JP6767878B2 - アペリン受容体(apj)アゴニストおよびそれらの使用 - Google Patents
アペリン受容体(apj)アゴニストおよびそれらの使用 Download PDFInfo
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- JP6767878B2 JP6767878B2 JP2016567569A JP2016567569A JP6767878B2 JP 6767878 B2 JP6767878 B2 JP 6767878B2 JP 2016567569 A JP2016567569 A JP 2016567569A JP 2016567569 A JP2016567569 A JP 2016567569A JP 6767878 B2 JP6767878 B2 JP 6767878B2
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- JP
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- Prior art keywords
- pyrazole
- formamide
- dimethoxyphenyl
- alkyl
- conr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000000556 agonist Substances 0.000 title description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 155
- 150000001875 compounds Chemical class 0.000 claims description 112
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 claims description 80
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 78
- 125000003118 aryl group Chemical group 0.000 claims description 72
- -1 alkyl tetrazole Chemical class 0.000 claims description 69
- 125000003545 alkoxy group Chemical group 0.000 claims description 51
- 201000010099 disease Diseases 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
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- 208000035475 disorder Diseases 0.000 claims description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 27
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- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 claims description 6
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- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
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- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
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- DBOPTADIAHPLNB-QHCPKHFHSA-N 5-(2,6-dimethoxyphenyl)-1-(2-methylpropyl)-N-[(2S)-1-oxo-4-phenyl-1-pyrrolidin-1-ylbutan-2-yl]pyrazole-3-carboxamide Chemical compound COC1=CC=CC(OC)=C1C1=CC(=NN1CC(C)C)C(=O)N[C@@H](CCC1=CC=CC=C1)C(=O)N1CCCC1 DBOPTADIAHPLNB-QHCPKHFHSA-N 0.000 claims 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 230000003247 decreasing effect Effects 0.000 claims 1
- MHPUGCYGQWGLJL-UHFFFAOYSA-N dimethyl pentanoic acid Natural products CC(C)CCCC(O)=O MHPUGCYGQWGLJL-UHFFFAOYSA-N 0.000 claims 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
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Classifications
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- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
アペリン受容体(APJ)は、オーファンGタンパク質共役受容体(GPCR)として、1993年にクローン化された。ヒトAPJ遺伝子は、11番染色体の長腕に位置し、377アミノ酸Gタンパク質共役受容体をコードする。APJの遺伝子は、2つの受容体間の配列類似性に起因して、アンジオテンシン受容体様1(AGTRL1)と命名された。非特許文献1。しかしながら、アンジオテンシンを含むアンジオテンシン受容体の既知のペプチド性リガンドのいずれも、APJを活性化しない。ペプチドアペリンがその内因性リガンドとして確認された1998年まで、APJはオーファンGPCRのままであった。非特許文献2;非特許文献3。
I
または薬学的に許容される塩、プロドラッグ、もしくはプロドラッグの塩であって、
式中、
R1は式:
で表され、
各Aは独立してC1-8アルキル、C1-8アルキル(アリール)、C1-8アルコキシ、C1-8アルコキシアリール、C2-8アルケニル、C3-8アルキニル、C3-8シクロアルキル、-CF3、-(CH2)xNR7R8、-CN、-CONR7R8、-COR7、-CO2(CH2)xNR7R8、-CO2R7、ハロゲン、ヒドロキシル、-N3、-NHCOR7、-NHSO2C1-8アルキル、-NHCO2C1-8アルキル、-NO2、-NR7R8、-O(CH2)xNR7R8、-O(CH2)xCO2R7、-OCOC1-8アルキル、-OCO(CH2)xNR7R8、-SO(1-3)R7、または-SR7であり;
