH2)p-이고, p는 0 내지 3이고; L 1 is -(CH 2 ) p -, and p is 0 to 3;

상기 L2는 -(CH2)q-이고, q는 0 내지 3이고;L 2 is -(CH 2 ) q -, and q is 0 to 3;

상기 L3은 -(CH2)r-이고, r은 1 내지 4이고;L 3 is -(CH 2 ) r -, and r is 1 to 4;

상기 Y는 C 또는 N이고;Y is C or N;

상기 R1은 -H, C1-8의 직쇄 또는 분지쇄 알킬, C3-7의 사이클로알킬, C3-7의 사이클로알킬 C1-4의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 6 원자의 헤테로사이클로알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6 원자의 헤테로사이클로알킬 C1-5의 직쇄 또는 분지쇄 알킬, 비치환 또는 치환된 C6-10의 아릴, 비치환 또는 치환된 C6-10의 아릴 C1-4의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 10 원자의 헤테로아릴 C1-8의 직쇄 또는 분지쇄 알킬이고,R 1 is -H, C 1-8 straight or branched chain alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-4 straight or branched chain alkyl, N, O and S An unsubstituted or substituted 5 to 6 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of, a 5 to 6 membered hetero containing at least one heteroatom selected from the group consisting of N, O and S Cycloalkyl C 1-5 straight or branched chain alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted C 6-10 aryl C 1-4 straight or branched chain alkyl, N, O And unsubstituted or substituted 5 to 10 membered heteroaryl containing at least one heteroatom selected from the group consisting of S, and unsubstituted or containing at least one heteroatom selected from the group consisting of N, O and S Substituted 5 to 10 membered heteroaryl C 1-8 straight or branched chain alkyl,

상기 치환된 5 내지 6 원자의 헤테로사이클로알킬은 C1-4의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알킬카보닐, 비치환 또는 치환된 C6의 아릴, 비치환 또는 치환된 C6의 아릴 C1-4의 직쇄 또는 분지쇄 알킬, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴 C1-8의 직쇄 또는 분지쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 5 내지 6 원자의 헤테로사이클로알킬이고,The substituted 5 to 6 membered heterocycloalkyl is C 1-4 straight or branched chain alkyl, C 1-3 straight or branched chain alkylcarbonyl, unsubstituted or substituted C 6 aryl, unsubstituted or substituted C 6 aryl C 1-4 straight or branched chain alkyl, and 5 to 6 membered heteroaryl C 1-8 containing at least one heteroatom selected from the group consisting of N, O and S straight chain or branched 5 to 6 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of chain alkyl,

상기 치환된 C6의 아릴은 하나 이상의 할로겐이 치환된 C6의 아릴이고,Aryl of the aryl-substituted C 6 is at least one halogen-substituted C 6,

상기 치환된 C6-10의 아릴 및 5 내지 10 원자의 헤테로아릴은 독립적으로 할로겐, -NH2 및 -NHR4NH2로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C6-10의 아릴 또는 5 내지 10 원자의 헤테로아릴이고,The substituted C 6-10 aryl and 5 to 10 membered heteroaryl are independently halogen, -NH 2 and -NHR 4 NH 2 wherein at least one substituent selected from the group consisting of substituted C 6-10 aryl Or 5 to 10 membered heteroaryl,

상기 R4는 C1-3의 직쇄 또는 분지쇄 알킬이고;R 4 is C 1-3 straight or branched chain alkyl;

상기 R2는,R 2 is,

상기 Y가 N일 경우, 부재이고; 및When Y is N, it is absent; And

상기 Y가 C일 경우, -H, C1-4의 직쇄 또는 분지쇄 알킬이거나, 상기 R1과 함께 연결되어 C3-7의 사이클로알킬을 형성할 수 있다.When Y is C, it may be -H, C 1-4 straight or branched chain alkyl, or may be linked with R 1 to form C 3-7 cycloalkyl.

또 다른 측면에서,On the other side,

상기 X는 S 또는 O이고;X is S or O;

상기 L1은 -(CH2)p-이고, p는 0 내지 2이고; L 1 is -(CH 2 ) p -, and p is 0 to 2;

상기 L2는 -(CH2)q-이고, q는 0 내지 2이고;L 2 is -(CH 2 ) q -, and q is 0 to 2;

상기 L3은 -(CH2)r-이고, r은 1 내지 3이고;L 3 is -(CH 2 ) r -, and r is 1 to 3;

상기 Y는 C 또는 N이고;Y is C or N;

상기 R1은 -H, C1-5의 직쇄 또는 분지쇄 알킬, C3-6의 사이클로알킬, C3-6의 사이클로알킬 C1-3의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 6 원자의 헤테로사이클로알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6 원자의 헤테로사이클로알킬 C1-3의 직쇄 또는 분지쇄 알킬, 비치환 또는 치환된 C6-8의 아릴, 비치환 또는 치환된 C6-8의 아릴 C1-3의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 6 원자의 헤테로아릴, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 6 원자의 헤테로아릴 C1-5의 직쇄 또는 분지쇄 알킬이고,R 1 is -H, C 1-5 straight or branched chain alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 straight or branched chain alkyl, N, O and S An unsubstituted or substituted 5 to 6 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of, a 5 to 6 membered hetero containing at least one heteroatom selected from the group consisting of N, O and S Cycloalkyl C 1-3 straight or branched chain alkyl, unsubstituted or substituted C 6-8 aryl, unsubstituted or substituted C 6-8 aryl C 1-3 straight or branched chain alkyl, N, O And unsubstituted or substituted 5 to 6 membered heteroaryl including at least one heteroatom selected from the group consisting of S, and unsubstituted or including at least one heteroatom selected from the group consisting of N, O and S Substituted 5 to 6 membered heteroaryl C 1-5 straight or branched chain alkyl,

상기 치환된 5 내지 6 원자의 헤테로사이클로알킬은 C1-3의 직쇄 또는 분지쇄 알킬, C1-2의 직쇄 또는 분지쇄 알킬카보닐, 비치환 또는 치환된 C6의 아릴, 비치환 또는 치환된 C6의 아릴 C1-3의 직쇄 또는 분지쇄 알킬, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴 C1-3의 직쇄 또는 분지쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 5 내지 6 원자의 헤테로사이클로알킬이고,The substituted 5 to 6 membered heterocycloalkyl is C 1-3 straight or branched chain alkyl, C 1-2 straight or branched chain alkylcarbonyl, unsubstituted or substituted C 6 aryl, unsubstituted or substituted C 6 aryl C 1-3 straight or branched chain alkyl, and 5 to 6 membered heteroaryl C 1-3 including one or more heteroatoms selected from the group consisting of N, O and S straight chain or branched 5 to 6 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of chain alkyl,

상기 치환된 C6의 아릴은 하나 이상의 할로겐이 치환된 C6의 아릴이고,Aryl of the aryl-substituted C 6 is at least one halogen-substituted C 6,

상기 치환된 C6-8의 아릴 및 5 내지 6 원자의 헤테로아릴은 독립적으로 할로겐, -NH2 및 -NHR4NH2로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C6-8의 아릴 또는 5 내지 6 원자의 헤테로아릴이고,The substituted C 6-8 aryl and 5 to 6 membered heteroaryl are independently halogen, -NH 2 and -NHR 4 NH 2 wherein at least one substituent selected from the group consisting of substituted C 6-8 aryl Or 5 to 6 membered heteroaryl,

상기 R4는 C1-3의 직쇄 또는 분지쇄 알킬이고;R 4 is C 1-3 straight or branched chain alkyl;

상기 R2는,R 2 is,

상기 Y가 N일 경우, 부재이고; 및When Y is N, it is absent; And

상기 Y가 C일 경우, -H, C1-3의 직쇄 또는 분지쇄 알킬이거나, 상기 R1과 함께 연결되어 C3-6의 사이클로알킬을 형성할 수 있다.When Y is C, it may be -H, C 1-3 linear or branched chain alkyl, or may be linked together with R 1 to form C 3-6 cycloalkyl.

또 다른 측면에서,On the other side,

상기 X는 S 또는 O이고;X is S or O;

상기 L1은 -(CH2)p-이고, p는 0이고; L 1 is -(CH 2 ) p -, and p is 0;

상기 L2는 -(CH2)q-이고, q는 0이고;L 2 is -(CH 2 ) q -, and q is 0;

상기 L3은 -(CH2)r-이고, r은 3이고;L 3 is -(CH 2 ) r -, and r is 3;

상기 Y는 C 또는 N이고;Y is C or N;

상기 R1은 -H, -CH3,

Figure 112019061617410-pat00003
,
Figure 112019061617410-pat00004
,
Figure 112019061617410-pat00005
,
Figure 112019061617410-pat00006
,
Figure 112019061617410-pat00007
,
Figure 112019061617410-pat00008
,
Figure 112019061617410-pat00009
,
Figure 112019061617410-pat00010
,
Figure 112019061617410-pat00011
,
Figure 112019061617410-pat00012
,
Figure 112019061617410-pat00013
,
Figure 112019061617410-pat00014
,
Figure 112019061617410-pat00015
,
Figure 112019061617410-pat00016
,
Figure 112019061617410-pat00017
,
Figure 112019061617410-pat00018
,
Figure 112019061617410-pat00019
,
Figure 112019061617410-pat00020
,
Figure 112019061617410-pat00021
,
Figure 112019061617410-pat00022
,
Figure 112019061617410-pat00023
,
Figure 112019061617410-pat00024
,
Figure 112019061617410-pat00025
,
Figure 112019061617410-pat00026
,
Figure 112019061617410-pat00027
,
Figure 112019061617410-pat00028
,
Figure 112019061617410-pat00029
,
Figure 112019061617410-pat00030
,
Figure 112019061617410-pat00031
,
Figure 112019061617410-pat00032
,
Figure 112019061617410-pat00033
,
Figure 112019061617410-pat00034
,
Figure 112019061617410-pat00035
,
Figure 112019061617410-pat00036
, 또는
Figure 112019061617410-pat00037
이고;R 1 is -H, -CH 3 ,
Figure 112019061617410-pat00003
,
Figure 112019061617410-pat00004
,
Figure 112019061617410-pat00005
,
Figure 112019061617410-pat00006
,
Figure 112019061617410-pat00007
,
Figure 112019061617410-pat00008
,
Figure 112019061617410-pat00009
,
Figure 112019061617410-pat00010
,
Figure 112019061617410-pat00011
,
Figure 112019061617410-pat00012
,
Figure 112019061617410-pat00013
,
Figure 112019061617410-pat00014
,
Figure 112019061617410-pat00015
,
Figure 112019061617410-pat00016
,
Figure 112019061617410-pat00017
,
Figure 112019061617410-pat00018
,
Figure 112019061617410-pat00019
,
Figure 112019061617410-pat00020
,
Figure 112019061617410-pat00021
,
Figure 112019061617410-pat00022
,
Figure 112019061617410-pat00023
,
Figure 112019061617410-pat00024
,
Figure 112019061617410-pat00025
,
Figure 112019061617410-pat00026
,
Figure 112019061617410-pat00027
,
Figure 112019061617410-pat00028
,
Figure 112019061617410-pat00029
,
Figure 112019061617410-pat00030
,
Figure 112019061617410-pat00031
,
Figure 112019061617410-pat00032
,
Figure 112019061617410-pat00033
,
Figure 112019061617410-pat00034
,
Figure 112019061617410-pat00035
,
Figure 112019061617410-pat00036
, or
Figure 112019061617410-pat00037
ego;

상기 R2는,R 2 is,

상기 Y가 N일 경우, 부재이고; 및When Y is N, it is absent; And

상기 Y가 C일 경우, -H, C1-2의 직쇄 또는 분지쇄 알킬이거나, 상기 R1과 함께 연결되어 C3-6의 사이클로알킬을 형성할 수 있다.When Y is C, it may be -H, C 1-2 linear or branched chain alkyl, or may be linked together with R 1 to form C 3-6 cycloalkyl.

다른 측면에서,On the other side,

상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염일 수 있다.The compound represented by Formula 1 may be a compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is any one selected from the following group of compounds.

(1) 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(1) 1-(3,4-dimethoxyphenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(2) 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(2) 1-(3,4-dimethoxyphenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(3) 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(3) 1-(3,4-dimethoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(4) 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(4) 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(5) 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(5) 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(6) 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(6) 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(7) 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(7) 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(8) 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(8) 1-cyclopentyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(9) 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(9) 1-cyclohexyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(10) 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(10) 1-benzyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(11) 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(11) 1-(3,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(12) 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(12) 1-(3-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(13) 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(13) 1-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(14) 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;(14) 1-(4-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;

(15) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일메틸)티오우레아;(15) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-ylmethyl)thiourea ;

(16) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)티오우레아;(16) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl)thio Urea;

(17) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(17) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(18) 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(18) 1-(3,4-dimethoxyphenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(19) 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(19) 1-(3,4-dimethoxyphenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(20) 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(20) 1-(3,4-dimethoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(21) 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(21) 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(22) 1-(사이클로펜틸메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)-프로필)우레아;(22) 1-(cyclopentylmethyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)-propyl)urea;

(23) 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(23) 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(24) 1-사이클로뷰틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(24) 1-cyclobutyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(25) 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(25) 1-cyclopentyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(26) 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(26) 1-cyclohexyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(27) 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(27) 1-benzyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(28) 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(28) 1-(3,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(29) 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(29) 1-(3-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(30) 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(30) 1-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(31) 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(31) 1-(4-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;

(32) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일-메틸)우레아;(32) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-yl-methyl)urea ;

(33) 1-(3,4-다이메톡시페닐)-1-((6-플루오로피리딘-3-일)메틸)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(33) 1-(3,4-dimethoxyphenyl)-1-((6-fluoropyridin-3-yl)methyl)-3-(3-(5-methyl-1H-imidazole-1- Work) propyl) urea;

(34) 1-((6-클로로피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(34) 1-((6-chloropyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl ) Propyl) urea;

(35) 1-((6-아미노피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(35) 1-((6-aminopyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl ) Propyl) urea;

(36) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)우레아;(36) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl)urea ;

(37) 1-((2-아미노피리딘-4-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(37) 1-((2-aminopyridin-4-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl ) Propyl) urea;

(38) 1-((2-아미노피리딘-4-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(38) 1-((2-aminopyridin-4-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl ) Propyl) urea;

(39) 1-(4-(2-아미노피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(39) 1-(4-(2-aminopyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1 -Yl)propyl)urea;

(40) 1-(4-(2-(2-아미노에틸아미노)피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(40) 1-(4-(2-(2-aminoethylamino)pyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl- 1H-imidazol-1-yl)propyl)urea;

(41) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-페닐우레아;(41) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-phenylurea;

(42) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-페닐우레아;(42) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-phenylurea;

(43) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(티아졸-2-일)우레아;(43) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(thiazol-2-yl)urea;

(44) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피페리딘-4-일)우레아;(44) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(piperidin-4-yl)urea ;

(45) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-메틸피레리딘-4-일)우레아;(45) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-methylpyreridine-4- Work) urea;

(46) 1-(3,4-다이메톡시페닐)-1-(1-에틸피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(46) 1-(3,4-dimethoxyphenyl)-1-(1-ethylpiperidin-4-yl)-3-(3-(5-methyl-1H-imidazol-1-yl) Propyl) urea;

(47) 1-(1-아세틸피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(47) 1-(1-acetylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl) Propyl) urea;

(48) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-페닐피페리딘-4-일)우레아;(48) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-phenylpiperidine-4- Work) urea;

(49) 1-(1-벤질피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(49) 1-(1-Benzylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl) Propyl) urea;

(50) 1-(3,4-다이메톡시페닐)-1-(1-(4-플루오로벤질)피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;(50) 1-(3,4-dimethoxyphenyl)-1-(1-(4-fluorobenzyl)piperidin-4-yl)-3-(3-(5-methyl-1H-imine) Dazol-1-yl)propyl)urea;

(51) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-(피리딘-3-일메틸)피페리딘-4-일)우레아;(51) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-(pyridin-3-ylmethyl ) Piperidin-4-yl) urea;

(52) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-(피페라진-1-일)에틸)우레아;(52) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(2-(piperazin-1-yl) )Ethyl)urea;

(53) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-모르폴리노에틸)우레아;(53) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(2-morpholinoethyl)urea;

(54) 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)아세트아미드;(54) 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)acetamide;

(55) 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)프로판아미드;(55) 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)propanamide;

(56) 2-(3,4-다이메톡시페닐)-2-메틸-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)프로판아미드;(56) 2-(3,4-dimethoxyphenyl)-2-methyl-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)propanamide;

(57) 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로프로판카복사미드;(57) 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclopropanecarboxamide;

(58) 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로뷰탄카복사미드;(58) 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclobutanecarboxamide;

(59) 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로펜탄카복사미드;(59) 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclopentanecarboxamide;

(60) 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로헥세인-1-카복사미드;(60) 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclohexane-1-carboxamide;

(61) 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)-3-페닐프로페인아미드; 및(61) 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-phenylpropaneamide; And

(62) 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)-3-페닐프로페인아미드.(62) 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-phenylpropaneamide.

본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Rate, sebacate, fumarate, maleate, butine-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다.The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid May be prepared by filtration and drying, or may be prepared by distilling a solvent and an excess of acid under reduced pressure and then drying to crystallize under an organic solvent.

또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 광학 이성질체, 수화물 등을 모두 포함한다.Furthermore, the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, optical isomers, and hydrates that may be prepared therefrom.

본 발명의 다른 일 측면은, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 치매, 픽(pick)병, 크루츠-야콥(Creutzfeldt-Jakob) 병, 두부손상에 의한 파킨슨(Parkinson) 병 및 헌팅턴(Huntington) 병으로 이루어지는 군으로부터 선택되는 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In another aspect of the present invention, dementia containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, pick disease, Creutzfeldt-Jakob disease, head injury It provides a pharmaceutical composition for the prevention or treatment of a disease selected from the group consisting of Parkinson's disease and Huntington's disease by.

다른 측면에서, 상기 화학식 1로 표시되는 화합물은 글루타미닐 사이클레이즈(Glutaminyl Cyclase)를 저해하는 것을 특징으로 하는 약학적 조성물일 수 있고,In another aspect, the compound represented by Formula 1 may be a pharmaceutical composition characterized in that it inhibits glutaminyl cyclase,

상기 치매는 구체적으로 알츠하이머병, 뇌혈관성 치매증, 두부 손상에 의한 치매, 다경색 치매, 알츠하이머병과 다경색 치매의 혼합형 또는 알코올성 치매일 수 있다.Specifically, the dementia may be Alzheimer's disease, cerebrovascular dementia, dementia due to head injury, multi-infarct dementia, a mixture of Alzheimer's disease and multi-infarct dementia, or alcoholic dementia.

상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다.The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations upon clinical administration. When formulated, it is prepared by using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, syrups, etc., but may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents. have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, and emulsions. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다.A pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how to do it.

이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, and the ampoule or vial unit dosage form It can be manufactured with. The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing, granulating It can be formulated according to the method of painting or coating.

경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (such as silica, talc, stearic acid and magnesium or calcium salts thereof and/or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases boron such as starch, agar, alginic acid or sodium salt thereof. It may contain release or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

본 발명의 또 다른 일 측면은, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 치매, 픽(pick)병, 크루츠-야콥(Creutzfeldt-Jakob) 병, 두부손상에 의한 파킨슨(Parkinson) 병 및 헌팅턴(Huntington) 병으로 이루어지는 군으로부터 선택되는 질환의 예방 또는 개선용 건강식품 조성물을 제공한다.In another aspect of the present invention, dementia containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, pick disease, Creutzfeldt-Jakob disease, tofu It provides a health food composition for preventing or improving diseases selected from the group consisting of Parkinson's disease and Huntington's disease due to damage.

다른 측면에서, 상기 치매는 구체적으로 알츠하이머병, 뇌혈관성 치매증, 두부 손상에 의한 치매, 다경색 치매, 알츠하이머병과 다경색 치매의 혼합형 또는 알코올성 치매일 수 있다.In another aspect, the dementia may specifically be Alzheimer's disease, cerebrovascular dementia, dementia caused by head injury, multi-infarct dementia, a mixture of Alzheimer's disease and multi-infarct dementia, or alcoholic dementia.

본 발명에 따른 상기 화학식 1로 표시되는 화합물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The compound represented by Formula 1 according to the present invention may be added to food as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the amount may be less than the above range, and there is no problem in terms of safety, so the active ingredient may be used in an amount above the above range.

또한, 본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates, etc. have. Examples of the natural carbohydrates described above include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

나아가, 상기 외에 본 발명에 따른 화학식 1로 표시되는 화합물은 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 본 발명의 화학식 1로 표시되는 화합물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.Further, in addition to the above, the compound represented by Formula 1 according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pects. Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, the compound represented by Chemical Formula 1 of the present invention may contain flesh for the manufacture of natural fruit juice and fruit juice beverages and vegetable beverages.

본 발명의 일 측면에서 제공되는 글루타미닐 사이클레이즈 저해제는 시험관내 (in vitro)에서 글루타미닐 사이클레이즈와 결합하여 50 nM 이하의 낮은 IC50 값으로 QC를 저해하며, BBB(blood-brain barrier)를 통과하여 뇌 내부의 QC를 저해할 수 있고, 생체 내(in vivo)에서 뇌에서의 AβN3pE-40, AβN3pE-42, Aβ1-40, 및 Aβ1-42의 농도를 현저하게 감소시킬 뿐만 아니라, 세포 독성이 없어 부작용의 우려가 적으므로, QC 활성 관련 질환인 알츠하이머병, 뇌혈관성 치매증, 두부 손상에 의한 치매, 다경색 치매, 알츠하이머병과 다경색 치매의 혼합형 또는 알코올성 치매 등을 포함하는 치매, 픽(pick)병, 크루츠-야콥(Creutzfeldt-Jakob)병, 두부손상에 의한 파킨슨(Parkinson)병, 헌팅턴(Huntington)병 등의 예방 또는 치료용 조성물의 개발에 큰 기여를 할 수 있으며, 이는 후술하는 실시예, 실험예에 의해 직접적으로 뒷받침될 수 있다.The glutaminyl cyclase inhibitor provided in one aspect of the present invention binds with glutaminyl cyclase in vitro to inhibit QC with a low IC 50 value of 50 nM or less, and the blood-brain barrier (BBB) ) Can inhibit QC inside the brain, and Aβ N3pE-40 in the brain in vivo, Aβ N3pE-42 , Aβ 1-40 , and Not only does it significantly reduce the concentration of Aβ 1-42 , but also has no cytotoxicity, so there is little risk of side effects.Therefore, it is different from Alzheimer's disease, cerebrovascular dementia, dementia due to head injury, multi-infarct dementia, and Alzheimer's disease. Prevention or treatment of dementia, including mixed type of infarct dementia or alcoholic dementia, pick's disease, Creutzfeldt-Jakob's disease, Parkinson's disease, and Huntington's disease due to head injury It can make a great contribution to the development of the composition for use, which can be directly supported by Examples and Experimental Examples to be described later.

본 발명의 구체적인 실시예 및 실험예에서, 본 발명자들은 본 발명의 실시예 화합물의 QC 저해활성을 평가하기 위하여 시험관 내(in vitro)에서 IC50값으로 계산하여 본 발명의 실시예 화합물이 우수한 QC 저해능을 나타냄을 확인하였다 (실험예 1, 표 1),In specific examples and experimental examples of the present invention, the present inventors calculated the IC 50 value in vitro in order to evaluate the QC inhibitory activity of the example compound of the present invention, so that the example compound of the present invention has excellent QC. It was confirmed that the inhibitory ability was shown (Experimental Example 1, Table 1),

또한, 본 발명에 따른 실시예 화합물의 세표 독성과 hERG 저해를 평가한 결과, 세포독성이 없어 부작용이 없음을 확인하였고 (실험예 2, 표 2), 생체 내(in vivo)에서 AβN3pE-40, AβN3pE-42, Aβ1-40, 및 Aβ1-42의 농도를 현저하게 감소시키는 것을 확인하였다 (실험예 3 및 4, 표 3 ). 이를 통해, 본 발명에 따른 실시예 화합물이 글루타미닐 사이클레이즈를 우수한 활성으로 저해하여 글루타미닐 사이클레이즈 활성 관련 질환의 예방 또는 치료 조성물 제조에 크게 기여할 수 있음을 확인하였다.Further, it was confirmed in Example was evaluated for toxicity and sepyo h ERG inhibition of the compounds, it does not have a cytotoxic no side effects according to the invention (Example 2, Table 2), in vivo (in vivo) Aβ N3pE- 40 , Aβ N3pE-42 , Aβ 1-40 , and It was confirmed that the concentration of Aβ 1-42 was significantly reduced (Experimental Examples 3 and 4, Table 3). Through this, it was confirmed that the example compound according to the present invention inhibits glutaminyl cyclase with excellent activity and can greatly contribute to the preparation of a composition for preventing or treating diseases related to glutaminyl cyclase activity.

이하, 본 발명을 후술하는 실시예 및 실험예를 통해 상세히 설명한다.Hereinafter, the present invention will be described in detail through examples and experimental examples to be described later.

단, 후술하는 실시예 및 실험예는 본 발명을 일부 예시하는 것일 뿐, 본 발명이 이에 한정되는 것은 아니다.However, the examples and experimental examples to be described later are merely illustrative of the present invention, and the present invention is not limited thereto.

일반적인 제조절차 1General Manufacturing Procedure 1

톨루엔 용매에서 1-(3-아자이도프로필)-5-메틸-1H-이미다졸 수용액 (1.0 eq)와 트리페닐포스핀 (1.2 eq)을 질소 기체 하에서 30분간 교반하고, 톨루엔 용매의 카본 다이설파이드 수용액 (1.1 eq)을 첨가하였다. 다음, 혼합물을 1시간 동안 교반하고, N-치환된 3,4-다이메톡시아닐린 (1.0 eq)을 첨가하였다. 다음, 40 ℃에서 밤새 교반한 후, 혼합물을 진공(in vacuo)에서 농축시킨 후, 용리액이 MeOH:CH2Cl2인 실리카겔 컬럼 크로마토그래피로 정제하여 목적 화합물을 수득하였다.1-(3-azidopropyl)-5-methyl-1H-imidazole aqueous solution (1.0 eq) and triphenylphosphine (1.2 eq) were stirred in a toluene solvent for 30 minutes under nitrogen gas, and carbon disulfide in a toluene solvent An aqueous solution (1.1 eq) was added. Then, the mixture was stirred for 1 hour, and N-substituted 3,4-dimethoxyaniline (1.0 eq) was added. Then, after stirring at 40° C. overnight, the mixture was concentrated in vacuo and then purified by silica gel column chromatography in which the eluent was MeOH:CH 2 Cl 2 to obtain the target compound.

일반적인 제조절차 2 (아자-비티히 커플링 반응, aza-Wittig coupling reaction)General manufacturing procedure 2 (aza-Wittig coupling reaction)

N-치환된 3,4-다이메톡시아닐린 (1.0 eq) 수용액과 1-(3-아자이도프로필)-5-메틸-1H-이미다졸 (1.1 eq)을 톨루엔 용매에서 교반한 후 트리페닐포스핀 (1.2 eq)을 첨가하였다. 다음, 반응 혼합물을 가스를 제거한 후, 이산화탄소를 첨가하였다. 80 ℃에서 4시간 내지 8시간동안 이산화탄소 기체 하에서 교반한 후, 혼합물을 진공(in vacuo)에서 농축시킨 후, 용리액이 MeOH:CH2Cl2인 실리카겔 컬럼 크로마토그래피로 정제하여 목적 화합물을 수득하였다.After stirring an N-substituted 3,4-dimethoxyaniline (1.0 eq) aqueous solution and 1-(3-azidopropyl)-5-methyl-1H-imidazole (1.1 eq) in a toluene solvent, Pin (1.2 eq) was added. Then, after degassing the reaction mixture, carbon dioxide was added. After stirring under carbon dioxide gas at 80° C. for 4 to 8 hours, the mixture was concentrated in vacuo and then purified by silica gel column chromatography in which the eluent was MeOH:CH 2 Cl 2 to obtain the target compound.

일반적인 제조절차 3 (Boc-탈보호화 반응, Boc-deprotection reaction ) General manufacturing procedure 3 (Boc-deprotection reaction )

CH2Cl2 용매에서 N-Boc 보호화된 아민화합물에 트리풀루오로아세트산 (10 eq)을 첨가하여 교반하였다. 반응 혼합물을 밤새 교반한 후 진공(in vacuo)에서 농축시키고 이온교환수지(음이온 교환수지, strongly basic form)로 정제하여 아민 화합물을 수득하였다.Trifluoroacetic acid (10 eq) was added to the N-Boc-protected amine compound in a CH 2 Cl 2 solvent, followed by stirring. The reaction mixture was stirred overnight, then concentrated in vacuo and purified with an ion exchange resin (anion exchange resin, strongly basic form) to obtain an amine compound.

일반적인 제조절차 4 (EDC 커플링 반응,EDC coupling reaction)General manufacturing procedure 4 (EDC coupling reaction)

CH2Cl2 용매에서 3-(5-메틸-1H-이미다졸-1-일)프로판-1-아민 수용액 (1.0 eq)에 트리에틸아민 (3.0 eq), 1-하이드록시벤조트리아졸 (HOBt, 1.2 eq), 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드·염화수소 (EDC·HCl, 1.2 eq), α-치환된 2-(3,4-다이메톡시페닐)아세트산 (1.2 eq)을 상온에서 순차적으로 첨가하였다. 밤새 교반한 후, 반응 혼합물을 CH2Cl2로 희석한 후 물로 몇차례 헹구었다. 다음, 유기흥을 MgSO4로 건조하고 진공(in vacuo)에서 농축시킨 후, 실리카겔 컬럼 크로마토그래피로 정제하여 목적 화합물을 수득하였다.Triethylamine (3.0 eq), 1-hydroxybenzotriazole (HOBt) in 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine aqueous solution (1.0 eq) in CH 2 Cl 2 solvent , 1.2 eq), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrogen chloride (EDC HCl, 1.2 eq), α-substituted 2-(3,4-dimethoxyphenyl)acetic acid (1.2 eq) was sequentially added at room temperature. After stirring overnight, the reaction mixture was diluted with CH 2 Cl 2 and then rinsed several times with water. Next, the organic compound was dried over MgSO 4 , concentrated in vacuo , and purified by silica gel column chromatography to obtain the target compound.

일반적인 제조절차 5 (환원성 아미노화, reductive amination)General manufacturing procedure 5 (reductive amination)

MeOH 용매의 3,4-다이메톡시아닐린 (1.0 eq)과 케톤 혹은 알데하이드의 혼합물에 아세트산 (5.0 eq)와 NaBH3CN (3.0 eq)을 차례로 첨가하였다. 40 ℃에서 4시간 동안 교반한 후, 반응 혼합물을 NaHCO3 수용액으로 염기화한 후 CH2Cl2로 추출하였다. 합쳐진 유기층을 진공(in vacuo)에서 농축시킨 후, 실리카겔 컬럼 크로마토그래피로 정제하여 2차 아민을 수득하였다. Acetic acid (5.0 eq) and NaBH 3 CN (3.0 eq) were sequentially added to a mixture of 3,4-dimethoxyaniline (1.0 eq) in a MeOH solvent and ketone or aldehyde. After stirring at 40° C. for 4 hours, the reaction mixture was basified with an aqueous NaHCO 3 solution and extracted with CH 2 Cl 2. The combined organic layers were concentrated in vacuo and then purified by silica gel column chromatography to obtain a secondary amine.

일반적인 제조절차 6 (탈황 반응, desulfurization)General manufacturing procedure 6 (desulfurization reaction, desulfurization)

설폰아마이드 혼합물 (1.0 eq)과 과량의 K2CO3 (in CH3CN)에 싸이오페놀 (2.0 eq)를 첨가하였다. 반응 혼합물을 상온에서 밤새 교반한 후, 묽은 NaOH를 첨가하고, CH2Cl2로 몇차례 추출하였다. 합쳐진 유기층을 물로 헹구고, MgSO4로 건조한 뒤 실리카겔 컬럼 크로마토그래피로 정제하였다.Thiophenol (2.0 eq) was added to the sulfonamide mixture (1.0 eq) and an excess of K 2 CO 3 (in CH 3 CN). The reaction mixture was stirred at room temperature overnight, diluted NaOH was added, and extracted several times with CH2Cl2. The combined organic layer was rinsed with water, dried over MgSO 4 and purified by silica gel column chromatography.

<실시예 1> 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 1> Preparation of 1-(3,4-dimethoxyphenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

Figure 112019061617410-pat00038
Figure 112019061617410-pat00038

단계 1: 3,4-다이메톡시-N-메틸아닐린의 제조Step 1: Preparation of 3,4-dimethoxy-N-methylaniline

설폰아마이드 혼합물이 N-(3,4-다이메톡시페닐)-N-메틸-2-나이트로벤젠설폰아마이드인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 3,4-다이메톡시-N-메틸아닐린을 제조하였다.The sulfonamide mixture is N-(3,4-dimethoxyphenyl)-N-methyl-2-nitrobenzenesulfonamide, and 3,4-dimethoxy-N- Methylaniline was prepared.

수율 85%, 엷은 노란색 고체.Yield 85%, pale yellow solid.

1H NMR (400 MHz, CDCl3) δ 7.01-6.98 (m, 2H), 6.87 (d, J = 9.00 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.01 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.01-6.98 (m, 2H), 6.87 (d, J = 9.00 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.01 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 3,4-다이메톡시-N-메틸아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-(3,4-dimethoxyaniline was prepared in the same manner as in General Preparation Procedure 1, wherein the N-substituted 3.4-dimethoxyaniline was 3,4-dimethoxy-N-methylaniline obtained in step 1 above. Phenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 52%, 흰색 고체, mp 80-81℃.Yield 52%, white solid, mp 80-81°C.

1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 6.90 (d, J = 8.48 Hz, 1H), 6.74 (dd, J = 8.37, 2.13 Hz, 1H), 6.70 (s, 1H), 6.65 (d, J = 2.16 Hz, 1H), 5.40 (br, NH), 3.89 (s, 3H), 3.84 (s, 3H), 3.82 (t, J = 7.16 Hz, 2H), 3.61 (s, 3H), 3.56 (q, J = 6.64 Hz, 2H), 2.12 (d, J = 0.96 Hz, 3H), 1.96 (quintet, J = 7.12 Hz, 2H); HRMS (ESI) calc. for C17H25N4O2S [M + H]+ 349.1693, found: 349.1697. 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (s, 1H), 6.90 (d, J = 8.48 Hz, 1H), 6.74 (dd, J = 8.37, 2.13 Hz, 1H), 6.70 (s, 1H) , 6.65 (d, J = 2.16 Hz, 1H), 5.40 (br, NH), 3.89 (s, 3H), 3.84 (s, 3H), 3.82 (t, J = 7.16 Hz, 2H), 3.61 (s, 3H), 3.56 (q, J = 6.64 Hz, 2H), 2.12 (d, J = 0.96 Hz, 3H), 1.96 (quintet, J = 7.12 Hz, 2H); HRMS (ESI) calc. for C 17 H 25 N 4 O 2 S [M + H] + 349.1693, found: 349.1697.

