KR100894713B1 - 4-arylpiperazin-1-ylpiperidine derivatives inhibiting beta-secretase's activity or pharmaceutical compositions containing the same and composition for prevention and treatment of neurodegenerative diseases containing the same as an active ingredient - Google Patents
4-arylpiperazin-1-ylpiperidine derivatives inhibiting beta-secretase's activity or pharmaceutical compositions containing the same and composition for prevention and treatment of neurodegenerative diseases containing the same as an active ingredient Download PDFInfo
- Publication number
- KR100894713B1 KR100894713B1 KR1020070101067A KR20070101067A KR100894713B1 KR 100894713 B1 KR100894713 B1 KR 100894713B1 KR 1020070101067 A KR1020070101067 A KR 1020070101067A KR 20070101067 A KR20070101067 A KR 20070101067A KR 100894713 B1 KR100894713 B1 KR 100894713B1
- Authority
- KR
- South Korea
- Prior art keywords
- piperazin
- piperidin
- naphthoate
- methoxyphenyl
- fluorophenyl
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 26
- 239000004480 active ingredient Substances 0.000 title claims abstract description 16
- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 15
- 230000004770 neurodegeneration Effects 0.000 title claims abstract description 14
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 title abstract description 37
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 title abstract description 36
- 230000002401 inhibitory effect Effects 0.000 title abstract description 23
- 230000000694 effects Effects 0.000 title abstract description 19
- 230000002265 prevention Effects 0.000 title abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 title description 3
- -1 piperidine compound Chemical group 0.000 claims abstract description 530
- 150000003053 piperidines Chemical group 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 22
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 18
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- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 131
- 238000000034 method Methods 0.000 claims description 42
- OTRHZCQHDKNSFX-UHFFFAOYSA-N O=C(C(C=C1)=CC=C1OC1=CC=CC=C1)OC1CNCCC1 Chemical compound O=C(C(C=C1)=CC=C1OC1=CC=CC=C1)OC1CNCCC1 OTRHZCQHDKNSFX-UHFFFAOYSA-N 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
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- RQVHCCINUIJDPQ-UHFFFAOYSA-N N1CC(CCC1)C1=C(C=CC(=C1)C(=O)ON1CCN(CC1)C1=CC=C(C=C1)F)C1=CC=CC=C1 Chemical compound N1CC(CCC1)C1=C(C=CC(=C1)C(=O)ON1CCN(CC1)C1=CC=C(C=C1)F)C1=CC=CC=C1 RQVHCCINUIJDPQ-UHFFFAOYSA-N 0.000 claims description 4
- CKGURSXMDQKFKB-UHFFFAOYSA-N N1CCC(CC1)C1=C(C=CC=C1C(=O)ON1CCN(CC1)C1=CC=C(C=C1)OC)C1=CC=CC=C1 Chemical compound N1CCC(CC1)C1=C(C=CC=C1C(=O)ON1CCN(CC1)C1=CC=C(C=C1)OC)C1=CC=CC=C1 CKGURSXMDQKFKB-UHFFFAOYSA-N 0.000 claims description 4
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- KGRQDBJHWIVVLS-UHFFFAOYSA-N N1CCC(CC1)C1=C(C=CC=C1C(=O)ON1CCN(CC1)C1=CC=C(C=C1)F)C1=CC=CC=C1 Chemical compound N1CCC(CC1)C1=C(C=CC=C1C(=O)ON1CCN(CC1)C1=CC=C(C=C1)F)C1=CC=CC=C1 KGRQDBJHWIVVLS-UHFFFAOYSA-N 0.000 claims description 3
- 150000007942 carboxylates Chemical class 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- RYAQFHLUEMJOMF-UHFFFAOYSA-M 4-phenoxybenzoate Chemical compound C1=CC(C(=O)[O-])=CC=C1OC1=CC=CC=C1 RYAQFHLUEMJOMF-UHFFFAOYSA-M 0.000 claims 1
- 125000004104 aryloxy group Chemical group 0.000 claims 1
- PARMADWNFXEEFC-UHFFFAOYSA-N bamethan sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[NH2+]CC(O)C1=CC=C(O)C=C1.CCCC[NH2+]CC(O)C1=CC=C(O)C=C1 PARMADWNFXEEFC-UHFFFAOYSA-N 0.000 claims 1
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- UXYLCUKYCTWDCJ-UHFFFAOYSA-N piperidin-4-yl naphthalene-1-carboxylate Chemical compound N1CCC(CC1)OC(=O)C1=CC=CC2=CC=CC=C12 UXYLCUKYCTWDCJ-UHFFFAOYSA-N 0.000 description 30
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
본 발명은 베타-세크리테아제의 활성을 저해하는 아릴피페라진이 치환된 피페리딘 화합물 또는 이의 약제학적으로 허용 가능한 염 및 이를 유효성분으로 함유하는 신경퇴행성 질환의 예방 또는 치료용 조성물에 관한 것으로, 본 발명에 따른 아릴 피페라진이 치환된 피페리딘 유도체는 베타-세크리테아제 저해 활성이 우수하므로, 알츠하이머, 다운증후군 등의 신경퇴행성 질환의 예방 및 치료에 유용하게 사용될 수 있다.The present invention relates to a piperidine compound substituted with an aryl piperazine inhibiting the activity of beta-secretase, or a pharmaceutically acceptable salt thereof, and a composition for preventing or treating neurodegenerative diseases containing the same as an active ingredient. Since the piperidine derivatives substituted with aryl piperazine according to the present invention have excellent beta-secretase inhibitory activity, they may be usefully used for the prevention and treatment of neurodegenerative diseases such as Alzheimer's and Down syndrome.
알츠하이머 질환, 피페리딘 화합물, 베타-세크리테아제, 노화, 신경퇴행성 질환, 베타-아밀로이드 Alzheimer's disease, piperidine compounds, beta-secretase, aging, neurodegenerative diseases, beta-amyloid
Description
본 발명은 베타-세크리테아제의 활성을 저해하는 신규한 아릴피페라진이 치환된 피페리딘 유도체 및 이를 유효성분으로 함유하는 신경퇴행성 질환 예방 또는 치료용 조성물, 또는 베타-세크리테아제의 활성 저해제에 관한 것이다.The present invention provides a novel aryl piperazine-substituted piperidine derivative that inhibits the activity of beta-secretase and a composition for preventing or treating neurodegenerative diseases containing the same as an active ingredient, or an inhibitor of beta-secretase activity It is about.
최근 급속한 경제성장과 새로운 의학기술의 발달로 인해 인간의 수명연장이 실현되고 있어 고령화 사회로 이행되는 과정에서 노인복지 정책은 국가차원에서 그 중요성이 증가하고 있다. 특히, 노인들에게 가장 문제가 되고 있는 신경퇴행성 질환인 알츠하이머 치매질환에 대한 사회적 경제적인 부담은 점점 증가추세에 있어 이에 대한 대책이 시급한 실정이다. 따라서 알츠하이머 치매질환 치료제의 개발은 이들 문제를 해결하기 위한 가장 직접적인 해결방안 중의 하나가 될 수 있다.In recent years, due to the rapid economic growth and the development of new medical technology, the longevity of humans is being realized, and the elderly welfare policy is increasing in importance in the process of transition to an aging society. In particular, the socio-economic burden on Alzheimer's dementia disease, a neurodegenerative disease that is most problematic for the elderly, is gradually increasing, and countermeasures are urgently needed. Therefore, the development of Alzheimer's disease treatment may be one of the most direct solutions to solve these problems.
알츠하이머 질환(AD)은 신경세포 손상으로 인해 기억력, 인지력, 추론력, 판단력 및 지남력의 상실을 특징으로 하는 노화와 밀접한 관련이 있는 신경퇴행성 질환이다. 알츠하이머병의 병리학적 특징으로 뇌의 인지활동과 관련된 영역에서 신경섬유다발의 세포내 축적과, 베타아밀로이드(β-amyloid, 이하 Aβ) 펩타이드가 주요성분으로 구성된 노인반점(senile plaque)의 세포외 침착을 나타낸다. 39-43개의 아미노산으로 구성된 Aβ 단백질은 신경세포 독성을 나타내는 것이 공지되어 있다. Alzheimer's disease (AD) is a neurodegenerative disorder that is closely related to aging characterized by loss of memory, cognition, reasoning, judgment and coping due to neuronal damage. Pathological characteristics of Alzheimer's disease include intracellular accumulation of nerve fiber bundles and extracellular deposition of senile plaques consisting of beta-amyloid (Aβ) peptides in areas related to cognitive activity of the brain. Indicates. Aβ proteins consisting of 39-43 amino acids are known to exhibit neuronal toxicity.
알츠하이머 치매 환자들에 공통적으로 나타나는 노인반점(senile plaques)의 주요 요소인 Aβ 펩타이드는 그 전구대사단백질인 아밀로이드 전구체 단백질(amyloid precursor protein, 이하 APP) 695, 751, 770으로부터 유래한다. 이 APP는 대부분의 경우, α-세크리테아제와 γ-세크리테아제라고 불리우는 프로테아제에 의하여 절단되어 P3 펩타이드와 세포의 바깥쪽으로 sAPPα라는 수용성 단백질을 방출하게 된다. 특이적으로 알츠하이머 치매 환자에서는 β-세크리테아제와 γ-세크리테아제가 활성화되어 Aβ 펩타이드와 sAPPβ라는 단백질이 세포밖으로 방출된다. 알츠하이머 치매 환자들 중에서 APP 유전인자의 돌연변이의 경우를 보면 대부분이 α, β, γ-세크리테아제들의 인지부분에 돌연변이가 생긴 경우로 이러한 돌연변이가 단백질의 구조를 변화시켜서 β와 γ-세크리테아제에 노출이 더 잘 되 어 정상인의 경우보다 많은 양의 Aβ 펩타이드가 생성되는 것으로 밝혀져 있다. Aβ 펩타이드는 42개의 아미노산 잔기로 이루어진 녹지 않는 성질을 가지며, 기억 및 인식과 관련된 뇌 영역에 침착되어 뇌세포의 아폽토시스를 유발하는 것으로 알려져 있다. 최근 보고에 의하면 APP 유전인자의 돌연변이가 caspase-6와 caspase-3라는 아폽토시스 분해효소(apoptotic protease)의 기질로 작용하여 절단이 되며, 이렇게 절단되어진 APP는 β-, γ-세크리테아제에 의하여 보다 용이하게 Aβ를 형성하게 된다고 알려져 있다. 알츠하이머 치매 환자에서 보이는 APP 돌연변이 유전인자를 과량 발현하는 APP 과다발현 형질전환 쥐의 경우, 치매 환자에서 보이는 노인반점과 특이적 증상인 공간지각 학습능력이 저하되는 결과가 나타났다고 보고되어 있다. 이러한 여러 가지 보고들을 종합하여 볼 때 알츠하이머 치매 환자에서 보이는 APP 유전인자의 변이는 Aβ 펩타이드의 생성량과 밀접한 관련이 있으며, 알츠하이머 치매질환의 발병에 중요한 역할을 하는 것으로 알려져 있다. Aβ peptides, a major component of the senile plaques that are common in Alzheimer's dementia patients, are derived from the amyloid precursor protein (APP) 695, 751, 770. In most cases, this APP is cleaved by proteases called α-secretase and γ-secretase to release P3 peptides and water-soluble proteins called sAPPα out of cells. Specifically, in patients with Alzheimer's dementia, β-secretase and γ-secretase are activated to release Aβ peptide and a protein called sAPPβ out of the cell. Among Alzheimer's dementia patients, most of the mutations in APP genes are mutations in the cognitive regions of α, β, and γ-secretases. These mutations alter the structure of the protein, resulting in β and γ-secretase. It has been shown that exposure to the chromophore results in higher amounts of Αβ peptide than normal individuals. Aβ peptides have insoluble properties consisting of 42 amino acid residues and are known to be deposited in brain regions associated with memory and recognition, leading to apoptosis of brain cells. According to recent reports, the mutation of APP gene factor acts as a substrate of the apoptotic protease caspase-6 and caspase-3, and the cleaved APP is cleaved by β- and γ-secretase. It is known to form Aβ easily. It has been reported that APP overexpressing transgenic mice overexpressing APP mutant genes in Alzheimer's dementia resulted in a decrease in the senile plaques and dementia-specific spatial perceptual learning in patients with dementia. Taken together, these reports suggest that mutations in APP genes in Alzheimer's dementia patients are closely related to the production of Aβ peptides and play an important role in the development of Alzheimer's disease.
따라서, BACE, Asp 또는 메맙신(Memapsin)으로도 명명되고 있는 β-세크레타아제 효소((a) Tang, J. et al., Proc . Natl . Acad . Sci . U. S. A. 2000, 97, 1456. (b) Hussain, I. et al., Mol . Cell Neurosci . 1999, 14, 419. (c) Yan, R. et al., Nature 1999, 402, 533. (d). Sinha, S, et al., Nature 1999, 402, 537. (e) Vassar, R.et al., Science 1999 , 286, 735.)의 활성을 저해하는 저해제는 알츠하이머 질환의 예방 및 근본적인 발병원인을 치료할 수 있는 약물로 인식되고 있으며, 많은 제약회사들이 새로운 저해제 개발을 위해 막대한 연구비를 투자하고 있다.Thus, the β-secretase enzyme, also called BACE, Asp or Memapsin ((a) Tang, J. et al., Proc . Natl . Acad . Sci . USA 2000 , 97 , 1456. ( b) Hussain, I. et al., Mol . Cell Neurosci . 1999 , 14 , 419. (c) Yan, R. et al., Nature 1999 , 402 , 533. (d). Sinha, S, et al., Nature 1999 , 402 , 537. (e) Inhibitors that inhibit the activity of Vassar, R. et al., Science 1999 , 286 , 735.) prevent the prophylactic and underlying pathogenesis of Alzheimer's disease. It is recognized as a treatable drug, and many pharmaceutical companies are investing huge research funds to develop new inhibitors.
β-세크리테아제 저해제 개발에 관한 많은 보고가 있는데, 주로 천연 아미노산을 이용한 펩티드 결합을 갖는 화합물이 대부분이다. 최근에는 천연 아미노산에서 유래한 펩티드 화합물과 구조가 다른 저해제들이 보고되고 있다((a) Stachel, S. J. et al., J. Med . Chem . 2004, 47, 6447. (b) Huang, D. et al., J. Med . Chem. 2005, 48, 5108. (c) Bhisetti, G. R. et al., PCT Int. Appl. WO 02/088101, 2002. (d) Garino, C. et al., Bioorg . Med . Chem . Lett. 2006, 16, 1995.).There are many reports on the development of β-secretase inhibitors, most of which have peptide bonds using mainly natural amino acids. Recently, inhibitors with different structures from peptide compounds derived from natural amino acids have been reported ((a) Stachel, SJ et al., J. Med . Chem . 2004 , 47 , 6447. (b) Huang, D. et al. ., J. Med. Chem. 2005 , 48, 5108. (c) Bhisetti, GR et al., PCT Int. Appl. WO 02/088101, 2002. (d) Garino, C. et al., Bioorg. Med . Chem. Lett. 2006, 16 , 1995.).
이에 본 발명자들은 베타-세크리테아제의 활성을 저해하는 능력이 뛰어난 베타-세크리테아제 저해제를 개발하고자 노력한 결과, 피페리딘 유도체에 아릴 대신 아릴피페라진이 치환된 피페리딘 유도체가 베타-세크리테아제의 활성을 저해하는 효능이 우수한 것을 확인하고 본 발명을 완성하였다.Accordingly, the present inventors have tried to develop a beta-secretase inhibitor that is excellent in inhibiting the activity of beta-secretase, and as a result, the piperidine derivative in which aryl piperazine is substituted for piperidine derivatives is substituted for beta-secret. It was confirmed that the efficacy of inhibiting the activity of thease is excellent and completed the present invention.
본 발명의 목적은 신규한 아릴피페라진이 치환된 피페리딘 유도체 및 이의 약학적으로 허용가능한 염을 제공하는 데 있다.An object of the present invention is to provide a piperidine derivative substituted with a novel aryl piperazine and a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 상기 유도체를 유효성분으로 하는 신경퇴행성 질환 예방 및 치료용 조성물을 제공하는 데 있다.Another object of the present invention to provide a composition for preventing and treating neurodegenerative diseases using the derivative as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 신규한 아릴피페라진이 치환된 피페리딘 유도체 및 이의 약학적으로 허용가능한 염을 제공한다.In order to achieve the above object, the present invention provides a piperidine derivative and a pharmaceutically acceptable salt thereof substituted with a novel aryl piperazine.
또한, 본 발명은 상기 유도체를 유효성분으로 하는 신경퇴행성 질환 예방 및 치료용 조성물 또는 베타-세크리테아제 저해제를 제공한다.The present invention also provides a composition or a beta-secretase inhibitor for the prevention and treatment of neurodegenerative diseases using the derivative as an active ingredient.
본 발명에 따른 하기 화학식 1로 표시되는 아릴 피페라진이 치환된 피페리딘 유도체는 베타-세크리테아제 저해 활성이 우수하므로, 알츠하이머, 다운증후군 등의 신경퇴행성 질환의 예방 및 치료에 유용하게 사용될 수 있다.The piperidine derivative substituted with aryl piperazine represented by the following Chemical Formula 1 according to the present invention has excellent beta-secretase inhibitory activity, and thus may be usefully used for the prevention and treatment of neurodegenerative diseases such as Alzheimer's and Down syndrome. have.
본 발명은 하기 화학식 1로 표시되는 아릴 피페라진이 치환된 피페리딘 유도 체 및 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a piperidine derivative substituted with an aryl piperazine represented by Formula 1 below, and a pharmaceutically acceptable salt thereof.
상기 화학식 1에서, In Chemical Formula 1,
R1 및 R2는 독립적으로 -O-CO-R4 또는 을 나타내고, 이때 R4는 C6 - 10아릴C1 - 4알킬기, C6 - 12아릴, C1 - 5알콕시 또는 C6 - 12아릴옥시가 치환된 C6 - 12아릴기이고, Z는 수소, 할로겐, C1 -4 직쇄 또는 측쇄 알킬기 또는 C1 - 5알콕시기이고, R 1 And R 2 is independently —O—CO—R 4 or A represents, wherein R 4 is C 6 - 10 aryl C 1 - 4 alkyl group, C 6 - 12 aryl, C 1 - 5 alkoxy or C 6 - 12 aryloxy-substituted C 6 - and 12 aryl group, Z is hydrogen 5 is an alkoxy group, - a halogen, C 1 -4 alkyl group or a linear or branched C 1
R3은 수소,-CO-NH-(CH2)m-R5 또는 -CO-NH-C(R6)(R7)-(CH2)m-COO-R8이고, 이때 R5는 1내지 2개의 C1 -4 직쇄 또는 측쇄 알킬 또는 C1 - 5알콕시 또는 할로겐이 치환된 C6 - 12아릴기이고, m은 0 내지 2의 정수를 나타내고, R6 및 R7는 독립적으로 수소, C1 -4 직쇄 또는 측쇄 알킬기 또는 벤질기이며, R8은 C1 -4 직쇄 또는 측쇄 알킬기이다.R 3 is hydrogen, -CO-NH- (CH 2 ) m -R 5 Or -CO-NH-C (R 6 ) (R 7) - (CH 2) m -COO-R 8 , and wherein R 5 is 1 to 2 C 1 -4 straight or branched alkyl or C 1 - 5 alkoxy or halogen-substituted C 6 - 12 aryl group, and, m is an integer of 0 to 2, R 6 And R 7 is independently hydrogen, C 1 -4 straight or branched alkyl group or benzyl group, R 8 is a C 1 -4 straight or branched alkyl group.
바람직하게는 본 발명에 따른 상기 R4는 나프틸, 바이페닐 또는 페녹시벤질이고, Z는 수소, 할로겐, 메틸 또는 메톡시이며,Preferably said R 4 according to the invention is naphthyl, biphenyl or phenoxybenzyl, Z is hydrogen, halogen, methyl or methoxy,
R3은R 3 is
로 이루어지는 군으로부터 선택되는 어느 하나이다.It is any one selected from the group consisting of.
상기 화학식 1로 표시되는 피페리딘 유도체를 보다 구체적으로 예시하면 다음과 같다.More specifically exemplified by the piperidine derivative represented by Formula 1 are as follows.
(1) 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트;(1) 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;
(2) 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트;(2) 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;
(3) 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트;(3) 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;
(4) 4-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트;(4) 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;
(5) 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트;(5) 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate;
(6) 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트;(6) 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate;
(7) 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트;(7) 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate;
(8) 4-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트;(8) 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate;
(9) 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트;(9) 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;
(10) 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트;(10) 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;
(11) 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트;(11) 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;
(12) 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-2-나프토에이트;(12) 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-2-naphthoate;
(13) 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(13) 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;
(14) 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(14) 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;
(15) 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(15) 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;
(16) 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(16) 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate;
(17) 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(17) 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate;
(18) 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(18) 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate;
(19) 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(19) 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate;
(20) 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트;(20) 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate;
(21) 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트;(21) 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate;
(22) 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트;(22) 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate;
(23) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-3-일-2-나프토에이트;(23) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;
(24) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-3-일-2-나프토에이트;(24) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;
(25) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-3-일-2-나프토에이트;(25) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-3 -Yl-2-naphthoate;
(26) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(26) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;
(27) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(27) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;
(28) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(28) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-3 -Yl-biphenyl-4-carboxylate;
(29) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(29) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;
(30) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(30) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;
(31) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(31) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-3 -Yl-4-phenoxybenzoate;
(32) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-3-일-2-나프토에이트;(32) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;
(33) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-3-일-2-나프토에이트;(33) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;
(34) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-3-일-2-나프토에이트;(34) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-3 -Yl-2-naphthoate;
(35) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(35) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;
(36) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(36) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;
(37) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(37) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-3 -Yl-biphenyl-4-carboxylate;
(38) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(38) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;
(39) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(39) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;
(40) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(40) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-3 -Yl-4-phenoxybenzoate;
(41) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-3-일-2-나프토에이트;(41) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;
(42) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-3-일-2-나프토에이트;(42) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-2-naphthoate;
(43) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-3-일-2-나프토에이트;(43) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-3 -Yl-2-naphthoate;
(44) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(44) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;
(45) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(45) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-biphenyl-4-carboxylate;
(46) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(46) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-3 -Yl-biphenyl-4-carboxylate;
(47) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(47) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;
(48) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(48) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 3-yl-4-phenoxybenzoate;
(49) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-3-일-2-나프토에이트;(49) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 2-naphthoate;
(50) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-3-일-2-나프토에이트;(50) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 2-naphthoate;
(51) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-3-일-2-나프토에이트;(51) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl-2 Naphthoate;
(52) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(52) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- Biphenyl-4-carboxylate;
(53) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(53) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- Biphenyl-4-carboxylate;
(54) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(54) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl-bi Phenyl-4-carboxylate;
(55) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(55) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 4-phenoxybenzoate;
(56) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트;(56) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-3-yl- 4-phenoxybenzoate;
(57) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-3-일-2-나프토에이트;(57) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;
(58) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-3-일-2-나프토에이트;(58) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;
(59) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-3-일-2-나프토에이트;(59) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;
(60) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(60) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;
(61) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(61) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;
(62) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(62) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate;
(63) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-3-일-4-페녹시벤조에이트;(63) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;
(64) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-3-일-4-페녹시벤조에이트;(64) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;
(65) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-3-일-2-나프토에이트;(65) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-2-naphthoate;
(66) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-3-일-2-나프토에이트;(66) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-2-naphthoate;
(67) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-3-일-2-나프토에이트;(67) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-2-naphthoate;
(68) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(68) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;
(69) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(69) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;
(70) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(70) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate;
(71) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-3-일-4-페녹시벤조에이트;(71) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;
(72) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-3-일-4-페녹시벤조에이트;(72) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;
(73) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-3-일-2-나프토에이트;(73) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;
(74) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-3-일-2-나프토에이트;(74) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;
(75) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-3-일-2-나프토에이트;(75) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2-naphthoate;
(76) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(76) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;
(77) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(77) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate ;
(78) 4-(4-(3-클로로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트;(78) 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate;
(79) 4-(4-(4-플루오로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-3-일-4-페녹시벤조에이트;(79) 4- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;
(80) 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-3-일-4-페녹시벤조에이트;(80) 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate;
(81) 1-(3,5-디클로로페닐카바모일)-4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트;(81) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;
(82) 1-(3,5-디클로로페닐카바모일)-4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트;(82) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;
(83) 1-(3,5-디클로로페닐카바모일)-4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트;(83) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate;
(84) 1-(3,5-디클로로페닐카바모일)-4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트;(84) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxyl Rate;
(85) 1-(3,5-디클로로페닐카바모일)-4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트;(85) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxyl Rate;
(86) 1-(3,5-디클로로페닐카바모일)-4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트;(86) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate ;
(87) 1-(3,5-디클로로페닐카바모일)-4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트;(87) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;
(88) 1-(3,5-디클로로페닐카바모일)-4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트;(88) 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate;
(89) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-4-일-1-나프토에이트;(89) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;
(90) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-4-일-1-나프토에이트;(90) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;
(91) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-4-일-1-나프토에이트;(91) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-4 -Yl-1-naphthoate;
(92) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(92) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;
(93) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(93) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;
(94) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(94) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine-4 -Yl-biphenyl-3-carboxylate;
(95) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-4-일-4-페녹시벤조에이트;(95) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;
(96) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소-3-페닐프로판-2-일카바모일)피페리딘-4-일-4-페녹시벤조에이트;(96) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxo-3-phenylpropan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;
(97) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-4-일-1-나프토에이트;(97) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;
(98) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-4-일-1-나프토에이트;(98) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;
(99) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-4-일-1-나프토에이트;(99) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-4 -Yl-1-naphthoate;
(100) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(100) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;
(101) 3-(4-(4-메톡시로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(101) 3- (4- (4-methoxyrophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine -4-yl-biphenyl-3-carboxylate;
(102) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(102) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine-4 -Yl-biphenyl-3-carboxylate;
(103) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-4-일-4-페녹시벤조에이트;(103) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;
(104) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥소펜탄-2-일카바모일)피페리딘-4-일-4-페녹시벤조에이트;(104) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-oxopentan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;
(105) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-4-일-1-나프토에이트;(105) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;
(106) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-4-일-1-나프토에이트;(106) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-1-naphthoate;
(107) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-4-일-1-나프토에이트;(107) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-4 -Yl-1-naphthoate;
(108) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(108) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;
(109) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(109) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-biphenyl-3-carboxylate;
(110) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(110) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine-4 -Yl-biphenyl-3-carboxylate;
(111) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-4-일-4-페녹시벤조에이트;(111) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;
(112) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-3-메틸-1-옥소부탄-2-일카바모일)피페리딘-4-일-4-페녹시벤조에이트;(112) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-3-methyl-1-oxobutan-2-ylcarbamoyl) piperidine- 4-yl-4-phenoxybenzoate;
(113) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-4-일-1-나프토에이트;(113) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 1-naphthoate;
(114) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-4-일-1-나프토에이트;(114) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 1-naphthoate;
(115) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-4-일-1-나프토에이트;(115) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl-1 Naphthoate;
(116) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(116) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- Biphenyl-3-carboxylate;
(117) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(117) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- Biphenyl-3-carboxylate;
(118) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(118) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl-bi Phenyl-3-carboxylate;
(119) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-4-일-4-페녹시벤조에이트;(119) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 4-phenoxybenzoate;
(120) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-1-옥소프로판-2-일카바모일)피페리딘-4-일-4-페녹시벤조에이트;(120) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-1-oxopropan-2-ylcarbamoyl) piperidin-4-yl- 4-phenoxybenzoate;
(121) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-4-일-1-나프토에이트;(121) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;
(122) 3-(4-(4-메톡시로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-4-일-1-나프토에이트;(122) 3- (4- (4-methoxyrophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;
(123) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-4-일-1-나프토에이트;(123) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;
(124) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(124) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;
(125) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(125) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;
(126) 3-(4-(3-클로로로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(126) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;
(127) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-4-일-4-페녹시벤조에이트;(127) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;
(128) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-4-일-4-페녹시벤조에이트;(128) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;
(129) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-4-일-1-나프토에이트;(129) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-1-naphthoate;
(130) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-4-일-1-나프토에이트;(130) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-1-naphthoate;
(131) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-4-일-1-나프토에이트;(131) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-1-naphthoate;
(132) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(132) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;
(133) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(133) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;
(134) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(134) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate;
(135) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-4-일-4-페녹시벤조에이트;(135) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;
(136) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(3-메톡시페닐카바모일)피페리딘-4-일-4-페녹시벤조에이트;(136) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (3-methoxyphenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;
(137) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-4-일-1-나프토에이트;(137) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;
(138) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-4-일-1-나프토에이트;(138) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;
(139) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-4-일-1-나프토에이트;(139) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-1-naphthoate;
(140) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(140) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;
(141) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(141) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate ;
(142) 3-(4-(3-클로로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-4-일-바이페닐-3-카르복실레이트;(142) 3- (4- (3-chlorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-biphenyl-3-carboxylate;
(143) 3-(4-(4-플루오로페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-4-일-4-페녹시벤조에이트;(143) 3- (4- (4-fluorophenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;
(144) 3-(4-(4-메톡시페닐)피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-4-일-4-페녹시벤조에이트;(144) 3- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-4-yl-4-phenoxybenzoate;
(145) 1-(3,5-디클로로페닐카바모일)-3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(145) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;
(146) 1-(3,5-디클로로페닐카바모일)-3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(146) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;
(147) 1-(3,5-디클로로페닐카바모일)-3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(147) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;
(148) 1-(3,5-디클로로페닐카바모일)-3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(148) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate;
(149) 1-(3,5-디클로로페닐카바모일)-3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(149) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate;
(150) 1-(3,5-디클로로페닐카바모일)-3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(150) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate ;
(151) 1-(3,5-디클로로페닐카바모일)-3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-3-페녹시벤조에이트;(151) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-3-phenoxybenzoate;
(152) 1-(3,5-디클로로페닐카바모일)-3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-3-페녹시벤조에이트;(152) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-3-phenoxybenzoate;
(153) 1-(3,5-디클로로페닐카바모일)-3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(153) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;
(154) 1-(3,5-디메톡시페닐카바모일)-3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(154) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;
(155) 1-(3-클로로-4-메톡시페닐카바모일)-3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(155) 1- (3-chloro-4-methoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphtho Eight;
(156) 1-(3,5-디클로로페닐카바모일)-3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(156) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate;
(157) 1-(3,5-디메톡시페닐카바모일)-3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(157) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-car Carboxylates;
(158) 1-(3-클로로-4-메톡시페닐카바모일)-3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트;(158) 1- (3-Chloro-4-methoxyphenylcarbamoyl) -3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3 Carboxylates;
(159) 1-(3,5-디메톡시페닐카바모일)-3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(159) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate;
(160) 1-(3-클로로-4-메톡시페닐카바모일)-3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트;(160) 1- (3-chloro-4-methoxyphenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphtho Eight;
(161) 1-(3,5-디클로로페닐카바모일)-3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트; 및(161) 1- (3,5-dichlorophenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxyl Rate; And
(162) 1-(3,5-디메톡시페닐카바모일)-3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트.(162) 1- (3,5-dimethoxyphenylcarbamoyl) -3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-car Carboxylate.
본 발명은 상기 화학식 1로 표시되는 피페리딘 유도체 및 이의 약학적으로 허용되는 염뿐만 아니라, 이로부터 제조될 수 있는 가능한 용매화물, 수화물, 라세미체 또는 입체이성질체를 모두 포함한다.The present invention includes not only piperidine derivatives represented by Formula 1 and pharmaceutically acceptable salts thereof, but also all possible solvates, hydrates, racemates or stereoisomers that can be prepared therefrom.
본 발명의 화학식 1의 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 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 또는 만델레이트를 포함한다.The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, 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 or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1의 유도체를 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다.The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.
동량의 화학식 1의 유도체 및 물 중의 산 또는 알코올을 가열하고, 이어서 이 혼합물을 증발시켜서 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알 칼리 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, 금속 염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble 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. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).
또한, 본 발명은 하기 반응식 1에 표시되는 바와 같이, In addition, the present invention, as shown in Scheme 1,
출발물질인 화학식 2의 화합물의 삼각고리를 아릴 피페라진 화합물으로 개환반응시켜 화학식 3(3a 또는 3b)의 화합물을 제조하는 단계(단계 1); Preparing a compound of Chemical Formula 3 (3a or 3b) by ring opening the tricyclic ring of the compound of Chemical Formula 2 as an aryl piperazine compound (Step 1);
상기 단계 1에서 제조된 화학식 3의 화합물을 에스테르화 반응시켜 화학식 4(4a 또는 4b)의 화합물을 제조하는 단계(단계 2); 및Preparing a compound of formula 4 (4a or 4b) by esterifying the compound of formula 3 prepared in step 1 (step 2); And
상기 단계 2에서 제조된 화학식 4의 화합물을 탈보호화시켜 화학식 1(1a 또는 1b)의 화합물을 제조하는 단계(단계 3)를 포함하여 이루어지는 아릴피페라진 치환된 피페리딘 유도체의 제조방법을 제공한다.It provides a method for preparing an aryl piperazine substituted piperidine derivative comprising the step (step 3) of preparing a compound of Formula 1 (1a or 1b) by deprotecting the compound of Formula 4 prepared in step 2. .
(상기 식에서, R4 및 Z는 상기 화학식 1에서 정의한 바와 같고, 상기 화학식 1a 및 화학식 1b는 본 발명의 화학식 1의 유도체에 포함된다)(Wherein R 4 And Z is as defined in Chemical Formula 1, wherein Chemical Formula 1a and Chemical Formula 1b are included in the derivative of Chemical Formula 1 of the present invention).
이하, 본 발명에 따른 제조방법을 단계별로 상세히 설명한다.Hereinafter, the manufacturing method according to the present invention will be described in detail step by step.
단계 1: 개환 반응Step 1: ring opening reaction
본 발명에 따른 상기 단계 1은 출발물질인 상기 화학식 2의 삼각 고리 위치를 아릴 피페라진 화합물이 공격하여 개환반응에 의해 화학식 3a 또는 3b의 화합물을 제조하는 단계이다.Step 1 according to the present invention is a step of preparing a compound of formula 3a or 3b by ring opening reaction by attacking the aryl piperazine compound in the triangular ring position of the formula (2) which is a starting material.
상기 출발물질인 화학식 2의 화합물은 시판 중인 1,2,3,6-테트라히드로피리딘으로부터 공지의 방법을 이용하여 얻을 수 있다[Heterocycles 1994, 39, 163].The starting compound of Formula 2 can be obtained from commercially available 1,2,3,6-tetrahydropyridine using known methods [Heterocycles 1994, 39, 163].
상기 아릴 피페라진 화합물은 상기 화학식 2에서 삼각 고리를 구성하는 3번 또는 4번 탄소를 공격할 수 있어 화학식 3a의 화합물과 화학식 3b의 화합물이 1:1의 비율로 생성되는 라세미체를 형성시킬 수 있다. 이때, 상기 아릴 피페라진 화합물의 페닐기는 할로겐, 메톡시기 등의 전자 끌개 치환기를 포함할 수 있다.The aryl piperazine compound may attack carbon 3 or 4 constituting the triangular ring in Formula 2 to form a racemate in which the compound of Formula 3a and the compound of Formula 3b are produced in a ratio of 1: 1 Can be. At this time, the phenyl group of the aryl piperazine compound may include an electron withdrawing substituent such as halogen, methoxy group.
본 발명에 따른 상기 단계 1의 화학식 3a 또는 3b의 화합물은 일반적으로 다음과 같은 방법으로 제조될 수 있다.In general, the compound of Chemical Formula 3a or 3b of Step 1 according to the present invention may be prepared by the following method.
일반적인 제조방법 AGeneral manufacturing method A
화학식 2의 화합물을 아세토니트릴에 녹인 후 LiClO4과 아릴피페라진을 가하고 5~6 시간 환류교반한다. 반응물을 감압농축 후 에틸 아세테이트로 희석시킨 후, 증류수로 세척하고 유기층을 건조 후(Na2SO4) 감압 농축한다. 잔류물을 칼럼크로마토그래피(헥산:에틸 아세테이트 = 2:1)로 분리하여 화학식 3a 또는 3b의 화합물을 얻는다.After dissolving the compound of Formula 2 in acetonitrile, LiClO 4 and aryl piperazine were added and stirred under reflux for 5-6 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed with distilled water, and the organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue is separated by column chromatography (hexane: ethyl acetate = 2: 1) to give a compound of formula 3a or 3b.
일반적 제조방법 BGeneral manufacturing method B
화학식 2의 화합물을 아세토니트릴에 녹인 후 LiClO4과 아릴피페라진을 가하고 마이크로 파를 이용하여 130 ℃에서 15~30 분간 가열한다. 반응물을 에틸 아세테이트로 묽히고 0.1N-염산수용액과 물로 세척한 후 유기층을 황산나트륨으로 수분을 제거한 후 감압 농축한다. 잔류물을 칼럼크로마토그래피(헥산/에틸 아세테이트 = 2/1)로 정제하여 화학식 3a 또는 3b의 화합물을 얻는다.After dissolving the compound of Formula 2 in acetonitrile, LiClO 4 and aryl piperazine were added and heated at 130 ° C. for 15-30 minutes using microwave. The reaction was diluted with ethyl acetate, washed with 0.1 N aqueous hydrochloric acid solution and water, and then the organic layer was concentrated under reduced pressure with sodium sulfate. The residue is purified by column chromatography (hexane / ethyl acetate = 2/1) to give the compound of formula 3a or 3b.
일반적 제조방법 CGeneral manufacturing method C
화학식 2의 화합물과 아릴피페라진을 무수 에탄올에 녹인 후 36~50시간 환류교반한다. 반응물을 감압농축 후 에틸 아세테이트로 희석시킨 후, 증류수로 세척하고 유기층을 건조 후(Na2SO4) 감압 농축한다. 잔류물을 칼럼크로마토그래피(헥산:에틸 아세테이트 = 2:1)로 분리하여 화학식 3a 또는 3b의 화합물을 얻는다.The compound of Formula 2 and aryl piperazine are dissolved in anhydrous ethanol and stirred under reflux for 36 to 50 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed with distilled water, and the organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue is separated by column chromatography (hexane: ethyl acetate = 2: 1) to give a compound of formula 3a or 3b.
단계 2: 에스테르 반응Step 2: ester reaction
본 발명에 따른 단계 2는 상기 단계 1에서 제조된 화학식 3의 화합물(3a,3b)의 수산화기를 유기산염화물을 이용하여 에스테르 반응시켜 화학식 4a 또는 화학식 4b의 화합물을 얻는 단계이다.Step 2 according to the present invention is a step of obtaining a compound of formula 4a or 4b by esterification of the hydroxyl group of the compound (3a, 3b) of formula 3 prepared in step 1 with an organic acid chloride.
상기 에스테르 반응은 기술분야에서 알려진 에스테르 반응 조건에 의해 특별한 제한 없이 수행될 수 있다.The ester reaction can be carried out without particular limitation by the ester reaction conditions known in the art.
구체적으로, 다음과 같은 방법으로 제조될 수 있다.Specifically, it may be prepared by the following method.
일반적 제조방법 AGeneral manufacturing method A
화학식 3a 및 3b의 혼합물과 유기산염화물, 트리에틸아과 4-N,N-디메틸아미노피리딘(DMAP)을 테트라히드로퓨란에 녹인 후 50~60시간 환류 교반한다. 반응물을 감압농축 후 에틸 아세테이트로 희석시킨 후, 1N 수산화 나트륨, 증류수로 세척한 후 유기층을 황산나트륨으로 건조하고 감압 농축한다. 잔류물을 칼럼크로마토그래피(헥산:에틸 아세테이트 = 4:1)로 분리하여 화학식 4a 또는 화학식 4b의 화합물을 각각 얻는다.A mixture of the formulas 3a and 3b, an organic acid chloride, triethyla and 4-N, N-dimethylaminopyridine (DMAP) are dissolved in tetrahydrofuran, and then stirred under reflux for 50 to 60 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed with 1N sodium hydroxide and distilled water, and then the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue is separated by column chromatography (hexane: ethyl acetate = 4: 1) to give the compound of formula 4a or 4b, respectively.
일반적 제조방법 BGeneral manufacturing method B
화학식 3a 및 3b의 혼합물을 피리딘에 녹인 후 유기산 염화물(1.1 당량)을 가하고 마이크로 파를 이용하여 150 ℃에서 3분간 가열한다. 반응물을 에틸 아세테이트로 묽히고 염산수용액과 물로 세척 후 유기층을 황산나트륨으로 수분을 제거한 후 감압 농축한다. 잔류물을 칼럼크로마토그래피(헥산/에틸 아세테이트 = 1/1)로 정제하여 화학식 4a 또는 화학식 4b의 화합물을 각각 얻는다.After dissolving the mixture of Formulas 3a and 3b in pyridine, organic acid chloride (1.1 equiv) is added and heated at 150 ° C. for 3 minutes using microwave. The reaction was diluted with ethyl acetate, washed with aqueous hydrochloric acid solution and water, and then the organic layer was concentrated under reduced pressure after removing moisture with sodium sulfate. The residue is purified by column chromatography (hexane / ethyl acetate = 1/1) to give the compound of formula 4a or 4b, respectively.
단계 3: Step 3: 탈보호Deprotection 단계 step
본 발명에 따른 단계 3은 상기 단계 2에서 제조된 화학식 4의 화합물을 탈보호화시켜 화학식 1(1a 또는 1b)의 화합물을 제조하는 단계이다.Step 3 according to the present invention is a step of preparing a compound of Formula 1 (1a or 1b) by deprotecting the compound of Formula 4 prepared in Step 2.
상기 탈보호는 통상적으로 사용하는 방법을 이용할 수 있으며, 바람직하게는 트리플루오로초산 용액, 디클로로메탄 또는 이들의 혼합 용액을 이용하여 t-부톡시카보닐기를 제거함으로써 탈보호할 수 있다.The deprotection may be carried out by a method commonly used, and may be preferably deprotected by removing t-butoxycarbonyl group using a trifluoroacetic acid solution, dichloromethane or a mixed solution thereof.
구체적으로는 화학식 4a 또는 화학식 4b의 화합물에 디클로로메탄-트리플루오로초산 용액(1:1)을 0 ℃에서 가하고 교반 후 실온에서 교반한다. 반응물을 감압농축 후 에틸 아세테이트로 묽히고 포화탄산나트륨과 물로 세척 후 유기층을 황 산나트륨으로 수분을 제거한 후 감압 농축한다. 잔류물을 칼럼크로마토그래피(헥산/에틸 아세테이트 = 1/2)로 정제하여 본 발명에 따른 화학식 1(1a 또는 1b)의 화합물을 얻을 수 있다.Specifically, dichloromethane-trifluoroacetic acid solution (1: 1) is added to the compound of Formula 4a or Formula 4b at 0 ° C., followed by stirring at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated sodium carbonate and water, and then the organic layer was concentrated under reduced pressure with sodium sulfate. The residue can be purified by column chromatography (hexane / ethyl acetate = 1/2) to afford the compound of formula 1 (1a or 1b) according to the present invention.
또한, 상기 단계 3에서 제조된 화학식 1(1a 또는 1b)의 화합물은 하기 반응식 2에 나타낸 바와 같이 이소시아네이트 유도체와 반응시켜 화학식 1의 유도체(1c 및 1d)를 제조하는 단계(단계 4)를 더 포함할 수 있다.In addition, the compound of formula 1 (1a or 1b) prepared in step 3 further comprises the step of preparing a derivative (1c and 1d) of formula 1 by reacting with an isocyanate derivative as shown in Scheme 2 (step 4) can do.
(상기 반응식 2에서 R3, R4 및 Z는 상기 화학식 1에서 정의한 바와 같고, 상기 화학식 1c 및 1d의 화합물은 본 발명의 화학식 1의 유도체에 포함된다)(R 3 , R 4 in Scheme 2 above) And Z is as defined in Formula 1, wherein the compounds of Formulas 1c and 1d are included in the derivative of Formula 1 of the present invention.)
이때, 사용되는 이소시아네이트 유도체로는 2-이소시아네이토 메틸에스테르, 아릴이소시아네이트 등을 사용할 수 있으며, 이들은 공지의 방법에 의하여 제조할 수 있다[Nowich, J. S. et al, J. Org . Chem ., 1992, 57, 7364-7366].In this case, as the isocyanate derivative used, 2-isocyanato methyl ester, aryl isocyanate and the like can be used, and these can be prepared by a known method [Nowich, JS et al, J. Org . Chem . , 1992 , 57, 7364-7366.
본 발명에 따른 화학식 1의 화합물의 제조 방법이 상기 반응식에 제한되는 것이 아니며, 공지의 유기 화학 반응들을 사용하여 제조할 수 있다.The method for preparing the compound of Formula 1 according to the present invention is not limited to the above scheme, and may be prepared using known organic chemical reactions.
나아가, 본 발명은 아릴 피페라진이 치환된 피페리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 베타-세크리테아제 억제제를 제공한다.Furthermore, the present invention provides a beta-secretase inhibitor containing an aryl piperazine-substituted piperidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 아릴 피페라진이 치환된 피페리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경퇴행성 질환의 예방 및 치료용 조성물을 제공한다.The present invention also provides a composition for the prevention and treatment of neurodegenerative diseases containing aryl piperazine-substituted piperidine derivatives or pharmaceutically acceptable salts thereof as an active ingredient.
알츠하이머 치매질환의 발병에 중요한 역할을 하는 베타아밀로이드(β-amyloid, 이하 Aβ) 펩타이드는 42개의 아미노산 잔기로 이루어진 녹지 않는 성질을 가지며, 기억 및 인식과 관련된 뇌 영역에 침착되어 뇌세포의 아폽토시스를 유발하는 것으로 알려져 있다. 이러한 Aβ 펩타이드는 그 전구대사단백질인 아밀로이드 전구체 단백질(amyloid precursor protein, 이하 APP)에 의해 생성되고, 구체적으로 APP 유전인자의 돌연변이가 caspase-6와 caspase-3라는 아폽토시스 분해효소(apoptotic protease)의 기질로 작용하여 절단이 되며, 이렇게 절단되어진 APP는 β-세크리테아제에 의하여 보다 용이하게 Aβ를 형성하게 된다고 알려져 있다.Beta-amyloid (Aβ) peptide, which plays an important role in the development of Alzheimer's disease, has insoluble properties consisting of 42 amino acid residues and is deposited in brain regions related to memory and recognition, leading to apoptosis of brain cells. It is known. These Αβ peptides are produced by the amyloid precursor protein (APP), which is a precursor metabolic protein. The cleaved APP is known to form Aβ more easily by β-secretase.