R7およびR8は、独立してアリール、C1-8アルキル、C1-8アルキルアルコール、C1-8アルキルアミノ、C1-8アルキルアミド、C1-8アルキル(アリール)、C1-8アルキル(C3-8シクロアルキル)、C1-8アルキルグアニジニル、C1-8アルキルヘテロアリール、C1-8アルキルイミダゾリル、C1-8アルキルインドリル、C1-8アルキルチオエーテル、C1-8アルキルチオール、C2-8アルケニル、C3-8アルキニル、C3-8シクロアルキル、-(CH2)xCONHR9、-(CH2)xCOR9、-(CH2)xCO2R9、もしくはHであるか;またはR7およびR8は一緒になって、1つ以上のヘテロ原子で置換されていてもよい4〜8員環を作り;
nは0、1、2、3、4または5であり;
各xは独立して0-8であり;
R2は、存在するかまたは存在せず、存在する場合は、アリール、C1-8アルキル、C1-8アルキル(アリール)、C1-8アルキル(C3-8シクロアルキル)、C3-8シクロアルキルであり;
R3は、存在するかまたは存在せず、R2が存在する場合は存在せず、存在する場合は、アリール、C1-8アルキル、C1-8アルキル(アリール)、C1-8アルキル(C3-8シクロアルキル)、C3-8シクロアルキルであり;
R4、R5、およびR6は、独立してアダマンタニル、アリール、C1-8アルキル、C1-8アルキルアルコール、C1-8アルキルアミノ、C1-8アルキルアミド、C1-8アルキル(アリール)、C1-8アルキル(C3-8シクロアルキル)、C1-8アルキル(C3-8シクロアルキル)-CO2R7、C1-8アルキルグアニジニル、C1-8アルキルヘテロアリール、C1-8アルキルイミダゾリル、C1-8アルキルインドリル、C1-8アルキルチオエーテル、C1-8アルキルチオール、C2-8アルケニル、C3-8アルキニル、C3-8シクロアルキル、C3-8シクロアルキル-CO2R7、-(CH2)xNR7R8、-(CH2)xOR7、-(CH2)xNHCOR7、-(CH2)xNHCO2R7、-(CH2)xCONR7R8、-(CH2)xCONR7(CH2)yCO2R9、-(CH2)xCONR7(CH2)yCONR7R8、-(CH2)xCONR7(CH2)yR9、-(CH2)xCOR7、-(CH2)xCO2R7、-CHR7COR9、-CHR7CONHCHR8COR9、-CONR7R8、-CONR7(CH2)xCO2R8、-CONR7CHR8CO2R9、-CO2R9、もしくはHであるか;またはR4およびR5は一緒になって、1つ以上のヘテロ原子で置換されていてもよく、もしくはR6を含む基から選択されてもよい4〜8員環を作り;
R9はアリール、C1-8アルコキシ、C1-8アルキル、C1-8アルキル(アリール)、C3-8シクロアルキル、H、ヘテロアリール、またはヒドロキシルであり;
各yは独立して1-8であり;ならびに
ZはH2または=Oである化合物を提供する。
I
または薬学的に許容される塩、プロドラッグ、もしくはプロドラッグの塩であって、
式中、
R1は式:
で表され、
各Aは独立してC1-8アルキル、C1-8アルキル(アリール)、C1-8アルコキシ、C1-8アルコキシアリール、C2-8アルケニル、C3-8アルキニル、C3-8シクロアルキル、-CF3、-(CH2)xNR7R8、-CN、-CONR7R8、-COR7、-CO2(CH2)xNR7R8、-CO2R7、ハロゲン、ヒドロキシル、-N3、-NHCOR7、-NHSO2C1-8アルキル、-NHCO2C1-8アルキル、-NO2、-NR7R8、-O(CH2)xNR7R8、-O(CH2)xCO2R7、-OCOC1-8アルキル、-OCO(CH2)xNR7R8、-SO(1-3)R7、または-SR7であり;
R7およびR8は、独立してアリール、C1-8アルキル、C1-8アルキルアルコール、C1-8アルキルアミノ、C1-8アルキルアミド、C1-8アルキル(アリール)、C1-8アルキル(C3-8シクロアルキル)、C1-8アルキルグアニジニル、C1-8アルキルヘテロアリール、C1-8アルキルイミダゾリル、C1-8アルキルインドリル、C1-8アルキルチオエーテル、C1-8アルキルチオール、C2-8アルケニル、C3-8アルキニル、C3-8シクロアルキル、-(CH2)xCONHR9、-(CH2)xCOR9、-(CH2)xCO2R9、もしくはHであるか;またはR7およびR8は一緒になって、1つ以上のヘテロ原子で置換されていてもよい4〜8員環を作り;
nは0、1、2、3、4または5であり;
各xは独立して0-8であり;
R2は、存在するかまたは存在せず、存在する場合は、アリール、C1-8アルキル、C1-8アルキル(アリール)、C1-8アルキル(C3-8シクロアルキル)、C3-8シクロアルキルであり;
R3は、存在するかまたは存在せず、R2が存在する場合は存在せず、存在する場合は、アリール、C1-8アルキル、C1-8アルキル(アリール)、C1-8アルキル(C3-8シクロアルキル)、C3-8シクロアルキルであり;
R4、R5、およびR6は、独立してアダマンタニル、アリール、C1-8アルキル、C1-8アルキルアルコール、C1-8アルキルアミノ、C1-8アルキルアミド、C1-8アルキル(アリール)、C1-8アルキル(C3-8シクロアルキル)、C1-8アルキル(C3-8シクロアルキル)-CO2R7、C1-8アルキルグアニジニル、C1-8アルキルヘテロアリール、C1-8アルキルイミダゾリル、C1-8アルキルインドリル、C1-8アルキルチオエーテル、C1-8アルキルチオール、C2-8アルケニル、C3-8アルキニル、C3-8シクロアルキル、C3-8シクロアルキル-CO2R7、-(CH2)xNR7R8、-(CH2)xOR7、-(CH2)xNHCOR7、-(CH2)xNHCO2R7、-(CH2)xCONR7R8、-(CH2)xCONR7(CH2)yCO2R9、-(CH2)xCONR7(CH2)yCONR7R8、-(CH2)xCONR7(CH2)yR9、-(CH2)xCOR7、-(CH2)xCO2R7、-CHR7COR9、-CHR7CONHCHR8COR9、-CONR7R8、-CONR7(CH2)xCO2R8、-CONR7CHR8CO2R9、-CO2R9、もしくはHであるか;またはR4およびR5は一緒になって、1つ以上のヘテロ原子で置換されていてもよく、もしくはR6を含む基から選択されてもよい4〜8員環を作り;
R9はアリール、C1-8アルコキシ、C1-8アルキル、C1-8アルキル(アリール)、C3-8シクロアルキル、H、ヘテロアリール、またはヒドロキシルであり;
各yは独立して1-8であり;ならびに
ZはH2または=Oである化合物を提供する。
(定義)
(医薬組成物)
(治療方法)
(キット)
157:(S)-5-(2,6-ジメトキシフェニル)-1-イソブチル-N-(5-メチル-1-オキソ-1-(プロピルアミノ)ヘキサン-3-イル)-1H-ピラゾール-3-カルボキサミド(図1/スキーム1も参照)。
実験の詳細:
工程1:4-(2,6-ジメトキシフェニル)-2,4-ジオキソブタン酸エチルの調製:ナトリウムエトキシドの溶液(EtOH中21%)(5.4mL、14.37ミリモル)に、シュウ酸ジエチル(1.85mL、13.690ミリモル)および2,6-ジメトキシアセトフェノン(2.45g、13.690ミリモル)の無水エタノール混合液(15mL)を滴下した。得られた混合液を室温で30分間攪拌すると、黄色の懸濁液が形成された。反応混合液を4時間加熱還流した。反応液を室温まで冷却した。エタノールを真空蒸発させた。得られた残留物をジエチルエーテル(30mL)でトリチュレートして濾過し、エチル4-(2,6-ジメトキシフェニル)-2,4-ジオキソブタン酸のナトリウム塩を黄色固体(4.0g、97%)として得た。
MS m/z: C14H16O6の計算値:280.09 [M]+, 実測値:279.3 [M-H]+.