<실시예 2> 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 2> Preparation of 1-(3,4-dimethoxyphenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

Figure 112019061617410-pat00039
Figure 112019061617410-pat00039

단계 1: N-에틸-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-ethyl-3,4-dimethoxyaniline

설폰아마이드 혼합물이 N-(3,4-다이메톡시페닐)-N-에틸-2-나이트로벤젠설폰아마이드인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 N-에틸-3,4-다이메톡시아닐린을 제조하였다.N-ethyl-3,4-dime by following the same method as in General Preparation 6, wherein the sulfonamide mixture is N-(3,4-dimethoxyphenyl)-N-ethyl-2-nitrobenzenesulfonamide. Toxianiline was prepared.

수율 51%, 흰색 고체.Yield 51%, white solid.

1H NMR (400 MHz, CDCl3) δ 7.00-6.99 (m, 1H), 6.96 (d, J = 2.55 Hz, 1H), 6.82 (d, J = 8.40 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.35 (q, J = 7.14 Hz, 2H), 1.33 (t, J = 7.35 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.00-6.99 (m, 1H), 6.96 (d, J = 2.55 Hz, 1H), 6.82 (d, J = 8.40 Hz, 1H), 3.87 (s, 3H) , 3.85 (s, 3H), 3.35 (q, J = 7.14 Hz, 2H), 1.33 (t, J = 7.35 Hz, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-에틸-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-(3,4-dimethoxyaniline is N-ethyl-3,4-dimethoxyaniline obtained in step 1, and 1-(3,4-dimethoxyaniline) was performed in the same manner as in General Preparation Procedure 1 above. Phenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 29%, 흰색 고체, mp 51-52℃.Yield 29%, white solid, mp 51-52°C.

1H NMR (300 MHz, CDCl3) 7.77 (s, 1H), 6.90 (d, J = 8.43 Hz, 2H), 6.77 (s, 1H), 6.69 (dd, J = 8.40, 2.37 Hz, 1H), 6.60 (d, J = 2.37 Hz, 1H), 5.39 (t, J = 6.60 Hz , 1H), 4.16 (q, J = 6.69 Hz, 2H), 3.90 (t, J = 7.68 Hz, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 3.58 (q, J = 6.57 Hz, 2H), 2.15 (s, 3H), 2.02 (quintet, J = 7.14 Hz, 2H), 1.17 (t, J = 7.14 Hz, 3H); HRMS (ESI) calc. for C18H27N4O2S [M + H]+ 363.1849, found: 363.1847. 1 H NMR (300 MHz, CDCl 3 ) 7.77 (s, 1H), 6.90 (d, J = 8.43 Hz, 2H), 6.77 (s, 1H), 6.69 (dd, J = 8.40, 2.37 Hz, 1H), 6.60 (d, J = 2.37 Hz, 1H), 5.39 (t, J = 6.60 Hz, 1H), 4.16 (q, J = 6.69 Hz, 2H), 3.90 (t, J = 7.68 Hz, 2H), 3.88 ( s, 3H), 3.82 (s, 3H), 3.58 (q, J = 6.57 Hz, 2H), 2.15 (s, 3H), 2.02 (quintet, J = 7.14 Hz, 2H), 1.17 (t, J = 7.14 Hz, 3H); HRMS (ESI) calc. for C 18 H 27 N 4 O 2 S [M + H] + 363.1849, found: 363.1847.

<실시예 3> 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 3> Preparation of 1-(3,4-dimethoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

Figure 112019061617410-pat00040
Figure 112019061617410-pat00040

단계 1: N-아이소프로필-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-isopropyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 아세톤인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-아이소프로필-3,4-다이메톡시아닐린을 제조하였다.N-isopropyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is acetone.

수율 65%, 갈색 고체.Yield 65%, brown solid.

1H NMR (300 MHz, CDCl3) δ 6.73 (d, J = 8.61 Hz, 1H), 6.24 (d, J = 2.58 Hz, 1H), 6.17 (dd, J = 8.61, 2.76, Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.59 (quintet, J = 6.78 Hz, 1H), 1.19 (s, 3H), 1.17 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.73 (d, J = 8.61 Hz, 1H), 6.24 (d, J = 2.58 Hz, 1H), 6.17 (dd, J = 8.61, 2.76, Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.59 (quintet, J = 6.78 Hz, 1H), 1.19 (s, 3H), 1.17 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-아이소프로필-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-(3,4-dimethoxyaniline is N-isopropyl-3,4-dimethoxyaniline obtained in step 1, and 1-(3,4-dimethoxyaniline) is performed in the same manner as in the general preparation procedure 1 above. Toxoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 78%, 흰색 고체, mp 59-60℃.Yield 78%, white solid, mp 59-60°C.

1H NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 6.92 (d, J = 8.61 Hz, 1H), 6.73 (s, 1H), 6.63 (dd, J = 8.43, 2.19 Hz, 1H), 6.52 (d, J = 2.22 Hz, 1H), 5.86 (quintet, J = 6.78 Hz, 1H), 5.21 (t, J = 5.67 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.81 (t, J = 7.14 Hz, 2H), 3.58 (q, J = 6.39 Hz, 2H), 2.13 (d, J = 0.90 Hz, 3H), 1.98 (quintet, J = 7.32 Hz, 2H), 1.08 (s, 3H), 1.06 (s, 3H); HRMS (ESI) calc. for C19H29N4O2S [M + H] + 377.2006, found: 377.2008. 1 H NMR (300 MHz, CDCl 3 ) δ 7.47 (s, 1H), 6.92 (d, J = 8.61 Hz, 1H), 6.73 (s, 1H), 6.63 (dd, J = 8.43, 2.19 Hz, 1H) , 6.52 (d, J = 2.22 Hz, 1H), 5.86 (quintet, J = 6.78 Hz, 1H), 5.21 (t, J = 5.67 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H) , 3.81 (t, J = 7.14 Hz, 2H), 3.58 (q, J = 6.39 Hz, 2H), 2.13 (d, J = 0.90 Hz, 3H), 1.98 (quintet, J = 7.32 Hz, 2H), 1.08 (s, 3H), 1.06 (s, 3H); HRMS (ESI) calc. for C 19 H 29 N 4 O 2 S [M + H] + 377.2006, found: 377.2008.

<실시예 4> 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 4> Preparation of 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

Figure 112019061617410-pat00041
Figure 112019061617410-pat00041

단계 1: N-아이소뷰틸-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-isobutyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 뷰탄-2-온인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-아이소뷰틸-3,4-다이메톡시아닐린을 제조하였다.N-isobutyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is butan-2-one.

수율 84%, 엷은 노란색 고체.Yield 84%, pale yellow solid.

1H NMR (300 MHz, CDCl3) δ 6.73 (d, J = 8.61 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.16 (dd, J = 8.58, 2.55 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.88 (d, J = 6.75 Hz, 2H), 1.90-1.81 (m, 1H), 0.98 (d, J = 6.57 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.73 (d, J = 8.61 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.16 (dd, J = 8.58, 2.55 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.88 (d, J = 6.75 Hz, 2H), 1.90-1.81 (m, 1H), 0.98 (d, J = 6.57 Hz, 6H).

단계 2: 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-아이소뷰틸-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-(3,4-dimethoxyaniline is N-isobutyl-3,4-dimethoxyaniline obtained in Step 1, and 1-(3,4-dime) is performed in the same manner as in General Preparation Procedure 1 above. Toxoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 65%, 흰색 고체, mp 76-77℃.Yield 65%, white solid, mp 76-77°C.

1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 6.91 (d, J = 8.43 Hz, 1H), 6.78 (s, 1H), 6.72 (dd, J = 8.43, 2.37 Hz, 1H), 6.62 (d, J = 2.40 Hz, 1H), 5.47 (t, J = 6.09 Hz, NH), 4.08 (t, J = 6.66 Hz, 2H), 3.89 (s, 3H), 3.88 (d, J = 7.89 Hz, 2H), 3.84 (s, 3H), 3.58 (q, J = 6.96 Hz, 2H), 2.16 (s, 3H), 1.98 (quintet, J = 7.32 Hz, 2H), 1.87-1.78 (m, 1H), 0.93 (d, J = 6.60 Hz, 6H); HRMS (ESI) calc. for C20H31N4O2S [M + H]+ 391.2162, found 391.2171. 1 H NMR (300 MHz, CDCl 3 ) δ 7.70 (s, 1H), 6.91 (d, J = 8.43 Hz, 1H), 6.78 (s, 1H), 6.72 (dd, J = 8.43, 2.37 Hz, 1H) , 6.62 (d, J = 2.40 Hz, 1H), 5.47 (t, J = 6.09 Hz, NH), 4.08 (t, J = 6.66 Hz, 2H), 3.89 (s, 3H), 3.88 (d, J = 7.89 Hz, 2H), 3.84 (s, 3H), 3.58 (q, J = 6.96 Hz, 2H), 2.16 (s, 3H), 1.98 (quintet, J = 7.32 Hz, 2H), 1.87-1.78 (m, 1H), 0.93 (d, J = 6.60 Hz, 6H); HRMS (ESI) calc. for C 20 H 31 N 4 O 2 S [M + H] + 391.2162, found 391.2171.

<실시예 5> 1-(사이클로펜틸메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 5> 1-(cyclopentylmethyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea Produce

Figure 112019061617410-pat00042
Figure 112019061617410-pat00042

단계 1: N-(사이클로펜틸메틸)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(cyclopentylmethyl)-3,4-dimethoxyaniline

설폰아마이드 혼합물이 N-(사이클로펜틸메틸)-N-(3,4-다이메톡시페닐)-2-나이트로벤젠설폰아마이드인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 N-(사이클로펜틸메틸)-3,4-다이메톡시아닐린을 제조하였다.N-(cyclopentylmethyl)-N-(3,4-dimethoxyphenyl)-2-nitrobenzenesulfonamide is N-(cyclopentylmethyl)-N-(cyclopentylmethyl) )-3,4-dimethoxyaniline was prepared.

수율 68%, 엷은 노란색 고체.Yield 68%, pale yellow solid.

1H NMR (500 MHz, CDCl3) δ 6.73 (d, J = 8.50 Hz, 1H), 6.24 (d, J = 2.40 Hz, 1H), 6.15 (dd, J = 8.55, 2.50 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.97 (d, J = 7.15 Hz, 2H), 2.15-2.09 (m, 1H), 1.84-1.77 (m, 2H), 1.64-1.58 (m, 2H), 1.55-1.52 (m, 2H), 1.28-1.22 (m, 2H). 1 H NMR (500 MHz, CDCl 3 ) δ 6.73 (d, J = 8.50 Hz, 1H), 6.24 (d, J = 2.40 Hz, 1H), 6.15 (dd, J = 8.55, 2.50 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.97 (d, J = 7.15 Hz, 2H), 2.15-2.09 (m, 1H), 1.84-1.77 (m, 2H), 1.64-1.58 (m, 2H) ), 1.55-1.52 (m, 2H), 1.28-1.22 (m, 2H).

단계 2: 1-(사이클로펜틸메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-(cyclopentylmethyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(사이클로펜틸메틸)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(사이클로펜틸메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아을 제조하였다.1-(cyclopentylmethyl) is N-(cyclopentylmethyl)-3,4-dimethoxyaniline obtained in step 1, and 1-(cyclopentylmethyl) is performed in the same manner as in the general preparation procedure 1 above. )-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 25%, 흰색 고체, mp 87-88℃.Yield 25%, white solid, mp 87-88°C.

1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 6.87 (d, J = 8.61 Hz, 1H), 6.70 (s, 1H), 6.67 (dd, J = 8.43, 2.37 Hz, 1H), 6.58 (d, J = 2.40 Hz, 1H), 5.36 (t, J = 5.85 Hz, 1H), 4.12 (d, J = 6.96 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 (t, J = 7.32 Hz, 2H), 3.54 (q, J = 7.68 Hz, 2H), 2.09 (s, 3H), 2.06-1.99 (m, 1H), 1.83 (quintet, J = 6.78 Hz, 2H), 1.57-1.42 (m, 4H), 1.21-1.18 (m, 2H), 0.80-0.76 (m, 2H); HRMS (ESI) calc. for C22H33N4O2S [M + H]+ 417.2319, found 417.2323. 1 H NMR (300 MHz, CDCl 3 ) δ 7.48 (s, 1H), 6.87 (d, J = 8.61 Hz, 1H), 6.70 (s, 1H), 6.67 (dd, J = 8.43, 2.37 Hz, 1H) , 6.58 (d, J = 2.40 Hz, 1H), 5.36 (t, J = 5.85 Hz, 1H), 4.12 (d, J = 6.96 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H) , 3.78 (t, J = 7.32 Hz, 2H), 3.54 (q, J = 7.68 Hz, 2H), 2.09 (s, 3H), 2.06-1.99 (m, 1H), 1.83 (quintet, J = 6.78 Hz, 2H), 1.57-1.42 (m, 4H), 1.21-1.18 (m, 2H), 0.80-0.76 (m, 2H); HRMS (ESI) calc. for C 22 H 33 N 4 O 2 S [M + H] + 417.2319, found 417.2323.

<실시예 6> 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 6> Preparation of 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

Figure 112019061617410-pat00043
Figure 112019061617410-pat00043

단계 1: N-사이클로프로필-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-cyclopropyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드 대신 1-에톡시-1-(트리메틸실릴옥시)사이클로프로페인을 사용한 것을 제외하고 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-사이클로프로필-3,4-다이메톡시아닐린을 제조하였다.N-cyclopropyl-3,4-dimethoxyaniline was prepared by following the same method as in General Preparation Procedure 5, except that 1-ethoxy-1-(trimethylsilyloxy)cyclopropane was used instead of ketone or aldehyde. I did.

수율 40%, 갈색 고체.Yield 40%, brown solid.

1H NMR (300MHz, CDCl3) δ 6.77 (d, J = 8.34 Hz, 1H), 6.39 (d, J = 2.73 Hz, 1H), 6.36 (dd, J = 8.22, 2.55 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 2.43-2.36 (m, 1H), 0.73-0.67 (m, 2H), 0.52-0.47 (m, 2H). 1 H NMR (300MHz, CDCl 3 ) δ 6.77 (d, J = 8.34 Hz, 1H), 6.39 (d, J = 2.73 Hz, 1H), 6.36 (dd, J = 8.22, 2.55 Hz, 1H), 3.73 ( s, 3H), 3.71 (s, 3H), 2.43-2.36 (m, 1H), 0.73-0.67 (m, 2H), 0.52-0.47 (m, 2H).

단계 2: 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-사이클로프로필-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-cyclopropyl-1-(3) by following the same method as in General Preparation Procedure 1, wherein the N-substituted 3.4-dimethoxyaniline is N-cyclopropyl-3,4-dimethoxyaniline obtained in step 1 above. ,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 34%, 흰색 고체, 159℃(분해, decomposition).Yield 34%, white solid, 159°C (decomposition, decomposition).

1H NMR (300 MHz, CD3OD) δ 7.49 (d, J = 1.08 Hz, 1H), 6.86 (d, J = 8.43 Hz, 1H), 6.59 (d, J = 2.22 Hz, 1H), 6.57 (s, 1H), 6.52 (dd, J = 8.43, 2.40 Hz, 1H), 3.87 (t, J = 7.14 Hz, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.58 (t, J = 6.96 Hz, 2H), 3.09-3.02 (m, 1H), 2.12 (d, J = 0.90 Hz, 3H), 1.96 (quintet, J = 6.96 Hz, 2H), 0.80-0.68 (m, 2H), 0.51-0.46 (m, 2H); HRMS (ESI) calc. for C19H27N4O2S [M + H]+ 375.1849, found 375.1846. 1 H NMR (300 MHz, CD 3 OD) δ 7.49 (d, J = 1.08 Hz, 1H), 6.86 (d, J = 8.43 Hz, 1H), 6.59 (d, J = 2.22 Hz, 1H), 6.57 ( s, 1H), 6.52 (dd, J = 8.43, 2.40 Hz, 1H), 3.87 (t, J = 7.14 Hz, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.58 (t, J = 6.96 Hz, 2H), 3.09-3.02 (m, 1H), 2.12 (d, J = 0.90 Hz, 3H), 1.96 (quintet, J = 6.96 Hz, 2H), 0.80-0.68 (m, 2H), 0.51 -0.46 (m, 2H); HRMS (ESI) calc. for C 19 H 27 N 4 O 2 S [M + H] + 375.1849, found 375.1846.

<실시예 7> 1-사이클로뷰틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 7> Preparation of 1-cyclobutyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

Figure 112019061617410-pat00044
Figure 112019061617410-pat00044

단계 1: N-사이클로뷰틸-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-cyclobutyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 사이클로뷰탄온인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-사이클로뷰틸-3,4-다이메톡시아닐린을 제조하였다.N-cyclobutyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is cyclobutanone.

수율 85%, 갈색 고체.Yield 85%, brown solid.

1H NMR (300 MHz, CDCl3) δ 6.71 (d, J = 8.61 Hz, 1H), 6.20 (d, J = 2.37 Hz, 1H), 6.09 (dd, J = 8.43, 2.58 Hz, 1H), 3.87-3.78 (m, 8H), 2.39-1.37 (m, 2H), 1.85-1.75 (m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.71 (d, J = 8.61 Hz, 1H), 6.20 (d, J = 2.37 Hz, 1H), 6.09 (dd, J = 8.43, 2.58 Hz, 1H), 3.87 -3.78 (m, 8H), 2.39-1.37 (m, 2H), 1.85-1.75 (m, 4H).

단계 2: 1-사이클로뷰틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-cyclobutyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-사이클로뷰틸-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-사이클로뷰틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-cyclobutyl-1-(3) by following the same method as in General Preparation Procedure 1, wherein the N-substituted 3.4-dimethoxyaniline is N-cyclobutyl-3,4-dimethoxyaniline obtained in step 1 above. ,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 52%, 흰색 고체, mp 126-127℃.Yield 52%, white solid, mp 126-127°C.

1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 6.93 (d, J = 8.43 Hz, 1H), 6.71 (s, 1H), 6.62 (dd, J = 8.40, 2.19 Hz, 1H), 6.51 (d, J = 2.01 Hz, 1H), 5.70 (quintet, J = 7.89 Hz, 1H), 5.25 (t, J = 5.67 Hz, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 3.80 (t, J = 7.32 Hz, 2H), 3.55 (q, J = 6.42 Hz, 2H), 2.20-2.16 (m, 2H), 2.12 (s, 3H), 1.93 (quintet, J = 7.14 Hz, 2H), 1.72-1.39 (m, 4H); HRMS (ESI) calc. for C20H29N4O2S [M + H]+ 389.2006, found 389.2014. 1 H NMR (300 MHz, CDCl 3 ) δ 7.40 (s, 1H), 6.93 (d, J = 8.43 Hz, 1H), 6.71 (s, 1H), 6.62 (dd, J = 8.40, 2.19 Hz, 1H) , 6.51 (d, J = 2.01 Hz, 1H), 5.70 (quintet, J = 7.89 Hz, 1H), 5.25 (t, J = 5.67 Hz, 1H), 3.91 (s, 3H), 3.83 (s, 3H) , 3.80 (t, J = 7.32 Hz, 2H), 3.55 (q, J = 6.42 Hz, 2H), 2.20-2.16 (m, 2H), 2.12 (s, 3H), 1.93 (quintet, J = 7.14 Hz, 2H), 1.72-1.39 (m, 4H); HRMS (ESI) calc. for C 20 H 29 N 4 O 2 S [M + H] + 389.2006, found 389.2014.

<실시예 8> 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 8> Preparation of 1-cyclopentyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

Figure 112019061617410-pat00045
Figure 112019061617410-pat00045

단계 1: N-사이클로펜틸-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-cyclopentyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 사이클로펜탄온인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-사이클로펜틸-3,4-다이메톡시아닐린을 제조하였다.N-cyclopentyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is cyclopentanone.

수율 80%, 갈색 고체.Yield 80%, brown solid.

1H NMR (300 MHz, CDCl3) δ 6.71 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.71 (quintet, J = 5.67 Hz, 1H), 2.03-1.93 (m, 2H), 1.76-1.41 (m, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.71 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.71 (quintet, J = 5.67 Hz, 1H), 2.03-1.93 (m, 2H), 1.76-1.41 (m, 6H).

단계 2: 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-cyclopentyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-사이클로펜틸-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-cyclopentyl-1-(3) by performing the same method as in General Preparation Procedure 1, wherein the N-substituted 3.4-dimethoxyaniline is N-cyclopentyl-3,4-dimethoxyaniline obtained in step 1 above. ,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 68%, 흰색 고체, mp 57-59℃.Yield 68%, white solid, mp 57-59°C.

1H NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 6.91 (d, J = 8.40 Hz, 1H), 6.75 (s, 1H), 6.62 (dd, J = 8.22, 2.19 Hz, 1H), 6.53 (d, J = 2.19 Hz, 1H), 5.76-5.64 (m, 1H), 5.24 (t, J = 5.31 Hz, 1H), 3.90 (s, 3H), 3.84 (t, J = 7.50 Hz, 2H), 3.83 (s, 3H), 3.59 (br, 2H), 2.14 (s, 3H), 1.98-1.91 (m, 4H), 1.56-1.44 (m, 4H), 1.23-1.94 (m, 2H); HRMS (ESI) calc. for C21H31N4O2S [M + H]+ 403.2162, found 403.2167. 1 H NMR (300 MHz, CDCl 3 ) δ 7.57 (s, 1H), 6.91 (d, J = 8.40 Hz, 1H), 6.75 (s, 1H), 6.62 (dd, J = 8.22, 2.19 Hz, 1H) , 6.53 (d, J = 2.19 Hz, 1H), 5.76-5.64 (m, 1H), 5.24 (t, J = 5.31 Hz, 1H), 3.90 (s, 3H), 3.84 (t, J = 7.50 Hz, 2H), 3.83 (s, 3H), 3.59 (br, 2H), 2.14 (s, 3H), 1.98-1.91 (m, 4H), 1.56-1.44 (m, 4H), 1.23-1.94 (m, 2H) ; HRMS (ESI) calc. for C 21 H 31 N 4 O 2 S [M + H] + 403.2162, found 403.2167.

<실시예 9> 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 9> Preparation of 1-cyclohexyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

Figure 112019061617410-pat00046
Figure 112019061617410-pat00046

단계 1: N-사이클로헥실-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-cyclohexyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 사이클로헥산온인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-사이클로헥실-3,4-다이메톡시아닐린을 제조하였다.N-cyclohexyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is cyclohexanone.

수율 91%, 갈색 고체.Yield 91%, brown solid.

1H NMR (300 MHz, CDCl3) δ 6.71 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.20-3.11 (m, 1H), 2.05-2.02 (m, 2H), 1.77-1.72 (m, 2H), 1.64-1.61 (m, 1H), 1.40-1.11 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.71 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.20-3.11 (m, 1H), 2.05-2.02 (m, 2H), 1.77-1.72 (m, 2H), 1.64-1.61 (m, 1H), 1.40 -1.11 (m, 5H).

단계 2: 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-cyclohexyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-사이클로헥실-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-cyclohexyl-1-(3) by following the same method as in General Preparation Procedure 1, wherein the N-substituted 3.4-dimethoxyaniline is N-cyclohexyl-3,4-dimethoxyaniline obtained in step 1 above. ,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 69%, 흰색 고체, mp 62-64℃.Yield 69%, white solid, mp 62-64°C.

1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 6.98 (d, J = 8.43 Hz, 1H), 6.79 (s, 1H), 6.60 (dd, J = 8.40, 2.19 Hz, 1H, 6.51 (d, J = 2.19 Hz, 1H), 5.40-5.27 (m, 1H), 5.17 (t, J = 5.52 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.83 (t, J = 7.05 Hz, 2H), 3.59 (brm, 2H), 2.15 (s, 3H), 1.96-1.92 (m, 4H), 1.71 (d, J = 12.63 Hz, 2H), 1.56 (d, J = 13.71 Hz, 1H), 1.47-1.36 (m, 2H), 1.04-0.81 (m, 3H); HRMS (ESI) calc. for C22H33N4O2S [M + H]+ 417.2319, found 417.2327. 1 H NMR (300 MHz, CDCl 3 ) δ 7.56 (s, 1H), 6.98 (d, J = 8.43 Hz, 1H), 6.79 (s, 1H), 6.60 (dd, J = 8.40, 2.19 Hz, 1H, 6.51 (d, J = 2.19 Hz, 1H), 5.40-5.27 (m, 1H), 5.17 (t, J = 5.52 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.83 (t , J = 7.05 Hz, 2H), 3.59 (brm, 2H), 2.15 (s, 3H), 1.96-1.92 (m, 4H), 1.71 (d, J = 12.63 Hz, 2H), 1.56 (d, J = 13.71 Hz, 1H), 1.47-1.36 (m, 2H), 1.04-0.81 (m, 3H); HRMS (ESI) calc. for C 22 H 33 N 4 O 2 S [M + H] + 417.2319, found 417.2327.

<실시예 10> 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 10> Preparation of 1-benzyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

Figure 112019061617410-pat00047
Figure 112019061617410-pat00047

단계 1: N-벤질-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-benzyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-벤질-3,4-다이메톡시아닐린을 제조하였다.N-benzyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is benzaldehyde.

수율 92%, 약간 갈색의 고체.Yield 92%, slightly brownish solid.

1H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 5H), 6.72 (d, J = 8.40 Hz, 1H), 6.31 (s, 1H), 6.25 (d, J = 8.04 Hz, 1H), 4.27 (s, 2H), 3.78 (s, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.38-7.24 (m, 5H), 6.72 (d, J = 8.40 Hz, 1H), 6.31 (s, 1H), 6.25 (d, J = 8.04 Hz, 1H) , 4.27 (s, 2H), 3.78 (s, 6H).

단계 2: 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-benzyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-벤질-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-benzyl-1-(3,4) by following the same method as in General Preparation Procedure 1, wherein the N-substituted 3.4-dimethoxyaniline is N-benzyl-3,4-dimethoxyaniline obtained in step 1 above. -Dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 50%, 흰색 고체 mp 157-159℃.Yield 50%, white solid mp 157-159°C.

1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.28-7.22 (m, 5H), 6.79 (d, J = 8.61 Hz, 1H), 6.77 (s, 1H), 6.50 (dd, J = 8.40, 2.37 Hz, 1H), 6.29 (d, J = 2.37 Hz, 1H), 5.53 (t, J = 5.67 Hz, 1H), 5.43 (s, 2H), 3.89 (t, J = 7.14 Hz, 2H), 3.84 (s, 3H), 3.63-3.59 (m, 5H), 2.17 (s, 3H), 2.01 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C23H29N4O2S [M + H]+ 425.2006, found 425.2013. 1 H NMR (300 MHz, CDCl 3 ) δ 7.70 (s, 1H), 7.28-7.22 (m, 5H), 6.79 (d, J = 8.61 Hz, 1H), 6.77 (s, 1H), 6.50 (dd, J = 8.40, 2.37 Hz, 1H), 6.29 (d, J = 2.37 Hz, 1H), 5.53 (t, J = 5.67 Hz, 1H), 5.43 (s, 2H), 3.89 (t, J = 7.14 Hz, 2H), 3.84 (s, 3H), 3.63-3.59 (m, 5H), 2.17 (s, 3H), 2.01 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 23 H 29 N 4 O 2 S [M + H] + 425.2006, found 425.2013.

<실시예 11> 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 11> 1-(3,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thio Urea production

Figure 112019061617410-pat00048
Figure 112019061617410-pat00048

단계 1: N-(3-플루오로벤질)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(3-fluorobenzyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 3-플루오로벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(3-플루오로벤질)-3,4-다이메톡시아닐린을 제조하였다.N-(3-fluorobenzyl)-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 3-fluorobenzaldehyde.

수율 88%, 갈색 고체.Yield 88%, brown solid.

1H NMR (400 MHz, CDCl3) δ 7.28 (qd, J = 7.80, 6.04 Hz, 1H), 7.12 (d, J = 7.60 Hz, 1H), 7.07 (d, J = 9.68 Hz, 1H), 6.93 (td, J = 8.40, 2.28 Hz, 1H), 6.71 (d, J = 8.56 Hz, 1H), 6.24 (d, J = 2.60 Hz, 1H), 6.12 (dd, J = 8.52, 2.72 Hz, 1H), 4.28 (s, 2H), 3.84 (br, 1H), 3.79 (s, 3H), 3.78 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (qd, J = 7.80, 6.04 Hz, 1H), 7.12 (d, J = 7.60 Hz, 1H), 7.07 (d, J = 9.68 Hz, 1H), 6.93 (td, J = 8.40, 2.28 Hz, 1H), 6.71 (d, J = 8.56 Hz, 1H), 6.24 (d, J = 2.60 Hz, 1H), 6.12 (dd, J = 8.52, 2.72 Hz, 1H) , 4.28 (s, 2H), 3.84 (br, 1H), 3.79 (s, 3H), 3.78 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea Produce

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3-플루오로벤질)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-(3) by performing the same method as in General Preparation Procedure 1, wherein the N-substituted 3.4-dimethoxyaniline is N-(3-fluorobenzyl)-3,4-dimethoxyaniline obtained in step 1 above. ,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 62%, 흰색 고체, mp 95-96℃.Yield 62%, white solid, mp 95-96°C.

1H NMR (300 MHz, CDCl3) δ 7.31 (s, 1H), 7.20 (qd, J = 8.25, 6.24 Hz, 1H), 7.08-7.03 (m, 2H), 6.92 (td, J = 8.61, 2.37 Hz, 1H), 6.80 (d, J = 8.58 Hz, 1H), 6.71 (s, 1H), 6.50 (dd, J = 8.40, 2.37 Hz, 1H), 6.35 (d, J = 2.37 Hz, 1H), 5.47 (t, J = 5.67 Hz, 1H), 5.42 (s, 2H), 3.85 (s, 3H), 3.82 (t, J = 7.14 Hz, 2H), 3.68 (s, 3H), 3.61 (q, J = 6.78 Hz, 2H), 2.13 (d, J = 0.90 Hz, 3H), 1.97 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C23H28FN4O2S [M + H]+ 443.1912, found 443.1921 1 H NMR (300 MHz, CDCl 3 ) δ 7.31 (s, 1H), 7.20 (qd, J = 8.25, 6.24 Hz, 1H), 7.08-7.03 (m, 2H), 6.92 (td, J = 8.61, 2.37 Hz, 1H), 6.80 (d, J = 8.58 Hz, 1H), 6.71 (s, 1H), 6.50 (dd, J = 8.40, 2.37 Hz, 1H), 6.35 (d, J = 2.37 Hz, 1H), 5.47 (t, J = 5.67 Hz, 1H), 5.42 (s, 2H), 3.85 (s, 3H), 3.82 (t, J = 7.14 Hz, 2H), 3.68 (s, 3H), 3.61 (q, J = 6.78 Hz, 2H), 2.13 (d, J = 0.90 Hz, 3H), 1.97 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 23 H 28 FN 4 O 2 S [M + H] + 443.1912, found 443.1921

<실시예 12> 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 12> 1-(3-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea Manufacture of

Figure 112019061617410-pat00049
Figure 112019061617410-pat00049

단계 1: N-(3-클로로벤질)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(3-chlorobenzyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 3-클로로벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(3-클로로로벤질)-3,4-다이메톡시아닐린을 제조하였다.N-(3-chlorobenzyl)-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 3-chlorobenzaldehyde.

수율 54%, 엷은 갈색 고체.Yield 54%, light brown solid.

1H NMR (300 MHz, CDCl3) δ 7.35 (s, 1H), 7.25-7.19 (m, 3H), 6.72 (d, J = 8.58 Hz, 1H), 6.24 (d, J = 2.55 Hz, 1H), 6.13 (dd, J = 8.61, 2.76 Hz, 1H), 4.26 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.35 (s, 1H), 7.25-7.19 (m, 3H), 6.72 (d, J = 8.58 Hz, 1H), 6.24 (d, J = 2.55 Hz, 1H) , 6.13 (dd, J = 8.61, 2.76 Hz, 1H), 4.26 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H).

단계 2: 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-(3-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3-클로로벤질)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.The N-substituted 3.4-dimethoxyaniline is N-(3-chlorobenzyl)-3,4-dimethoxyaniline obtained in step 1, and 1-(3- Chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 43%, 흰색 고체, mp 90-91℃.Yield 43%, white solid, mp 90-91°C.

1H NMR (300 MHz, CDCl3) δ 7.42 (s, 1H), 7.29 (s, 1H), 7.21-7.18 (m, 3H), 6.82 (d, J = 8.43 Hz, 1H), 6.73 (s, 1H), 6.52 (dd, J = 8.43, 2.37 Hz, 1H), 6.35 (d, J = 2.19 Hz, 1H), 5.48 (t, J = 6.06 Hz, NH), 5.40 (s, 2H), 3.85 (s, 3H), 3.84 (t, J = 7.14 Hz, 2H), 3.69 (s, 3H), 3.62 (q, J = 6.57 Hz, 2H), 2.15 (s, 3H), 2.01 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C23H28ClN4O2S [M + H]+ 459.1616, found 459.1620. 1 H NMR (300 MHz, CDCl 3 ) δ 7.42 (s, 1H), 7.29 (s, 1H), 7.21-7.18 (m, 3H), 6.82 (d, J = 8.43 Hz, 1H), 6.73 (s, 1H), 6.52 (dd, J = 8.43, 2.37 Hz, 1H), 6.35 (d, J = 2.19 Hz, 1H), 5.48 (t, J = 6.06 Hz, NH), 5.40 (s, 2H), 3.85 ( s, 3H), 3.84 (t, J = 7.14 Hz, 2H), 3.69 (s, 3H), 3.62 (q, J = 6.57 Hz, 2H), 2.15 (s, 3H), 2.01 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 23 H 28 ClN 4 O 2 S [M + H] + 459.1616, found 459.1620.

<실시예 13> 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 13> 1-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thio Urea production

Figure 112019061617410-pat00050
Figure 112019061617410-pat00050

단계 1: N-(4-플루오로벤질)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(4-fluorobenzyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 4-플루오로벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(4-플루오로벤질)-3,4-다이메톡시아닐린을 제조하였다.N-(4-fluorobenzyl)-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 4-fluorobenzaldehyde.

수율 97%, 약간 갈색의 고체.Yield 97%, slightly brownish solid.

1H NMR (300 MHz, CDCl3) δ 7.32 (dd, J = 8.25, 5.52 Hz, 2H), 7.00 (t, J = 8.61 Hz, 2H), 6.71 (d, J = 8.61 Hz, 1H), 6.26 (d, J = 2.37 Hz, 1H), 6.15 (dd, J = 8.40, 2.55 Hz, 1H), 4.24 (s, 2H), 3.79 (s, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.32 (dd, J = 8.25, 5.52 Hz, 2H), 7.00 (t, J = 8.61 Hz, 2H), 6.71 (d, J = 8.61 Hz, 1H), 6.26 (d, J = 2.37 Hz, 1H), 6.15 (dd, J = 8.40, 2.55 Hz, 1H), 4.24 (s, 2H), 3.79 (s, 6H).