따라서, β-세크리테아제의 활성을 억제하면 알츠하이머 질환을 유발시키는 Aβ 펩타이드의 생성을 억제시킬 수 있기 때문에 β-세크레타아제 활성 저해제는 알츠하이머 질환의 예방 및 근본적인 발병원인을 치료할 수 있는 약물로 인식되고 있다[(a) Tang, J. et al., Proc . Natl . Acad . Sci . U. S. A. 2000, 97, 1456. (b) Hussain, I. et al., Mol . Cell Neurosci . 1999, 14, 419. (c) Yan, R. et al., Nature 1999, 402, 533. (d). Sinha, S, et al., Nature 1999, 402, 537. (e) Vassar, R.et al., Science 1999 , 286, 735].Therefore, inhibiting the activity of β-secretase can inhibit the production of Aβ peptides that cause Alzheimer's disease. Thus, β-secretase activity inhibitors are recognized as drugs that can prevent and treat the underlying causes of Alzheimer's disease. [(A) Tang, J. et al., Proc . Natl . Acad . Sci . USA 2000 , 97 , 1456. (b) Hussain, I. et al., Mol . Cell Neurosci . 1999 , 14 , 419. (c) Yan, R. et al., Nature 1999 , 402 , 533. (d). Sinha, S, et al., Nature 1999 , 402 , 537. (e) Vassar, R. et al., Science 1999 , 286 , 735].
한편, 본 발명에 따른 상기 화학식 1로 표시되는 아릴 피페라진이 치환된 피페리딘 유도체는 베타-세크리테아제 효소를 대상으로 한 활성 저해 실험에서 종래 피페라진 유도체보다 10~20 배 정도의 저해활성을 나타내었다.Meanwhile, the piperidine derivative substituted with the aryl piperazine represented by Chemical Formula 1 according to the present invention has about 10 to 20 times higher inhibitory activity than the conventional piperazine derivative in an activity inhibition experiment with beta-secretase enzyme. Indicated.
그러므로, 본 발명에 따른 상기 화학식 1로 표시되는 아릴 피페라진이 치환된 피페리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 조성물은 베타-세크리테아제의 활성을 억제하여 Aβ 펩타이드의 생성을 저해함으로써 Aβ 펩타이드로 인해 유발되는 알츠하이머 질환, 다운증후군 질환 등과 같은 신경성퇴행 질환의 치료 및 예방제로 사용할 수 있다.Therefore, the composition containing the piperidine derivative substituted with the aryl piperazine represented by the formula (1) according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient inhibits the activity of beta-secretase to inhibit the Aβ peptide. It can be used as a treatment and prevention of neurodegenerative diseases such as Alzheimer's disease, Down's syndrome and the like caused by Aβ peptide by inhibiting the production of.
본 발명의 조성물을 의약품으로 사용하는 경우, 상기 화학식 1로 표시되는 피페리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화 되어 투여될 수 있으나, 이에 한정되는 것은 아니다.When using the composition of the present invention as a medicine, the pharmaceutical composition containing the piperidine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient may be various oral or parenteral It may be formulated in a dosage form and administered, but is not limited thereto.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제 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 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 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, etc. These formulations may contain, in addition to the active ingredients, diluents (e.g., lactose, dextrose). Rose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and optionally such as starch, agar, alginic acid or its sodium salt. Disintegrant or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
상기 화학식 1로 표시되는 유도체를 유효 성분으로 하는 약학 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. The pharmaceutical composition comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and the parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1의 피페리딘 유도체 또는 이의 약학적으로 허용되는 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. In this case, the piperidine derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is administered in ampoules or vials. It can be manufactured in a mold. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
유효 성분으로서 화학식 1의 유도체는 사람을 포함하는 포유동물에 대해서 하루 0.1 내지 500 mg/kg(체중), 바람직하게는 0.5 내지 100 mg/kg(체중)의 양으로 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여할 수 있다. As an active ingredient, the derivative of formula 1 may be used orally once a day or in divided doses in an amount of 0.1 to 500 mg / kg body weight, preferably 0.5 to 100 mg / kg body weight, for mammals including humans. Or by parenteral routes.
이하, 실시예 및 실험예를 통해 본 발명을 상세히 설명한다. 단, 하기의 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples.
<< 실시예Example 1> 4-(4-(4- 1> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-3-일-2-) Piperazin-1-yl) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
단계 1: t-부틸 4-(4-(4-Step 1: t-butyl 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-3-Piperazin-1-yl) -3- 하이드록시피페리딘Hydroxypiperidine -1-카르복실-1-carboxyl 레이트Rate 의 제조Manufacture
화학식 2의 화합물(5 mmol)을 아세토니트릴(10 mL)에 녹인 후 LiClO4(5.5 mmol)과 1-(4-플루오로페닐)피페라진(5.5 mmol)을 가하고 5~6 시간 환류교반하였다. 이후 반응물을 감압농축하고 에틸 아세테이트(50 mL)로 희석시킨 후, 증류수(20 mL)로 세척 하고 유기층을 건조 후(Na2SO4) 감압 농축하였다. 잔류물을 칼럼크로마토그래피(헥산:에틸아세테이트 = 2:1)로 분리하여 t-부틸-4-(4-(4-플루오로페닐)피페라진-1-일)-3-하이드록시피페리딘-1-카르복실레이트를 수득하였다(수율: 90 %).After dissolving the compound of Formula 2 (5 mmol) in acetonitrile (10 mL), LiClO 4 (5.5 mmol) and 1- (4-fluorophenyl) piperazine (5.5 mmol) were added and stirred under reflux for 5-6 hours. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with distilled water (20 mL), and the organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 2: 1) to give t-butyl-4- (4- (4-fluorophenyl) piperazin-1-yl) -3-hydroxypiperidine -1-carboxylate was obtained (yield: 90%).
1H NMR(CDCl3, 300 MHz): δ1.46 (br.s, 18H), 1.76-1.82 (m, 1H), 2.05-2.10 (m, 1H), 2.32-2.39 (m, 2H), 2.42-2.73 (m, 8H), 2.86-2.92 (m, 2H), 2.97-3.04 (m, 2H), 3.06-3.18 (m, 8H), 3.40-3.49 (m, 1H), 3.57-3.65 (m, 2H), 4.02-4.18 (m, 1H), 4.20-4.36 (m, 1H), 4.38-4.54 (m, 1H), 6.84-6.90 (m,4H), 6.92-7.00(m,4H) 1 H NMR (CDCl 3 , 300 MHz): δ 1.46 (br.s, 18H), 1.76-1.82 (m, 1H), 2.05-2.10 (m, 1H), 2.32-2.39 (m, 2H), 2.42 -2.73 (m, 8H), 2.86-2.92 (m, 2H), 2.97-3.04 (m, 2H), 3.06-3.18 (m, 8H), 3.40-3.49 (m, 1H), 3.57-3.65 (m, 2H), 4.02-4.18 (m, 1H), 4.20-4.36 (m, 1H), 4.38-4.54 (m, 1H), 6.84-6.90 (m, 4H), 6.92-7.00 (m, 4H)
단계 2: t-부틸3-(2-나프토일록시)-4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-1-카르복실레이트의 제조Step 2: Preparation of t-butyl3- (2-naphthoyloxy) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidine-1-carboxylate
상기 단계 1에서 제조된 t-부틸-4-(4-(4-플루오로페닐)피페라진-1-일)-3-하이드록시피페리딘-1-카르복실레이트(2 mmol)와 2-나프토산 염화물(4 mmol), 트리에틸아민(4 mmol)과 4-N,N-디메틸아미노피리딘(DMAP, 0.2 mmol)을 테트라히드로퓨란(10 mL)에 녹인 후 50-60시간 환류 교반하였다. 반응물을 감압농축 후 에틸 아세테이트(20 mL)로 희석시킨 후, 1N 수산화나트륨(2×10 mL), 증류수(20 mL)로 세척 후 유기층을 건조 후(Na2SO4) 감압 농축하였다. 잔류물을 칼럼크로마토그래피(헥산:에틸 아세테이트 = 4:1)로 분리하여 t-부틸3-(2-나프토일록시)-4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-1-카르복실레이트를 수득하였다(수율: 46%).T-butyl-4- (4- (4-fluorophenyl) piperazin-1-yl) -3-hydroxypiperidine-1-carboxylate (2 mmol) and 2-prepared in step 1 Naphthoic acid chloride (4 mmol), triethylamine (4 mmol) and 4-N, N-dimethylaminopyridine (DMAP, 0.2 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred under reflux for 50-60 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 mL), washed with 1N sodium hydroxide (2 x 10 mL), distilled water (20 mL), and then dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 4: 1) to give t-butyl3- (2-naphthoyloxy) -4- (4- (4-fluorophenyl) piperazin-1-yl ) Piperidine-1-carboxylate was obtained (yield: 46%).
1H NMR(CDCl3, 200 MHz): δ1.50 (s, 9H), 1.70-1.90 (m, 1H), 2.10-2.30 (m, 1H), 2.65-2.85 (m, 3H), 2.90-3.12 (m, 8H), 3.95-4.20 (m, 2H), 5.34-5.46 (m, 1H), 6.74-6.93 (m, 4H), 7.50-7.64 (m, 2H), 7.85-7.90 (m, 2H), 7.93-7.97 (m, 1H), 8.02-8.07 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 200 MHz): δ1.50 (s, 9H), 1.70-1.90 (m, 1H), 2.10-2.30 (m, 1H), 2.65-2.85 (m, 3H), 2.90-3.12 (m, 8H), 3.95-4.20 (m, 2H), 5.34-5.46 (m, 1H), 6.74-6.93 (m, 4H), 7.50-7.64 (m, 2H), 7.85-7.90 (m, 2H) , 7.93-7.97 (m, 1 H), 8.02-8.07 (m, 1 H), 8.59 (s, 1 H).
13C NMR(CDCl3, 200 MHz): δ28.4, 30.0, 41.6, 42.6, 49.3, 50.6, 63.8, 70.5, 79.9, 115.0, 115.5, 117.7, 125.1, 126.6, 127.6, 127.7, 128.1, 128.2, 129.2, 131.0, 132.4, 135.5, 147.8, 154.6, 159.3, 165.9. 13 C NMR (CDCl 3 , 200 MHz): δ 28.4, 30.0, 41.6, 42.6, 49.3, 50.6, 63.8, 70.5, 79.9, 115.0, 115.5, 117.7, 125.1, 126.6, 127.6, 127.7, 128.1, 128.2, 129.2 , 131.0, 132.4, 135.5, 147.8, 154.6, 159.3, 165.9.
단계 3: 4-(4-(4-Step 3: 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-3-일-2-) Piperazin-1-yl) piperidin-3-yl-2- 나프토에이Naphthoei 트의 제조Manufacturing
상기 단계 2에서 제조된 t-부틸3-(2-나프토일록시)-4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-1-카르복실레이트에 디클로로메탄-트리플루오로초산 용액(1:1)을 0 ℃에서 가하고 15분간 교반 후 실온에서 2~4시간 교반하였다. 반응물을 감압농축 후 에틸 아세테이트(50 mL)로 묽히고 포화탄산나트륨(50 mL)과 물(50 mL)로 세척 후 유기층을 황산나트륨으로 수분을 제거한 후 감압 농축하였다. 잔류물을 칼럼크로마토그래피(헥산/에틸 아세테이트 = 1/2)로 정제하여 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 수득하였다(수율: 98%). Dichloromethane in t-butyl3- (2-naphthoyloxy) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidine-1-carboxylate prepared in step 2 above Trifluoroacetic acid solution (1: 1) was added at 0 ° C. and stirred for 15 minutes, followed by stirring at room temperature for 2-4 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with saturated sodium carbonate (50 mL) and water (50 mL), and the organic layer was concentrated under reduced pressure with sodium sulfate. The residue was purified by column chromatography (hexane / ethyl acetate = 1/2) to give 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphtho The yield was obtained (yield: 98%).
1H NMR(CDCl3, 200 MHz): δ 2.00-2.20 (m, 1H), 2.30-2.50 (m, 1H), 2.74-2.85 (m, 3H), 2.92-3.22 (m, 8H), 3.44-3.58 (m, 2H), 5.41-5.51 (m, 1H), 6.70-6.79 (m, 2H), 6.81-6.91 (m, 2H), 7.52-7.65 (m, 2H), 7.87-7.89 (m, 2H), 7.96- 8.00 (m, 1H), 8.02-8.07 m, 1H), 8.61 (s, 1H). 1 H NMR (CDCl 3 , 200 MHz): δ 2.00-2.20 (m, 1H), 2.30-2.50 (m, 1H), 2.74-2.85 (m, 3H), 2.92-3.22 (m, 8H), 3.44- 3.58 (m, 2H), 5.41-5.51 (m, 1H), 6.70-6.79 (m, 2H), 6.81-6.91 (m, 2H), 7.52-7.65 (m, 2H), 7.87-7.89 (m, 2H ), 7.96- 8.00 (m, 1H), 8.02-8.07 m, 1H), 8.61 (s, 1H).
13C NMR(CDCl3, 200 MHz): δ27.8, 42.2, 43.5, 49.2, 50.4, 53.3, 61.7, 68.4, 115.0, 115.4, 117.5, 117.7, 124.9, 126.7, 126.9, 127.6, 128.3, 128.4, 129.3, 131.2, 132.3, 135.5, 147.6, 147.6, 154.5, 159.3, 165.6. 13 C NMR (CDCl 3 , 200 MHz): δ 27.8, 42.2, 43.5, 49.2, 50.4, 53.3, 61.7, 68.4, 115.0, 115.4, 117.5, 117.7, 124.9, 126.7, 126.9, 127.6, 128.3, 128.4, 129.3 , 131.2, 132.3, 135.5, 147.6, 147.6, 154.5, 159.3, 165.6.
<< 실시예Example 2> 4-(4-(3- 2> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-3-일-2-) Piperazin-1-yl) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
단계 1: t-부틸-4-(4-(3-Step 1: t-butyl-4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-3-Piperazin-1-yl) -3- 하이드록시피페리딘Hydroxypiperidine -1-카르복실-1-carboxyl 레이트Rate 의 제조Manufacture
화학식 2의 화합물(5 mmol)을 아세토니트릴(10 mL)에 녹인 후 LiClO4(5.5 mmol)와 1-(3-클로로페닐)피페라진(5.5 mmol)을 가하고 5~6 시간 환류교반하였다. 이후 반응물을 감압농축하고 에틸 아세테이트(50 mL)로 희석시킨 후, 증류수(20 mL)로 세척하고 유기층을 건조 후(Na2SO4) 감압 농축하였다. 잔류물을 칼럼크로마토그래피(헥산:에틸아세테이트 = 2:1)로 분리하여 t-부틸-4-(4-(3-클로로페닐)피페라진-1-일)-3-하이드록시피페리딘-1-카르복실레이트를 수득하였다(수율: 90%).After dissolving the compound of Formula 2 (5 mmol) in acetonitrile (10 mL), LiClO 4 (5.5 mmol) and 1- (3-chlorophenyl) piperazine (5.5 mmol) were added and stirred under reflux for 5-6 hours. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with distilled water (20 mL), and the organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 2: 1) to give t-butyl-4- (4- (3-chlorophenyl) piperazin-1-yl) -3-hydroxypiperidine- 1-carboxylate was obtained (yield: 90%).
1H NMR(CDCl3, 300 MHz): δ1.46 (br.s, 18H), 1.70-1.80 (m, 1H), 2.03-2.09 (m, 1H), 2.30-2.43 (m, 2H), 2.50-2.75 (m, 8H), 2.80-2.89 (m, 2H), 2.95-3.01 (m, 2H), 3.10-3.26 (m, 8H), 3.40-3.47 (m, 1H), 3.57-3.65 (m, 2H), 4.00- 4.16 (m, 1H), 4.18-4.34 (m, 1H), 4.36-4.50 (m, 1H), 6.74-6.84 (m,4H), 6.86 (br.s, 2H), 7.15 (t, J=8 Hz, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.46 (br.s, 18H), 1.70-1.80 (m, 1H), 2.03-2.09 (m, 1H), 2.30-2.43 (m, 2H), 2.50 -2.75 (m, 8H), 2.80-2.89 (m, 2H), 2.95-3.01 (m, 2H), 3.10-3.26 (m, 8H), 3.40-3.47 (m, 1H), 3.57-3.65 (m, 2H), 4.00- 4.16 (m, 1H), 4.18-4.34 (m, 1H), 4.36-4.50 (m, 1H), 6.74-6.84 (m, 4H), 6.86 (br.s, 2H), 7.15 ( t, J = 8 Hz, 2H).
단계 2: t-부틸-3-(2-Step 2: t-butyl-3- (2- 나프토일록시Naphthoyloxy )-4-(4-(3-) -4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-1-카르복실) Piperazin-1-yl) piperidine-1-carboxyl 레이트의Rate 제조 Produce
상기 단계 1에서 제조된 t-부틸-4-(4-(3-클로로페닐)피페라진-1-일)-3-하이드록시피페리딘-1-카르복실레이트(2 mmol)에 실시예 1의 단계 2와 동일한 방법을 수행하여 t-부틸3-(2-나프토일록시)-4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-1-카르복실레이트를 수득하였다(수율: 51%).Example 1 in t-butyl-4- (4- (3-chlorophenyl) piperazin-1-yl) -3-hydroxypiperidine-1-carboxylate (2 mmol) prepared in step 1 In the same manner as in step 2 of t-butyl3- (2-naphthoyloxy) -4- (4- (3-chlorophenyl) piperazin-1-yl) piperidine-1-carboxylate Obtained (yield 51%).
1H NMR(CDCl3, 200 MHz): δ1.46 (s, 9H), 1.60-1.80 (m, 1H), 1.90-2.10 (m, 1H), 2.60-2.84 (m, 3H), 2.90-3.17 (m, 8H), 4.00-4.10 (m, 1H), 4.20-4.40 (m, 1H), 5.18-5.30 (m, 1H), 6.74-6.94 (m, 4H), 7.49-7.63 (m, 2H), 7.87 (m, 2H), 7.92-7.96 (m, 1H), 8.01-8.07 (m, 1H), 8.57 (s, 1H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.46 (s, 9H), 1.60-1.80 (m, 1H), 1.90-2.10 (m, 1H), 2.60-2.84 (m, 3H), 2.90-3.17 (m, 8H), 4.00-4.10 (m, 1H), 4.20-4.40 (m, 1H), 5.18-5.30 (m, 1H), 6.74-6.94 (m, 4H), 7.49-7.63 (m, 2H) , 7.87 (m, 2 H), 7.92-7.96 (m, 1 H), 8.01-8.07 (m, 1 H), 8.57 (s, 1 H).
단계 3: 4-(4-(3-Step 3: 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-3-일-2-) Piperazin-1-yl) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
실시예 1의 단계 3과 동일한 방법으로 수행하여 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 수득하였다(수율: 99%).In the same manner as in Step 3 of Example 1, 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate was obtained (yield: 99 %).
1H NMR(CDCl3, 300 MHz): δ 1.60-1.85 (m, 1H), 1.90-2.20 (m, 1H), 2.60-2.72(m, 2H), 2.75-2.84 (m, 2H), 2.85-2.95 (m, 2H), 3.00-3.10 (m, 4H), 3.15-3.35 (m, 1H), 3.40-3.65 (m, 1H), 3.70-4.05 (m, 1H), 5.25-5.40 (m, 1H), 6.66-6.77 (m, 3H), 7.08 (t, J=8.0 Hz, 1H), 7.50-7.60 (m, 2H), 7.87-7.92 (m, 2H), 7.95-8.00 (m, 1H), 8.01-8.07 (m, 1H), 8.61 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.60-1.85 (m, 1H), 1.90-2.20 (m, 1H), 2.60-2.72 (m, 2H), 2.75-2.84 (m, 2H), 2.85- 2.95 (m, 2H), 3.00-3.10 (m, 4H), 3.15-3.35 (m, 1H), 3.40-3.65 (m, 1H), 3.70-4.05 (m, 1H), 5.25-5.40 (m, 1H ), 6.66-6.77 (m, 3H), 7.08 (t, J = 8.0 Hz, 1H), 7.50-7.60 (m, 2H), 7.87-7.92 (m, 2H), 7.95-8.00 (m, 1H), 8.01-8.07 (m, 1 H), 8.61 (s, 1 H).
<< 실시예Example 3> 4-(4-(4- 3> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-2-) Piperazin-1-yl) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
단계 1: t-부틸-4-(4-(4-Step 1: t-butyl-4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-3-Piperazin-1-yl) -3- 하이드록시피페리딘Hydroxypiperidine -1-카르복실-1-carboxyl 레이트Rate 의 제조Manufacture
화학식 2의 화합물(5 mmol)과 1-(2-메톡시페닐)피페라진(5.5 mmol)을 무수 에탄올(10 mL)에 녹인 후 36~50시간 환류교반하였다. 반응물을 감압농축 후 에틸 아세테이트(50 mL)로 희석시킨 후, 증류수(20 mL)로 세척하고 유기층을 건조 후(Na2SO4) 감압 농축하였다. 잔류물을 칼럼크로마토그래피(헥산:에틸 아세테이트 = 2:1)로 분리하여 t-부틸-4-(4-(4-메톡시페닐)피페라진-1-일)-3-하이드록시피페리딘-1-카르복실레이트를 수득하였다(수율: 77%).Compound (5 mmol) and 1- (2-methoxyphenyl) piperazine (5.5 mmol) in Chemical Formula 2 were dissolved in anhydrous ethanol (10 mL) and stirred under reflux for 36 to 50 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with distilled water (20 mL), and the organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 2: 1) to give t-butyl-4- (4- (4-methoxyphenyl) piperazin-1-yl) -3-hydroxypiperidine -1-carboxylate was obtained (yield: 77%).
1H NMR(CDCl3, 300 MHz): δ1.46 (br.s, 18H), 1.75-1.85 (m, 1H), 2.05-2.10 (m, 1H), 2.32-2.44 (m, 2H), 2.50-2.75 (m, 8H), 2.84-2.94 (m, 2H), 2.96- 3.16 (m, 10H), 3.38-3.50 (m, 1H), 3.56-3.67 (m, 2H), 3.76 (br.s, 6H), 4.02-4.18 (m, 1H), 4.20-4.36 (m, 1H), 4.38-4.56 (m, 1H), 6.80-6.93 (m, 8H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.46 (br.s, 18H), 1.75-1.85 (m, 1H), 2.05-2.10 (m, 1H), 2.32-2.44 (m, 2H), 2.50 -2.75 (m, 8H), 2.84-2.94 (m, 2H), 2.96-3.16 (m, 10H), 3.38-3.50 (m, 1H), 3.56-3.67 (m, 2H), 3.76 (br.s, 6H), 4.02-4.18 (m, 1H), 4.20-4.36 (m, 1H), 4.38-4.56 (m, 1H), 6.80-6.93 (m, 8H).
단계 2: t-부틸-3-(2-Step 2: t-butyl-3- (2- 나프토일록시Naphthoyloxy )-4-(4-(4-) -4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-1-카르복실) Piperazin-1-yl) piperidine-1-carboxyl 레이트의Rate 제조 Produce
상기 단계 1에서 제조된 t-부틸-4-(4-(4-메톡시페닐)피페라진-1-일)-3-하이드록시피페리딘-1-카르복실레이트를 피리딘(3 mL)에 녹인 후 2-나프토산 염화물(1.1 당량)을 가하고 마이크로 파를 이용하여 150 ℃에서 3분간 가열하였다. 반응물을 에틸 아세테이트(50 mL)로 묽히고 0.1N-염산수용액(50 mL)와 물(50 mL)로 세척 후 유기층을 Na2SO4로 수분을 제거 후 감압 농축하였다. 잔류물을 칼럼크로마토그래피 (헥산/에틸 아세테이트 = 1/1)로 정제하여 t-부틸-3-(2-나프토일록시)-4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-1-카르복실레이트를 수득하였다(수율: 57%).T-butyl-4- (4- (4-methoxyphenyl) piperazin-1-yl) -3-hydroxypiperidine-1-carboxylate prepared in step 1 was added to pyridine (3 mL). After dissolving, 2-naphthoic acid chloride (1.1 equiv) was added and heated at 150 ° C. for 3 minutes using microwave. The reaction was diluted with ethyl acetate (50 mL), washed with 0.1 N aqueous hydrochloric acid solution (50 mL) and water (50 mL), and then the organic layer was concentrated under reduced pressure with Na 2 SO 4 . The residue was purified by column chromatography (hexane / ethyl acetate = 1/1) to give t-butyl-3- (2-naphthoyloxy) -4- (4- (4-methoxyphenyl) piperazin-1- I) piperidine-1-carboxylate was obtained (yield: 57%).
1H NMR(CDCl3, 300 MHz): δ1.50 (s, 9H), 1.68-1.84 (m, 1H), 2.14-2.24 (m, 1H), 2.65-2.82 (m, 3H), 2.90-3.11 (m, 8H), 3.72 (s, 3H), 3.90-4.05 (m, 1H), 4.06-4.25 (m, 1H), 5.36-5.43 (m, 1H), 6.74-6.82 (m, 4H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.03-8.07 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ1.50 (s, 9H), 1.68-1.84 (m, 1H), 2.14-2.24 (m, 1H), 2.65-2.82 (m, 3H), 2.90-3.11 (m, 8H), 3.72 (s, 3H), 3.90-4.05 (m, 1H), 4.06-4.25 (m, 1H), 5.36-5.43 (m, 1H), 6.74-6.82 (m, 4H), 7.51 -7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.03-8.07 (m, 1H), 8.59 (s, 1H).
13C NMR(CDCl3, 200 MHz): δ28.4, 30.0, 42.5, 49.5, 51.2, 55.5, 63.9, 68.0, 70.5, 79.9, 114.3, 118.0, 125.2, 126.6, 127.7, 128.1, 128.2, 129.3, 131.0, 132.4, 135.5, 145.6, 153.7, 154.6, 166.0 13 C NMR (CDCl 3 , 200 MHz): δ 28.4, 30.0, 42.5, 49.5, 51.2, 55.5, 63.9, 68.0, 70.5, 79.9, 114.3, 118.0, 125.2, 126.6, 127.7, 128.1, 128.2, 129.3, 131.0 , 132.4, 135.5, 145.6, 153.7, 154.6, 166.0
단계 3: 4-(4-(4-Step 3: 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-2-) Piperazin-1-yl) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
실시예 1의 단계 3과 동일한 방법으로 수행하여 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 수득하였다(수율: 97%).In the same manner as in Step 3 of Example 1, 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate was obtained (yield: 97%).
1H NMR(CDCl3, 200 MHz): δ 1.62-1.90 (m, 1H), 2.10-2.35 (m, 1H), 2.60-2.85 (m, 3H), 2.90-3.00 (m, 8H), 3.20-3.40 (m, 1H), 3.70 (s, 3H), 5.28-5.45 (m, 1H), 6.64-6.82 (m, 4H), 7.48-7.61 (m, 2H), 7.84-7.88 (m, 2H), 7.90-8.00 (m, 1H), 8.02-8.07 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.62-1.90 (m, 1H), 2.10-2.35 (m, 1H), 2.60-2.85 (m, 3H), 2.90-3.00 (m, 8H), 3.20- 3.40 (m, 1H), 3.70 (s, 3H), 5.28-5.45 (m, 1H), 6.64-6.82 (m, 4H), 7.48-7.61 (m, 2H), 7.84-7.88 (m, 2H), 7.90-8.00 (m, 1 H), 8.02-8.07 (m, 1 H), 8.59 (s, 1 H).
13C NMR(CDCl3, 200 MHz): δ31.9, 44.2, 45.5, 49.2, 50.9, 55.1, 65.3, 70.9, 113.9, 117.6, 125.0, 126.3, 127.4, 127.7, 127.8, 128.9, 130.6, 132.1, 135.1, 145.4, 153.2, 165.6. 13 C NMR (CDCl 3 , 200 MHz): δ 31.9, 44.2, 45.5, 49.2, 50.9, 55.1, 65.3, 70.9, 113.9, 117.6, 125.0, 126.3, 127.4, 127.7, 127.8, 128.9, 130.6, 132.1, 135.1 , 145.4, 153.2, 165.6.
<< 실시예Example 4> 4-(4-(2- 4> 4- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-2-) Piperazin-1-yl) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
단계 1: t-부틸-4-(4-(2-Step 1: t-butyl-4- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)-3-Piperazin-1-yl) -3- 하이드록시피페리딘Hydroxypiperidine - 1-카르복실1-carboxyl 레이트Rate 의 제조Manufacture
화학식 2의 화합물(5 mmol)을 아세토니트릴(10 mL)에 녹인 후 LiClO4(5.5 mmol)과 1-(2-메톡시페닐)피페라진(5.5 mmol)을 가하고 마이크로파를 이용하여 130 ℃에서 15 분간 반응시켰다. 반응물을 감압농축 후 에틸 아세테이트(50 mL)로 희석시킨 후, 증류수(20 mL)로 세척하고 유기층을 건조 후(Na2SO4) 감압 농축하였다. 잔류물을 칼럼크로마토그래피(헥산:에틸 아세테이트 = 2:1)로 분리하여 t-부틸-4-(4-(4-메톡시페닐)피페라진-1-일)-3-하이드록시피페리딘-1-카르복실레이트를 수득하였다(수율: 77%).Dissolve compound (5 mmol) in acetonitrile (10 mL) and add LiClO 4 (5.5 mmol) and 1- (2-methoxyphenyl) piperazine (5.5 mmol). The reaction was carried out for a minute. The reaction was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with distilled water (20 mL), and the organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was separated by column chromatography (hexane: ethyl acetate = 2: 1) to give t-butyl-4- (4- (4-methoxyphenyl) piperazin-1-yl) -3-hydroxypiperidine -1-carboxylate was obtained (yield: 77%).
1H NMR(CDCl3, 300 MHz): δ1.46 (br.s, 18H), 1.75-1.85 (m, 1H), 2.05-2.15 (m, 1H), 2.30-2.44 (m, 2H), 2.55-2.80 (m, 8H), 2.89-2.98 (m, 3H), 3.00-3.20 (m, 9H), 3.38-3.50 (m, 1H), 3.56-3.66 (m, 1H), 3.68-3.82 (m, 2H), 3.87 (br.s, 6H), 4.20-4.36 (m, 2H), 4.38-4.56 (m, 2H), 6.84-6.90 (m, 2H), 6.92-6.97 (m, 4H), 6.98-7.05 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.46 (br.s, 18H), 1.75-1.85 (m, 1H), 2.05-2.15 (m, 1H), 2.30-2.44 (m, 2H), 2.55 -2.80 (m, 8H), 2.89-2.98 (m, 3H), 3.00-3.20 (m, 9H), 3.38-3.50 (m, 1H), 3.56-3.66 (m, 1H), 3.68-3.82 (m, 2H), 3.87 (br.s, 6H), 4.20-4.36 (m, 2H), 4.38-4.56 (m, 2H), 6.84-6.90 (m, 2H), 6.92-6.97 (m, 4H), 6.98- 7.05 (m, 2 H).
단계 2: t-부틸-3-(2-Step 2: t-butyl-3- (2- 나프토일록시Naphthoyloxy )-4-(4-(2-) -4- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-1-카르복실) Piperazin-1-yl) piperidine-1-carboxyl 레이트의Rate 제조 Produce
상기 단계 1에서 제조된 t-부틸-4-(4-(2-메톡시페닐)피페라진-1-일)-3-하이드록시피페리딘-1-카르복실레이트를 실시예 3의 단계 2와 동일한 방법으로 수행하여 t-부틸-3-(2-나프토일록시)-4-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-1-카르 복실레이트를 수득하였다(수율: 39%).T-butyl-4- (4- (2-methoxyphenyl) piperazin-1-yl) -3-hydroxypiperidine-1-carboxylate prepared in Step 1 was prepared according to Example 3 In the same manner as in t-butyl-3- (2-naphthoyloxy) -4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidine-1-carboxylate (Yield 39%).
1H NMR(CDCl3, 300 MHz): δ 1.49 (s, 9H), 1.71-1.86 (m, 1H), 2.15-2.24 (m, 1H), 2.65-2.83 (m, 3H), 2.87-2.98 (m, 4H), 3.00-3.15 (m, 4H), 3.79 (s, 3H), 3.90-4.05 (m, 1H), 4.10-4.22(m, 1H), 5.35-5.44 (m, 1H), 6.78-6.87 (m, 3H), 6.90-6.96 (m,1H), 7.51-7.62 (m, 2H), 7.86-7.90 (m, 1H), 8.04-8.08 (m, 1H), 8.60 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.49 (s, 9H), 1.71-1.86 (m, 1H), 2.15-2.24 (m, 1H), 2.65-2.83 (m, 3H), 2.87-2.98 ( m, 4H), 3.00-3.15 (m, 4H), 3.79 (s, 3H), 3.90-4.05 (m, 1H), 4.10-4.22 (m, 1H), 5.35-5.44 (m, 1H), 6.78- 6.87 (m, 3H), 6.90-6.96 (m, 1H), 7.51-7.62 (m, 2H), 7.86-7.90 (m, 1H), 8.04-8.08 (m, 1H), 8.60 (s, 1H).
단계 3: 4-(4-(2-Step 3: 4- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-2-) Piperazin-1-yl) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
실시예 1의 단계 3과 동일한 방법으로 수행하여 4-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 수득하였다(수율: 99%)In the same manner as in Step 3 of Example 1, 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate was obtained (yield: 99%)
1H NMR(CDCl3, 300 MHz): δ 1.98-2.13 (m, 1H), 2.35-2.45 (m, 1H), 2.75-2.85 (m, 2H), 2.90-3.17 (m, 9H), 3.40-3.50 (m, 1H), 3.54-3.60 (m, 1H), 3.76 (s, 3H), 5.45-5.52 (m, 1H), 6.76-6.86 (m, 3H), 6.90-6.96 (m,1H), 7.52-7.63 (m, 2H), 7.87-7.91 (m, 2H), 7.95-8.01 (m, 1H), 8.04-8.07 (m, 1H), 8.62 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.98-2.13 (m, 1H), 2.35-2.45 (m, 1H), 2.75-2.85 (m, 2H), 2.90-3.17 (m, 9H), 3.40- 3.50 (m, 1H), 3.54-3.60 (m, 1H), 3.76 (s, 3H), 5.45-5.52 (m, 1H), 6.76-6.86 (m, 3H), 6.90-6.96 (m, 1H), 7.52-7.63 (m, 2H), 7.87-7.91 (m, 2H), 7.95-8.01 (m, 1H), 8.04-8.07 (m, 1H), 8.62 (s, 1H).
<< 실시예Example 5> 4-(4-(4- 5> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-3-일-) Piperazin-1-yl) piperidin-3-yl- 바이페닐Biphenyl -4-카르복 실-4-carboxyl 레이트의Rate 제조 Produce
단계 1Step 1
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2Step 2
2-나프토산 염화물 대신 바이페닐-4-카르복실산 염화물을 사용한 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 46%).The target compound was obtained in the same manner as Step 2 of Example 1, except that biphenyl-4-carboxylic acid chloride was used instead of 2-naphthoic acid chloride (yield: 46%).
1H NMR(CDCl3, 200 MHz): δ1.49 (s, 9H), 1.60-1.81 (m, 1H), 2.10-2.22 (m, 1H), 2.65-2.83 (m, 3H), 2.90-3.09 (m, 8H), 3.90-4.20 (m, 2H), 5.30-5.41 (m, 1H), 6.76-6.95 (m, 4H), 7.38-7.51 (m, 3H), 7.59-7.67 (m, 4H), 8.03-8.12 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.49 (s, 9H), 1.60-1.81 (m, 1H), 2.10-2.22 (m, 1H), 2.65-2.83 (m, 3H), 2.90-3.09 (m, 8H), 3.90-4.20 (m, 2H), 5.30-5.41 (m, 1H), 6.76-6.95 (m, 4H), 7.38-7.51 (m, 3H), 7.59-7.67 (m, 4H) , 8.03-8.12 (m, 2 H).
13C NMR(CDCl3, 200 MHz): δ 28.2, 29.8, 41.4, 42.4,49.2, 50.4, 63.6, 70.2, 79.7, 114.9, 115.3, 117.4, 117.5, 126.5, 126.8, 127.0, 127.9, 128.7, 128.9, 129.9, 130.1, 139.6, 145.4, 147.7, 154.4, 159.1, 165.4. 13 C NMR (CDCl 3 , 200 MHz): δ 28.2, 29.8, 41.4, 42.4,49.2, 50.4, 63.6, 70.2, 79.7, 114.9, 115.3, 117.4, 117.5, 126.5, 126.8, 127.0, 127.9, 128.7, 128.9, 129.9, 130.1, 139.6, 145.4, 147.7, 154.4, 159.1, 165.4.
단계 3Step 3
실시예 1의 단계 3과 동일한 방법을 수행하여 4-(4-(4-플루오로페닐)피페라 진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 수득하였다(수율: 86%).The same procedure as in Step 3 of Example 1 was carried out to yield 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate (Yield 86%).
1H NMR(CDCl3, 200 MHz): δ 1.62-1.81 (m, 1H), 2.03-2.25 (m, 1H), 2.64-2.82 (m, 5H), 2.93-2.97 (m, 6H), 3.09-3.16 (m, 1H), 3.22-3.35 (m, 1H), 5.24-5.35 (m, 1H), 6.75-6.94 (m, 4H), 7.34-7.51 (m, 3H), 7.59-7.68 (m, 4H), 8.08-8.13 (dd, J=7.0 Hz & 2.0 Hz, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.62-1.81 (m, 1H), 2.03-2.25 (m, 1H), 2.64-2.82 (m, 5H), 2.93-2.97 (m, 6H), 3.09- 3.16 (m, 1H), 3.22-3.35 (m, 1H), 5.24-5.35 (m, 1H), 6.75-6.94 (m, 4H), 7.34-7.51 (m, 3H), 7.59-7.68 (m, 4H ), 8.08-8.13 (dd, J = 7.0 Hz & 2.0 Hz, 2H).
13C NMR(CDCl3, 200 MHz): δ 26.2, 45.2, 48.6, 50.4, 65.6, 70.0, 114.8, 115.2, 117.1, 117.3, 126.7, 126.9, 127.8, 128.6, 129.1, 129.8, 139.6, 145.1, 147.7, 147.8, 154.2, 158.9, 165.4. 13 C NMR (CDCl 3 , 200 MHz): δ 26.2, 45.2, 48.6, 50.4, 65.6, 70.0, 114.8, 115.2, 117.1, 117.3, 126.7, 126.9, 127.8, 128.6, 129.1, 129.8, 139.6, 145.1, 147.7, 147.8, 154.2, 158.9, 165.4.
<< 실시예Example 6> 4-(4-(3- 6> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-3-일-) Piperazin-1-yl) piperidin-3-yl- 바이페닐Biphenyl -4-카르복실-4-carboxyl 레re 이트의 제조Manufacture of wight
단계 1Step 1
실시예 2의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 2.
단계 2Step 2
2-나프토산 염화물 대신 바이페닐-4-카르복실산 염화물을 사용한 것을 제외하고는 실시예 2의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 51%).The target compound was obtained in the same manner as Step 2 of Example 2, except that biphenyl-4-carboxylic acid chloride was used instead of 2-naphthoic acid chloride (yield: 51%).
1H NMR(CDCl3, 200 MHz): δ1.49 (s, 9H), 1.65-1.85 (m, 1H), 2.10--2.25 (m, 1H), 2.60-2.85 (m, 3H), 2.93-3.15 (m, 8H), 3.95-4.18 (m, 2H), 5.28-5.40 (m, 1H), 6.63-6.81 (m, 3H), 7.10 (t, J =7.8 Hz, 1H), 7.38-7.52 (m, 3H), 7.58-7.69 (m, 4H), 8.06-8.12 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.49 (s, 9H), 1.65-1.85 (m, 1H), 2.10--2.25 (m, 1H), 2.60-2.85 (m, 3H), 2.93- 3.15 (m, 8H), 3.95-4.18 (m, 2H), 5.28-5.40 (m, 1H), 6.63-6.81 (m, 3H), 7.10 (t, J = 7.8 Hz, 1H), 7.38-7.52 ( m, 3H), 7.58-7.69 (m, 4H), 8.06-8.12 (m, 2H).
단계 3Step 3
실시예 2의 단계 3과 동일한 방법을 수행하여 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 수득하였다(수율: 98%).The same method as in Step 3 of Example 2 was carried out to obtain 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate ( Yield: 98%).
1H NMR(CDCl3, 200 MHz): δ 1.90-2.05 (m, 1H), 2.25--2.40 (m, 1H), 2.65-2.80 (m, 3H), 2.89-3.10 (m, 8H), 3.30-3.55 (m, 2H), 5.30-5.45 (m, 1H), 6.66-6.80 (m, 3H), 7.09 (t, J =8.2 Hz, 1H), 7.39-7.51 (m, 3H), 7.59-7.70 (m, 4H), 8.10 (d, J =8.2 Hz, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.90-2.05 (m, 1H), 2.25--2.40 (m, 1H), 2.65-2.80 (m, 3H), 2.89-3.10 (m, 8H), 3.30 -3.55 (m, 2H), 5.30-5.45 (m, 1H), 6.66-6.80 (m, 3H), 7.09 (t, J = 8.2 Hz, 1H), 7.39-7.51 (m, 3H), 7.59-7.70 (m, 4H), 8.10 (d, J = 8.2 Hz, 2H).
<< 실시예Example 7> 4-(4-(4- 7> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-) Piperazin-1-yl) piperidin-3-yl- 바이페닐Biphenyl -4-카르복실-4-carboxyl 레re 이트의 제조Manufacture of wight
단계 1Step 1
실시예 3의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as Step 1 of Example 3.
단계 2Step 2
2-나프토산 염화물 대신 바이페닐-4-카르복실산 염화물을 사용한 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 41%).The target compound was obtained in the same manner as Step 2 of Example 3, except that biphenyl-4-carboxylic acid chloride was used instead of 2-naphthoic acid chloride (yield: 41%).
1H NMR(CDCl3, 300 MHz): δ 1.49 (s, 9H), 1.64-1.80 (m, 1H), 2.12-2.22 (m, 1H), 2.66-3.07 (m, 3H), 2.95-3.07 (m, 8H), 3.73 (s, 3H), 3.95-4.02 (m, 1H), 4.04-4.20(m, 1H), 5.31-5.38 (m, 1H), 6.77-6.85 (m, 4H), 7.36-7.50 (m, 3H), 7.59-7.68 (m, 4H), 8.08-8.12 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.49 (s, 9H), 1.64-1.80 (m, 1H), 2.12-2.22 (m, 1H), 2.66-3.07 (m, 3H), 2.95-3.07 ( m, 8H), 3.73 (s, 3H), 3.95-4.02 (m, 1H), 4.04-4.20 (m, 1H), 5.31-5.38 (m, 1H), 6.77-6.85 (m, 4H), 7.36- 7.50 (m, 3H), 7.59-7.68 (m, 4H), 8.08-8.12 (m, 2H).
13C NMR(CDCl3, 200 MHz): δ28.4, 30.0, 41.4, 42.7, 49.5, 51.1, 55.5, 63.9, 70.5, 79.9, 114.3, 117.9, 126.8, 127.0, 127.2, 128.1, 128.9, 129.2, 130.1, 140.0, 145.7, 153.6, 154.6, 165.7. 13 C NMR (CDCl 3 , 200 MHz): δ 28.4, 30.0, 41.4, 42.7, 49.5, 51.1, 55.5, 63.9, 70.5, 79.9, 114.3, 117.9, 126.8, 127.0, 127.2, 128.1, 128.9, 129.2, 130.1 , 140.0, 145.7, 153.6, 154.6, 165.7.
단계 3Step 3
실시예 3의 단계 3과 동일한 방법을 수행하여 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 수득하였다(수율: 98%).The same procedure as in Step 3 of Example 3 was carried out to obtain 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate. (Yield 98%).
1H NMR(CDCl3, 200 MHz): δ 1.64-1.81 (m, 1H), 2.13-2.24 (m, 1H), 2.64-2.83 (m, 5H), 2.90-3.00 (m, 6H), 3.08-3.22 (m, 1H), 3.26-3.31 (m, 1H), 3.72 (s, 3H), 5.24-5.34 (m, 1H), 6.75-6.84 (m, 4H), 7.34-7.51 (m, 3H), 7.60-7.67 (m, 4H), 8.11 (d, J=8.6 Hz, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.64-1.81 (m, 1H), 2.13-2.24 (m, 1H), 2.64-2.83 (m, 5H), 2.90-3.00 (m, 6H), 3.08- 3.22 (m, 1H), 3.26-3.31 (m, 1H), 3.72 (s, 3H), 5.24-5.34 (m, 1H), 6.75-6.84 (m, 4H), 7.34-7.51 (m, 3H), 7.60-7.67 (m, 4H), 8.11 (d, J = 8.6 Hz, 2H).
<< 실시예Example 8> 4-(4-(2- 8> 4- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트의 제조Preparation of Piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate
단계 1Step 1
실시예 4의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 4.
단계 2Step 2
2-나프토산 염화물 대신 바이페닐-4-카르복실산 염화물을 사용한 것을 제외하고는 실시예 4의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 36%).The target compound was obtained in the same manner as Step 2 of Example 4, except that biphenyl-4-carboxylic acid chloride was used instead of 2-naphthoic acid chloride (yield: 36%).