工程2:イソブチルヒドラジントリフルオロ酢酸の調製:tert-ブチル-2-イソブチルヒドラジンカルボン酸の調製:メタノール中(20mL)のイソブチルアルデヒド(1.0g、13.867ミリモル)およびtert-ブチルカルバゼート(1.8g、13.867ミリモル)を室温で1時間撹拌した。溶媒を蒸発させ、得られた固体を真空乾燥させ、(E)-tert-ブチル2-(2-メチルプロピリデン)ヒドラジンカルボキシレートの白色固体を定量的収率で得た。シアノ水素化ホウ素ナトリウム(1.2g、20.134ミリモル)を、75%酢酸水溶液中(25mL)の(E)-tert-ブチル-2-(2-メチルプロピリデン)ヒドラジンカルボキシレート(2.5g、13.423ミリモル)の混合液に室温で少しずつ加えた。得られた溶液を3時間室温で撹拌した。反応混合液を1N NaOHで中和し、CH2Cl2(3×25mL)で抽出し、飽和NaHCO3で洗浄し、Na2SO4で乾燥させ、濾過し、蒸発させ、表題化合物を油状物(2.4g、95%)として得た。
1H NMR (CDCl3 , 300 MHz) δ 0.93 (d, J=6.78 Hz, 6 H), 1.46 (s, 9 H), 1.64 - 1.82 (m, 1 H), 2.43 (br. s., 1 H), 2.67 (d, J=6.78 Hz, 2 H). MS m/z: C9H20N2O2の計算値:188.15 [M]+, 実測値:189.3 [M+H]+
1H NMR (CDCl3 , 300 MHz) δ 1.04 (dd, J=9.04, 6.78 Hz, 6 H), 2.04 - 2.25 (m, 1 H), 3.02 (dd, J=6.97, 3.96 Hz, 2 H). MS m/z: C4H12N2の計算値:88.10 [M]+, 実測値:89.4 [M+H]+.
工程3:5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボン酸エチルの調製:4-(2,6-ジメトキシフェニル)-2,4-ジオキソブタン酸エチルのナトリウム塩(1.2g、3.965ミリモル)およびイソブチルヒドラジントリフルオロ酢酸(0.962g、4.758ミリモル)を氷酢酸(25mL)および濃HCl(0.6mL)と混合した。反応混合液を3.5時間加熱還流した。冷却後、反応混合液を水(25mL)に注いだ。水層をCH2Cl2(3×30mL)で抽出し、合わせたCH2Cl2層を飽和NaHCO3水溶液で洗浄した。有機層をその後飽和塩水で洗浄し、Na2SO4で乾燥させ、続いて濾過した。溶媒を真空蒸発させた。残渣をシリカゲルフラッシュクロマトグラフィー(EtOAc:ヘキサン)により精製し、表題化合物を油状物(0.535g、40%)として得た。
1H NMR (CDCl3 , 300 MHz) δ 0.72 (d, J=6.78 Hz, 6 H), 1.39 (t, J=7.15 Hz, 3 H), 2.10-2.24 (m, 1 H), 3.72 (d, J=6.0 Hz, 2 H), 3.74 (s, 6 H), 4.41 (q, J=7.16 Hz, 2 H), 6.62 (d, J=8.67 Hz, 2 H), 6.73 (s, 1 H), 7.38 (t, J=8.48 Hz, 1 H). MS m/z: C18H24N2O4の計算値:332.17 [M]+, 実測値:333.4 [M+H]+.
工程4:5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボン酸の調製:水1mL中の水酸化リチウム一水和物(189mg、4.513ミリモル)を、5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボン酸エチル(500mg、1.504ミリモル)のMeOH(11mL)およびTHF(2mL)溶液に添加した。混合液を室温で18時間撹拌した。反応混合液を濃縮して約半分の容積にし、次いでエーテル(2×15mL)で抽出した。水層を1N HClで酸性化し、CH2Cl2(3×25mL)で抽出した。合わせた有機層を水、塩水で洗浄し、次いでNa2SO4で乾燥させた。溶媒を真空蒸発させ、表題化合物を白色固体(440mg、96%)として得た。
1H NMR (CDCl3 , 300 MHz) δ 0.74 (d, J=6.40 Hz, 6 H), 2.10-2.24 (m, 1 H), 3.72 (d, J=7.54 Hz, 2 H), 3.75 (s, 6 H), 6.63 (d, J=9.0 Hz, 2 H), 6.79 (s, 1 H), 7.40 (t, J=8.48 Hz, 1 H). MS m/z: C16H20N2O4の計算値:304.14 [M]+, 実測値:303.3 [M-H]+.