단계 2: 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea Produce

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(4-플루오로벤질)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.1-(3) by carrying out the same method as in General Preparation Procedure 1, wherein the N-substituted 3.4-dimethoxyaniline is N-(4-fluorobenzyl)-3,4-dimethoxyaniline obtained in step 1 above. ,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 55%, 흰색 고체, mp 54-56℃Yield 55%, white solid, mp 54-56℃

1H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.26 (dd, J = 8.43, 5.49 Hz, 2H), 6.92 (t, J = 8.61 Hz, 2H), 6.79 (d, J = 7.89 Hz, 1H), 6.75 (s, 1H), 6.46 (dd, J = 8.43, 2.40 Hz, 1H), 6.31 (d, J = 2.22 Hz, 1H), 5.50 (t-like, 1H), 5.39 (s, 2H), 3.86 (t, J = 7.14 Hz, 2H), 3,85 (s, 3H), 3.67 (s, 3H), 3.61 (q, J = 6.96 Hz, 2H), 2.16 (s, 3H), 1.97 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C23H28FN4O3S [M + H]+ 443.1912, found 443.1909. 1 H NMR (300 MHz, CDCl 3 ) δ 7.59 (s, 1H), 7.26 (dd, J = 8.43, 5.49 Hz, 2H), 6.92 (t, J = 8.61 Hz, 2H), 6.79 (d, J = 7.89 Hz, 1H), 6.75 (s, 1H), 6.46 (dd, J = 8.43, 2.40 Hz, 1H), 6.31 (d, J = 2.22 Hz, 1H), 5.50 (t-like, 1H), 5.39 ( s, 2H), 3.86 (t, J = 7.14 Hz, 2H), 3,85 (s, 3H), 3.67 (s, 3H), 3.61 (q, J = 6.96 Hz, 2H), 2.16 (s, 3H ), 1.97 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 23 H 28 FN 4 O 3 S [M + H] + 443.1912, found 443.1909.

<실시예 14> 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조<Example 14> 1-(4-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea Manufacture of

Figure 112019061617410-pat00051
Figure 112019061617410-pat00051

단계 1: N-(4-클로로벤질)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(4-chlorobenzyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 4-클로로벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(4-클로로벤질)-3,4-다이메톡시아닐린을 제조하였다.N-(4-chlorobenzyl)-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 4-chlorobenzaldehyde.

수율 81%, 갈색 고체.Yield 81%, brown solid.

1H NMR (300MHz, CDCl3) δ7.24 (d, J = 8.44 Hz, 2H), 7.15 (d, J = 8.36 Hz, 2H),6.72 (d, J = 8.58 Hz, 1H), 6.24 (d, J = 2.55 Hz, 1H), 6.13 (dd, J = 8.61, 2.67 Hz, 1H), 4.24 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H). 1 H NMR (300MHz, CDCl 3 ) δ 7.24 (d, J = 8.44 Hz, 2H), 7.15 (d, J = 8.36 Hz, 2H),6.72 (d, J = 8.58 Hz, 1H), 6.24 (d, J = 2.55 Hz, 1H), 6.13 (dd, J = 8.61, 2.67 Hz, 1H), 4.24 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H).

단계 2: 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아의 제조Step 2: Preparation of 1-(4-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(4-클로로벤질)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아를 제조하였다.The N-substituted 3.4-dimethoxyaniline is N-(4-chlorobenzyl)-3,4-dimethoxyaniline obtained in step 1, and 1-(4- Chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea was prepared.

수율 34%, 흰색 고체, mp 71-72℃.Yield 34%, white solid, mp 71-72°C.

1H NMR (300 MHz, CDCl3) δ 7.34 (s, 1H), 7.26-7.21 (m, 4H), 6.82 (d, J = 8.43 Hz, 1H), 6.73 (s, 1H), 6.50 (dd, J = 8.43, 2.37 Hz, 1H), 6.36 (d, J = 2.37 Hz, 1H), 5.51 (t, J = 5.70 Hz, NH), 5.41 (s, 2H), 3.99 (s, 3H), 3.99 (t, J = 8.25 Hz, 2H), 3.87 (s, 3H), 3.65 (q, J = 7.32 Hz, 2H), 2.17 (s, 3H), 2.08 (quintet, J = 6.60 Hz, 2H); HRMS (ESI) calc. for C23H28ClN4O2S [M + H]+ 459.1616, found 459.1615. 1 H NMR (300 MHz, CDCl 3 ) δ 7.34 (s, 1H), 7.26-7.21 (m, 4H), 6.82 (d, J = 8.43 Hz, 1H), 6.73 (s, 1H), 6.50 (dd, J = 8.43, 2.37 Hz, 1H), 6.36 (d, J = 2.37 Hz, 1H), 5.51 (t, J = 5.70 Hz, NH), 5.41 (s, 2H), 3.99 (s, 3H), 3.99 ( t, J = 8.25 Hz, 2H), 3.87 (s, 3H), 3.65 (q, J = 7.32 Hz, 2H), 2.17 (s, 3H), 2.08 (quintet, J = 6.60 Hz, 2H); HRMS (ESI) calc. for C 23 H 28 ClN 4 O 2 S [M + H] + 459.1616, found 459.1615.

<실시예 15> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일메틸)티오우레아의 제조<Example 15> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-ylmethyl) Preparation of thiourea

Figure 112019061617410-pat00052
Figure 112019061617410-pat00052

단계 1: 3,4-다이메톡시-N-(피리딘-3-일메틸)아닐린의 제조Step 1: Preparation of 3,4-dimethoxy-N-(pyridin-3-ylmethyl)aniline

케톤 혹은 알데하이드가 3-니코틴알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 3,4-다이메톡시-N-(피리딘-3-일메틸)아닐린을 제조하였다.3,4-dimethoxy-N-(pyridin-3-ylmethyl)aniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 3-nicotinaldehyde.

수율 74%, 약간 갈색의 고체.Yield 74%, slightly brownish solid.

1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 1.16 Hz, 1H), 8.52 (d, J = 6.00 Hz, 1H), 7.69 (d, J = 7.64 Hz, 1H), 7.25 (dd, J = 7.64, 2.80 Hz, 1H), 6.71 (d, J = 8.52 Hz, 1H), 6.25 (d, J = 2.44 Hz, 1H), 6.13 (dd, J = 8.40, 2.16 Hz, 1H), 4.30 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J = 1.16 Hz, 1H), 8.52 (d, J = 6.00 Hz, 1H), 7.69 (d, J = 7.64 Hz, 1H), 7.25 (dd , J = 7.64, 2.80 Hz, 1H), 6.71 (d, J = 8.52 Hz, 1H), 6.25 (d, J = 2.44 Hz, 1H), 6.13 (dd, J = 8.40, 2.16 Hz, 1H), 4.30 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일메틸)티오우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-ylmethyl)thiourea Manufacture of

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 3,4-다이메톡시-N-(피리딘-3-일메틸)아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일메틸)티오우레아를 제조하였다.The N-substituted 3.4-dimethoxyaniline is 3,4-dimethoxy-N-(pyridin-3-ylmethyl)aniline obtained in step 1, and 1-( 3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-ylmethyl)thiourea was prepared.

수율 78%, 흰색 고체, mp 58-60℃.Yield 78%, white solid, mp 58-60°C.

1H NMR (300 MHz, CD3OD) δ 8.41 (d, J = 2.19 Hz, 1H), 8.40 (dd, J = 4.95, 1.47 Hz, 1H), 7.88 (dt, J = 8.04, 2.19 Hz, 1H), 7.55 (d, J = 0.90 Hz, 1H), 7.36 (dd, J = 7.86, 4.38 Hz, 1H), 6.93 (d, J = 8.40 Hz, 1H), 6.66 (s, 1H), 6.59 (d, J = 2.37 Hz, 1H), 6.52 (dd, J = 8.43, 2.73 Hz, 1H), 5.52 (s, 2H), 3.90 (t, J = 7.14 Hz, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 3.59 (t, J = 6.78 Hz, 2H), 2.19 (d, J = 0.93 Hz, 3H), 1.99 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C22H28N5O2S [M + H]+ 426.1958, found 426.1969. 1 H NMR (300 MHz, CD 3 OD) δ 8.41 (d, J = 2.19 Hz, 1H), 8.40 (dd, J = 4.95, 1.47 Hz, 1H), 7.88 (dt, J = 8.04, 2.19 Hz, 1H ), 7.55 (d, J = 0.90 Hz, 1H), 7.36 (dd, J = 7.86, 4.38 Hz, 1H), 6.93 (d, J = 8.40 Hz, 1H), 6.66 (s, 1H), 6.59 (d , J = 2.37 Hz, 1H), 6.52 (dd, J = 8.43, 2.73 Hz, 1H), 5.52 (s, 2H), 3.90 (t, J = 7.14 Hz, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 3.59 (t, J = 6.78 Hz, 2H), 2.19 (d, J = 0.93 Hz, 3H), 1.99 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C 22 H 28 N 5 O 2 S [M + H] + 426.1958, found 426.1969.

<실시예 16> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)티오우레아의 제조<Example 16> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl ) Preparation of thiourea

Figure 112019061617410-pat00053
Figure 112019061617410-pat00053

단계 1: 3,4-다이메톡시-N-(피리딘-4-일메틸)아닐린의 제조Step 1: Preparation of 3,4-dimethoxy-N-(pyridin-4-ylmethyl)aniline

케톤 혹은 알데하이드가 4-피리딜메틸카복스알데하이드인 상기 일반적인 제조철차 5와 동일한 방법을 수행하여 3,4-다이메톡시-N-(피리딘-4-일메틸)아닐린을 제조하였다.3,4-dimethoxy-N-(pyridin-4-ylmethyl)aniline was prepared by performing the same method as in General Train 5, wherein the ketone or aldehyde is 4-pyridylmethylcarboxaldehyde.

수율 62%, 엷은 갈색 고체.Yield 62%, pale brown solid.

1H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 6.60, 1.62 Hz, 2H), 7.30 (dd, J = 5.82, 1.44 Hz, 2H), 6.70 (d, J = 8.58 Hz, 1H), 6.22 (d, J = 2.55 Hz, 1H), 6.06 (dd, J = 8.61, 2.76 Hz, 1H), 4.32 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.55 (d, J = 6.60, 1.62 Hz, 2H), 7.30 (dd, J = 5.82, 1.44 Hz, 2H), 6.70 (d, J = 8.58 Hz, 1H) , 6.22 (d, J = 2.55 Hz, 1H), 6.06 (dd, J = 8.61, 2.76 Hz, 1H), 4.32 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)티오우레아Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl)thio Urea

N-치환된 3.4-다이메톡시아닐린이 상기 단계 1에서 얻은 3,4-다이메톡시-N-(피리딘-4-일메틸)아닐린인 상기 일반적인 제조절차 1과 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)티오우레아를 제조하였다.N-substituted 3.4-dimethoxyaniline is 3,4-dimethoxy-N-(pyridin-4-ylmethyl)aniline obtained in step 1, and 1-( 3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl)thiourea was prepared.

수율 59%, 흰색 고체, 61-62℃.Yield 59%, white solid, 61-62°C.

1H NMR (300 MHz, CDCl3) δ 8.51 (d, J = 6.06, 1.65 Hz, 2H), 7.83 (s, 1H), 7.25 (t, J = 4.38, 1.44 Hz, 2H), 6.82 (d, J = 8.40 Hz, 1H), 6.79 (s, 1H), 6.56 (dd, J = 8.43, 2.40 Hz, 1H), 6.43 (d, J = 2.37 Hz, 1H), 5.68 (t, J = 5.31 Hz, NH), 5.42 (s, 2H), 3.94 (t, J = 6.96 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.66 (q, J = 6.78 Hz, 2H), 2.18 (d, J = 0.90 Hz, 3H), 2.08 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C22H27N5O2S [M + H]+ 426.1958, found 426.1930. 1 H NMR (300 MHz, CDCl 3 ) δ 8.51 (d, J = 6.06, 1.65 Hz, 2H), 7.83 (s, 1H), 7.25 (t, J = 4.38, 1.44 Hz, 2H), 6.82 (d, J = 8.40 Hz, 1H), 6.79 (s, 1H), 6.56 (dd, J = 8.43, 2.40 Hz, 1H), 6.43 (d, J = 2.37 Hz, 1H), 5.68 (t, J = 5.31 Hz, NH), 5.42 (s, 2H), 3.94 (t, J = 6.96 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.66 (q, J = 6.78 Hz, 2H), 2.18 ( d, J = 0.90 Hz, 3H), 2.08 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 22 H 27 N 5 O 2 S [M + H] + 426.1958, found 426.1930.

<실시예 17> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 17> Preparation of 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00054
Figure 112019061617410-pat00054

N-치환된 3.4-다이메톡시아닐린이 3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.1-(3,4-dimethoxyphenyl)-3-(3-( 5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 56%, 흰색 고체, mp 100-101℃.Yield 56%, white solid, mp 100-101°C.

1H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.42 (s, 1H), 7.17 (d, J = 2.40 Hz, 1H), 6.77-6.74 (m, 2H), 6.67 (dd, J = 8.61, 2.37 Hz, 1H), 5.76 (t, J = 4.95 Hz, NH), 3.94 (t, J = 6.75 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.23 (q, J = 6.21 Hz, 2H), 2.19 (s, 3H), 1.98 (quintet, J = 6.60 Hz, 2H); HRMS (ESI) calc. for C16H23N4O3 [M + H]+ 319.1765, found 319.1780. 1 H NMR (300 MHz, CDCl 3 ) δ 7.59 (s, 1H), 7.42 (s, 1H), 7.17 (d, J = 2.40 Hz, 1H), 6.77-6.74 (m, 2H), 6.67 (dd, J = 8.61, 2.37 Hz, 1H), 5.76 (t, J = 4.95 Hz, NH), 3.94 (t, J = 6.75 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.23 (q, J = 6.21 Hz, 2H), 2.19 (s, 3H), 1.98 (quintet, J = 6.60 Hz, 2H); HRMS (ESI) calc. for C 16 H 23 N 4 O 3 [M + H] + 319.1765, found 319.1780.

<실시예 18> 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 18> Preparation of 1-(3,4-dimethoxyphenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00055
Figure 112019061617410-pat00055

단계 1: 3,4-다이메톡시-N-메틸아닐린의 제조Step 1: Preparation of 3,4-dimethoxy-N-methylaniline

설폰아마이드 혼합물이 N-(3,4-다이메톡시페닐)-N-메틸-2-나이트로벤젠설폰아마이드인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 3,4-다이메톡시-N-메틸아닐린을 제조하였다.The sulfonamide mixture is N-(3,4-dimethoxyphenyl)-N-methyl-2-nitrobenzenesulfonamide, and 3,4-dimethoxy-N- Methylaniline was prepared.

수율 85%, 엷은 노란색 고체.Yield 85%, pale yellow solid.

1H NMR (400 MHz, CDCl3) δ 7.01-6.98 (m, 2H), 6.87 (d, J = 9.00 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.01 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.01-6.98 (m, 2H), 6.87 (d, J = 9.00 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.01 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 3,4-다이메톡시-N-메틸아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아을 제조하였다.1-(3,4-di by carrying out the same method as in General Preparation Procedure 2, wherein the N-substituted 3,4-dimethoxyaniline is 3,4-dimethoxy-N-methylaniline obtained in step 1 above. Methoxyphenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 32%, 흰색 고체, mp 103-104℃.Yield 32%, white solid, mp 103-104°C.

1H NMR (300 MHz, CDCl3) δ 7.31 (s, 1H), 6.86 (d, J = 8.43 Hz, 1H), 6.77 (dd, J = 8.40, 2.37 Hz, 1H), 6.70-6.69 (m, 2H), 6.65 (d, J = 2.16 Hz, 1H), 4.34 (t, J = 5.85 Hz, NH), 3.87 (s, 3H), 3.85 (s, 3H), 3.82 (t, J = 7.32 Hz, 2H), 3.20 (s, 3H), 3.19 (q, J = 6.60 Hz, 2H), 2.12 (d, J = 0.75 Hz, 3H), 1.86 (quintet, J = 7.12 Hz, 2H); HRMS (ESI) calc. for C17H25N4O3 [M + H]+ 333.1921, found 333.1929. 1 H NMR (300 MHz, CDCl 3 ) δ 7.31 (s, 1H), 6.86 (d, J = 8.43 Hz, 1H), 6.77 (dd, J = 8.40, 2.37 Hz, 1H), 6.70-6.69 (m, 2H), 6.65 (d, J = 2.16 Hz, 1H), 4.34 (t, J = 5.85 Hz, NH), 3.87 (s, 3H), 3.85 (s, 3H), 3.82 (t, J = 7.32 Hz, 2H), 3.20 (s, 3H), 3.19 (q, J = 6.60 Hz, 2H), 2.12 (d, J = 0.75 Hz, 3H), 1.86 (quintet, J = 7.12 Hz, 2H); HRMS (ESI) calc. for C 17 H 25 N 4 O 3 [M + H] + 333.1921, found 333.1929.

<실시예 19> 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 19> Preparation of 1-(3,4-dimethoxyphenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00056
Figure 112019061617410-pat00056

단계 1: N-에틸-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-ethyl-3,4-dimethoxyaniline

설폰아마이드 혼합물이 N-(3,4-다이메톡시페닐)-N-에틸-2-나이트로벤젠설폰아마이드인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 N-에틸-3,4-다이메톡시아닐린을 제조하였다.N-ethyl-3,4-dime by following the same method as in General Preparation 6, wherein the sulfonamide mixture is N-(3,4-dimethoxyphenyl)-N-ethyl-2-nitrobenzenesulfonamide. Toxianiline was prepared.

수율 51%, 흰색 고체.Yield 51%, white solid.

1H NMR (400 MHz, CDCl3) δ 7.00-6.99 (m, 1H), 6.96 (d, J = 2.55 Hz, 1H), 6.82 (d, J = 8.40 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.35 (q, J = 7.14 Hz, 2H), 1.33 (t, J = 7.35 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.00-6.99 (m, 1H), 6.96 (d, J = 2.55 Hz, 1H), 6.82 (d, J = 8.40 Hz, 1H), 3.87 (s, 3H) , 3.85 (s, 3H), 3.35 (q, J = 7.14 Hz, 2H), 1.33 (t, J = 7.35 Hz, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-에틸-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아을 제조하였다.1-(3,4-di by carrying out the same method as in General Preparation Procedure 2, wherein the N-substituted 3,4-dimethoxyaniline is N-ethyl-3,4-dimethoxyaniline obtained in step 1 above. Methoxyphenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 35%, 흰색 고체, mp 110-111℃.Yield 35%, white solid, mp 110-111°C.

1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 6.83 (d, J = 8.25 Hz, 1H), 6.70-6.66 (m, 2H), 6.62 (d, J = 2.22 Hz, 1H), 4.18 (t, J = 5.88 Hz, NH), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 (t, J = 7.14 Hz, 2H), 3.65 (q, J = 7.14 Hz, 2H), 3.14 (q, J = 6.60 Hz, 2H), 2.08 (d, J = 0.90 Hz, 3H), 1.83 (quintet, J = 7.14 Hz, 2H), 1.05 (t, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C18H26N4O3 [M + H]+ 347.2078, found 347.2079. 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (s, 1H), 6.83 (d, J = 8.25 Hz, 1H), 6.70-6.66 (m, 2H), 6.62 (d, J = 2.22 Hz, 1H) , 4.18 (t, J = 5.88 Hz, NH), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 (t, J = 7.14 Hz, 2H), 3.65 (q, J = 7.14 Hz, 2H) , 3.14 (q, J = 6.60 Hz, 2H), 2.08 (d, J = 0.90 Hz, 3H), 1.83 (quintet, J = 7.14 Hz, 2H), 1.05 (t, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 18 H 26 N 4 O 3 [M + H] + 347.2078, found 347.2079.

<실시예 20> 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 20> Preparation of 1-(3,4-dimethoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00057
Figure 112019061617410-pat00057

단계 1: N-아이소프로필-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-isopropyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 아세톤인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-아이소프로필-3,4-다이메톡시아닐린을 제조하였다.N-isopropyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is acetone.

수율 65%, 갈색 고체.Yield 65%, brown solid.

1H NMR (300 MHz, CDCl3) δ 6.73 (d, J = 8.61 Hz, 1H), 6.24 (d, J = 2.58 Hz, 1H), 6.17 (dd, J = 8.61, 2.76, Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.59 (quintet, J = 6.78 Hz, 1H), 1.19 (s, 3H), 1.17 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.73 (d, J = 8.61 Hz, 1H), 6.24 (d, J = 2.58 Hz, 1H), 6.17 (dd, J = 8.61, 2.76, Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.59 (quintet, J = 6.78 Hz, 1H), 1.19 (s, 3H), 1.17 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-아이소프로필-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.1-(3,4- Dimethoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 73%, 흰색 고체, mp 60-61℃.Yield 73%, white solid, mp 60-61°C.

1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 6.83 (d, J = 8.43 Hz, 1H), 6.68 (s, 1H), 6.65 (dd, J = 8.43, 2.40 Hz, 1H), 6.55 (d, J = 2.19 Hz, 1H), 4.81 (quintet, J = 6.78 Hz. 1H), 4.04 (t, J = 5.85 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.76 (t, J = 7.14 Hz, 2H), 3.12 (q, J = 6.39 Hz, 2H), 2.08 (d, J = 0.90 Hz, 3H), 1.87 (quintet, J = 7.14 Hz, 2H), 0.99 (s, 3H), 0.97 (s, 3H); HRMS (ESI) calc. for C19H29N4O3 [M + H]+ 361.2234, found 361.2237. 1 H NMR (300 MHz, CDCl 3 ) δ 7.40 (s, 1H), 6.83 (d, J = 8.43 Hz, 1H), 6.68 (s, 1H), 6.65 (dd, J = 8.43, 2.40 Hz, 1H) , 6.55 (d, J = 2.19 Hz, 1H), 4.81 (quintet, J = 6.78 Hz. 1H), 4.04 (t, J = 5.85 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H) , 3.76 (t, J = 7.14 Hz, 2H), 3.12 (q, J = 6.39 Hz, 2H), 2.08 (d, J = 0.90 Hz, 3H), 1.87 (quintet, J = 7.14 Hz, 2H), 0 .99 (s, 3H), 0.97 (s, 3H); HRMS (ESI) calc. for C 19 H 29 N 4 O 3 [M + H] + 361.2234, found 361.2237.

<실시예 21> 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 21> Preparation of 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00058
Figure 112019061617410-pat00058

단계 1: N-아이소뷰틸-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-isobutyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 뷰탄-2-온인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-아이소뷰틸-3,4-다이메톡시아닐린을 제조하였다.N-isobutyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is butan-2-one.

수율 84%, 엷은 노란색 고체.Yield 84%, pale yellow solid.

1H NMR (300 MHz, CDCl3) δ 6.73 (d, J = 8.61 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.16 (dd, J = 8.58, 2.55 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.88 (d, J = 6.75 Hz, 2H), 1.90-1.81 (m, 1H), 0.98 (d, J = 6.57 Hz, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.73 (d, J = 8.61 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.16 (dd, J = 8.58, 2.55 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.88 (d, J = 6.75 Hz, 2H), 1.90-1.81 (m, 1H), 0.98 (d, J = 6.57 Hz, 6H).

단계 2: 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-아이소뷰틸-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.1-(3,4- Dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 64%, 흰색 고체, mp 55-56℃.Yield 64%, white solid, mp 55-56°C.

1H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H), 6.86 (d, J = 8.43 Hz, 1H), 6.76 (dd, J = 8.25, 2.37 Hz, 1H), 6.73 (s, 1H), 6.67 (d, J = 2.19 Hz, 1H), 4.29 (t, J = 6.03 Hz, 1H), 3.88 (s. 3H), 3.84 (s, 3H), 3.82 (t, J = 7.32 Hz, 2H), 3.46 (d, J = 7.50 Hz, 2H), 3.18 (q, J = 6.60 Hz, 2H), 2.13 (d, J = 0.90 Hz, 3H), 1.88 (quintet, J = 6.96 Hz, 2H), 1.74-1.62 (m, 1H), 0.89 (d, J = 6.78 Hz, 6H); HRMS (ESI) calc. for C20H31N4O3 [M + H]+ 375.2391, found 375.2426. 1 H NMR (300 MHz, CDCl 3 ) δ 7.45 (s, 1H), 6.86 (d, J = 8.43 Hz, 1H), 6.76 (dd, J = 8.25, 2.37 Hz, 1H), 6.73 (s, 1H) , 6.67 (d, J = 2.19 Hz, 1H), 4.29 (t, J = 6.03 Hz, 1H), 3.88 (s. 3H), 3.84 (s, 3H), 3.82 (t, J = 7.32 Hz, 2H) , 3.46 (d, J = 7.50 Hz, 2H), 3.18 (q, J = 6.60 Hz, 2H), 2.13 (d, J = 0.90 Hz, 3H), 1.88 (quintet, J = 6.96 Hz, 2H), 1.74 -1.62 (m, 1H), 0.89 (d, J = 6.78 Hz, 6H); HRMS (ESI) calc. for C 20 H 31 N 4 O 3 [M + H] + 375.2391, found 375.2426.

<실시예 22> 1-(사이클로펜틸메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)-프로필)우레아의 제조<Example 22> 1-(cyclopentylmethyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)-propyl)urea Produce

Figure 112019061617410-pat00059
Figure 112019061617410-pat00059

단계 1: N-(사이클로펜틸메틸)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(cyclopentylmethyl)-3,4-dimethoxyaniline

설폰아마이드 혼합물이 N-(사이클로펜틸메틸)-N-(3,4-다이메톡시페닐)-2-나이트로벤젠설폰아마이드인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 N-(사이클로펜틸메틸)-3,4-다이메톡시아닐린을 제조하였다.N-(cyclopentylmethyl)-N-(3,4-dimethoxyphenyl)-2-nitrobenzenesulfonamide is N-(cyclopentylmethyl)-N-(cyclopentylmethyl) )-3,4-dimethoxyaniline was prepared.

수율 68%, 엷은 노란색 고체.Yield 68%, pale yellow solid.

1H NMR (500 MHz, CDCl3) δ 6.73 (d, J = 8.50 Hz, 1H), 6.24 (d, J = 2.40 Hz, 1H), 6.15 (dd, J = 8.55, 2.50 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.97 (d, J = 7.15 Hz, 2H), 2.15-2.09 (m, 1H), 1.84-1.77 (m, 2H), 1.64-1.58 (m, 2H), 1.55-1.52 (m, 2H), 1.28-1.22 (m, 2H). 1 H NMR (500 MHz, CDCl 3 ) δ 6.73 (d, J = 8.50 Hz, 1H), 6.24 (d, J = 2.40 Hz, 1H), 6.15 (dd, J = 8.55, 2.50 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.97 (d, J = 7.15 Hz, 2H), 2.15-2.09 (m, 1H), 1.84-1.77 (m, 2H), 1.64-1.58 (m, 2H) ), 1.55-1.52 (m, 2H), 1.28-1.22 (m, 2H).

단계 2: 1-(사이클로펜틸메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)-프로필)우레아의 제조Step 2: Preparation of 1-(cyclopentylmethyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)-propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(사이클로펜틸메틸)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(사이클로펜틸메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)-프로필)우레아를 제조하였다.1-(cyclopentylmethyl)-3,4-dimethoxyaniline obtained in step 1 is carried out in the same manner as in the general preparation procedure 2 above to obtain 1-(cyclopentylmethyl)-3,4-dimethoxyaniline. Pentylmethyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)-propyl)urea was prepared.

수율 33%, 흰색 고체, mp 55-56℃.Yield 33%, white solid, mp 55-56°C.

1H NMR (300 MHz, CDCl3) δ 7.42 (s, 1H), 6.83 (d, J = 8.43 Hz, 1H), 6.71 (m, 2H), 6.63 (d, J = 2.37 Hz, 1H), 4.23 (t, J = 5.85 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 (t, J = 7.32 Hz, 2H), 3.54 (d, J = 7.68 Hz, 2H), 3.14 (q, J = 6.60 Hz, 2H), 2.09 (s, 3H), 1.97 (quintet, J = 6.96 Hz, 1H), 1.83 (quintet, J = 6.78 Hz, 2H), 1.57-1.42 (m, 4H), 1.21-1.18 (m, 2H), 0.80-0.76 (m, 2H); HRMS (ESI) calc. for C22H33N4O3 [M + H]+ 401.2547, found 401.2560. 1 H NMR (300 MHz, CDCl 3 ) δ 7.42 (s, 1H), 6.83 (d, J = 8.43 Hz, 1H), 6.71 (m, 2H), 6.63 (d, J = 2.37 Hz, 1H), 4.23 (t, J = 5.85 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 (t, J = 7.32 Hz, 2H), 3.54 (d, J = 7.68 Hz, 2H), 3.14 (q, J = 6.60 Hz, 2H), 2.09 (s, 3H), 1.97 (quintet, J = 6.96 Hz, 1H), 1.83 (quintet, J = 6.78 Hz, 2H), 1.57-1.42 (m, 4H) , 1.21-1.18 (m, 2H), 0.80-0.76 (m, 2H); HRMS (ESI) calc. for C 22 H 33 N 4 O 3 [M + H] + 401.2547, found 401.2560.

<실시예 23> 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 23> Preparation of 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00060
Figure 112019061617410-pat00060

단계 1: N-사이클로프로필-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-cyclopropyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드 대신 1-에톡시-1-(트리메틸실릴옥시)사이클로프로페인을 사용한 것을 제외하고 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-사이클로프로필-3,4-다이메톡시아닐린을 제조하였다.N-cyclopropyl-3,4-dimethoxyaniline was prepared by following the same method as in General Preparation Procedure 5, except that 1-ethoxy-1-(trimethylsilyloxy)cyclopropane was used instead of ketone or aldehyde. I did.

수율 40%, 갈색 고체.Yield 40%, brown solid.

1H NMR (300MHz, CDCl3) δ 6.77 (d, J = 8.34 Hz, 1H), 6.39 (d, J = 2.73 Hz, 1H), 6.36 (dd, J = 8.22, 2.55 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 2.43-2.36 (m, 1H), 0.73-0.67 (m, 2H), 0.52-0.47 (m, 2H). 1 H NMR (300MHz, CDCl 3 ) δ 6.77 (d, J = 8.34 Hz, 1H), 6.39 (d, J = 2.73 Hz, 1H), 6.36 (dd, J = 8.22, 2.55 Hz, 1H), 3.73 ( s, 3H), 3.71 (s, 3H), 2.43-2.36 (m, 1H), 0.73-0.67 (m, 2H), 0.52-0.47 (m, 2H).

단계 2: 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-사이클로프로필-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.1-cyclopropyl-1- (3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 28%, 흰색 고체, mp 84-85℃Yield 28%, white solid, mp 84-85℃

1H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 7.62-7.60 (m, 2H), 6.67 (s, 1H), 6.66 (d, J = 6.70 Hz, 1H), 5.00 (s, 1H), 3.95 (t, J = 6.95 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.25 (q, J = 6.25 Hz, 2H), 2.96-2.93 (m, 1H), 2.19 (s, 3H), 1.97-1.94 (m, 2H), 0.82-0.78 (m, 2H). 0.55-0.52 (m, 2H); HRMS (ESI) calc. for C19H37N4O3 [M + H]+ 359.2078, found 359.2082. 1 H NMR (500 MHz, CDCl 3 ) δ 7.93 (s, 1H), 7.62-7.60 (m, 2H), 6.67 (s, 1H), 6.66 (d, J = 6.70 Hz, 1H), 5.00 (s, 1H), 3.95 (t, J = 6.95 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.25 (q, J = 6.25 Hz, 2H), 2.96-2.93 (m, 1H), 2.19 (s, 3H), 1.97-1.94 (m, 2H), 0.82-0.78 (m, 2H). 0.55-0.52 (m, 2H); HRMS (ESI) calc. for C 19 H 37 N 4 O 3 [M + H] + 359.2078, found 359.2082.

<실시예 24> 1-사이클로뷰틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 24> Preparation of 1-cyclobutyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00061
Figure 112019061617410-pat00061

단계 1: N-사이클로뷰틸-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-cyclobutyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 사이클로뷰탄온인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-사이클로뷰틸-3,4-다이메톡시아닐린을 제조하였다.N-cyclobutyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is cyclobutanone.

수율 85%, 갈색 고체.Yield 85%, brown solid.

1H NMR (300 MHz, CDCl3) δ 6.71 (d, J = 8.61 Hz, 1H), 6.20 (d, J = 2.37 Hz, 1H), 6.09 (dd, J = 8.43, 2.58 Hz, 1H), 3.87-3.78 (m, 8H), 2.39-1.37 (m, 2H), 1.85-1.75 (m, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.71 (d, J = 8.61 Hz, 1H), 6.20 (d, J = 2.37 Hz, 1H), 6.09 (dd, J = 8.43, 2.58 Hz, 1H), 3.87 -3.78 (m, 8H), 2.39-1.37 (m, 2H), 1.85-1.75 (m, 4H).

단계 2: 1-사이클로뷰틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-cyclobutyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-사이클로뷰틸-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-사이클로뷰틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.1-cyclobutyl-1- (3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 50%, 흰색 고체, mp 77-78.Yield 50%, white solid, mp 77-78.

1H NMR (500 MHz, CDCl3) δ 7.51 (s, 1H), 6.89 (d, J = 8.40 Hz, 1H), 6.74 (s, 1H), 6.67 (dd, J = 8.35, 2.15 Hz, 1H), 6.58 (d, J = 2.10 Hz, 1H), 4.94 (quintet, J = 7.90 Hz, 1H), 4.11 (t, J = 5.60 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.82 (t, J = 7.15 Hz, 2H), 3.13 (q, J = 6.35 Hz, 2H), 2.13 (s, 3H), 2.11-2.07 (m, 2H), 1.83 (quintet, J = 6.70 Hz, 2H), 1.77-1.69 (m, 2H), 1.58-1.49 (m, 1H), 1.45-1.39 (m, 1H); HRMS (ESI) calc. for C20H29N4O3 [M + H]+ 373.2234, found 373.2236. 1 H NMR (500 MHz, CDCl 3 ) δ 7.51 (s, 1H), 6.89 (d, J = 8.40 Hz, 1H), 6.74 (s, 1H), 6.67 (dd, J = 8.35, 2.15 Hz, 1H) , 6.58 (d, J = 2.10 Hz, 1H), 4.94 (quintet, J = 7.90 Hz, 1H), 4.11 (t, J = 5.60 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H) , 3.82 (t, J = 7.15 Hz, 2H), 3.13 (q, J = 6.35 Hz, 2H), 2.13 (s, 3H), 2.11-2.07 (m, 2H), 1.83 (quintet, J = 6.70 Hz, 2H), 1.77-1.69 (m, 2H), 1.58-1.49 (m, 1H), 1.45-1.39 (m, 1H); HRMS (ESI) calc. for C 20 H 29 N 4 O 3 [M + H] + 373.2234, found 373.2236.

<실시예 25> 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 25> Preparation of 1-cyclopentyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00062
Figure 112019061617410-pat00062

단계 1: N-사이클로펜틸-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-cyclopentyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 사이클로펜탄온인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-사이클로펜틸-3,4-다이메톡시아닐린을 제조하였다.N-cyclopentyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is cyclopentanone.

수율 80%, 갈색 고체.Yield 80%, brown solid.

1H NMR (300 MHz, CDCl3) δ 6.71 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.71 (quintet, J = 5.67 Hz, 1H), 2.03-1.93 (m, 2H), 1.76-1.41 (m, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.71 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.71 (quintet, J = 5.67 Hz, 1H), 2.03-1.93 (m, 2H), 1.76-1.41 (m, 6H).