1H NMR(CDCl3, 300 MHz): δ 1.49 (s, 9H), 1.64-1.80 (m, 1H), 2.12-2.22 (m, 1H), 2.60-2.74 (m, 1H), 2.75-2.85 (m, 2H), 2.90-3.13 (m, 8H), 3.81 (s, 3H), 3.90-4.05 (m, 1H), 4.06-4.20 (m, 1H), 5.31-5.39 (m, 1H), 6.80-6.86 (m, 3H), 6.89-6.97 (m,1H), 7.37-7.50 (m, 3H), 7.60-7.67 (m, 4H), 8.09-8.12 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.49 (s, 9H), 1.64-1.80 (m, 1H), 2.12-2.22 (m, 1H), 2.60-2.74 (m, 1H), 2.75-2.85 ( m, 2H), 2.90-3.13 (m, 8H), 3.81 (s, 3H), 3.90-4.05 (m, 1H), 4.06-4.20 (m, 1H), 5.31-5.39 (m, 1H), 6.80- 6.86 (m, 3H), 6.89-6.97 (m, 1H), 7.37-7.50 (m, 3H), 7.60-7.67 (m, 4H), 8.09-8.12 (m, 2H).
단계 3Step 3
실시예 4의 단계 3과 동일한 방법을 수행하여 4-(4-(2-메톡시페닐)피페라진- 1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 수득하였다(수율: 97%).The same procedure as in Step 3 of Example 4 was conducted to obtain 4- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate. (Yield 97%).
1H NMR(CDCl3, 300 MHz): δ 1.83-2.07 (m, 1H), 2.24-2.43 (m, 1H), 2.72-2.88 (m, 2H), 2.90-3.14 (m, 9H), 3.36-3.60 (m, 2H), 3.79 (s, 3H), 5.32-5.48 (m, 1H), 6.76-6.88 (m, 3H), 6.89-6.99 (m,1H), 7.35-7.52 (m, 3H), 7.60-7. 07 (m, 4H), 8.09-8.13 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.83-2.07 (m, 1H), 2.24-2.43 (m, 1H), 2.72-2.88 (m, 2H), 2.90-3.14 (m, 9H), 3.36- 3.60 (m, 2H), 3.79 (s, 3H), 5.32-5.48 (m, 1H), 6.76-6.88 (m, 3H), 6.89-6.99 (m, 1H), 7.35-7.52 (m, 3H), 7.60-7. 07 (m, 4 H), 8.09-8.13 (m, 2 H).
<< 실시예Example 9> 4-(4-(4- 9> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of Piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate
단계 1Step 1
실시예 1의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 1.
단계 2Step 2
2-나프토산 염화물 대신 4-페녹시벤조산 염화물을 사용한 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 62%).A target compound was obtained in the same manner as Step 2 of Example 1, except that 4-phenoxybenzoic acid chloride was used instead of 2-naphthoic acid chloride (yield: 62%).
1H NMR(CDCl3, 200 MHz): δ1.48 (s, 9H), 1.60-1.80 (m, 1H), 2..09--2.20 (m, 1H), 2.60-2.77 (m, 3H), 2.85-3.07 (m, 8H), 3.90-4.20 (m, 2H), 5.24-5.35 (m, 1H), 6.76-7..08 (m, 8H), 7.15-7.26 (m, 1H), 7.31-7.42 (m, 2H), 7.95-8.02 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.48 (s, 9H), 1.60-1.80 (m, 1H), 2..09--2.20 (m, 1H), 2.60-2.77 (m, 3H) , 2.85-3.07 (m, 8H), 3.90-4.20 (m, 2H), 5.24-5.35 (m, 1H), 6.76-7..08 (m, 8H), 7.15-7.26 (m, 1H), 7.31 -7.42 (m, 2 H), 7.95-8.02 (m, 2 H).
13C NMR(CDCl3, 200 MHz): δ 28.2, 29.8, 41.4, 42.6, 49.2, 50.4, 63.6, 70.1, 79.6, 114.9, 115.3, 117.2, 119.8, 124.5, 131.5, 147.7, 154.3, 155.3, 159.0, 161.6, 164.9. 13 C NMR (CDCl 3 , 200 MHz): δ 28.2, 29.8, 41.4, 42.6, 49.2, 50.4, 63.6, 70.1, 79.6, 114.9, 115.3, 117.2, 119.8, 124.5, 131.5, 147.7, 154.3, 155.3, 159.0, 161.6, 164.9.
단계 3Step 3
실시예 1의 단계 3과 동일한 방법을 수행하여 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 수득하였다(수율: 99%).The same procedure as in Step 3 of Example 1 was carried out to obtain 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate (yield) : 99%).
1H NMR(CDCl3, 200 MHz): δ 1.80-2.00 (m, 1H), 2..25--2.40 (m, 1H), 2.70-2.81 (m, 3H), 2.85-3.05(m, 8H), 3.29-3.45 (m, 2H), 5.26-5.40 (m, 1H), 6.75-7.10 (m, 8H), 7.15-7.23 (m, 1H), 7.32-7.44 (m, 2H), 7.96-8.03 (m, 2H).13C NMR(CDCl3, 200 MHz): δ 28.9, 42.8, 44.3, 49.3, 50.5, 62.6, 68.9, 115.1, 115.5, 117.2, 117.5, 117.7, 120.1, 124.0, 124.5, 129.9, 131.7, 147.6, 147.7, 155.3, 162.0, 164.9. 1 H NMR (CDCl 3 , 200 MHz): δ 1.80-2.00 (m, 1H), 2..25--2.40 (m, 1H), 2.70-2.81 (m, 3H), 2.85-3.05 (m, 8H ), 3.29-3.45 (m, 2H), 5.26-5.40 (m, 1H), 6.75-7.10 (m, 8H), 7.15-7.23 (m, 1H), 7.32-7.44 (m, 2H), 7.96-8.03 (m, 2 H). 13 C NMR (CDCl 3 , 200 MHz): δ 28.9, 42.8, 44.3, 49.3, 50.5, 62.6, 68.9, 115.1, 115.5, 117.2, 117.5, 117.7, 120.1, 124.0, 124.5, 129.9, 131.7, 147.6, 147.7, 155.3, 162.0, 164.9.
<< 실시예Example 10> 4-(4-(3- 10> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of Piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate
단계 1Step 1
실시예 2의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 2.
단계 2Step 2
2-나프토산 염화물 대신 4-페녹시벤조산 염화물을 사용한 것을 제외하고는 실시예 2의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 49%).A target compound was obtained in the same manner as Step 2 of Example 2, except that 4-phenoxybenzoic acid chloride was used instead of 2-naphthoic acid chloride (yield: 49%).
1H NMR(CDCl3, 200 MHz): δ1.48 (s, 9H), 1.61-1.74 (m, 1H), 2.09--2.17 (m, 1H), 2.63-2.76 (m, 3H), 2.90-3.07 (m, 8H), 3.90-4.20 (m, 2H), 5.25-5.33 (m, 1H), 6.70-6.84 (m, 3H), 6.95-7.02 (m, 2H), 7.04-7.22 (m, 4H), 7.35-7.42 (m, 2H), 7.96-8.01 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.48 (s, 9H), 1.61-1.74 (m, 1H), 2.09--2.17 (m, 1H), 2.63-2.76 (m, 3H), 2.90- 3.07 (m, 8H), 3.90-4.20 (m, 2H), 5.25-5.33 (m, 1H), 6.70-6.84 (m, 3H), 6.95-7.02 (m, 2H), 7.04-7.22 (m, 4H ), 7.35-7.42 (m, 2H), 7.96-8.01 (m, 2H).
단계 3Step 3
실시예 2의 단계 3과 동일한 방법을 수행하여 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 수득하였다(수율: 74%).The same procedure as in Step 3 of Example 2 was carried out to yield 4- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate (yield: 74%).
1H NMR(CDCl3, 200 MHz): δ 1.65-1.85 (m, 1H), 2.15-2.30 (m, 1H), 2.71-2.82 (m, 6H), 2.85-2.96 (m, 2H), 3.00-3.07 (m, 3H), 3.10-3.25 (m, 1H), 3.28-3.33 (m, 1H), 5.21-5.35 (m, 1H), 6.66-6.81 (m, 3H), 6.95-7.02 (m, 2H), 7.04-7.11 (m, 2H), 7.15-7.23 (m, 2H), 7.32-7.43 (m, 2H), 7.96-8.02 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.65-1.85 (m, 1H), 2.15-2.30 (m, 1H), 2.71-2.82 (m, 6H), 2.85-2.96 (m, 2H), 3.00- 3.07 (m, 3H), 3.10-3.25 (m, 1H), 3.28-3.33 (m, 1H), 5.21-5.35 (m, 1H), 6.66-6.81 (m, 3H), 6.95-7.02 (m, 2H ), 7.04-7.11 (m, 2H), 7.15-7.23 (m, 2H), 7.32-7.43 (m, 2H), 7.96-8.02 (m, 2H).
<< 실시예Example 11> 4-(4-(4- 11> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of Piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate
단계 1Step 1
실시예 3의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as Step 1 of Example 3.
단계 2Step 2
2-나프토산 염화물 대신 4-페녹시벤조산 염화물을 사용한 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 46%).A target compound was obtained in the same manner as Step 2 of Example 3, except that 4-phenoxybenzoic acid chloride was used instead of 2-naphthoic acid chloride (yield: 46%).
1H NMR(CDCl3, 200 MHz): δ1.48 (s, 9H), 1.50-1.95 (m, 1H), 2.10--2.12 (m, 1H), 2.16-2.81 (m, 3H), 2.95-3.07 (m, 8H), 3.74 (s, 3H), 3.93-4.25 (m, 2H), 5.26-5.31 (m, 1H), 6.77-6.86 (m, 4H), 6.94-7.15 (m, 4H), 7.17-7.22 (m, 1H), 7.33-7.42 (m, 2H), 7.96-8.03 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.48 (s, 9H), 1.50-1.95 (m, 1H), 2.10--2.12 (m, 1H), 2.16-2.81 (m, 3H), 2.95- 3.07 (m, 8H), 3.74 (s, 3H), 3.93-4.25 (m, 2H), 5.26-5.31 (m, 1H), 6.77-6.86 (m, 4H), 6.94-7.15 (m, 4H), 7.17-7.22 (m, 1 H), 7.33-7.42 (m, 2 H), 7.96-8.03 (m, 2 H).
13C NMR(CDCl3, 200 MHz): δ28.2, 29.8, 41.3, 42.6, 49.3, 50.9, 55.2, 63.6, 70.2, 79.6, 114.1, 117.1, 117.7, 119.8, 124.2, 124.6, 129.8, 131.5, 145.5, 153.4, 154.4, 155.4, 161.6, 165.0. 13 C NMR (CDCl 3 , 200 MHz): δ 28.2, 29.8, 41.3, 42.6, 49.3, 50.9, 55.2, 63.6, 70.2, 79.6, 114.1, 117.1, 117.7, 119.8, 124.2, 124.6, 129.8, 131.5, 145.5 , 153.4, 154.4, 155.4, 161.6, 165.0.
단계 3Step 3
실시예 3의 단계 3과 동일한 방법을 수행하여 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 수득하였다(수율: 99%).The same procedure as in Step 3 of Example 3 was carried out to yield 4- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate (yield) : 99%).
1H NMR(CDCl3, 200 MHz): δ 1.66-1.86 (m, 1H), 2.17--2.26 (m, 1H), 2.71-2.83 (m, 3H), 2.90-3.00 (m, 8H), 3.05-3.25 (m, 1H), 3.30-3.35 (m, 1H), 3.74 (s, 3H), 5.22-5.33 (m, 1H), 6.75-6.85 (m, 4H), 6.95-7.09 (m, 4H), 7.14-7.22 (m, 1H), 7.32-7.44 (m, 2H), 7.96-8.03 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.66-1.86 (m, 1H), 2.17--2.26 (m, 1H), 2.71-2.83 (m, 3H), 2.90-3.00 (m, 8H), 3.05 -3.25 (m, 1H), 3.30-3.35 (m, 1H), 3.74 (s, 3H), 5.22-5.33 (m, 1H), 6.75-6.85 (m, 4H), 6.95-7.09 (m, 4H) , 7.14-7.22 (m, 1 H), 7.32-7.44 (m, 2 H), 7.96-8.03 (m, 2H).
13C NMR(CDCl3, 200 MHz): δ30.9, 43.8, 45.8, 45.3, 49.5, 51.1, 55.4, 64.4, 70.2, 114.2, 117.2, 117.8, 119.9, 124.4, 124.6, 129.9, 131.6, 145.6, 153.5, 155.5, 161.7, 165.1. 13 C NMR (CDCl 3 , 200 MHz): δ 30.9, 43.8, 45.8, 45.3, 49.5, 51.1, 55.4, 64.4, 70.2, 114.2, 117.2, 117.8, 119.9, 124.4, 124.6, 129.9, 131.6, 145.6, 153.5 , 155.5, 161.7, 165.1.
<< 실시예Example 12> 3-(4-(4- 12> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
단계 1Step 1
실시예 1의 단계 1과 동일한 방법으로 수행하여 목적 화합물을 수득하였다(수율: 42%)The target compound was obtained by the same method as the step 1 of Example 1 (yield: 42%).
단계 2Step 2
1-나프토산 염화물을 사용한 것을 제외하고는 실시예 1의 단계 2와 동일한 방법으로 수행하여 목적 화합물을 수득하였다(수율: 52%).The desired compound was obtained in the same manner as Step 2 of Example 1, except that 1-naphthoic acid chloride was used (yield: 52%).
1H NMR(CDCl3, 200 MHz): δ1.46 (s, 9H), 1.60-1.80 (m, 1H), 1.90-2.10 (m, 1H), 2.60-2.84 (m, 3H), 2.90-3.17 (m, 8H), 4.00-4.10 (m, 1H), 4.20-4.40 (m, 1H), 5.18-5.30 (m, 1H), 6.74-6.94 (m, 4H), 7.49-7.63 (m, 2H), 7.87 (m, 2H), 7.92-7.96 (m, 1H), 8.01-8.07 (m, 1H), 8.57 (s, 1H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.46 (s, 9H), 1.60-1.80 (m, 1H), 1.90-2.10 (m, 1H), 2.60-2.84 (m, 3H), 2.90-3.17 (m, 8H), 4.00-4.10 (m, 1H), 4.20-4.40 (m, 1H), 5.18-5.30 (m, 1H), 6.74-6.94 (m, 4H), 7.49-7.63 (m, 2H) , 7.87 (m, 2 H), 7.92-7.96 (m, 1 H), 8.01-8.07 (m, 1 H), 8.57 (s, 1 H).
단계 3Step 3
실시예 1의 단계 3과 동일한 방법을 수행하여 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 수득하였다(수율: 99%).The same procedure as in Step 3 of Example 1 was followed to obtain 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate (yield: 99%).
1H NMR(CDCl3, 300 MHz): δ 1.85-2.04 (m, 1H), 2.05-2.30 (m, 1H), 2.64-2.74 (m, 2H), 2.75-2.90 (m, 3H), 2.95-3.15 (m, 6H), 3.22-3.42 (m, 1H), 3.50-3.80 (m, 1H), 5.40-5.60 (m, 1H), 6.74-6.81 (m, 2H), 6.85-6.93 (m, 2H), 7.47-7.59 (m, 2H), 7.79-7.87 (m, 2H), 7.89-7.92 (m, 1H), 8.02-8.05 (m, 1H), 8.62 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.85-2.04 (m, 1H), 2.05-2.30 (m, 1H), 2.64-2.74 (m, 2H), 2.75-2.90 (m, 3H), 2.95- 3.15 (m, 6H), 3.22-3.42 (m, 1H), 3.50-3.80 (m, 1H), 5.40-5.60 (m, 1H), 6.74-6.81 (m, 2H), 6.85-6.93 (m, 2H ), 7.47-7.59 (m, 2H), 7.79-7.87 (m, 2H), 7.89-7.92 (m, 1H), 8.02-8.05 (m, 1H), 8.62 (s, 1H).
<< 실시예Example 13> 3-(4-(3- 13> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-4-일-1-나프토에이트의 제조Preparation of Piperazin-1-yl) piperidin-4-yl-1-naphthoate
단계 1Step 1
실시예 2의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 2.
단계 2Step 2
1-나프토산 염화물을 사용한 것을 제외하고는 실시예 2의 단계 2와 동일한 방법으로 수행하여 목적 화합물을 수득하였다(수율: 47%).The desired compound was obtained in the same manner as Step 2 of Example 2, except that 1-naphthoic acid chloride was used (yield: 47%).
1H NMR(CDCl3, 200 MHz): δ 1.46 (s, 9H), 1.60-1.80 (m, 1H), 1.90-2.00 (m, 1H), 2.60-2.75(m, 3H), 2.80-3.15 (m, 8H), 4.00-4.15 (m, 1H), 4.20-4.35 (m, 1H), 5.15-5.30 (m, 1H), 6.66-6.79 (m, 3H), 7.09 (t, J=8.2 Hz, 1H), 7.44-7.62 (m, 2H), 7.85-7.89 (m, 2H), 7.92-7.97 (m, 1H), 8.01-8.06 (m, 1H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.46 (s, 9H), 1.60-1.80 (m, 1H), 1.90-2.00 (m, 1H), 2.60-2.75 (m, 3H), 2.80-3.15 ( m, 8H), 4.00-4.15 (m, 1H), 4.20-4.35 (m, 1H), 5.15-5.30 (m, 1H), 6.66-6.79 (m, 3H), 7.09 (t, J = 8.2 Hz, 1H), 7.44-7.62 (m, 2H), 7.85-7.89 (m, 2H), 7.92-7.97 (m, 1H), 8.01-8.06 (m, 1H), 8.58 (s, 1H).
단계 3Step 3
실시예 2의 단계 3과 동일한 방법을 수행하여 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 수득하였다(수율: 98%).The same procedure as in Step 3 of Example 2 was carried out to yield 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate (yield: 98 %).
1H NMR(CDCl3, 200 MHz): δ 1.90-2.10 (m, 1H), 2.30-2.50 (m, 1H), 2.65-2.85 (m, 2H), 2.90-3.20 (m, 7H), 3.30-3.60 (m, 2H), 5.00-5.30 (m, 2H), 5.40-5.50 (m, 1H), 6.64-6.75 (m, 3H), 7.07 (t, J=8.0 Hz, 1H), 7.50-7.65 (m, 2H), 7.84-7.87 (m, 2H), 7.96-8.00 (m, 1H), 8.02-8.07 (m, 1H), 8.61 (s, 1H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.90-2.10 (m, 1H), 2.30-2.50 (m, 1H), 2.65-2.85 (m, 2H), 2.90-3.20 (m, 7H), 3.30- 3.60 (m, 2H), 5.00-5.30 (m, 2H), 5.40-5.50 (m, 1H), 6.64-6.75 (m, 3H), 7.07 (t, J = 8.0 Hz, 1H), 7.50-7.65 ( m, 2H), 7.84-7.87 (m, 2H), 7.96-8.00 (m, 1H), 8.02-8.07 (m, 1H), 8.61 (s, 1H).
<< 실시예Example 14> 3-(4-(4- 14> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
단계 1Step 1
실시예 3의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as Step 1 of Example 3.
단계 2Step 2
1-나프토산 염화물을 사용한 것을 제외하고는 실시예 3의 단계 2와 동일한 방법으로 수행하여 목적 화합물을 수득하였다(수율: 45%).Except for using 1-naphthoic acid chloride in the same manner as in Step 2 of Example 3 to obtain the target compound (yield: 45%).
1H NMR(CDCl3, 300 MHz): δ1.45 (s, 9H), 1.60-1.78 (m, 1H), 1.90-2.00 (m, 1H), 2.65-2.80 (m, 3H), 2.85-3.02 (m, 7H), 3.05-3.20 (m,1H), 3.72 (s, 3H), 4.00-4.10 (m, 1H), 4.15-4.40 (m, 1H), 5.19-5.27 (m, 1H), 6.75-6.83 (m, 4H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.02-8.06 (m, 1H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.45 (s, 9H), 1.60-1.78 (m, 1H), 1.90-2.00 (m, 1H), 2.65-2.80 (m, 3H), 2.85-3.02 (m, 7H), 3.05-3.20 (m, 1H), 3.72 (s, 3H), 4.00-4.10 (m, 1H), 4.15-4.40 (m, 1H), 5.19-5.27 (m, 1H), 6.75 -6.83 (m, 4H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.02-8.06 (m, 1H), 8.58 (s, 1H) .
단계 3Step 3
실시예 3의 단계 3과 동일한 방법을 수행하여 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 수득하였다(수율: 92%).The same procedure as in Step 3 of Example 3 was carried out to yield 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate (yield: 92%).
1H NMR(CDCl3, 300 MHz): δ 1.53-1.71 (m, 1H), 1.93-2.01 (m, 1H), 2.59-2.85 (m, 3H), 2.90-3.05 (m, 8H), 3.05-3.25 (m,1H), 3.35-3.48 (m, 1H), 3.71 (s, 3H), 5.15-5.27 (m, 1H), 6.72-6.82 (m, 4H), 7.48-7.62 (m, 2H), 7.84-7.88 ( m, 2H), 7.92-7.97 (m, 1H), 8.02-8.07 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.53-1.71 (m, 1H), 1.93-2.01 (m, 1H), 2.59-2.85 (m, 3H), 2.90-3.05 (m, 8H), 3.05- 3.25 (m, 1H), 3.35-3.48 (m, 1H), 3.71 (s, 3H), 5.15-5.27 (m, 1H), 6.72-6.82 (m, 4H), 7.48-7.62 (m, 2H), 7.84-7.88 (m, 2H), 7.92-7.97 (m, 1H), 8.02-8.07 (m, 1H), 8.59 (s, 1H).
<< 실시예Example 15> 3-(4-(2- 15> 3- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-1-) Piperazin-1-yl) piperidin-3-yl-1- 나프토에이트의Naphthoate 제조 Produce
단계 1Step 1
실시예 4의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as step 1 of Example 4.
단계 2Step 2
1-나프토산 염화물을 사용한 것을 제외하고는 실시예 4의 단계 2와 동일한 방법으로 수행하여 목적 화합물을 수득하였다(수율: 44%).The desired compound was obtained in the same manner as Step 2 of Example 4, except that 1-naphthoic acid chloride was used (yield: 44%).
1H NMR(CDCl3, 300 MHz): δ1.45 (s, 9H), 1.62-1.78 (m, 1H), 1.92-2.04 (m, 1H), 2.65-2.80 (m, 3H), 2.85-3.05 (m, 7H), 3.10-3.25 (m,1H), 3.80 (s, 3H), 3.95-4.05 (m, 1H), 4.15-4.40 (m, 1H), 5.19-5.25 (m, 1H), 6.79-6.87 (m, 3H), 6.91-6.97 (m, 1H), 7.51-7.62 (m, 2H), 7.86-7.89 ( m, 2H), 7.94 (m, 1H), 8.04-8.07 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.45 (s, 9H), 1.62-1.78 (m, 1H), 1.92-2.04 (m, 1H), 2.65-2.80 (m, 3H), 2.85-3.05 (m, 7H), 3.10-3.25 (m, 1H), 3.80 (s, 3H), 3.95-4.05 (m, 1H), 4.15-4.40 (m, 1H), 5.19-5.25 (m, 1H), 6.79 -6.87 (m, 3H), 6.91-6.97 (m, 1H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.94 (m, 1H), 8.04-8.07 (m, 1H) , 8.59 (s, 1 H).
단계 3Step 3
실시예 4의 단계 3과 동일한 방법을 수행하여 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-3-일-1-나프토에이트를 수득하였다(수율: 99%).The same procedure as in Step 3 of Example 4 was followed to obtain 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-3-yl-1-naphthoate (yield: 99%).
11H NMR(CDCl3, 300 MHz): δ 1.75-1.95 (m, 1H), 2.00-2.25 (m, 1H), 2.65-2.82 (m, 3H), 2.85-3.10 (m, 8H), 3.20-3.35 (m, 1H), 3.52-3.57 (m, 1H), 3.81 (s, 3H), 5.33-5.44 (m, 1H), 6.79-6.89 (m, 3H), 6.91-6.98 (m,1H), 7.48-7.59 (m, 2H), 7.82-7.86 (m, 2H), 7.93-7.96 (m, 1H), 8.05-8.09 (m, 1H), 8.65 (s, 1H). 11 H NMR (CDCl 3 , 300 MHz): δ 1.75-1.95 (m, 1H), 2.00-2.25 (m, 1H), 2.65-2.82 (m, 3H), 2.85-3.10 (m, 8H), 3.20- 3.35 (m, 1H), 3.52-3.57 (m, 1H), 3.81 (s, 3H), 5.33-5.44 (m, 1H), 6.79-6.89 (m, 3H), 6.91-6.98 (m, 1H), 7.48-7.59 (m, 2H), 7.82-7.86 (m, 2H), 7.93-7.96 (m, 1H), 8.05-8.09 (m, 1H), 8.65 (s, 1H).
<< 실시예Example 16> 3-(4-(4- 16> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실레이트의 제조Preparation of 3-carboxylate
단계 1Step 1
실시예 12의 단계 1과 동일한 방법으로 수행하였다.It carried out in the same manner as Step 1 of Example 12.
단계 2Step 2
1-나프토산 염화물 대신 바이페닐-3-카르복실산 염화물을 사용한 것을 제외하고는 실시예 12의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 52%).The target compound was obtained in the same manner as Step 2 of Example 12, except that biphenyl-3-carboxylic acid chloride was used instead of 1-naphthoic acid chloride (yield: 52%).
1H NMR(CDCl3, 200 MHz): δ1.49 (s, 9H), 1.55-1.77 (m, 1H), 1.91--2.00 (m, 1H), 2.60-2.80 (m, 3H), 2.88-3.15 (m, 8H), 3.95-4.11 (m, 1H), 4.15-4.30 (m, 1H), 5.13-5.24 (m, 1H), 6.77-6.96 (m, 4H), 7.35-7.51 (m, 3H), 7.58-7.67 (m, 4H), 8.06-8.12 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.49 (s, 9H), 1.55-1.77 (m, 1H), 1.91--2.00 (m, 1H), 2.60-2.80 (m, 3H), 2.88- 3.15 (m, 8H), 3.95-4.11 (m, 1H), 4.15-4.30 (m, 1H), 5.13-5.24 (m, 1H), 6.77-6.96 (m, 4H), 7.35-7.51 (m, 3H ), 7.58-7.67 (m, 4 H), 8.06-8.12 (m, 2 H).
단계 3Step 3
실시예 12의 단계 3과 동일한 방법을 수행하여 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 수득하였다(수율: 97%).The same procedure as in Step 3 of Example 12 was conducted to obtain 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate. (Yield 97%).
1H NMR(CDCl3, 300 MHz): δ 1.55-1.75 (m, 1H), 1.85--2.10 (m, 1H), 2.15-2.45 (m, 2H), 2.55-2.80 (m, 4H), 2.89-2.99 (m, 5H), 3.10-3.20 (m, 1H), 3.30-3.55 (m, 1H), 5.15-5.21 (m, 1H), 6.76-6.82 (m, 2H), 6.86-6.94 (m, 2H), 7.35-7.48 (m, 3H), 7.58-7.66 (m, 4H), 8.08-8.11 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.55-1.75 (m, 1H), 1.85--2.10 (m, 1H), 2.15-2.45 (m, 2H), 2.55-2.80 (m, 4H), 2.89 -2.99 (m, 5H), 3.10-3.20 (m, 1H), 3.30-3.55 (m, 1H), 5.15-5.21 (m, 1H), 6.76-6.82 (m, 2H), 6.86-6.94 (m, 2H), 7.35-7.48 (m, 3H), 7.58-7.66 (m, 4H), 8.08-8.11 (m, 2H).
<< 실시예Example 17> 3-(4-(3- 17> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실레이트의 제조Preparation of 3-carboxylate
단계 1Step 1
실시예 13의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as Step 1 of Example 13.
단계 2Step 2
1-나프토산 염화물 대신 바이페닐-3-카르복실산 염화물을 사용한 것을 제외하고는 실시예 13의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 48%).Except for using biphenyl-3-carboxylic acid chloride instead of 1- naphthoic acid chloride was carried out in the same manner as in Step 2 of Example 13 to obtain the target compound (yield: 48%).
1H NMR(CDCl3, 200 MHz): δ1.46 (s, 9H), 1.55-1.77 (m, 1H), 1.85-1.97 (m, 1H), 2.60-2.78 (m, 3H), 2.80-2.95 (m, 2H), 2.99-3.08 (m, 6H), 3.95-4.10 (m, 1H), 4.15-4.35 (m, 1H), 5.12-5.23 (m, 1H), 6.65-6.81 (m, 3H), 7.11 (t, J =8.2 Hz, 1H), 7.38-7.51 (m, 3H), 7.58-7.67 (m, 4H), 8.02-8.12 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.46 (s, 9H), 1.55-1.77 (m, 1H), 1.85-1.97 (m, 1H), 2.60-2.78 (m, 3H), 2.80-2.95 (m, 2H), 2.99-3.08 (m, 6H), 3.95-4.10 (m, 1H), 4.15-4.35 (m, 1H), 5.12-5.23 (m, 1H), 6.65-6.81 (m, 3H) , 7.11 (t, J = 8.2 Hz, 1H), 7.38-7.51 (m, 3H), 7.58-7.67 (m, 4H), 8.02-8.12 (m, 2H).
단계 3Step 3
실시예 13의 단계 3과 동일한 방법을 수행하여 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 수득하였다(수율: 99%).Example 13 steps 3 and performing the same method of 3 - (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate was obtained ( Yield: 99%).
1H NMR(CDCl3, 200 MHz): δ 1.65-1.90 (m, 1H), 1.95-2.15 (m, 1H), 2.63-2.77 (m, 3H), 2.80-2.92 (m, 3H), 3.00-3.09 (m, 4H), 3.15-3.35 (m, 1H), 3.45-3.60 (m, 1H), 4.65-4.90 (m, 1H), 5.25-5.40 (m, 1H), 6.77-6.81 (m, 3H), 7.11 (t, J =8.2 Hz, 1H), 7.37-7.50 (m, 3H), 7.56-7.67 (m, 4H), 8.10 (d, J=8.6 Hz, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.65-1.90 (m, 1H), 1.95-2.15 (m, 1H), 2.63-2.77 (m, 3H), 2.80-2.92 (m, 3H), 3.00- 3.09 (m, 4H), 3.15-3.35 (m, 1H), 3.45-3.60 (m, 1H), 4.65-4.90 (m, 1H), 5.25-5.40 (m, 1H), 6.77-6.81 (m, 3H ), 7.11 (t, J = 8.2 Hz, 1H), 7.37-7.50 (m, 3H), 7.56-7.67 (m, 4H), 8.10 (d, J = 8.6 Hz , 2H).
<< 실시예Example 18> 3-(4-(4- 18> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3--3- 카르복실레이트의Carboxylate 제조 Produce
단계 1Step 1
실시예 14의 단계 1과 동일한 방법으로 수행하였다.It carried out in the same manner as Step 1 of Example 14.
단계 2Step 2
1-나프토산 염화물 대신 바이페닐-3-카르복실산 염화물을 사용한 것을 제외하고는 실시예 14의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 27%).Except for using biphenyl-3-carboxylic acid chloride instead of 1- naphthoic acid chloride was carried out in the same manner as in Step 2 of Example 14 to obtain the target compound (yield: 27%).
1H NMR(CDCl3, 300 MHz): δ1.45 (s, 9H), 1.60-1.75 (m, 1H), 1.85-1.97 (m, 1H), 2.62-2.76 (m, 3H), 2.85-3.97 (m, 8H), 3.74 (s, 3H), 3.95-4.06 (m, 1H), 4.18-4.35 (m, 1H), 5.14-5.22 (m, 1H), 6.77-6.85 (m, 4H), 7.37-7.49 (m, 3H), 7.61-7.66 (m, 4H), 8.08 (d, J=8.3 Hz, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.45 (s, 9H), 1.60-1.75 (m, 1H), 1.85-1.97 (m, 1H), 2.62-2.76 (m, 3H), 2.85-3.97 (m, 8H), 3.74 (s, 3H), 3.95-4.06 (m, 1H), 4.18-4.35 (m, 1H), 5.14-5.22 (m, 1H), 6.77-6.85 (m, 4H), 7.37 -7.49 (m, 3H), 7.61-7.66 (m, 4H), 8.08 (d, J = 8.3 Hz , 2H).
단계 3Step 3
실시예 14의 단계 3과 동일한 방법을 수행하여 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 수득하였다(수율: 66%).The same procedure as in Step 3 of Example 14 was followed to obtain 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate. (Yield 66%).
1H NMR(CDCl3, 200 MHz): δ 1.57-1.70 (m, 1H), 1.90-2.00 (m, 1H), 2.58- 2.82 (m, 5H), 2.90-3.00 (m, 6H), 3.10-3.20 (m, 1H), 3.36-3.44 (m, 1H), 3.73 (s, 3H), 5.09-5.22 (m, 1H), 6.75-6.85 (m, 4H), 7.34-7.51 (m, 3H), 7.59-7.66 (m, 4H), 8.07-8.11 (dd, J=6.4 Hz & 2 Hz, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.57-1.70 (m, 1H), 1.90-2.00 (m, 1H), 2.58-2.82 (m, 5H), 2.90-3.00 (m, 6H), 3.10- 3.20 (m, 1H), 3.36-3.44 (m, 1H), 3.73 (s, 3H), 5.09-5.22 (m, 1H), 6.75-6.85 (m, 4H), 7.34-7.51 (m, 3H), 7.59-7.66 (m, 4H), 8.07-8.11 (dd, J = 6.4 Hz & 2 Hz , 2H).
<< 실시예Example 19> 3-(4-(2- 19> 3- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
단계 1Step 1
실시예 15의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as Step 1 of Example 15.
단계 2Step 2
1-나프토산 염화물 대신 바이페닐-3-카르복실산 염화물을 사용한 것을 제외하고는 실시예 15의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 40%).Except for using biphenyl-3-carboxylic acid chloride instead of 1- naphthoic acid chloride was carried out in the same manner as in Step 2 of Example 15 to obtain the target compound (yield: 40%).
1H NMR(CDCl3, 300 MHz): δ1.45 (s, 9H), 1.63-1.79 (m, 1H), 1.90-2.00 (m, 1H), 2.60-2.74 (m, 3H), 2.85-3.05 (m, 7H), 3.06-3.20 (m, 1H), 3.82 (s, 3H), 3.95-4.03 (m, 1H), 4.17-4.30 (m, 1H), 5.15-5.22 (m, 1H), 6.80-6.90 (m, 3H), 6.91-6.98 (m,1H), 7.36-7.50 (m, 3H), 7.60-7.67 (m, 4H), 8.08-8.11 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.45 (s, 9H), 1.63-1.79 (m, 1H), 1.90-2.00 (m, 1H), 2.60-2.74 (m, 3H), 2.85-3.05 (m, 7H), 3.06-3.20 (m, 1H), 3.82 (s, 3H), 3.95-4.03 (m, 1H), 4.17-4.30 (m, 1H), 5.15-5.22 (m, 1H), 6.80 -6.90 (m, 3H), 6.91-6.98 (m, 1H), 7.36-7.50 (m, 3H), 7.60-7.67 (m, 4H), 8.08-8.11 (m, 2H).
단계 3Step 3
실시예 15의 단계 3과 동일한 방법을 수행하여 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 수득하였다(수율: 99%).The same procedure as in Step 3 of Example 15 was followed to obtain 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate. (Yield 99%).
1H NMR(CDCl3, 300 MHz): δ 1.72-1.96 (m, 1H), 2.00-2.22 (m, 1H), 2.64-2.80 (m, 3H), 2.82-3.08 (m, 8H), 3.36-3.60 (m, 2H), 3.28-3.36 (m, 1H), 3.48-3.64 (m, 1H), 3.82 (s, 3H), 5.30-5.42 (m, 1H), 6.80-6.89 (m, 3H), 6.90-7.01 (m,1H), 7.34-7.49 (m, 3H), 7.57-7.66 (m, 4H), 8.12-8.16 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.72-1.96 (m, 1H), 2.00-2.22 (m, 1H), 2.64-2.80 (m, 3H), 2.82-3.08 (m, 8H), 3.36- 3.60 (m, 2H), 3.28-3.36 (m, 1H), 3.48-3.64 (m, 1H), 3.82 (s, 3H), 5.30-5.42 (m, 1H), 6.80-6.89 (m, 3H), 6.90-7.01 (m, 1H), 7.34-7.49 (m, 3H), 7.57-7.66 (m, 4H), 8.12-8.16 (m, 2H).
<< 실시예Example 20> 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트의 제조 20> Preparation of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate
단계 1Step 1
실시예 12의 단계 1과 동일한 방법으로 수행하였다.It carried out in the same manner as Step 1 of Example 12.
단계 2Step 2
1-나프토산 염화물 대신 4-페녹시벤조산 염화물을 사용한 것을 제외하고는 실시예 12의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 46%).The desired compound was obtained in the same manner as Step 2 of Example 12, except that 4-phenoxybenzoic acid chloride was used instead of 1-naphthoic acid chloride (yield: 46%).
1H NMR(CDCl3, 200 MHz): δ1.45 (s, 9H), 1.60-1.75 (m, 1H), 1.80--2.00 (m, 1H), 2.55-2.75 (m, 3H), 2.80-3.15 (m, 8H), 3.95-4.10 (m, 1H), 4.15-4.30 (m, 1H), 5.05-5.20 (m, 1H), 6.77-7..07 (m, 8H), 7.15-7.26 (m, 1H), 7.35-7.42 (t, J=7.8 Hz, 2H), 7.98 (d, J=8.6 Hz, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.45 (s, 9H), 1.60-1.75 (m, 1H), 1.80--2.00 (m, 1H), 2.55-2.75 (m, 3H), 2.80- 3.15 (m, 8H), 3.95-4.10 (m, 1H), 4.15-4.30 (m, 1H), 5.05-5.20 (m, 1H), 6.77-7..07 (m, 8H), 7.15-7.26 ( m, 1H), 7.35-7.42 (t, J = 7.8 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H).
단계 3Step 3
실시예 12의 단계 3과 동일한 방법을 수행하여 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 수득하였다(수율: 98%).The same procedure as in Step 3 of Example 12 was carried out to yield 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield) : 98%).
1H NMR(CDCl3, 200 MHz): δ 1.68-1.90 (m, 1H), 1.95--2.10 (m, 1H), 2.60-2.75 (m, 3H), 2.80-2.90 (m, 2H), 2.95-3.10 (m, 6H), 3.15-3.30 (m, 1H), 3.45-3.54 (m, 1H), 5.22-5.33 (m, 1H), 6.77-6.86 (m, 4H), 6.88-7.08 (m, 4H), 7.14-7.22 (m, 1H), 7.31-7.43 (m, 2H), 7.98-8.05 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.68-1.90 (m, 1H), 1.95--2.10 (m, 1H), 2.60-2.75 (m, 3H), 2.80-2.90 (m, 2H), 2.95 -3.10 (m, 6H), 3.15-3.30 (m, 1H), 3.45-3.54 (m, 1H), 5.22-5.33 (m, 1H), 6.77-6.86 (m, 4H), 6.88-7.08 (m, 4H), 7.14-7.22 (m, 1H), 7.31-7.43 (m, 2H), 7.98-8.05 (m, 2H).
<< 실시예Example 21> 3-(4-(3- 21> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-4-일-4-) Piperazin-1-yl) piperidin-4-yl-4- 페녹시벤조에이트Phenoxybenzoate 의 제조Manufacture
단계 1Step 1
실시예 13의 단계 1과 동일한 방법으로 수행하였다.It was carried out in the same manner as Step 1 of Example 13.
단계 2Step 2
1-나프토산 염화물 대신 4-페녹시벤조산 염화물을 사용한 것을 제외하고는 실시예 13의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 33%).A target compound was obtained in the same manner as Step 2 of Example 13, except that 4-phenoxybenzoic acid chloride was used instead of 1-naphthoic acid chloride (yield: 33%).
1H NMR(CDCl3, 200 MHz): δ1.45 (s, 9H), 1.63-1.70 (m, 1H), 1.85-1.95 (m, 1H), 2.58-2.74 (m, 3H), 2.84-2.96 (m, 2H), 3.02-3.08 (m, 6H), 3.90-4.07 (m, 1H), 4.15-4.30 (m, 1H), 5.11-5.20 (m, 1H), 6.71-6.81 (m, 3H), 6.94-7.00 (m, 2H), 7.04-7.22 (m, 4H), 7.35-7.42 (m, 2H), 7.96-8.05 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.45 (s, 9H), 1.63-1.70 (m, 1H), 1.85-1.95 (m, 1H), 2.58-2.74 (m, 3H), 2.84-2.96 (m, 2H), 3.02-3.08 (m, 6H), 3.90-4.07 (m, 1H), 4.15-4.30 (m, 1H), 5.11-5.20 (m, 1H), 6.71-6.81 (m, 3H) , 6.94-7.00 (m, 2H), 7.04-7.22 (m, 4H), 7.35-7.42 (m, 2H), 7.96-8.05 (m, 2H).
단계 3Step 3
실시예 13의 단계 3과 동일한 방법을 수행하여 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 수득하였다(수율: 63%).The same procedure as in Step 3 of Example 13 was followed to obtain 3- (4- (3-chlorophenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield: 63%).
1H NMR(CDCl3, 300 MHz): δ 1.50-1.70 (m, 1H), 1.85-2.02 (m, 1H), 2.56-2.78 (m, 6H), 2.84-2.96 (m,2H), 3.00-3.08 (m, 3H), 3.10-3.20 (m, 1H), 3.35-3.45 (m, 1H), 5.05-5.20 (m, 1H), 6.69-6.81 (m, 3H), 6.95-7.01 (m, 2H), 7.04-7.20 (m, 4H), 7.38 (t, J=8.1 Hz, 2H), 7.96-8.00 (dd, J=8.7 Hz & 1.7 Hz, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.50-1.70 (m, 1H), 1.85-2.02 (m, 1H), 2.56-2.78 (m, 6H), 2.84-2.96 (m, 2H), 3.00- 3.08 (m, 3H), 3.10-3.20 (m, 1H), 3.35-3.45 (m, 1H), 5.05-5.20 (m, 1H), 6.69-6.81 (m, 3H), 6.95-7.01 (m, 2H ), 7.04-7.20 (m, 4H), 7.38 (t, J = 8.1 Hz, 2H), 7.96-8.00 (dd, J = 8.7 Hz & 1.7 Hz, 2H).
<< 실시예Example 22> 3-(4-(4- 22> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-4-) Piperazin-1-yl) piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
단계 1Step 1
실시예 14의 단계 1과 동일한 방법으로 수행하였다.It carried out in the same manner as Step 1 of Example 14.
단계 2Step 2
1-나프토산 염화물 대신 4-페녹시벤조산 염화물 염화물을 사용한 것을 제외하고는 실시예 14의 단계 2와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 33%).The desired compound was obtained in the same manner as Step 2 of Example 14, except that 4-phenoxybenzoic acid chloride was used instead of 1-naphthoic acid chloride (yield: 33%).
1H NMR(CDCl3, 200 MHz): δ1.45 (s, 9H), 1.55-1.80 (m, 1H), 1.85--2.04 (m, 1H), 2.64-2.75 (m, 3H), 2.86-3.96 (m, 8H), 3.74 (s, 3H), 3.98-4.05 (m, 1H), 4.17-4.20 (m, 1H), 5.08-5.17 (m, 1H), 6.77-6.94 (m, 4H), 6.95-7.08 (m, 4H), 7.14-7.22 (m, 1H), 7.33-7.42 (m, 2H), 7.93-8.00 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.45 (s, 9H), 1.55-1.80 (m, 1H), 1.85--2.04 (m, 1H), 2.64-2.75 (m, 3H), 2.86- 3.96 (m, 8H), 3.74 (s, 3H), 3.98-4.05 (m, 1H), 4.17-4.20 (m, 1H), 5.08-5.17 (m, 1H), 6.77-6.94 (m, 4H), 6.95-7.08 (m, 4H), 7.14-7.22 (m, 1H), 7.33-7.42 (m, 2H), 7.93-8.00 (m, 2H).
단계 3Step 3
실시예 14의 단계 3과 동일한 방법을 수행하여 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 수득하였다(수율: 98%).The same procedure as in Step 3 of Example 14 was followed to obtain 3- (4- (4-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield) : 98%).
1H NMR(CDCl3, 200 MHz): δ 1.55-1.75 (m, 1H), 1.90-2.05 (m, 1H), 2.30-2.50 (m, 2H), 2.60-2.80 (m, 4H), 2.84-3.00 (m, 5H), 3.05-3.20 (m, 1H), 3.35-3.45 m, 1H), 3.74 (s, 3H), 5.08-5.20 (m, 1H), 6.76-6.86 (m, 4H), 6.94-7.08 (m, 4H), 7.14-7.22 (m, 1H), 7.31-7.42 (m, 2H), 7.96-8.03 (m, 2H). 1 H NMR (CDCl 3 , 200 MHz): δ 1.55-1.75 (m, 1H), 1.90-2.05 (m, 1H), 2.30-2.50 (m, 2H), 2.60-2.80 (m, 4H), 2.84- 3.00 (m, 5H), 3.05-3.20 (m, 1H), 3.35-3.45 m, 1H), 3.74 (s, 3H), 5.08-5.20 (m, 1H), 6.76-6.86 (m, 4H), 6.94 -7.08 (m, 4H), 7.14-7.22 (m, 1H), 7.31-7.42 (m, 2H), 7.96-8.03 (m, 2H).