工程5:(S)-tert-ブチル3-(5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサノエートの調製:5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボン酸(50mg、0.164ミリモル)をTHF(1.5mL)に溶解させた。溶液に、ベンゾトリアゾール-1-イル-オキシ-トリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェート(BOP)(72mg、0.164 mmol)およびトリエチルアミン(0.050mL、0.493ミリモル)を添加した。得られた混合液を室温で15分間撹拌した。THF 0.3mL中の(S)-tert-ブチル-3-アミノ-5-メチルヘキサノエート(36mg、0.180ミリモル)を滴下し、室温で1.5時間撹拌した。THFを真空蒸発させ、残留物に水を加え、水層をCH2Cl2(3×15mL)で抽出した。合わせた有機層を水、塩水で洗浄し、次いでNa2SO4で乾燥させ、濾過した。溶媒を真空蒸発させた。残渣をシリカゲルフラッシュクロマトグラフィー(EtOAc:ヘキサン)により精製し、表題化合物を油状物(61mg、76%)として得た。
1H NMR (CDCl3 , 300 MHz) δ 0.74 (d, J=6.40 Hz, 3 H), 0.73 (d, J=6.78 Hz, 3 H), 0.97 (d, J=7.91 Hz, 6 H), 1.35 - 1.44 (m, 1 H), 1.47 (s, 9 H), 1.56 - 1.80 (m, 2 H), 2.07-2.19 (m, 1 H), 2.54 (d, J=5.65 Hz, 2 H), 3.63 (d, J=6.15 Hz, 2 H), 3.72(s, 3 H), 3.73 (s, 3 H), 4.45 - 4.57 (m, 1 H), 6.61 (d, J=8.29 Hz, 2 H), 6.69 (s, 1 H), 7.19 (d, J=9.42 Hz, 1 H),7.37 (t, J=8.29 Hz, 1 H). MS m/z: C27H41N3O5の計算値:487.30 [M]+, 実測値:488.7 [M+H]+.
工程6:(S)-3-(5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸の調製:トリフルオロ酢酸(0.4mL)を(S)-tert-ブチル3-(5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサノエート(40mg、0.820ミリモル)のCH2Cl2溶液(1mL)に滴下した。反応混合液を室温で1時間撹拌した。溶媒を真空蒸発させた。残留物にエーテル/ヘキサン(1:2)を添加してトリチュレートし、濾過し、表題化合物を白色固体(36mg、86%)として得た。
1H NMR (CDCl3 , 300 MHz) δ 0.74 (d, J=6.78 Hz, 6 H), 0.97 (d, J=6.22 Hz, 6 H), 1.42 - 1.57 (m, 1 H), 1.64 - 1.84 (m, 2 H), 2.02-2.18 (m, 1 H), 2.71 (d, J=5.27 Hz, 2 H), 3.65 (d, J=7.54 Hz, 2 H), 3.74 (s, 6 H), 4.41-4.53 (m, 1 H), 6.62 (d, J=8.29 Hz, 2 H), 6.71 (s, 1 H), 7.29 - 7.42 (m, 2 H). MS m/z: C23H33N3O5の計算値:431.24 [M]+, 実測値:430.5 [M-H]+.
工程7:(S)-5-(2,6-ジメトキシフェニル)-1-イソブチル-N-(5-メチル-1-オキソ-1-(プロピルアミノ)ヘキサン-3-イル)-1H-ピラゾール-3-カルボキサミドの調製。(S)-3-(5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸(30mg、0.069ミリモル)をTHF(1.5mL)に溶解した。溶液に、ベンゾトリアゾール-1-イル-オキシ-トリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェート(BOP)(31mg、0.069 mmol)およびトリエチルアミン(0.029mL、0.208ミリモル)を添加した。得られた混合液を室温で15分間撹拌した。THF 0.2mL中の1-プロピルアミン(4.5mg、0.0759ミリモル)を滴下し、室温で2時間撹拌した。THFを真空蒸発させ、残留物に水を加え、水層をCH2Cl2(3×15mL)で抽出した。合わせた有機層を水、塩水で洗浄し、その後Na2SO4で乾燥させ、続いて濾過した。溶媒を真空蒸発させた。残渣をシリカゲルフラッシュクロマトグラフィー(EtOAc:ヘキサン)により精製し、表題化合物を白色固体(25mg、76%)として得た。
収率76%;1H NMR (CDCl3 , 300 MHz) δ 0.73 (dd, J=6.78, 1.88 Hz, 6 H), 0.87 (t, J=7.35 Hz, 3 H), 0.95 (d, J=6.78 Hz, 6 H), 1.40 - 1.56 (m, 3 H), 1.61 - 1.82 (m, 2 H), 2.05 - 2.19 (m, 1 H), 2.54 (d, J=6.03 Hz, 2 H), 3.14 - 3.26 (m, 2 H), 3.63 (d, J=7.54 Hz, 2 H), 3.74 (s, 6 H), 4.34 - 4.46 (m, 1 H), 6.48-6.57 (m, 1 H), 6.62 (d, J=8.29 Hz, 2 H), 6.67 (s, 1 H), 7.08 (d, J=9.04 Hz, 1 H), 7.37 (t, J=8.48 Hz, 1 H). MS m/z: C26H40N4O4の計算値:472.62 [M]+, 実測値:473.9 [M+H]+.
(選択された化合物の特性評価)
71:(S)-2-シクロヘキシル-2-(5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-カルボキサミド)酢酸:収率94%;1HNMR (MeOH-d4 , 300 MHz) δ 1.11 - 1.41 (m, 5 H), 1.60-1.86 (m, 5 H), 1.89-2.04 (m, 1 H), 3.60 (br. s., 6 H), 4.57 (d, J=6.03 Hz, 1 H), 6.62 (d, J=8.29 Hz, 2 H), 6.80 (s, 1 H), 7.02-7.10 (m, 2 H), 7.25 - 7.38 (m, 4 H). MS m/z: C26H28FN3O5の計算値:481.20 [M]+, 実測値:482.5 [M+H]+.