단계 2: 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-cyclopentyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-사이클로펜틸-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.1-cyclopentyl-1- (3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 79%, 흰색 고체, mp 50-51℃Yield 79%, white solid, mp 50-51℃

1H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H), 6.86 (d, J = 8.40 Hz, 1H), 6.77 (s, 1H), 6.68 (dd, J = 8.30, 1.90 Hz, 1H), 6.60 (d, J = 1.85 Hz, 1H), 4.79-4.73 (m, 1H), 4.08 (t, J = 5.50 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.85 (t, J = 8.50 Hz, 2H), 3.14 (q, J = 6.35 Hz, 2H), 2.15 (s, 3H), 1.85-1.81 (m, 4H), 1.50-1.48 (m, 4H), 1.29-1.23 (m, 2H); HRMS (ESI) calc. for C21H31N4O3 [M + H]+ 387.2391, found 387.2387. 1 H NMR (500 MHz, CDCl 3 ) δ 7.61 (s, 1H), 6.86 (d, J = 8.40 Hz, 1H), 6.77 (s, 1H), 6.68 (dd, J = 8.30, 1.90 Hz, 1H) , 6.60 (d, J = 1.85 Hz, 1H), 4.79-4.73 (m, 1H), 4.08 (t, J = 5.50 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.85 ( t, J = 8.50 Hz, 2H), 3.14 (q, J = 6.35 Hz, 2H), 2.15 (s, 3H), 1.85-1.81 (m, 4H), 1.50-1.48 (m, 4H), 1.29-1.23 (m, 2H); HRMS (ESI) calc. for C 21 H 31 N 4 O 3 [M + H] + 387.2391, found 387.2387.

<실시예 26> 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 26> Preparation of 1-cyclohexyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00063
Figure 112019061617410-pat00063

단계 1: N-사이클로헥실-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-cyclohexyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 사이클로헥산온인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-사이클로헥실-3,4-다이메톡시아닐린을 제조하였다.N-cyclohexyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is cyclohexanone.

수율 91%, 갈색 고체.Yield 91%, brown solid.

1H NMR (300 MHz, CDCl3) δ 6.71 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.20-3.11 (m, 1H), 2.05-2.02 (m, 2H), 1.77-1.72 (m, 2H), 1.64-1.61 (m, 1H), 1.40-1.11 (m, 5H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.71 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.20-3.11 (m, 1H), 2.05-2.02 (m, 2H), 1.77-1.72 (m, 2H), 1.64-1.61 (m, 1H), 1.40 -1.11 (m, 5H).

단계 2: 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-cyclohexyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-사이클로헥실-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.1-cyclohexyl-1- (3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 48%, 흰색 고체, mp 53-55℃.Yield 48%, white solid, mp 53-55°C.

1H NMR (500 MHz, CDCl3) δ 7.66 (s, 1H), 6.85 (d, J = 8.40 Hz, 1H), 6.78 (s, 1H), 6.67 (dd, J = 8.35, 2.05 Hz, 1H), 6.58 (d, J = 2.10 Hz, 1H), 4.36 (tt, J = 11.90, 3.20 Hz, 1H), 4.05 (t, J = 5.60 Hz, 1H), 3.89 (s, 3H), 3.87-3.85 (m, 5H), 3.14 (q, J = 6.25 Hz, 2H), 2.16 (s, 3H), 1.87-1.80 (m, 4H), 1.72-1.69 (m, 2H), 1.56-1.54 (m, 1H), 1.40-1.34 (m, 2H), 1.01 (qd, J = 12.4, 3.15 Hz, 2H), 0.89 (qt, J = 13.1, 3.40 Hz, 1H); HRMS (ESI) calc. for C22H33N4O3 [M + H]+ 401.2547, found 401.2554. 1 H NMR (500 MHz, CDCl 3 ) δ 7.66 (s, 1H), 6.85 (d, J = 8.40 Hz, 1H), 6.78 (s, 1H), 6.67 (dd, J = 8.35, 2.05 Hz, 1H) , 6.58 (d, J = 2.10 Hz, 1H), 4.36 (tt, J = 11.90, 3.20 Hz, 1H), 4.05 (t, J = 5.60 Hz, 1H), 3.89 (s, 3H), 3.87-3.85 ( m, 5H), 3.14 (q, J = 6.25 Hz, 2H), 2.16 (s, 3H), 1.87-1.80 (m, 4H), 1.72-1.69 (m, 2H), 1.56-1.54 (m, 1H) , 1.40-1.34 (m, 2H), 1.01 (qd, J = 12.4, 3.15 Hz, 2H), 0.89 (qt, J = 13.1, 3.40 Hz, 1H); HRMS (ESI) calc. for C 22 H 33 N 4 O 3 [M + H] + 401.2547, found 401.2554.

<실시예 27> 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 27> Preparation of 1-benzyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00064
Figure 112019061617410-pat00064

단계 1: N-벤질-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-benzyl-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-벤질-3,4-다이메톡시아닐린을 제조하였다.N-benzyl-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is benzaldehyde.

수율 92%, 약간 갈색의 고체.Yield 92%, slightly brownish solid.

1H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 5H), 6.72 (d, J = 8.40 Hz, 1H), 6.31 (s, 1H), 6.25 (d, J = 8.04 Hz, 1H), 4.27 (s, 2H), 3.78 (s, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.38-7.24 (m, 5H), 6.72 (d, J = 8.40 Hz, 1H), 6.31 (s, 1H), 6.25 (d, J = 8.04 Hz, 1H) , 4.27 (s, 2H), 3.78 (s, 6H).

단계 2: 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-benzyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-벤질-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.1-benzyl-1-(3) by performing the same method as in General Preparation Procedure 2, wherein the N-substituted 3,4-dimethoxyaniline is N-benzyl-3,4-dimethoxyaniline obtained in step 1 above. ,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 51%, 흰색 고체, mp 112-113℃.Yield 51%, white solid, mp 112-113°C.

1H NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 7.27-7.19 (m, 5H), 6.77 (d, J = 8.61 Hz, 1H), 6.76 (s, 1H), 6.58 (dd, J = 8.43, 2.37 Hz, 1H), 6.39 (d, J = 2.40 Hz, 1H), 4.77 (s, 2H), 4.34 (t, J = 5.85 Hz, 1H), 3.86 (t, J = 7.14 Hz, 2H), 3.84 (s, 3H), 3.67 (s, 3H), 3.19 (q, J = 6.60 Hz, 2H), 2.15 (d, J = 0.75 Hz, 3H), 1.87 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C23H29N4O3 [M + H]+ 409.2234, found 409.2237. 1 H NMR (300 MHz, CDCl 3 ) δ 7.57 (s, 1H), 7.27-7.19 (m, 5H), 6.77 (d, J = 8.61 Hz, 1H), 6.76 (s, 1H), 6.58 (dd, J = 8.43, 2.37 Hz, 1H), 6.39 (d, J = 2.40 Hz, 1H), 4.77 (s, 2H), 4.34 (t, J = 5.85 Hz, 1H), 3.86 (t, J = 7.14 Hz, 2H), 3.84 (s, 3H), 3.67 (s, 3H), 3.19 (q, J = 6.60 Hz, 2H), 2.15 (d, J = 0.75 Hz, 3H), 1.87 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 23 H 29 N 4 O 3 [M + H] + 409.2234, found 409.2237.

<실시예 28> 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 28> 1-(3,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea Manufacture of

Figure 112019061617410-pat00065
Figure 112019061617410-pat00065

단계 1: N-(3-플루오로벤질)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(3-fluorobenzyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 3-플루오로벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(3-플루오로벤질)-3,4-다이메톡시아닐린을 제조하였다.N-(3-fluorobenzyl)-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 3-fluorobenzaldehyde.

수율 88%, 갈색 고체.Yield 88%, brown solid.

1H NMR (400 MHz, CDCl3) δ 7.28 (qd, J = 7.80, 6.04 Hz, 1H), 7.12 (d, J = 7.60 Hz, 1H), 7.07 (d, J = 9.68 Hz, 1H), 6.93 (td, J = 8.40, 2.28 Hz, 1H), 6.71 (d, J = 8.56 Hz, 1H), 6.24 (d, J = 2.60 Hz, 1H), 6.12 (dd, J = 8.52, 2.72 Hz, 1H), 4.28 (s, 2H), 3.84 (br, 1H), 3.79 (s, 3H), 3.78 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (qd, J = 7.80, 6.04 Hz, 1H), 7.12 (d, J = 7.60 Hz, 1H), 7.07 (d, J = 9.68 Hz, 1H), 6.93 (td, J = 8.40, 2.28 Hz, 1H), 6.71 (d, J = 8.56 Hz, 1H), 6.24 (d, J = 2.60 Hz, 1H), 6.12 (dd, J = 8.52, 2.72 Hz, 1H) , 4.28 (s, 2H), 3.84 (br, 1H), 3.79 (s, 3H), 3.78 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3-플루오로벤질)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.N-substituted 3,4-dimethoxyaniline is N-(3-fluorobenzyl)-3,4-dimethoxyaniline obtained in step 1, by following the same method as in General Preparation Procedure 2 (3,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 56%, 흰색 고체, mp 123-125℃.Yield 56%, white solid, mp 123-125°C.

1H NMR (300 MHz, CDCl3) δ 7.28 (s, 1H), 7.16 (qd, J = 7.86, 5.67 Hz, 1H), 6.94-6.84 (m, 3H), 6.73 (d, J = 8.43 Hz, 1H), 6.67 (s, 1H), 6.54 (dd, J = 8.43, 2.40 Hz, 1H), 6.39 (d, J = 2.19 Hz, 1H), 4.72 (s, 2H), 4.28 (t, J = 5.88 Hz, 1H), 3.81 (s, 3H), 3.77 (t, J = 7.14 Hz, 2H), 3.67 (s, 3H), 3.15 (q, J = 6.39 Hz, 2H), 2.09 (s, 3H), 1.82 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C23H28FN4O3 [M + H]+ 427.2140, found 427.2155. 1 H NMR (300 MHz, CDCl 3 ) δ 7.28 (s, 1H), 7.16 (qd, J = 7.86, 5.67 Hz, 1H), 6.94-6.84 (m, 3H), 6.73 (d, J = 8.43 Hz, 1H), 6.67 (s, 1H), 6.54 (dd, J = 8.43, 2.40 Hz, 1H), 6.39 (d, J = 2.19 Hz, 1H), 4.72 (s, 2H), 4.28 (t, J = 5.88 Hz, 1H), 3.81 (s, 3H), 3.77 (t, J = 7.14 Hz, 2H), 3.67 (s, 3H), 3.15 (q, J = 6.39 Hz, 2H), 2.09 (s, 3H), 1.82 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 23 H 28 FN 4 O 3 [M + H] + 427.2140, found 427.2155.

<실시예 29> 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 29> 1-(3-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea Produce

Figure 112019061617410-pat00066
Figure 112019061617410-pat00066

단계 1: N-(3-클로로벤질)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(3-chlorobenzyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 3-클로로벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(3-클로로벤질)-3,4-다이메톡시아닐린을 제조하였다.N-(3-chlorobenzyl)-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 3-chlorobenzaldehyde.

수율 54%, 엷은 갈색 고체.Yield 54%, light brown solid.

1H NMR (300 MHz, CDCl3) δ 7.35 (s, 1H), 7.25-7.19 (m, 3H), 6.72 (d, J = 8.58 Hz, 1H), 6.24 (d, J = 2.55 Hz, 1H), 6.13 (dd, J = 8.61, 2.76 Hz, 1H), 4.26 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.35 (s, 1H), 7.25-7.19 (m, 3H), 6.72 (d, J = 8.58 Hz, 1H), 6.24 (d, J = 2.55 Hz, 1H) , 6.13 (dd, J = 8.61, 2.76 Hz, 1H), 4.26 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H).

단계 2: 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-(3-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3-클로로벤질)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The N-substituted 3,4-dimethoxyaniline is N-(3-chlorobenzyl)-3,4-dimethoxyaniline obtained in step 1, and 1-( 3-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 54%, 흰색 고체, mp 53-54℃.Yield 54%, white solid, mp 53-54°C.

1H NMR (300 MHz, CDCl3) δ 7.32 (s, 1H), 7.17-7.13 (m, 3H), 7.06-7.03 (m, 1H), 6.75 (d, J = 8.43 Hz, 1H), 6.67 (s, 1H), 6.55 (dd, J = 8.40, 2.37 Hz, 1H), 6.39 (d, J = 2.40 Hz, 1H), 4.70 (s, 2H), 4.29 (t, J = 5.67 Hz, NH), 3.81 (s, 3H), 3.77 (t, J = 7.32 Hz, 2H), 3.67 (s, 3H), 3.18 (q, J = 6.78 Hz, 2H), 2.09 (s, 3H), 1.86 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C23H28ClN4O3 [M + H]+ 443.1844, found 443.1899. 1 H NMR (300 MHz, CDCl 3 ) δ 7.32 (s, 1H), 7.17-7.13 (m, 3H), 7.06-7.03 (m, 1H), 6.75 (d, J = 8.43 Hz, 1H), 6.67 ( s, 1H), 6.55 (dd, J = 8.40, 2.37 Hz, 1H), 6.39 (d, J = 2.40 Hz, 1H), 4.70 (s, 2H), 4.29 (t, J = 5.67 Hz, NH), 3.81 (s, 3H), 3.77 (t, J = 7.32 Hz, 2H), 3.67 (s, 3H), 3.18 (q, J = 6.78 Hz, 2H), 2.09 (s, 3H), 1.86 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C 23 H 28 ClN 4 O 3 [M + H] + 443.1844, found 443.1899.

<실시예 30> 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 30> 1-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea Manufacture of

Figure 112019061617410-pat00067
Figure 112019061617410-pat00067

단계 1: N-(4-플루오로벤질)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(4-fluorobenzyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 4-플루오로벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(4-플루오로벤질)-3,4-다이메톡시아닐린을 제조하였다.N-(4-fluorobenzyl)-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 4-fluorobenzaldehyde.

수율 97%, 약간 갈색의 고체.Yield 97%, slightly brownish solid.

1H NMR (300 MHz, CDCl3) δ 7.32 (dd, J = 8.25, 5.52 Hz, 2H), 7.00 (t, J = 8.61 Hz, 2H), 6.71 (d, J = 8.61 Hz, 1H), 6.26 (d, J = 2.37 Hz, 1H), 6.15 (dd, J = 8.40, 2.55 Hz, 1H), 4.24 (s, 2H), 3.79 (s, 6H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.32 (dd, J = 8.25, 5.52 Hz, 2H), 7.00 (t, J = 8.61 Hz, 2H), 6.71 (d, J = 8.61 Hz, 1H), 6.26 (d, J = 2.37 Hz, 1H), 6.15 (dd, J = 8.40, 2.55 Hz, 1H), 4.24 (s, 2H), 3.79 (s, 6H).

단계 2: 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(4-플루오로벤질)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.N-substituted 3,4-dimethoxyaniline is N-(4-fluorobenzyl)-3,4-dimethoxyaniline obtained in step 1, by following the same method as in the general preparation procedure 2, 1- (3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 52%, 흰색 고체, mp 87-88℃.Yield 52%, white solid, mp 87-88°C.

1H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.16 (dd, J = 8.04, 5.49 Hz, 2H), 6.93 (t, J = 7.86 Hz, 2H), 6.78 (d, J = 8.43 Hz, 1H), 6.76 (s, 1H), 6.54 (dd, J = 8.43, 1.47 Hz, 1H), 6.40 (d, J = 1.83 Hz, 1H), 4.73 (s, 2H), 4.33 (t, J = 5.85 Hz, 1H), 3.85 (s, 3H), 3.85 (t, J = 7.14 Hz, 2H), 3.71 (s, 3H), 3.18 (q, J = 6.60 Hz, 2H), 2.15 (s, 3H), 1.86 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C23H28FN4O3 [M + H]+ 427.2140, found 427.2147. 1 H NMR (300 MHz, CDCl 3 ) δ 7.59 (s, 1H), 7.16 (dd, J = 8.04, 5.49 Hz, 2H), 6.93 (t, J = 7.86 Hz, 2H), 6.78 (d, J = 8.43 Hz, 1H), 6.76 (s, 1H), 6.54 (dd, J = 8.43, 1.47 Hz, 1H), 6.40 (d, J = 1.83 Hz, 1H), 4.73 (s, 2H), 4.33 (t, J = 5.85 Hz, 1H), 3.85 (s, 3H), 3.85 (t, J = 7.14 Hz, 2H), 3.71 (s, 3H), 3.18 (q, J = 6.60 Hz, 2H), 2.15 (s, 3H), 1.86 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C 23 H 28 FN 4 O 3 [M + H] + 427.2140, found 427.2147.

<실시예 31> 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조 <Example 31> 1-(4-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea Article

Figure 112019061617410-pat00068
Figure 112019061617410-pat00068

단계 1: N-(4-클로로벤질)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-(4-chlorobenzyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 4-클로로벤즈알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(4-클로로벤질)-3,4-다이메톡시아닐린을 제조하였다.N-(4-chlorobenzyl)-3,4-dimethoxyaniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 4-chlorobenzaldehyde.

수율 81%, 갈색 고체.Yield 81%, brown solid.

1H NMR (300MHz, CDCl3) δ7.24 (d, J = 8.44 Hz, 2H), 7.15 (d, J = 8.36 Hz, 2H),6.72 (d, J = 8.58 Hz, 1H), 6.24 (d, J = 2.55 Hz, 1H), 6.13 (dd, J = 8.61, 2.67 Hz, 1H), 4.24 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H). 1 H NMR (300MHz, CDCl 3 ) δ 7.24 (d, J = 8.44 Hz, 2H), 7.15 (d, J = 8.36 Hz, 2H),6.72 (d, J = 8.58 Hz, 1H), 6.24 (d, J = 2.55 Hz, 1H), 6.13 (dd, J = 8.61, 2.67 Hz, 1H), 4.24 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H).

단계 2: 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: Preparation of 1-(4-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(4-클로로벤질)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The N-substituted 3,4-dimethoxyaniline is N-(4-chlorobenzyl)-3,4-dimethoxyaniline obtained in step 1, and 1-( 4-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 25%, 흰색 고체, mp 54-55℃Yield 25%, white solid, mp 54-55℃

1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.24 (d, J = 8.44 Hz, 2H), 7.15 (d, J = 8.36 Hz, 2H), 6.78 (d, J = 8.52 Hz, 1H), 6.71 (s, 1H), 6.57 (dd, J = 8.52, 2.40 Hz, 1H), 6.42 (s, 1H), 4.73 (s, 2H), 4.30 (t, J = 5.72 Hz, NH), 3.85 (s, 3H), 3.83 (t, J = 7.08 Hz, 2H), 3.72 (s, 3H), 3.21 (q, J = 6.52 Hz, 2H), 2.12 (s, 3H), 1.89 (quintet, J = 6.88 Hz, 2H); HRMS (ESI) calc. for C23H28ClN4O3 [M + H]+ 443.1844, found 443.1851. 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (s, 1H), 7.24 (d, J = 8.44 Hz, 2H), 7.15 (d, J = 8.36 Hz, 2H), 6.78 (d, J = 8.52 Hz , 1H), 6.71 (s, 1H), 6.57 (dd, J = 8.52, 2.40 Hz, 1H), 6.42 (s, 1H), 4.73 (s, 2H), 4.30 (t, J = 5.72 Hz, NH) , 3.85 (s, 3H), 3.83 (t, J = 7.08 Hz, 2H), 3.72 (s, 3H), 3.21 (q, J = 6.52 Hz, 2H), 2.12 (s, 3H), 1.89 (quintet, J = 6.88 Hz, 2H); HRMS (ESI) calc. for C 23 H 28 ClN 4 O 3 [M + H] + 443.1844, found 443.1851.

<실시예 32> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일-메틸)우레아의 제조<Example 32> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-yl-methyl ) Preparation of urea

Figure 112019061617410-pat00069
Figure 112019061617410-pat00069

단계 1: 3,4-다이메톡시-N-(피리딘-3-일메틸)아닐린의 제조Step 1: Preparation of 3,4-dimethoxy-N-(pyridin-3-ylmethyl)aniline

케톤 혹은 알데하이드가 3-니코틴알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 3,4-다이메톡시-N-(피리딘-3-일메틸)아닐린을 제조하였다.3,4-dimethoxy-N-(pyridin-3-ylmethyl)aniline was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 3-nicotinaldehyde.

수율 74%, 약간 갈색의 고체.Yield 74%, slightly brownish solid.

1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 1.16 Hz, 1H), 8.52 (d, J = 6.00 Hz, 1H), 7.69 (d, J = 7.64 Hz, 1H), 7.25 (dd, J = 7.64, 2.80 Hz, 1H), 6.71 (d, J = 8.52 Hz, 1H), 6.25 (d, J = 2.44 Hz, 1H), 6.13 (dd, J = 8.40, 2.16 Hz, 1H), 4.30 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (d, J = 1.16 Hz, 1H), 8.52 (d, J = 6.00 Hz, 1H), 7.69 (d, J = 7.64 Hz, 1H), 7.25 (dd , J = 7.64, 2.80 Hz, 1H), 6.71 (d, J = 8.52 Hz, 1H), 6.25 (d, J = 2.44 Hz, 1H), 6.13 (dd, J = 8.40, 2.16 Hz, 1H), 4.30 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일-메틸)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-yl-methyl)urea Manufacture of

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 3,4-다이메톡시-N-(피리딘-3-일메틸)아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일-메틸)우레아를 제조하였다.N-substituted 3,4-dimethoxyaniline is 3,4-dimethoxy-N-(pyridin-3-ylmethyl)aniline obtained in step 1, by performing the same method as in the general preparation procedure 2, 1 -(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-yl-methyl)urea was prepared.

수율 76%, 흰색 고체, mp 94-95℃.Yield 76%, white solid, mp 94-95°C.

1H NMR (300 MHz, CD3OD) δ 8.41 (dd, J = 4.95, 1.65 Hz, 1H), 8.35 (d, J = 1.65 Hz, 1H), 7.74 (dt, J = 7.89, 1.83 Hz, 1H), 7.55 (s, 1H), 7.38 (dd, J = 7.89, 4.77 Hz, 1H), 6.91 (d, J = 8.58 Hz, 1H), 6.66 (d, J = 2.40 Hz, 1H), 6.65 (s, 1H), 6.60 (dd, J = 8.61, 2.55 Hz, 1H), 4.85 (s, 2H), 3.90 (t, J = 7.14 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 3.16 (t, J = 6.60 Hz, 2H), 2.18 (d, J = 1.11 Hz, 3H), 1.86 (quintet, J = 7.08 Hz, 2H); HRMS (ESI) calc. for C22H28N5O3 [M + H]+ 410.2187, found 410.2189. 1 H NMR (300 MHz, CD 3 OD) δ 8.41 (dd, J = 4.95, 1.65 Hz, 1H), 8.35 (d, J = 1.65 Hz, 1H), 7.74 (dt, J = 7.89, 1.83 Hz, 1H ), 7.55 (s, 1H), 7.38 (dd, J = 7.89, 4.77 Hz, 1H), 6.91 (d, J = 8.58 Hz, 1H), 6.66 (d, J = 2.40 Hz, 1H), 6.65 (s , 1H), 6.60 (dd, J = 8.61, 2.55 Hz, 1H), 4.85 (s, 2H), 3.90 (t, J = 7.14 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H) , 3.16 (t, J = 6.60 Hz, 2H), 2.18 (d, J = 1.11 Hz, 3H), 1.86 (quintet, J = 7.08 Hz, 2H); HRMS (ESI) calc. for C 22 H 28 N 5 O 3 [M + H] + 410.2187, found 410.2189.

<실시예 33> 1-(3,4-다이메톡시페닐)-1-((6-플루오로피리딘-3-일)메틸)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조 < Example 33> 1-(3,4-dimethoxyphenyl)-1-((6-fluoropyridin-3-yl)methyl)-3-(3-(5-methyl-1H-imidazole- Preparation of 1-yl)propyl)urea

Figure 112019061617410-pat00070
Figure 112019061617410-pat00070

단계 1: N-((6-플루오로피리딘-3-일)메틸)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-((6-fluoropyridin-3-yl)methyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 2-플루오로-4-피리딘카복스알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-((6-플루오로피리딘-3-일)메틸)-3,4-다이메톡시아닐린를 제조하였다.N-((6-fluoropyridin-3-yl)methyl)-3,4-dime by following the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 2-fluoro-4-pyridinecarboxaldehyde. Toxianiline was prepared.

수율 56%, 갈색 반액체.Yield 56%, brown semi-liquid.

1H NMR (300 MHz, CDCl3) δ 8.19 (s, 1H), 7.82 (td, J = 7.89, 2.58 Hz, 1H), 6.90 (dd, J = 8.25, 2.94 Hz, 1H), 6.72 (d, J = 8.61 Hz, 1H), 6.24 (d, J = 2.58 Hz, 1H), 6.13 (dd, J = 8.43, 2.58 Hz, 1H), 4.28 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.19 (s, 1H), 7.82 (td, J = 7.89, 2.58 Hz, 1H), 6.90 (dd, J = 8.25, 2.94 Hz, 1H), 6.72 (d, J = 8.61 Hz, 1H), 6.24 (d, J = 2.58 Hz, 1H), 6.13 (dd, J = 8.43, 2.58 Hz, 1H), 4.28 (s, 2H), 3.79 (s, 3H), 3.78 ( s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-((6-플루오로피리딘-3-일)메틸)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-1-((6-fluoropyridin-3-yl)methyl)-3-(3-(5-methyl-1H-imidazole-1- 1) Preparation of propyl) urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-((6-플루오로피리딘-3-일)메틸)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-((6-플루오로피리딘-3-일)메틸)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The general preparation procedure 2 above, wherein the N-substituted 3,4-dimethoxyaniline is N-((6-fluoropyridin-3-yl)methyl)-3,4-dimethoxyaniline obtained in step 1 above. 1-(3,4-dimethoxyphenyl)-1-((6-fluoropyridin-3-yl)methyl)-3-(3-(5-methyl-1H-imidazole- 1-yl)propyl)urea was prepared.

수율 54%, 흰색 고체, mp 59-60℃.Yield 54%, white solid, mp 59-60°C.

1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.85 (dt, J = 8.25, 2.55 Hz, 1H), 7.36 (s, 1H), 6.91 (dd, J = 8.43, 2.94 Hz, 1H), 6.84 (d, J = 8.43 Hz, 1H), 6.74 (s, 1H), 6.57 (dd, J = 8.40, 2.37 Hz, 1H), 6.50 (d, J = 2.37 Hz, 1H), 4.80 (s, 2H), 4.36 (t, J = 6.24 Hz, NH), 3.90 (s, 3H), 3.84 (t, J = 7.14 Hz, 2H), 3.80 (s, 3H), 3.25 (q, J = 6.78 Hz, 2H), 2.16 (d, J = 0.75 Hz, 3H), 1.94 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C22H27FN5O3 [M + H]+ 428.2092, found 428.2088. 1 H NMR (300 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.85 (dt, J = 8.25, 2.55 Hz, 1H), 7.36 (s, 1H), 6.91 (dd, J = 8.43, 2.94 Hz, 1H), 6.84 (d, J = 8.43 Hz, 1H), 6.74 (s, 1H), 6.57 (dd, J = 8.40, 2.37 Hz, 1H), 6.50 (d, J = 2.37 Hz, 1H), 4.80 (s, 2H), 4.36 (t, J = 6.24 Hz, NH), 3.90 (s, 3H), 3.84 (t, J = 7.14 Hz, 2H), 3.80 (s, 3H) , 3.25 (q, J = 6.78 Hz, 2H), 2.16 (d, J = 0.75 Hz, 3H), 1.94 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 22 H 27 FN 5 O 3 [M + H] + 428.2092, found 428.2088.

<실시예 34> 1-((6-클로로피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 34> 1-((6-chloropyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1 Preparation of -yl)propyl)urea

Figure 112019061617410-pat00071
Figure 112019061617410-pat00071

단계 1: N-((6-클로로피리딘-3-일)메틸)-3,4-다이메톡시아닐린의 제조Step 1: Preparation of N-((6-chloropyridin-3-yl)methyl)-3,4-dimethoxyaniline

케톤 혹은 알데하이드가 2-클로로-4-피리딘카복스알데하이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-((6-클로로피리딘-3-일)메틸)-3,4-다이메톡시아닐린을 제조하였다.N-((6-chloropyridin-3-yl)methyl)-3,4-dimethoxyaniline Was prepared.

수율 76%, 엷은 노란색 고체.Yield 76%, pale yellow solid.

1H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 2.00 Hz, 1H), 7.66 (dd, J = 8.20, 2.55 Hz, 1H), 7.28 (d, J = 8.20 Hz, 1H), 6.71 (d, J = 8.50 Hz, 1H), 6.23 (d, J = 2.50 Hz, 1H), 6.10 (dd, J = 8.45, 2.55 Hz, 1H), 4.29 (s, 2H), 3.79 (s, 3H), 3.78 (s, 2H). 1 H NMR (500 MHz, CDCl 3 ) δ 8.38 (d, J = 2.00 Hz, 1H), 7.66 (dd, J = 8.20, 2.55 Hz, 1H), 7.28 (d, J = 8.20 Hz, 1H), 6.71 (d, J = 8.50 Hz, 1H), 6.23 (d, J = 2.50 Hz, 1H), 6.10 (dd, J = 8.45, 2.55 Hz, 1H), 4.29 (s, 2H), 3.79 (s, 3H) , 3.78 (s, 2H).

단계 2: 1-((6-클로로피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-((6-chloropyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl )Propyl)Urea Preparation

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-((6-클로로피리딘-3-일)메틸)-3,4-다이메톡시아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-((6-클로로피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The N-substituted 3,4-dimethoxyaniline is N-((6-chloropyridin-3-yl)methyl)-3,4-dimethoxyaniline obtained in step 1, which is the same as in the general preparation procedure 2 above. Follow the method to 1-((6-chloropyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1- Il) propyl) urea was prepared.

수율 87%, 흰색 고체, mp 72-73℃.Yield 87%, white solid, mp 72-73°C.

1H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 2.37 Hz, 1H), 7.65 (dd, J = 8.07, 2.40 Hz, 1H), 7.31-7.24 (m, 2H), 6.80 (d, J = 8.43 Hz, 1H), 6.70 (s, 1H), 6.52-6.74 (m, 2H), 4.75 (s, 2H), 4.32 (t, J = 5.88 Hz, NH), 3.85 (s, 3H), 3.82 (t, J = 7.14 Hz, 2H), 3.76 (s, 3H), 3.20 (q, J = 6.42 Hz, 2H), 2.12 (d, J = 0.90 Hz, 3H), 1.89 (quintet, J = 6.78 Hz, 2H); HRMS (ESI) calc. for C22H27ClN5O3 [M + H]+ 444.1797, found 444.1792. 1 H NMR (300 MHz, CDCl 3 ) δ 8.14 (d, J = 2.37 Hz, 1H), 7.65 (dd, J = 8.07, 2.40 Hz, 1H), 7.31-7.24 (m, 2H), 6.80 (d, J = 8.43 Hz, 1H), 6.70 (s, 1H), 6.52-6.74 (m, 2H), 4.75 (s, 2H), 4.32 (t, J = 5.88 Hz, NH), 3.85 (s, 3H), 3.82 (t, J = 7.14 Hz, 2H), 3.76 (s, 3H), 3.20 (q, J = 6.42 Hz, 2H), 2.12 (d, J = 0.90 Hz, 3H), 1.89 (quintet, J = 6.78 Hz, 2H); HRMS (ESI) calc. for C 22 H 27 ClN 5 O 3 [M + H] + 444.1797, found 444.1792.

<실시예 35> 1-((6-아미노피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 35> 1-((6-aminopyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1 Preparation of -yl)propyl)urea

Figure 112019061617410-pat00072
Figure 112019061617410-pat00072

단계 1: 2-(Diboc-아미노)-4-((3,4-다이메톡시페닐아미노)메틸)피리딘의 제조Step 1: Preparation of 2-(Diboc-amino)-4-((3,4-dimethoxyphenylamino)methyl)pyridine

설폰아마이드 혼합물이 N-((6-(Diboc-아미노)피리딘-3-일)메틸)-N-(3,4-다이메톡시페닐)-2-나이트로벤젠설폰아마이드인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 2-(Diboc-아미노)-4-((3,4-다이메톡시페닐아미노)메틸)피리딘을 제조하였다.The above general preparation procedure 6 wherein the sulfonamide mixture is N-((6-(Diboc-amino)pyridin-3-yl)methyl)-N-(3,4-dimethoxyphenyl)-2-nitrobenzenesulfonamide 2-(Diboc-amino)-4-((3,4-dimethoxyphenylamino)methyl)pyridine was prepared by performing the same method as described above.

수율 65%, 갈색 고체.Yield 65%, brown solid.

1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 5.13 Hz, 1H), 7.24-7.19 (m, 2H), 6.67 (d, J = 8.61 Hz, 1H), 6.21 (d, J = 2.55 Hz, 1H), 6.02 (dd, J = 8.43, 2.55 Hz, 1H), 4.34 (s, 2H), 3.97 (brs, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 1.40 (s, 18H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.40 (d, J = 5.13 Hz, 1H), 7.24-7.19 (m, 2H), 6.67 (d, J = 8.61 Hz, 1H), 6.21 (d, J = 2.55 Hz, 1H), 6.02 (dd, J = 8.43, 2.55 Hz, 1H), 4.34 (s, 2H), 3.97 (brs, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 1.40 ( s, 18H).

단계 2: 1-((6-아미노피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-((6-aminopyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl )Propyl)Urea Preparation

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 2-(Diboc-아미노)-4-((3,4-다이메톡시페닐아미노)메틸)피리딘인 상기 일반적인 제조절차 2와 동일한 방법을 수행한 다음, 상기 일반적인 제조절차 3와 동일한 방법을 수행하여 1-((6-아미노피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The general preparation procedure 2 above, wherein the N-substituted 3,4-dimethoxyaniline is 2-(Diboc-amino)-4-((3,4-dimethoxyphenylamino)methyl)pyridine obtained in step 1 above. After performing the same method, 1-((6-aminopyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-( 3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 67%, 흰색 고체, mp 155-157℃.Yield 67%, white solid, mp 155-157°C.

1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 2.01 Hz, 1H), 7.36 (dd, J = 8.43, 2.40 Hz, 1H), 7.26 (d, J = 0.93 Hz, 1H), 7.72 (d, J = 8.61 Hz, 1H), 6.65 (s, 1H), 6.47 (dd, J = 8.43, 2.37 Hz, 1H), 6.40 (d, J = 2.37 Hz, 1H), 6.37 (d, J = 8.43 Hz, 1H), 4.58 (s, 2H), 4.31 (s, 2H), 4.21 (t, J = 5.85 Hz, 1H), 3.80 (s, 3H), 3.76 (t, J = 7.14 Hz, 2H), 3.69 (s, 3H), 3.12 (q, J = 6.24 Hz, 2H), 2.06 (d, J = 0.90 Hz, 3H), 1.79 (quintet, J = 7.32 Hz, 2H); HRMS (ESI) calc. for C22H29N6O3 [M + H]+ 425.2296, found 425.2296. 1 H NMR (300 MHz, CDCl 3 ) δ 7.71 (d, J = 2.01 Hz, 1H), 7.36 (dd, J = 8.43, 2.40 Hz, 1H), 7.26 (d, J = 0.93 Hz, 1H), 7.72 (d, J = 8.61 Hz, 1H), 6.65 (s, 1H), 6.47 (dd, J = 8.43, 2.37 Hz, 1H), 6.40 (d, J = 2.37 Hz, 1H), 6.37 (d, J = 8.43 Hz, 1H), 4.58 (s, 2H), 4.31 (s, 2H), 4.21 (t, J = 5.85 Hz, 1H), 3.80 (s, 3H), 3.76 (t, J = 7.14 Hz, 2H) , 3.69 (s, 3H), 3.12 (q, J = 6.24 Hz, 2H), 2.06 (d, J = 0.90 Hz, 3H), 1.79 (quintet, J = 7.32 Hz, 2H); HRMS (ESI) calc. for C 22 H 29 N 6 O 3 [M + H] + 425.2296, found 425.2296.