<< 실시예Example 23> 4-(4-(4- 23> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-2-Piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
실시예 1에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트(48 mg, 0.11 mmol)와 트리에틸아민(0.04 mL, 0.29 mmol)을 디클로로메탄(1.5 mL)에 용해시켰다. 공지의 방법[Nowich, J. S. et al, J. Org . Chem , 1992, 57, 7364-7366]으로 페닐알라닌 메틸에스테르로부터 제조한 (S)-메틸 2-이소시아네이토페닐프로판오에이트(0.13 mmol)를 상기 반응물에 넣고 상온에서 3시간 동안 교반시켰다. 반응물을 에틸 아세테이트(10 mL)로 희석시키고 물로 세척한 후 Na2SO4로 유기층의 수분을 제거하였다. 이후 감압하에서 유기 용매를 제거하고, 칼럼크로마토그래피(에틸아세테이트:헥산 = 2:3)로 정제하여 목적화합물을 수득하였다(수율: 93%)4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate (48 mg, 0.11 mmol) and triethylamine prepared in Example 1 ( 0.04 mL, 0.29 mmol) was dissolved in dichloromethane (1.5 mL). Known methods [Nowich, JS et al, J. Org . Chem , 1992, 57, 7364-7366] (S) -methyl 2-isocyanatophenylpropanoate (0.13 mmol) prepared from phenylalanine methylester was added to the reaction and stirred at room temperature for 3 hours. Dilute the reaction with ethyl acetate (10 mL), wash with water and then with Na 2 SO 4 . Water in the organic layer was removed. Then, the organic solvent was removed under reduced pressure, and purified by column chromatography (ethyl acetate: hexane = 2: 3) to obtain the target compound (yield: 93%).
1H NMR(CDCl3, 300 MHz): δ 1.68-1.85 (m, 2H), 2.17-2.25 (m, 2H), 2.68-2.82 (m,6H), 2.92-3.07 (m, 14H), 3.09-3.25 (m,4H), 3.75 (s, 6H), 3.80-4.05 (m,4H), 4.77-4.85 (m,2H), 4.94-4.99 (m,2H), 5.34-5.43 (m,2H), 6.72-6.79 (m, 4H), 6.84-6.92 (m,4H),7.11-7.15 (m, 4H),7.22-7.32 (m,6H), 7.52-7.62 (m, 4H),7.86-7.90 (m, 4H), 7.91-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.68-1.85 (m, 2H), 2.17-2.25 (m, 2H), 2.68-2.82 (m, 6H), 2.92-3.07 (m, 14H), 3.09- 3.25 (m, 4H), 3.75 (s, 6H), 3.80-4.05 (m, 4H), 4.77-4.85 (m, 2H), 4.94-4.99 (m, 2H), 5.34-5.43 (m, 2H), 6.72-6.79 (m, 4H), 6.84-6.92 (m, 4H), 7.71-7.15 (m, 4H), 7.22-7.32 (m, 6H), 7.52-7.62 (m, 4H), 7.86-7.90 (m , 4H), 7.91-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H).
<< 실시예Example 24> 4-(4-(4- 24> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2-일 -2 days 카바모Cabamo 일)피페리딘-3-일-2-I) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 3에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 82%).4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 23 to obtain the target compound (yield: 82%).
1H NMR(CDCl3, 300 MHz): δ1.65-1.83 (m, 2H), 2.16-2.25 (m, 2H), 2.65-2.85 (m,6H), 2.90-3.04 (m, 14H), 3.06-3.21 (m,4H), 3.74 (s, 6H), 3.75 (s, 6H), 3.77-4.05 (m,4H), 4.75-4.85 (m,2H), 4.94-4.97 (m,2H), 5.34-5.41 (m,2H), 6.74-6.85 (m, 8H), 7.12-7.18 (m, 4H), 7.22-7.35 (m,6H), 7.51-7.62 (m, 4H),7.86-7.89 (m, 4H), 7.91-7.96 (m, 2H), 8.02-8.06 (m, 2H), 8.58 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.65-1.83 (m, 2H), 2.16-2.25 (m, 2H), 2.65-2.85 (m, 6H), 2.90-3.04 (m, 14H), 3.06 -3.21 (m, 4H), 3.74 (s, 6H), 3.75 (s, 6H), 3.77-4.05 (m, 4H), 4.75-4.85 (m, 2H), 4.94-4.97 (m, 2H), 5.34 -5.41 (m, 2H), 6.74-6.85 (m, 8H), 7.12-7.18 (m, 4H), 7.22-7.35 (m, 6H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.91-7.96 (m, 2H), 8.02-8.06 (m, 2H), 8.58 (s, 2H).
<< 실시예Example 25> 4-(4-(3- 25> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-2-Piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 2에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 95%).4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 23, the target compound was obtained (yield: 95%).
1H NMR(CDCl3, 300 MHz): δ1.69-1.85 (m, 2H), 2.15-2.25 (m, 2H), 2.65- 2.85 (m,4H), 2.90-2.98 (m, 4H), 3.01-3.10 (m, 12H), 3.15-3.23 (m,4H), 3.71 (s, 3H), 3.76 (s, 3H), 3.80-4.05 (m,4H), 4.75-4.85 (m,2H), 4.90-5.00 (m,2H), 5.30-5.45 (m,2H), 6.65-6.80 (m, 4H), 7.05-7.16 (m, 6H), 7.21-7.35 (m,8H), 7.52-7.62 (m, 4H),7.87-7.90 (m, 4H), 7.95-7.98 (m, 2H), 8.02-8.06 (m, 2H), 8.58 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.69-1.85 (m, 2H), 2.15-2.25 (m, 2H), 2.65- 2.85 (m, 4H), 2.90-2.98 (m, 4H), 3.01 -3.10 (m, 12H), 3.15-3.23 (m, 4H), 3.71 (s, 3H), 3.76 (s, 3H), 3.80-4.05 (m, 4H), 4.75-4.85 (m, 2H), 4.90 -5.00 (m, 2H), 5.30-5.45 (m, 2H), 6.65-6.80 (m, 4H), 7.05-7.16 (m, 6H), 7.21-7.35 (m, 8H), 7.52-7.62 (m, 4H), 7.87-7.90 (m, 4H), 7.95-7.98 (m, 2H), 8.02-8.06 (m, 2H), 8.58 (s, 2H).
<< 실시예Example 26> 4-(4-(4- 26> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-Piperidin-3-yl- 바이페닐Biphenyl -4-카르복실-4-carboxyl 레이트의Rate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 5에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 97%).4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 23 to obtain the target compound (yield: 97% ).
1H NMR(CDCl3, 300 MHz): δ1.60-1.80 (m, 2H), 2.15-2.20 (m, 2H), 2.66-2.80 (m,6H), 2.85-3.04 (m, 14H), 3.05-3.23 (m, 4H), 3.75 (s, 6H), 3.80-4.02 (m,4H), 4.75-4.85 (m,2H), 4.95-5.00 (m,2H), 5.30-5.40 (m,2H), 6.75-6.83 (m, 4H), 6.85-6.95 (m, 24H), 7.08-7.20 (m, 4H), 7.21-7.31 (m,6H), 7.34-7.54 (m, 6H), 7.59-7.72 (m, 8H), 8.08 (d, J= 8.5 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.60-1.80 (m, 2H), 2.15-2.20 (m, 2H), 2.66-2.80 (m, 6H), 2.85-3.04 (m, 14H), 3.05 -3.23 (m, 4H), 3.75 (s, 6H), 3.80-4.02 (m, 4H), 4.75-4.85 (m, 2H), 4.95-5.00 (m, 2H), 5.30-5.40 (m, 2H) , 6.75-6.83 (m, 4H), 6.85-6.95 (m, 24H), 7.08-7.20 (m, 4H), 7.21-7.31 (m, 6H), 7.34-7.54 (m, 6H), 7.59-7.72 ( m, 8H), 8.08 (d, J = 8.5 Hz, 4H).
<< 실시예Example 27> 4-(4-(4- 27> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2-일 -2 days 카바모Cabamo 일)피페리딘-3-일-1) piperidin-3-yl- 바이페닐Biphenyl -4-카르복실-4-carboxyl 레이트의Rate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 7에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 69%).4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 23 to obtain the target compound (yield: 69%).
1H NMR(CDCl3, 300 MHz): δ 1.60-1.80(m, 2H), 2.10-2.20 (m, 2H), 2.64-2.80 (m,6H), 2.85-3.00 (m, 14H), 3.05-3.22 (m, 4H), 3.73 (s, 6H), 3.75 (s, 6H), 3.80-4.05 (m,4H), 4.75-4.85 (m,2H), 4.95-5.05 (m,2H), 5.30-5.40 (m,2H), 6.75-6.85 (m, 8H), 7.08-7.20 (m, 4H), 7.25-7.34 (m,6H), 7.36-7.51 (m, 6H), 7.60-7.67 (m, 8H), 8.09 (d, J= 8.4 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.60-1.80 (m, 2H), 2.10-2.20 (m, 2H), 2.64-2.80 (m, 6H), 2.85-3.00 (m, 14H), 3.05- 3.22 (m, 4H), 3.73 (s, 6H), 3.75 (s, 6H), 3.80-4.05 (m, 4H), 4.75-4.85 (m, 2H), 4.95-5.05 (m, 2H), 5.30- 5.40 (m, 2H), 6.75-6.85 (m, 8H), 7.08-7.20 (m, 4H), 7.25-7.34 (m, 6H), 7.36-7.51 (m, 6H), 7.60-7.67 (m, 8H ), 8.09 (d, J = 8.4 Hz, 4H).
<< 실시예Example 28> 4-(4-(3- 28> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-1) piperidin-3-yl- 바이페닐Biphenyl -4-카르복실-4-carboxyl 레이트의Rate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 6에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 35%).4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 23 to obtain the target compound (yield: 35%).
1H NMR(CDCl3, 300 MHz): δ1.60-1.80 (m, 2H), 2.14-2.25 (m, 2H), 2.64- 2.79 (m,6H), 2.85-3.00 (m, 4H), 3.02-3.10 (m, 10H), 3.13-3.23 (m, 4H), 3.76 (s, 6H), 3.78-4.14 (m,4H), 4.76-4.84 (m,2H), 4.91-4.97 (m,2H), 5.30-5.38 (m,2H), 6.69-6.82 (m, 6H), 7.08-7.19 (m, 6H), 7.23-7.32 (m,6H), 7.34-7.50 (m, 6H), 7.61-7.71 (m, 8H), 8.09 (d, J= 8.6 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.60-1.80 (m, 2H), 2.14-2.25 (m, 2H), 2.64- 2.79 (m, 6H), 2.85-3.00 (m, 4H), 3.02 -3.10 (m, 10H), 3.13-3.23 (m, 4H), 3.76 (s, 6H), 3.78-4.14 (m, 4H), 4.76-4.84 (m, 2H), 4.91-4.97 (m, 2H) , 5.30-5.38 (m, 2H), 6.69-6.82 (m, 6H), 7.08-7.19 (m, 6H), 7.23-7.32 (m, 6H), 7.34-7.50 (m, 6H), 7.61-7.71 ( m, 8H), 8.09 (d, J = 8.6 Hz, 4H).
<< 실시예Example 29> 4-(4-(4- 29> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-4-Piperidin-3-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 9에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 76%).4- (4- (4-fluorophenyl) prepared in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 23 to obtain the target compound (yield: 76%).
1H NMR(CDCl3, 300 MHz): δ 1.50-1.74 (m, 2H), 2.06-2.20 (m, 2H), 2.60-2.75 (m,6H), 2.84-3.04 (m, 14H), 3.05-3.24 (m, 4H), 3.74 (s, 6H), 3.75-4.00 (m,4H), 4.75-4.85 (m,2H), 4.93-5.00 (m,2H), 5.25-5.35 (m,2H), 6.75-6.82 (m, 4H), 6.87-7.01 (m, 8H), 7.03-7.09 (m, 4H), 7.11-7.23 (m,6H), 7.24-7.36 (m, 6H), 7.38-7.42 (m, 4H), 7.95 -8.01 (m,4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.50-1.74 (m, 2H), 2.06-2.20 (m, 2H), 2.60-2.75 (m, 6H), 2.84-3.04 (m, 14H), 3.05- 3.24 (m, 4H), 3.74 (s, 6H), 3.75-4.00 (m, 4H), 4.75-4.85 (m, 2H), 4.93-5.00 (m, 2H), 5.25-5.35 (m, 2H), 6.75-6.82 (m, 4H), 6.87-7.01 (m, 8H), 7.03-7.09 (m, 4H), 7.11-7.23 (m, 6H), 7.24-7.36 (m, 6H), 7.38-7.42 (m , 4H), 7.95 -8.01 (m, 4H).
<< 실시예Example 30> 4-(4-(4- 30> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of 2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 11에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 68%).4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 23 to obtain the target compound (yield: 68%).
1H NMR(CDCl3, 300 MHz): δ1.55-1.72 (m, 2H), 2.10-2.20 (m, 2H), 2.60-2.80 (m,6H), 2.85-3.01 (m, 14H), 3.04-3.25 (m, 4H), 3.70 (s, 6H), 3.74 (s, 6H), 3.76-4.00 (m,4H), 4.75-4.85 (m,2H), 4.93-5.00 (m,2H), 5.25-5.35 (m,2H), 6.77-6.85 (m, 8H), 6.95-7.02 (m, 4H), 7.04-7.19 (m,8H), 7.20-7.33 (m, 8H), 7.36-7.41 (m, 4H), 7.95-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.55-1.72 (m, 2H), 2.10-2.20 (m, 2H), 2.60-2.80 (m, 6H), 2.85-3.01 (m, 14H), 3.04 -3.25 (m, 4H), 3.70 (s, 6H), 3.74 (s, 6H), 3.76-4.00 (m, 4H), 4.75-4.85 (m, 2H), 4.93-5.00 (m, 2H), 5.25 -5.35 (m, 2H), 6.77-6.85 (m, 8H), 6.95-7.02 (m, 4H), 7.04-7.19 (m, 8H), 7.20-7.33 (m, 8H), 7.36-7.41 (m, 4H), 7.95-8.01 (m, 4H).
<< 실시예Example 31> 4-(4-(3- 31> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-4-1) piperidin-3-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 10에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 97%).4- (4- (3-chlorophenyl) obtained in Example 10 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 23 to obtain the target compound (yield: 97%).
1H NMR(CDCl3, 300 MHz): δ 1.55-1.75 (m, 2H), 2.10-2.20 (m, 2H), 2.60-2.75 (m,6H), 2.84-2.96 (m, 4H), 2.98-3.10 (m, 10H), 3.11-3.23 (m, 4H), 3.70 (s, 3H), 3.74 (s, 3H), 3.76-4.00 (m,4H), 4.73-4.83 (m, 2H), 4.90-4.96 (m,2H), 5.23-5.33 (m,2H), 6.67-6.81 (m, 6H), 6.95-7.02 (m, 4H), 7.04-7.35 (m,18H), 7.36-7.42 (m, 4H), 7.95-8.00 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.55-1.75 (m, 2H), 2.10-2.20 (m, 2H), 2.60-2.75 (m, 6H), 2.84-2.96 (m, 4H), 2.98- 3.10 (m, 10H), 3.11-3.23 (m, 4H), 3.70 (s, 3H), 3.74 (s, 3H), 3.76-4.00 (m, 4H), 4.73-4.83 (m, 2H), 4.90- 4.96 (m, 2H), 5.23-5.33 (m, 2H), 6.67-6.81 (m, 6H), 6.95-7.02 (m, 4H), 7.04-7.35 (m, 18H), 7.36-7.42 (m, 4H ), 7.95-8.00 (m, 4H).
<< 실시예Example 32> 4-(4-(4- 32> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-2-I) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
실시예 1에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 48 mg(0.11 mmol)과 공지의 방법[Nowich, J. S. et al, J. Org . Chem, 1992, 57, 7364-7366]으로 루이신 메틸에스테르로부터 제조한 (S)-메틸 2-이소시아네이토-4-메틸펜탄오에이트(0.13 mmol)를 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 91%).48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and a known method [Nowich] , JS et al, J. Org . Example 23, except that (S) -methyl 2-isocyanato-4-methylpentaneoate (0.13 mmol) prepared from leucine methylester was reacted with Chem, 1992, 57, 7364-7366. The target compound was obtained in the same manner as in (yield: 91%).
1H NMR(CDCl3, 300 MHz): δ0.88-0.99 (m, 12H), 1.50-1.89 (m, 8H), 2.20-2.28 (m, 2H), 2.75-2.89 (m,6H), 2.90-3.14 (m, 14H), 3.76 (s, 6H), 3.85-3.95 (m,2H), 4.05-4.15 (m, 2H), 4.49-4.58 (m,2H), 4.90-4.95 (m,2H), 5.36-5.45 (m,2H), 6.74-6.80 (m, 4H), 6.84-6.91 (m,4H), 7.52-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.99 (m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.98-0.99 (m, 12H), 1.50-1.89 (m, 8H), 2.20-2.28 (m, 2H), 2.75-2.89 (m, 6H), 2.90 -3.14 (m, 14H), 3.76 (s, 6H), 3.85-3.95 (m, 2H), 4.05-4.15 (m, 2H), 4.49-4.58 (m, 2H), 4.90-4.95 (m, 2H) , 5.36-5.45 (m, 2H), 6.74-6.80 (m, 4H), 6.84-6.91 (m, 4H), 7.52-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.99 ( m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 33> 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(1-메톡시-4-메틸-1-옥 33> 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (1-methoxy-4-methyl-1-jade 소펜탄Sopentane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-2-I) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 3에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 32와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 88%).4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 32 to obtain the target compound (yield: 88%).
1H NMR(CDCl3, 300 MHz): δ 0.97 (d, J= 6.2 Hz, 12H), 1.50-1.78 (m, 8H), 2.20-2.27 (m, 2H), 2.78-2.89 (m,6H), 2.90-3.15 (m, 14H), 3.71 (s, 6H), 3.76 (s, 6H), 3.85-3.95 (m,2H), 4.04-4.15 (m, 2H), 4.49-4.58 (m,2H), 4.90-5.00 (m, 2H), 5.37-5.45 (m,2H), 6.74-6.81 (m, 8H), 7.52-7.61 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.99 (m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.97 (d, J = 6.2 Hz, 12H), 1.50-1.78 (m, 8H), 2.20-2.27 (m, 2H), 2.78-2.89 (m, 6H) , 2.90-3.15 (m, 14H), 3.71 (s, 6H), 3.76 (s, 6H), 3.85-3.95 (m, 2H), 4.04-4.15 (m, 2H), 4.49-4.58 (m, 2H) , 4.90-5.00 (m, 2H), 5.37-5.45 (m, 2H), 6.74-6.81 (m, 8H), 7.52-7.61 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.99 ( m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 34> 4-(4-(3- 34> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-2-I) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 2에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 32와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 96%).4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 32 to obtain the target compound (yield: 96%).
1H NMR(CDCl3, 300 MHz): δ 0.98 (d, J= 6.0 Hz, 12H), 1.50-1.89 (m, 8H), 2.20-2.26 (m, 2H), 2.75-2.90 (m,6H), 2.93-3.12 (m, 14H), 3.76 (s, 6H), 3.85- 3.95 (m,2H), 4.05-4.15 (m, 2H), 4.49-4.58 (m,2H), 4.90-5.00 (m, 2H), 5.35-5.45 (m,2H), 6.65-6.77 (m, 6H), 7.07 (t, J= 8.1 Hz, 2H), 7.51-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.98 (d, J = 6.0 Hz, 12H), 1.50-1.89 (m, 8H), 2.20-2.26 (m, 2H), 2.75-2.90 (m, 6H) , 2.93-3.12 (m, 14H), 3.76 (s, 6H), 3.85-3.95 (m, 2H), 4.05-4.15 (m, 2H), 4.49-4.58 (m, 2H), 4.90-5.00 (m, 2H), 5.35-5.45 (m, 2H), 6.65-6.77 (m, 6H), 7.07 (t, J = 8.1 Hz, 2H), 7.51-7.62 (m, 4H), 7.86-7.90 (m, 4H) , 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 35> 4-(4-(4- 35> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2-일카바모일)피페리딘-3-일-바이페닐-4-카르복실레이트의 제조Preparation of 2-ylcarbamoyl) piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 5에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 32와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 99%).4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 32 to obtain the target compound (yield: 99% ).
1H NMR(CDCl3, 300 MHz): δ 0.97 (d, J= 6.0 Hz, 12H), 1.50-1.80 (m, 8H), 2.19-2.35 (m, 2H), 2.74-2.90 (m, 6H), 2.93-3.12 (m, 14H), 3.75 (s, 6H), 3.85-3.95 (m,2H), 4.04-4.15 (m, 2H), 4.48-4.57 (m,2H), 4.91-4.95 (m, 2H), 5.31-5.40 (m, 2H), 6.76-6.83 (m, 4H), 6.86-6.93 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.11 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.97 (d, J = 6.0 Hz, 12H), 1.50-1.80 (m, 8H), 2.19-2.35 (m, 2H), 2.74-2.90 (m, 6H) , 2.93-3.12 (m, 14H), 3.75 (s, 6H), 3.85-3.95 (m, 2H), 4.04-4.15 (m, 2H), 4.48-4.57 (m, 2H), 4.91-4.95 (m, 2H), 5.31-5.40 (m, 2H), 6.76-6.83 (m, 4H), 6.86-6.93 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.11 (m, 4H).
<< 실시예Example 36> 4-(4-(4- 36> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-바이페닐-4-카르복실레이트의 제조I) Preparation of Piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실 시예 7에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 32와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 76%).4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 32 to obtain the target compound (yield: 76% ).
1H NMR(CDCl3, 300 MHz): δ 0.93 (d, J= 6.4 Hz, 3H), 0.94 (d, J= 6.4 Hz, 3H), 0.97 (d, J= 6.4 Hz, 6H), 1.50-1.77 (m, 8H), 2.15-2.25 (m, 2H), 2.72-2.90 (m, 6H), 2.94-3.10 (m, 14H), 3.72 (s, 3H), 3.73 (m, 3H), 3.75 (s, 6H), 3.85-3.95 (m,2H), 4.00-4.10 (m, 2H), 4.45-4.58 (m, 2H), 4.90-4.95 (m, 2H), 5.30-5.40(m, 2H), 6.76-6.84 (m, 8H), 7.35-7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.11 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.93 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.4 Hz, 6H), 1.50- 1.77 (m, 8H), 2.15-2.25 (m, 2H), 2.72-2.90 (m, 6H), 2.94-3.10 (m, 14H), 3.72 (s, 3H), 3.73 (m, 3H), 3.75 ( s, 6H), 3.85-3.95 (m, 2H), 4.00-4.10 (m, 2H), 4.45-4.58 (m, 2H), 4.90-4.95 (m, 2H), 5.30-5.40 (m, 2H), 6.76-6.84 (m, 8H), 7.35-7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.11 (m, 4H).
<< 실시예Example 37> 4-(4-(3- 37> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-바이페닐-4-카르복실레이트의 제조I) Preparation of Piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 6에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 32와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 85%).4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 32, the target compound was obtained (yield: 85%) .
1H NMR(CDCl3, 300 MHz): δ 0.93 (d, J= 6.3 Hz, 3H), 0.94 (d, J= 6.3 Hz, 3H), 0.97 (d, J= 6.3 Hz, 6H), 1.50-1.84 (m, 8H), 2.15-2.25 (m, 2H), 2.75- 2.85 (m, 6H), 2.93-3.10 (m, 14H), 3.72 s, 3H), 3.76 (s, 3H), 3.85-3.95 (m,2H), 4.00-4.10 (m, 2H), 4.45-4.60 (m, 2H), 4.94-5.00 (m, 2H), 5.31-5.39 (m, 2H), 6.68-6.80 (m, 6H), 7.10 (t, J=8.1 Hz, 2H), 7.35-7.54 (m, 6H), 7.59-7.71 (m, 8H), 8.07-8.11 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.93 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.3 Hz, 3H), 0.97 (d, J = 6.3 Hz, 6H), 1.50- 1.84 (m, 8H), 2.15-2.25 (m, 2H), 2.75-2.85 (m, 6H), 2.93-3.10 (m, 14H), 3.72 s, 3H), 3.76 (s, 3H), 3.85-3.95 (m, 2H), 4.00-4.10 (m, 2H), 4.45-4.60 (m, 2H), 4.94-5.00 (m, 2H), 5.31-5.39 (m, 2H), 6.68-6.80 (m, 6H) , 7.10 (t, J = 8.1 Hz, 2H), 7.35-7.54 (m, 6H), 7.59-7.71 (m, 8H), 8.07-8.11 (m, 4H).
<< 실시예Example 38> 4-(4-(4- 38> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of 2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 9에서 수득한 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 32와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 96%).4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 32 to obtain the target compound (yield: 96%).
1H NMR(CDCl3, 300 MHz): δ 0.96 (d, J= 6.3 Hz, 12H), 1.49-1.75 (m, 8H), 2.15-2.25 (m, 2H), 2.74-2.85 (m, 6H), 2.90-3.09 (m, 14H), 3.72 s, 3H), 3.75 (s, 3H), 3.82-3.92 (m, 2H), 3.95-4.10 (m, 2H), 4.45-4.55 (m, 2H), 4.90-4.95 (m, 2H), 5.27-5.35 (m, 2H), 6.77-6.83 (m, 4H), 6.87-6.94 (m, 4H), 6,95-7.00 (m, 4H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.41 (m, 4H), 7.96-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.96 (d, J = 6.3 Hz, 12H), 1.49-1.75 (m, 8H), 2.15-2.25 (m, 2H), 2.74-2.85 (m, 6H) , 2.90-3.09 (m, 14H), 3.72 s, 3H), 3.75 (s, 3H), 3.82-3.92 (m, 2H), 3.95-4.10 (m, 2H), 4.45-4.55 (m, 2H), 4.90-4.95 (m, 2H), 5.27-5.35 (m, 2H), 6.77-6.83 (m, 4H), 6.87-6.94 (m, 4H), 6,95-7.00 (m, 4H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.41 (m, 4H), 7.96-8.01 (m, 4H).
<< 실시예Example 39> 4-(4-(4- 39> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1-옥소펜탄- 2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of -1-oxopentan-2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 11에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 32와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 93%).4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 32 to obtain the target compound (yield: 93%).
1H NMR(CDCl3, 300 MHz): δ 0.96 (d, J= 6.4 Hz, 12H), 1.49-1.74 (m, 8H), 2.15-2.25 (m, 2H), 2.70-2.85 (m, 6H), 2.93-3.10 (m, 14H), 3.74 (s, 12H), 3.85-3.93 (m,2H), 3.95-4.06 (m, 2H), 4.45-4.58 (m, 2H), 4.89-4.93 (m, 2H), 5.27-5.35 (m, 2H), 6.77-6.85 (m, 8H), 6.95-7.02 (m, 4H), 7.03-7.08 (m, 4H), 7.15-7.22 (m, 2H), 7.35-7.41 (m, 4H), 7.96-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.96 (d, J = 6.4 Hz, 12H), 1.49-1.74 (m, 8H), 2.15-2.25 (m, 2H), 2.70-2.85 (m, 6H) , 2.93-3.10 (m, 14H), 3.74 (s, 12H), 3.85-3.93 (m, 2H), 3.95-4.06 (m, 2H), 4.45-4.58 (m, 2H), 4.89-4.93 (m, 2H), 5.27-5.35 (m, 2H), 6.77-6.85 (m, 8H), 6.95-7.02 (m, 4H), 7.03-7.08 (m, 4H), 7.15-7.22 (m, 2H), 7.35-7.41 (m, 4H), 7.96-8.01 (m, 4H).
<< 실시예Example 40> 4-(4-(3- 40> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1-옥소펜탄-2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of -1-oxopentan-2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 10에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 32와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 43%).4- (4- (3-chlorophenyl) obtained in Example 10 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 32 to obtain the target compound (yield: 43%).
1H NMR(CDCl3, 300 MHz): δ 0.96 (d, J= 6.3 Hz, 12H), 1.50-1.80 (m, 8H), 2.15-2.25 (m, 2H), 2.70-2.85 (m, 6H), 2.89-3.09 (m, 14H), 3.75 (s, 6H), 3.84-3.92 (m,2H), 3.95-4.10 (m, 2H), 4.45-4.55 (m, 2H), 4.85-4.93 (m, 2H), 5.24-5.34 (m, 2H), 6.69-6.80 (m, 6H), 6.96-00 (m, 4H), 7.05-7.22 (m, 8H), 7.36-7.42 (m, 4H), 7.95-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.96 (d, J = 6.3 Hz, 12H), 1.50-1.80 (m, 8H), 2.15-2.25 (m, 2H), 2.70-2.85 (m, 6H) , 2.89-3.09 (m, 14H), 3.75 (s, 6H), 3.84-3.92 (m, 2H), 3.95-4.10 (m, 2H), 4.45-4.55 (m, 2H), 4.85-4.93 (m, 2H), 5.24-5.34 (m, 2H), 6.69-6.80 (m, 6H), 6.96-00 (m, 4H), 7.05-7.22 (m, 8H), 7.36-7.42 (m, 4H), 7.95-8.01 (m, 4H).
<< 실시예Example 41> 4-(4-(4- 41> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-2-I) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
실시예 1에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 48 mg(0.11 mmol)과 공지의 방법[Nowich, J. S. et al, J. Org . Chem, 1992, 57, 7364-7366]으로 발린 메틸에스테르로부터 제조한 (S)-메틸 2-이소시아네이토-4-메틸부탄오에이트(0.13 mmol)를 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 97%).48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and a known method [Nowich] , JS et al, J. Org . Chem, 1992, 57, 7364-7366], except that the reaction of (S) -methyl 2-isocyanato-4-methylbutanate (0.13 mmol) prepared from methyl esters valine with The target compound was obtained in the same manner (yield: 97%).
1H NMR(CDCl3, 300 MHz): δ 0.94 (d, J= 6.9 Hz, 6H), 0.99 (d, J= 6.9 Hz, 6H), 1.78-1.87 (m, 2H), 2.13-2.29 (m, 4H), 2.75-2.89 (m,6H), 2.90-3.02 (m, 12H), 3.03-3.16 (m, 2H), 3.76 (s, 6H), 3.88-3.98 (m,2H), 4.05-4.13 (m, 2H), 4.44-4.50 (m,2H), 5.03-5.06 (m,2H), 5.35-5.45 (m,2H), 6.74-6.80 (m, 4H), 6.84-6.91 (m,4H), 7.52-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.94 (d, J = 6.9 Hz, 6H), 0.99 (d, J = 6.9 Hz, 6H), 1.78-1.87 (m, 2H), 2.13-2.29 (m , 4H), 2.75-2.89 (m, 6H), 2.90-3.02 (m, 12H), 3.03-3.16 (m, 2H), 3.76 (s, 6H), 3.88-3.98 (m, 2H), 4.05-4.13 (m, 2H), 4.44-4.50 (m, 2H), 5.03-5.06 (m, 2H), 5.35-5.45 (m, 2H), 6.74-6.80 (m, 4H), 6.84-6.91 (m, 4H) , 7.52-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 42> 4-(4-(4- 42> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-2-나프토에이트의 제조Preparation of Piperidin-3-yl-2-naphthoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 3에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 41과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 75%).4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 41 to obtain the target compound (yield: 75%).
1H NMR(CDCl3, 300 MHz): δ 0.94 (d, J= 6.9 Hz, 6H), 0.99 (d, J= 6.9 Hz, 6H), 1.75-1.90 (m, 2H), 2.13-2.29 (m, 4H), 2.75-2.89 (m,6H), 2.90-2.96 (m, 12H), 3.00-3.17 (m, 2H), 3.72 (s, 6H), 3.76 (s, 6H), 3.90-4.00 (m,2H), 4.05-4.15 (m, 2H), 4.44-4.50 (m,2H), 5.02-5.06 (m, 2H), 5.36-5.44 (m, 2H), 6.74-6.82 (m, 8H), 7.52-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.94 (d, J = 6.9 Hz, 6H), 0.99 (d, J = 6.9 Hz, 6H), 1.75-1.90 (m, 2H), 2.13-2.29 (m , 4H), 2.75-2.89 (m, 6H), 2.90-2.96 (m, 12H), 3.00-3.17 (m, 2H), 3.72 (s, 6H), 3.76 (s, 6H), 3.90-4.00 (m , 2H), 4.05-4.15 (m, 2H), 4.44-4.50 (m, 2H), 5.02-5.06 (m, 2H), 5.36-5.44 (m, 2H), 6.74-6.82 (m, 8H), 7.52 -7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.03-8.06 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 43> 4-(4-(3- 43> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2-일카바모일)피페리딘-3-일-2-나프토에이트의 제조Preparation of 2-ylcarbamoyl) piperidin-3-yl-2-naphthoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 2에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 41과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 84%).4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 41, the target compound was obtained (yield: 84%).
1H NMR(CDCl3, 300 MHz): δ 0.94 (d, J= 6.8 Hz, 6H), 0.99 (d, J= 6.8 Hz, 6H), 1.75-1.90 (m, 2H), 2.13-2.28 (m, 4H), 2.73-2.88 (m,6H), 2.90-3.14 (m, 14H), 3.77 (s, 6H), 3.90-4.00 (m,2H), 4.05-4.15 (m, 2H), 4.44-4.50 (m,2H), 5.03-5.06 (m, 2H), 5.37-5.45 (m, 2H), 6.66-6.77 (m, 6H), 7.07 (t, J= 8.1 Hz, 2H),, 7.52-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.94 (d, J = 6.8 Hz, 6H), 0.99 (d, J = 6.8 Hz, 6H), 1.75-1.90 (m, 2H), 2.13-2.28 (m , 4H), 2.73-2.88 (m, 6H), 2.90-3.14 (m, 14H), 3.77 (s, 6H), 3.90-4.00 (m, 2H), 4.05-4.15 (m, 2H), 4.44-4.50 (m, 2H), 5.03-5.06 (m, 2H), 5.37-5.45 (m, 2H), 6.66-6.77 (m, 6H), 7.07 (t, J = 8.1 Hz, 2H) ,, 7.52-7.62 ( m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 44> 4-(4-(4- 44> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-바이페닐-4-카르복실레이트의 제조Preparation of Piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 5에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 41과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 91%).4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 41 to obtain the target compound (yield: 91% ).
1H NMR(CDCl3, 300 MHz): δ 0.94 (d, J= 6.8 Hz, 6H), 0.99 (d, J= 6.8 Hz, 6H), 1.70-1.82 (m, 2H), 2.10-2.30 (m, 4H), 2.73-2.88 (m,6H), 2.90-2.99 (m, 12H), 3.00-3.14 (m, 2H), 3.76 (s, 6H), 3.85-3.95 (m 2H), 4.04-4.14 (m, 2H), 4.44-4.50 (m,2H), 5.02-5.05 (m, 2H), 5.32-5.41 (m, 2H), 6.77-6.83 (m, 4H), 6.85-6.94 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.08-8.11 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.94 (d, J = 6.8 Hz, 6H), 0.99 (d, J = 6.8 Hz, 6H), 1.70-1.82 (m, 2H), 2.10-2.30 (m , 4H), 2.73-2.88 (m, 6H), 2.90-2.99 (m, 12H), 3.00-3.14 (m, 2H), 3.76 (s, 6H), 3.85-3.95 (m 2H), 4.04-4.14 ( m, 2H), 4.44-4.50 (m, 2H), 5.02-5.05 (m, 2H), 5.32-5.41 (m, 2H), 6.77-6.83 (m, 4H), 6.85-6.94 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.08-8.11 (m, 4H).
<< 실시예Example 45> 4-(4-(4- 45> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-바이페닐-4-카르복실레이트의 제조Preparation of Piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 7에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 41과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 87%).4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 41 to obtain the target compound (yield: 87% ).
1H NMR(CDCl3, 300 MHz): δ 0.94 (d, J= 6.8 Hz, 6H), 0.98 (d, J= 6.8 Hz, 6H), 1.70-1.85 (m, 2H), 2.11-2.26 (m, 4H), 2.73-2.89 (m, 6H), 2.90-3.00 (m, 12H), 3.01-3.14 (m, 2H), 3.73 (s, 6H), 3.76 (s, 6H), 3.85-3.95 (m 2H), 4.00-4.12 (m, 2H), 4.44-4.50 (m,2H), 5.02-5.05 (m, 2H), 5.32-5.41 (m, 2H), 6.76-6.84 (m, 8H), 6.85-6.94 (m, 4H), 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.09 (d, J= 8.3 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.94 (d, J = 6.8 Hz, 6H), 0.98 (d, J = 6.8 Hz, 6H), 1.70-1.85 (m, 2H), 2.11-2.26 (m , 4H), 2.73-2.89 (m, 6H), 2.90-3.00 (m, 12H), 3.01-3.14 (m, 2H), 3.73 (s, 6H), 3.76 (s, 6H), 3.85-3.95 (m 2H), 4.00-4.12 (m, 2H), 4.44-4.50 (m, 2H), 5.02-5.05 (m, 2H), 5.32-5.41 (m, 2H), 6.76-6.84 (m, 8H), 6.85- 6.94 (m, 4H), 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.09 (d, J = 8.3 Hz, 4H).
<< 실시예Example 46> 4-(4-(3- 46> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-바이페닐-4-카르복실레이트의 제조Preparation of Piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 6에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 41과 동일한 방법으로 수행하 여 목적화합물을 수득하였다(수율: 77%).4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate, the procedure was carried out in the same manner as in Example 41, to obtain the target compound (yield: 77% ).
1H NMR(CDCl3, 300 MHz): δ 0.94 (d, J= 6.8 Hz, 3H), 0.95 (d, J= 6.8 Hz, 3H), 0.98 (d, J= 6.8 Hz, 6H), 1.73-1.88 (m, 2H), 2.05-2.28 (m, 4H), 2.72-2.85 (m, 6H), 2.90-3.00 (m, 2H), 3.04-3.12 (m, 12H), 3.72 (s, 3H), 3.76 (s, 3H), 3.85-3.95 (m 2H), 4.02-4.13 (m, 2H), 4.39-4.50 (m, 2H), 5.03-5.06 (m, 2H), 5.32-5.40 (m, 2H), 6.68-6.80 (m, 6H), 7.10 (t, J=8.1 Hz, 2H), 7.36-7.49 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.10 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.94 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 6H), 1.73- 1.88 (m, 2H), 2.05-2.28 (m, 4H), 2.72-2.85 (m, 6H), 2.90-3.00 (m, 2H), 3.04-3.12 (m, 12H), 3.72 (s, 3H), 3.76 (s, 3H), 3.85-3.95 (m 2H), 4.02-4.13 (m, 2H), 4.39-4.50 (m, 2H), 5.03-5.06 (m, 2H), 5.32-5.40 (m, 2H) , 6.68-6.80 (m, 6H), 7.10 (t, J = 8.1 Hz, 2H), 7.36-7.49 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.10 (m, 4H).
<< 실시예Example 47> 4-(4-(4- 47> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of Piperidin-3-yl-4-phenoxybenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 9에서 수득한 4-(4-(4-플로오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 41과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 82%).4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 41 to obtain the target compound (yield: 82%).
1H NMR(CDCl3, 300 MHz): δ 0.93 (d, J= 6.8 Hz, 6H), 0.97 (d, J= 6.8 Hz, 6H), 1.68-1.80 (m, 2H), 2.11-2.20 (m, 4H), 2.70-2.82 (m, 6H), 2.93-3.11 (m, 14H), 3.75 (s, 6H), 3.85-3.95 (m 2H), 4.02-4.10 (m, 2H), 4.42-4.50 (m, 2H), 5.01-5.05 (m, 2H), 5.28-5.36 (m, 2H), 6.76-6.83 (m, 4H), 6.87-7.04 (m, 8H), 7.05-7.08 (m, 4H), 7.16-7.21 (m, 2H), 7.35-7.41 (m, 4H), 7.97-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.93 (d, J = 6.8 Hz, 6H), 0.97 (d, J = 6.8 Hz, 6H), 1.68-1.80 (m, 2H), 2.11-2.20 (m , 4H), 2.70-2.82 (m, 6H), 2.93-3.11 (m, 14H), 3.75 (s, 6H), 3.85-3.95 (m 2H), 4.02-4.10 (m, 2H), 4.42-4.50 ( m, 2H), 5.01-5.05 (m, 2H), 5.28-5.36 (m, 2H), 6.76-6.83 (m, 4H), 6.87-7.04 (m, 8H), 7.05-7.08 (m, 4H), 7.16-7.21 (m, 2H), 7.35-7.41 (m, 4H), 7.97-8.01 (m, 4H).
<< 실시예Example 48> 4-(4-(4- 48> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소Oxo 부탄-2-Butane-2- 일카바모일Ilkaba Mole )피페리딘-3-일-4-Piperidin-3-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 11에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 41과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 80%).4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 41 to obtain the target compound (yield: 80%).
1H NMR(CDCl3, 300 MHz): δ0.91 -0.98 (m, 12H), 1.65-1.76 (m, 2H), 2.11-2.21 (m, 4H), 2.70-2.85 (m, 6H), 2.90-3.11 (m, 14H), 3.74 (s, 6H), 3.75 (s, 6H), 3.85-3.95 (m 2H), 4.02-4.10 (m, 2H), 4.42-4.48 (m, 2H), 5.01-5.05 (m, 2H), 5.28-5.38 (m, 2H), 6.76-6.84 (m, 8H), 6.95-7.00 (m, 4H), 7.05-7.08 (m, 4H), 7.15-7.21 (m, 2H), 7.35-7.41 (m, 4H), 7.97-8.00 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.91 -0.98 (m, 12H), 1.65-1.76 (m, 2H), 2.11-2.21 (m, 4H), 2.70-2.85 (m, 6H), 2.90 -3.11 (m, 14H), 3.74 (s, 6H), 3.75 (s, 6H), 3.85-3.95 (m 2H), 4.02-4.10 (m, 2H), 4.42-4.48 (m, 2H), 5.01- 5.05 (m, 2H), 5.28-5.38 (m, 2H), 6.76-6.84 (m, 8H), 6.95-7.00 (m, 4H), 7.05-7.08 (m, 4H), 7.15-7.21 (m, 2H ), 7.35-7.41 (m, 4H), 7.97-8.00 (m, 4H).
<< 실시예Example 49> 4-(4-(4- 49> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-2-Piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
실시예 1에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 48 mg(0.11 mmol)과 공지의 방법(Nowich, J. S. et al, J. Org. Chem, 1992, 57, 7364-7366)으로 알라닌 메틸에스테르로부터 제조한 (S)-메틸 2-이 소시아네이토프로판오에이트(0.13 mmol)를 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 83%).48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and a known method (Nowich , JS et al, J. Org.Chem, 1992, 57, 7364-7366), except for reacting (S) -methyl 2-isocyanatopropanoate (0.13 mmol) prepared from alanine methylester. Was carried out in the same manner as in Example 23 to obtain the target compound (yield: 83%).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.44 (d, J= 7.2 Hz, 3H), 1.78-1.85 (m, 2H), 2.20-2.30 (m, 2H), 2.75-2.89 (m,6H), 2.95-3.00 (m, 12H), 3.01-3.15 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 3.87-3.97 (m,2H), 4.03-4.13 (m, 2H), 4.45-4.57 (m,2H), 5.11-5.17 (m, 2H), 5.35-5.45 (m, 2H), 6.73-6.80 (m, 4H), 6.83-6.91 (m, 4H), 7.51-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 3H), 1.78-1.85 (m, 2H), 2.20-2.30 (m , 2H), 2.75-2.89 (m, 6H), 2.95-3.00 (m, 12H), 3.01-3.15 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 3.87-3.97 (m , 2H), 4.03-4.13 (m, 2H), 4.45-4.57 (m, 2H), 5.11-5.17 (m, 2H), 5.35-5.45 (m, 2H), 6.73-6.80 (m, 4H), 6.83 -6.91 (m, 4H), 7.51-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H) .
<< 실시예Example 50> 4-(4-(4- 50> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-2-I) piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 3에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 49와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 88%).4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 49 to obtain the target compound (yield: 88%).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.44 (d, J= 7.2 Hz, 3H), 1.75-1.85 (m, 2H), 2.20-2.30 (m, 2H), 2.75-2.89 (m,6H), 2.94-2.96 (m, 12H), 2.99-3.16 (m, 2H), 3.71 (s, 6H), 3.77 (s, 6H), 3.87-3.97 (m,2H), 4.03- 4.13 (m, 2H), 4.45-4.55 (m,2H), 5.11-5.16 (m, 2H), 5.36-5.45 (m, 2H), 6.73-6.81 (m, 8H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 3H), 1.75-1.85 (m, 2H), 2.20-2.30 (m , 2H), 2.75-2.89 (m, 6H), 2.94-2.96 (m, 12H), 2.99-3.16 (m, 2H), 3.71 (s, 6H), 3.77 (s, 6H), 3.87-3.97 (m , 2H), 4.03- 4.13 (m, 2H), 4.45-4.55 (m, 2H), 5.11-5.16 (m, 2H), 5.36-5.45 (m, 2H), 6.73-6.81 (m, 8H), 7.51 -7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).
..
<< 실시예Example 51> 4-(4-(3-클로로페닐)피페라진-1-일)-1-(1- 51> 4- (4- (3-chlorophenyl) piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-2-나프토에이트의 제조Preparation of Piperidin-3-yl-2-naphthoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 2에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 49와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 86%).4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 49, the target compound was obtained (yield: 86%).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.44 (d, J= 7.2 Hz, 3H), 1.73-1.86 (m, 2H), 2.20-2.29 (m, 2H), 2.75-2.89 (m,6H), 2.93-3.12 (m, 14H), 3.74 (s, 3H), 3.78 (s, 3H), 3.85-3.95 (m,2H), 4.04-4.12 (m, 2H), 4.45-4.55 (m, 2H), 5.10-5.14 (m, 2H), 5.36-5.44 (m, 2H), 6.65-6.77 (m, 6H), 7.07 (t, J= 8.1 Hz 2H), 7.51-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 3H), 1.73-1.86 (m, 2H), 2.20-2.29 (m , 2H), 2.75-2.89 (m, 6H), 2.93-3.12 (m, 14H), 3.74 (s, 3H), 3.78 (s, 3H), 3.85-3.95 (m, 2H), 4.04-4.12 (m , 2H), 4.45-4.55 (m, 2H), 5.10-5.14 (m, 2H), 5.36-5.44 (m, 2H), 6.65-6.77 (m, 6H), 7.07 (t, J = 8.1 Hz 2H) , 7.51-7.62 (m, 4H), 7.86-7.90 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 52> 4-(4-(4- 52> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2--2- 일카바모일Ilkaba Mole )피페리딘-3-일-Piperidin-3-yl- 바이페닐Biphenyl -4-카르복실-4-carboxyl 레이트의Rate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 5에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 49와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 49 to obtain the target compound (yield: 100% ).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.44 (d, J= 7.2 Hz, 3H), 1.70-1.83 (m, 2H), 2.15-2.28 (m, 2H), 2.74-2.86 (m,6H), 2.91-3.13 (m, 14H), 3.74 (s, 3H), 3.77 (s, 3H), 3.85-3.95 (m,2H), 4.02-4.08 (m, 2H), 4.45-4.56 (m, 2H), 5.10-5.12 (m, 2H), 5.31-5.40 (m, 2H), 6.76-6.82 (m, 4H), 6.86-6.93 (m, 4H), 7.36-7.49 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.11 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 3H), 1.70-1.83 (m, 2H), 2.15-2.28 (m , 2H), 2.74-2.86 (m, 6H), 2.91-3.13 (m, 14H), 3.74 (s, 3H), 3.77 (s, 3H), 3.85-3.95 (m, 2H), 4.02-4.08 (m , 2H), 4.45-4.56 (m, 2H), 5.10-5.12 (m, 2H), 5.31-5.40 (m, 2H), 6.76-6.82 (m, 4H), 6.86-6.93 (m, 4H), 7.36 -7.49 (m, 6H), 7.59-7.68 (m, 8H), 8.07-8.11 (m, 4H).