56:(S)-3-(5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率81%;1HNMR (CDCl3 , 300 MHz) δ 0.96 (t, J=6.78 Hz, 6 H), 1.40 - 1.51 (m, 1 H), 1.62 - 1.82 (m, 2 H), 2.70 (d, J=5.27 Hz, 2 H), 3.52 (s, 3 H), 3.59 (m, 3 H), 4.47-4.60 (m, 1 H), 6.50 (d, J=8.67 Hz, 2 H), 6.93 - 7.02 (m, 2 H), 7.22 - 7.35 (m, 5 H). MS m/z: C25H28FN3O5の計算値:469.20 [M]+, 実測値:470.6 [M+H]+.
62:(S)-メチル6-((tert-ブトキシカルボニル)アミノ)-2-(5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-カルボキサミド)ヘキサン酸:収率57%;1HNMR (CDCl3 , 300 MHz) δ 1.42 (s, 9 H), 1.44 - 1.58 (m, 4 H), 1.70 - 1.87 (m, 1 H), 1.90 - 2.04 (m, 1 H), 3.03 - 3.19 (m, 2 H), 3.55 (s, 3 H), 3.61 (s, 3 H), 3.77 (s, 3 H), 4.57 (br. s., 1 H), 4.81-4.88 (m, 1 H), 6.51 (t, J=7.54 Hz, 2 H), 6.93 - 7.01 (m, 2 H), 7.23 - 7.33 (m, 4 H), 7.41 (d, J=8.29 Hz, 1 H). MS m/z: C30H37FN4O7の計算値:584.26 [M]+, 実測値:585.8 [M+H]+.
77:(S)-2-(3-(5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサンアミド)酢酸:収率64%;1H NMR (CDCl3 , 300 MHz) δ 0.93 (d, J=6.40 Hz, 6 H), 1.13 - 1.35 (m, 1 H), 1.46 - 1.59 (m, 1 H), 1.62-1.81 (m, 1 H), 2.49 (dd, J=13.94, 7.54 Hz, 1 H), 2.84 (dd, J=14.32, 6.03 Hz, 1 H), 3.58 (s, 6 H), 4.01 - 4.19 (m, 2 H), 4.51 (br. s., 1 H), 6.50 (d, J=8.29 Hz, 2 H), 6.91 (s, 1 H), 6.97 (t, J=9.0 Hz, 2 H), 7.18 - 7.40 (m, 5 H). MS m/z: C27H31FN4O6の計算値:526.22 [M]+, 実測値:525.6 [M-H]+.
79:(S)-3-(1-シクロヘキシル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率92%;1HNMR (CDCl3 , 300 MHz) δ 0.97 (d, J=6.40 Hz, 6 H), 1.11 - 1.32 (m, 4 H), 1.43 - 1.57 (m, 1 H), 1.60 - 1.98 (m, 8 H), 2.65 - 2.79 (m, 2 H), 3.59 - 3.70 (m, 1 H), 3.74 (s, 6 H), 4.36 - 4.51 (m, 1 H), 6.62 (s, 1 H), 6.66 (d, J=7.54 Hz, 2 H), 7.22 (br. s, 1 H), 7.38 (t, J=8.29 Hz, 1 H). MS m/z: C25H35N3O5の計算値:457.26 [M]+, 実測値:456.3 [M-H]+.
80:(S)-3-(5-(2,6-ジクロロフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率77%;1HNMR (CDCl3 , 300 MHz) δ 0.97 (dd, J=8.10, 6.59 Hz, 6 H), 1.41 - 1.53 (m, 1 H), 1.63 - 1.82 (m, 2 H), 2.72 (d, J=5.65 Hz, 2 H), 4.51 - 4.62 (m, 1 H), 6.96 - 7.05 (m, 3 H), 7.24 - 7.37 (m, 6 H). MS m/z: C23H22Cl2FN3O3の計算値:477.10 [M]+, 実測値:476.5 [M-H]+.
81:(S)-2-(3-(1-シクロヘキシル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサンアミド)酢酸:収率80%;1H NMR (CDCl3 , 300 MHz) δ 0.95 (t, J=6.40 Hz, 6 H), 1.09 - 1.35 (m, 3 H), 1.49 - 1.76 (m, 5 H), 1.77-1.95 (m, 5 H), 2.48 (dd, J=14.13, 7.35 Hz, 1 H), 2.86 (dd, J=13.75, 6.22 Hz, 1 H), 3.61-3.70 (m, 1 H), 3.75 (s, 6 H), 3.99 - 4.19 (m, 2 H), 4.38-4.52 (m, 1 H), 6.63 (d, J=3.01 Hz, 2 H), 6.65 (s, 1 H), 7.13 (d, J=8.67 Hz, 1 H), 7.38 (t, J=8.29 Hz, 1 H), 7.51 (t, J=4.52 Hz, 1 H). MS m/z: C27H38N4O6の計算値:514.28 [M]+, 実測値:513.5 [M-H]+.
82:(3S)-3-(5-(2-(ベンジルオキシ)-6-メトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率85%;1HNMR (CDCl3 , 300 MHz) δ 0.97 (t, J=6.40 Hz, 6 H), 1.39 - 1.55 (m, 1 H), 1.61 - 1.82 (m, 2 H), 2.71 (d, J=2.64 Hz, 2 H), 3.61 (d, J=6.78 Hz, 3 H), 4.46-4.62 (m, 1 H), 4.86 (dd, J=12.62, 8.10 Hz, 1 H), 4.98 (dd, J=12.62, 6.22 Hz, 1 H), 6.50 (d, J=8.29 Hz, 2 H), 6.92 (t, J=9.0, 1 H), 6.98 (s, 1 H), 7.07 (br. s., 1 H), 7.03 - 7.11 (m, 2 H), 7.15 - 7.34 (m, 7 H). MS m/z: C31H32 FN3O5の計算値:545.23 [M]+, 実測値:544.7 [M-H]+.