<실시예 36> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)우레아의 제조<Example 36> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl ) Preparation of urea

Figure 112019061617410-pat00073
Figure 112019061617410-pat00073

단계 1: 3,4-다이메톡시-N-(피리딘-4-일메틸)아닐린의 제조Step 1: Preparation of 3,4-dimethoxy-N-(pyridin-4-ylmethyl)aniline

케톤 혹은 알데하이드가 4-피리딜메틸카복스알데하이드인 상기 일반적인 제조철차 5와 동일한 방법을 수행하여 3,4-다이메톡시-N-(피리딘-4-일메틸)아닐린을 제조하였다.3,4-dimethoxy-N-(pyridin-4-ylmethyl)aniline was prepared by performing the same method as in General Train 5, wherein the ketone or aldehyde is 4-pyridylmethylcarboxaldehyde.

율 62%, 엷은 갈색 고체.Yield 62%, light brown solid.

1H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 6.60, 1.62 Hz, 2H), 7.30 (dd, J = 5.82, 1.44 Hz, 2H), 6.70 (d, J = 8.58 Hz, 1H), 6.22 (d, J = 2.55 Hz, 1H), 6.06 (dd, J = 8.61, 2.76 Hz, 1H), 4.32 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.55 (d, J = 6.60, 1.62 Hz, 2H), 7.30 (dd, J = 5.82, 1.44 Hz, 2H), 6.70 (d, J = 8.58 Hz, 1H) , 6.22 (d, J = 2.55 Hz, 1H), 6.06 (dd, J = 8.61, 2.76 Hz, 1H), 4.32 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl)urea Manufacture of

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 3,4-다이메톡시-N-(피리딘-4-일메틸)아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)우레아를 제조하였다.N-substituted 3,4-dimethoxyaniline is 3,4-dimethoxy-N-(pyridin-4-ylmethyl)aniline obtained in step 1, by performing the same method as in the general preparation procedure 2, 1 -(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl)urea was prepared.

수율 54%, 흰색 고체, mp 79-80℃.Yield 54%, white solid, mp 79-80°C.

1H NMR (300 MHz, CDCl3) δ 8.46 (dd, J = 4.41, 1.65 Hz, 2H), 7.29 (s, 1H), 7.13 (dd, J = 4.38, 1.47 Hz, 2H), 6.75 (d, J = 8.40 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J = 8.43, 2.37 Hz, 1H), 6.45 (d, J = 2.37 Hz, 1H), 4.73 (s, 2H), 4.36 (t, J = 5.85 Hz, NH), 3.80 (s, 3H), 3.77 (t, J = 7.14 Hz, 2H), 3.69 (s, 3H), 3.19 (q, J = 6.75 Hz, 2H), 2.08 (d, J = 0.90 Hz, 3H), 1.87 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C22H28N5O3 [M + H ]+ 410.2187, found 410.2181. 1 H NMR (300 MHz, CDCl 3 ) δ 8.46 (dd, J = 4.41, 1.65 Hz, 2H), 7.29 (s, 1H), 7.13 (dd, J = 4.38, 1.47 Hz, 2H), 6.75 (d, J = 8.40 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J = 8.43, 2.37 Hz, 1H), 6.45 (d, J = 2.37 Hz, 1H), 4.73 (s, 2H), 4.36 ( t, J = 5.85 Hz, NH), 3.80 (s, 3H), 3.77 (t, J = 7.14 Hz, 2H), 3.69 (s, 3H), 3.19 (q, J = 6.75 Hz, 2H), 2.08 ( d, J = 0.90 Hz, 3H), 1.87 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 22 H 28 N 5 O 3 [M + H] + 410.2187, found 410.2181.

<실시예 37> 1-((2-아미노피리딘-4-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 37> 1-((2-aminopyridin-4-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1 Preparation of -yl)propyl)urea

Figure 112019061617410-pat00074
Figure 112019061617410-pat00074

단계 1: 2-(Diboc-아미노)-5-((3,4-다이메톡시페닐아미노)메틸)피리딘의 제조Step 1: Preparation of 2-(Diboc-amino)-5-((3,4-dimethoxyphenylamino)methyl)pyridine

설폰아마이드 혼합물이 N-((2-(Diboc-아미노)피리딘-4-일)메틸)-N-(3,4-다이메톡시페닐)-2-나이트로벤젠설폰아마이드인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 2-(Diboc-아미노)-5-((3,4-다이메톡시페닐아미노)메틸)피리딘을 제조하였다.The general preparation procedure 6 above, wherein the sulfonamide mixture is N-((2-(Diboc-amino)pyridin-4-yl)methyl)-N-(3,4-dimethoxyphenyl)-2-nitrobenzenesulfonamide 2-(Diboc-amino)-5-((3,4-dimethoxyphenylamino)methyl)pyridine was prepared in the same manner as described above.

수율 69%, 갈색 고체.Yield 69%, brown solid.

1H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 1.83 Hz, 1H), 7.73 (dd, J = 8.07, 2.55 Hz, 1H), 7.18 (d, J = 8.25 Hz, 1H), 6.69 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.11 (dd, J = 8.61, 2.55 Hz, 1H), 4.32 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 1.43 (s, 18H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.47 (d, J = 1.83 Hz, 1H), 7.73 (dd, J = 8.07, 2.55 Hz, 1H), 7.18 (d, J = 8.25 Hz, 1H), 6.69 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.11 (dd, J = 8.61, 2.55 Hz, 1H), 4.32 (s, 2H), 3.80 (s, 3H) , 3.78 (s, 3H), 1.43 (s, 18H).

단계 2: 1-((2-아미노피리딘-4-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-((2-aminopyridin-4-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl )Propyl)Urea Preparation

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 2-(Diboc-아미노)-5-((3,4-다이메톡시페닐아미노)메틸)피리딘인 상기 일반적인 제조절차 2와 동일한 방법을 수행한 다음, 상기 일반적인 제조절차 3와 동일한 방법을 수행하여 1-((2-아미노피리딘-4-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The general preparation procedure 2 above, wherein the N-substituted 3,4-dimethoxyaniline is 2-(Diboc-amino)-5-((3,4-dimethoxyphenylamino)methyl)pyridine obtained in step 1 above. After performing the same method, 1-((2-aminopyridin-4-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-( 3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 52%, 흰색 고체, mp 105-107 ℃.Yield 52%, white solid, mp 105-107 °C.

1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 5.13 Hz, 1H), 7.29 (s, 1H), 6.73 (d, J = 8.43 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J = 8.43, 2.00 Hz, 1H), 6.47 (d, J = 2.40 Hz, 1H), 6.44 (dd, J = 5.28, 1.26 Hz, 1H), 6.36 (s, 1H), 4.60 (s, 2H), 4.44 (s, 2H), 4.31 (t, J = 5.85 Hz, 1H), 3.80 (s, 3H), 3.77 (t, J = 7.14 Hz, 2H), 3.70 (s, 3H), 3.16 (q, J = 6.21 Hz, 2H), 2.08 (d, J = 0.75 Hz, 3H), 1.82 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C23H29N6O3 [M + H]+ 425.2296, found 425.2293. 1 H NMR (300 MHz, CDCl 3 ) δ 7.89 (d, J = 5.13 Hz, 1H), 7.29 (s, 1H), 6.73 (d, J = 8.43 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J = 8.43, 2.00 Hz, 1H), 6.47 (d, J = 2.40 Hz, 1H), 6.44 (dd, J = 5.28, 1.26 Hz, 1H), 6.36 (s, 1H), 4.60 (s, 2H), 4.44 (s, 2H), 4.31 (t, J = 5.85 Hz, 1H), 3.80 (s, 3H), 3.77 (t, J = 7.14 Hz, 2H), 3.70 (s, 3H), 3.16 ( q, J = 6.21 Hz, 2H), 2.08 (d, J = 0.75 Hz, 3H), 1.82 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C 23 H 29 N 6 O 3 [M + H] + 425.2296, found 425.2293.

<실시예 38> 1-(2-(2-아미노피리딘-4-일)에틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 38> 1-(2-(2-aminopyridin-4-yl)ethyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole Preparation of -1-yl)propyl)urea

Figure 112019061617410-pat00075
Figure 112019061617410-pat00075

단계 1: tert-뷰틸(4-(2-((3,4-다이메톡시페닐)아미노)에틸)피리딘-2-일)카바메이트의 제조Step 1: Preparation of tert-butyl(4-(2-((3,4-dimethoxyphenyl)amino)ethyl)pyridin-2-yl)carbamate

설폰아마이드 혼합물이 tert-뷰틸(4-(2-((N-(3,4-다이메톡시페닐)-2-나이트로페닐)설폰아마이도)에틸)피리딘-2-일)카바메이트인인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 tert-뷰틸(4-(2-((3,4-다이메톡시페닐)아미노)에틸)피리딘-2-일)카바메이트를 제조하였다.Wherein the sulfonamide mixture is tert-butyl(4-(2-((N-(3,4-dimethoxyphenyl)-2-nitrophenyl)sulfonamide)ethyl)pyridin-2-yl)carbamate. Tert-butyl(4-(2-((3,4-dimethoxyphenyl)amino)ethyl)pyridin-2-yl)carbamate was prepared by performing the same method as in General Preparation Procedure 6.

수율 55%, 엷은 노란색 고체.Yield 55%, pale yellow solid.

1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 5.05 Hz, 1H), 7.82 (s, 1H), 7.33 (s, 1H), 6.81 (d, J = 5.00 Hz, 1H), 6.74 (d, J = 8.45 Hz, 1H), 6.22 (dd, J = 7.45, 2.40 Hz, 1H), 3.82 (s, 3H), 3.79 (s 3H), 3.39 (t, J = 6.85 Hz, 2H), 2.90 (t, J = 6.75 Hz, 2H), 1.53 (s, 9H). 1 H NMR (500 MHz, CDCl 3 ) δ 8.13 (d, J = 5.05 Hz, 1H), 7.82 (s, 1H), 7.33 (s, 1H), 6.81 (d, J = 5.00 Hz, 1H), 6.74 (d, J = 8.45 Hz, 1H), 6.22 (dd, J = 7.45, 2.40 Hz, 1H), 3.82 (s, 3H), 3.79 (s 3H), 3.39 (t, J = 6.85 Hz, 2H), 2.90 (t, J = 6.75 Hz, 2H), 1.53 (s, 9H).

단계 2: 1-(2-(2-아미노피리딘-4-일)에틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-(2-(2-aminopyridin-4-yl)ethyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1 Preparation of -yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 tert-뷰틸(4-(2-((3,4-다이메톡시페닐)아미노)에틸)피리딘-2-일)카바메이트인 상기 일반적인 제조절차 2와 동일한 방법을 수행한 다음, 상기 일반적인 제조절차 3와 동일한 방법을 수행하여 1-(2-(2-아미노피리딘-4-일)에틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.N-substituted 3,4-dimethoxyaniline is tert-butyl (4-(2-((3,4-dimethoxyphenyl)amino)ethyl)pyridin-2-yl)carbamate obtained in step 1 above. Phosphorus 1-(2-(2-aminopyridin-4-yl)ethyl)-1-(3,4- Dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 83%, 흰색 고체, mp 223-224 ℃.Yield 83%, white solid, mp 223-224 °C.

1H NMR (300 MHz, CD3OD) δ 7.74 (d, J = 5.13 Hz, 1H), 7.52 (s, 1H), 6.99 (d, J = 8.43 Hz, 1H), 6.74 (dd, J = 8.25, 2.37 Hz, 1H), 6.64 (s, 1H), 6.63 (d, J = 2.37 Hz, 1H), 6.45-6.41 (m, 2H), 3.89-3.81 (m, 7H), 3.76 (s, 3H), 3.14 (t, J = 6.78 Hz, 2H), 2.75 (t, J = 6.93 Hz, 2H), 2.17 (d, J = 0.93 Hz, 3H), 1.89 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C23H30N6O3 [M + H]+ 439.1837, found 439.1847. 1 H NMR (300 MHz, CD 3 OD) δ 7.74 (d, J = 5.13 Hz, 1H), 7.52 (s, 1H), 6.99 (d, J = 8.43 Hz, 1H), 6.74 (dd, J = 8.25 , 2.37 Hz, 1H), 6.64 (s, 1H), 6.63 (d, J = 2.37 Hz, 1H), 6.45-6.41 (m, 2H), 3.89-3.81 (m, 7H), 3.76 (s, 3H) , 3.14 (t, J = 6.78 Hz, 2H), 2.75 (t, J = 6.93 Hz, 2H), 2.17 (d, J = 0.93 Hz, 3H), 1.89 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C 23 H 30 N 6 O 3 [M + H] + 439.1837, found 439.1847.

<실시예 39> 1-(4-(2-아미노피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 39> 1-(4-(2-aminopyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole Preparation of -1-yl)propyl)urea

Figure 112019061617410-pat00076
Figure 112019061617410-pat00076

단계 1: tert-뷰틸 4-(4-(3,4-다이메톡시페닐아미노)뷰틸)피리딘-2-일카바메이트의 제조Step 1: Preparation of tert-butyl 4-(4-(3,4-dimethoxyphenylamino)butyl)pyridin-2-ylcarbamate

설폰아마이드 혼합물이 tert-뷰틸(4-(4-((N-(3,4-다이메톡시페닐)-2-나이트로페닐)설폰아마이도)뷰틸)피리딘-2-일)카바메이트인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 tert-뷰틸 4-(4-(3,4-다이메톡시페닐아미노)뷰틸)피리딘-2-일카바메이트를 제조하였다.Wherein the sulfonamide mixture is tert-butyl(4-(4-((N-(3,4-dimethoxyphenyl)-2-nitrophenyl)sulfonamide)butyl)pyridin-2-yl)carbamate. Tert-butyl 4-(4-(3,4-dimethoxyphenylamino)butyl)pyridin-2-ylcarbamate was prepared by performing the same method as in General Preparation Procedure 6.

수율 56%, 약간 갈색의 고체.Yield 56%, slightly brownish solid.

1H NMR (300 MHz, CDCl3) δ 8.09 (d, J = 5.13 Hz, 1H), 7.80 (s, 1H), 7.76 (br, 1H), 6.78 (dd, J = 5.13 Hz, 1H), 6.73 (d, J = 8.43 Hz, 1H), 6.28 (d, J = 2.40 Hz, 1H), 6.19 (dd, J = 8.25, 2.19 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.07 (t, J = 6.78 Hz, 2H), 2.63 (d, J = 7.14 Hz, 2H), 1.74-1.65 (m, 4H), 1.51 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (d, J = 5.13 Hz, 1H), 7.80 (s, 1H), 7.76 (br, 1H), 6.78 (dd, J = 5.13 Hz, 1H), 6.73 (d, J = 8.43 Hz, 1H), 6.28 (d, J = 2.40 Hz, 1H), 6.19 (dd, J = 8.25, 2.19 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H) , 3.07 (t, J = 6.78 Hz, 2H), 2.63 (d, J = 7.14 Hz, 2H), 1.74-1.65 (m, 4H), 1.51 (s, 9H).

단계 2: 1-(4-(2-아미노피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-(4-(2-aminopyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1 Preparation of -yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 tert-뷰틸 4-(4-(3,4-다이메톡시페닐아미노)뷰틸)피리딘-2-일카바메이트인 상기 일반적인 제조절차 2와 동일한 방법을 수행한 다음, 상기 일반적인 제조절차 3와 동일한 방법을 수행하여 1-(4-(2-아미노피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The above general preparation wherein N-substituted 3,4-dimethoxyaniline is tert-butyl 4-(4-(3,4-dimethoxyphenylamino)butyl)pyridin-2-ylcarbamate obtained in step 1 above. After carrying out the same method as in Step 2, 1-(4-(2-aminopyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl) by carrying out the same method as in General Preparation Step 3 above. )-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 94%, 흰색 고체, 150-151 ℃.Yield 94%, white solid, 150-151 °C.

1H NMR (300 MHz, CD3OD) δ 7.71 (d, J = 5.31 Hz, 1H), 7.53 (s, 1H), 6.98 (d, J = 8.43 Hz, 1H), 6.77 (d, J = 2.37 Hz, 1H), 6.72 (dd, J = 8.43, 2.40 Hz, 1H), 6.64 (s, 1H), 6.41 (d, J = 5.31 Hz, 1H), 6.38 (s, 1H), 3.87 (t, J = 7.14 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.63 (t, J = 7.32 Hz, 2H), 3.11 (t, J = 6.60 Hz, 2H), 2.48 (t, J = 7.14 Hz, 2H), 2.16 (d, J = 0.93 Hz, 3H), 1.83 (quintet, J = 7.14 Hz, 2H), 1.64-1.46 (m, 4H); HRMS (ESI) calc. for C25H35N6O3 [M + H]+ 467.2765, found 467.2767. 1 H NMR (300 MHz, CD 3 OD) δ 7.71 (d, J = 5.31 Hz, 1H), 7.53 (s, 1H), 6.98 (d, J = 8.43 Hz, 1H), 6.77 (d, J = 2.37 Hz, 1H), 6.72 (dd, J = 8.43, 2.40 Hz, 1H), 6.64 (s, 1H), 6.41 (d, J = 5.31 Hz, 1H), 6.38 (s, 1H), 3.87 (t, J = 7.14 Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.63 (t, J = 7.32 Hz, 2H), 3.11 (t, J = 6.60 Hz, 2H), 2.48 (t, J = 7.14 Hz, 2H), 2.16 (d, J = 0.93 Hz, 3H), 1.83 (quintet, J = 7.14 Hz, 2H), 1.64-1.46 (m, 4H); HRMS (ESI) calc. for C 25 H 35 N 6 O 3 [M + H] + 467.2765, found 467.2767.

<실시예 40> 1-(4-(2-(2-아미노에틸아미노)피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 40> 1-(4-(2-(2-aminoethylamino)pyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5- Preparation of methyl-1H-imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00077
Figure 112019061617410-pat00077

단계 1: tert-뷰틸 (2-((tert-뷰톡시카보닐)아미노)에틸)(4-(4-((3,4-다이메톡시페닐)아미노)뷰틸)피리딘-2-일)카바메이트의 제조Step 1: tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)(4-(4-((3,4-dimethoxyphenyl)amino)butyl)pyridin-2-yl)carba Preparation of Mate

설폰아마이드 혼합물이 tert-뷰틸(2-((tert-뷰톡시카보닐)아미노)에틸)(4-(4-((N-(3,4-다이메톡시페닐)-2-나이트로페닐)설폰아마이도)뷰틸)피리딘-2-일)카바메이트인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 tert-뷰틸 (2-((tert-뷰톡시카보닐)아미노)에틸)(4-(4-((3,4-다이메톡시페닐)아미노)뷰틸)피리딘-2-일)카바메이트를 제조하였다.The sulfonamide mixture is tert-butyl(2-((tert-butoxycarbonyl)amino)ethyl)(4-(4-((N-(3,4-dimethoxyphenyl)-2-nitrophenyl)) Sulfonamido)butyl)pyridin-2-yl)carbamate, tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)(4-(4 -((3,4-dimethoxyphenyl)amino)butyl)pyridin-2-yl)carbamate was prepared.

수율 71%, 약간 갈색의 고체.Yield 71%, slightly brownish solid.

1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.49 (s, 1H), 6.97 (d, J = 5.43 Hz, 1H), 6.87-6.77 (m, 3H), 4.03 (br, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.24 (br, 2H), 3.14 (br, 2H), 2.72 (br, 2H), 1.80-1.58 (m, 4H), 1.43 (s, 9H), 1.27 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.49 (s, 1H), 7.49 (s, 1H), 6.97 (d, J = 5.43 Hz, 1H), 6.87-6.77 (m, 3H), 4.03 (br, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.24 (br, 2H), 3.14 (br, 2H), 2.72 (br, 2H), 1.80-1.58 (m, 4H), 1.43 (s , 9H), 1.27 (s, 9H).

단계 2: 1-(4-(2-(2-아미노에틸아미노)피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-(4-(2-(2-aminoethylamino)pyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl- Preparation of 1H-imidazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 tert-뷰틸 (2-((tert-뷰톡시카보닐)아미노)에틸)(4-(4-((3,4-다이메톡시페닐)아미노)뷰틸)피리딘-2-일)카바메이트인 상기 일반적인 제조절차 2와 동일한 방법을 수행한 다음, 상기 일반적인 제조절차 3와 동일한 방법을 수행하여 1-(4-(2-(2-아미노에틸아미노)피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.N-substituted 3,4-dimethoxyaniline is obtained in step 1 above tert-butyl (2-((tert-butoxycarbonyl) amino) ethyl) (4-(4-((3,4-di Methoxyphenyl) amino) butyl) pyridin-2-yl) carbamate, 1-(4-(2-( 2-Aminoethylamino)pyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea Was prepared.

수율 89%, 흰색 고체, mp 64-65 ℃.Yield 89%, white solid, mp 64-65 °C.

1H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 5.13 Hz, 1H), 7.28 (s, 1H), 6.79 (d, J = 8.40 Hz, 1H), 6.65 (d, J = 2.37 Hz, 1H), 6.63 (dd, J = 8.43, 2.37 Hz, 1H), 6.58 (d, J = 2.22 Hz, 1H), 6.31 (d, J = 4.02 Hz, 1H), 6.14 (s, 1H), 4.69 (br, 1H), 4.16 (t, J = 6.06 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.75 (t, J = 6.96 Hz, 2H), 3.58 (t, J = 6.93 Hz, 2H), 3.27 (q, J = 5.67 Hz, 2H), 3.10 (q, J = 6.24 Hz, 2H), 2.87 (t, J = 5.70 Hz, 2H), 2.42 (t, J = 7.14 Hz, 2H), 2.07 (s, 3H), 1.78 (quintet, J = 7.14 Hz, 2H), 1.56-1.42 (m, 4H); HRMS (ESI) calc. for C27H40N7O3 [M + H]+ 510.3187, found 510.3186. 1 H NMR (300 MHz, CDCl 3 ) δ 7.87 (d, J = 5.13 Hz, 1H), 7.28 (s, 1H), 6.79 (d, J = 8.40 Hz, 1H), 6.65 (d, J = 2.37 Hz , 1H), 6.63 (dd, J = 8.43, 2.37 Hz, 1H), 6.58 (d, J = 2.22 Hz, 1H), 6.31 (d, J = 4.02 Hz, 1H), 6.14 (s, 1H), 4.69 (br, 1H), 4.16 (t, J = 6.06 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.75 (t, J = 6.96 Hz, 2H), 3.58 (t, J = 6.93 Hz, 2H), 3.27 (q, J = 5.67 Hz, 2H), 3.10 (q, J = 6.24 Hz, 2H), 2.87 (t, J = 5.70 Hz, 2H), 2.42 (t, J = 7.14 Hz , 2H), 2.07 (s, 3H), 1.78 (quintet, J = 7.14 Hz, 2H), 1.56-1.42 (m, 4H); HRMS (ESI) calc. for C 27 H 40 N 7 O 3 [M + H] + 510.3187, found 510.3186.

<실시예 41> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-페닐우레아의 제조<Example 41> Preparation of 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-phenylurea

Figure 112019061617410-pat00078
Figure 112019061617410-pat00078

톨루엔 용매의 3,4-다이메톡시-N-페닐아닐린 수용액 (1.0 eq)을 0 ℃까지 냉각한 후, 피리딘 (1.0 eq), 트리포스젠 (0.34 eq)를 첨가하였다. 반응 혼합물을 70 ℃에서 2시간 동안 교반한 후, 0 ℃까지 냉각하였다. 다음, 3-(5-메틸-1H-이미다졸-1-일)프로페인-1-아민 (1.0 eq)과 피리딘 (1.0 eq)를 첨가하고, 반응 혼합물을 밤새 reflux 하였다. 다음, 혼합물을 NaHCO3 수용액, 물, 브라인(brine)으로 헹군 후, 진공(in vacuo)에서 농축시켰다. 잔여물을 실리카겔 크로마토그래피로 정제하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-페닐우레아를 제조하였다.After cooling an aqueous 3,4-dimethoxy-N-phenylaniline solution (1.0 eq) in a toluene solvent to 0°C, pyridine (1.0 eq) and triposgene (0.34 eq) were added. The reaction mixture was stirred at 70 °C for 2 hours and then cooled to 0 °C. Next, 3-(5-methyl-1H-imidazol-1-yl)propane-1-amine (1.0 eq) and pyridine (1.0 eq) were added, and the reaction mixture was refluxed overnight. Next, the mixture was rinsed with NaHCO 3 aqueous solution, water, brine, and then concentrated in vacuo. The residue was purified by silica gel chromatography to prepare 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-phenylurea. I did.

수율 51%, 흰색 고체, mp 117-118 ℃.Yield 51%, white solid, mp 117-118 °C.

1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 7.33-7.22 (m, 4H), 7.13 (t, J = 7.14 Hz, 1H), 6.85-6.80 (m, 2H), 6.78 (s, 1H), 6.73 (s, 1H), 4.63 (t, J = 5.85 Hz, 1H), 3.87 (t, J = 7.32 Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.23 (q, J = 6.24 Hz, 2H), 2.15 (s, 3H), 1.95 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C22H27N4O3 [M + H]+ 395.2078, found 395.2080. 1 H NMR (300 MHz, CDCl 3 ) δ 7.46 (s, 1H), 7.33-7.22 (m, 4H), 7.13 (t, J = 7.14 Hz, 1H), 6.85-6.80 (m, 2H), 6.78 ( s, 1H), 6.73 (s, 1H), 4.63 (t, J = 5.85 Hz, 1H), 3.87 (t, J = 7.32 Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.23 (q, J = 6.24 Hz, 2H), 2.15 (s, 3H), 1.95 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C 22 H 27 N 4 O 3 [M + H] + 395.2078, found 395.2080.

<실시예 42> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(옥사졸-2-일)우레아의 제조<Example 42> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(oxazol-2-yl) Urea production

Figure 112019061617410-pat00079
Figure 112019061617410-pat00079

단계 1: N-(3,4-다이메톡시페닐)옥사졸-2-아민의 제조Step 1: Preparation of N-(3,4-dimethoxyphenyl)oxazol-2-amine

CH2Cl2 용매의 3,4-다이메톡시아닐린 수용액을 0 ℃까지 냉각시키고, CH2Cl2 용매의 페닐클로로포름산염과 트리에틸아민을 차례로 천천히 첨가하였다. 다음, 반응 혼합물을 상온에서 30분간 교반하고 2,2-다이메톡시에테인-1-아민을 첨가하였다. 밤새 교반한 후 혼합물을 CH2Cl2로 묽히고, H20로 헹구고, 진공에서(in vacuo) 농축시켰다. 잔여물을 실리카겔 컬럼 크로마토그래피로 정제하여 황백색 고체의 우레아를 91% 수율로 얻었다.CH 2 Cl cooled to 3,4-dimethoxy aniline in aqueous solution to the second solvent ℃ 0, was added slowly phenyl chloroform salt and triethylamine in CH 2 Cl 2 solvent in sequence. Next, the reaction mixture was stirred at room temperature for 30 minutes, and 2,2-dimethoxyethane-1-amine was added. After stirring overnight, the mixture was diluted with CH 2 Cl 2 , rinsed with H 2 O, and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain urea as an off-white solid in 91% yield.

1H NMR (300 MHz, CDCl3) δ 6.97 (d, J = 2.37 Hz, 1H), 6.77 (d, J = 8.61 Hz, 1H), 6.69 (dd, J = 8.61, 2.40 Hz, 1H), 6.42 (br, 1H), 4.38 (t, J = 5.13 Hz, 2H), 3.85-3.84 (m, 6H), 3.40-3.34 (m, 8H) 1 H NMR (300 MHz, CDCl 3 ) δ 6.97 (d, J = 2.37 Hz, 1H), 6.77 (d, J = 8.61 Hz, 1H), 6.69 (dd, J = 8.61, 2.40 Hz, 1H), 6.42 (br, 1H), 4.38 (t, J = 5.13 Hz, 2H), 3.85-3.84 (m, 6H), 3.40-3.34 (m, 8H)

상기에서 얻은 우레아(in MeOH)에 HCl(in MeOH) 수용액 (v:v=1:1)을 상온에서 첨가하였다. 2시간 교반한 다음, 반응 혼합물 NaHCO3 수용액으로 염기화한 다음, CH2Cl2으로 추출하였다. 다음, 유기층을 H20로 헹군다음 농축시켜 N-(3,4-다이메톡시페닐)옥사졸-2-아민을 제조하였다.HCl (in MeOH) aqueous solution (v:v=1:1) was added to the obtained urea (in MeOH) at room temperature. After stirring for 2 hours, the reaction mixture was basified with an aqueous NaHCO 3 solution and extracted with CH 2 Cl 2. Next, the organic layer was rinsed with H 2 O and then concentrated to prepare N-(3,4-dimethoxyphenyl)oxazol-2-amine.

수율 55%, 약간 갈색의 고체.Yield 55%, slightly brownish solid.

1H NMR (300 MHz, CD3OD) δ 7.21 (d, J = 1.83 Hz, 1H), 7.05-6.98 (m, 2H), 6.73 (d, J = 3.09 Hz, 1H), 6.52 (d, J = 2.91 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H). 1 H NMR (300 MHz, CD 3 OD) δ 7.21 (d, J = 1.83 Hz, 1H), 7.05-6.98 (m, 2H), 6.73 (d, J = 3.09 Hz, 1H), 6.52 (d, J = 2.91 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(옥사졸-2-일)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(oxazol-2-yl)urea Produce

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3,4-다이메톡시페닐)옥사졸-2-아민인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(옥사졸-2-일)우레아를 제조하였다.The N-substituted 3,4-dimethoxyaniline is N-(3,4-dimethoxyphenyl)oxazol-2-amine obtained in Step 1, by following the same method as in General Preparation Procedure 2 (3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(oxazol-2-yl)urea was prepared.

수율 61%, 흰색 고체, mp 139-140 ℃.Yield 61%, white solid, mp 139-140 °C.

1H NMR (300 MHz, CDCl3) δ 8.81 (t, J = 5.44 Hz, 1H), 7.42 (s, 1H), 7.07-7.05 (m, 2H), 6.94-6.82 (m, 2H), 6.72 (s, 1H), 6.53 (d, J = 3.30 Hz, 1H), 3.91-3.82 (m, 8H), 3.37 (q, J = 6.03 Hz, 2H), 2.15 (d, J = 0.90 Hz, 3H), 1.99 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C19H24N5O4 [M + H]+ 386.1823, found 386.1839. 1 H NMR (300 MHz, CDCl 3 ) δ 8.81 (t, J = 5.44 Hz, 1H), 7.42 (s, 1H), 7.07-7.05 (m, 2H), 6.94-6.82 (m, 2H), 6.72 ( s, 1H), 6.53 (d, J = 3.30 Hz, 1H), 3.91-3.82 (m, 8H), 3.37 (q, J = 6.03 Hz, 2H), 2.15 (d, J = 0.90 Hz, 3H), 1.99 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C 19 H 24 N 5 O 4 [M + H] + 386.1823, found 386.1839.

<실시예 43> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(티아졸-2-일)우레아의 제조<Example 43> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(thiazol-2-yl) Urea production

Figure 112019061617410-pat00080
Figure 112019061617410-pat00080

단계 1: N-(3,4-다이메톡시페닐)싸이아졸-2-아민의 제조Step 1: Preparation of N-(3,4-dimethoxyphenyl)thiazol-2-amine

3,4-다이메톡시아닐린 (1.0 eq), 2-클로로-1,3-싸이아졸 (1.5 eq) 그리고 TsOH (1.5 eq)를 EtOH 용매에서 밤새 reflux 하였다. 반응 혼합물을 H20로 희석시키고, NaHCO3 수용액으로 염기화한 다음 CH2Cl2로 추출하였다. 유기층을 H20로 헹군다음 진공에서(in vacuo) 농축시켰다. 잔여물을 실리카겔 크로마토그래피로 정제하여 N-(3,4-다이메톡시페닐)싸이아졸-2-아민을 제조하였다.3,4-dimethoxyaniline (1.0 eq), 2-chloro-1,3-thiazole (1.5 eq) and TsOH (1.5 eq) were refluxed overnight in EtOH solvent. The reaction mixture was diluted with H 2 O, basified with an aqueous NaHCO 3 solution, and extracted with CH 2 Cl 2. The organic layer was rinsed with H 2 O and then concentrated in vacuo. The residue was purified by silica gel chromatography to prepare N-(3,4-dimethoxyphenyl)thiazol-2-amine.

수율 76%, 흰색 고체.Yield 76%, white solid.

1H NMR (300 MHz, CDCl3) δ 7.25 (d, J = 3.30 Hz, 1H), 6.92 (d, J = 2.19 Hz, 1H), 6.87 (d, J = 2.37 Hz, 1H), 6.85 (s, 1H), 6.53 (d, J = 3.66 Hz, 1H), 3.86 (s, 6H). ESI-MS [M + H]+ 236. 1 H NMR (300 MHz, CDCl 3 ) δ 7.25 (d, J = 3.30 Hz, 1H), 6.92 (d, J = 2.19 Hz, 1H), 6.87 (d, J = 2.37 Hz, 1H), 6.85 (s , 1H), 6.53 (d, J = 3.66 Hz, 1H), 3.86 (s, 6H). ESI-MS [M + H] + 236.

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(티아졸-2-일)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(thiazol-2-yl)urea Produce

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3,4-다이메톡시페닐)싸이아졸-2-아민인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(티아졸-2-일)우레아를 제조하였다.N-substituted 3,4-dimethoxyaniline is N-(3,4-dimethoxyphenyl)thiazol-2-amine obtained in step 1, by performing the same method as in the general preparation procedure 2, 1- (3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(thiazol-2-yl)urea was prepared.

수율 62%, 흰색 고체, mp 140-141 ℃.Yield 62%, white solid, mp 140-141 °C.

1H NMR (300 MHz, CD3OD) δ 7.58 (d, J = 1.08 Hz, 1H), 7.27 (d, J = 3.66 Hz, 1H), 7.11 (d, J = 8.43 Hz, 1H), 7.02 (d, J = 3.87 Hz, 1H), 6.93-6.87 (m, 2H), 6.65 (s, 1H), 4.00 (t, J = 6.96 Hz, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.26 (t, J = 6.66 Hz, 2H), 2.21 (d, J = 1.08 Hz, 3H), 2.01 (quintet, J = 6.75 Hz, 2H); HRMS (ESI) calc. for C19H24N5O3S 402.1594, found 402.1599. 1 H NMR (300 MHz, CD 3 OD) δ 7.58 (d, J = 1.08 Hz, 1H), 7.27 (d, J = 3.66 Hz, 1H), 7.11 (d, J = 8.43 Hz, 1H), 7.02 ( d, J = 3.87 Hz, 1H), 6.93-6.87 (m, 2H), 6.65 (s, 1H), 4.00 (t, J = 6.96 Hz, 2H), 3.95 (s, 3H), 3.81 (s, 3H) ), 3.26 (t, J = 6.66 Hz, 2H), 2.21 (d, J = 1.08 Hz, 3H), 2.01 (quintet, J = 6.75 Hz, 2H); HRMS (ESI) calc. for C 19 H 24 N 5 O 3 S 402.1594, found 402.1599.