<< 실시예Example 53> 4-(4-(4- 53> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-바이페닐-4-카르복실레이트의 제조I) Preparation of Piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 7에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 49와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 88%).4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 49 to obtain the target compound (yield: 88% ).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.43 (d, J= 7.2 Hz, 3H), 1.65-1.85 (m, 2H), 2.19-2.28 (m, 2H), 2.75-2.85 (m,6H), 2.90-3.14 (m, 14H), 3.73 (s, 6H), 3.77 (s, 6H), 3.85-3.95 (m,2H), 4.00-4.08 (m, 2H), 4.45-4.56 (m, 2H), 5.08-5.13 (m, 2H), 5.30-5.40 (m, 2H), 6.76-6.84 (m, 8H), 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.08-8.11 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.85 (m, 2H), 2.19-2.28 (m , 2H), 2.75-2.85 (m, 6H), 2.90-3.14 (m, 14H), 3.73 (s, 6H), 3.77 (s, 6H), 3.85-3.95 (m, 2H), 4.00-4.08 (m , 2H), 4.45-4.56 (m, 2H), 5.08-5.13 (m, 2H), 5.30-5.40 (m, 2H), 6.76-6.84 (m, 8H), 7.36-7.49 (m, 6H), 7.60 -7.67 (m, 8 H), 8.08-8.11 (m, 4H).
<< 실시예Example 54> 4-(4-(3- 54> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2-일-2 days 카바모Cabamo 일)피페리딘-3-일-1) piperidin-3-yl- 바이페닐Biphenyl -4-카르복실-4-carboxyl 레이트의Rate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 6에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 49와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 49, the target compound was obtained (yield: 100%) .
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.43 (d, J= 7.2 Hz, 3H), 1.65-1.85 (m, 2H), 2.17-2.28 (m, 2H), 2.78-2.85 (m,6H), 2.90-3.03 (m, 4H) 3.04-3.11 (m, 10H), 3.74 (s, 3H), 3.77 (s, 3H), 3.85-3.95 (m,2H), 4.02-4.10 (m, 2H), 4.45-4.56 (m, 2H), 5.10-5.15 (m, 2H), 5.31-5.38 (m, 2H), 6.88-6.80 (m, 6H), 7.10 (t, J= 8.1 Hz, 2H), 7.36-7.50 (m, 6H), 7.59-7.67 (m, 8H), 8.07-8.11 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.85 (m, 2H), 2.17-2.28 (m , 2H), 2.78-2.85 (m, 6H), 2.90-3.03 (m, 4H) 3.04-3.11 (m, 10H), 3.74 (s, 3H), 3.77 (s, 3H), 3.85-3.95 (m, 2H), 4.02-4.10 (m, 2H), 4.45-4.56 (m, 2H), 5.10-5.15 (m, 2H), 5.31-5.38 (m, 2H), 6.88-6.80 (m, 6H), 7.10 ( t, J = 8.1 Hz, 2H), 7.36-7.50 (m, 6H), 7.59-7.67 (m, 8H), 8.07-8.11 (m, 4H).
<< 실시예Example 55> 4-(4-(4- 55> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2-일카바모일)피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of 2-ylcarbamoyl) piperidin-3-yl-4-phenoxybenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 9에서 수득한 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 49와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 84%).4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 49 to obtain the target compound (yield: 84%).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.43 (d, J= 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 2.17-2.21 (m, 2H), 2.75-2.81 (m,6H), 2.90-3.07 (m, 14H) 3.74 (s, 3H), 3.76 (s, 3H), 3.85-3.95 (m,2H), 4.00-4.07 (m, 2H), 4.45-4.55 (m, 2H), 5.09-5.13 (m, 2H), 5.26-5.35 (m, 2H), 6.78-6.82 (m, 4H), 6.87-7.01 (m, 8H), 7.04-7.09 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.96-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 2.17-2.21 (m , 2H), 2.75-2.81 (m, 6H), 2.90-3.07 (m, 14H) 3.74 (s, 3H), 3.76 (s, 3H), 3.85-3.95 (m, 2H), 4.00-4.07 (m, 2H), 4.45-4.55 (m, 2H), 5.09-5.13 (m, 2H), 5.26-5.35 (m, 2H), 6.78-6.82 (m, 4H), 6.87-7.01 (m, 8H), 7.04- 7.09 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.96-8.01 (m, 4H).
<< 실시예Example 56> 4-(4-(4- 56> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소프로판-2--1-oxopropane-2- 일카바모일Ilkaba Mole )피페리딘-3-일-4-Piperidin-3-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 11에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 49와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 95%).4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 49 to obtain the target compound (yield: 95%).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.43 (d, J= 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 2.15-2.25 (m, 2H), 2.72-2.84 (m,6H), 2.88-3.07 (m, 14H) 3.73 (s, 3H), 3.74 (s, 6H), 3.76 (s, 3H), 3.85-3.95 (m, 2H), 3.91-4.05 (m, 2H), 4.45-4.53(m, 2H), 5.09-5.14 (m, 2H),5.26-5.35 (m, 2H), 6.78-6.85 (m, 8H), 6.95-7.01 (m, 4H), 7.04-7.09 (m, 4H), 7.15-7.22 (m, 2H), 7.35-7.41 (m, 4H), 7.96-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 2.15-2.25 (m , 2H), 2.72-2.84 (m, 6H), 2.88-3.07 (m, 14H) 3.73 (s, 3H), 3.74 (s, 6H), 3.76 (s, 3H), 3.85-3.95 (m, 2H) , 3.91-4.05 (m, 2H), 4.45-4.53 (m, 2H), 5.09-5.14 (m, 2H), 5.26-5.35 (m, 2H), 6.78-6.85 (m, 8H), 6.95-7.01 ( m, 4H), 7.04-7.09 (m, 4H), 7.15-7.22 (m, 2H), 7.35-7.41 (m, 4H), 7.96-8.01 (m, 4H).
<< 실시예Example 57> 4-(4-(4- 57> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모Fluorophenylcarbamo 일)피페리딘-3-일-2-I) piperidin-3-yl-2- 나프Naf 토에이트의 제조Preparation of Toate
실시예 1에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 48 mg(0.11 mmol)과 2-플루오로페닐이소시아네이트 18 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 94%).48 mg (0.11 mmol) and 2-fluorophenyl of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 A target compound was obtained in the same manner as in Example 23, except that 18 mg (0.13 mmol) of isocyanate was reacted (yield: 94%).
1H NMR(CDCl3, 300 MHz):δ 1.83- 1.96 (m, 1H), 2.27-2.36 (m, 1H), 2.78-2.96(m, 3H), 2.97-3.03 (m, 6H), 3.14-3.28 (m, 2H), 3.96-4.05 (m, 1H), 4.15-4.22 (m, 1H), 5.42-5.52 (m, 1H), 6.71 (d, J=3.8 Hz, 1H), 6.73-6.80 (m, 2H), 6.84-6.92 (m, 2H), 6.94-7.05 (m, 1H), 7.07-7.15 (m, 2H), 7.51-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.93-7.97 (m, 1H), 8.03-8.11 (m, 2H), 8.60 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.83-1.96 (m, 1H), 2.27-2.36 (m, 1H), 2.78-2.96 (m, 3H), 2.97-3.03 (m, 6H), 3.14- 3.28 (m, 2H), 3.96-4.05 (m, 1H), 4.15-4.22 (m, 1H), 5.42-5.52 (m, 1H), 6.71 (d, J = 3.8 Hz, 1H), 6.73-6.80 ( m, 2H), 6.84-6.92 (m, 2H), 6.94-7.05 (m, 1H), 7.07-7.15 (m, 2H), 7.51-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.93-7.97 (m, 1 H), 8.03-8.11 (m, 2 H), 8.60 (s, 1 H).
<< 실시예Example 58> 4-(4-(4- 58> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모 일Fluorophenylcarbamoyl )피페리딘-3-일-2-Piperidin-3-yl-2- 나프Naf 토에이트의 제조Preparation of Toate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 3에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 57과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 57 to obtain the target compound (yield: 100%).
1H 1H NMR(CDCl3, 300 MHz):δ1.82- 1.96 (m, 1H), 2.27-2.37 (m, 1H), 2.81-2.86 (m, 2H), 2.89-3.05 (m, 7H), 3.14-3.29 (m, 2H), 3.71 (s, 3H), 3.94-4.05 (m, 1H), 4.12-4.20 (m, 1H), 5.42-5.52 (m, 1H), 6.70 (d, J=4.1 Hz, 1H), 6.73-6.82 (m, 4H), 6.94-7.15 (m, 3H), 7.51-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.94-7.97 (m, 1H), 8.03-8.12 (m, 2H), 8.60 (s, 1H). 1 H 1 H NMR (CDCl 3 , 300 MHz): δ 1.82- 1.96 (m, 1H), 2.27-2.37 (m, 1H), 2.81-2.86 (m, 2H), 2.89-3.05 (m, 7H) , 3.14-3.29 (m, 2H), 3.71 (s, 3H), 3.94-4.05 (m, 1H), 4.12-4.20 (m, 1H), 5.42-5.52 (m, 1H), 6.70 (d, J = 4.1 Hz, 1H), 6.73-6.82 (m, 4H), 6.94-7.15 (m, 3H), 7.51-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.94-7.97 (m, 1H) , 8.03-8.12 (m, 2H), 8.60 (s, 1H).
<< 실시예Example 59> 4-(4-(3- 59> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(2-플루오로페닐카바모일)피페리딘-3-일-2-) Piperazin-1-yl) -1- (2-fluorophenylcarbamoyl) piperidin-3-yl-2- 나프Naf 토에이트의 제조Preparation of Toate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 2에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 57과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 75%).4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 57, the target compound was obtained (yield: 75%).
1H NMR(CDCl3, 300 MHz):δ 1.82-1.96 (m, 1H), 2.26-2.37 (m, 1H), 2.78- 2.89 (m, 3H), 2.90-2.99 (m, 2H), 3.02-3.10 (m, 4H), 3.14-3.27 (m, 2H), 3.95-4.05 (m, 1H), 4.15-4.22 (m, 1H), 5.42-5.50 (m, 1H), 6.66-6.80 (m, 4H), 6.95-7.15 (m, 4H), 7.51-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.94-7.97 (m, 1H), 8.02-8.12 (m, 2H), 8.60 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.82-1.96 (m, 1H), 2.26-2.37 (m, 1H), 2.78-2.89 (m, 3H), 2.90-2.99 (m, 2H), 3.02- 3.10 (m, 4H), 3.14-3.27 (m, 2H), 3.95-4.05 (m, 1H), 4.15-4.22 (m, 1H), 5.42-5.50 (m, 1H), 6.66-6.80 (m, 4H ), 6.95-7.15 (m, 4H), 7.51-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.94-7.97 (m, 1H), 8.02-8.12 (m, 2H), 8.60 (s , 1H).
<< 실시예Example 60> 4-(4-(4- 60> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-Piperidin-3-yl- 바이페Bype 닐-4-카르복실레이트의 제조Preparation of Neyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 5에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 57과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 57 to obtain the target compound (yield: 100% ).
1H NMR(CDCl3, 300 MHz):δ 1.77-1.91 (m, 1H), 2.25-2.34 (m, 1H), 2.78-2.89 (m, 3H), 2.95-3.07 (m, 6H), 3.12-3.26 (m, 2H), 3.95-4.05 (m, 1H), 4.12-4.20 (m, 1H), 5.37-5.45 (m, 1H), 6.71 (d, J=4.1 Hz, 1H), 6.75-6.83 (m, 2H), 6.86-6.91 (m, 2H), 6.92-7.15 (m, 3H), 7.36-7.49 (m, 3H), 7.59-7.68 (m, 4H), 8.04-8.12 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.77-1.91 (m, 1H), 2.25-2.34 (m, 1H), 2.78-2.89 (m, 3H), 2.95-3.07 (m, 6H), 3.12- 3.26 (m, 2H), 3.95-4.05 (m, 1H), 4.12-4.20 (m, 1H), 5.37-5.45 (m, 1H), 6.71 (d, J = 4.1 Hz, 1H), 6.75-6.83 ( m, 2H), 6.86-6.91 (m, 2H), 6.92-7.15 (m, 3H), 7.36-7.49 (m, 3H), 7.59-7.68 (m, 4H), 8.04-8.12 (m, 3H).
<< 실시예Example 61> 4-(4-(4- 61> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-Piperidin-3-yl- 바이페Bype 닐-4-카르복실레이트의 제조Preparation of Neyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 7에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 57과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 57 to obtain the target compound (yield: 100% ).
1H NMR(CDCl3, 300 MHz):δ1.78- 1.90 (m, 1H), 2.25-2.32 (m, 1H), 2.80-2.90 (m, 4H), 2.95-3.07 (m, 5H), 3.12-3.27 (m, 2H), 3.73 (s, 3H), 3.95-4.05 (m, 1H), 4.10-4.18 (m, 1H), 5.37-5.44 (m, 1H), 6.70 (d, J=3.8 Hz, 1H), 6.75-6.84 (m, 4H), 6.96-7.15 (m, 3H), 7.36-7.50 (m, 3H), 7.59-7.68 (m, 4H), 8.04-8.12 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.78-1.90 (m, 1H), 2.25-2.32 (m, 1H), 2.80-2.90 (m, 4H), 2.95-3.07 (m, 5H), 3.12 -3.27 (m, 2H), 3.73 (s, 3H), 3.95-4.05 (m, 1H), 4.10-4.18 (m, 1H), 5.37-5.44 (m, 1H), 6.70 (d, J = 3.8 Hz , 1H), 6.75-6.84 (m, 4H), 6.96-7.15 (m, 3H), 7.36-7.50 (m, 3H), 7.59-7.68 (m, 4H), 8.04-8.12 (m, 3H).
<< 실시예Example 62> 4-(4-(3- 62> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-Piperidin-3-yl- 바이페닐Biphenyl -4--4- 카르복실레이트의Carboxylate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 6에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 57과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 86%).4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 57, the target compound was obtained (yield: 86%) .
1H NMR(CDCl3, 300 MHz):δ 1.77- 1.90 (m, 1H), 2.24-2.33 (m, 1H), 2.75-2.84 (m, 3H), 2.86-3.03 (m, 2H), 2.86-3.03 (m, 2H), 3.06-3.10 (m, 4H), 3.12- 3.25 (m, 2H), 3.93-4.05 (m, 1H), 4.10-4.19 (m, 1H), 5.37-5.44 (m, 1H), 6.68-6.80 (m, 4H), 6.95-7.15 (m, 4H), 7.36-7.49 (m, 3H), 7.60-7.68 (m, 4H), 8.04-8.11 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.77-1.90 (m, 1H), 2.24-2.33 (m, 1H), 2.75-2.84 (m, 3H), 2.86-3.03 (m, 2H), 2.86- 3.03 (m, 2H), 3.06-3.10 (m, 4H), 3.12- 3.25 (m, 2H), 3.93-4.05 (m, 1H), 4.10-4.19 (m, 1H), 5.37-5.44 (m, 1H ), 6.68-6.80 (m, 4H), 6.95-7.15 (m, 4H), 7.36-7.49 (m, 3H), 7.60-7.68 (m, 4H), 8.04-8.11 (m, 3H).
<< 실시예Example 63> 4-(4-(4- 63> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-4-Piperidin-3-yl-4- 페닐Phenyl 벤조에이트의 제조Preparation of benzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 9에서 수득한 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페닐벤조에이트를 사용하는 것을 제외하고는 실시예 57과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 80%).4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenylbenzoate in the same manner as in Example 57 to obtain the target compound (yield: 80%).
1H NMR(CDCl3, 300 MHz):δ1.73- 1.86 (m, 1H), 2.23-2.32 (m, 1H), 2.77-2.90 (m, 4H), 2.92-3.08 (m, 5H), 3.10-3.24 (m, 2H), 3.93-4.05 (m, 1H), 4.10-4.19 (m, 1H), 5.32-5.42 (m, 1H), 6.68 (d, J=3.7 Hz, 1H), 6.78-6.83 (m, 2H), 6.87-7.26 (m, 8H), 7.39 (t, J=7.8 Hz, 4H), 7.97-8.09 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ1.73- 1.86 (m, 1H), 2.23-2.32 (m, 1H), 2.77-2.90 (m, 4H), 2.92-3.08 (m, 5H), 3.10 -3.24 (m, 2H), 3.93-4.05 (m, 1H), 4.10-4.19 (m, 1H), 5.32-5.42 (m, 1H), 6.68 (d, J = 3.7 Hz, 1H), 6.78-6.83 (m, 2H), 6.87-7.26 (m, 8H), 7.39 (t, J = 7.8 Hz, 4H), 7.97-8.09 (m, 3H).
<< 실시예Example 64> 4-(4-(4- 64> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-4-Piperidin-3-yl-4- 페닐Phenyl 벤조에이트의 제조Preparation of benzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 11에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페닐벤조 에이트를 사용하는 것을 제외하고는 실시예 57과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenylbenzoate in the same manner as in Example 57 to obtain the target compound (yield: 100%).
1H NMR(CDCl3, 300 MHz):δ 1.72- 1.85 (m, 1H), 2.23-2.32 (m, 1H), 2.78-2.90 (m, 6H), 2.92-3.05 (m, 6H), 3.10-3.24 (m, 2H), 3.74 (s, 3H), 3.93-4.04 (m, 1H), 4.08-4.15 (m, 1H), 5.32-5.41 (m, 1H), 6.68 (d, J=3.8 Hz, 1H), 6.78-6.85 (m, 4H), 6.95-7.01 (m, 3H), 7.03-7.14 (m,, 4H), 7.15-7.22 (m, 1H), 7.35-7.42 (m,2H), 7.97-8.09 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.72- 1.85 (m, 1H), 2.23-2.32 (m, 1H), 2.78-2.90 (m, 6H), 2.92-3.05 (m, 6H), 3.10- 3.24 (m, 2H), 3.74 (s, 3H), 3.93-4.04 (m, 1H), 4.08-4.15 (m, 1H), 5.32-5.41 (m, 1H), 6.68 (d, J = 3.8 Hz, 1H), 6.78-6.85 (m, 4H), 6.95-7.01 (m, 3H), 7.03-7.14 (m, 4H), 7.15-7.22 (m, 1H), 7.35-7.42 (m, 2H), 7.97 -8.09 (m, 3 H).
<< 실시예Example 65> 4-(4-(4- 65> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-3-일-2-Piperidin-3-yl-2- 나프토에이트의Naphthoate 제조 Produce
실시예 1에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 48 mg(0.11 mmol)과 3-메톡시페닐이소시아네이트 20 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 93%).48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and 3-methoxyphenyl A target compound was obtained in the same manner as in Example 23, except that 20 mg (0.13 mmol) of isocyanate was reacted (yield: 93%).
1H NMR(CDCl3, 300 MHz):δ 1.80- 1.91 (m, 1H), 2.25-2.35 (m, 1H), 2.77-3.03 (m, 9H), 3.08-3.22 (m, 2H), 3.79 (s, 3H), 3.95-4.05 (m, 1H), 4.13-4.20 (m, 1H), 5.40-5.48 (m, 1H), 6.56-6.65 (m, 2H), 6.73-6.81 (m, 2H), 6.83-6.93 (m, 3H), 7.13-7.28 (m, 2H), 7.86-7.90 (m, 2H), 7.94-7.97 (m, 1H), 8.02-8.06 (m, 1H), 8.60 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.80- 1.91 (m, 1H), 2.25-2.35 (m, 1H), 2.77-3.03 (m, 9H), 3.08-3.22 (m, 2H), 3.79 ( s, 3H), 3.95-4.05 (m, 1H), 4.13-4.20 (m, 1H), 5.40-5.48 (m, 1H), 6.56-6.65 (m, 2H), 6.73-6.81 (m, 2H), 6.83-6.93 (m, 3H), 7.13-7.28 (m, 2H), 7.86-7.90 (m, 2H), 7.94-7.97 (m, 1H), 8.02-8.06 (m, 1H), 8.60 (s, 1H ).
<< 실시예Example 66> 4-(4-(4- 66> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-3-일-2-Piperidin-3-yl-2- 나프토Naphtho 에이트의 제조Manufacture of Eight
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 3에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 65와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 94%).4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate A target compound was obtained in the same manner as in Example 65 except for using the piperazin-1-yl) piperidin-3-yl-2-naphthoate (yield: 94%).
1H NMR(CDCl3, 300 MHz):δ 1.80- 1.90 (m, 1H), 2.22-2.33 (m, 1H), 2.78-3.05 (m, 9H), 3.07-3.22 (m, 2H), 3.71(s, 3H), 3.80 (s, 3H), 3.95-4.05 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.59-6.64 (m, 2H), 6.73-6.81 (m, 4H), 6.85-6.90 (m, 1H), 7.13-7.21 (m, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.97 (m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.80- 1.90 (m, 1H), 2.22-2.33 (m, 1H), 2.78-3.05 (m, 9H), 3.07-3.22 (m, 2H), 3.71 ( s, 3H), 3.80 (s, 3H), 3.95-4.05 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.59-6.64 (m, 2H), 6.73- 6.81 (m, 4H), 6.85-6.90 (m, 1H), 7.13-7.21 (m, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.97 (m, 1H ), 8.02-8.06 (m, 1 H), 8.59 (s, 1 H).
<< 실시예Example 67> 4-(4-(3- 67> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-3-일-2-Piperidin-3-yl-2- 나프토Naphtho 에이트의 제조Manufacture of Eight
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 2에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 65와 동일한 방법으로 수행하여 목적화합물 을 수득하였다(수율: 70%).4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 65, the target compound was obtained (yield: 70%).
1H NMR(CDCl3, 300 MHz):δ1.80- 1.93 (m, 1H), 2.24-2.32 (m, 1H), 2.75-2.81 (m, 2H), 2.82-2.99 (m, 3H), 3.00-3.08 (m, 4H), 3.09-3.20 (m, 2H), 3.80 (s, 3H), 3.97-4.05 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.58-6.80 (m, 5H), 6.85-6.89 (m, 1H), 7.04-7.30 (m, 3H), 7.51-7.62 (m, 2H), 7.86-7.90 (m, 2H), 7.94-7.97 (m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ1.80- 1.93 (m, 1H), 2.24-2.32 (m, 1H), 2.75-2.81 (m, 2H), 2.82-2.99 (m, 3H), 3.00 -3.08 (m, 4H), 3.09-3.20 (m, 2H), 3.80 (s, 3H), 3.97-4.05 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H) , 6.58-6.80 (m, 5H), 6.85-6.89 (m, 1H), 7.04-7.30 (m, 3H), 7.51-7.62 (m, 2H), 7.86-7.90 (m, 2H), 7.94-7.97 ( m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H).
<< 실시예Example 68> 4-(4-(4- 68> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-3-일-Piperidin-3-yl- 바이페닐Biphenyl -4-카르복실레이트의 제조Preparation of 4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 5에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 65와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 97%).4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 65 to obtain the target compound (yield: 97% ).
1H NMR(CDCl3, 300 MHz):δ1.72- 1.83 (m, 1H), 2.20-2.30 (m, 1H), 2.77-2.88 (m, 3H), 2.90-3.01 (m, 6H), 3.02-3.18 (m, 2H), 3.79 (s, 3H), 3.95-4.03 (m, 1H), 4.10-4.18 (m, 1H), 5.33-5.42 (m, 1H), 6.59-6.65 (m, 2H), 6.74-6.82 (m, 2H), 6.85-6.94 (m, 3H), 7.12-7.21 (m, 2H), 7.36-7.49 (m, 3H), 7.58-7.68 (m, 4H), 8.07-8.12 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ1.72- 1.83 (m, 1H), 2.20-2.30 (m, 1H), 2.77-2.88 (m, 3H), 2.90-3.01 (m, 6H), 3.02 -3.18 (m, 2H), 3.79 (s, 3H), 3.95-4.03 (m, 1H), 4.10-4.18 (m, 1H), 5.33-5.42 (m, 1H), 6.59-6.65 (m, 2H) , 6.74-6.82 (m, 2H), 6.85-6.94 (m, 3H), 7.12-7.21 (m, 2H), 7.36-7.49 (m, 3H), 7.58-7.68 (m, 4H), 8.07-8.12 ( m, 2H).
<< 실시예Example 69> 4-(4-(4- 69> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-3-일-Piperidin-3-yl- 바이페닐Biphenyl -4-카르복실레이트의 제조Preparation of 4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 7에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 65와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 96%).4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 65 to obtain the target compound (yield: 96% ).
1H NMR(CDCl3, 300 MHz):δ 1.73- 1.87 (m, 1H), 2.20-2.32 (m, 1H), 2.75-2.90 (m, 3H), 2.92-3.00 (m, 6H), 3.01-3.21 (m, 2H), 3.73 (s, 3H), 3.80 (s, 3H), 3.95-4.03 (m, 1H), 4.06-4.14 (m, 1H), 5.33-5.41 (m, 1H), 6.58-6.63 (m, 2H), 6.76-6.88 (m, 5H), 7.13-7.21 (m, 2H), 7.36-7.49 (m, 3H), 7.60-7.67 (m, 4H), 8.10 (d, J=8.1 Hz, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.73-1.87 (m, 1H), 2.20-2.32 (m, 1H), 2.75-2.90 (m, 3H), 2.92-3.00 (m, 6H), 3.01- 3.21 (m, 2H), 3.73 (s, 3H), 3.80 (s, 3H), 3.95-4.03 (m, 1H), 4.06-4.14 (m, 1H), 5.33-5.41 (m, 1H), 6.58- 6.63 (m, 2H), 6.76-6.88 (m, 5H), 7.13-7.21 (m, 2H), 7.36-7.49 (m, 3H), 7.60-7.67 (m, 4H), 8.10 (d, J = 8.1 Hz, 2H).
<< 실시예Example 70> 4-(4-(3- 70> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-3-일-바이페닐-4-카르복실레이트의 제조Preparation of Piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 6에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 65와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 42%).4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 65, the target compound was obtained (yield: 42%) .
1H NMR(CDCl3, 300 MHz):δ1.62- 1.85 (m, 1H), 2.24-2.32 (m, 1H), 2.79-2.90 (m, 3H), 2.91-2.98 (m, 2H), 3.05-3.10 (m, 4H), 3.11-3.21 (m, 1H), 3.73 (s, 3H), 3.81 (s, 3H), 3.95-4.03 (m, 1H), 4.10-4.17 (m, 1H), 4.25-4.35 (m, 1H), 5.35-5.43 (m, 1H), 6.48 (s, 1H), 6.60-6.64 (m, 1H), 6.69-6.80 (m, 3H), 6.83-6.88 (m, 1H), 7.07-7.22 (m, 3H), 7.37-7.54 (m, 3H), 7.59-7.73 (m, 4H), 8.07-8.12 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.62- 1.85 (m, 1H), 2.24-2.32 (m, 1H), 2.79-2.90 (m, 3H), 2.91-2.98 (m, 2H), 3.05 -3.10 (m, 4H), 3.11-3.21 (m, 1H), 3.73 (s, 3H), 3.81 (s, 3H), 3.95-4.03 (m, 1H), 4.10-4.17 (m, 1H), 4.25 -4.35 (m, 1H), 5.35-5.43 (m, 1H), 6.48 (s, 1H), 6.60-6.64 (m, 1H), 6.69-6.80 (m, 3H), 6.83-6.88 (m, 1H) , 7.07-7.22 (m, 3H), 7.37-7.54 (m, 3H), 7.59-7.73 (m, 4H), 8.07-8.12 (m, 2H).
<< 실시예Example 71> 4-(4-(4- 71> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-3-일-4-페녹시벤조에이트의 제조Preparation of Piperidin-3-yl-4-phenoxybenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 9에서 수득한 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 65와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 73%).4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 65 to obtain the target compound (yield: 73%).
1H NMR(CDCl3, 300 MHz):δ1.70- 1.83 (m, 1H), 2.20-2.30 (m, 1H), 2.75-2.90 (m, 3H), 2.91-2.99 (m, 6H), 3.02-3.18 (m, 2H), 3.79 (s, 3H), 3.94-4.02 (m, 1H), 4.06-4.16 (m, 1H), 5.30-5.38 (m, 1H), 6.52 (s, 1H), 6.58-6.63 (m, 1H), 6.77-7.00 (m, 7H), 7.03-7.10 (m, 2H), 7.11-7.22 (m, 3H), 7.35-7.42 (m, 2H), 7.96-8.02 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ1.70- 1.83 (m, 1H), 2.20-2.30 (m, 1H), 2.75-2.90 (m, 3H), 2.91-2.99 (m, 6H), 3.02 -3.18 (m, 2H), 3.79 (s, 3H), 3.94-4.02 (m, 1H), 4.06-4.16 (m, 1H), 5.30-5.38 (m, 1H), 6.52 (s, 1H), 6.58 -6.63 (m, 1H), 6.77-7.00 (m, 7H), 7.03-7.10 (m, 2H), 7.11-7.22 (m, 3H), 7.35-7.42 (m, 2H), 7.96-8.02 (m, 2H).
<< 실시예Example 72> 4-(4-(4- 72> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-3-일-4-Piperidin-3-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 11에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 65와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 89%).4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 65 to obtain the target compound (yield: 89%).
1H NMR(CDCl3, 300 MHz):δ 1.69- 1.82 (m, 1H), 2.17-2.27 (m, 1H), 2.74-2.87 (m, 3H), 2.90-2.97 (m, 6H), 3.01-3.18 (m, 2H), 3.74 (s, 3H), 3.79 (s, 3H), 3.94-4.04 (m, 1H), 4.05-4.14 (m, 1H), 5.29-5.38 (m, 1H), 6.57-6.64 (m, 2H), 6.77-6.88 (m, 5H), 6.95-7.00 (m, 2H), 7.04-7.08 (m, 2H), 7.11-7.21 (m, 3H), 7.34-7.42 (m, 2H), 7.96-8.02 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.69-1.82 (m, 1H), 2.17-2.27 (m, 1H), 2.74-2.87 (m, 3H), 2.90-2.97 (m, 6H), 3.01- 3.18 (m, 2H), 3.74 (s, 3H), 3.79 (s, 3H), 3.94-4.04 (m, 1H), 4.05-4.14 (m, 1H), 5.29-5.38 (m, 1H), 6.57- 6.64 (m, 2H), 6.77-6.88 (m, 5H), 6.95-7.00 (m, 2H), 7.04-7.08 (m, 2H), 7.11-7.21 (m, 3H), 7.34-7.42 (m, 2H ), 7.96-8.02 (m, 2 H).
<< 실시예Example 73> 4-(4-(4- 73> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-2-Piperidin-3-yl-2- 나프Naf 토에이트의 제조Preparation of Toate
실시예 1에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 48 mg(0.11 mmol)과 4-플루오로페닐이소시아네이트 18 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 74%).48 mg (0.11 mmol) of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 and 4-fluorophenyl Except for reacting 18 mg (0.13 mmol) of isocyanate, the same procedure as in Example 23 was carried out to obtain the target compound (yield: 74%).
1H NMR(CDCl3, 300 MHz):δ1.80- 1.93 (m, 1H), 2.25-2.34 (m, 1H), 2.78-2.93 (m, 3H), 2.94-3.02 (m, 6H), 3.08-3.23 (m, 2H), 3.93-4.05 (m, 1H), 4.12-4.18 (m, 1H), 5.41-5.48 (m, 1H), 6.51 (s, 1H), 6.72-6.80 (m, 2H), 6.84-6.91 (m, 2H), 6.96-7.05 (m, 2H), 7.29-7.35 (m, 2H), 7.52-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.94-7.97 (m, 1H), 8.03-8.07 (m, 1H), 8.60 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ1.80- 1.93 (m, 1H), 2.25-2.34 (m, 1H), 2.78-2.93 (m, 3H), 2.94-3.02 (m, 6H), 3.08 -3.23 (m, 2H), 3.93-4.05 (m, 1H), 4.12-4.18 (m, 1H), 5.41-5.48 (m, 1H), 6.51 (s, 1H), 6.72-6.80 (m, 2H) , 6.84-6.91 (m, 2H), 6.96-7.05 (m, 2H), 7.29-7.35 (m, 2H), 7.52-7.62 (m, 2H), 7.87-7.90 (m, 2H), 7.94-7.97 ( m, 1H), 8.03-8.07 (m, 1H), 8.60 (s, 1H).
<< 실시예Example 74> 4-(4-(4- 74> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-2-Piperidin-3-yl-2- 나프Naf 토에이트의 제조Preparation of Toate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 3에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 73과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 95%).4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 73 to obtain the target compound (yield: 95%).
1H NMR(CDCl3, 300 MHz):δ1.80- 1.92 (m, 1H), 2.24-2.33 (m, 1H), 2.78-2.93 (m, 3H), 2.94-3.02 (m, 6H), 3.05-3.21 (m, 2H), 3.70 (s, 3H), 3.94-4.06 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.66 (s, 1H), 6.73-6.81 (m, 4H), 6.96-7.03 (m, 2H), 7.28-7.35 (m, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.03-8.06 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ1.80- 1.92 (m, 1H), 2.24-2.33 (m, 1H), 2.78-2.93 (m, 3H), 2.94-3.02 (m, 6H), 3.05 -3.21 (m, 2H), 3.70 (s, 3H), 3.94-4.06 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.66 (s, 1H), 6.73 -6.81 (m, 4H), 6.96-7.03 (m, 2H), 7.28-7.35 (m, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.03-8.06 (m, 1H), 8.59 (s, 1H).
<< 실시예Example 75> 4-(4-(3- 75> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(4-플루오로페닐카바모일)피페리딘-3-일-2-) Piperazin-1-yl) -1- (4-fluorophenylcarbamoyl) piperidin-3-yl-2- 나프Naf 토에이트의 제조Preparation of Toate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 2에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 73과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 71%).4- (4- (3-chlorophenyl) obtained in Example 2 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 73, the target compound was obtained (yield: 71%).
1H NMR(CDCl3, 300 MHz):δ1.76- 1.89 (m, 1H), 2.25-2.32 (m, 1H), 2.74-2.84 (m, 2H), 2.85-3.00 (m, 3H), 3.02-3.08 (m, 4H), 3.10-3.21 (m, 2H), 3.95-4.04 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.53 (s, 1H), 6.65-6.79 (m, 3H), 6.97-7.10 (m, 3H), 7.29-7.37 (m, 2H), 7.51-7.63 (m, 2H), 7.87-7.90 (m, 2H), 7.93-7.97 (m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ1.76- 1.89 (m, 1H), 2.25-2.32 (m, 1H), 2.74-2.84 (m, 2H), 2.85-3.00 (m, 3H), 3.02 -3.08 (m, 4H), 3.10-3.21 (m, 2H), 3.95-4.04 (m, 1H), 4.10-4.18 (m, 1H), 5.39-5.47 (m, 1H), 6.53 (s, 1H) , 6.65-6.79 (m, 3H), 6.97-7.10 (m, 3H), 7.29-7.37 (m, 2H), 7.51-7.63 (m, 2H), 7.87-7.90 (m, 2H), 7.93-7.97 ( m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H).
<< 실시예Example 76> 4-(4-(4- 76> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-Piperidin-3-yl- 바이페Bype 닐-4-카르복실레이트의 제조Preparation of Neyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 5에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 73과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 88%).4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate A target compound was obtained in the same manner as in Example 73, except that the piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate was used (yield: 88%) ).
1H NMR(CDCl3, 300 MHz):δ1.72- 1.87 (m, 1H), 2.21-2.30 (m, 1H), 2.76-2.90 (m, 3H), 2.92-3.04 (m, 6H), 3.05-3.19 (m, 2H), 3.92-4.04 (m, 1H), 4.06-4.17 (m, 1H), 5.34-5.42 (m, 1H), 6.59 (s, 1H), 6.76-6.82 (m, 2H), 6.86-6.94 (m, 2H), 6.95-7.04 (m, 2H), 7.28-7.34 (m, 2H), 7.36-7.49 (m, 3H), 7.59-7.69 (m, 4H), 8.07-8.12 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ1.72- 1.87 (m, 1H), 2.21-2.30 (m, 1H), 2.76-2.90 (m, 3H), 2.92-3.04 (m, 6H), 3.05 -3.19 (m, 2H), 3.92-4.04 (m, 1H), 4.06-4.17 (m, 1H), 5.34-5.42 (m, 1H), 6.59 (s, 1H), 6.76-6.82 (m, 2H) , 6.86-6.94 (m, 2H), 6.95-7.04 (m, 2H), 7.28-7.34 (m, 2H), 7.36-7.49 (m, 3H), 7.59-7.69 (m, 4H), 8.07-8.12 ( m, 2H).
<< 실시예Example 77> 4-(4-(4-메톡시페닐)피페라진-1-일)-1-(4-플루오로페닐카바모 77> 4- (4- (4-methoxyphenyl) piperazin-1-yl) -1- (4-fluorophenylcarbamo 일Work )피페리딘-3-일-Piperidin-3-yl- 바이페Bype 닐-4-카르복실레이트의 제조Preparation of Neyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 7에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 73과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 86%).4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate A target compound was obtained in the same manner as in Example 73, except that the piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate was used (yield: 86% ).
1H NMR(CDCl3, 300 MHz):δ 1.73- 1.87 (m, 1H), 2.23-2.31 (m, 1H), 2.76-2.90 (m, 3H), 2.92-3.04 (m, 6H), 3.05-3.22 (m, 2H), 3.73 (s, 3H), 3.93-4.04 (m, 1H), 4.06-4.15 (m, 1H), 5.35-5.43 (m, 1H), 6.53 (s, 1H), 6.76-6.84 (m, 4H), 6.95-7.04 (m, 2H), 7.28-7.35 (m, 2H), 7.36-7.50 (m, 3H), 7.59-7.68 (m, 4H), 8.08-8.12 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.73-1.87 (m, 1H), 2.23-2.31 (m, 1H), 2.76-2.90 (m, 3H), 2.92-3.04 (m, 6H), 3.05- 3.22 (m, 2H), 3.73 (s, 3H), 3.93-4.04 (m, 1H), 4.06-4.15 (m, 1H), 5.35-5.43 (m, 1H), 6.53 (s, 1H), 6.76- 6.84 (m, 4H), 6.95-7.04 (m, 2H), 7.28-7.35 (m, 2H), 7.36-7.50 (m, 3H), 7.59-7.68 (m, 4H), 8.08-8.12 (m, 2H ).
<< 실시예Example 78> 4-(4-(3- 78> 4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-바이페닐-4-카르복실레이트의 제조Preparation of Piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 6에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 73과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 75%).4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 73, the target compound was obtained (yield: 75%) .
1H NMR(CDCl3, 300 MHz):δ1.74- 1.88 (m, 1H), 2.22-2.31 (m, 1H), 2.75-2.89 (m, 3H), 2.90-3.00 (m, 2H), 3.02-3.18 (m, 6H), 3.92-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.34-5.42 (m, 1H), 6.53 (s, 1H), 6.68-6.80 (m, 3H), 6.97-7.04 (m, 2H), 7.10 (t, J=8.1 Hz, 1H), 7.28-7.35 (m,2H), 7.36-7.50 (m, 3H), 7.59-7.69 (m, 4H), 8.07-8.11 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ1.74- 1.88 (m, 1H), 2.22-2.31 (m, 1H), 2.75-2.89 (m, 3H), 2.90-3.00 (m, 2H), 3.02 -3.18 (m, 6H), 3.92-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.34-5.42 (m, 1H), 6.53 (s, 1H), 6.68-6.80 (m, 3H) , 6.97-7.04 (m, 2H), 7.10 (t, J = 8.1 Hz, 1H), 7.28-7.35 (m, 2H), 7.36-7.50 (m, 3H), 7.59-7.69 (m, 4H), 8.07 -8.11 (m, 2 H).
<< 실시예Example 79> 4-(4-(4- 79> 4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-3-일-4-Piperidin-3-yl-4- 페녹Phenoxy 시벤조에이트의 제조Preparation of Cibenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 9에서 수득한 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 73과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 80%).4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 73 to obtain the target compound (yield: 80%).
1H NMR(CDCl3, 300 MHz):δ1.68- 1.82 (m, 1H), 2.17-2.28 (m, 1H), 2.76-2.88 (m, 3H), 2.90-3.04 (m, 6H), 3.05-3.17 (m, 2H), 3.91-4.02 (m, 1H), 4.06-4.14 (m, 1H), 5.29-5.38 (m, 1H), 6.56 (s, 1H), 6.76-6.83 (m, 2H), 6.87-6.91 (m, 2H), 6.92-7.02 (m, 4H), 7.04-7.08 (m, 2H), 7.16-7.21 (m, 1H), 7.26-7.33 (m, 2H), 7.35-7.41 (m, 2H), 7.96-8.02 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.68-1.82 (m, 1H), 2.17-2.28 (m, 1H), 2.76-2.88 (m, 3H), 2.90-3.04 (m, 6H), 3.05 -3.17 (m, 2H), 3.91-4.02 (m, 1H), 4.06-4.14 (m, 1H), 5.29-5.38 (m, 1H), 6.56 (s, 1H), 6.76-6.83 (m, 2H) , 6.87-6.91 (m, 2H), 6.92-7.02 (m, 4H), 7.04-7.08 (m, 2H), 7.16-7.21 (m, 1H), 7.26-7.33 (m, 2H), 7.35-7.41 ( m, 2H), 7.96-8.02 (m, 2H).
<< 실시예Example 80> 4-(4-(4- 80> 4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모Fluorophenylcarbamo 일)피페리딘-3-일-4-1) piperidin-3-yl-4- 페녹Phenoxy 시벤조에이트의 제조Preparation of Cibenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 11에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 73과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 89%).4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 73 to obtain the target compound (yield: 89%).
1H NMR(CDCl3, 300 MHz):δ1.67- 1.81 (m, 1H), 2.17-2.27 (m, 1H), 2.75-2.86 (m, 3H), 2.88-3.02 (m, 6H), 3.04-3.16 (m, 2H), 3.74 (s, 3H), 3.93-4.03 (m, 1H), 4.05-4.12 (m, 1H), 5.29-5.37 (m, 1H), 6.63 (s, 1H), 6.77-6.84 (m, 4H), 6.93-7.02 (m, 4H), 7.03-7.08 (m, 2H), 7.16-7.21 (m, 1H), 7.25-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.96-8.01 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.67-1.81 (m, 1H), 2.17-2.27 (m, 1H), 2.75-2.86 (m, 3H), 2.88-3.02 (m, 6H), 3.04 -3.16 (m, 2H), 3.74 (s, 3H), 3.93-4.03 (m, 1H), 4.05-4.12 (m, 1H), 5.29-5.37 (m, 1H), 6.63 (s, 1H), 6.77 -6.84 (m, 4H), 6.93-7.02 (m, 4H), 7.03-7.08 (m, 2H), 7.16-7.21 (m, 1H), 7.25-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.96-8.01 (m, 2H).
<< 실시예Example 81> 1-(3,5- 81> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-4-(4-(4-) -4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-3-일-2-나프토에이트의 제조Preparation of Piperazin-1-yl) piperidin-3-yl-2-naphthoate
실시예 1에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 48 mg(0.11 mmol)과 3,5-디클로로페닐이소시아네이트 25 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 80%).48 mg (0.11 mmol) and 3,5-dichloro 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate prepared in Example 1 A target compound was obtained in the same manner as in Example 23, except that 25 mg (0.13 mmol) of phenylisocyanate was reacted (yield: 80%).
1H NMR(CDCl3, 300 MHz):δ1.78- 1.92 (m, 1H), 2.25-2.34 (m, 1H), 2.75-2.92 (m, 3H), 2.94-3.04 (m, 6H), 3.08-3.23 (m, 2H), 3.95-4.04 (m, 1H), 4.10-4.17 (m, 1H), 5.40-5.48 (m, 1H), 6.72-6.79 (m, 2H), 6.81-6.91 (m, 3H), 7.02 (t, J=1.8 Hz, 1H), 7.34 (d, J=1.8 Hz,, 2H), 7.51-7.63 (m, 2H), 7.86-7.90 (m, 2H), 7.93-7.96 (m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.78-1.92 (m, 1H), 2.25-2.34 (m, 1H), 2.75-2.92 (m, 3H), 2.94-3.04 (m, 6H), 3.08 -3.23 (m, 2H), 3.95-4.04 (m, 1H), 4.10-4.17 (m, 1H), 5.40-5.48 (m, 1H), 6.72-6.79 (m, 2H), 6.81-6.91 (m, 3H), 7.02 (t, J = 1.8 Hz, 1H), 7.34 (d, J = 1.8 Hz ,, 2H), 7.51-7.63 (m, 2H), 7.86-7.90 (m, 2H), 7.93-7.96 ( m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H).
<< 실시예Example 82> 1-(3,5- 82> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-4-(4-(4-) -4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-2-나프토에이트의 제조Preparation of Piperazin-1-yl) piperidin-3-yl-2-naphthoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 3에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 81과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 94%).4- (4- (4-methoxyphenyl) obtained in Example 3 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 81 to obtain the target compound (yield: 94%).