93:(S)-2-シクロヘキシル-2-(1-シクロヘキシル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-カルボキサミド)酢酸:87%収率;1HNMR (CDCl3 , 300 MHz) δ 1.08 - 1.39 (m, 8 H), 1.59 - 1.73 (m, 2 H), 1.74-1.98 (m, 10 H), 2.01-2.16 (m, 1 H), 3.62-3.70 (m, 1 H), 3.73 (s, 3 H), 3.75 (s, 3 H), 4.50 - 4.59 (m, 1 H), 6.63 (d, J=8.29 Hz, 2 H), 6.68 (s, 1 H), 7.38 (t, J=8.48 Hz, 1 H), 7.46 (d, J=7.91 Hz, 1 H). MS m/z: C26H35N3O5の計算値:469.26 [M]+, 実測値:468.5 [M-H]+.
94:(S)-3-(1-ベンジル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率93%;1HNMR (CDCl3 , 300 MHz) δ 0.96 (dd, J=6.40, 3.01 Hz, 6 H), 1.39 - 1.58 (m, 1 H), 1.62 - 1.80 (m, 2 H), 2.63 - 2.76 (m, 2 H), 3.59 (s, 3 H), 3.61 (s, 3 H), 4.39-4.51 (m, 1 H), 5.09 (s, 2 H), 6.53 (d, J=8.29 Hz, 2 H), 6.78 (s, 1 H), 6.91 - 6.99 (m, 2 H), 7.16 - 7.24 (m, 3 H), 7.33 (t, J=8.48 Hz, 2 H). MS m/z: C26H31N3O5の計算値:465.23 [M]+, 実測値:464.6 [M-H]+.
95:(S)-3-(1-(シクロヘキシルメチル)-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率82%;1HNMR (CDCl3 , 300 MHz) δ 0.64-0.80 (m, 2 H), 0.97 (d, J=6.40 Hz, 6 H), 1.02 - 1.18 (m, 3 H), 1.42 - 1.64 (m, 7 H), 1.65 - 1.83 (m, 3 H), 2.65 - 2.78 (m, 2 H), 3.68 (d, J=7.16 Hz, 2 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 4.39-4.53 (m, 1 H), 6.61-6.65 (m, 1 H), 6.62 (t, J=8.48 Hz, 2 H), 6.70 (s, 1 H), 7.38 (t, J=9.0 Hz, 1 H). MS m/z: C26H37N3O5の計算値:471.27 [M]+, 実測値:470.6[M-H]+.
96:(S)-3-(5-(2,6-ジメトキシフェニル)-1-(ナフタレン-2-イルメチル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率93%;1HNMR (CDCl3 , 300 MHz) δ 0.96 (d, J=4.90 Hz, 3 H), 0.94 (d, J=4.90 Hz, 3 H), 1.37 - 1.50 (m, 1 H), 1.62 - 1.80 (m, 2 H), 2.62 - 2.75 (m, 2 H), 3.51 (s, 3 H), 3.52 (s, 3 H), 4.39-4.53 (m, 1 H), 5.25 (s, 2 H), 6.50 (d, , J=6.10 Hz, 1 H), 6.80 (s, 1 H), 7.15 (dd, J=8.48, 1.70 Hz, 1 H), 7.25 - 7.37 (m, 4 H), 7.39 - 7.45 (m, 2 H), 7.63 - 7.75 (m, 3 H). MS m/z: C30H33N3O5の計算値:515.24 [M]+, 実測値:514.6 [M-H]+.
103:(S)-メチル2-(3-(1-シクロヘキシル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサンアミド)アセテート:収率90%;1H NMR (CDCl3 , 300 MHz) δ 0.95 (d, J=6.40 Hz, 6 H), 1.09 - 1.35 (m, 4 H), 1.34 - 1.54 (m, 1 H), 1.56 - 1.69 (m, 2 H), 1.71 - 1.98 (m, 7 H), 2.61 (d, J=6.40 Hz, 2 H), 3.65 (s, 3 H), 3.74 (s, 6 H), 4.04 (d, J=5.27 Hz, 2 H), 4.43-4.55 (m, 1 H), 6.59 - 6.69 (m, 3 H), 7.08 (t, J=5.27 Hz, 1 H), 7.15 (d, J=9.04 Hz, 1 H), 7.38 (t, J=8.48 Hz, 1 H). MS m/z: C28H40N4O6の計算値:528.64 [M]+, 実測値:529.8 [M+H]+.
125:(S)-3-(1-シクロオクチル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率94%;1HNMR (CDCl3 , 300 MHz) δ 0.97 (d, J=6.40 Hz, 6 H), 1.23 - 1.45 (m, 6 H), 1.48 - 1.63 (m, 4 H), 1.66 - 1.86 (m, 5 H), 2.03 - 2.19 (m, 2 H), 2.72 (t, J=5.46 Hz, 2 H), 3.74 (s, 6 H), 3.94 - 4.05 (m, 1 H), 4.37 - 4.49 (m, 1 H), 6.63 (d, J=8.29 Hz, 2 H), 6.67 (s, 1 H), 7.23 (s, 1 H), 7.38 (t, J=8.48 Hz, 1 H). MS m/z: C27H39N3O5の計算値:485.29[M]+, 実測値:484.5 [M-H]+.
126:(3S)-3-(5-(2-(ベンジルオキシ)-6-メトキシフェニル)-1-シクロヘキシル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率98%;1H NMR (CDCl3 , 300 MHz) δ 0.98 (dd, J=6.40, 1.51 Hz, 6 H), 1.10 -1.31 (m, 4 H), 1.45-1.58 (m, 2 H), 1.58 - 1.70 (m, 2 H), 1.71-1.95 (m, 8 H), 2.70 - 2.76 (m, 2 H), 3.64 - 3.72 (m, 1 H), 4.36-4.49 (m, 1 H), 5.05 (s, 2 H), 6.63 (dd, J=8.48, 2.45 Hz, 2 H), 6.71 (s, 1 H), 7.16 - 7.35 (m, 7 H). MS m/z: C31H39N3O5の計算値:533.29 [M]+, 実測値:532.6 [M-H]+.