<실시예 44> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피페리딘-4-일)우레아의 제조<Example 44> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(piperidin-4-yl ) Preparation of urea

Figure 112019061617410-pat00081
Figure 112019061617410-pat00081

실시예 49의 화합물에 Pd/C (10 mol%)와 HCl 2 방울 (in MeOH)가 수소 벌룬으로 1시간 동안 수소화하였다. 다음, 혼합물을 셀라이트(Celite)를 통해 필터하고, MeOH로 헹구었다. 여과된 액체를 진공에서(in vacuo) 농축시킨 후 잔여물을 PLC로 정제하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피페리딘-4-일)우레아를 제조하였다.The compound of Example 49 was hydrogenated with Pd/C (10 mol%) and 2 drops of HCl (in MeOH) for 1 hour with a hydrogen balloon. Next, the mixture was filtered through Celite and rinsed with MeOH. The filtered liquid was concentrated in vacuo and the residue was purified by PLC to 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1- Il)propyl)-1-(piperidin-4-yl)urea was prepared.

수율 93%, 흰색 고체, mp 11-121 ℃.Yield 93%, white solid, mp 11-121 °C.

1H NMR (300 MHz, CD3OD) δ 7.52 (s, 1H), 7.02 (d, J = 8.25 Hz, 1H), 6.73 (dd, J = 8.46, 2.37 Hz, 1H), 6.64 (s, 1H), 3.87 (t, J = 7.14 Hz, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.11 (t, J = 6.75 Hz, 2H), 3.01 (d, J = 12.27 Hz, 2H), 2.68-2.60 (m, 2H), 2.17 (d, J = 0.93 Hz, 3H), 1.84-1.79 (m, 4H), 1.29 (qd, J = 12.09, 4.32 Hz, 2H); HRMS (ESI) calc. for C21H32N5O3 [M + H]+ 402.2500, found 402.2491. 1 H NMR (300 MHz, CD 3 OD) δ 7.52 (s, 1H), 7.02 (d, J = 8.25 Hz, 1H), 6.73 (dd, J = 8.46, 2.37 Hz, 1H), 6.64 (s, 1H ), 3.87 (t, J = 7.14 Hz, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.11 (t, J = 6.75 Hz, 2H), 3.01 (d, J = 12.27 Hz, 2H) ), 2.68-2.60 (m, 2H), 2.17 (d, J = 0.93 Hz, 3H), 1.84-1.79 (m, 4H), 1.29 (qd, J = 12.09, 4.32 Hz, 2H); HRMS (ESI) calc. for C 21 H 32 N 5 O 3 [M + H] + 402.2500, found 402.2491.

<실시예 45> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-메틸피레리딘-4-일)우레아의 제조<Example 45> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-methylpyreridine- 4-day) Preparation of urea

Figure 112019061617410-pat00082
Figure 112019061617410-pat00082

단계 1: N-(3,4-다이메톡시페닐)-1-메틸피페리딘-4-아민의 제조Step 1: Preparation of N-(3,4-dimethoxyphenyl)-1-methylpiperidin-4-amine

케톤 혹은 알데하이드가 N-메틸-4-피페리돈 하이드로클로라이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(3,4-다이메톡시페닐)-1-메틸피페리딘-4-아민을 제조하였다.N-(3,4-dimethoxyphenyl)-1-methylpiperidin-4-amine was prepared by following the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is N-methyl-4-piperidone hydrochloride. Was prepared.

수율 85%, 엷은 갈색 고체.Yield 85%, pale brown solid.

1H NMR (300 MHz, CDCl3) δ 6.71 (d, J = 8.43 Hz, 1H), 6.21 (d, J = 2.55 Hz, 1H), 6.14 (dd, J = 8.43, 2.58 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.22-3.16 (m, 1H), 2.83-2.79 (br, 2H), 2.29 (s, 3H), 2.15-2.01 (m, 4H), 1.52-1.40 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.71 (d, J = 8.43 Hz, 1H), 6.21 (d, J = 2.55 Hz, 1H), 6.14 (dd, J = 8.43, 2.58 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.22-3.16 (m, 1H), 2.83-2.79 (br, 2H), 2.29 (s, 3H), 2.15-2.01 (m, 4H), 1.52-1.40 (m, 2H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-메틸피레리딘-4-일)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-methylpyreridine-4- Work) urea production

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3,4-다이메톡시페닐)-1-메틸피페리딘-4-아민인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-메틸피레리딘-4-일)우레아를 제조하였다.The same method as in General Preparation Procedure 2, wherein the N-substituted 3,4-dimethoxyaniline is N-(3,4-dimethoxyphenyl)-1-methylpiperidin-4-amine obtained in step 1 above. To 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-methylpyreridine-4- Il) Urea was prepared.

수율 65%, 흰색 고체, mp 85-86 ℃.Yield 65%, white solid, mp 85-86 °C.

1H NMR (300 MHz, CD3OD) δ 7.54 (s, 1H), 7.02 (d, J = 9.15 Hz, 1H), 6.75-6.71 (m, 2H), 6.64 (s, 1H), 4.36-4.28 (m, 1H), 3.89-3.84 (m, 5H), 3.81 (s, 3H), 3.10 (t, J = 6.78 Hz, 2H), 2.88 (d, J = 11.73 Hz, 2H), 2.20 (s, 3H), 2.17 (d, J = 0.93 Hz, 3H), 2.14 (t, J = 5.13 Hz, 2H), 1.86-1.79 (m, 4H), 1.52-1.36 (m, 2H); HRMS (ESI) calc. for C22H34N5O3 416.2656, found 416.2655. 1 H NMR (300 MHz, CD 3 OD) δ 7.54 (s, 1H), 7.02 (d, J = 9.15 Hz, 1H), 6.75-6.71 (m, 2H), 6.64 (s, 1H), 4.36-4.28 (m, 1H), 3.89-3.84 (m, 5H), 3.81 (s, 3H), 3.10 (t, J = 6.78 Hz, 2H), 2.88 (d, J = 11.73 Hz, 2H), 2.20 (s, 3H), 2.17 (d, J = 0.93 Hz, 3H), 2.14 (t, J = 5.13 Hz, 2H), 1.86-1.79 (m, 4H), 1.52-1.36 (m, 2H); HRMS (ESI) calc. for C 22 H 3 4 N 5 O 3 416.2656, found 416.2655.

<실시예 46> 1-(3,4-다이메톡시페닐)-1-(1-에틸피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 46> 1-(3,4-dimethoxyphenyl)-1-(1-ethylpiperidin-4-yl)-3-(3-(5-methyl-1H-imidazole-1- 1) Preparation of propyl) urea

Figure 112019061617410-pat00083
Figure 112019061617410-pat00083

단계 1: N-(3,4-다이메톡시페닐)-1-에틸피페리딘-4-아민의 제조Step 1: Preparation of N-(3,4-dimethoxyphenyl)-1-ethylpiperidin-4-amine

케톤 혹은 알데하이드가 N-에틸-4-피페리돈 하이드로클로라이드인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(3,4-다이메톡시페닐)-1-에틸피페리딘-4-아민을 제조하였다.N-(3,4-dimethoxyphenyl)-1-ethylpiperidin-4-amine was prepared in the same manner as in General Preparation Procedure 5, wherein the ketone or aldehyde is N-ethyl-4-piperidone hydrochloride. Was prepared.

수율 76%, 엷은 갈색 고체.Yield 76%, light brown solid.

1H NMR (300 MHz, CDCl3) δ 6.71 (d, J = 8.40 Hz, 1H), 6.22 (d, J = 2.55 Hz, 1H), 6.13 (dd, J = 8.61, 2.76 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.26 (br, 1H), 2.99 (d-like, 2H), 2.54 (q-like, 2H), 2.23-2.01 (m, 4H), 1.61 (q-like, 2H), 1.16 (t, J = 7.14 Hz, 3H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.71 (d, J = 8.40 Hz, 1H), 6.22 (d, J = 2.55 Hz, 1H), 6.13 (dd, J = 8.61, 2.76 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.26 (br, 1H), 2.99 (d-like, 2H), 2.54 (q-like, 2H), 2.23-2.01 (m, 4H), 1.61 (q -like, 2H), 1.16 (t, J = 7.14 Hz, 3H).

단계 2: 1-(3,4-다이메톡시페닐)-1-(1-에틸피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-1-(1-ethylpiperidin-4-yl)-3-(3-(5-methyl-1H-imidazol-1-yl) Profile) urea production

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3,4-다이메톡시페닐)-1-에틸피페리딘-4-아민인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-(1-에틸피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The same method as in General Preparation Procedure 2, wherein the N-substituted 3,4-dimethoxyaniline is N-(3,4-dimethoxyphenyl)-1-ethylpiperidin-4-amine obtained in step 1 above. To 1-(3,4-dimethoxyphenyl)-1-(1-ethylpiperidin-4-yl)-3-(3-(5-methyl-1H-imidazol-1-yl) Propyl) urea was prepared.

수율 51%, 흰색 고체, mp 76-77 ℃.Yield 51%, white solid, mp 76-77 °C.

1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), 6.79 (d, J = 8.43 Hz, 1H), 6.65 (s, 1H), 6.62 (dd, J = 8.40, 2.37 Hz, 1H), 6.52 (d, J = 2.37 Hz, 1H), 4.43-4.34 (m, 1H), 4.04 (t, J = 6.06 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.76 (t, J = 7.32 Hz, 2H), 3.12 (q, J = 6.39 Hz, 2H), 2.93-2.89 (br, 2H), 2.35 (q, J = 7.14 Hz, 2H), 2.07 (d, J = 0.90 Hz, 3H), 2.03-1.96 (m, 2H), 1.82-1.72 (m, 4H), 1.44-1.33 (m, 2H), 0.99 (t, J = 7.14 Hz, 3H); HRMS (ESI) calc. for C23H36N5O3 430.2813, found 430.2813. 1 H NMR (300 MHz, CDCl 3 ) δ 7.26 (s, 1H), 6.79 (d, J = 8.43 Hz, 1H), 6.65 (s, 1H), 6.62 (dd, J = 8.40, 2.37 Hz, 1H) , 6.52 (d, J = 2.37 Hz, 1H), 4.43-4.34 (m, 1H), 4.04 (t, J = 6.06 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.76 ( t, J = 7.32 Hz, 2H), 3.12 (q, J = 6.39 Hz, 2H), 2.93-2.89 (br, 2H), 2.35 (q, J = 7.14 Hz, 2H), 2.07 (d, J = 0.90 Hz, 3H), 2.03-1.96 (m, 2H), 1.82-1.72 (m, 4H), 1.44-1.33 (m, 2H), 0.99 (t, J = 7.14 Hz, 3H); HRMS (ESI) calc. for C 23 H 36 N 5 O 3 430.2813, found 430.2813.

<실시예 47> 1-(1-아세틸피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조 < Example 47> 1-(1-acetylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1- 1) Preparation of propyl) urea

Figure 112019061617410-pat00084
Figure 112019061617410-pat00084

단계 1: 1-(4-((3,4-다이메톡시페닐)아미노)피페리딘-1-일)에테인-1-온의 제조Step 1: Preparation of 1-(4-((3,4-dimethoxyphenyl)amino)piperidin-1-yl)ethane-1-one

케톤 혹은 알데하이드가 1-아세틸피페리딘-4-온인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 1-(4-((3,4-다이메톡시페닐)아미노)피페리딘-1-일)에테인-1-온을 제조하였다.1-(4-((3,4-dimethoxyphenyl)amino)piperidin-1-yl by following the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is 1-acetylpiperidin-4-one. ) Ethein-1-one was prepared.

수율 94%, 갈색 고체.Yield 94%, brown solid.

1H NMR (300MHz, CDCl3) δ 6.72 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 4.65-4.55 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H),3.78-3.71 (m, 1H), 3.26-3.18 (m, 1H), 3.16-3.05 (m, 1H), 2.56-2.51 (m, 1H),1.99 (s, 3H), 1.82-1.76 (m, 2H), 1.38-1.12 (m, 2H). 1 H NMR (300MHz, CDCl 3 ) δ 6.72 (d, J = 8.43 Hz, 1H), 6.25 (d, J = 2.55 Hz, 1H), 6.17 (dd, J = 8.43, 2.58 Hz, 1H), 4.65- 4.55 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.78-3.71 (m, 1H), 3.26-3.18 (m, 1H), 3.16-3.05 (m, 1H), 2.56- 2.51 (m, 1H), 1.99 (s, 3H), 1.82-1.76 (m, 2H), 1.38-1.12 (m, 2H).

단계 2: 1-(1-아세틸피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-(1-acetylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl) Profile) urea production

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3,4-다이메톡시페닐)-1-아세틸피페리딘-4-아민인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(1-아세틸피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.N-substituted 3,4-dimethoxyaniline is N-(3,4-dimethoxyphenyl)-1-acetylpiperidin-4-amine obtained in step 1, the same method as in the general preparation procedure 2 1-(1-acetylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl) Propyl) urea was prepared.

수율 84%, 흰색 고체, mp 58-59 ℃.Yield 84%, white solid, mp 58-59 °C.

1H NMR (300 MHz, CDCl3) δ 7.27 (s, 1H), 6.81 (d, J = 8.43 Hz, 1H), 6.66 (s, 1H), 6.58 (dd, J = 8.25, 2.22 Hz, 1H), 6.48 (d, J = 2.37 Hz, 1H), 4.63-4.55 (m, 2H), 4.02 (t, J = 4.41 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.74 (t, J = 7.14 Hz, 2H), 3.79-3.72 (m, 1H), 3.13-3.05 (m, 3H), 2.53 (t, J = 10.8 Hz, 1H), 2.07 (s, 3H), 1.94 (s, 3H), 1.82-1.76 (m, 4H), 1.20-1.12 (m, 2H); HRMS (ESI) calc. for C23H34N5O4 [M + H]+ 444.2605, found 444.2612. 1 H NMR (300 MHz, CDCl 3 ) δ 7.27 (s, 1H), 6.81 (d, J = 8.43 Hz, 1H), 6.66 (s, 1H), 6.58 (dd, J = 8.25, 2.22 Hz, 1H) , 6.48 (d, J = 2.37 Hz, 1H), 4.63-4.55 (m, 2H), 4.02 (t, J = 4.41 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.74 ( t, J = 7.14 Hz, 2H), 3.79-3.72 (m, 1H), 3.13-3.05 (m, 3H), 2.53 (t, J = 10.8 Hz, 1H), 2.07 (s, 3H), 1.94 (s , 3H), 1.82-1.76 (m, 4H), 1.20-1.12 (m, 2H); HRMS (ESI) calc. for C 23 H 3 4 N 5 O 4 [M + H] + 444.2605, found 444.2612.

<실시예 48> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-페닐피페리딘-4-일)우레아의 제조<Example 48> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-phenylpiperidine- 4-day) Preparation of urea

Figure 112019061617410-pat00085
Figure 112019061617410-pat00085

단계 1: N-(3,4-다이메톡시페닐)-1-페닐피페리딘-4-아민의 제조Step 1: Preparation of N-(3,4-dimethoxyphenyl)-1-phenylpiperidin-4-amine

케톤 혹은 알데하이드가 N-페닐-4-피페리돈인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(3,4-다이메톡시페닐)-1-페닐피페리딘-4-아민을 제조하였다.N-(3,4-dimethoxyphenyl)-1-phenylpiperidin-4-amine was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is N-phenyl-4-piperidone. .

수율 49%, 노란색 고체.Yield 49%, yellow solid.

1H NMR (300 MHz, CDCl3) δ 7.22-7.16 (m, 2H), 6.90-6.87 (m, 2H), 6.80 (t, J = 7.14 Hz, 1H), 6.69 (d, J = 8.61 Hz, 1H), 6.20 (d, J = 2.58 Hz, 1H), 6.14 (dd, J = 8.43, 2.58 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.60-3.50 (m, 2H), 3.35-3.26 (m, 1H), 2.87-2.75 (m, 2H), 2.11-2.08 (m, 2H), 1.57-1.44 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.22-7.16 (m, 2H), 6.90-6.87 (m, 2H), 6.80 (t, J = 7.14 Hz, 1H), 6.69 (d, J = 8.61 Hz, 1H), 6.20 (d, J = 2.58 Hz, 1H), 6.14 (dd, J = 8.43, 2.58 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.60-3.50 (m, 2H) ), 3.35-3.26 (m, 1H), 2.87-2.75 (m, 2H), 2.11-2.08 (m, 2H), 1.57-1.44 (m, 2H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-페닐피페리딘-4-일)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-phenylpiperidin-4- Work) urea production

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3,4-다이메톡시페닐)-1-페닐피페리딘-4-아민인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-페닐피페리딘-4-일)우레아를 제조하였다.The same method as in General Preparation Procedure 2, wherein the N-substituted 3,4-dimethoxyaniline is N-(3,4-dimethoxyphenyl)-1-phenylpiperidin-4-amine obtained in step 1 above. To 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-phenylpiperidine-4- Il) Urea was prepared.

수율 56%, 흰색 고체, mp 87-88 ℃.Yield 56%, white solid, mp 87-88 °C.

1H NMR (300 MHz, CDCl3) δ 7.55 (s, 1H), 7.22-7.16 (m, 2H), 6.87-6.84 (m, 3H), 6.82-6.77 (m, 2H), 6.71 (dd, J = 8.43, 2.37 Hz, 1H), 6.59 (d, J = 2.19 Hz, 1H), 4.55-4.50 (m, 1H), 4.11 (t, J = 5.55 Hz, NH), 3.88 (s, 3H), 3.85 (s, 3H), 3.82 (t, J = 7.14 Hz, 2H), 3.65-3.61 (br, 2H), 3.17 (q, J = 6.21 Hz, 2H), 2.84-2.76 (m, 2H), 2.15 (d, J = 0.90 Hz, 3H), 1.87-1.82 (m, 4H), 1.51-1.41 (m, 2H); HRMS (ESI) calc. for C27H36N5O3 478.2813, found 478.2823. 1 H NMR (300 MHz, CDCl 3 ) δ 7.55 (s, 1H), 7.22-7.16 (m, 2H), 6.87-6.84 (m, 3H), 6.82-6.77 (m, 2H), 6.71 (dd, J = 8.43, 2.37 Hz, 1H), 6.59 (d, J = 2.19 Hz, 1H), 4.55-4.50 (m, 1H), 4.11 (t, J = 5.55 Hz, NH), 3.88 (s, 3H), 3.85 (s, 3H), 3.82 (t, J = 7.14 Hz, 2H), 3.65-3.61 (br, 2H), 3.17 (q, J = 6.21 Hz, 2H), 2.84-2.76 (m, 2H), 2.15 ( d, J = 0.90 Hz, 3H), 1.87-1.82 (m, 4H), 1.51-1.41 (m, 2H); HRMS (ESI) calc. for C 27 H 36 N 5 O 3 478.2813, found 478.2823.

<실시예 49> 1-(1-벤질피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 49> 1-(1-Benzylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1- 1) Preparation of propyl) urea

Figure 112019061617410-pat00086
Figure 112019061617410-pat00086

단계 1: 1-벤질-N-(3,4-다이메톡시페닐)피페리딘-4-아민의 제조Step 1: Preparation of 1-benzyl-N- (3,4-dimethoxyphenyl) piperidin-4-amine

케톤 혹은 알데하이드가 N-벤질-4-피페리돈인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 1-벤질-N-(3,4-다이메톡시페닐)피페리딘-4-아민을 제조하였다.1-benzyl-N-(3,4-dimethoxyphenyl)piperidin-4-amine was prepared by performing the same method as in General Preparation Procedure 5, wherein the ketone or aldehyde is N-benzyl-4-piperidone. .

수율 40%, 약간 갈색의 고체.Yield 40%, slightly brownish solid.

1H NMR (300 MHz, CDCl3) δ 7.31-7.21 (m, 5H), 6.70 (d, J = 8.58 Hz, 1H), 6.21 (d, J = 2.55 Hz, 1H), 6.12 (dd, J = 8.43, 2.55 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.51 (s, 2H), 3.25-3.17 (m, 1H), 2.86-2.82 (m, 2H), 2.12 (t, J = 11.52 Hz, 2H), 2.04-1.99 (m, 2H), 1.44 (qd, J = 10.26, 3.27 Hz, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.31-7.21 (m, 5H), 6.70 (d, J = 8.58 Hz, 1H), 6.21 (d, J = 2.55 Hz, 1H), 6.12 (dd, J = 8.43, 2.55 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.51 (s, 2H), 3.25-3.17 (m, 1H), 2.86-2.82 (m, 2H), 2.12 (t , J = 11.52 Hz, 2H), 2.04-1.99 (m, 2H), 1.44 (qd, J = 10.26, 3.27 Hz, 2H).

단계 2: 1-(1-벤질피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-(1-Benzylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl) Profile) urea production

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 1-벤질-N-(3,4-다이메톡시페닐)피페리딘-4-아민인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(1-벤질피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The same method as in General Preparation Procedure 2, wherein the N-substituted 3,4-dimethoxyaniline is 1-benzyl-N-(3,4-dimethoxyphenyl) piperidin-4-amine obtained in step 1 above. To 1-(1-benzylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl) Propyl) urea was prepared.

수율 78%, 흰색 고체, mp 53-55 ℃.Yield 78%, white solid, mp 53-55 °C.

1H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 0.75 Hz, 1H), 7.25-7.16 (m, 5H), 6.84 (d, J = 8.40 Hz, 1H), 6.94 (s, 1H), 6.64 (dd, J = 8.40, 2.19 Hz, 1H), 6.55 (d, J = 2.19 Hz, 1H), 4.43 (tt, J = 12.09, 4.05 Hz, 1H), 4.03 (t, J = 5.67 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.77 (t, J = 7.14 Hz, 2H), 3.42 (s, 2H), 3.12 (q, J = 6.60 Hz, 2H), 2.85 (d, J = 11.37 Hz, 2H), 2.11 (d, J = 0.90 Hz, 3H), 2.07 (t, J = 10.26 Hz, 2H), 1.81 (quintet, J = 7.14 Hz, 2H), 1.76-1.72 (m, 2H), 1.38 (qd, J = 12.09, 3.66 Hz, 2H); HRMS (ESI) calc. for C28H38N5O3 [M + H]+ 492.2969, found 492.2973. 1 H NMR (300 MHz, CDCl 3 ) δ 7.29 (d, J = 0.75 Hz, 1H), 7.25-7.16 (m, 5H), 6.84 (d, J = 8.40 Hz, 1H), 6.94 (s, 1H) , 6.64 (dd, J = 8.40, 2.19 Hz, 1H), 6.55 (d, J = 2.19 Hz, 1H), 4.43 (tt, J = 12.09, 4.05 Hz, 1H), 4.03 (t, J = 5.67 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.77 (t, J = 7.14 Hz, 2H), 3.42 (s, 2H), 3.12 (q, J = 6.60 Hz, 2H), 2.85 ( d, J = 11.37 Hz, 2H), 2.11 (d, J = 0.90 Hz, 3H), 2.07 (t, J = 10.26 Hz, 2H), 1.81 (quintet, J = 7.14 Hz, 2H), 1.76-1.72 ( m, 2H), 1.38 (qd, J = 12.09, 3.66 Hz, 2H); HRMS (ESI) calc. for C 28 H 38 N 5 O 3 [M + H] + 492.2969, found 492.2973.

<실시예 50> 1-(3,4-다이메톡시페닐)-1-(1-(4-플루오로벤질)피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조<Example 50> 1-(3,4-dimethoxyphenyl)-1-(1-(4-fluorobenzyl)piperidin-4-yl)-3-(3-(5-methyl-1H) Preparation of -imidazol-1-yl)propyl)urea

Figure 112019061617410-pat00087
Figure 112019061617410-pat00087

단계 1: N-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)피페리딘-4-아민의 제조Step 1: Preparation of N-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)piperidin-4-amine

케톤 혹은 알데하이드가 N-(4-플루오로벤질)-4-피페리돈인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)피페리딘-4-아민을 제조하였다.N-(3,4-dimethoxyphenyl)-1-(4-fluoro Benzyl) piperidin-4-amine was prepared.

수율 66%, 갈색의 반액체.Yield 66%, brown semi-liquid.

1H NMR (300 MHz, CDCl3) δ 7.26-7.24 (m, 2H), 7.01 (t, J = 8.61 Hz, 2H), 6.71 (d, J = 8.61 Hz, 1H), 6.21 (d, J = 2.37 Hz, 1H), 6.13 (dd, J = 8.61, 2.55 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.48 (s, 2H), 3.20-3.15 (m, 1H), 2.86-2.80 (m, 2H), 2.12-1.99 (m, 4H), 1.46-1.40 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.26-7.24 (m, 2H), 7.01 (t, J = 8.61 Hz, 2H), 6.71 (d, J = 8.61 Hz, 1H), 6.21 (d, J = 2.37 Hz, 1H), 6.13 (dd, J = 8.61, 2.55 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.48 (s, 2H), 3.20-3.15 (m, 1H), 2.86-2.80 (m, 2H), 2.12-1.99 (m, 4H), 1.46-1.40 (m, 2H).

단계 2: 1-(3,4-다이메톡시페닐)-1-(1-(4-플루오로벤질)피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-1-(1-(4-fluorobenzyl)piperidin-4-yl)-3-(3-(5-methyl-1H-imine Preparation of dazol-1-yl)propyl)urea

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)피페리딘-4-아민인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-1-(1-(4-플루오로벤질)피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아를 제조하였다.The general formula wherein N-substituted 3,4-dimethoxyaniline is N-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)piperidin-4-amine obtained in step 1 above. Perform the same method as in Preparation Procedure 2 to obtain 1-(3,4-dimethoxyphenyl)-1-(1-(4-fluorobenzyl)piperidin-4-yl)-3-(3-(5). -Methyl-1H-imidazol-1-yl)propyl)urea was prepared.

수율 45%, 흰색 고체, mp 48-49 ℃.Yield 45%, white solid, mp 48-49 °C.

1H NMR (300 MHz, CDCl3) δ 7.27 (s, 1H), 7.17 (dd, J = 8.43, 5.49 Hz, 2H), 6.91 (t, J = 8.61 Hz, 2H), 6.80 (d, J = 8.43 Hz, 1H), 6.65 (s, 1H), 6.62 (dd, J = 8.43, 2.19 Hz, 1H), 6.51 (d, J = 2.19 Hz, 1H), 4.42-4.34 (m, 1H), 4.01 (t, J = 5.31, NH), 3.83 (s, 3H), 3.78 (s, 3H), 3.75 (t, J = 7.14 Hz, 2H), 3.36 (s, 2H), 3.11 (q, J = 6.03 Hz, 2H), 2.82-2.79 (br, 2H), 2.06 (d, J = 0.90 Hz, 3H), 2.05-2.01 (m, 2H), 1.81 (quintet, J = 6.96 Hz, 2H), 1.74-1.68 (br, 2H), 1.38-1.34 (m, 2H); HRMS (ESI) calc. for C28H37FN5O3 510.2875, found: 510.2871. 1 H NMR (300 MHz, CDCl 3 ) δ 7.27 (s, 1H), 7.17 (dd, J = 8.43, 5.49 Hz, 2H), 6.91 (t, J = 8.61 Hz, 2H), 6.80 (d, J = 8.43 Hz, 1H), 6.65 (s, 1H), 6.62 (dd, J = 8.43, 2.19 Hz, 1H), 6.51 (d, J = 2.19 Hz, 1H), 4.42-4.34 (m, 1H), 4.01 ( t, J = 5.31, NH), 3.83 (s, 3H), 3.78 (s, 3H), 3.75 (t, J = 7.14 Hz, 2H), 3.36 (s, 2H), 3.11 (q, J = 6.03 Hz , 2H), 2.82-2.79 (br, 2H), 2.06 (d, J = 0.90 Hz, 3H), 2.05-2.01 (m, 2H), 1.81 (quintet, J = 6.96 Hz, 2H), 1.74-1.68 ( br, 2H), 1.38-1.34 (m, 2H); HRMS (ESI) calc. for C 28 H 37 FN 5 O 3 510.2875, found: 510.2871.

<실시예 51> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-(피리딘-3-일메틸)피페리딘-4-일)우레아의 제조<Example 51> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-(pyridin-3- Preparation of ylmethyl)piperidin-4-yl)urea

Figure 112019061617410-pat00088
Figure 112019061617410-pat00088

단계 1: N-(3,4-다이메톡시페닐)-1-(피리딘-3-일메틸)피페리딘-4-아민의 제조Step 1: Preparation of N-(3,4-dimethoxyphenyl)-1-(pyridin-3-ylmethyl)piperidin-4-amine

케톤 혹은 알데하이드가 N-(3-피리딜메틸)-4-피페리돈인 상기 일반적인 제조절차 5와 동일한 방법을 수행하여 N-(3,4-다이메톡시페닐)-1-(피리딘-3-일메틸)피페리딘-4-아민을 제조하였다.N-(3,4-dimethoxyphenyl)-1-(pyridin-3- Monomethyl) piperidin-4-amine was prepared.

수율 52%, 갈색 고체.Yield 52%, brown solid.

1H NMR (300 MHz, CDCl3) δ 8.52 (d, J = 1.65 Hz, 1H), 8.49 (dd, J = 4.77, 1.65 Hz, 1H), 7.64 (d, J = 7.89 Hz, 1H), 7.25-7.21 (m, 1H), 6.71 (d, J = 8.61 Hz, 1H), 6.21 (d, J = 2.37 Hz, 1H), 6.12 (dd, J = 8.40, 2.55 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.51 (s, 2H), 3.36 (br, 1H), 3.24-3.17 (m, 1H), 2.83-2.79 (m, 2H), 2.14 (t, J = 11.19 Hz, 2H), 1.04-1.99 (m, 2H), 1.47-1.37 (m, 2H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.52 (d, J = 1.65 Hz, 1H), 8.49 (dd, J = 4.77, 1.65 Hz, 1H), 7.64 (d, J = 7.89 Hz, 1H), 7.25 -7.21 (m, 1H), 6.71 (d, J = 8.61 Hz, 1H), 6.21 (d, J = 2.37 Hz, 1H), 6.12 (dd, J = 8.40, 2.55 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.51 (s, 2H), 3.36 (br, 1H), 3.24-3.17 (m, 1H), 2.83-2.79 (m, 2H), 2.14 (t, J = 11.19 Hz , 2H), 1.04-1.99 (m, 2H), 1.47-1.37 (m, 2H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-(피리딘-3-일메틸)피페리딘-4-일)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-(pyridin-3-ylmethyl ) Piperidin-4-yl) urea preparation

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 N-(3,4-다이메톡시페닐)-1-(피리딘-3-일메틸)피페리딘-4-아민인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-(피리딘-3-일메틸)피페리딘-4-일)우레아를 제조하였다.Wherein the N-substituted 3,4-dimethoxyaniline is N-(3,4-dimethoxyphenyl)-1-(pyridin-3-ylmethyl)piperidin-4-amine obtained in step 1 above. 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1- (Pyridin-3-ylmethyl)piperidin-4-yl)urea was prepared.

수율 74%, 흰색 고체, mp 116-117 ℃.Yield 74%, white solid, mp 116-117 °C.

1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 1.65 Hz, 1H), 8.39 (dd, J = 4.74, 1.65 Hz, 1H), 7.51 (dt, J = 7.68, 1.83 Hz, 1H), 7.26 (s, 1H), 7.14 (dd, J = 7.86, 4.92 Hz, 1H), 6.80 (d, J = 8.43 Hz, 1H), 6.65 (s, 1H), 6.60 (dd, J = 8.43, 2.37 Hz, 1H), 6.51 (d, J = 2.19 Hz, 1H), 4.38 (tt, J = 12.09, 3.87 Hz, 1H), 4.01 (t, J = 5.88 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.73 (t, J = 7.14 Hz, 2H), 3.37 (s, 2H), 3.08 (q, J = 6.21 Hz, 2H), 2.77 (d, J = 11.55 Hz, 2H), 2.16-2.02 (m, 2H), 2.06 (d, J = 0.72 Hz, 3H), 1.77 (quintet, J = 7.14 Hz, 2H), 1.70 (d, J = 10.80 Hz, 2H), 1.32 (qd, J = 12.09, 3.66 Hz, 2H); HRMS (ESI) calc. for C27H36N6O3 [M + H]+ 510.3187, found 510.3188. 1 H NMR (300 MHz, CDCl 3 ) δ 8.40 (d, J = 1.65 Hz, 1H), 8.39 (dd, J = 4.74, 1.65 Hz, 1H), 7.51 (dt, J = 7.68, 1.83 Hz, 1H) , 7.26 (s, 1H), 7.14 (dd, J = 7.86, 4.92 Hz, 1H), 6.80 (d, J = 8.43 Hz, 1H), 6.65 (s, 1H), 6.60 (dd, J = 8.43, 2.37 Hz, 1H), 6.51 (d, J = 2.19 Hz, 1H), 4.38 (tt, J = 12.09, 3.87 Hz, 1H), 4.01 (t, J = 5.88 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.73 (t, J = 7.14 Hz, 2H), 3.37 (s, 2H), 3.08 (q, J = 6.21 Hz, 2H), 2.77 (d, J = 11.55 Hz, 2H), 2.16-2.02 (m, 2H), 2.06 (d, J = 0.72 Hz, 3H), 1.77 (quintet, J = 7.14 Hz, 2H), 1.70 (d, J = 10.80 Hz, 2H), 1.32 (qd, J = 12.09, 3.66 Hz, 2H); HRMS (ESI) calc. for C 27 H 36 N 6 O 3 [M + H] + 510.3187, found 510.3188.

<실시예 52> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-(피페라진-1-일)에틸)우레아의 제조<Example 52> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(2-(piperazin-1) Preparation of -yl)ethyl)urea

Figure 112019061617410-pat00089
Figure 112019061617410-pat00089

단계 1: tert-뷰틸 4-(2-((3,4-다이메톡시페닐)아미노)에틸)피페라진-1-카복실레이트의 제조Step 1: Preparation of tert-butyl 4-(2-((3,4-dimethoxyphenyl)amino)ethyl)piperazine-1-carboxylate

설폰아마이드 혼합물이 tert-뷰틸4-(2-((N-(3,4-다이메톡시페닐)-2-나이트로페닐)설폰아마이도)에틸)피페라진-1-카복실레이트인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 tert-뷰틸 4-(2-((3,4-다이메톡시페닐)아미노)에틸)피페라진-1-카복실레이트를 제조하였다.The above general preparation wherein the sulfonamide mixture is tert-butyl 4-(2-((N-(3,4-dimethoxyphenyl)-2-nitrophenyl)sulfonamide)ethyl)piperazine-1-carboxylate The same procedure as in Procedure 6 was followed to prepare tert-butyl 4-(2-((3,4-dimethoxyphenyl)amino)ethyl)piperazine-1-carboxylate.

수율 84%, 흰색 고체.Yield 84%, white solid.