1H NMR(CDCl3, 300 MHz):δ1.77- 1.90 (m, 1H), 2.25-2.34 (m, 1H), 2.75-2.92 (m, 3H), 2.93-3.02 (m, 6H), 3.06-3.24 (m, 2H), 3.71 (s, 3H), 3.95-4.03 (m, 1H), 4.10-4.16 (m, 1H), 5.40-5.46 (m, 1H), 6.51 (s, 1H), 6.73-6.80 (m, 4H), 6.87 (s, 1H), 7.02 (t, J=1.8 Hz,, 1H), 7.35 (d, J=1.8 Hz,, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.77-1.90 (m, 1H), 2.25-2.34 (m, 1H), 2.75-2.92 (m, 3H), 2.93-3.02 (m, 6H), 3.06 -3.24 (m, 2H), 3.71 (s, 3H), 3.95-4.03 (m, 1H), 4.10-4.16 (m, 1H), 5.40-5.46 (m, 1H), 6.51 (s, 1H), 6.73 -6.80 (m, 4H), 6.87 (s, 1H), 7.02 (t, J = 1.8 Hz ,, 1H), 7.35 (d, J = 1.8 Hz ,, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.02-8.06 (m, 1H), 8.59 (s, 1H).
<< 실시예Example 83> 1-(3,5- 83> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-4-(4-(3-) -4- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-3-일-2-) Piperazin-1-yl) piperidin-3-yl-2- 나I 프토에이트의 제조Preparation of Ptoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 4에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 81과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 70%).4- (4- (3-chlorophenyl) obtained in Example 4 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 81 to obtain the target compound (yield: 70%).
1H NMR(CDCl3, 300 MHz):δ1.78- 1.90 (m, 1H), 2.23-2.34 (m, 1H), 2.72-2.81 (m, 2H), 2.82-2.98 (m, 3H), 3.00-3.08 (m, 4H), 3.09-3.19 (m, 2H), 3.95-4.06 (m, 1H), 4.09-4.18 (m, 1H), 5.38-5.46 (m, 1H), 6.64-6.76 (m, 3H), 6.87 (s, 1H), 6.87 (s, 1H), 7.01-7.03 (t, J=1.8 Hz, 1H), 7.06 (t, J=8.1 Hz, 1H), 7.34 (d, J=1.8 Hz,2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.01-8.05 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.78-1.90 (m, 1H), 2.23-2.34 (m, 1H), 2.72-2.81 (m, 2H), 2.82-2.98 (m, 3H), 3.00 -3.08 (m, 4H), 3.09-3.19 (m, 2H), 3.95-4.06 (m, 1H), 4.09-4.18 (m, 1H), 5.38-5.46 (m, 1H), 6.64-6.76 (m, 3H), 6.87 (s, 1H), 6.87 (s, 1H), 7.01-7.03 (t, J = 1.8 Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 1.8 Hz, 2H), 7.51-7.62 (m, 2H), 7.86-7.89 (m, 2H), 7.93-7.96 (m, 1H), 8.01-8.05 (m, 1H), 8.59 (s, 1H).
<< 실시예Example 84> 1-(3,5- 84> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-4-(4-(4-) -4- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-3-일-) Piperazin-1-yl) piperidin-3-yl- 바bar 이페닐-4-카르복실레이트의 제조Preparation of Diphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 5에서 제조된 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 81과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 96%).4- (4- (4-fluorophenyl) prepared in Example 5 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 81 to obtain the target compound (yield: 96% ).
1H NMR(CDCl3, 300 MHz):δ1.72- 1.86 (m, 1H), 2.22-2.28 (m, 1H), 2.74-2.88 (m, 3H), 2.89-3.02 (m, 6H), 3.04-3.18 (m, 2H), 3.95-4.04 (m, 1H), 4.08-4.17 (m, 1H), 5.33-5.42 (m, 1H), 6.75-6.81 (m, 2H), 6.85-6.95 (m, 3H), 7.01 (t, J=1.8 Hz, 1H), 7.33 (d, J=1.8 Hz,, 2H), 7.36-7.50 (m, 3H), 7.58-7.68 (m, 4H), 8.06-8.11 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ1.72- 1.86 (m, 1H), 2.22-2.28 (m, 1H), 2.74-2.88 (m, 3H), 2.89-3.02 (m, 6H), 3.04 -3.18 (m, 2H), 3.95-4.04 (m, 1H), 4.08-4.17 (m, 1H), 5.33-5.42 (m, 1H), 6.75-6.81 (m, 2H), 6.85-6.95 (m, 3H), 7.01 (t, J = 1.8 Hz, 1H), 7.33 (d, J = 1.8 Hz ,, 2H), 7.36-7.50 (m, 3H), 7.58-7.68 (m, 4H), 8.06-8.11 ( m, 2H).
<< 실시예Example 85> 1-(3,5- 85> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-4-(4-(4-) -4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트의 제조Preparation of Piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 7에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 81과 동일한 방법으로 수행하 여 목적화합물을 수득하였다(수율: 99%).4- (4- (4-methoxyphenyl) obtained in Example 7 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate A target compound was obtained by the same method as Example 81 except for using the piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate (yield: 99). %).
1H NMR(CDCl3, 300 MHz):δ 1.70- 1.85 (m, 1H), 2.20-2.28 (m, 1H), 2.74-2.88 (m, 3H), 2.89-3.01 (m, 6H), 3.02-3.18 (m, 2H), 3.72 (s, 3H), 3.95-4.04 (m, 1H), 4.07-4.17 (m, 1H), 5.33-5.41 (m, 1H), 6.75-6.82 (m, 4H), 7.01 (t [singlet overlapped triplet], J=1.8 Hz, 2H), 7.33 (d, J=1.8 Hz,, 2H), 7.35-7.49 (m, 3H), 7.58-7.67 (m, 4H), 8.06-8.10 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.70- 1.85 (m, 1H), 2.20-2.28 (m, 1H), 2.74-2.88 (m, 3H), 2.89-3.01 (m, 6H), 3.02- 3.18 (m, 2H), 3.72 (s, 3H), 3.95-4.04 (m, 1H), 4.07-4.17 (m, 1H), 5.33-5.41 (m, 1H), 6.75-6.82 (m, 4H), 7.01 (t [singlet overlapped triplet], J = 1.8 Hz, 2H), 7.33 (d, J = 1.8 Hz ,, 2H), 7.35-7.49 (m, 3H), 7.58-7.67 (m, 4H), 8.06- 8.10 (m, 2 H).
<< 실시예Example 86> 1-(3,5- 86> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-4-(4-() -4- (4- ( 3-클로로페닐3-chlorophenyl )피페라진-1-일)피페리딘-3-일-) Piperazin-1-yl) piperidin-3-yl- 바이bye 페닐-4-카르복실레이트의 제조Preparation of Phenyl-4-carboxylate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 6에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-3-일-바이페닐-4-카르복실레이트를 사용하는 것을 제외하고는 실시예 81과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 81%).4- (4- (3-chlorophenyl) obtained in Example 6 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-biphenyl-4-carboxylate in the same manner as in Example 81, the target compound was obtained (yield: 81%). .
1H NMR(CDCl3, 300 MHz):δ1.70- 1.87 (m, 1H), 2.21-2.30 (m, 1H), 2.74-2.88 (m, 3H), 2.89-2.99 (m, 2H), 3.02-3.19 (m, 6H), 3.92-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.35-5.42 (m, 1H), 6.67-6.80 (m, 4H), 7.02 (t, J=1.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.34 (d, J=1.8 Hz,, 2H), 7.36-7.49 (m, 3H), 7.58-7.68 (m, 4H), 8.07-8.10 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ1.70- 1.87 (m, 1H), 2.21-2.30 (m, 1H), 2.74-2.88 (m, 3H), 2.89-2.99 (m, 2H), 3.02 -3.19 (m, 6H), 3.92-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.35-5.42 (m, 1H), 6.67-6.80 (m, 4H), 7.02 (t, J = 1.8 Hz, 1H), 7.10 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 1.8 Hz, 2H), 7.36-7.49 (m, 3H), 7.58-7.68 (m, 4H), 8.07 -8.10 (m, 2 H).
<< 실시예Example 87> 1-(3,5-디클로로페닐카바모일)-4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트의 제조 Preparation of 1- (3,5-dichlorophenylcarbamoyl) -4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트 대신 실시예 9에서 수득한 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 81과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 89%).4- (4- (4-fluorophenyl) obtained in Example 9 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-3-yl-2-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 81 to obtain the target compound (yield: 89%).
1H NMR(CDCl3, 300 MHz):δ1.68- 1.89 (m, 1H), 2.19-2.27 (m, 1H), 2.74-2.86 (m, 3H), 2.88-3.02 (m, 6H), 3.03-3.17 (m, 2H), 3.92-4.02 (m, 1H), 4.06-4.13 (m, 1H), 5.28-5.36 (m, 1H), 6.76-6.83 (m, 3H), 6.87-7.02 (m, 5H), 7.03-7.10 (m, 2H), 7.16-7.23 (m, 1H), 7.32 (d, d, J=1.8 Hz,, 2H), 7.34-7.42 (m, 2H), 7.95-8.01 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.68-1.89 (m, 1H), 2.19-2.27 (m, 1H), 2.74-2.86 (m, 3H), 2.88-3.02 (m, 6H), 3.03 -3.17 (m, 2H), 3.92-4.02 (m, 1H), 4.06-4.13 (m, 1H), 5.28-5.36 (m, 1H), 6.76-6.83 (m, 3H), 6.87-7.02 (m, 5H), 7.03-7.10 (m, 2H), 7.16-7.23 (m, 1H), 7.32 (d, d, J = 1.8 Hz, 2H), 7.34-7.42 (m, 2H), 7.95-8.01 (m , 2H).
<< 실시예Example 88> 1-(3,5- 88> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-4-(4-(4-) -4- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-3-일-4-) Piperazin-1-yl) piperidin-3-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-43일-2-나프토에이트 대신 실시예 11에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 81과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 89%).4- (4- (4-methoxyphenyl) obtained in Example 11 instead of 4- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-43yl-2-naphthoate Except for using piperazin-1-yl) piperidin-3-yl-4-phenoxybenzoate in the same manner as in Example 81 to obtain the target compound (yield: 89%).
1H NMR(CDCl3, 300 MHz):δ 1.66- 1.78 (m,1H), 2.16-2.25 (m, 1H), 2.74-2.84 (m, 3H), 2.86-3.03 (m, 6H), 3.04-3.16 (m, 2H), 3.74 (s, 3H), 3.92-4.02 (m, 1H), 4.05-4.14 (m, 1H), 5.28-5.37 (m, 1H), 6.76-6.83 (m, 4H), 6.94-7.00 (m, 4H), 7.03-7.08 (m, 2H), 7.16-7.22 (m, 1H), 7.32 (d, J=1.8 Hz,, 2H), 7.33-7.42 (m, 2H), 7.95-8.01 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.66- 1.78 (m, 1H), 2.16-2.25 (m, 1H), 2.74-2.84 (m, 3H), 2.86-3.03 (m, 6H), 3.04- 3.16 (m, 2H), 3.74 (s, 3H), 3.92-4.02 (m, 1H), 4.05-4.14 (m, 1H), 5.28-5.37 (m, 1H), 6.76-6.83 (m, 4H), 6.94-7.00 (m, 4H), 7.03-7.08 (m, 2H), 7.16-7.22 (m, 1H), 7.32 (d, J = 1.8 Hz, 2H), 7.33-7.42 (m, 2H), 7.95 -8.01 (m, 2 H).
<< 실시예Example 89> 3-(4-(4- 89> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 12에서 제조된 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 48 mg(0.11 mmol)과 (S)-메틸 2-이소시아네이토페닐프로판오에이트(0.13 mmol)를 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 85%).48 mg (0.11 mmol) and (S) -methyl 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23 except for reacting 2-isocyanatophenylpropanoate (0.13 mmol) (yield: 85%).
1H NMR(CDCl3, 300 MHz): δ 1.55-1.75 (m, 2H), 1.86-1.98 (m, 2H), 2.65-2.72 (m, 4H), 2.78-2.97 (m, 14H), 3.02-3.22 (m, 6H), 3.68 (s, 3H), 3.73 (s, 3H), 3.80-4.15 (m,4H), 4.72-5.04 (m,2H), 5.05-5.15 (m,2H), 5.16-5.26 (m,21H), 6.75-6.80 (m, 4H), 6.89 (t, J=8.7 Hz, 4H),7.12-7.33 (m, 10H), 7.52-7.62 (m,4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.55-1.75 (m, 2H), 1.86-1.98 (m, 2H), 2.65-2.72 (m, 4H), 2.78-2.97 (m, 14H), 3.02- 3.22 (m, 6H), 3.68 (s, 3H), 3.73 (s, 3H), 3.80-4.15 (m, 4H), 4.72-5.04 (m, 2H), 5.05-5.15 (m, 2H), 5.16- 5.26 (m, 21H), 6.75-6.80 (m, 4H), 6.89 (t, J = 8.7 Hz, 4H), 7.12-7.33 (m, 10H), 7.52-7.62 (m, 4H), 7.86-7.89 ( m, 4H), 7.94-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H).
<< 실시예Example 90> 3-(4-(4- 90> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2-일-2 days 카바모Cabamo 일)피페리딘-4-일-1-1) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 14에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 89와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 93%).4- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 89 to obtain the target compound (yield: 93%).
1H NMR는 하기 표 2에 나타내었다. 1 H NMR is shown in Table 2 below.
<< 실시예Example 91> 3-(4-(3- 91> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3-페닐프로판-2--1-oxo-3-phenylpropane-2- 일카바모일Ilkaba Mole )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 13에서 수득한 4-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 89와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 93%).4- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 89, the target compound was obtained (yield: 93%).
1H NMR(CDCl3, 300 MHz): δ1.55-1.70 (m, 2H), 1.85-2.00 (m, 2H), 2.62-2.73 (m,4H), 2.76-2.92 (m, 6H), 2.94-3.22 (m, 14H), 3.69 (s, 3H), 3.73 (s, 3H), 3.80-4.05 (m,2H), 4.06-4.20 (m,2H), 4.70-4.90 (m,2H), 5.00-5.10 (m,2H), 5.12-5.25 (m, 2H), 6.67-6.78 (m, 6H), 7.06-7.18 (m, 6H), 7.21-7.33 (m,6H), 7.51-7.62 (m, 4H),7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.01-8.05 (m, 2H), 8.58 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.55-1.70 (m, 2H), 1.85-2.00 (m, 2H), 2.62-2.73 (m, 4H), 2.76-2.92 (m, 6H), 2.94 -3.22 (m, 14H), 3.69 (s, 3H), 3.73 (s, 3H), 3.80-4.05 (m, 2H), 4.06-4.20 (m, 2H), 4.70-4.90 (m, 2H), 5.00 -5.10 (m, 2H), 5.12-5.25 (m, 2H), 6.67-6.78 (m, 6H), 7.06-7.18 (m, 6H), 7.21-7.33 (m, 6H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.01-8.05 (m, 2H), 8.58 (s, 2H).
<< 실시예Example 92> 3-(4-(4- 92> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 16에서 수득한 4-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 89와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 90%).4- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using the piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 89 to obtain the target compound (yield: 90%).
1H NMR(CDCl3, 300 MHz): δ1.50-1.75 (m, 2H), 1.85-2.00 (m, 2H), 2.64-2.82 (m,6H), 2.84-2.92 (m, 4H), 2.93-3.02 (m, 10H), 3.04-3.22 (m, 4H), 3.70 (s, 3H), 3.73 (s, 3H), 3.80-4.13 (m,4H), 4.71-4.85 (m,2H), 4.99-5.05 (m,2H), 5.08-5.21 (m,2H), 6.77-6.83 (m, 4H), 6.87-6.94 (m, 4H), 7.11-7.18 (m, 4H), 7.19-7.34 (m, 6H), 7.37-7.50 (m, 6H), 7.61-7.67 (m,, 8H), 8.07-8.10 (dd, J= 8.3 Hz & 1.0 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ1.50-1.75 (m, 2H), 1.85-2.00 (m, 2H), 2.64-2.82 (m, 6H), 2.84-2.92 (m, 4H), 2.93 -3.02 (m, 10H), 3.04-3.22 (m, 4H), 3.70 (s, 3H), 3.73 (s, 3H), 3.80-4.13 (m, 4H), 4.71-4.85 (m, 2H), 4.99 -5.05 (m, 2H), 5.08-5.21 (m, 2H), 6.77-6.83 (m, 4H), 6.87-6.94 (m, 4H), 7.11-7.18 (m, 4H), 7.19-7.34 (m, 6H), 7.37-7.50 (m, 6H), 7.61-7.67 (m, 8H), 8.07-8.10 (dd, J = 8.3 Hz & 1.0 Hz, 4H).
<< 실시예Example 93> 3-(4-(4- 93> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3-페닐프로판-2--1-oxo-3-phenylpropane-2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실 시예 18에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 89와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using the piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 89 to obtain the target compound (yield: 100% ).
1H NMR(CDCl3, 300 MHz): δ1.55-1.75 (m, 2H), 1.85-2.20 (m, 2H), 2.64-2.82 (m,6H), 2.83-2.92 (m, 4H), 2.93-3.04 (m, 10H), 3.05-3.20 (m, 4H), 3.69 (s, 6H), 3.72 (m, 3H), 3.73 (s, 3H), 3.83-4.15 (m,4H), 4.71-4.85 (m,2H), 5.05-5.09 (m, 2H), 5.11-5.21 (m,2H), 6.76-6.85 (m, 8H), 7.10-7.19 (m, 4H), 7.20-7.34 (m, 6H), 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.07-8.10 (dd, J= 8.6 Hz & 1.2 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.55-1.75 (m, 2H), 1.85-2.20 (m, 2H), 2.64-2.82 (m, 6H), 2.83-2.92 (m, 4H), 2.93 -3.04 (m, 10H), 3.05-3.20 (m, 4H), 3.69 (s, 6H), 3.72 (m, 3H), 3.73 (s, 3H), 3.83-4.15 (m, 4H), 4.71-4.85 (m, 2H), 5.05-5.09 (m, 2H), 5.11-5.21 (m, 2H), 6.76-6.85 (m, 8H), 7.10-7.19 (m, 4H), 7.20-7.34 (m, 6H) , 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.07-8.10 (dd, J = 8.6 Hz & 1.2 Hz, 4H).
<< 실시예Example 94> 3-(4-(3- 94> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3-페닐프로판-2--1-oxo-3-phenylpropane-2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 17에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 89와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 89, the target compound was obtained (yield: 100%) .
1H NMR(CDCl3, 300 MHz): δ1.55-1.75 (m, 2H), 1.85-2.20 (m, 2H), 2.64-2.82 (m,6H), 2.83-2.92 (m, 4H), 2.93-3.04 (m, 10H), 3.05-3.20 (m, 4H), 3.69 (s, 6H), 3.72 (m, 3H), 3.73 (s, 3H), 3.83-4.15 (m,4H), 4.71-4.85 (m,2H), 5.05-5.09 (m, 2H), 5.11-5.21 (m,2H), 6.76-6.85 (m, 8H), 7.10-7.19 (m, 4H), 7.20-7.34 (m, 6H), 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.07-8.10 (dd, J= 8.6 Hz & 1.2 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.55-1.75 (m, 2H), 1.85-2.20 (m, 2H), 2.64-2.82 (m, 6H), 2.83-2.92 (m, 4H), 2.93 -3.04 (m, 10H), 3.05-3.20 (m, 4H), 3.69 (s, 6H), 3.72 (m, 3H), 3.73 (s, 3H), 3.83-4.15 (m, 4H), 4.71-4.85 (m, 2H), 5.05-5.09 (m, 2H), 5.11-5.21 (m, 2H), 6.76-6.85 (m, 8H), 7.10-7.19 (m, 4H), 7.20-7.34 (m, 6H) , 7.36-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.07-8.10 (dd, J = 8.6 Hz & 1.2 Hz, 4H).
<< 실시예Example 95> 3-(4-(4- 95> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3--1-oxo-3- 페닐프로판Phenylpropane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 20에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 89와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 85%).3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 89 to obtain the target compound (yield: 85%).
1H NMR(CDCl3, 300 MHz): δ1.50-1.69 (m, 2H), 1.80-1.92 (m, 2H), 2.60-2.78 (m, 6H), 2.80-2.89 (m, 4H), 2.90-3.03 (m, 10H), 3.05-3.20 (m, 4H), 3.70 (s, 3H), 3.72 (s, 3H), 3.80-4.13 (m,4H), 4.71-4.83 (m, 2H), 4.99-5.17 (m, 4H), 6.75-6.82 (m, 4H), 6.78-6.83 (m, 4H), 6.87-7.00 (m, 8H), 7.04-7.32 (m, 16H), 7.35-7.42 (m, 4H), 7.96-8.00 (m,4H). 1 H NMR (CDCl 3 , 300 MHz): δ1.50-1.69 (m, 2H), 1.80-1.92 (m, 2H), 2.60-2.78 (m, 6H), 2.80-2.89 (m, 4H), 2.90 -3.03 (m, 10H), 3.05-3.20 (m, 4H), 3.70 (s, 3H), 3.72 (s, 3H), 3.80-4.13 (m, 4H), 4.71-4.83 (m, 2H), 4.99 -5.17 (m, 4H), 6.75-6.82 (m, 4H), 6.78-6.83 (m, 4H), 6.87-7.00 (m, 8H), 7.04-7.32 (m, 16H), 7.35-7.42 (m, 4H), 7.96-8.00 (m, 4H).
<< 실시예Example 96> 3-(4-(4- 96> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1-옥소-3-페닐프로판-2--1-oxo-3-phenylpropane-2- 일카바모일Ilkaba Mole )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 22에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 89와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 90%).3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 89 to obtain the target compound (yield: 90%).
11H NMR(CDCl3, 300 MHz): δ 1.55-1.70 (m, 2H), 1.85-1.95 (m, 2H), 2.65-2.78 (m, 6H), 2.80-2.90 (m, 4H), 2.91-3.02 (m, 10H), 3.03-3.13 (m, 4H), 3.70 (s, 3H), 3.72 (m, 3H), 3.74 (s, 6H), 3.80-4.13 (m,4H), 4.70-4.83 (m,2H), 5.00-5.15 (m,4H), 6.78-6.86 (m, 8H), 6.95-7.01 (m, 4H), 7.04-7.20 (m,8H), 7.21-7.33 (m, 8H), 7.35-7.41 (m, 4H), 7.95-8.01 (m, 4H). 11 H NMR (CDCl 3 , 300 MHz): δ 1.55-1.70 (m, 2H), 1.85-1.95 (m, 2H), 2.65-2.78 (m, 6H), 2.80-2.90 (m, 4H), 2.91- 3.02 (m, 10H), 3.03-3.13 (m, 4H), 3.70 (s, 3H), 3.72 (m, 3H), 3.74 (s, 6H), 3.80-4.13 (m, 4H), 4.70-4.83 ( m, 2H), 5.00-5.15 (m, 4H), 6.78-6.86 (m, 8H), 6.95-7.01 (m, 4H), 7.04-7.20 (m, 8H), 7.21-7.33 (m, 8H), 7.35-7.41 (m, 4 H), 7.95-8.01 (m, 4 H).
<< 실시예Example 97> 3-(4-(4- 97> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2-일-2 days 카바모Cabamo 일)피페리딘-4-일-1-1) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 12에서 제조된 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 48 mg(0.11 mmol)과 (S)-메틸 2-이소시아네이토-4-메틸펜탄오에이트(0.13 mmol)를 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 86%).48 mg (0.11 mmol) and (S) -methyl 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23 except for reacting 2-isocyanato-4-methylpentaneoate (0.13 mmol) (yield: 86%).
1H NMR(CDCl3, 300 MHz): δ 0.87 (d,J=6.5 Hz 6H), 0.97 (d, J=6.5 Hz 6H), 1.48-1.78 (m, 8H), 1.95-2.01 (m, 2H), 2.67-2.80 (m,4H), 2.83-3.05 (m, 14H), 3.08-3.17 (m, 2H), 3.70 (s, 3H), 3.74 (s, 3H), 3.95-4.06 (m,2H), 4.10-4.18 (m, 2H), 4.44-4.57 (m,2H), 4.97-5.04 (m, 2H), 5.18-5.27 (m, 2H), 6.74-6.80 (m, 4H), 6.84-6.92 (m,4H), 7.52-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.87 (d, J = 6.5 Hz 6H), 0.97 (d, J = 6.5 Hz 6H), 1.48-1.78 (m, 8H), 1.95-2.01 (m, 2H ), 2.67-2.80 (m, 4H), 2.83-3.05 (m, 14H), 3.08-3.17 (m, 2H), 3.70 (s, 3H), 3.74 (s, 3H), 3.95-4.06 (m, 2H ), 4.10-4.18 (m, 2H), 4.44-4.57 (m, 2H), 4.97-5.04 (m, 2H), 5.18-5.27 (m, 2H), 6.74-6.80 (m, 4H), 6.84-6.92 (m, 4H), 7.52-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 98> 3-(4-(4- 98> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1-옥소펜탄-2--1-oxopentan-2- 일카바모일Ilkaba Mole )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 14에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이를 사용하는 것을 제외하고는 실시예 97과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 59%).3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoA in the same manner as in Example 97 to obtain the target compound (yield: 59%).
1H NMR(CDCl3, 300 MHz): δ 0.85 (d,J=6.4 Hz 6H), 0.97 (d, J=6.4 Hz 6H), 1.50-1.80 (m, 8H), 1.95-2.03 (m, 2H), 2.68-2.80 (m,4H), 2.83-3.02 (m, 14H), 3.03-3.19 (m, 2H), 3.70 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.74 (s, 3H), 3.95-4.06 (m,2H), 4.10-4.20 (m, 2H), 4.45-4.55 (m, 2H), 4.96-5.02 (m, 2H), 5.19-5.30 (m, 2H), 6.74-6.83 (m, 8H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.95 (m, 2H), 8.02-8.05 (m,2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.85 (d, J = 6.4 Hz 6H), 0.97 (d, J = 6.4 Hz 6H), 1.50-1.80 (m, 8H), 1.95-2.03 (m, 2H ), 2.68-2.80 (m, 4H), 2.83-3.02 (m, 14H), 3.03-3.19 (m, 2H), 3.70 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.74 (s, 3H), 3.95-4.06 (m, 2H), 4.10-4.20 (m, 2H), 4.45-4.55 (m, 2H), 4.96-5.02 (m, 2H), 5.19-5.30 (m, 2H ), 6.74-6.83 (m, 8H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.95 (m, 2H), 8.02-8.05 (m, 2H), 8.59 (s , 2H).
<< 실시예Example 99> 3-(4-(3- 99> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane - 2-- 2- 일카바모일Ilkaba Mole )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 13에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 97과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 81%).3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphate , the same procedure as in Example 97 was carried out to obtain the target compound (yield: 81%).
1H NMR(CDCl3, 300 MHz): δ 0.89 (d, J= 6.5 Hz, 6H), 0.97 (d, J= 6.5 Hz, 6H), 1.49-1.75 (m, 8H), 1.90-2.05 (m, 2H), 2.64-2.74 (m, 4H), 2.80-2.92 (m, 6H), 2.94-3.16 (m, 10H), 3.71 (s, 3H), 3.74 (s, 3H), 3.95-4.07 (m,2H), 4.10-4.18 (m, 2H), 4.46-4.57 (m, 2H), 4.99-5.05 (m, 2H), 5.19-5.30 (m, 2H), 6.66-6.79 (m, 6H), 7.05-7.11 (m, 2H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.89 (d, J = 6.5 Hz, 6H), 0.97 (d, J = 6.5 Hz, 6H), 1.49-1.75 (m, 8H), 1.90-2.05 (m , 2H), 2.64-2.74 (m, 4H), 2.80-2.92 (m, 6H), 2.94-3.16 (m, 10H), 3.71 (s, 3H), 3.74 (s, 3H), 3.95-4.07 (m , 2H), 4.10-4.18 (m, 2H), 4.46-4.57 (m, 2H), 4.99-5.05 (m, 2H), 5.19-5.30 (m, 2H), 6.66-6.79 (m, 6H), 7.05 -7.11 (m, 2H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H).
<< 실시예Example 100> 3-(4-(4- 100> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 16에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 97과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 75%).3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 97 to obtain the target compound (yield: 75% ).
1H NMR(CDCl3, 300 MHz): δ 0.91 (d, J= 6.4 Hz, 3H), 0.92 (d, J= 6.4 Hz, 3H) 0.97 (d, J= 6.4 Hz, 6H), 1.49-1.76 (m, 8H), 1.90-2.05 (m, 2H), 2.69-2.82 (m, 4H), 2.83-2.94 (m, 4H), 2.97-3.03 (m, 10H), 3.04-3.13 (m, 2H), 3.72 (s, 3H), 3.74 (s, 3H), 3.92-4.05 (m,2H), 4.10-4.16 (m, 2H), 4.46-4.56 (m, 2H), 4.97-5.03 (m, 2H), 5.12-5.25 (m, 2H), 6.77-6.85 (m, 4H), 6.87-6.95 (m, 4H), 7.36-7.49 (m, 6H), 7.60-7.68 (m, 8H), 8.08 (d, J=8.0 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.91 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H) 0.97 (d, J = 6.4 Hz, 6H), 1.49-1.76 (m, 8H), 1.90-2.05 (m, 2H), 2.69-2.82 (m, 4H), 2.83-2.94 (m, 4H), 2.97-3.03 (m, 10H), 3.04-3.13 (m, 2H) , 3.72 (s, 3H), 3.74 (s, 3H), 3.92-4.05 (m, 2H), 4.10-4.16 (m, 2H), 4.46-4.56 (m, 2H), 4.97-5.03 (m, 2H) , 5.12-5.25 (m, 2H), 6.77-6.85 (m, 4H), 6.87-6.95 (m, 4H), 7.36-7.49 (m, 6H), 7.60-7.68 (m, 8H), 8.08 (d, J = 8.0 Hz, 4H).
<< 실시예Example 101> 3-(4-(4- 101> 3- (4- (4- 메톡시로페닐Methoxylophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 18에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 97과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 96%).3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 97 to obtain the target compound (yield: 96% ).
1H NMR(CDCl3, 300 MHz): δ 0.91 (d, J= 6.5 Hz, 3H), 0.92 (d, J= 6.5 Hz, 3H) 0.97 (d, J= 6.5 Hz, 6H), 1.50-1.77 (m, 8H), 1.90-2.05 (m, 2H), 2.69-2.82 (m, 6H), 2.83-2.94 (m, 4H), 2.95-3.01 (m, 8H), 3.04-3.14 (m, 2H), 3.70 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.74 (s, 3H), 3.92-4.05 (m, 2H), 4.08-4.15 (m, 2H), 4.45-4.56 (m, 2H), 4.98-5.04 (m, 2H), 5.15-5.25 (m, 2H), 6.77- 6.86 (m, 8H), 7.35-7.49 (m, 6H), 7.58-7.67 (m, 8H), 8.07-8.10 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.91 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H) 0.97 (d, J = 6.5 Hz, 6H), 1.50-1.77 (m, 8H), 1.90-2.05 (m, 2H), 2.69-2.82 (m, 6H), 2.83-2.94 (m, 4H), 2.95-3.01 (m, 8H), 3.04-3.14 (m, 2H) , 3.70 (s, 3H), 3.72 (s, 3H), 3.73 (s, 3H), 3.74 (s, 3H), 3.92-4.05 (m, 2H), 4.08-4.15 (m, 2H), 4.45-4.56 (m, 2H), 4.98-5.04 (m, 2H), 5.15-5.25 (m, 2H), 6.77-6.86 (m, 8H), 7.35-7.49 (m, 6H), 7.58-7.67 (m, 8H), 8.07-8.10 (m, 4H).
<< 실시예Example 102> 3-(4-(3- 102> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1-옥소펜탄-2--1-oxopentan-2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 17에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 97과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 81%).3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 97, the target compound was obtained (yield: 81%) .
1H NMR(CDCl3, 300 MHz): δ0.91-0.98 (m, 12H), 1.45-1.79 (m, 8H), 1.90-2.00 (m, 2H), 2.66-2.82 (m, 4H), 2.84-2.91 (m, 6H), 2.95-3.12 (m, 10H), 3.72 (s, 3H), 3.74 (s, 3H), 3.92-4.06 (m, 2H), 4.08-4.15 (m, 2H), 4.45-4.56 (m, 2H), 4.97-5.06 (m, 2H), 5.10-5.25 (m, 2H), 6.69-6.84 (m, 6H), 7.08-7.15 (m, 2H), 7.36-7.49 (m, 6H), 7.60-7.68 (m, 8H), 8.07 (d, J= 8.0 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.91-0.98 (m, 12H), 1.45-1.79 (m, 8H), 1.90-2.00 (m, 2H), 2.66-2.82 (m, 4H), 2.84 -2.91 (m, 6H), 2.95-3.12 (m, 10H), 3.72 (s, 3H), 3.74 (s, 3H), 3.92-4.06 (m, 2H), 4.08-4.15 (m, 2H), 4.45 -4.56 (m, 2H), 4.97-5.06 (m, 2H), 5.10-5.25 (m, 2H), 6.69-6.84 (m, 6H), 7.08-7.15 (m, 2H), 7.36-7.49 (m, 6H), 7.60-7.68 (m, 8H), 8.07 (d, J = 8.0 Hz, 4H).
<< 실시예Example 103> 3-(4-(4- 103> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1--One- 옥소펜탄Oxopentane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 20에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 97과 동일한 방법으로 수행하여 목 적화합물을 수득하였다(수율: 63%).3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate A target compound was obtained in the same manner as in Example 97 except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield: 63%). .
1H NMR(CDCl3, 300 MHz): δ 0.92 (d, J= 6.4 Hz, 3H), 0.93 (d, J= 6.4 Hz, 3H), 0.96 (d, J= 6.4 Hz, 6H), 1.45-1.79 (m, 8H), 1.90-2.00 (m, 2H), 2.66-2.85 (m, 6H), 2.86-2.94 (m, 4H), 2.97-3.02 (m, 8H), 3.04-3.10 (m, 2H), 3.72 (s, 3H), 3.73 (s, 3H), 3.90-4.00 (m, 2H), 4.02-4.11 (m, 2H), 4.43-4.55 (m, 2H), 4.95-5.03 (m, 2H), 5.09-5.19 (m, 2H), 6.78-6.85 (m, 4H), 6.88-7.01 (m, 8H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.96-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.92 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 6.4 Hz, 6H), 1.45- 1.79 (m, 8H), 1.90-2.00 (m, 2H), 2.66-2.85 (m, 6H), 2.86-2.94 (m, 4H), 2.97-3.02 (m, 8H), 3.04-3.10 (m, 2H ), 3.72 (s, 3H), 3.73 (s, 3H), 3.90-4.00 (m, 2H), 4.02-4.11 (m, 2H), 4.43-4.55 (m, 2H), 4.95-5.03 (m, 2H) ), 5.09-5.19 (m, 2H), 6.78-6.85 (m, 4H), 6.88-7.01 (m, 8H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.96-8.01 (m, 4H).
<< 실시예Example 104> 3-(4-(4- 104> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -4--4- 메틸methyl -1-옥소펜탄-2--1-oxopentan-2- 일카바모일Ilkaba Mole )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 22에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 97과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 62%).3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 97 to obtain the target compound (yield: 62%).
1H NMR(CDCl3, 300 MHz): δ 0.92 (d, J= 6.3 Hz, 3H), 0.93 (d, J= 6.3 Hz, 3H), 0.96 (d, J= 6.3 Hz, 6H), 1.50-1.78 (m, 8H), 1.90-2.00 (m, 2H), 2.66-2.80 (m, 6H), 2.83-2.92 (m, 4H), 2.95-3.04 (m, 8H), 3.05-3.10 (m, 2H), 3.72 (s, 3H), 3.73 (s, 3H), 3.75 (s, 6H), 3.90-4.00 (m, 2H), 4.02-4.13 (m, 2H), 4.42-4.55 (m, 2H), 4.95-5.02 (m, 2H), 5.07-5.20 (m, 2H), 6.78-6.86 (m, 8H), 6.98 (d, J=8.8 Hz, 4H), 7.07 (d, J=8.3 Hz, 4H), 7.19 (t, J=7.4 Hz, 2H 2H), 7.35-7.42 (m, 4H), 7.97-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.92 (d, J = 6.3 Hz, 3H), 0.93 (d, J = 6.3 Hz, 3H), 0.96 (d, J = 6.3 Hz, 6H), 1.50- 1.78 (m, 8H), 1.90-2.00 (m, 2H), 2.66-2.80 (m, 6H), 2.83-2.92 (m, 4H), 2.95-3.04 (m, 8H), 3.05-3.10 (m, 2H ), 3.72 (s, 3H), 3.73 (s, 3H), 3.75 (s, 6H), 3.90-4.00 (m, 2H), 4.02-4.13 (m, 2H), 4.42-4.55 (m, 2H), 4.95-5.02 (m, 2H), 5.07-5.20 (m, 2H), 6.78-6.86 (m, 8H), 6.98 (d, J = 8.8 Hz, 4H), 7.07 (d, J = 8.3 Hz, 4H), 7.19 (t, J = 7.4 Hz, 2H 2H), 7.35-7.42 (m, 4H), 7.97-8.01 (m, 4H).
<< 실시예Example 105> 3-(4-(4- 105> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 12에서 제조된 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 48 mg(0.11 mmol)과 (S)-메틸 2-이소시아네이토-3-메틸부탄오에이트(0.13 mmol)를 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 78%).48 mg (0.11 mmol) and (S) -methyl 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23 except that 2-isocyanato-3-methylbutanoate (0.13 mmol) was reacted (yield: 78%).
H NMR(CDCl3, 300 MHz): δ0.90-1.00 (m, 12H), 1.65-1.76 (m, 2H), 1.95-2.05 (m, 2H), 2.10-2.20 (m, 2H), 2.68-2.78 (m,4H), 2.80-2.94 (m, 2H), 2.96-3.04 (m, 12H), 3.08-3.18 (m, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 3.99-4.12 (m, 2H), 4.13-4.21 (m, 2H), 4.40-4.49 (m,2H), 5.10-5.15 (m, 2H), 5.18-5.30 (m,2H), 6.74-6.82 (m, 4H), 6.86-6.92 (m, 4H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m,, 2H), 8.59 (s, 2H).H NMR (CDCl 3 , 300 MHz): δ 0.90-1.00 (m, 12H), 1.65-1.76 (m, 2H), 1.95-2.05 (m, 2H), 2.10-2.20 (m, 2H), 2.68- 2.78 (m, 4H), 2.80-2.94 (m, 2H), 2.96-3.04 (m, 12H), 3.08-3.18 (m, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 3.99- 4.12 (m, 2H), 4.13-4.21 (m, 2H), 4.40-4.49 (m, 2H), 5.10-5.15 (m, 2H), 5.18-5.30 (m, 2H), 6.74-6.82 (m, 4H ), 6.86-6.92 (m, 4H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.02-8.06 (m ,, 2H), 8.59 ( s, 2H).
<< 실시예Example 106> 3-(4-(4- 106> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1-옥소부탄- 2--1-oxobutane-2 일카바모일Ilkaba Mole )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 14에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 105와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 84%).3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 105 to obtain the target compound (yield: 84%).
1H NMR(CDCl3, 300 MHz): δ0.88-1.00 (m, 12H), 1.65-1.81 (m, 2H), 1.95-2.05 (m, 2H), 2.10-2.20 (m, 2H), 2.68-2.78 (m, 4H), 2.80-3.00 (m, 12H), 3.01-3.20 (m, 4H), 3.69 (s, 3H), 3.73 (s, 6H), 3.74 (s, 3H), 3.95-4.11 (m, 2H), 4.13-4.20 (m, 2H), 4.40-4.49 (m, 2H), 5.08-5.13 (m, 2H), 5.18-5.30 (m,2H), 6.75-6.82 (m, 8H), 7.51-7.62 (m, 4H), 7.85-7.89 (m, 4H), 7.94-7.7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.98-1.00 (m, 12H), 1.65-1.81 (m, 2H), 1.95-2.05 (m, 2H), 2.10-2.20 (m, 2H), 2.68 -2.78 (m, 4H), 2.80-3.00 (m, 12H), 3.01-3.20 (m, 4H), 3.69 (s, 3H), 3.73 (s, 6H), 3.74 (s, 3H), 3.95-4.11 (m, 2H), 4.13-4.20 (m, 2H), 4.40-4.49 (m, 2H), 5.08-5.13 (m, 2H), 5.18-5.30 (m, 2H), 6.75-6.82 (m, 8H) , 7.51-7.62 (m, 4H), 7.85-7.89 (m, 4H), 7.94-7.7.97 (m, 2H), 8.02-8.06 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 107> 3-(4-(3- 107> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1-옥소부탄-2--1-oxobutane-2- 일카바모일Ilkaba Mole )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 13에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 105와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 82%).3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 105, the target compound was obtained (yield: 82%).
1H NMR(CDCl3, 300 MHz): δ0.88-1.00 (m, 12H), 1.65-1.80 (m, 2H), 1.95-2.05 (m, 2H), 2.09-2.19 (m, 2H), 2.65-2.78 (m, 4H), 2.80-2.95 (m, 6H), 2.96-3.07 (m, 8H), 3.09-3.17 (m, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 3.95-4.09 (m, 2H), 4.10-4.22 (m, 2H), 4.41-4.49 (m, 2H), 5.09-5.15 (m, 2H), 5.18-5.29 (m, 2H), 6.67-6.79 (m, 6H), 7.05-7.11 (m, 2H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-8.01 (m, 2H), 8.02-8.05 (m, 2H), 8.58 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.98-1.00 (m, 12H), 1.65-1.80 (m, 2H), 1.95-2.05 (m, 2H), 2.09-2.19 (m, 2H), 2.65 -2.78 (m, 4H), 2.80-2.95 (m, 6H), 2.96-3.07 (m, 8H), 3.09-3.17 (m, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 3.95 -4.09 (m, 2H), 4.10-4.22 (m, 2H), 4.41-4.49 (m, 2H), 5.09-5.15 (m, 2H), 5.18-5.29 (m, 2H), 6.67-6.79 (m, 6H), 7.05-7.11 (m, 2H), 7.51-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-8.01 (m, 2H), 8.02-8.05 (m, 2H), 8.58 ( s, 2H).
<< 실시예Example 108> 3-(4-(4- 108> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 16에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 105와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 88%).3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 105 to obtain the target compound (yield: 88% ).
1H NMR(CDCl3, 300 MHz): δ0.90-1.00 (m, 12H), 1.65-1.80 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.70-2.84 (m, 4H), 2.85-2.95 (m, 4H), 2.96-3.04 (m, 10H), 3.05-3.13 (m, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 3.95-4.05 (m, 2H), 4.10-4.18 (m, 2H), 4.39-4.48 (m, 2H), 5.08-5.15 (m, 2H), 5.17-5.25 (m, 2H), 6.77-6.84 (m, 4H), 6.87-6.95 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.67 (m, 8H), 8.09 (d, J= 8.1 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.90-1.00 (m, 12H), 1.65-1.80 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.70 -2.84 (m, 4H), 2.85-2.95 (m, 4H), 2.96-3.04 (m, 10H), 3.05-3.13 (m, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 3.95 -4.05 (m, 2H), 4.10-4.18 (m, 2H), 4.39-4.48 (m, 2H), 5.08-5.15 (m, 2H), 5.17-5.25 (m, 2H), 6.77-6.84 (m, 4H), 6.87-6.95 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.67 (m, 8H), 8.09 (d, J = 8.1 Hz, 4H).
<< 실시예Example 109> 3-(4-(4- 109> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1-옥소부탄-2--1-oxobutane-2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 18에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 105와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 82%).3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 105 to obtain the target compound (yield: 82% ).
1H NMR(CDCl3, 300 MHz): δ0.91-1.00 (m, 12H), 1.65-1.80 (m, 2H), 1.92-2.01 (m, 2H), 2.10-2.20 (m, 2H), 2.69-2.80 (m, 4H), 2.82-2.92 (m, 4H), 2.96-3.02 (m, 10H), 3.04-3.14 (m, 2H), 3.71 (s, 3H), 3.74 (s, 6H), 3.75 (s, 3H), 3.95-4.05 (m, 2H), 4.08-4.17 (m, 2H), 4.39-4.48 (m, 2H), 5.08-5.13 (m, 2H), 5.16-5.22 (m, 2H), 6.77-6.86 (m, 8H), 7.37-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.09 (d, J= 8.1 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.91-1.00 (m, 12H), 1.65-1.80 (m, 2H), 1.92-2.01 (m, 2H), 2.10-2.20 (m, 2H), 2.69 -2.80 (m, 4H), 2.82-2.92 (m, 4H), 2.96-3.02 (m, 10H), 3.04-3.14 (m, 2H), 3.71 (s, 3H), 3.74 (s, 6H), 3.75 (s, 3H), 3.95-4.05 (m, 2H), 4.08-4.17 (m, 2H), 4.39-4.48 (m, 2H), 5.08-5.13 (m, 2H), 5.16-5.22 (m, 2H) , 6.77-6.86 (m, 8H), 7.37-7.49 (m, 6H), 7.60-7.67 (m, 8H), 8.09 (d, J = 8.1 Hz, 4H).
<< 실시예Example 110> 3-(4-(3- 110> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1-옥소부탄-2--1-oxobutane-2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 17에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3- 카르복실레이트를 사용하는 것을 제외하고는 실시예 105와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 77%).3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3- carboxylate in the same manner as in Example 105, the target compound was obtained (yield: 77%) .
1H NMR(CDCl3, 300 MHz): δ0.91-1.00 (m, 12H), 1.65-1.73 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.66-2.77 (m, 4H), 2.78-2.92 (m, 6H), 2.94-3.12 (m, 10H), 3.72 (s, 3H), 3.75 (s, 3H), 3.95-4.06 (m, 2H), 4.08-4.17 (m, 2H), 4.39-4.48 (m, 2H), 5.08-5.14 (m, 2H), 5.16-5.22 (m, 2H), 6.70-6.84 (m, 6H), 7.08-7.13 (m, 2H), 7.36-7.49 (m, 6H), 7.59-7.67 (m, 8H), 8.08 (d, J= 8.0 Hz, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.91-1.00 (m, 12H), 1.65-1.73 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.66 -2.77 (m, 4H), 2.78-2.92 (m, 6H), 2.94-3.12 (m, 10H), 3.72 (s, 3H), 3.75 (s, 3H), 3.95-4.06 (m, 2H), 4.08 -4.17 (m, 2H), 4.39-4.48 (m, 2H), 5.08-5.14 (m, 2H), 5.16-5.22 (m, 2H), 6.70-6.84 (m, 6H), 7.08-7.13 (m, 2H), 7.36-7.49 (m, 6H), 7.59-7.67 (m, 8H), 8.08 (d, J = 8.0 Hz, 4H).