127:メチル2-((3S)-3-(5-(2-(ベンジルオキシ)-6-メトキシフェニル)-1-シクロヘキシル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサンアミド)アセテート:収率34%;1HNMR (CDCl3 , 300 MHz) δ 0.97 (dd, J=6.22, 2.07 Hz, 6 H), 1.09 - 1.31 (m, 4 H), 1.42 - 1.57 (m, 3 H), 1.68 - 1.94 (m, 6 H), 2.62 (d, J=6.03 Hz, 2 H), 3.65 (s, 3 H), 3.66-3.72 (m, 1 H), 3.74 (s, 3 H), 4.03 (t, J=5.27 Hz, 2 H), 4.42 - 4.55 (m, 1 H), 5.05 (s, 2 H), 6.63 (dd, J=8.29, 3.01 Hz, 2 H), 6.68 (s, 1 H), 7.07 (d, J=6.03 Hz, 1 H), 7.13 - 7.23(m, 3 H), 7.25 - 7.39 (m, 4 H). MS m/z: C34H44N4O6の計算値:604.74 [M]+, 実測値:605.8 [M+H]+.
128:(S)-メチル-2-(3-(1-シクロオクチル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサンアミド)アセテート:87%収率;1H NMR (CDCl3 , 300 MHz) δ 0.96 (d, J=6.78 Hz, 6 H), 1.22 - 1.46 (m, 6 H), 1.48 - 1.56 (m, 4 H), 1.65-1.84 (m, 5 H), 2.06 - 2.18 (m, 2 H), 2.58 - 2.64 (m, 2 H), 3.66 (s, 3 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 3.93 - 4.02 (m, 1 H), 4.04 (d, J=5.65 Hz, 2 H), 4.42 - 4.51 (m, 1 H), 6.60 - 6.67 (m, 3 H), 7.06 - 7.16 (m, 2 H), 7.32 - 7.42 (m, 1 H). MS m/z: C30H44N4O6の計算値:556.33 [M]+, 実測値:557.9 [M+H]+.
129:2-((3S)-3-(5-(2-(ベンジルオキシ)-6-メトキシフェニル)-1-シクロヘキシル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサンアミド)酢酸:82%収率;1H NMR (CDCl3 , 300 MHz) δ 0.90 - 1.04 (m, 6 H), 1.09 - 1.38 (m, 4 H), 1.52 - 1.91 (m, 9 H), 2.50 (ddd, J=14.32, 6.97, 2.83 Hz, 1 H), 2.78 - 2.88 (m, 1 H), 2.89 (s, 1 H), 3.74 (d, J=1.51 Hz, 4 H), 3.98 - 4.24 (m, 2 H), 4.46 (br. s., 1 H), 5.05 (s, 2 H), 6.41 - 6.71 (m, 3 H), 7.05 - 7.38 (m, 7 H), 7.47 (d, J=3.01 Hz, 1 H). MS m/z: C33H42N4O6の計算値:590.31 [M]+, 実測値:589.7 [M-H]+.
130:(S)-メチル2-(3-(5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサンアミド)アセテート:69%収率;1HNMR (CDCl3 , 300 MHz) δ 0.74 (dd, J=6.78, 1.88 Hz, 6 H), 0.95 (dd, J=6.40, 1.51 Hz, 6 H), 1.37 - 1.51 (m, 1 H), 1.61 - 1.83 (m, 2 H), 2.05 - 2.16 (m, 1 H), 2.61 (d, J=5.65 Hz, 2 H), 3.63 (d, J=7.16 Hz, 2 H), 3.68 (s, 3 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 4.04 (d, J=5.65 Hz, 2 H), 4.42-4.54 (m, 1 H), 6.62 (d, J=8.67 Hz, 2 H), 6.68 (s, 1 H), 6.99 (t, J=5.09 Hz, 1 H), 7.14 (d, J=9.04 Hz, 1 H), 7.38 (t, J=8.48 Hz, 1 H). MS m/z: C26H38N4O6の計算値:502.28 [M]+, 実測値:503.9 [M+H]+.
133:5-(2-(ベンジルオキシ)-6-メトキシフェニル)-N-((S)-1-(ブチルアミノ)-5-メチル-1-オキソヘキサン-3-イル)-1-シクロヘキシル-1H-ピラゾール-3-カルボキサミド:収率66%;1HNMR (CDCl3 , 300 MHz) δ 0.85 (t, J=6.35 Hz, 3 H), 0.96 (dd, J=6.40, 1.88 Hz, 6 H), 1.08-1.33 (m, 5 H), 1.38 - 1.53 (m, 4 H), 1.63 - 1.96 (m, 5 H), 2.55 (d, J=6.10 Hz, 2 H), 3.17 - 3.29 (m, 2 H), 3.62 - 3.72 (m, 4 H), 3.74 (s, 3 H), 4.34-4.49 (m, 1 H), 5.05 (s, 2 H), 6.55 - 6.66 (m, 3 H), 6.68 (s, 1 H), 7.08 (d, J=9.42 Hz, 1 H), 7.16 - 7.23 (m, 2 H), 7.24 - 7.34 (m, 4 H). MS m/z: C35H48N4O4の計算値:588.37 [M]+, 実測値:589.5 [M+H]+.