1H NMR (300 MHz, CDCl3) δ 6.75 (d, J = 8.43 Hz, 1H), 6.26 (d, J = 2.73 Hz, 1H), 6.16 (dd, J = 8.43, 2.58 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.42 (t, J = 4.74 Hz, 4H), 3.13 (t, J = 5.67 Hz, 2H), 2.63 (t, J = 6.03 Hz, 2H), 2.39 (t, J = 4.95 Hz, 4H), 1.43 (s, 9H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.75 (d, J = 8.43 Hz, 1H), 6.26 (d, J = 2.73 Hz, 1H), 6.16 (dd, J = 8.43, 2.58 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.42 (t, J = 4.74 Hz, 4H), 3.13 (t, J = 5.67 Hz, 2H), 2.63 (t, J = 6.03 Hz, 2H), 2.39 (t, J = 4.95 Hz, 4H), 1.43 (s, 9H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-(피페라진-1-일)에틸)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(2-(piperazin-1-yl ) Ethyl) urea production

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 tert-뷰틸 4-(2-((3,4-다이메톡시페닐)아미노)에틸)피페라진-1-카복실레이트인 상기 일반적인 제조절차 2와 동일한 방법을 수행한 다음, 상기 일반적인 제조절차 3와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-(피페라진-1-일)에틸)우레아를 제조하였다.Wherein the N-substituted 3,4-dimethoxyaniline is tert-butyl 4-(2-((3,4-dimethoxyphenyl)amino)ethyl)piperazine-1-carboxylate obtained in step 1 above. After carrying out the same method as in General Manufacturing Procedure 2, 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole) was carried out in the same manner as in General Manufacturing Procedure 3 -1-yl)propyl)-1-(2-(piperazin-1-yl)ethyl)urea was prepared.

수율 91%, 흰색 고체, mp 108-109 ℃.Yield 91%, white solid, mp 108-109 °C.

1H NMR (300 MHz, CD3OD) δ 7.53 (s, 1H), 7.01 (d, J = 8.40 Hz, 1H), 6.89 (d, J = 2.37 Hz, 1H), 6.85 (dd, J = 8.43, 2.37 Hz, 1H), 6.64 (s, 1H), 3.91 (t, J = 7.32 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.78 (t, J = 6.75 Hz, 2H), 3.13 (t, J = 6.78 Hz, 2H), 2.80 (t, J = 4.95 Hz, 4H), 2.49-2.44 (m, 6H), 2.18 (d, J = 1.11 Hz, 3H), 1.88 (quintet, J = 6.78 Hz, 2H); HRMS (ESI) calc. for C22H35N6O3 [M + H]+ 431.27645, found 431.2773. 1 H NMR (300 MHz, CD 3 OD) δ 7.53 (s, 1H), 7.01 (d, J = 8.40 Hz, 1H), 6.89 (d, J = 2.37 Hz, 1H), 6.85 (dd, J = 8.43 , 2.37 Hz, 1H), 6.64 (s, 1H), 3.91 (t, J = 7.32 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.78 (t, J = 6.75 Hz, 2H ), 3.13 (t, J = 6.78 Hz, 2H), 2.80 (t, J = 4.95 Hz, 4H), 2.49-2.44 (m, 6H), 2.18 (d, J = 1.11 Hz, 3H), 1.88 (quintet , J = 6.78 Hz, 2H); HRMS (ESI) calc. for C 22 H 35 N 6 O 3 [M + H] + 431.27645, found 431.2773.

<실시예 53> 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-모르폴리-노에틸)우레아의 제조<Example 53> 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(2-morpholin-noethyl ) Preparation of urea

Figure 112019061617410-pat00090
Figure 112019061617410-pat00090

단계 1: 3,4-다이메톡시-N-(2-몰포리노에틸)아닐린의 제조Step 1: Preparation of 3,4-dimethoxy-N-(2-morpholinoethyl)aniline

설폰아마이드 혼합물이 N-(3,4-다이메톡시페닐)-N-(2-모르폴리노에틸)-2-나이트로벤젠설폰아마이드인 상기 일반적인 제조절차 6과 동일한 방법을 수행하여 3,4-다이메톡시-N-(2-몰포리노에틸)아닐린을 제조하였다.The sulfonamide mixture was N-(3,4-dimethoxyphenyl)-N-(2-morpholinoethyl)-2-nitrobenzenesulfonamide, and 3,4 -Dimethoxy-N-(2-morpholinoethyl)aniline was prepared.

수율 96%, 흰색 고체.Yield 96%, white solid.

1H NMR (300 MHz, CDCl3) δ 6.75 (d, J = 8.43 Hz, 1H), 6.26 (d, J = 2.49 Hz, 1H), 6.16 (dd, J = 8.43, 2.55 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.71 (t, J = 4.41 Hz, 4H), 3.13 (t, J = 5.49 Hz, 2H), 2.62 (t, J = 6.03 Hz, 2H), 2.46 (t, J = 4.38 Hz, 4H). 1 H NMR (300 MHz, CDCl 3 ) δ 6.75 (d, J = 8.43 Hz, 1H), 6.26 (d, J = 2.49 Hz, 1H), 6.16 (dd, J = 8.43, 2.55 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.71 (t, J = 4.41 Hz, 4H), 3.13 (t, J = 5.49 Hz, 2H), 2.62 (t, J = 6.03 Hz, 2H), 2.46 (t, J = 4.38 Hz, 4H).

단계 2: 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-모르폴리-노에틸)우레아의 제조Step 2: 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(2-morpholin-noethyl)urea Manufacture of

N-치환된 3,4-다이메톡시아닐린이 상기 단계 1에서 얻은 3,4-다이메톡시-N-(2-몰포리노에틸)아닐린인 상기 일반적인 제조절차 2와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-모르폴리-노에틸)우레아를 제조하였다.N-substituted 3,4-dimethoxyaniline is 3,4-dimethoxy-N-(2-morpholinoethyl)aniline obtained in step 1, by following the same method as in General Preparation Procedure 2 (3,4-Dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(2-morpholino-noethyl)urea was prepared.

수율 54%, 흰색 고체, mp 59-60 ℃.Yield 54%, white solid, mp 59-60 °C.

1H NMR (300 MHz, CDCl3) δ 7.27 (s, 1H), 6.82 (d, J = 8.43 Hz, 1H), 6.75-6.70 (m, 2H), 6.65 (s, 1H), 4.26 (t, J = 6.06 Hz, NH), 3.84 (s, 3H), 3.80 (s, 3H), 3.77-3.68 (m, 4H), 3.61 (t, J = 4.56 Hz, 4H), 3.13 (q, J = 6.57 Hz, 2H), 2.42-2.37 (m, 6H), 2.08 (d, J = 1.11 Hz, 3H), 1.83 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C22H34N5O4 [M + H]+ 432.2605, found 432.2601. 1 H NMR (300 MHz, CDCl 3 ) δ 7.27 (s, 1H), 6.82 (d, J = 8.43 Hz, 1H), 6.75-6.70 (m, 2H), 6.65 (s, 1H), 4.26 (t, J = 6.06 Hz, NH), 3.84 (s, 3H), 3.80 (s, 3H), 3.77-3.68 (m, 4H), 3.61 (t, J = 4.56 Hz, 4H), 3.13 (q, J = 6.57 Hz, 2H), 2.42-2.37 (m, 6H), 2.08 (d, J = 1.11 Hz, 3H), 1.83 (quintet, J = 7.14 Hz, 2H); HRMS (ESI) calc. for C 22 H 3 4 N 5 O 4 [M + H] + 432.2605, found 432.2601.

<실시예 54> 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)아세트아미드의 제조<Example 54> Preparation of 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)acetamide

Figure 112019061617410-pat00091
Figure 112019061617410-pat00091

α-치환된 2-(3,4-다이메톡시페닐)아세트산이 2-(3,4-다이메톡시페닐)아세트산인 상기 일반적인 제조절차 4와 동일한 방법을 수행하여 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)아세트아미드를 제조하였다.2-(3,4-dimethoxyphenyl)acetic acid is 2-(3,4-dimethoxyphenyl)acetic acid. Dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)acetamide was prepared.

수율 67%, 흰색 고체, mp 85-86 ℃.Yield 67%, white solid, mp 85-86 °C.

1H NMR (300 MHz, CDCl3) 7.32 (s, 1H), 6.82 (d, J = 8.61 Hz, 1H), 6.75-6.70 (m, 3H), 5.75 (br, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.79 (t, J = 7.14 Hz, 2H), 3.46 (s, 2H), 3.22 (q, J = 6.57 Hz, 2H), 2.10 (s, 3H), 1.89 (quintet, J = 6.96 Hz, 2H); HRMS (ESI) calc. for C17H24N3O3 [M + H]+ 318.1789, found 318.1801. 1 H NMR (300 MHz, CDCl 3 ) 7.32 (s, 1H), 6.82 (d, J = 8.61 Hz, 1H), 6.75-6.70 (m, 3H), 5.75 (br, 1H), 3.84 (s, 3H) ), 3.83 (s, 3H), 3.79 (t, J = 7.14 Hz, 2H), 3.46 (s, 2H), 3.22 (q, J = 6.57 Hz, 2H), 2.10 (s, 3H), 1.89 (quintet , J = 6.96 Hz, 2H); HRMS (ESI) calc. for C 17 H 24 N 3 O 3 [M + H] + 318.1789, found 318.1801.

<실시예 55> 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)프로판아미드의 제조<Example 55> Preparation of 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)propanamide

Figure 112019061617410-pat00092
Figure 112019061617410-pat00092

α-치환된 2-(3,4-다이메톡시페닐)아세트산이 2-(3,4-다이메톡시페닐)프로피온산인 상기 일반적인 제조절차 4와 동일한 방법을 수행하여 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)프로판아미드를 제조하였다.α-substituted 2-(3,4-dimethoxyphenyl)acetic acid is 2-(3,4-dimethoxyphenyl)propionic acid, and 2-(3,4- Dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)propanamide was prepared.

수율 16%, 흰색 고체, mp 88-89 ℃.Yield 16%, white solid, mp 88-89 °C.

1H NMR (300 MHz, CDCl3) δ 7.33 (s, 1H), 6.86-6.79 (m, 3H), 6.75 (s, 1H), 5.39 (br, 1H), 3.88 (s, 6H), 3.77 (t, J = 7.14 Hz, 2H), 3.47 (q, J = 7.14 Hz, 1H), 3.22 (q, J = 8.06 Hz, 2H), 2.11 (s, 3H), 1.86 (quintet, J = 6.96 Hz, 2H), 1.50 (d, J = 7.14 Hz, 3H); HRMS (ESI) calc. for C18H26N3O3 [M + H]+ 332.1969, found 332.1962. 1 H NMR (300 MHz, CDCl 3 ) δ 7.33 (s, 1H), 6.86-6.79 (m, 3H), 6.75 (s, 1H), 5.39 (br, 1H), 3.88 (s, 6H), 3.77 ( t, J = 7.14 Hz, 2H), 3.47 (q, J = 7.14 Hz, 1H), 3.22 (q, J = 8.06 Hz, 2H), 2.11 (s, 3H), 1.86 (quintet, J = 6.96 Hz, 2H), 1.50 (d, J = 7.14 Hz, 3H); HRMS (ESI) calc. for C 18 H 26 N 3 O 3 [M + H] + 332.1969, found 332.1962.

<실시예 56> 2-(3,4-다이메톡시페닐)-2-메틸-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)프로판아미드의 제조<Example 56> Preparation of 2-(3,4-dimethoxyphenyl)-2-methyl-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)propanamide

Figure 112019061617410-pat00093
Figure 112019061617410-pat00093

α-치환된 2-(3,4-다이메톡시페닐)아세트산이 2-(3,4-다이메톡시페닐)-2-메틸프로피온산인 상기 일반적인 제조절차 4와 동일한 방법을 수행하여 2-(3,4-다이메톡시페닐)-2-메틸-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)프로판아미드를 제조하였다.α-substituted 2-(3,4-dimethoxyphenyl)acetic acid is 2-(3,4-dimethoxyphenyl)-2-methylpropionic acid, and 2-( 3,4-dimethoxyphenyl)-2-methyl-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)propanamide was prepared.

수율 59%, 흰색 고체, mp 89-91 ℃.Yield 59%, white solid, mp 89-91 °C.

1H NMR (300 MHz, CDCl3): δ 7.30 (s, 1H), 6.93-6.83 (m, 3H), 6.73 (s, 1H), 5.23 (br, NH), 3.89 (d, J = 6.78 Hz, 6H), 3.78 (t, J = 6.96 Hz, 2H), 3.21 (quintet, J = 6.60 Hz, 2H), 2.12 (s, 3H), 1.88 (quintet, J = 7.14 Hz, 2H), 1.55 (s, 6H); HRMS (FAB): calcd for C19H28N3O3 [M + H]+ 346.2125, found 346.2131. 1 H NMR (300 MHz, CDCl 3 ): δ 7.30 (s, 1H), 6.93-6.83 (m, 3H), 6.73 (s, 1H), 5.23 (br, NH), 3.89 (d, J = 6.78 Hz , 6H), 3.78 (t, J = 6.96 Hz, 2H), 3.21 (quintet, J = 6.60 Hz, 2H), 2.12 (s, 3H), 1.88 (quintet, J = 7.14 Hz, 2H), 1.55 (s , 6H); HRMS (FAB): calcd for C 19 H 28 N 3 O 3 [M + H] + 346.2125, found 346.2131.

<실시예 57> 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로프로판카복사미드의 제조<Example 57> Preparation of 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclopropanecarboxamide

Figure 112019061617410-pat00094
Figure 112019061617410-pat00094

α-치환된 2-(3,4-다이메톡시페닐)아세트산이 1-(3,4-다이메톡시페닐)사이클로프로페인-1-카복실산인 상기 일반적인 제조절차 4와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로프로판카복사미드를 제조하였다.α-substituted 2-(3,4-dimethoxyphenyl)acetic acid is 1-(3,4-dimethoxyphenyl)cyclopropane-1-carboxylic acid. -(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclopropanecarboxamide was prepared.

수율 47%, 흰색 고체, mp 71-73 ℃.Yield 47%, white solid, mp 71-73 °C.

1H NMR (300 MHz, CD3OD) δ 7.51 (d, J = 0.90 Hz, 1H), 6.96-6.94 (m, 3H), 6.65 (m, 1H), 3.85 (t, J = 7.14 Hz, 2H), 3.82 (s, 6H), 3.14 (t, J = 6.78 Hz, 2H), 2.16 (d, J = 0.90 Hz, 3H), 1.82 (quintet, J = 6.75 Hz, 2H), 1.45 (dd, J = 6.75, 3.84 Hz, 2H), 1.04 (dd, J = 6.60, 3.66 Hz, 2H); HRMS (ESI) calc. for C19H26N3O3 [M + H]+ 344.1969, found 344.1964. 1 H NMR (300 MHz, CD 3 OD) δ 7.51 (d, J = 0.90 Hz, 1H), 6.96-6.94 (m, 3H), 6.65 (m, 1H), 3.85 (t, J = 7.14 Hz, 2H ), 3.82 (s, 6H), 3.14 (t, J = 6.78 Hz, 2H), 2.16 (d, J = 0.90 Hz, 3H), 1.82 (quintet, J = 6.75 Hz, 2H), 1.45 (dd, J = 6.75, 3.84 Hz, 2H), 1.04 (dd, J = 6.60, 3.66 Hz, 2H); HRMS (ESI) calc. for C 19 H 26 N 3 O 3 [M + H] + 344.1969, found 344.1964.

<실시예 58> 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로뷰탄카복사미드의 제조<Example 58> Preparation of 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclobutanecarboxamide

Figure 112019061617410-pat00095
Figure 112019061617410-pat00095

α-치환된 2-(3,4-다이메톡시페닐)아세트산이 1-(3,4-다이메톡시페닐)사이클로뷰테인-1-카복실산인 상기 일반적인 제조절차 4와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로뷰탄카복사미드를 제조하였다.α-substituted 2-(3,4-dimethoxyphenyl)acetic acid is 1-(3,4-dimethoxyphenyl)cyclobutane-1-carboxylic acid. -(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclobutanecarboxamide was prepared.

수율 22%, 흰색 고체, mp 75-77 ℃.Yield 22%, white solid, mp 75-77 °C.

1H NMR (300MHz, CDCl3) δ 7.30 (s, 1H), 6.87-6.82 (m, 2H), 6.73 (br, 2H), 5.14 (br, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.71 (t, J = 7.32 Hz, 2H), 3.17 (q, J = 6.60 Hz, 2H), 2.76 (br, 2H), 2.45 (br, 2H), 2.19 (br, 1H), 2.10 (s, 3H), 1.83-1.79 (m, 3H); HRMS (ESI) calc. for C20H28N3O3 [M + H]+ 358.2125, found 358.2117. 1 H NMR (300MHz, CDCl 3 ) δ 7.30 (s, 1H), 6.87-6.82 (m, 2H), 6.73 (br, 2H), 5.14 (br, 1H), 3.90 (s, 3H), 3.87 (s , 3H), 3.71 (t, J = 7.32 Hz, 2H), 3.17 (q, J = 6.60 Hz, 2H), 2.76 (br, 2H), 2.45 (br, 2H), 2.19 (br, 1H), 2.10 (s, 3H), 1.83-1.79 (m, 3H); HRMS (ESI) calc. for C 20 H 28 N 3 O 3 [M + H] + 358.2125, found 358.2117.

<실시예 59> 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로펜탄카복사미드의 제조<Example 59> Preparation of 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclopentanecarboxamide

Figure 112019061617410-pat00096
Figure 112019061617410-pat00096

α-치환된 2-(3,4-다이메톡시페닐)아세트산이 1-(3,4-다이메톡시페닐)사이클로펜테인-1-카복실산인 상기 일반적인 제조절차 4와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로펜탄카복사미드를 제조하였다.α-substituted 2-(3,4-dimethoxyphenyl)acetic acid is 1-(3,4-dimethoxyphenyl)cyclopentane-1-carboxylic acid. -(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclopentanecarboxamide was prepared.

수율 32%, 흰색 고체, mp 76-77 ℃.Yield 32%, white solid, mp 76-77 °C.

1H NMR (300 MHz, CD3OD): δ 7.38 (d, J = 0.93 Hz, 1H), 6.97-6.94 (m, 2H), 6.91-6.88 (m, 1H), 6.61 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.71 (t, J = 7.35 Hz, 2H), 3.17 (t, J = 6.60 Hz, 2H), 2.49-2.44 (m, 2H), 2.04 (d, J = 0.93 Hz, 3H), 2.01-1.91 (m, 2H), 1.83 (quintet, J = 6.57 Hz, 2H), 1.72-1.68 (m, 4H); HRMS (FAB) calcd for C21H30N3O3 [M + H]+ 372.2287, found: 372.2287. 1 H NMR (300 MHz, CD 3 OD): δ 7.38 (d, J = 0.93 Hz, 1H), 6.97-6.94 (m, 2H), 6.91-6.88 (m, 1H), 6.61 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.71 (t, J = 7.35 Hz, 2H), 3.17 (t, J = 6.60 Hz, 2H), 2.49-2.44 (m, 2H), 2.04 (d , J = 0.93 Hz, 3H), 2.01-1.91 (m, 2H), 1.83 (quintet, J = 6.57 Hz, 2H), 1.72-1.68 (m, 4H); HRMS (FAB) calcd for C 21 H 30 N 3 O 3 [M + H] + 372.2287, found: 372.2287 .

<실시예 60> 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로헥세인-1-카복사미드의 제조<Example 60> Preparation of 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclohexane-1-carboxamide

Figure 112019061617410-pat00097
Figure 112019061617410-pat00097

α-치환된 2-(3,4-다이메톡시페닐)아세트산이 1-(3,4-다이메톡시페닐)사이클로뷰테인-1-카복실산인 상기 일반적인 제조절차 4와 동일한 방법을 수행하여 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로헥세인-1-카복사미드를 제조하였다.α-substituted 2-(3,4-dimethoxyphenyl)acetic acid is 1-(3,4-dimethoxyphenyl)cyclobutane-1-carboxylic acid. -(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclohexane-1-carboxamide was prepared.

수율 43%, 흰색 고체, mp 79-80 ℃.Yield 43%, white solid, mp 79-80 °C.

1H NMR (300 MHz, CDCl3) δ 7.22 (s, 1H), 6.89-6.74 (m, 3H), 6.65 (s, 1H), 5.34 (t, J = 5.67 Hz, NH), 3.81 (s, 3H), 3.79 (s, 3H), 3.65 (t, J = 7.14 Hz, 2H), 3.12 (q, J = 6.60 Hz, 2H), 2.19-2.11 (m, 2H), 2.02 (s, 3H), 1.90-1.83 (m, 2H), 1.77 (p, J = 6.96 Hz, 2H), 1.54-1.45 (m, 4H), 1.36-1.29 (m, 2H); HRMS (ESI) calc. for C22H32N3O3 [M + H]+ 386.2441, found 386.2441. 1 H NMR (300 MHz, CDCl 3 ) δ 7.22 (s, 1H), 6.89-6.74 (m, 3H), 6.65 (s, 1H), 5.34 (t, J = 5.67 Hz, NH), 3.81 (s, 3H), 3.79 (s, 3H), 3.65 (t, J = 7.14 Hz, 2H), 3.12 (q, J = 6.60 Hz, 2H), 2.19-2.11 (m, 2H), 2.02 (s, 3H), 1.90-1.83 (m, 2H), 1.77 (p, J = 6.96 Hz, 2H), 1.54-1.45 (m, 4H), 1.36-1.29 (m, 2H); HRMS (ESI) calc. for C 22 H 32 N 3 O 3 [M + H]+ 386.2441, found 386.2441.

<실시예 61> 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)-3-페닐프로페인아미드의 제조<Example 61> Preparation of 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-phenylpropaneamide

Figure 112019061617410-pat00098
Figure 112019061617410-pat00098

α-치환된 2-(3,4-다이메톡시페닐)아세트산이 2-(3,4-다이메톡시페닐)-3-페닐프로피온산인 상기 일반적인 제조절차 4와 동일한 방법을 수행하여 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)-3-페닐프로페인아미드를 제조하였습니다.α-substituted 2-(3,4-dimethoxyphenyl)acetic acid is 2-(3,4-dimethoxyphenyl)-3-phenylpropionic acid by following the same method as in General Preparation 4, 2-( 3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-phenylpropaneamide was prepared.

수율 57%, 흰색 고체, mp 85-86 ℃.Yield 57%, white solid, mp 85-86 °C.

1H NMR (300 MHz, CDCl3) δ 7.18-7.12 (m, 3H), 7.10-7.06 (m, 3H), 6.81-6.69 (m, 3H), 6.63 (s, 1H), 5.90 (t, J = 5.67 Hz, NH), 3.78 (s, 3H), 3.77 (s, 3H), 3.60-3.52 (m, 2H), 3.49-3.36 (m, 2H), 3.21-3.10 (m, 1H), 3.03-2.94 (m, 1H), 2.91 (dd, J = 5.10, 12.03 Hz, 1H), 1.99 (s, 3H), 1.73 (quintet, J = 6.78 Hz, 2H); HRMS (ESI) calc. for C24H30N3O3 [M + H]+ 408.2282, found 408.2317. 1 H NMR (300 MHz, CDCl 3 ) δ 7.18-7.12 (m, 3H), 7.10-7.06 (m, 3H), 6.81-6.69 (m, 3H), 6.63 (s, 1H), 5.90 (t, J = 5.67 Hz, NH), 3.78 (s, 3H), 3.77 (s, 3H), 3.60-3.52 (m, 2H), 3.49-3.36 (m, 2H), 3.21-3.10 (m, 1H), 3.03- 2.94 (m, 1H), 2.91 (dd, J = 5.10, 12.03 Hz, 1H), 1.99 (s, 3H), 1.73 (quintet, J = 6.78 Hz, 2H); HRMS (ESI) calc. for C 24 H 30 N 3 O 3 [M + H] + 408.2282, found 408.2317.

<실시예 62> 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)-3-(피리딘-3-일)프로페인아미드의 제조<Example 62> 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(pyridin-3-yl)pro Preparation of Painamide

Figure 112019061617410-pat00099
Figure 112019061617410-pat00099

α-치환된 2-(3,4-다이메톡시페닐)아세트산이 2-(3,4-다이메톡시페닐)-3-(피리딘-3-일)프로피온산인 상기 일반적인 제조절차 4와 동일한 방법을 수행하여 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)-3-(피리딘-3-일)프로페인아미드를 제조하였다.α-substituted 2-(3,4-dimethoxyphenyl)acetic acid is 2-(3,4-dimethoxyphenyl)-3-(pyridin-3-yl)propionic acid. 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-(pyridin-3-yl)propaneamide Was prepared.

수율 51%, 흰색 고체, mp 109-110 ℃.Yield 51%, white solid, mp 109-110 °C.

1H NMR (300 MHz, CDCl3) δ 8.36-8.35 (m, 2H), 7.42-7.38 (m, 2H), 7.12 (dd, J = 7.68, 4.77 Hz, 1H), 6.84 (d, J = 1.44 Hz, 1H), 6.76-6.74 (m, 2H), 6.68 (s, 1H), 6.49 (br, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.66 (t, J = 7.14 Hz, 2H), 3.57 (t, J = 7.89 Hz, 1H), 3.47 (dd, J = 13.38, 8.07 Hz, 1H), 3.19-3.02 (m, 2H), 2.97 (dd, J = 13.26, 6.78 Hz, 1H), 2.05 (s, 3H), 1.82 (quintet, J = 6.60 Hz, 2H); HRMS (ESI) calc. for C23H29N4O3 [M + H]+ 408.2160, found 408.2178. 1 H NMR (300 MHz, CDCl 3 ) δ 8.36-8.35 (m, 2H), 7.42-7.38 (m, 2H), 7.12 (dd, J = 7.68, 4.77 Hz, 1H), 6.84 (d, J = 1.44 Hz, 1H), 6.76-6.74 (m, 2H), 6.68 (s, 1H), 6.49 (br, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.66 (t, J = 7.14 Hz , 2H), 3.57 (t, J = 7.89 Hz, 1H), 3.47 (dd, J = 13.38, 8.07 Hz, 1H), 3.19-3.02 (m, 2H), 2.97 (dd, J = 13.26, 6.78 Hz, 1H), 2.05 (s, 3H), 1.82 (quintet, J = 6.60 Hz, 2H); HRMS (ESI) calc. for C 23 H 29 N 4 O 3 [M + H] + 408.2160, found 408.2178.

<실험예 1> N-치환된 티오우레아 또는 우레아 유도체의 글루타미닐 사이클레이즈(Glutaminyl cyclase, QC) 저해 정도 평가<Experimental Example 1> Evaluation of the degree of inhibition of glutaminyl cyclase (QC) of N-substituted thiourea or urea derivative

본 발명에 따른 실시예 화합물의 QC 저해정도를 평가하기 위하여, 하기와 같은 실험을 수행아여 그 결과를 표 1에 나타내었다.In order to evaluate the degree of QC inhibition of the example compounds according to the present invention, the following experiment was performed and the results are shown in Table 1.

본 실험은 형광 기질, Gln-AMC (L-glutamine 7-amido-4-methylcoumarin) 및 보조효소로서 파이로글루타밀 펩티데이즈(pyroglutamyl peptidase, pGAPase)를 사용하였다.In this experiment, a fluorescent substrate, Gln-AMC (L-glutamine 7-amido-4-methylcoumarin), and pyroglutamyl peptidase (pGAPase) were used as a coenzyme.

완충액은 HCl pH 7.0로 조정된 25 mM HEPES (Sigma)를, 기질 H-Gln-AMC 하이드로브로마이드 (L-glutamine 7-amido-4-methylcoumarin, BACHEM, Switzerland)은 0.4 mM의 농도로 사용하였으며, 보조 효소인 pGAPase (50 units, Qiagen, Germany)는 미리 HEPES에 1:250(pGAPase:HEPES)로 희석하였으며, 인간 QC (10 ug/ml, rhQPCT, R&D systems)도 미리 HEPES에 1:250(rhQPCT:HEPES)로 희석하였다. 기질 25 μL, 실시예 화합물 50 μL 및 pGAPase 25 μL로 반응 혼합액을 구성하였다. 37 ℃에서 10 분간 96-웰 검정 플레이트 (Greiner, Austria)에서 배양 한 후, 50 μL의 hQC 용액을 첨가하여 반응을 시작 하였다.The buffer was 25 mM HEPES (Sigma) adjusted to HCl pH 7.0, and the substrate H-Gln-AMC hydrobromide (L-glutamine 7-amido-4-methylcoumarin, BACHEM, Switzerland) was used at a concentration of 0.4 mM. The enzyme pGAPase (50 units, Qiagen, Germany) was previously diluted 1:250 (pGAPase:HEPES) in HEPES, and human QC (10 ug/ml, rhQPCT, R&D systems) was previously diluted 1:250 (rhQPCT: HEPES). A reaction mixture was composed of 25 μL of the substrate, 50 μL of the example compound, and 25 μL of pGAPase. After incubation in a 96-well assay plate (Greiner, Austria) at 37° C. for 10 minutes, 50 μL of hQC solution was added to initiate the reaction.

글루타미닐 사이클레이즈는 먼저 Gln-AMC를 pGlu-AMC로 전환시킨 다음, 상기 pGlu-AMC가 pGAP에 의해 가수분해되어 AMC를 생성시킨다. AMC는 380 및 460 nm의 여기 및 방출 파장에서 형광을 측정하였으며, 그 결과를 IC50값으로 계산하여 그 결과를 하기 표 1에 나타내었다.Glutaminyl cyclase first converts Gln-AMC to pGlu-AMC, and then the pGlu-AMC is hydrolyzed by pGAP to produce AMC. AMC measured fluorescence at excitation and emission wavelengths of 380 and 460 nm, and the results were calculated as IC 50 values, and the results are shown in Table 1 below.

화합물compound IC50 (nM)IC 50 (nM) 실시예 1Example 1 12.4 (±1.8)12.4 (±1.8) 실시예 2Example 2 8.8 (±1.2)8.8 (±1.2) 실시예 3Example 3 2.8 (±2.4)2.8 (±2.4) 실시예 4Example 4 6.8 (±2.7)6.8 (±2.7) 실시예 5Example 5 5.7 (±6.3)5.7 (±6.3) 실시예 6Example 6 25.6 (±4.3)25.6 (±4.3) 실시예 7Example 7 8.6 (±0.8)8.6 (±0.8) 실시예 8Example 8 6.5 (±0.8)6.5 (±0.8) 실시예 9Example 9 4.7 (±0.4) 4.7 (±0.4) 실시예 10Example 10 4.6 (±0.4)4.6 (±0.4) 실시예 11Example 11 3.4 (±0.9)3.4 (±0.9) 실시예 12Example 12 3.5 (±2.0)3.5 (±2.0) 실시예 13Example 13 1.3 (±0.8)1.3 (±0.8) 실시예 14Example 14 5.2 (±0.8)5.2 (±0.8) 실시예 15Example 15 5.4 (±3.7)5.4 (±3.7) 실시예 16Example 16 5.6 (±3.4)5.6 (±3.4) 실시예 17Example 17 162 (±18.5)162 (±18.5) 실시예 18Example 18 78.7 (±20.6)78.7 (±20.6) 실시예 19Example 19 27.0 (±1.4)27.0 (±1.4) 실시예 20Example 20 17.5 (±0.6)17.5 (±0.6) 실시예 21Example 21 7.6 (±3.4)7.6 (±3.4) 실시예 22Example 22 6.2 (±1.9)6.2 (±1.9) 실시예 23Example 23 38.5 (±16.3)38.5 (±16.3) 실시예 24Example 24 26.5 (±2.1)26.5 (±2.1) 실시예 25Example 25 19.4 (±5.1)19.4 (±5.1) 실시예 26Example 26 4.5 (±0.1)4.5 (±0.1) 실시예 27Example 27 13.3 (±1.3)13.3 (±1.3) 실시예 28Example 28 20.5 (±0.7)20.5 (±0.7) 실시예 29Example 29 12.9 (±6.5)12.9 (±6.5) 실시예 30Example 30 3.9 (±0.5)3.9 (±0.5) 실시예 31Example 31 12.5 (±2.1)12.5 (±2.1) 실시예 32Example 32 8.7 (±1.4)8.7 (±1.4) 실시예 33Example 33 30.6 (±13.3)30.6 (±13.3) 실시예 34Example 34 32.5 (±6.4)32.5 (±6.4) 실시예 35Example 35 23.5 (±9.1)23.5 (±9.1) 실시예 36Example 36 11.0 (±1.4)11.0 (±1.4) 실시예 37Example 37 17.6 (±7.3)17.6 (±7.3) 실시예 38Example 38 36.9 (±5.2)36.9 (±5.2) 실시예 39Example 39 3.6 (±1.1)3.6 (±1.1) 실시예 40Example 40 1.6 (±0.3)1.6 (±0.3) 실시예 41Example 41 93.0 (±18.4)93.0 (±18.4) 실시예 42Example 42 69.6 (±11.4)69.6 (±11.4) 실시예 43Example 43 98.8 (±9.3)98.8 (±9.3) 실시예 44Example 44 8.2 (±0.9)8.2 (±0.9) 실시예 45Example 45 6.1 (±1.5)6.1 (±1.5) 실시예 46Example 46 81.0 (±30.5)81.0 (±30.5) 실시예 47Example 47 53.9 (±5.2)53.9 (±5.2) 실시예 48Example 48 16.4 (±5.8)16.4 (±5.8) 실시예 49Example 49 7.5 (±1.9)7.5 (±1.9) 실시예 50Example 50 13.6 (±3.5)13.6 (±3.5) 실시예 51Example 51 23.3 (±6.4)23.3 (±6.4) 실시예 52Example 52 15.0 (±3.9)15.0 (±3.9) 실시예 53Example 53 25.0 (±3.8)25.0 (±3.8) 실시예 54Example 54 183 (±12.7)183 (±12.7) 실시예 55Example 55 112 (±34.5)112 (±34.5) 실시예 56Example 56 77.3 (±18.5)77.3 (±18.5) 실시예 57Example 57 24.3 (±4.5)24.3 (±4.5) 실시예 58Example 58 37.1 (±12.2)37.1 (±12.2) 실시예 59Example 59 22.9 (±4.2)22.9 (±4.2) 실시예 60Example 60 77.5 (±0.7)77.5 (±0.7) 실시예 61Example 61 39.0 (±1.4)39.0 (±1.4) 실시예 62Example 62 81.6 (±18.9)81.6 (±18.9)

상기 표 1에 나타난 바와 같이,As shown in Table 1 above,

본 발명에 따른 N-치환된 티오우레아 또는 우레아 유도체는 전체적으로 50 nM 이하의 낮은 IC50 값으로 인간 QC를 저해하여, 우수한 QC 저해능을 나타냄을 알 수 있으며, 특히, 실시예 2, 4, 5, 7, 8, 14, 15, 16, 21, 22, 32, 44, 45 및 49 화합물은 10 nM 이하, 실시예 3, 9, 10, 11, 12, 13, 26, 30, 39 및 40 화합물은 5 nM 이하의 현저하게 낮은 농도에서도 인간 QC를 저해하는 것을 확인하였다.It can be seen that the N-substituted thiourea or urea derivative according to the present invention inhibits human QC with a low IC 50 value of 50 nM or less as a whole, thereby exhibiting excellent QC inhibitory ability, and in particular, Examples 2, 4, 5, 7, 8, 14, 15, 16, 21, 22, 32, 44, 45 and 49 compounds are 10 nM or less, Examples 3, 9, 10, 11, 12, 13, 26, 30, 39 and 40 compounds It was confirmed that even at a significantly low concentration of 5 nM or less, human QC was inhibited.

<실험예 2> N-치환된 티오우레아 또는 우레아 유도체의 세포독성 평가<Experimental Example 2> Evaluation of cytotoxicity of N-substituted thiourea or urea derivative

본 발명에 따른 N-치환된 티오우레아 또는 우레아 유도체의 세포 독성을 평가하기 위하여, 하기와 같은 실험을 수행하였으며, 그 결과를 표 2에 나타내었다.In order to evaluate the cytotoxicity of the N-substituted thiourea or urea derivative according to the present invention, the following experiment was performed, and the results are shown in Table 2.