<< 실시예Example 111> 3-(4-(4- 111> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1--One- 옥소부탄Oxobutane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 20에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 105와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 86%).3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 105 to obtain the target compound (yield: 86%).
1H NMR(CDCl3, 300 MHz): δ0.90-0.99 (m, 12H), 1.65-1.79 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.67-2.80 (m, 6H), 2.81-2.92 (m, 4H), 2.93-3.01 (m, 8H), 3.05-3.09 (m, 2H), 3.72 (s, 3H), 3.74 (s, 3H), 3.95-4.04 (m, 2H), 4.05-4.15 (m, 2H), 4.38-4.47 (m, 2H), 5.07-5.12 (m, 2H), 5.13-5.20 (m, 2H), 6.78-6.83 (m, 4H), 6.88-7.00 (m, 8H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.96-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.90-0.99 (m, 12H), 1.65-1.79 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.67 -2.80 (m, 6H), 2.81-2.92 (m, 4H), 2.93-3.01 (m, 8H), 3.05-3.09 (m, 2H), 3.72 (s, 3H), 3.74 (s, 3H), 3.95 -4.04 (m, 2H), 4.05-4.15 (m, 2H), 4.38-4.47 (m, 2H), 5.07-5.12 (m, 2H), 5.13-5.20 (m, 2H), 6.78-6.83 (m, 4H), 6.88-7.00 (m, 8H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.96-8.01 (m, 4H).
<< 실시예Example 112> 3-(4-(4- 112> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -3--3- 메틸methyl -1-옥소부탄-2--1-oxobutane-2- 일카바모일Ilkaba Mole )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 22에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 105와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 58%).3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 105 to obtain the target compound (yield: 58%).
1H NMR(CDCl3, 300 MHz): δ0.92-0.99 (m, 12H), 1.63-1.78 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.69-2.80 (m, 6H), 2.82-2.90 (m, 4H), 2.95-3.00 (m, 8H), 3.01-3.10 (m, 2H), 3.72 (s, 3H), 3.74 (s, 6H), 3.75 (s, 3H), 3.94-4.04 (m, 2H), 4.05-4.15 (m, 2H), 4.38-4.47 (m, 2H), 5.05-5.11 (m, 2H), 5.12-5.20 (m, 2H), 6.78-6.86 (m, 8H), 6.96-7.01 (m, 4H), 7.04-7.08 (m, 4H), 7.15-7.25 (m, 2H), 7.36-7.42 (m, 4H), 7.96-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 0.92-0.99 (m, 12H), 1.63-1.78 (m, 2H), 1.90-2.00 (m, 2H), 2.10-2.20 (m, 2H), 2.69 -2.80 (m, 6H), 2.82-2.90 (m, 4H), 2.95-3.00 (m, 8H), 3.01-3.10 (m, 2H), 3.72 (s, 3H), 3.74 (s, 6H), 3.75 (s, 3H), 3.94-4.04 (m, 2H), 4.05-4.15 (m, 2H), 4.38-4.47 (m, 2H), 5.05-5.11 (m, 2H), 5.12-5.20 (m, 2H) , 6.78-6.86 (m, 8H), 6.96-7.01 (m, 4H), 7.04-7.08 (m, 4H), 7.15-7.25 (m, 2H), 7.36-7.42 (m, 4H), 7.96-8.01 ( m, 4H).
<< 실시예Example 113> 3-(4-(4- 113> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2-일카바모일)피페리딘-4-일-1--2-ylcarbamoyl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 12에서 제조된 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 48 mg(0.11 mmol)과 (S)-메틸 2-이소시아네이토프로판오에이트(0.13 mmol)를 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 85%).48 mg (0.11 mmol) and (S) -methyl 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23 except for reacting 2-isocyanatopropaneoate (0.13 mmol) (yield: 85%).
1H NMR(CDCl3, 300 MHz): δ 1.37 (d, J= 7.2 Hz, 3H), 1.42 (d, J= 7.2 Hz, 3H), 1.65-1.75 (m, 2H), 1.95-2.05 (m, 2H), 2.68-2.78 (m,4H), 2.80-3.02 (m, 14H), 3.05-3.15 (m, 2H), 3.72 (s, 3H), 3.76 (s, 3H), 3.95-4.08 (m,2H), 4.10-4.20 (m, 2H), 4.42-4.55 (m, 2H), 5.17-5.28 (m, 4H), 6.74-6.81 (m, 4H), 6.84-6.92 (m, 4H), 7.51-7.62 (m, 4H), 7.86-7.89(m,4H),7.94-7.97(m, 2H), 8.01-8.05 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.37 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 7.2 Hz, 3H), 1.65-1.75 (m, 2H), 1.95-2.05 (m , 2H), 2.68-2.78 (m, 4H), 2.80-3.02 (m, 14H), 3.05-3.15 (m, 2H), 3.72 (s, 3H), 3.76 (s, 3H), 3.95-4.08 (m , 2H), 4.10-4.20 (m, 2H), 4.42-4.55 (m, 2H), 5.17-5.28 (m, 4H), 6.74-6.81 (m, 4H), 6.84-6.92 (m, 4H), 7.51 -7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.84-7.97 (m, 2H), 8.01-8.05 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 114> 3-(4-(4- 114> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 14에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 113과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 86%).3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 113 to give the target compound (yield: 86%).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.45 (d, J= 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 1.95-2.05 (m, 2H), 2.65-2.78 (m,4H), 2.80-3.00 (m, 14H), 3.01-3.16 (m, 2H), 3.71 (s, 6H), 3.72 (s, 3H), 3.75 (s, 3H), 3.95-4.08 (m,2H), 4.10-4.20 (m, 2H), 4.42-4.55 (m, 2H), 5.10-5.28 (m, 4H), 6.71-6.83 (m, 8H), 7.49-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.95-7.99 (m, 2H), 8.00-8.05 (m, 2H), 8.59 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.45 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 1.95-2.05 (m , 2H), 2.65-2.78 (m, 4H), 2.80-3.00 (m, 14H), 3.01-3.16 (m, 2H), 3.71 (s, 6H), 3.72 (s, 3H), 3.75 (s, 3H ), 3.95-4.08 (m, 2H), 4.10-4.20 (m, 2H), 4.42-4.55 (m, 2H), 5.10-5.28 (m, 4H), 6.71-6.83 (m, 8H), 7.49-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.95-7.99 (m, 2H), 8.00-8.05 (m, 2H), 8.59 (s, 2H).
<< 실시예Example 115> 3-(4-(3- 115> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 13에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 113과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 91%).3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 113, the target compound was obtained (yield: 91%).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.45 (d, J= 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 1.92-2.00 (m, 2H), 2.65-2.75 (m,4H), 2.80-3.00 (m, 6H), 3.01-3.09 (m, 8H), 3.10-3.17 (m, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 3.95-4.08 (m,2H), 4.10-4.20 (m, 2H), 4.42-4.55 (m, 2H), 5.10-5.28 (m, 4H), 6.66-6.80 (m, 6H), 7.05-7.11 (m, 2H), 7.52-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.01-8.05 (m, 2H), 8.58 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.45 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 1.92-2.00 (m , 2H), 2.65-2.75 (m, 4H), 2.80-3.00 (m, 6H), 3.01-3.09 (m, 8H), 3.10-3.17 (m, 2H), 3.72 (s, 3H), 3.75 (s , 3H), 3.95-4.08 (m, 2H), 4.10-4.20 (m, 2H), 4.42-4.55 (m, 2H), 5.10-5.28 (m, 4H), 6.66-6.80 (m, 6H), 7.05 -7.11 (m, 2H), 7.52-7.62 (m, 4H), 7.86-7.89 (m, 4H), 7.94-7.97 (m, 2H), 8.01-8.05 (m, 2H), 8.58 (s, 2H) .
<< 실시예Example 116> 3-(4-(4- 116> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2-일카바모일)피페리딘-4-일-2-ylcarbamoyl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 16에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 113과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 113 to obtain the target compound (yield: 100% ).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.45 (d, J= 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 1.92-2.02 (m, 2H), 2.65-2.86 (m,6H), 2.88-2.94 (m, 4H), 2.95-3.11 (m, 10H), 3.73 (s, 3H), 3.76 (s, 3H), 3.95-4.05 (m, 2H), 4.08-4.18 (m, 2H), 4.42-4.55 (m, 2H), 5.11-5.25 (m, 4H), 6.77-6.84 (m, 4H), 6.86-6.95 (m, 4H), 7.36-7.50 (m, 6H), 7.59-7.68(m,8H),8.06-8.11(m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.45 (d, J = 7.2 Hz, 3H), 1.65-1.80 (m, 2H), 1.92-2.02 (m , 2H), 2.65-2.86 (m, 6H), 2.88-2.94 (m, 4H), 2.95-3.11 (m, 10H), 3.73 (s, 3H), 3.76 (s, 3H), 3.95-4.05 (m , 2H), 4.08-4.18 (m, 2H), 4.42-4.55 (m, 2H), 5.11-5.25 (m, 4H), 6.77-6.84 (m, 4H), 6.86-6.95 (m, 4H), 7.36 -7.50 (m, 6H), 7.59-7.68 (m, 8H), 8.06-8.11 (m, 4H).
<< 실시예Example 117> 3-(4-(4- 117> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 18에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 113과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 113 to obtain the target compound (yield: 100% ).
1H NMR(CDCl3, 300 MHz): δ 1.37 (d, J= 7.2 Hz, 3H), 1.43 (d, J= 7.2 Hz, 3H), 1.65-1.78 (m, 2H), 1.93-2.00 (m, 2H), 2.66-2.83 (m,6H), 2.86-3.11 (m, 14H), 3.73 (s, 6H), 3.74 (s, 3H), 3.76 (s, 3H), 3.95-4.05 (m, 2H), 4.08-4.18 (m, 2H), 4.42-4.55 (m, 2H), 5.13-5.25 (m, 4H), 6.77-6.85 (m, 8H), 7.36-7.49 (m, 6H), 7.59-7.67 (m, 8H), 8.06-8.10 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.37 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.65-1.78 (m, 2H), 1.93-2.00 (m , 2H), 2.66-2.83 (m, 6H), 2.86-3.11 (m, 14H), 3.73 (s, 6H), 3.74 (s, 3H), 3.76 (s, 3H), 3.95-4.05 (m, 2H ), 4.08-4.18 (m, 2H), 4.42-4.55 (m, 2H), 5.13-5.25 (m, 4H), 6.77-6.85 (m, 8H), 7.36-7.49 (m, 6H), 7.59-7.67 (m, 8 H), 8.06-8.10 (m, 4 H).
<< 실시예Example 118> 3-(4-(3- 118> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 17에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 113과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 95%).3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 113, the target compound was obtained (yield: 95%) .
1H NMR(CDCl3, 300 MHz): δ 1.37 (d, J= 7.2 Hz, 3H), 1.43 (d, J= 7.2 Hz, 3H), 1.62-1.76 (m, 2H), 1.91-1.98 (m, 2H), 2.63-2.75 (m,4H), 2.76-2.90 (m, 6H), 2.91-3.09 (m, 10H), 3.73 (s, 6H), 3.74 (s, 3H), 3.76 (s, 3H), 3.95-4.08 (m, 2H), 4.10-4.18 (m, 2H), 4.42-4.54 (m, 2H), 5.16-5.24(m, 4H), 6.70-6.81 (m, 6H), 7.07-7.13 (m, 2H), 7.36-7.49 (m, 6H), 7.59-7.67 (m, 8H), 8.06-8.10 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.37 (d, J = 7.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.62-1.76 (m, 2H), 1.91-1.98 (m , 2H), 2.63-2.75 (m, 4H), 2.76-2.90 (m, 6H), 2.91-3.09 (m, 10H), 3.73 (s, 6H), 3.74 (s, 3H), 3.76 (s, 3H ), 3.95-4.08 (m, 2H), 4.10-4.18 (m, 2H), 4.42-4.54 (m, 2H), 5.16-5.24 (m, 4H), 6.70-6.81 (m, 6H), 7.07-7.13 (m, 2H), 7.36-7.49 (m, 6H), 7.59-7.67 (m, 8H), 8.06-8.10 (m, 4H).
<< 실시예Example 119> 3-(4-(4- 119> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2-일카바모일)피페리딘-4-일-4--2-ylcarbamoyl) piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 20에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 113과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 87%).3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 113 to obtain the target compound (yield: 87%).
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.42 (d, J= 7.2 Hz, 3H), 1.62-1.73 (m, 2H), 1.90-1.98 (m, 2H), 2.65-2.80 (m,6H), 2.81-2.89 (m, 4H), 2.92-3.06 (m, 10H), 3.73 (s, 3H), 3.75 (s, 3H), 3.93-4.04 (m, 2H), 4.05-4.15 (m, 2H), 4.42-4.55 (m, 2H), 5.10-5.21 (m, 4H), 6.78-6.83 (m, 4H), 6.88-7.00 (m, 8H), 7.04-7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.36-7.41 (m, 4H), 7.96-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 7.2 Hz, 3H), 1.62-1.73 (m, 2H), 1.90-1.98 (m , 2H), 2.65-2.80 (m, 6H), 2.81-2.89 (m, 4H), 2.92-3.06 (m, 10H), 3.73 (s, 3H), 3.75 (s, 3H), 3.93-4.04 (m , 2H), 4.05-4.15 (m, 2H), 4.42-4.55 (m, 2H), 5.10-5.21 (m, 4H), 6.78-6.83 (m, 4H), 6.88-7.00 (m, 8H), 7.04 -7.08 (m, 4H), 7.16-7.22 (m, 2H), 7.36-7.41 (m, 4H), 7.96-8.01 (m, 4H).
<< 실시예Example 120> 3-(4-(4- 120> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(1-Piperazin-1-yl) -1- (1- 메톡시Methoxy -1--One- 옥소프로판Oxopropane -2--2- 일카바모일Ilkaba Mole )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 22에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 113과 동일한 방법으로 수행하여 목 적화합물을 수득하였다(수율: 92%).3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate A target compound was obtained by the same method as Example 113 except for using the piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate (yield: 92%) .
1H NMR(CDCl3, 300 MHz): δ 1.38 (d, J= 7.2 Hz, 3H), 1.42 (d, J= 7.2 Hz, 3H), 1.62-1.78 (m, 2H), 1.90-1.99 (m, 2H), 2.65-2.78 (m,6H), 2.82-2.91 (m, 4H), 2.92-3.05 (m, 10H), 3.72 (s, 3H), 3.73 (s, 3H), 3.75 (s, 6H), 3.93-4.00 (m, 2H), 4.02-4.15 (m, 2H), 4.43-4.51 (m, 2H), 5.10-5.20 (m, 4H), 6.77-6.87 (m, 8H), 6.95-7.01 (m, 4H), 7.04-7.08 (m, 4H), 7.15-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.95-8.01 (m, 4H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.38 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 7.2 Hz, 3H), 1.62-1.78 (m, 2H), 1.90-1.99 (m , 2H), 2.65-2.78 (m, 6H), 2.82-2.91 (m, 4H), 2.92-3.05 (m, 10H), 3.72 (s, 3H), 3.73 (s, 3H), 3.75 (s, 6H ), 3.93-4.00 (m, 2H), 4.02-4.15 (m, 2H), 4.43-4.51 (m, 2H), 5.10-5.20 (m, 4H), 6.77-6.87 (m, 8H), 6.95-7.01 (m, 4H), 7.04-7.08 (m, 4H), 7.15-7.22 (m, 2H), 7.35-7.42 (m, 4H), 7.95-8.01 (m, 4H).
<< 실시예Example 121> 3-(4-(4- 121> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 12에서 제조된 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 48 mg(0.11 mmol)과 2-플루오로페닐이소시아네이트 18 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 95%).48 mg (0.11 mmol) and 2-fluorophenyl of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 Except for reacting 18 mg (0.13 mmol) of isocyanate, the same procedure as in Example 23 was carried out to obtain the target compound (yield: 95%).
1H NMR(CDCl3, 300 MHz):δ 1.74-1.90 (m, 1H), 2.00-2.10 (m, 1H), 2.70-2.80 (m, 2H), 2.82-3.05 (m, 7H), 3.13-3.29 (m, 2H), 4.02-4.12 (m, 1H), 4.22-4.32 (m, 1H), 5.25-5.35 (m, 1H), 6.71-6.81 (m, 3H), 6.83-7.02 (m, 3H), 7.04-7.08 (m, 2H), 7.50-7.62 (m, 2H), 7.85-7.93 (m, 3H), 8.02-8.09 (m, 2H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.74-1.90 (m, 1H), 2.00-2.10 (m, 1H), 2.70-2.80 (m, 2H), 2.82-3.05 (m, 7H), 3.13- 3.29 (m, 2H), 4.02-4.12 (m, 1H), 4.22-4.32 (m, 1H), 5.25-5.35 (m, 1H), 6.71-6.81 (m, 3H), 6.83-7.02 (m, 3H ), 7.04-7.08 (m, 2H), 7.50-7.62 (m, 2H), 7.85-7.93 (m, 3H), 8.02-8.09 (m, 2H), 8.59 (s, 1H).
<< 실시예Example 122> 3-(4-(4- 122> 3- (4- (4- 메톡시로페닐Methoxylophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 14에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 121과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 121 to obtain the target compound (yield: 100%).
1H NMR(CDCl3, 300 MHz):δ1.75-1.89 (m, 1H), 2.01-2.12 (m, 1H), 2.71-2.80 (m, 2H), 2.82-2.94 (m, 3H), 2.95-3.00 (m, 4H), 3.12-3.34 (m, 2H), 3.73 (s, 3H), 4.05-4.10 (m, 1H), 4.22-4.30 (m, 1H), 5.26-5.34 (m, 1H), 6.75-6.85 (m, 5H), 6.91-7.11 (m, 3H), 7.50-7.61 (m, 2H), 7.84-7.93 (m, 3H), 8.02-8.09 (m, 2H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.75-1.89 (m, 1H), 2.01-2.12 (m, 1H), 2.71-2.80 (m, 2H), 2.82-2.94 (m, 3H), 2.95 -3.00 (m, 4H), 3.12-3.34 (m, 2H), 3.73 (s, 3H), 4.05-4.10 (m, 1H), 4.22-4.30 (m, 1H), 5.26-5.34 (m, 1H) , 6.75-6.85 (m, 5H), 6.91-7.11 (m, 3H), 7.50-7.61 (m, 2H), 7.84-7.93 (m, 3H), 8.02-8.09 (m, 2H), 8.58 (s, 1H).
<< 실시예Example 123> 3-(4-(3- 123> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 13에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 121과 동일한 방법으로 수행하여 목적화 합물을 수득하였다(수율: 95%).3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 121, the target compound was obtained (yield: 95%).
1H NMR(CDCl3, 300 MHz):δ1.72-1.86 (m, 1H), 2.00-2.08 (m, 1H), 2.65-2.76 (m, 2H), 2.83-2.93 (m, 3H), 3.02-3.10 (m, 4H), 3.11-3.32 (m, 2H), 4.05-4.15 (m, 1H), 4.24-4.32 (m, 1H), 5.25-5.33 (m, 1H), 6.68-6.80 (m, 4H), 6.91-7.00 (m, 1H), 7.01-7.12 (m, 3H), 7.50-7.62 (m, 2H), 7.85-7.93 (m, 3H), 8.01-8.09 (m, 2H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ1.72-1.86 (m, 1H), 2.00-2.08 (m, 1H), 2.65-2.76 (m, 2H), 2.83-2.93 (m, 3H), 3.02 -3.10 (m, 4H), 3.11-3.32 (m, 2H), 4.05-4.15 (m, 1H), 4.24-4.32 (m, 1H), 5.25-5.33 (m, 1H), 6.68-6.80 (m, 4H), 6.91-7.00 (m, 1H), 7.01-7.12 (m, 3H), 7.50-7.62 (m, 2H), 7.85-7.93 (m, 3H), 8.01-8.09 (m, 2H), 8.58 ( s, 1 H).
<< 실시예Example 124> 3-(4-(4- 124> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 16에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 121과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 121 to obtain the target compound (yield: 100% ).
1H NMR(CDCl3, 300 MHz):δ1.73-1.88 (m, 1H), 2.00-2.10 (m, 1H), 2.70-2.78 (m, 2H), 2.80-2.98 (m, 3H), 3.00-3.10 (m, 4H), 3.11-3.28 (m, 2H), 4.03-4.13 (m, 1H), 4.21-4.26 (m, 1H), 5.25-5.29 (m, 1H), 6.74 (d, J=3.8 Hz, 1H), 6.79-6.85 (m, 2H), 6.87-7.12 (m, 5H), 7.36-7.50 (m, 3H), 7.58-7.66 (m, 4H), 8.02-8.10 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.73-1.88 (m, 1H), 2.00-2.10 (m, 1H), 2.70-2.78 (m, 2H), 2.80-2.98 (m, 3H), 3.00 -3.10 (m, 4H), 3.11-3.28 (m, 2H), 4.03-4.13 (m, 1H), 4.21-4.26 (m, 1H), 5.25-5.29 (m, 1H), 6.74 (d, J = 3.8 Hz, 1H), 6.79-6.85 (m, 2H), 6.87-7.12 (m, 5H), 7.36-7.50 (m, 3H), 7.58-7.66 (m, 4H), 8.02-8.10 (m, 3H) .
<< 실시예Example 125> 3-(4-(4- 125> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 18에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 121과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 100%).3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 121 to obtain the target compound (yield: 100% ).
1H NMR(CDCl3, 300 MHz):δ 1.74-1.88 (m, 1H), 2.01-2.10 (m, 1H), 2.71-2.80 (m, 2H), 2.81-2.92 (m, 3H), 2.93-3.02 (m, 4H), 3.12-3.29 (m, 2H), 3.73 (s, 3H), 4.03-4.11 (m, 1H), 4.20-4.29 (m, 1H), 5.21-5.29 (m, 1H), 6.75 (d, J=3.8 Hz, 1H), 6.76-6.87 (m, 4H), 6.92-7.12 (m, 3H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.01-8.11 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.74-1.88 (m, 1H), 2.01-2.10 (m, 1H), 2.71-2.80 (m, 2H), 2.81-2.92 (m, 3H), 2.93- 3.02 (m, 4H), 3.12-3.29 (m, 2H), 3.73 (s, 3H), 4.03-4.11 (m, 1H), 4.20-4.29 (m, 1H), 5.21-5.29 (m, 1H), 6.75 (d, J = 3.8 Hz, 1H), 6.76-6.87 (m, 4H), 6.92-7.12 (m, 3H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.01- 8.11 (m, 3 H).
<< 실시예Example 126> 3-(4-(3- 126> 3- (4- (3- 클로로로페닐Chlorophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 17에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 121과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 94%).3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 121, the target compound was obtained (yield: 94%) .
1H NMR(CDCl3, 300 MHz):δ 1.71-1.85 (m, 1H), 1.97-2. 08 (m, 1H), 2.68-2.76 (m, 2H), 2.80-2.92 (m, 3H), 3.02-3.11 (m, 4H), 3.13-3.27 (m, 2H), 4.04-4.12 (m, 1H), 4.22-4.31 (m, 1H), 5.20-5.30 (m, 1H), 6.70-6.82 (m, 4H), 6.92-7.14 (m, 4H), 7.36-7.50 (m, 3H), 7.58-7.66 (m, 4H), 8.02-8.10 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.71-1.85 (m, 1H), 1.97-2. 08 (m, 1H), 2.68-2.76 (m, 2H), 2.80-2.92 (m, 3H), 3.02-3.11 (m, 4H), 3.13-3.27 (m, 2H), 4.04-4.12 (m, 1H ), 4.22-4.31 (m, 1H), 5.20-5.30 (m, 1H), 6.70-6.82 (m, 4H), 6.92-7.14 (m, 4H), 7.36-7.50 (m, 3H), 7.58-7.66 (m, 4H), 8.02-8.10 (m, 3H).
<< 실시예Example 127> 3-(4-(4- 127> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 20에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 121과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 91%).3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 121 to obtain the target compound (yield: 91%).
1H NMR(CDCl3, 300 MHz):δ 1.70-1.85 (m, 1H), 1.97-2. 07 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.91 (m, 3H), 3.00-3.04 (m, 4H), 3.09-3.24 (m, 2H), 4.02-4.10 (m, 1H), 4.17-4.25 (m, 1H), 5.16-5.25 (m, 1H), 6.73 (d, J=3.8 Hz, 1H), 6.78-6.85 (m, 2H), 6.88-7.01 (m, 5H), 7.03-7.11 (m, 4H), 7.16-7.21 (m, 1H), 7.35-7.42 (m, 2H), 7.95-8.07 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.70-1.85 (m, 1H), 1.97-2. 07 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.91 (m, 3H), 3.00-3.04 (m, 4H), 3.09-3.24 (m, 2H), 4.02-4.10 (m, 1H ), 4.17-4.25 (m, 1H), 5.16-5.25 (m, 1H), 6.73 (d, J = 3.8 Hz, 1H), 6.78-6.85 (m, 2H), 6.88-7.01 (m, 5H), 7.03-7.11 (m, 4H), 7.16-7.21 (m, 1H), 7.35-7.42 (m, 2H), 7.95-8.07 (m, 3H).
<< 실시예Example 128> 3-(4-(4- 128> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(2-Piperazin-1-yl) -1- (2- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페 리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 22에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 121과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 77%).3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 121 to obtain the target compound (yield: 77%).
1H NMR(CDCl3, 300 MHz):δ 1.71-1.85 (m, 1H), 1.96-2. 07 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.91 (m, 3H), 2.95-3.05 (m, 4H), 3.11-3.26 (m, 2H), 3.74 (s, 3H), 4.02-4.10 (m, 1H), 4.17-4.25 (m, 1H), 5.16-5.24 (m, 1H), 6.73 (d, J=3.8 Hz, 1H), 6.78-6.86 (m, 4H), 6.92-7.01 (m, 3H), 7.03-7.12 (m, 4H), 7.16-7.22 (m, 1H), 7.35-7.42 (m, 2H), 7.96-8.07 (m, 3H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.71-1.85 (m, 1H), 1.96-2. 07 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.91 (m, 3H), 2.95-3.05 (m, 4H), 3.11-3.26 (m, 2H), 3.74 (s, 3H), 4.02-4.10 (m, 1H), 4.17-4.25 (m, 1H), 5.16-5.24 (m, 1H), 6.73 (d, J = 3.8 Hz, 1H), 6.78-6.86 (m, 4H), 6.92- 7.01 (m, 3H), 7.03-7.12 (m, 4H), 7.16-7.22 (m, 1H), 7.35-7.42 (m, 2H), 7.96-8.07 (m, 3H).
<< 실시예Example 129> 3-(4-(4- 129> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 12에서 제조된 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 48 mg(0.11 mmol)과 3-메톡시페닐이소시아네이트 20 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 91%).48 mg (0.11 mmol) of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 and 3-methoxyphenyl A target compound was obtained in the same manner as in Example 23, except that 20 mg (0.13 mmol) of isocyanate was reacted (yield: 91%).
1H NMR(CDCl3, 300 MHz):δ 1.72-1.84 (m, 1H), 1.95-2.05 (m, 1H), 2.70- 2.78 (m, 2H), 2.85-2.91 (m, 3H), 2.92-3.00 (m, 4H), 3.01-3.25 (m, 2H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.20-4.27 (m, 1H), 5.19-5.27 (m, 1H), 6.56-6.60 (m, 1H), 6.75-6.82 (m, 3H), 6.85-6.93 (m, 3H), 7.12-7.18 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 8.02-8.05 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.72-1.84 (m, 1H), 1.95-2.05 (m, 1H), 2.70-2.78 (m, 2H), 2.85-2.91 (m, 3H), 2.92- 3.00 (m, 4H), 3.01-3.25 (m, 2H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.20-4.27 (m, 1H), 5.19-5.27 (m, 1H), 6.56-6.60 (m, 1H), 6.75-6.82 (m, 3H), 6.85-6.93 (m, 3H), 7.12-7.18 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m , 1H), 8.02-8.05 (m, 1H), 8.59 (s, 1H).
<< 실시예Example 130> 3-(4-(4- 130> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 14에서 수득한 4-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-3-일-2-나프토에이트를 사용하는 것을 제외하고는 실시예 129와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 81%).4- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-3-yl-2-naphthoate in the same manner as in Example 129 to obtain the target compound (yield: 81%).
1H NMR(CDCl3, 300 MHz):δ 1.70-1.84 (m, 1H), 1.95-2.03 (m, 1H), 2.71-2.80 (m, 2H), 2.85-2.90 (m, 3H), 2.91-3.01 (m, 4H), 3.05-3.26 (m, 2H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.20-4.27 (m, 1H), 5.19-5.26 (m, 1H), 6.55-6.60 (m, 1H), 6.75-6.89 (m, 5H), 7.12-7.18 (m, 2H), 7.51-7.62 (m, 3H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 8.01-8.05 (m, 1H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.70-1.84 (m, 1H), 1.95-2.03 (m, 1H), 2.71-2.80 (m, 2H), 2.85-2.90 (m, 3H), 2.91- 3.01 (m, 4H), 3.05-3.26 (m, 2H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.20-4.27 (m, 1H), 5.19-5.26 (m, 1H), 6.55-6.60 (m, 1H), 6.75-6.89 (m, 5H), 7.12-7.18 (m, 2H), 7.51-7.62 (m, 3H), 7.85-7.88 (m, 2H), 7.90-7.93 (m , 1H), 8.01-8.05 (m, 1H), 8.58 (s, 1H).
<< 실시예Example 131> 3-(4-(3- 131> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 13에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 129와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 86%).3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 129 to obtain the target compound (yield: 86%).
1H NMR(CDCl3, 300 MHz):δ 1.65-1.80 (m, 1H), 1.95-2.03 (m, 1H), 2.66-2.75 (m, 2H), 2.82-2.92 (m, 3H), 3.01-3.11 (m, 5H), 3.15-3.24 (m, 1H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.20-4.27 (m, 1H), 5.18-5.25 (m, 1H), 6.56-6.60 (m, 1H), 6.66-6.80 (m, 4H), 6.86-6.91 (m, 1H), 7.05-7.18 (m, 3H), 7.51-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 8.01-8.04 (m, 1H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.65-1.80 (m, 1H), 1.95-2.03 (m, 1H), 2.66-2.75 (m, 2H), 2.82-2.92 (m, 3H), 3.01- 3.11 (m, 5H), 3.15-3.24 (m, 1H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.20-4.27 (m, 1H), 5.18-5.25 (m, 1H), 6.56-6.60 (m, 1H), 6.66-6.80 (m, 4H), 6.86-6.91 (m, 1H), 7.05-7.18 (m, 3H), 7.51-7.62 (m, 2H), 7.85-7.88 (m , 2H), 7.90-7.93 (m, 1 H), 8.01-8.04 (m, 1 H), 8.58 (s, 1 H).
<< 실시예Example 132> 3-(4-(4- 132> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 16에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 129와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 94%).3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 129, the target compound was obtained (yield: 94% ).
1H NMR(CDCl3, 300 MHz):δ1.69-1.81 (m, 1H), 1.95-2.02 (m, 1H), 2.70- 2.80 (m, 2H), 2.81-2.93 (m, 3H), 2.97-3.05 (m, 5H), 3.06-3.20 (m, 1H), 3.78 (s, 3H), 4.06-4.23 (m, 2H), 5.13-5.21 (m, 1H), 6.56-6.61 (m, 1H), 6.77-6.83 (m, 3H), 6.86-6.97 (m, 3H), 7.13-7.19 (m, 2H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.06-8.10 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.69-1.81 (m, 1H), 1.95-2.02 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.93 (m, 3H), 2.97 -3.05 (m, 5H), 3.06-3.20 (m, 1H), 3.78 (s, 3H), 4.06-4.23 (m, 2H), 5.13-5.21 (m, 1H), 6.56-6.61 (m, 1H) , 6.77-6.83 (m, 3H), 6.86-6.97 (m, 3H), 7.13-7.19 (m, 2H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.06-8.10 ( m, 2H).
<< 실시예Example 133> 3-(4-(4- 133> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3--3- 카르복실레이트의Carboxylate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 18에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 129와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 95%).3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using the piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 129 to obtain the target compound (yield: 95% ).
1H NMR(CDCl3, 300 MHz):δ 1.67-1.82 (m, 1H), 1.96-2.03 (m, 1H), 2.71-2.78 (m, 2H), 2.81-2.91 (m, 3H), 2.97-3.00 (m, 4H), 3.01-3.21 (m, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 4.06-4.22 (m, 2H), 5.14-5.21 (m, 1H), 6.57-6.61 (m, 1H), 6.77-6.89 (m, 6H), 7.13-7.19 (m, 2H), 7.39-7.49 (m, 3H), 7.59-7.66 (m, 4H), 8.06-8.10 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.67-1.82 (m, 1H), 1.96-2.03 (m, 1H), 2.71-2.78 (m, 2H), 2.81-2.91 (m, 3H), 2.97- 3.00 (m, 4H), 3.01-3.21 (m, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 4.06-4.22 (m, 2H), 5.14-5.21 (m, 1H), 6.57- 6.61 (m, 1H), 6.77-6.89 (m, 6H), 7.13-7.19 (m, 2H), 7.39-7.49 (m, 3H), 7.59-7.66 (m, 4H), 8.06-8.10 (m, 2H ).
<< 실시예Example 134> 3-(4-(3- 134> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 17에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 129와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 36%).3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 129, the target compound was obtained (yield: 36%) .
1H NMR(CDCl3, 300 MHz):δ1.68-1.83 (m, 1H), 1.95-2.03 (m, 1H), 2.70-2.77 (m, 2H), 2.80-2.90 (m, 3H), 3.01-3.20 (m, 6H), 3.79 (s, 3H), 4.10-4.23 (m, 2H), 5.13-5.21 (m, 1H), 6.57-6.62 (m, 1H), 6.70-6.82 (m, 4H), 6.85-6.90 (m, 1H), 7.08-7.17 (m, 3H), 7.37-7.50 (m, 3H), 7.58-7.67 (m, 4H), 8.09 (d, J=8.3 Hz, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.68-1.83 (m, 1H), 1.95-2.03 (m, 1H), 2.70-2.77 (m, 2H), 2.80-2.90 (m, 3H), 3.01 -3.20 (m, 6H), 3.79 (s, 3H), 4.10-4.23 (m, 2H), 5.13-5.21 (m, 1H), 6.57-6.62 (m, 1H), 6.70-6.82 (m, 4H) , 6.85-6.90 (m, 1H), 7.08-7.17 (m, 3H), 7.37-7.50 (m, 3H), 7.58-7.67 (m, 4H), 8.09 (d, J = 8.3 Hz, 2H).
<< 실시예Example 135> 3-(4-(4- 135> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 20에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 129와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 91%).3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 129 to obtain the target compound (yield: 91%).
1H NMR(CDCl3, 300 MHz):δ 1.70-1.81(m, 1H), 1.93-2.03 (m, 1H), 2.71-2.78 (m, 2H), 2.79-2.89 (m, 3H), 2.98-3.01 (m, 5H), 3.02-3.17 (m, 1H), 3.78 (s, 3H), 4.07-4.19 (m, 2H), 5.09-5.16 (m, 1H), 6.57-6.61 (m, 1H), 6.71 (s, 1H), 6.78-7.00 (m, 7H), 7.03-7.08 (m, 2H), 7.13-7.22 (m, 3H), 7.35-7.43 (m, 2H), 7.96-8.01 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.70-1.81 (m, 1H), 1.93-2.03 (m, 1H), 2.71-2.78 (m, 2H), 2.79-2.89 (m, 3H), 2.98- 3.01 (m, 5H), 3.02-3.17 (m, 1H), 3.78 (s, 3H), 4.07-4.19 (m, 2H), 5.09-5.16 (m, 1H), 6.57-6.61 (m, 1H), 6.71 (s, 1H), 6.78-7.00 (m, 7H), 7.03-7.08 (m, 2H), 7.13-7.22 (m, 3H), 7.35-7.43 (m, 2H), 7.96-8.01 (m, 2H ).
<< 실시예Example 136> 3-(4-(4- 136> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(3-Piperazin-1-yl) -1- (3- 메톡시페닐카바모일Methoxyphenylcarbamoyl )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 22에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 129와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 92%).3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 129 to obtain the target compound (yield: 92%).
1H NMR(CDCl3, 300 MHz):δ 1.71-1.81 (m, 1H), 1.93-2.02 (m, 1H), 2.71-2.79 (m, 2H), 2.80-2.89 (m, 3H), 2.97-3.01 (m, 4H), 3.02-3.18 (m, 2H), 3.74 (s, 3H), 3.78 (s, 3H), 4.06-4.19 (m, 2H), 5.09-5.17 (m, 1H), 6.56-6.62 (m, 1H), 6.72 (s, 1H), 6.78-7.88 (m, 5H), 6.94-7.01 (m, 2H), 7.03-7.08 (m, 2H), 7.13-7.22 (m, 3H), 7.35-7.42 (m, 2H), 7.96-8.01 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.71-1.81 (m, 1H), 1.93-2.02 (m, 1H), 2.71-2.79 (m, 2H), 2.80-2.89 (m, 3H), 2.97- 3.01 (m, 4H), 3.02-3.18 (m, 2H), 3.74 (s, 3H), 3.78 (s, 3H), 4.06-4.19 (m, 2H), 5.09-5.17 (m, 1H), 6.56- 6.62 (m, 1H), 6.72 (s, 1H), 6.78-7.88 (m, 5H), 6.94-7.01 (m, 2H), 7.03-7.08 (m, 2H), 7.13-7.22 (m, 3H), 7.35-7.42 (m, 2 H), 7.96-8.01 (m, 2 H).
<< 실시예Example 137> 3-(4-(4- 137> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 12에서 제조된 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일- 1-나프토에이트 48 mg(0.11 mmol)과 4-플루오로페닐이소시아네이트 18 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 80%).48 mg (0.11 mmol) and 4-fluorophenyl of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 A target compound was obtained in the same manner as in Example 23, except that 18 mg (0.13 mmol) of isocyanate was reacted (yield: 80%).
11H NMR(CDCl3, 300 MHz):δ 1.68-1.82 (m, 1H), 1.95-2.04 (m, 1H), 2.70-2.78 (m, 2H), 2.84-2.94 (m, 3H), 2.96-3.12 (m, 5H), 3.15-3.23 (m, 1H), 4.08-4.25 (m, 2H), 5.19-5.25 (m, 1H), 6.74-6.81 (m, 3H), 6.84-6.99 (m, 4H), 7.28-7.35 (m, 2H), 7.51-7.63 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 8.01-8.05 (m, 1H), 8.58 (s, 1H). 11 H NMR (CDCl 3 , 300 MHz): δ 1.68-1.82 (m, 1H), 1.95-2.04 (m, 1H), 2.70-2.78 (m, 2H), 2.84-2.94 (m, 3H), 2.96- 3.12 (m, 5H), 3.15-3.23 (m, 1H), 4.08-4.25 (m, 2H), 5.19-5.25 (m, 1H), 6.74-6.81 (m, 3H), 6.84-6.99 (m, 4H ), 7.28-7.35 (m, 2H), 7.51-7.63 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 8.01-8.05 (m, 1H), 8.58 (s , 1H).
<< 실시예Example 138> 3-(4-(4- 138> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 14에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 137과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 94%).3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 137 to obtain the target compound (yield: 94%).
1H NMR(CDCl3, 300 MHz):δ 1.68-1.85 (m, 1H), 1.96-2.03(m, 1H), 2.70-2.79 (m, 2H), 2.82-2.93 (m, 3H), 2.94-3.00 (m, 4H), 3.02-3.13 (m, 1H), 3.16-3.24 (m, 1H), 3.72 (s, 3H), 4.06-4.23 (m, 2H), 5.18-5.25 (m, 1H), 6.74-6.83 (m, 5H), 6.90-6.97 (m, 2H), 7.29-7.35 (m, 2H), 7.51-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 8.01-8.05 (m, 1H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.68-1.85 (m, 1H), 1.96-2.03 (m, 1H), 2.70-2.79 (m, 2H), 2.82-2.93 (m, 3H), 2.94- 3.00 (m, 4H), 3.02-3.13 (m, 1H), 3.16-3.24 (m, 1H), 3.72 (s, 3H), 4.06-4.23 (m, 2H), 5.18-5.25 (m, 1H), 6.74-6.83 (m, 5H), 6.90-6.97 (m, 2H), 7.29-7.35 (m, 2H), 7.51-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m , 1H), 8.01-8.05 (m, 1H), 8.58 (s, 1H).
<< 실시예Example 139> 3-(4-(3- 139> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-1-Piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 13에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 137과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 85%).3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 137, the target compound was obtained (yield: 85%).
1H NMR(CDCl3, 300 MHz):δ 1.66-1.80 (m, 1H), 1.94-2.02 (m, 1H), 2.66-2.76 (m, 2H), 2.82-2.92 (m, 3H), 3.00-3.10 (m, 5H), 3.14-3.23 (m, 1H), 4.09-4.24 (m, 2H), 5.16-5.24 (m, 1H), 6.66-6.78 (m, 4H), 6.91-6.99 (m, 2H), 7.08 (t, J=8.1 Hz, 1H), 7.28-7.36 (m, 2H), 7.51-7.63 (m, 2H), 7.85-7.89 (m, 2H), 7.90-7.94 (m, 1H), 8.01-8.04 (m, 1H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.66-1.80 (m, 1H), 1.94-2.02 (m, 1H), 2.66-2.76 (m, 2H), 2.82-2.92 (m, 3H), 3.00- 3.10 (m, 5H), 3.14-3.23 (m, 1H), 4.09-4.24 (m, 2H), 5.16-5.24 (m, 1H), 6.66-6.78 (m, 4H), 6.91-6.99 (m, 2H ), 7.08 (t, J = 8.1 Hz, 1H), 7.28-7.36 (m, 2H), 7.51-7.63 (m, 2H), 7.85-7.89 (m, 2H), 7.90-7.94 (m, 1H), 8.01-8.04 (m, 1 H), 8.58 (s, 1 H).
<< 실시예Example 140> 3-(4-(4- 140> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 16에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐- 3-카르복실레이트를 사용하는 것을 제외하고는 실시예 137과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 86%).3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 137 to obtain the target compound (yield: 86% ).
1H NMR(CDCl3, 300 MHz):δ1.67-1.81 (m, 1H), 1.94-2.02 (m, 1H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 3H), 2.96-3.09 (m, 5H), 3.10-3.18 (m, 1H), 4.07-4.21 (m, 2H), 5.12-5.19 (m, 1H), 6.77-6.82 (m, 3H), 6.83-7.00 (m, 4H), 7.29-7.34 (m, 2H), 7.37-7.49 (m, 3H), 7.58-7.67 (m, 4H), 8.06-8.11 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.67-1.81 (m, 1H), 1.94-2.02 (m, 1H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 3H), 2.96 -3.09 (m, 5H), 3.10-3.18 (m, 1H), 4.07-4.21 (m, 2H), 5.12-5.19 (m, 1H), 6.77-6.82 (m, 3H), 6.83-7.00 (m, 4H), 7.29-7.34 (m, 2H), 7.37-7.49 (m, 3H), 7.58-7.67 (m, 4H), 8.06-8.11 (m, 2H).
<< 실시예Example 141> 3-(4-(4- 141> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3--3- 카르복실레이트의Carboxylate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 18에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 137과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 98%).3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 137 to obtain the target compound (yield: 98% ).
1H NMR(CDCl3, 300 MHz):δ 1.67-1.85 (m, 1H), 1.95-2.03 (m, 1H), 2.72-2.80 (m, 2H), 2.81-2.92 (m, 3H), 2.94-3.02 (m, 4H), 3.03-3.10 (m, 1H), 3.11-3.19 (m, 1H), 3.73 (s, 3H), 4.07-4.21 (m, 2H), 5.12-5.20 (m, 1H), 6.76-6.85 (m, 5H), 6.92-7.00 (m, 2H), 7.25-7.34 (m, 2H), 7.37-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.07-8.10 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.67-1.85 (m, 1H), 1.95-2.03 (m, 1H), 2.72-2.80 (m, 2H), 2.81-2.92 (m, 3H), 2.94- 3.02 (m, 4H), 3.03-3.10 (m, 1H), 3.11-3.19 (m, 1H), 3.73 (s, 3H), 4.07-4.21 (m, 2H), 5.12-5.20 (m, 1H), 6.76-6.85 (m, 5H), 6.92-7.00 (m, 2H), 7.25-7.34 (m, 2H), 7.37-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.07-8.10 (m , 2H).
<< 실시예Example 142> 3-(4-(3- 142> 3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-Piperidin-4-yl 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 17에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 137과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 88%).3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 137, the target compound was obtained (yield: 88%) .
1H NMR(CDCl3, 300 MHz):δ1.65-1.80 (m, 1H), 1.93-2.00 (m, 1H), 2.68-2.76 (m, 2H), 2.80-2.90 (m, 3H), 2.97-3.17 (m, 6H), 4.07-4.22 (m, 2H), 5.11-5.19 (m, 1H), 6.69-6.81 (m, 4H), 6.93-7.00 (m, 2H), 7.10 (t, J=8.1 Hz, 1H), 7.28-7.35 (m, 2H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.06-8.10 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.65-1.80 (m, 1H), 1.93-2.00 (m, 1H), 2.68-2.76 (m, 2H), 2.80-2.90 (m, 3H), 2.97 -3.17 (m, 6H), 4.07-4.22 (m, 2H), 5.11-5.19 (m, 1H), 6.69-6.81 (m, 4H), 6.93-7.00 (m, 2H), 7.10 (t, J = 8.1 Hz, 1H), 7.28-7.35 (m, 2H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.06-8.10 (m, 2H).