마우스의 신경세포주인 HT22를 DMEM(Dulbecco's Modified Eagle's Medium, Gibco-BRL)배지에 10 % FBS(Fetal Bovine Serum, Hyclone))와 1 % 페니실린/스트렙토마이신(sigma 사)이 첨가된 배지를 사용하여 37℃, 5 % CO2 조건의 배양기(Forma)에서 배양하였다. 실험에 들어가기 전 HT22 세포를 96 웰 플레이트에 5×103 세포/웰의 밀도로 평판 배양한 후 시료를 처리하기 전 혈청이 제거된 DMEM 배지에서 1시간 동안 배양하였다. 10 μM 농도로 본 발명에 따른 실시예 2, 3, 4, 5 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 21, 22, 26, 30, 32, 39, 40, 44, 45 및 49 화합물을 첨가하여 18시간 동안 배양하였다. 18시간 동안 배양한 후 5 mg/ml MTT(3-(4,5-디메틸-2-티아졸릴)-2,5-디페닐-2H-테트라졸륨 브로마이드) 용액을 웰 당 15 μl씩 넣고, 4시간 배양하였다. 4시간 배양한 후 배지를 모두 제거해주고 용해화 완충액 100 % 디메틸설폭사이드(DMSO)을 150 μl씩 첨가하였다. 마이크로 플레이트 리더(sunrise, TECAN)를 이용하여 570 nm/630 nm에서 흡광도를 측정하였다. 또한, hPERG 저해도를 평가하여 그 결과를 하기 표 2에 나타내었다.HT22, the neuronal cell line of the mouse, was added to DMEM (Dulbecco's Modified Eagle's Medium, Gibco-BRL) medium with 10% FBS (Fetal Bovine Serum, Hyclone)) and 1% penicillin/streptomycin (Sigma). It was cultured in an incubator (Forma) under conditions of ℃, 5% CO 2. Before entering the experiment, HT22 cells were plate-cultured in a 96-well plate at a density of 5×10 3 cells/well, and then cultured in DMEM medium from which serum was removed for 1 hour before processing the sample. Examples 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 21, 22, 26, 30, 32, 39, according to the invention at a concentration of 10 μM Compounds 40, 44, 45 and 49 were added and incubated for 18 hours. After incubation for 18 hours, 5 mg/ml MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) solution was added at 15 μl per well, and 4 Incubated for time. After incubation for 4 hours, all the medium was removed, and 150 μl of lysis buffer 100% dimethyl sulfoxide (DMSO) was added. Absorbance was measured at 570 nm/630 nm using a micro plate reader (sunrise, TECAN). In addition, h PERG inhibition was evaluated and the results are shown in Table 2 below.

화합물compound 세포독성
(10 μM, % of control)Cytotoxicity
(10 μM,% of control) hERG FP
(10 μM, 저해율%) h ERG FP
(10 μM,% inhibition) 실시예 2Example 2 88.488.4 실시예 3Example 3 100100 46.346.3 실시예 4Example 4 100100 39.939.9 실시예 5Example 5 100100 60.060.0 실시예 7Example 7 86.786.7 11.511.5 실시예 8Example 8 81.781.7 31.831.8 실시예 9Example 9 78.378.3 59.459.4 실시예 10Example 10 80.480.4 71.571.5 실시예 11Example 11 91.791.7 77.677.6 실시예 12Example 12 88.288.2 86.086.0 실시예 13Example 13 100100 83.583.5 실시예 14Example 14 100100 86.886.8 실시예 15Example 15 89.389.3 34.534.5 실시예 16Example 16 100100 32.332.3 실시예 21Example 21 100100 23.723.7 실시예 22Example 22 100100 29.629.6 실시예 26Example 26 88.688.6 12.212.2 실시예 30Example 30 90.790.7 40.640.6 실시예 32Example 32 100100 33.233.2 실시예 39Example 39 100100 48.048.0 실시예 40Example 40 82.282.2 40.840.8 실시예 44Example 44 88.388.3 26.326.3 실시예 45Example 45 100100 46.146.1 실시예 49Example 49 92.492.4 73.573.5

상기 표 2에 나타난 바와 같이,As shown in Table 2 above,

본 발명에 따른 실시예 화합물 중에서 특히 3, 4, 5, 13, 14, 16, 21, 22, 32, 39 및 45 화합물은 10 μM 농도에서 세포 독성을 나타내지 않는 것을 확인하였다. 또한, 본 발명에 따른 실시예 화합물 3, 4, 7, 8, 15, 16, 21, 22, 26, 30, 32, 39, 40, 44 및 45 화합물은 10 μM 농도에서 50% 이하의 hERG 저해를 보이는 것을 확인하였다.Among the example compounds according to the present invention, it was confirmed that in particular 3, 4, 5, 13, 14, 16, 21, 22, 32, 39 and 45 compounds did not exhibit cytotoxicity at a concentration of 10 μM. In addition, Example compounds 3, 4, 7, 8, 15, 16, 21, 22, 26, 30, 32, 39, 40, 44 and 45 compounds according to the present invention are 50% or less h ERG at 10 μM concentration. It was confirmed that it showed inhibition.

따라서, 본 발명에 따른 N-치환된 티오우레아 또는 우레아 유도체는 세포 독성을 나타내지 않는 것을 알 수 있다.Therefore, it can be seen that the N-substituted thiourea or urea derivative according to the present invention does not exhibit cytotoxicity.

<실험예 3> N-치환된 티오우레아 또는 우레아 유도체의 베타아밀로이드 (Aβ<Experimental Example 3> Beta amyloid of N-substituted thiourea or urea derivative (Aβ N3pE-40N3pE-40 )의 형성 저해율 측정) Formation inhibition rate measurement

본 발명에 따른 N-치환된 티오우레아 또는 우레아 유도체의 베타아밀로이드(AβN3pE-40)의 형성 저해율을 측정하기 위하여, 하기와 같은 실험을 수행하였다.In order to measure the inhibition rate of formation of beta amyloid (Aβ N3pE-40 ) of the N-substituted thiourea or urea derivative according to the present invention, the following experiment was performed.

급성 모델 연구를 위하여, ICR 마우스 (수컷, 6 주령)에 인간 Aβ3-40 5 μg 및 본 발명에 따른 실시예 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 21, 22, 26, 30, 32, 39, 40, 44, 45 및 49의 화합물 25 mg/kg을 뇌실 내에 (i.c.v.) 주사하였다. 다음날, 마우스의 뇌 추출물에서 인간 AβN3pE-40의 수준을 측정하여 그 결과를 하기 표 3에 나타내었다. 또한, 혈액-뇌장벽(blood-brain barrier, BBB)에 침구하는 능력으로 해석될 수 있는 생체 내 효능을 평가하기 위하여 본 발명에 따른 실시예 32, 39, 44 및 45 화합물을 복강(i.p.) 내 주사하고, 다음날, 마우스의 뇌 추출물에서 인간 AβN3pE-40의 수준을 측정하여 형성 저해 활성을 측정하여, 하기 표 3에 나타내었다.For the acute model study, ICR mice (male, 6 weeks old) in human Aβ 3-40 5 μg and Examples 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 according to the present invention , 14, 15, 16, 21, 22, 26, 30, 32, 39, 40, 44, 45 and 49 compounds 25 mg/kg were injected into the ventricle (icv). The next day, the level of human Aβ N3pE-40 was measured in the mouse brain extract, and the results are shown in Table 3 below. In addition, in order to evaluate the in vivo efficacy that can be interpreted as the ability to acupuncture the blood-brain barrier (BBB), the compounds of Examples 32, 39, 44 and 45 according to the present invention were administered in the abdominal cavity (ip). The next day after injection, the level of human Aβ N3pE-40 in the brain extract of the mouse was measured to measure the formation inhibitory activity, and it is shown in Table 3 below.

구체적으로, 모든 실험에는 수컷 ICR 마우스(샘타코, 한국, 25 g, 5주령, n = 4)를 사용하였다. 상기 ICR 마우스에 인간 Aβ3-40(in PBS, 5 μg/5 μL)을 주사하였다. 본 발명에 따른 실시예 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 21, 22, 26, 30, 32, 39, 40, 44, 45 및 49의 화합물을 뇌실 내에 (i.c.v.) 주사하고, 실시예 32, 39, 44 및 45 화합물을 복강(i.p.) 내 주사하였다. 뇌실 내 주사의 경우, 상기 마우스를 Zoletil50 및 2 % Rumpun (1 : 2 비율, 0.4 mL / kg)으로 마취시킨 후, 입체정위 틀(stereotaxic frame)에 고정시켰다. 뼈의 정중선 위로 작은 절개(1 cm)를 만들고, 두개골(bregma and lambda)의 표식을 노출시켰다. 두개골에 작은 구멍을 만들고, 인간 Aβ3-40를 심부피질/해마(cortical/hippocampus)에 주사하였다(브레그마(bregma)로부터 AP -2.0 mm, ML 1.2 mm, DV 1.0 mm위치에 27-게이지 가이드 바늘(gauge guide needle)을 가진 Hamilton 25 μL 주사기를 사용하여 Aβ3-40 전달).Specifically, male ICR mice (Samtaco, Korea, 25 g, 5 weeks old, n = 4) were used for all experiments. Human Aβ 3-40 (in PBS, 5 μg/5 μL) was injected into the ICR mice. Examples 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 21, 22, 26, 30, 32, 39, 40, 44, according to the present invention Compounds of 45 and 49 were injected into the ventricle (icv), and compounds of Examples 32, 39, 44 and 45 were injected intraperitoneally (ip). In the case of intraventricular injection, the mouse was anesthetized with Zoletil50 and 2% Rumpun (1: 2 ratio, 0.4 mL / kg), and then fixed to a stereotaxic frame. A small incision (1 cm) was made above the midline of the bone, and the skull (bregma and lambda) marks were exposed. A small hole was made in the skull, and human Aβ 3-40 was injected into the cortical/hippocampus (27-gauge guide from Bregma, AP -2.0 mm, ML 1.2 mm, DV 1.0 mm). Aβ 3-40 delivery using a Hamilton 25 μL syringe with a gauge guide needle).

화합물compound AβN3pE-40 형성 저해율%Aβ N3pE-40 formation inhibition% i.c.v. 주사i.c.v. injection i.p. 주사i.p. injection 실시예 2Example 2 NENE 실시예 3Example 3 6.06.0 실시예 4Example 4 NENE 실시예 5Example 5 2.962.96 실시예 7Example 7 NENE 실시예 8Example 8 1.171.17 실시예 9Example 9 4.014.01 실시예 10Example 10 15.2815.28 실시예 11Example 11 6.666.66 실시예 12Example 12 NENE 실시예 13Example 13 NENE 실시예 14Example 14 0.730.73 실시예 15Example 15 5.315.31 실시예 16Example 16 11.5811.58 실시예 21Example 21 NENE 실시예 22Example 22 2.962.96 실시예 26Example 26 NENE 실시예 30Example 30 NENE 실시예 32Example 32 25.9825.98 22.8722.87 실시예 39Example 39 24.3824.38 22.7422.74 실시예 40Example 40 13.7013.70 실시예 44Example 44 26.2626.26 NTNT 실시예 45Example 45 35.4635.46 26.1026.10 실시예 49Example 49 19.4019.40

상기 표 3에 나타난 바와 같이,As shown in Table 3 above,

i.c.v.주사의 경우, 본 발명에 따른 실시예 3, 5, 8, 9, 10, 11, 14, 15, 16, 22, 32, 39, 40, 44, 45 및 49 화합물은 AβN3pE-40의 형성을 저해하며, 특히, 실시예 32, 39, 40, 44, 45 및 49ghkgkqanfdms 높은 저해율로 AβN3pE-40의 형성을 저해함으로써, 본 발명에 따른 화학식 1로 표시되는 화합물의 AβN3pE-40의 형성 저해능이 현저하게 우수함을 확인하였다.In the case of icv injection, the compounds of Examples 3, 5, 8, 9, 10, 11, 14, 15, 16, 22, 32, 39, 40, 44, 45 and 49 according to the present invention form Aβ N3pE-40 Inhibiting, in particular, Examples 32, 39, 40, 44, 45 and 49ghkgkqanfdms By inhibiting the formation of Aβ N3pE-40 with a high inhibition rate, the ability of the compound represented by Formula 1 according to the present invention to inhibit the formation of Aβ N3pE-40 It was confirmed that this remarkably excellent.

i.p. 주사의 경우, 본 발명에 따른 실시예 32. 39 및 45 화합물이 AβN3pE-40 의 형성 저해효과를 나타내었다.In the case of ip injection, the compounds of Examples 32. 39 and 45 according to the present invention exhibited an inhibitory effect on the formation of Aβ N3pE-40.

<실험예 4> N-치환된 티오우레아 또는 우레아 유도체의 뇌 내 베타아밀로이드(Aβ<Experimental Example 4> Beta amyloid in the brain of N-substituted thiourea or urea derivative (Aβ N3pE-40N3pE-40 ) 감소 여부 평가) Evaluation of reduction

본 발명에 따른 N-치환된 티오우레아 또는 우레아 유도체의 뇌 내의 베타아밀로이드(AβN3pE-40)를 감소시킬 수 있는지에 대하여 평가하기 위하여 본 발명에 따른 실시예 45 화합물을 사용하여 하기와 같은 실험을 수행하였으며, 그 결과를 도 2에 나타내었다.In order to evaluate whether the N-substituted thiourea or urea derivative according to the present invention can reduce beta amyloid (Aβ N3pE-40 ) in the brain, the following experiment was performed using the compound of Example 45 according to the present invention. Was carried out, and the results are shown in FIG. 2.

본 실험은 5XFAD 유전자 이식(transgenic) 쥐를 이용하여 장기간의 in vivo 연구를 통해 이루어졌다. 5XFAD 쥐는 뇌에서 Aβ와 pyriform Aβ를 증가시켜 심한 알츠하이머병을 일으킨다고 알려져있으므로 본 발명의 Aβ-유도 실험을 위한 모델에 적합하다.This experiment was conducted through long-term in vivo studies using 5XFAD transgenic mice. 5XFAD mice are known to cause severe Alzheimer's disease by increasing Aβ and pyriform Aβ in the brain, so they are suitable for the model for the Aβ-induction experiment of the present invention.

구체적으로, 실시예 45 화합물 25 mg/kg을 32주 5XFAD 쥐에 매일 4주간 i.p.주사gkduTrh, 4주 후 뇌의 AβN3pE-40/42 및 Aβ40/42 농도를 sandwhich ELISA를 이용하여 측정하였다.Specifically, 25 mg/kg of the compound of Example 45 was injected daily for 4 weeks in 5XFAD mice at 32 weeks, gkduTrh, and the concentrations of Aβ N3pE-40/42 and Aβ 40/42 in the brain after 4 weeks were measured using sandwhich ELISA.

도 2에 나타난 바와 같이, 실시예 45 화합물은 대조군에 비해 뇌의 AβN3pE-40/42 및 Aβ40/42 농도를 57.9% 및 50.5%로 감소시켰다 (도 (a) 및 (b)). 또한, 실시예 45 화합물은 Aβ40 및 Aβ42 수치도 심한 독성 없이 36.6% 및 35.1%로 감소시킴으로써 본 발명에 따른 실시예 화합물의 우수한 QC 저해 능력 뿐 아니라 뇌의 pE-Aβ와 Aβ 수치의 전체적인 감소 효과를 확인할 수 있었다.As shown in FIG. 2, the compound of Example 45 reduced the concentration of Aβ N3pE-40/42 and Aβ 40/42 in the brain to 57.9% and 50.5% compared to the control group (FIGS. (a) and (b)). In addition, the compound of Example 45 also reduced the levels of Aβ 40 and Aβ 42 to 36.6% and 35.1% without severe toxicity, thereby reducing overall levels of pE-Aβ and Aβ levels in the brain as well as the excellent QC inhibitory ability of the Example compound according to the present invention The effect could be confirmed.

한편, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.Meanwhile, the compound represented by Formula 1 according to the present invention can be formulated in various forms depending on the purpose. The following illustrates some formulation methods in which the compound represented by Formula 1 according to the present invention is contained as an active ingredient, and the present invention is not limited thereto.

<제제예 1> 약학적 제제의 제조<Formulation Example 1> Preparation of pharmaceutical formulation

1-1. 산제의 제조1-1. Preparation of powder

화학식 1의 화합물 500 ㎎500 mg of the compound of formula 1

유당 100 ㎎100 mg lactose

탈크 10 ㎎Talc 10 mg

상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

1-2. 정제의 제조1-2. Manufacture of tablets

화학식 1의 화합물 500 ㎎500 mg of the compound of formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎100 mg lactose

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet preparation method.

1-3. 캅셀제의 제조1-3. Preparation of capsules

화학식 1의 화합물 500 ㎎500 mg of the compound of formula 1

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎100 mg lactose

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare a capsule.

1-4. 주사제의 제조1-4. Preparation of injections

화학식 1의 화합물 500 ㎎500 mg of the compound of formula 1

주사용 멸균 증류수 적량Proper amount of sterile distilled water for injection

pH 조절제 적량proper amount of pH adjuster

통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다.It is prepared with the above ingredients per ampoule (2 ml) according to a conventional injection preparation method.

1-5. 액제의 제조1-5. Preparation of liquid

화학식 1의 화합물 100 ㎎100 mg of the compound of formula 1

이성화당 10 g10 g of isomerized sugar

만니톨 5 g5 g of mannitol

정제수 적량Purified water appropriate amount

통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색 병에 충진하여 멸균시켜 액체를 제조한다.According to the usual preparation method of liquid preparation, add and dissolve each component in purified water, add lemon scent, mix the above ingredients, add purified water, add purified water, adjust the total to 100 ml, and fill in a brown bottle. The liquid is prepared by sterilization.

이상, 본 발명을 바람직한 제조예, 실시예 및 실험예를 통해 상세히 설명하였으나, 본 발명의 범위는 특성 실시예에 한정되는 것은 아니며, 첨부된 특허청구범위에 의하여 해석되어야 할 것이다. 또한, 이 기술분야에서 통상의 지식을 습득한 자라면, 본 발명의 범위에서 벗어나지 않으면서도 많은 수정과 변형이 가능함을 이해하여야 할 것이다.Above, the present invention has been described in detail through preferred manufacturing examples, examples, and experimental examples, but the scope of the present invention is not limited to specific examples, and should be interpreted by the appended claims. In addition, those who have acquired ordinary knowledge in this technical field should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (10)

하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염:
[화학식 1]
Figure 112020142478732-pat00100

상기 화학식 1에서,

상기 X는 S 또는 O이고;

상기 L1은 -(CH2)p-이고, p는 0이고;
상기 L2는 -(CH2)q-이고, q는 0이고;
상기 L3은 -(CH2)r-이고, r은 3이고;

상기 Y는 C 또는 N이고;

상기 R1은 C1-5의 직쇄 또는 분지쇄 알킬, C3-6의 사이클로알킬, C3-6의 사이클로알킬 C1-3의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 6 원자의 헤테로사이클로알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6 원자의 헤테로사이클로알킬 C1-3의 직쇄 또는 분지쇄 알킬, 비치환 또는 할로겐이 치환된 페닐, 비치환 또는 할로겐이 치환된 페닐 C1-3의 직쇄 또는 분지쇄 알킬, N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 6 원자의 헤테로아릴, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 비치환 또는 치환된 5 내지 6 원자의 헤테로아릴 C1-5의 직쇄 또는 분지쇄 알킬이고,
상기 치환된 5 내지 6 원자의 헤테로사이클로알킬은 C1-3의 직쇄 또는 분지쇄 알킬, C1-2의 직쇄 또는 분지쇄 알킬카보닐, 비치환 또는 할로겐이 치환된 페닐, 비치환 또는 할로겐이 페닐 C1-3의 직쇄 또는 분지쇄 알킬, 및 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 5 내지 6원자의 헤테로아릴 C1-3의 직쇄 또는 분지쇄 알킬로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 5 내지 6 원자의 헤테로사이클로알킬이고,
상기 치환된 5 내지 6 원자의 헤테로아릴은 할로겐, -NH2 및 -NHR4NH2로 이루어지는 군으로부터 선택되는 1종 이상의 치환체가 치환된 C6-8의 아릴 또는 5 내지 6 원자의 헤테로아릴이고,
상기 R4는 C1-3의 직쇄 또는 분지쇄 알킬이고;

상기 R2는,
상기 Y가 N일 경우, 부재이고; 및
상기 Y가 C일 경우, -H, C1-3의 직쇄 또는 분지쇄 알킬이거나, 상기 R1과 함께 연결되어 C4-6의 사이클로알킬을 형성한다.
A compound represented by the following Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
Figure 112020142478732-pat00100

In Chemical Formula 1,

X is S or O;

L 1 is -(CH 2 ) p -, and p is 0;
L 2 is -(CH 2 ) q -, and q is 0;
L 3 is -(CH 2 ) r -, and r is 3;

Y is C or N;

R 1 is from the group consisting of C 1-5 straight or branched chain alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 straight or branched alkyl, N, O and S Unsubstituted or substituted 5 to 6 membered heterocycloalkyl containing at least one selected heteroatom, 5 to 6 membered heterocycloalkyl C including at least one heteroatom selected from the group consisting of N, O and S 1-3 straight or branched chain alkyl, unsubstituted or halogen-substituted phenyl, unsubstituted or halogen-substituted phenyl C 1-3 straight or branched chain alkyl, one selected from the group consisting of N, O and S Unsubstituted or substituted 5 to 6 membered heteroaryl including more heteroatoms, and unsubstituted or substituted 5 to 6 membered heteroaryl including at least one heteroatom selected from the group consisting of N, O and S C 1-5 straight or branched chain alkyl,
The substituted 5 to 6 membered heterocycloalkyl is C 1-3 straight or branched chain alkyl, C 1-2 straight or branched chain alkylcarbonyl, unsubstituted or halogen-substituted phenyl, unsubstituted or halogen Phenyl C 1-3 straight or branched chain alkyl, and 5 to 6 membered heteroaryl C 1-3 straight or branched chain alkyl containing one or more heteroatoms selected from the group consisting of N, O and S At least one substituent selected from the group is substituted 5 to 6 membered heterocycloalkyl
The substituted 5 to 6 membered heteroaryl is a C 6-8 aryl or 5 to 6 membered heteroaryl substituted with one or more substituents selected from the group consisting of halogen, -NH 2 and -NHR 4 NH 2 ,
R 4 is C 1-3 straight or branched chain alkyl;

R 2 is,
When Y is N, it is absent; And
When Y is C, -H, C 1-3 linear or branched chain alkyl, or is linked together with R 1 to form C 4-6 cycloalkyl.
삭제delete 삭제delete 제1항에 있어서,
상기 X는 S 또는 O이고;

상기 R1은 -CH3,
Figure 112020142478732-pat00101
,
Figure 112020142478732-pat00102
,
Figure 112020142478732-pat00103
,
Figure 112020142478732-pat00104
,
Figure 112020142478732-pat00105
,
Figure 112020142478732-pat00106
,
Figure 112020142478732-pat00107
,
Figure 112020142478732-pat00108
,
Figure 112020142478732-pat00109
,
Figure 112020142478732-pat00110
,
Figure 112020142478732-pat00111
,
Figure 112020142478732-pat00112
,
Figure 112020142478732-pat00113
,
Figure 112020142478732-pat00114
,
Figure 112020142478732-pat00115
,
Figure 112020142478732-pat00116
,
Figure 112020142478732-pat00117
,
Figure 112020142478732-pat00118
,
Figure 112020142478732-pat00119
,
Figure 112020142478732-pat00120
,
Figure 112020142478732-pat00121
,
Figure 112020142478732-pat00122
,
Figure 112020142478732-pat00123
,
Figure 112020142478732-pat00124
,
Figure 112020142478732-pat00125
,
Figure 112020142478732-pat00126
,
Figure 112020142478732-pat00127
,
Figure 112020142478732-pat00128
,
Figure 112020142478732-pat00129
,
Figure 112020142478732-pat00130
,
Figure 112020142478732-pat00131
,
Figure 112020142478732-pat00132
,
Figure 112020142478732-pat00133
,
Figure 112020142478732-pat00134
, 또는
Figure 112020142478732-pat00135
이고;

상기 R2는,
상기 Y가 N일 경우, 부재이고; 및
상기 Y가 C일 경우, -H, C1-2의 직쇄 또는 분지쇄 알킬이거나, 상기 R1과 함께 연결되어 C4-6의 사이클로알킬을 형성하는 것을 특징으로 하는 화합물, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염.
The method of claim 1,
X is S or O;

R 1 is -CH 3 ,
Figure 112020142478732-pat00101
,
Figure 112020142478732-pat00102
,
Figure 112020142478732-pat00103
,
Figure 112020142478732-pat00104
,
Figure 112020142478732-pat00105
,
Figure 112020142478732-pat00106
,
Figure 112020142478732-pat00107
,
Figure 112020142478732-pat00108
,
Figure 112020142478732-pat00109
,
Figure 112020142478732-pat00110
,
Figure 112020142478732-pat00111
,
Figure 112020142478732-pat00112
,
Figure 112020142478732-pat00113
,
Figure 112020142478732-pat00114
,
Figure 112020142478732-pat00115
,
Figure 112020142478732-pat00116
,
Figure 112020142478732-pat00117
,
Figure 112020142478732-pat00118
,
Figure 112020142478732-pat00119
,
Figure 112020142478732-pat00120
,
Figure 112020142478732-pat00121
,
Figure 112020142478732-pat00122
,
Figure 112020142478732-pat00123
,
Figure 112020142478732-pat00124
,
Figure 112020142478732-pat00125
,
Figure 112020142478732-pat00126
,
Figure 112020142478732-pat00127
,
Figure 112020142478732-pat00128
,
Figure 112020142478732-pat00129
,
Figure 112020142478732-pat00130
,
Figure 112020142478732-pat00131
,
Figure 112020142478732-pat00132
,
Figure 112020142478732-pat00133
,
Figure 112020142478732-pat00134
, or
Figure 112020142478732-pat00135
ego;

R 2 is,
When Y is N, it is absent; And
When Y is C, -H, C 1-2 straight or branched chain alkyl, or a compound characterized in that it is linked together with R 1 to form C 4-6 cycloalkyl, stereoisomers thereof, and Hydrate or a pharmaceutically acceptable salt thereof.
 제1항에 있어서,
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염:
(1) 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(2) 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(3) 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(4) 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(5) 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(6) 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(7) 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(8) 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(9) 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(10) 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(11) 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(12) 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(13) 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(14) 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)티오우레아;
(15) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일메틸)티오우레아;
(16) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)티오우레아;
(18) 1-(3,4-다이메톡시페닐)-1-메틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(19) 1-(3,4-다이메톡시페닐)-1-에틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(20) 1-(3,4-다이메톡시페닐)-1-아이소프로필-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(21) 1-(3,4-다이메톡시페닐)-1-아이소뷰틸-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(22) 1-(사이클로펜틸메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)-프로필)우레아;
(23) 1-사이클로프로필-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(24) 1-사이클로뷰틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(25) 1-사이클로펜틸-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(26) 1-사이클로헥실-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(27) 1-벤질-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(28) 1-(3,4-다이메톡시페닐)-1-(3-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(29) 1-(3-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(30) 1-(3,4-다이메톡시페닐)-1-(4-플루오로벤질)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(31) 1-(4-클로로벤질)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(32) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-3-일-메틸)우레아;
(33) 1-(3,4-다이메톡시페닐)-1-((6-플루오로피리딘-3-일)메틸)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(34) 1-((6-클로로피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(35) 1-((6-아미노피리딘-3-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(36) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피리딘-4-일-메틸)우레아;
(37) 1-((2-아미노피리딘-4-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(38) 1-((2-아미노피리딘-4-일)메틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(39) 1-(4-(2-아미노피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(40) 1-(4-(2-(2-아미노에틸아미노)피리딘-4-일)뷰틸)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(41) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-페닐우레아;
(42) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-페닐우레아;
(43) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(티아졸-2-일)우레아;
(44) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(피페리딘-4-일)우레아;
(45) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-메틸피레리딘-4-일)우레아;
(46) 1-(3,4-다이메톡시페닐)-1-(1-에틸피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(47) 1-(1-아세틸피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(48) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-페닐피페리딘-4-일)우레아;
(49) 1-(1-벤질피페리딘-4-일)-1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(50) 1-(3,4-다이메톡시페닐)-1-(1-(4-플루오로벤질)피페리딘-4-일)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)우레아;
(51) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(1-(피리딘-3-일메틸)피페리딘-4-일)우레아;
(52) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-(피페라진-1-일)에틸)우레아;
(53) 1-(3,4-다이메톡시페닐)-3-(3-(5-메틸-1H-이미다졸-1-일)프로필)-1-(2-모르폴리노에틸)우레아;
(54) 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)아세트아미드;
(55) 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)프로판아미드;
(56) 2-(3,4-다이메톡시페닐)-2-메틸-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)프로판아미드;
(58) 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로뷰탄카복사미드;
(59) 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로펜탄카복사미드;
(60) 1-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)사이클로헥세인-1-카복사미드;
(61) 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)-3-페닐프로페인아미드; 및
(62) 2-(3,4-다이메톡시페닐)-N-(3-(5-메틸-1H-이미다졸-1-일)프로필)-3-페닐프로페인아미드.
The method of claim 1,
The compound represented by Formula 1 is a compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is any one selected from the following group of compounds:
(1) 1-(3,4-dimethoxyphenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(2) 1-(3,4-dimethoxyphenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(3) 1-(3,4-dimethoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(4) 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(5) 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(6) 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(7) 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(8) 1-cyclopentyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(9) 1-cyclohexyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(10) 1-benzyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(11) 1-(3,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(12) 1-(3-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(13) 1-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(14) 1-(4-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)thiourea;
(15) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-ylmethyl)thiourea ;
(16) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl)thio Urea;
(18) 1-(3,4-dimethoxyphenyl)-1-methyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(19) 1-(3,4-dimethoxyphenyl)-1-ethyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(20) 1-(3,4-dimethoxyphenyl)-1-isopropyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(21) 1-(3,4-dimethoxyphenyl)-1-isobutyl-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(22) 1-(cyclopentylmethyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)-propyl)urea;
(23) 1-cyclopropyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(24) 1-cyclobutyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(25) 1-cyclopentyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(26) 1-cyclohexyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(27) 1-benzyl-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(28) 1-(3,4-dimethoxyphenyl)-1-(3-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(29) 1-(3-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(30) 1-(3,4-dimethoxyphenyl)-1-(4-fluorobenzyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(31) 1-(4-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)urea;
(32) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-3-yl-methyl)urea ;
(33) 1-(3,4-dimethoxyphenyl)-1-((6-fluoropyridin-3-yl)methyl)-3-(3-(5-methyl-1H-imidazole-1- Work) propyl) urea;
(34) 1-((6-chloropyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl ) Propyl) urea;
(35) 1-((6-aminopyridin-3-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl ) Propyl) urea;
(36) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(pyridin-4-yl-methyl)urea ;
(37) 1-((2-aminopyridin-4-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl ) Propyl) urea;
(38) 1-((2-aminopyridin-4-yl)methyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl ) Propyl) urea;
(39) 1-(4-(2-aminopyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazole-1 -Yl)propyl)urea;
(40) 1-(4-(2-(2-aminoethylamino)pyridin-4-yl)butyl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl- 1H-imidazol-1-yl)propyl)urea;
(41) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-phenylurea;
(42) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-phenylurea;
(43) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(thiazol-2-yl)urea;
(44) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(piperidin-4-yl)urea ;
(45) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-methylpyreridine-4- Work) urea;
(46) 1-(3,4-dimethoxyphenyl)-1-(1-ethylpiperidin-4-yl)-3-(3-(5-methyl-1H-imidazol-1-yl) Propyl) urea;
(47) 1-(1-acetylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl) Propyl) urea;
(48) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-phenylpiperidine-4- Work) urea;
(49) 1-(1-Benzylpiperidin-4-yl)-1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl) Propyl) urea;
(50) 1-(3,4-dimethoxyphenyl)-1-(1-(4-fluorobenzyl)piperidin-4-yl)-3-(3-(5-methyl-1H-imine) Dazol-1-yl)propyl)urea;
(51) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(1-(pyridin-3-ylmethyl ) Piperidin-4-yl) urea;
(52) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(2-(piperazin-1-yl) )Ethyl)urea;
(53) 1-(3,4-dimethoxyphenyl)-3-(3-(5-methyl-1H-imidazol-1-yl)propyl)-1-(2-morpholinoethyl)urea;
(54) 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)acetamide;
(55) 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)propanamide;
(56) 2-(3,4-dimethoxyphenyl)-2-methyl-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)propanamide;
(58) 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclobutanecarboxamide;
(59) 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclopentanecarboxamide;
(60) 1-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)cyclohexane-1-carboxamide;
(61) 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-phenylpropaneamide; And
(62) 2-(3,4-dimethoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-3-phenylpropaneamide.
 제1항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 치매, 픽(pick)병, 크루츠-야콥(Creutzfeldt-Jakob) 병, 두부손상에 의한 파킨슨(Parkinson) 병 및 헌팅턴(Huntington) 병으로 이루어지는 군으로부터 선택되는 질환의 예방 또는 치료용 약학적 조성물.
Dementia, Pick's disease, Creutzfeldt-Jakob's disease, Parkinson's caused by head injury, containing the compound represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for preventing or treating a disease selected from the group consisting of disease and Huntington disease.
 제6항에 있어서,
상기 화학식 1로 표시되는 화합물은 글루타미닐 사이클레이즈(Glutaminyl Cyclase)를 저해하는 것을 특징으로 하는 약학적 조성물.
The method of claim 6,
The compound represented by Formula 1 is a pharmaceutical composition, characterized in that inhibiting glutaminyl cyclase (Glutaminyl Cyclase).
 제6항에 있어서,
상기 치매는 알츠하이머병, 뇌혈관성 치매증, 두부 손상에 의한 치매, 다경색 치매, 알츠하이머병과 다경색 치매의 혼합형 또는 알코올성 치매인 것을 특징으로 하는 약학적 조성물.
The method of claim 6,
The dementia is Alzheimer's disease, cerebrovascular dementia, dementia due to head injury, multi-infarct dementia, a combination of Alzheimer's disease and multi-infarct dementia, or alcoholic dementia.
 제1항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 치매, 픽(pick)병, 크루츠-야콥(Creutzfeldt-Jakob) 병, 두부손상에 의한 파킨슨(Parkinson) 병 및 헌팅턴(Huntington) 병으로 이루어지는 군으로부터 선택되는 질환의 예방 또는 개선용 건강식품 조성물.
Dementia, Pick's disease, Creutzfeldt-Jakob's disease, Parkinson's caused by head injury, containing the compound represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient A health food composition for preventing or improving a disease selected from the group consisting of disease and Huntington disease.
 제9항에 있어서,
상기 치매는 알츠하이머병, 뇌혈관성 치매증, 두부 손상에 의한 치매, 다경색 치매, 알츠하이머병과 다경색 치매의 혼합형 또는 알코올성 치매인 것을 특징으로 하는 건강식품 조성물.The method of claim 9,
The dementia is Alzheimer's disease, cerebrovascular dementia, dementia due to head injury, multi-infarct dementia, a combination of Alzheimer's disease and multi-infarct dementia, or alcoholic dementia.
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