<< 실시예Example 143> 3-(4-(4- 143> 3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 20에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 137과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 91%).3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 137 to obtain the target compound (yield: 91%).
1H NMR(CDCl3, 300 MHz):δ 1.67-1.82 (m, 1H), 1.92-2.03 (m, 1H), 2.69-2.80 (m, 2H), 2.81-2.90 (m, 3H), 2.96-3.06 (m, 5H), 3.07-3.15 (m, 1H), 4.06-4.18 (m, 2H), 5.08-5.15 (m, 1H), 6.73 (s, 1H), 6.78-6.85 (m, 2H), 6.88-7.00 (m, 6H), 7.03-7.08 (m, 2H), 7.17-7.23 (m, 1H), 7.29-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.96-8.01 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.67-1.82 (m, 1H), 1.92-2.03 (m, 1H), 2.69-2.80 (m, 2H), 2.81-2.90 (m, 3H), 2.96- 3.06 (m, 5H), 3.07-3.15 (m, 1H), 4.06-4.18 (m, 2H), 5.08-5.15 (m, 1H), 6.73 (s, 1H), 6.78-6.85 (m, 2H), 6.88-7.00 (m, 6H), 7.03-7.08 (m, 2H), 7.17-7.23 (m, 1H), 7.29-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.96-8.01 (m , 2H).
<< 실시예Example 144> 3-(4-(4- 144> 3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)-1-(4-Piperazin-1-yl) -1- (4- 플루오로페닐카바모일Fluorophenylcarbamoyl )피페리딘-4-일-4-Piperidin-4-yl-4- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 22에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 137과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 98%).3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 137 to obtain the target compound (yield: 98%).
1H NMR(CDCl3, 300 MHz):δ 1.65-1.80 (m, 1H), 1.90-2.00 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.90 (m, 3H), 2.94-3.05 (m, 5H), 3.06-3.15 (m, 1H), 3.74 (s, 3H), 4.05-4.17 (m, 2H), 5.07-5.15 (m, 1H), 6.77-6.86 (m, 5H), 6.91-7.01 (m, 4H), 7.03-7.09 (m, 2H), 7.16-7.22 (m, 1H), 7.27-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.95-8.00 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.65-1.80 (m, 1H), 1.90-2.00 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.90 (m, 3H), 2.94- 3.05 (m, 5H), 3.06-3.15 (m, 1H), 3.74 (s, 3H), 4.05-4.17 (m, 2H), 5.07-5.15 (m, 1H), 6.77-6.86 (m, 5H), 6.91-7.01 (m, 4H), 7.03-7.09 (m, 2H), 7.16-7.22 (m, 1H), 7.27-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.95-8.00 (m , 2H).
<< 실시예Example 145> 1-(3,5- 145> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(4-) -3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 12에서 제조된 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 48 mg(0.11 mmol)과 3,5-디클로로페닐이소시아네이트 25 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 85%).48 mg (0.11 mmol) and 3,5-dichloro 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 12 Except for reacting 25 mg (0.13 mmol) of phenylisocyanate, the same procedure as in Example 23 was carried out to obtain the target compound (yield: 85%).
1H NMR(CDCl3, 300 MHz):δ 1.67-1.80 (m, 1H), 1.97-2.06 (m, 1H), 2.67-2.76 (m, 2H), 2.80-2.90 (m, 3H), 2.92-3.01 (m, 4H), 3.04-3.16 (m, 1H), 3.19-3.27 (m, 1H), 4.02-4.10 (m, 1H), 4.15-4.22 (m, 1H), 5.14-5.21 (m, 1H), 6.73-6.80 (m, 2H), 6.86-6.92 (m, 2H), 6.94 (t, J=1.8 Hz, 1H), 7.07 (s, 1H), 7.33 (d, J=1.8 Hz, 2H), 7.50-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 7.99-8.03 (m, 1H), 8.56 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.67-1.80 (m, 1H), 1.97-2.06 (m, 1H), 2.67-2.76 (m, 2H), 2.80-2.90 (m, 3H), 2.92- 3.01 (m, 4H), 3.04-3.16 (m, 1H), 3.19-3.27 (m, 1H), 4.02-4.10 (m, 1H), 4.15-4.22 (m, 1H), 5.14-5.21 (m, 1H ), 6.73-6.80 (m, 2H), 6.86-6.92 (m, 2H), 6.94 (t, J = 1.8 Hz, 1H), 7.07 (s, 1H), 7.33 (d, J = 1.8 Hz, 2H) , 7.50-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 7.99-8.03 (m, 1H), 8.56 (s, 1H).
<< 실시예Example 146> 1-(3,5- 146> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(4-) -3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 14에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 145와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 99%).3- (4- (4-methoxyphenyl) obtained in Example 14 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 145 to obtain the target compound (yield: 99%).
1H NMR(CDCl3, 300 MHz):δ1.69-1.85 (m, 1H), 1.97-2.06 (m, 1H), 2.69-2.78 (m, 2H), 2.81-2.91 (m, 3H), 2.92-3.00 (m, 4H), 3.08-3.20 (m, 1H), 3.21-3.28 (m, 1H), 3.72 (s, 3H), 4.02-4.08 (m, 1H), 4.13-4.22 (m, 1H), 5.14-5.21 (m, 1H), 6.75-6.84 (m, 4H), 6.94 (t, J=1.8 Hz, 1H), 7.02 (s, 1H), 7.33 (d, J=1.8 Hz, 2H), 7.50-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 7.99-8.03 (m, 1H), 8.56 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.69-1.85 (m, 1H), 1.97-2.06 (m, 1H), 2.69-2.78 (m, 2H), 2.81-2.91 (m, 3H), 2.92 -3.00 (m, 4H), 3.08-3.20 (m, 1H), 3.21-3.28 (m, 1H), 3.72 (s, 3H), 4.02-4.08 (m, 1H), 4.13-4.22 (m, 1H) , 5.14-5.21 (m, 1H), 6.75-6.84 (m, 4H), 6.94 (t, J = 1.8 Hz, 1H), 7.02 (s, 1H), 7.33 (d, J = 1.8 Hz, 2H), 7.50-7.62 (m, 2H), 7.85-7.88 (m, 2H), 7.90-7.93 (m, 1H), 7.99-8.03 (m, 1H), 8.56 (s, 1H).
<< 실시예Example 147> 1-(3,5- 147> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(3-) -3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 13에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 145와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 94%).3- (4- (3-chlorophenyl) obtained in Example 13 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-1-naphthoate in the same manner as in Example 145, the target compound was obtained (yield: 94%).
1H NMR(CDCl3, 300 MHz):δ1.62-1.76 (m, 1H), 1.90-2.01 (m, 1H), 2.61-2.71 (m, 2H), 2.74-2.88 (m, 3H), 2.96-3.06 (m, 4H), 3.07-3.16 (m, 1H), 3.17-3.25 (m, 1H), 3.97-4.10 (m, 1H), 4.15-4.22 (m, 1H), 5.12-5.19 (m, 1H), 6.64-6.68 (m, 1H), 6.72-6.76 (m, 2H), 6.93 (t, J=1.8 Hz, 1H), 7.08 (t, J=7.9 Hz, 1H), 7.13 (s, 1H), 7.33 (d, J=1.8 Hz, 2H), 7.50-7.62 (m, 2H), 7.84-7.87 (m, 2H), 7.89-7.92 (m, 1H), 7.98-8.02 (m, 1H), 8.55 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ1.62-1.76 (m, 1H), 1.90-2.01 (m, 1H), 2.61-2.71 (m, 2H), 2.74-2.88 (m, 3H), 2.96 -3.06 (m, 4H), 3.07-3.16 (m, 1H), 3.17-3.25 (m, 1H), 3.97-4.10 (m, 1H), 4.15-4.22 (m, 1H), 5.12-5.19 (m, 1H), 6.64-6.68 (m, 1H), 6.72-6.76 (m, 2H), 6.93 (t, J = 1.8 Hz, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.13 (s, 1H ), 7.33 (d, J = 1.8 Hz, 2H), 7.50-7.62 (m, 2H), 7.84-7.87 (m, 2H), 7.89-7.92 (m, 1H), 7.98-8.02 (m, 1H), 8.55 (s, 1 H).
<< 실시예Example 148> 1-(3,5- 148> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(4-) -3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 16에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 145와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 96%).3- (4- (4-fluorophenyl) obtained in Example 16 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 145, the target compound was obtained (yield: 96% ).
1H NMR(CDCl3, 300 MHz):δ1.63-1.78 (m, 1H), 1.93-2.02 (m, 1H), 2.66-2.76 (m, 2H), 2.77-2.88 (m, 3H), 2.94-3.03 (m, 4H), 3.04-3.13 (m, 1H), 3.14-3.22 (m, 1H), 4.00-4.10 (m, 1H), 4.13-4.22 (m, 1H), 5.09-5.17 (m, 1H), 6.74-6.81 (m, 2H), 6.85-6.94 (m, 2H), 6.95 (t, J=1.8 Hz, 1H), 7.15 (s, 1H), 7.33 (d, J=1.8 Hz, 2H), 7.35-7.48 (m, 3H), 7.57-7.65 (m, 4H), 8.04-8.08 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ1.63-1.78 (m, 1H), 1.93-2.02 (m, 1H), 2.66-2.76 (m, 2H), 2.77-2.88 (m, 3H), 2.94 -3.03 (m, 4H), 3.04-3.13 (m, 1H), 3.14-3.22 (m, 1H), 4.00-4.10 (m, 1H), 4.13-4.22 (m, 1H), 5.09-5.17 (m, 1H), 6.74-6.81 (m, 2H), 6.85-6.94 (m, 2H), 6.95 (t, J = 1.8 Hz, 1H), 7.15 (s, 1H), 7.33 (d, J = 1.8 Hz, 2H ), 7.35-7.48 (m, 3H), 7.57-7.65 (m, 4H), 8.04-8.08 (m, 2H).
<< 실시예Example 149> 1-(3,5- 149> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(4-) -3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 18에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 145와 동일한 방법으로 수행하 여 목적화합물을 수득하였다(수율: 100%).3- (4- (4-methoxyphenyl) obtained in Example 18 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 145, the target compound was obtained (yield: 100 %).
1H NMR(CDCl3, 300 MHz):δ1.65-1.80 (m, 1H), 1.95-2.04 (m, 1H), 2.68-2.76 (m, 2H), 2.77-2.89 (m, 3H), 2.92-3.02 (m, 4H), 3.04-3.14 (m, 1H), 3.15-3.23 (m, 1H), 3.74 (s, 3H), 3.96-4.08 (m, 1H), 4.12-4.20 (m, 1H), 5.10-5.17 (m, 1H), 6.75-6.83 (m, 4H), 6.96 (t, J=1.8 Hz, 1H), 7.13 (s, 1H), 7.33 (d, J=1.8 Hz, 2H), 7.34-7.48 (m, 3H), 7.57-7.65 (m, 4H), 8.04-8.08 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.65-1.80 (m, 1H), 1.95-2.04 (m, 1H), 2.68-2.76 (m, 2H), 2.77-2.89 (m, 3H), 2.92 -3.02 (m, 4H), 3.04-3.14 (m, 1H), 3.15-3.23 (m, 1H), 3.74 (s, 3H), 3.96-4.08 (m, 1H), 4.12-4.20 (m, 1H) , 5.10-5.17 (m, 1H), 6.75-6.83 (m, 4H), 6.96 (t, J = 1.8 Hz, 1H), 7.13 (s, 1H), 7.33 (d, J = 1.8 Hz, 2H), 7.34-7.48 (m, 3H), 7.57-7.65 (m, 4H), 8.04-8.08 (m, 2H).
<< 실시예Example 150> 1-(3,5- 150> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(3-) -3- (4- (3- 클로로페닐Chlorophenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 17에서 수득한 3-(4-(3-클로로페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 145와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 93%).3- (4- (3-chlorophenyl) obtained in Example 17 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 145, the target compound was obtained (yield: 93%) .
1H NMR(CDCl3, 300 MHz):δ1.64-1.78 (m, 1H), 1.92-2.02 (m, 1H), 2.65-2.74 (m, 2H), 2.76-2.87 (m, 3H), 3.02-3.10 (m, 4H), 3.11-3.21 (m, 2H), 4.00-4.10 (m, 1H), 4.12-4.20 (m, 1H), 5.08-5.15 (m, 1H), 6.67-6.68 (m, 1H), 6.70-6.80 (m, 2H), 6.96 (t, J=1.8 Hz, 1H), 7.07 (s, 1H),7.09 (t, J=8.1 Hz, 1H), 7.33 (d, J=1.8 Hz, 2H), 7.35-7.48 (m, 3H), 7.57-7.66 (m, 4H), 8.04-8.08 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.64-1.78 (m, 1H), 1.92-2.02 (m, 1H), 2.65-2.74 (m, 2H), 2.76-2.87 (m, 3H), 3.02 -3.10 (m, 4H), 3.11-3.21 (m, 2H), 4.00-4.10 (m, 1H), 4.12-4.20 (m, 1H), 5.08-5.15 (m, 1H), 6.67-6.68 (m, 1H), 6.70-6.80 (m, 2H), 6.96 (t, J = 1.8 Hz, 1H), 7.07 (s, 1H), 7.09 (t, J = 8.1 Hz, 1H), 7.33 (d, J = 1.8 Hz, 2H), 7.35-7.48 (m, 3H), 7.57-7.66 (m, 4H), 8.04-8.08 (m, 2H).
<< 실시예Example 151> 1-(3,5- 151> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(4-) -3- (4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)피페리딘-4-일-3-) Piperazin-1-yl) piperidin-4-yl-3- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 20에서 수득한 3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 145와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 31%).3- (4- (4-fluorophenyl) obtained in Example 20 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 145 to obtain the target compound (yield: 31%).
1H NMR(CDCl3, 300 MHz):δ1.67-1.84 (m, 1H), 1.96-2.04 (m, 1H), 2.73-2.90 (m, 5H), 2.98-3.06 (m, 4H), 3.07-3.22 (m, 2H), 4.00-4.16 (m, 2H), 5.04-5.12 (m, 1H), 6.79-6.85 (m, 3H), 6.88-7.01 (m, 5H), 7.03-7.08 (m, 2H), 7.17-7.25 (m, 2H), 7.33 (d, J=1.8 Hz, 2H), 7.36-7.42 (m, 1H), 7.95-8.00 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.67-1.84 (m, 1H), 1.96-2.04 (m, 1H), 2.73-2.90 (m, 5H), 2.98-3.06 (m, 4H), 3.07 -3.22 (m, 2H), 4.00-4.16 (m, 2H), 5.04-5.12 (m, 1H), 6.79-6.85 (m, 3H), 6.88-7.01 (m, 5H), 7.03-7.08 (m, 2H), 7.17-7.25 (m, 2H), 7.33 (d, J = 1.8 Hz, 2H), 7.36-7.42 (m, 1H), 7.95-8.00 (m, 2H).
<< 실시예Example 152> 1-(3,5- 152> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(4-) -3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-3-) Piperazin-1-yl) piperidin-4-yl-3- 페녹시벤조에이트의Of phenoxybenzoate 제조 Produce
3-(4-(4-플루오로페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 22에서 수득한 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-4-페녹시벤조에이트를 사용하는 것을 제외하고는 실시예 145와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 94%).3- (4- (4-methoxyphenyl) obtained in Example 22 instead of 3- (4- (4-fluorophenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using) piperazin-1-yl) piperidin-4-yl-4-phenoxybenzoate in the same manner as in Example 145 to obtain the target compound (yield: 94%).
1H NMR(CDCl3, 300 MHz):δ 1.67-1.80 (m, 1H), 1.92-2.03 (m, 1H), 2.70-2.88 (m, 5H), 2.94-3.02 (m, 4H), 3.04-3.20 (m, 2H), 3.74 (s, 3H), 3.98-4.15 (m, 2H), 5.06-5.12 (m, 1H), 6.77-6.84 (m, 3H), 6.94-6.98 (m, 3H), 7.03-7.07 (m, 3H), 7.16-7.22 (m, 1H), 7.31-7.32 (m, 2H), 7.35-7.41 (m, 2H), 7.94-7.99 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.67-1.80 (m, 1H), 1.92-2.03 (m, 1H), 2.70-2.88 (m, 5H), 2.94-3.02 (m, 4H), 3.04- 3.20 (m, 2H), 3.74 (s, 3H), 3.98-4.15 (m, 2H), 5.06-5.12 (m, 1H), 6.77-6.84 (m, 3H), 6.94-6.98 (m, 3H), 7.03-7.07 (m, 3H), 7.16-7.22 (m, 1H), 7.31-7.32 (m, 2H), 7.35-7.41 (m, 2H), 7.94-7.99 (m, 2H).
<< 실시예Example 153> 1-(3,5- 153> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(2-) -3- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 15에서 제조된 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 49 mg(0.11 mmol)과 3,5-디클로로페닐이소시아네이트 25 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 87%).49 mg (0.11 mmol) and 3,5-dichloro 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 15 A target compound was obtained in the same manner as in Example 23, except that 25 mg (0.13 mmol) of phenylisocyanate was reacted (yield: 87%).
1H NMR(CDCl3, 300 MHz):δ 1.70-1.86 (m, 1H), 2.00-2.10 (m, 1H), 2.69-2.78 (m, 2H), 2.72-2.82 (m, 2H), 2.84-3.04 (m, 7H), 3.12-3.22 (m, 1H), 3.24-3.34 (m, 1H), 3.80 (s, 3H), 3.98-4.08 (m, 1H), 4.12-4.23 (m, 1H), 5.15-5.22 (m, 1H), 6.79 (s, 1H), 6.82-6.89 (m, 2H), 6.92-6.98 (m, 3H), 7.33 (d, J=1.8 Hz, 2H), 7.51-7.62 (m, 2H), 7.85-7.94 (m, 3H), 8.01-8.04 (m, 1H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.70-1.86 (m, 1H), 2.00-2.10 (m, 1H), 2.69-2.78 (m, 2H), 2.72-2.82 (m, 2H), 2.84- 3.04 (m, 7H), 3.12-3.22 (m, 1H), 3.24-3.34 (m, 1H), 3.80 (s, 3H), 3.98-4.08 (m, 1H), 4.12-4.23 (m, 1H), 5.15-5.22 (m, 1H), 6.79 (s, 1H), 6.82-6.89 (m, 2H), 6.92-6.98 (m, 3H), 7.33 (d, J = 1.8 Hz, 2H), 7.51-7.62 ( m, 2H), 7.85-7.94 (m, 3H), 8.01-8.04 (m, 1H), 8.58 (s, 1H).
<< 실시예Example 154> 1-(3,5- 154> 1- (3,5- 디메톡시페닐카바모일Dimethoxyphenylcarbamoyl )-3-(4-(2-) -3- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 15에서 제조된 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 49 mg(0.11 mmol)과 3,5-디메톡시페닐이소시아네이트 25 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 94%).49 mg (0.11 mmol) and 3,5-dimethic 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 15 Except for reacting 25 mg (0.13 mmol) of oxyphenylisocyanate, the same procedure as in Example 23 was carried out to obtain the target compound (yield: 94%).
1H NMR(CDCl3, 300 MHz):δ 1.76-1.90 (m, 1H), 2.04-2.13 (m, 1H), 2.72-2.90 (m, 3H), 2.91-3.04 (m, 6H), 3.20-3.40 (m, 2H), 3.76 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 3.98-4.09 (m, 1H), 4.20-4.28 (m, 1H), 5.28-5.36 (m, 1H), 6.44-6.49 (m, 1H), 6.72 (d, J=8.9 Hz, 1H), 6.80 (s, 1H), 6.82-6.88 (m, 2H), 6.92-6.98 (m, 1H), 7.32 (s, 1H), 7.50-7.61 (m, 2H), 7.84-7.90 (m, 4H), 8.03-8.07 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.76-1.90 (m, 1H), 2.04-2.13 (m, 1H), 2.72-2.90 (m, 3H), 2.91-3.04 (m, 6H), 3.20- 3.40 (m, 2H), 3.76 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 3.98-4.09 (m, 1H), 4.20-4.28 (m, 1H), 5.28-5.36 ( m, 1H), 6.44-6.49 (m, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.80 (s, 1H), 6.82-6.88 (m, 2H), 6.92-6.98 (m, 1H) , 7.32 (s, 1H), 7.50-7.61 (m, 2H), 7.84-7.90 (m, 4H), 8.03-8.07 (m, 1H), 8.59 (s, 1H).
<< 실시예Example 155> 1-(3- 155> 1- (3- 클로로Chloro -4--4- 메톡시페닐카바모일Methoxyphenylcarbamoyl )-3-(4-(2-) -3- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
실시예 15에서 제조된 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 49 mg(0.11 mmol)과 3-클로로-4-메톡시페닐이소시아네이트 24 mg(0.13 mmol)을 반응시키는 것을 제외하고는 실시예 23과 동일한 방법으로 수행하 여 목적화합물을 수득하였다(수율: 94%).49 mg (0.11 mmol) and 3-chloro-4 of 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate prepared in Example 15 A target compound was obtained in the same manner as in Example 23, except that 24 mg (0.13 mmol) of methoxyphenylisocyanate was reacted (yield: 94%).
1H NMR(CDCl3, 300 MHz):δ 1.72-1.86 (m, 1H), 2.00-2.10 (m, 1H), 2.73-2.82 (m, 2H), 2.83-3.04 (m, 7H), 3.08-3.20 (m, 1H), 3.22-3.30 (m, 1H), 3.80 (s, 3H), 3.81 (s, 3H), 4.03-4.10 (m, 1H), 4.15-4.25 (m, 1H), 5.18-5.26 (m, 1H), 6.71 (s, 1H), 6.74-6.79 (m, 1H), 6.82-6.87 (m, 2H), 6.94-6.98 (m, 1H), 7.17-7.21 (m, 1H), 7.24-7.26 (m, 1H), 7.38-7.41 (m, 1H), 7.51-7.62 (m, 2H), 7.85-7.94 (m, 3H), 8.02-8.06 (m, 1H), 8.59 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.72-1.86 (m, 1H), 2.00-2.10 (m, 1H), 2.73-2.82 (m, 2H), 2.83-3.04 (m, 7H), 3.08- 3.20 (m, 1H), 3.22-3.30 (m, 1H), 3.80 (s, 3H), 3.81 (s, 3H), 4.03-4.10 (m, 1H), 4.15-4.25 (m, 1H), 5.18- 5.26 (m, 1H), 6.71 (s, 1H), 6.74-6.79 (m, 1H), 6.82-6.87 (m, 2H), 6.94-6.98 (m, 1H), 7.17-7.21 (m, 1H), 7.24-7.26 (m, 1H), 7.38-7.41 (m, 1H), 7.51-7.62 (m, 2H), 7.85-7.94 (m, 3H), 8.02-8.06 (m, 1H), 8.59 (s, 1H ).
<< 실시예Example 156> 1-(3,5- 156> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(2-) -3- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3--3- 카르복실레이트의Carboxylate 제조 Produce
3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 19에서 수득한 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 153과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 80%).3- (4- (2-methoxyphenyl) obtained in Example 19 instead of 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 153 to obtain the target compound (yield: 80% ).
1H NMR(CDCl3, 300 MHz):δ 1.70-1.80 (m, 1H), 1.98-2.08 (m, 1H), 2.73-2.82 (m, 2H), 2.83-2.94 (m, 3H), 2.96-3.06 (m, 4H), 3.10-3.28 (m, 2H), 3.81 (s, 3H), 3.96-4.07 (m, 1H), 4.10-4.18 (m, 1H), 5.10-5.18 (m, 1H), 6.80 (s, 1H), 6.83-6.88 (m, 2H), 6.92-6.99 (m, 3H), 7.33 (d, J=1.8 Hz, 2H), 7.36-7.49 (m, 3H), 7.58-7.66 (m, 4H), 8.06-8.10 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.70-1.80 (m, 1H), 1.98-2.08 (m, 1H), 2.73-2.82 (m, 2H), 2.83-2.94 (m, 3H), 2.96- 3.06 (m, 4H), 3.10-3.28 (m, 2H), 3.81 (s, 3H), 3.96-4.07 (m, 1H), 4.10-4.18 (m, 1H), 5.10-5.18 (m, 1H), 6.80 (s, 1H), 6.83-6.88 (m, 2H), 6.92-6.99 (m, 3H), 7.33 (d, J = 1.8 Hz, 2H), 7.36-7.49 (m, 3H), 7.58-7.66 ( m, 4H), 8.06-8.10 (m, 2H).
<< 실시예Example 157> 1-(3,5- 157> 1- (3,5- 디메톡시페닐카바모일Dimethoxyphenylcarbamoyl )-3-(4-(2-) -3- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 19에서 수득한 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카르복실레이트를 사용하는 것을 제외하고는 실시예 154와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 84%).3- (4- (2-methoxyphenyl) obtained in Example 19 instead of 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 154 to obtain the target compound (yield: 84% ).
1H NMR(CDCl3, 300 MHz):δ 1.74-1.88 (m, 1H), 2.02-2.12 (m, 1H), 2.72-2.86 (m, 3H), 2.90-3.06 (m, 6H), 3.16-3.32 (m, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 3.98-4.08 (m, 1H), 4.18-4.27 (m, 1H), 5.23-5.30 (m, 1H), 6.46-6.50 (m, 1H), 6.73 (d, J=8.9 Hz, 1H), 6.80-6.88 (m, 3H), 6.92-6.99 (m, 1H), 7.30 (s, 1H), 7.36-7.50 (m, 3H), 7.59-7.65 (m, 4H), 7.88 (d, J =3.0 Hz, 1H), 8.08-8.11 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.74-1.88 (m, 1H), 2.02-2.12 (m, 1H), 2.72-2.86 (m, 3H), 2.90-3.06 (m, 6H), 3.16- 3.32 (m, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 3.98-4.08 (m, 1H), 4.18-4.27 (m, 1H), 5.23-5.30 ( m, 1H), 6.46-6.50 (m, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.80-6.88 (m, 3H), 6.92-6.99 (m, 1H), 7.30 (s, 1H) , 7.36-7.50 (m, 3H), 7.59-7.65 (m, 4H), 7.88 (d, J = 3.0 Hz, 1H), 8.08-8.11 (m, 2H).
<< 실시예Example 158> 1-(3- 158> 1- (3- 클로로Chloro -4-메톡시페닐카바모일)-3-(4-(2--4-methoxyphenylcarbamoyl) -3- (4- (2- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이의Ray's 제조 Produce
3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 실시예 19에서 수득한 3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-바이페닐-3-카 르복실레이트를 사용하는 것을 제외하고는 실시예 155와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 91%).3- (4- (2-methoxyphenyl) obtained in Example 19 instead of 3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate Except for using piperazin-1-yl) piperidin-4-yl-biphenyl-3-carboxylate in the same manner as in Example 155 to obtain the target compound (yield: 91 %).
1H NMR(CDCl3, 300 MHz):δ 1.72-1.86 (m, 1H), 1.98-2.10 (m, 1H), 2.74-2.83 (m, 2H), 2.84-2.96 (m, 3H), 2.97-3.06 (m, 4H), 3.08-3.26 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.00-4.08 (m, 1H), 4.12-4.20 (m, 1H), 5.12-5.22 (m, 1H), 6.63 (s, 1H), 6.78-6.84 (m, 2H), 6.85-6.88 (m,2H), 6.94-7.00 (m, 1H), 7.18-7.23 (m, 1H), 7.26 (s, 1H), 7.37-7.50 (m, 3H), 7.59-7.68 (m, 4H), 7.88 (d, J =3.0 Hz, 1H), 8.08-8.12 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.72-1.86 (m, 1H), 1.98-2.10 (m, 1H), 2.74-2.83 (m, 2H), 2.84-2.96 (m, 3H), 2.97- 3.06 (m, 4H), 3.08-3.26 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.00-4.08 (m, 1H), 4.12-4.20 (m, 1H), 5.12- 5.22 (m, 1H), 6.63 (s, 1H), 6.78-6.84 (m, 2H), 6.85-6.88 (m, 2H), 6.94-7.00 (m, 1H), 7.18-7.23 (m, 1H), 7.26 (s, 1 H), 7.37-7.50 (m, 3 H), 7.59-7.68 (m, 4 H), 7.88 (d, J = 3.0 Hz, 1 H), 8.08-8.12 (m, 2H).
<< 실시예Example 159> 1-(3,5- 159> 1- (3,5- 디메톡시페닐카바모일Dimethoxyphenylcarbamoyl )-3-(4-(4-) -3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 154와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 91%).3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate instead of 3- (4- (4-methoxyphenyl) piperazin-1- (I) A target compound was obtained in the same manner as in Example 154 except for using piperidin-4-yl-1-naphthoate (yield: 91%).
1H NMR(CDCl3, 300 MHz):δ 1.74-1.89 (m, 1H), 2.01-2.11 (m, 1H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 3H), 2.94-3.04 (m, 4H), 3.16-3.35 (m, 2H), 3.73 (s, 3H), 3.76 (s, 3H), 3.78 (s, 3H), 4.00-4.10 (m, 1H), 4.20-4.28 (m, 1H), 5.28-5.35 (m, 1H), 6.45-6.50 (m, 1H), 6.72 (d, J=8.9 Hz, 1H), 6.73-6.84 (m, 4H), 7.32 (s, 1H), 7.49-7.61 (m, 2H), 7.84-7.91 (m, 4H), 8.02-8.05 (m, 1H), 8.56 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.74-1.89 (m, 1H), 2.01-2.11 (m, 1H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 3H), 2.94- 3.04 (m, 4H), 3.16-3.35 (m, 2H), 3.73 (s, 3H), 3.76 (s, 3H), 3.78 (s, 3H), 4.00-4.10 (m, 1H), 4.20-4.28 ( m, 1H), 5.28-5.35 (m, 1H), 6.45-6.50 (m, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.73-6.84 (m, 4H), 7.32 (s, 1H) , 7.49-7.61 (m, 2H), 7.84-7.91 (m, 4H), 8.02-8.05 (m, 1H), 8.56 (s, 1H).
<< 실시예Example 160> 1-(3- 160> 1- (3- 클로로Chloro -4-메톡시페닐카바모일)-3-(4-(4--4-methoxyphenylcarbamoyl) -3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-1-) Piperazin-1-yl) piperidin-4-yl-1- 나프토에이트의Naphthoate 제조 Produce
3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 155와 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 99%).3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate instead of 3- (4- (4-methoxyphenyl) piperazin-1- (I) A target compound was obtained in the same manner as in Example 155 except for using piperidin-4-yl-1-naphthoate (yield: 99%).
1H NMR(CDCl3, 300 MHz):δ 1.68-1.83(m, 1H), 1.96-2.04 (m, 1H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 3H), 2.94-3.00 (m, 4H), 3.04-3.16 (m, 1H), 3.18-3.26 (m, 1H), 3.72 (s, 3H), 3.82 (s, 3H), 4.04-4.12 (m, 1H), 4.15-4.22 (m, 1H), 5.17-5.25 (m, 1H), 6.71-6.83 (m, 5H), 7.18-7.27 (m, 2H), 7.41 (d, J =2.6 Hz, 1H), 7.50-7.62 (m, 2H), 7.85-7.93 (m, 3H), 8.00-8.04 (m, 1H), 8.58 (s, 1H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.68-1.83 (m, 1H), 1.96-2.04 (m, 1H), 2.70-2.80 (m, 2H), 2.82-2.92 (m, 3H), 2.94- 3.00 (m, 4H), 3.04-3.16 (m, 1H), 3.18-3.26 (m, 1H), 3.72 (s, 3H), 3.82 (s, 3H), 4.04-4.12 (m, 1H), 4.15- 4.22 (m, 1H), 5.17-5.25 (m, 1H), 6.71-6.83 (m, 5H), 7.18-7.27 (m, 2H), 7.41 (d, J = 2.6 Hz, 1H), 7.50-7.62 ( m, 2H), 7.85-7.93 (m, 3H), 8.00-8.04 (m, 1H), 8.58 (s, 1H).
<< 실시예Example 161> 1-(3,5- 161> 1- (3,5- 디클로로페닐카바모일Dichlorophenylcarbamoyl )-3-(4-(4-) -3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3-카르복실-3-carboxyl 레이트의Rate 제조 Produce
3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 157과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 84%).3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate instead of 3- (4- (4-methoxyphenyl) piperazin-1- I) A target compound was obtained in the same manner as in Example 157 except for using piperidin-4-yl-1-naphthoate (yield: 84%).
1H NMR(CDCl3, 300 MHz):δ 1.72-1.87 (m, 1H), 1.99-2.09 (m, 1H), 2.70-2.79 (m, 2H), 2.80-2.96 (m, 3H), 2.98-3.03 (m, 4H), 3.14-3.29 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 3.81 (s, 3H), 4.00-4.10 (m, 1H), 4.18-4.25 (m, 1H), 5.23-5.30 (m, 1H), 6.46-6.51 (m, 1H), 6.74 (d, J=8.9 Hz, 1H), 6.77-6.87 (m, 4H), 7.30 (s, 1H), 7.36-7.50 (m, 3H), 7.59-7.65 (m, 4H), 7.88 (d, J =3.0 Hz, 1H), 8.06-8.10 (m, 2H 1 H NMR (CDCl 3 , 300 MHz): δ 1.72-1.87 (m, 1H), 1.99-2.09 (m, 1H), 2.70-2.79 (m, 2H), 2.80-2.96 (m, 3H), 2.98- 3.03 (m, 4H), 3.14-3.29 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 3.81 (s, 3H), 4.00-4.10 (m, 1H), 4.18-4.25 ( m, 1H), 5.23-5.30 (m, 1H), 6.46-6.51 (m, 1H), 6.74 (d, J = 8.9 Hz, 1H), 6.77-6.87 (m, 4H), 7.30 (s, 1H) , 7.36-7.50 (m, 3H), 7.59-7.65 (m, 4H), 7.88 (d, J = 3.0 Hz, 1H), 8.06-8.10 (m, 2H
<< 실시예Example 162> 1-(3,5- 162> 1- (3,5- 디메톡시페닐카바모일Dimethoxyphenylcarbamoyl )-3-(4-(4-) -3- (4- (4- 메톡시페닐Methoxyphenyl )피페라진-1-일)피페리딘-4-일-) Piperazin-1-yl) piperidin-4-yl- 바이페닐Biphenyl -3--3- 카르복실레이트의Carboxylate 제조 Produce
3-(4-(2-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트 대신 3-(4-(4-메톡시페닐)피페라진-1-일)피페리딘-4-일-1-나프토에이트를 사용하는 것을 제외하고는 실시예 158과 동일한 방법으로 수행하여 목적화합물을 수득하였다(수율: 86%).3- (4- (2-methoxyphenyl) piperazin-1-yl) piperidin-4-yl-1-naphthoate instead of 3- (4- (4-methoxyphenyl) piperazin-1- (I) A target compound was obtained in the same manner as in Example 158 except for using piperidin-4-yl-1-naphthoate (yield: 86%).
1H NMR(CDCl3, 300 MHz):δ 1.68-1.83 (m, 1H), 1.94-2.03 (m, 1H), 2.70- 2.80 (m, 2H), 2.81-2.92 (m, 3H), 2.94-3.04 (m, 4H), 3.06-3.22 (m, 2H), 3.74 (s, 3H), 3.82 (s, 3H), 4.00-4.19 (m, 2H), 5.12-5.21 (m, 1H), 6.71 (s, 1H), 6.75-6.85 (m, 5H), 7.19-7.24 (m, 1H), 7.36-7.49 (m, 3H), 7.59-7.67 (m, 3H), 8.06-8.10 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 1.68-1.83 (m, 1H), 1.94-2.03 (m, 1H), 2.70-2.80 (m, 2H), 2.81-2.92 (m, 3H), 2.94- 3.04 (m, 4H), 3.06-3.22 (m, 2H), 3.74 (s, 3H), 3.82 (s, 3H), 4.00-4.19 (m, 2H), 5.12-5.21 (m, 1H), 6.71 ( s, 1H), 6.75-6.85 (m, 5H), 7.19-7.24 (m, 1H), 7.36-7.49 (m, 3H), 7.59-7.67 (m, 3H), 8.06-8.10 (m, 2H).
본 발명의 실시예의 제조방법에 따라 얻어진 상기 화학식 1로 표시되는 피페리딘 유도체의 수율, 녹는점 및 1H NMR은 하기 표 1에 나타내었다.The yield, melting point and 1 H NMR of the piperidine derivative represented by Chemical Formula 1 obtained according to the preparation method of the embodiment of the present invention are shown in Table 1 below.
<비교예> 4-페닐피페리딘-3-일 바이페닐-4-카르복실레이트의 제조Comparative Example Preparation of 4-phenylpiperidin-3-yl biphenyl-4-carboxylate
국제공개공보 제03/43987호(WO0343987)에 기재된 방법으로 4-페닐피페리딘-3-일 바이페닐-4-카르복실레이트를 제조하였다.4-phenylpiperidin-3-yl biphenyl-4-carboxylate was prepared by the method described in International Publication No. 03/43987 (WO0343987).
<< 실험예Experimental Example 1> 베타- 1> beta- 세크리테아제Secretase 활성 저해 효과 실험 1 Active inhibitory effect experiment 1
본 발명의 피페리딘 유도체에 의한 베타-세크리테아제 활성 저해 효과를 알아보기 위해, 하기와 같은 실험을 수행하였다.In order to determine the beta-secretase activity inhibitory effect by the piperidine derivative of the present invention, the following experiment was performed.
베타-세크리테아제-1 기질(substrate) 용액(Rh-EVNLDAEFK-Quencher, 750 nM in assay buffer)에 실시예 1~152에서 제조된 화합물 및 비교예로서 종래 베타-세크리테아제 저해 활성을 갖는 피페리딘 화합물인 4-페닐피페리딘-3-일 바이페닐-4-카르복실레이트를 10 ㎕ 가하고 가볍게 혼합한 다음, 정제된 바쿨로비루스에서 발현된(baculovirus-expressed) 베타-세크리테아제-1 효소(1.0 unit/mL in assay buffer) 용액 10 ㎕를 첨가하여 반응을 유도한 후 실온에서 60분간 배양(incubation)하였다. 배양완료 후 즉시 반응액에 10 ㎕의 종결 용액(stop solution)을 가하여 반응을 정지시킨 후 FlexStation을 이용하여 545 nm(excitation) 및 585 nm(emission)에서 그 형광을 측정하여 효소 활성도를 측정하여 베타-세크리테아제에 대한 저해 활성을 측정하였다. 위의 실험의 총 부피는 40 ㎕이며 384-블랙 마이크로웰 플레이트(384-black microwell plate)상에서 실시하였고, 저해 활성은 IC50으로 나타내었다. 시험에 사용된 효소, 기질, 종결 용액(stop solution), 어세이 버퍼(assay buffer) 등의 자세한 조성을 표 2에 나타내었다.Compounds prepared in Examples 1 to 152 in a beta-secretase-1 substrate solution (Rh-EVNLDAEFK-Quencher, 750 nM in assay buffer) and blood having a conventional beta-secretase inhibitory activity as a comparative example 10 [mu] l of 4-phenylpiperidin-3-yl biphenyl-4-carboxylate, a ferridine compound, was added and mixed lightly, and then the baculovirus-expressed beta-secretase- 10 μl of a solution of 1 enzyme (1.0 unit / mL in assay buffer) was added to induce a reaction and then incubated at room temperature for 60 minutes. Immediately after completion of the culture, 10 µl of a stop solution was added to the reaction solution to stop the reaction, and the enzyme activity was measured by measuring its fluorescence at 545 nm (excitation) and 585 nm (emission) using FlexStation. Inhibitory activity against secretase was measured. The total volume of the above experiment was 40 μl and was performed on a 384-black microwell plate, and the inhibitory activity is shown as IC 50 . Detailed compositions of enzymes, substrates, stop solutions, assay buffers, and the like used in the test are shown in Table 2.
실험결과를 표 3에 나타내었다.The experimental results are shown in Table 3.
표 3에 나타낸 바와 같이, 본 발명에 따른 피페리딘 유도체의 베타-세크리테아제 저해 활성은 IC50이 0.6~10 μM로써 기존 피페리딘 화합물(11 μM)보다 매우 적은 양을 사용하여 베타-세크리테아제의 활성을 저해할 수 있음을 알 수 있다.As shown in Table 3, the present invention avoid beta of piperidine derivatives of the - to sekeuri protease inhibitory activity IC 50 uses a small amount than the conventional piperidine compound (11 μM) as a 0.6 ~ 10 μM beta- It can be seen that it can inhibit the activity of secretase.
<< 실험예Experimental Example 2> 베타- 2> beta- 세크리테아제Secretase 활성 저해 효과 실험 2 Activity inhibitory effect experiment 2
본 발명의 피페리딘 유도체에 의한 베타-세크리테아제 활성 저해 효과를 알아보기 위해, 세포를 기준으로 한 하기와 같은 실험을 수행하였다.In order to determine the inhibitory effect of beta-secretase activity by the piperidine derivative of the present invention, the following experiments based on cells were performed.
PC12tet-off pTRE2puro-APPsw stable cell line을 RPMI 1640 (10% FBS, 5% HS, 1% Penicillin/Streptomycin)에서 전체 부피당 100 ㎍/㎖의 G418(Clontech), 1 ㎍/㎖의 Doxicyclin (Clontech), 3 ㎍/㎖ Puromycin(Clontech)이 되게 넣어주고 5% CO2, 37 ℃로 배양하였다. 배양된 세포를 0.05% PEI-코팅된 6-웰 플레이트에 1.2× 106 세포/웰로 나누고 24시간 후에 condition media(5% HS, 1% FBS, 0.5% P/S) 2 ml로 교환하여 24시간 배양하였다. 다음으로 실험예 1에서 베타-세크리테아제의 저해 활성이 특히 뛰어났던 실시예 2, 6, 10, 13, 16, 17, 101, 129, 130, 138, 146 및 152의 화합물을 10 μM 처리하고 24시간 동안 반응시킨 뒤 Media를 제거하고 cell extraction buffer(R&D, FP002)를 200 ㎕를 가한 후 각각 마이크로웰 플레이트를 에펜돌프 튜브에 옮겨 얼음위에서 10~15분 동안 반응시켰다. 반응시킨 샘플을 4 ℃, 14,000 rpm에서 10분 동안 원심분리하고 상층액을 BACE FRET 측정방법으로 320 nm(excitation) 및 405 nm(emission)에서 형광을 측정하여 효소 활성 저해율을 측정하여 표 4에 나타내었다. 이때, 저해율이 50~60%일 경우에는 A, 저해율이 40~50%일 경우에는 B, 저해율이 40% 미만일 경우에는 C로 나타내었다.PC12tet-off pTRE2puro-APPsw stable cell lines were prepared in RPMI 1640 (10% FBS, 5% HS, 1% Penicillin / Streptomycin) at 100 μg / ml G418 (Clontech), 1 μg / ml Doxicyclin (Clontech), 3 ㎍ / ㎖ Puromycin (Clontech) was added and incubated at 5% CO 2 , 37 ℃. Cultured cells were divided into 1.2 × 10 6 cells / well in 0.05% PEI-coated 6-well plates and 24 hours later exchanged with 2 ml of condition media (5% HS, 1% FBS, 0.5% P / S) for 24 hours. Incubated. Next, 10 μM of the compounds of Examples 2, 6, 10, 13, 16, 17, 101, 129, 130, 138, 146, and 152, in which the inhibitory activity of beta-secretase was particularly excellent in Experimental Example 1, After reacting for 24 hours, the media was removed, 200 μl of cell extraction buffer (R & D, FP002) was added, and each microwell plate was transferred to an eppendorf tube and allowed to react on ice for 10-15 minutes. The reacted samples were centrifuged at 4 ° C. and 14,000 rpm for 10 minutes, and the supernatants were measured for fluorescence at 320 nm (excitation) and 405 nm (emission) by BACE FRET. It was. In this case, when the inhibition rate is 50 to 60%, A, when the inhibition rate is 40 to 50%, B, and when the inhibition rate is less than 40%, C is indicated.
표 4에 나타낸 바와 같이, 본 발명에 따른 피페리딘 유도체는 세포시험에서도 베타-세크리테아제 효소 저해 효능이 있으며, 실시예 2 및 13일 경우에는 50~60% 저해 효능을 나타내는 것을 알 수 있다.As shown in Table 4, the piperidine derivative according to the present invention has a beta-secretase enzyme inhibitory effect even in a cell test, and in Examples 2 and 13, it can be seen that the inhibitory effect is 50-60%. .
따라서 본 발명에 따른 피페리딘 유도체는 베타-세크리테아제 효소의 활성을 저해하여 이에 의해 발생되는 알츠하이머, 다운증후군 등의 신경퇴행성 질환의 예방 및 치료에 유용하게 사용될 수 있다.Therefore, the piperidine derivative according to the present invention can be usefully used for the prevention and treatment of neurodegenerative diseases such as Alzheimer's and Down syndrome caused by inhibiting the activity of beta-secretase enzyme.
한편, 본 발명에 따른 상기 화학식 1로 표시되는 피페리딘 유도체는 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 piperidine derivative represented by Chemical Formula 1 according to the present invention may be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
<< 제제예Formulation example 1> 정제(직접 가압) 1> tablet (direct pressure)
화학식 1의 피페리딘 유도체 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 제조하였다.After sifting 5.0 mg of piperidine derivative of Formula 1, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to prepare a tablet.
<< 제제예Formulation example 2> 정제(습식 조립) 2> tablets (wet assembly)
화학식 1의 피페리딘 유도체 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 제조하였다.5.0 mg of piperidine derivative of Formula 1 was sieved, followed by mixing 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed to make tablets.
<< 제제예Formulation example 3> 분말과 3> with powder 캡슐제Capsule
활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 혼합하였다. 상기 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.After sifting 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.
<< 제제예Formulation example 4> 주사제 4> Injection
활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4·12H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.Injectables were prepared by containing 100 mg as the active ingredient, followed by 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.
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KR20050044533A (en) * | 2001-11-19 | 2005-05-12 | 엘란 파마슈티칼스, 인크. | (4-phenyl) piperidin-3-yl-phenylcarboxylate derivatives and related compounds as beta-secretase inhibitors for the treatment of alzheimer's disease |
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