134:5-(2-(ベンジルオキシ)-6-メトキシフェニル)-1-シクロヘキシル-N-((S)-5-メチル-1-((オキサゾール-2-イルメチル)アミノ)-1-オキソヘキサン-3-イル)-1H-ピラゾール-3-カルボキサミド:収率72%;1H NMR (CDCl3 , 300 MHz) δ 0.93 - 0.99 (m, 6 H), 1.12 - 1.23 (m, 3 H), 1.45-1.56 (m, 1 H), 1.62-1.72 (m, 2 H), 1.73-1.80 (m, 4 H), 1.81-1.92 (m, 4 H), 2.65-2.72 (m, 2 H), 3. 74 (s, 3 H), 4.43-4.53 (m, 1 H), 4.53 - 4.64 (m, 2 H), 5.06 (d, J=3.91 Hz, 2 H), 6.61 - 6.69 (m, 3 H), 6.93 (s, 1 H), 7.16 - 7.23 (m, 3 H), 7.25 - 7.36 (m, 5 H), 7.45 (s, 1 H). MS m/z: C35H43N5O5の計算値:613.33 [M]+, 実測値:614.7 [M+H]+.
136:5-(2-(ベンジルオキシ)-6-メトキシフェニル)-1-シクロヘキシル-N-((S)-1-((2-(ジメチルアミノ)-2-オキソエチル)アミノ)-5-メチル-1-オキソヘキサン-3-イル)-1H-ピラゾール-3-カルボキサミド:収率46%;1H NMR (CDCl3 , 500 MHz) δ 0.93 - 0.96 (m, 3 H), 0.97 (dd, J=7.32, 2.44 Hz, 3 H), 1.12 - 1.30 (m, 3 H), 1.40 - 1.50 (m, 2 H), 1.61 - 1.71 (m, 1 H), 1.72 - 1.82 (m, 3 H), 1.83 - 1.97 (m, 4 H), 2.58 - 2.63 (m, 2 H), 2.98 (s, 3 H), 2.97 (d, J=8.10, 3 H), 3.66-3.71 (m, 1 H), 3.73 (s, 3 H), 4.05 - 4.12 (m, 2 H), 4.50 - 4.58 (m, 1 H), 5.05 (s, 2 H), 6.61 (d, J=5.10, 2 H), 6.69 (s, 1 H), 6.82 (br. s., 1 H), 7.17 - 7.26 (m, 2 H), 7.27 - 7.34 (m, 4 H), 7.38 - 7.45 (m, 1 H). MS m/z: C35H47N5O5の計算値:617.36 [M]+, 実測値:616.7 [M-H]+.
138:エチル3-((3S)-3-(5-(2-(ベンジルオキシ)-6-メトキシフェニル)-1-シクロヘキシル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサンアミド)プロパノエート:収率65%;1HNMR (CDCl3 , 300 MHz) δ 0.95 (d, J=6.78 Hz, 6 H), 1.10 - 1.33 (m, 4 H), 1.08-1.18 (m, 2 H), 1.24 (t, J=7.16 Hz, 3 H), 1.39-1.53 (m, 1 H), 1.62 - 1.81 (m, 4 H), 1.82-1.97 (m, 2 H), 2.46 - 2.58 (m, 3 H), 3.44 - 3.61 (m, 3 H), 3.63-3.75 (m, 1 H), 3.73 (s, 3 H), 4.05 - 4.16 (m, 2 H), 4.34-4.49 (m, 1 H), 5.05 (s, 2 H), 6.63 (dd, J=8.48, 1.32 Hz, 1 H), 6.68 (s, 1 H), 6.76 (d, J=6.03 Hz, 1 H), 7.10 - 7.24 (m, 3 H), 7.24 - 7.42 (m, 5 H). MS m/z: C36H48N4O6の計算値:632.36 [M]+, 実測値:631.6 [M-H]+.
140:(S)-5-(2,6-ジメトキシフェニル)-1-イソブチル-N-(5-メチル1-((オキサゾール-2-イルメチル)アミノ)-1-オキソヘキサン-3-イル)-1H-ピラゾール-3-カルボキサミド:収率36%;1HNMR (CDCl3 , 300 MHz) δ 0.73 (d, J=6.78 Hz, 6 H), 0.95 (d, J=6.40 Hz, 6 H), 1.40-1.53 (m, 1 H), 1.61 - 1.84 (m, 2 H), 2.02 - 2.18 (m, 1 H), 2.64 (d, J=6.03 Hz, 2 H), 3.62 (d, J=7.54 Hz, 2 H), 3.74 (s, 6 H), 4.41-4.50 (m, 1 H), 4.55 - 4.63 (m, 2 H), 6.63 (d, J=8.29 Hz, 2 H), 6.66 (s, 1 H), 7.00 (s, 1 H), 7.14 (d, J=7.91 Hz, 2 H), 7.38 (t, J=8.48 Hz, 1 H), 7.49 (s, 1 H). MS m/z: C27H37N5O5の計算値:511.28 [M]+, 実測値:512.3 [M+H]+.
141:(S)-5-(2,6-ジメトキシフェニル)-1-イソブチル-N-(5-メチル-1-(メチルアミノ)-1-オキソヘキサン-3-イル)-1H-ピラゾール-3-カルボキサミド:収率61%1H NMR (CDCl3 , 300 MHz) δ 0.74 (d, J=6.78 Hz, 6 H), 0.94 (d, J=6.40 Hz, 6 H), 1.37-1.51 (m, 1 H), 1.60 - 1.82 (m, 2 H), 2.07 - 2.20 (m, 1 H), 2.54 (d, J=6.03 Hz, 2 H), 2.80 (d, J=4.90 Hz, 3 H), 3.63 (d, J=7.16 Hz, 2 H), 3.74 (s, 6 H), 4.34 - 4.49 (m, 1 H), 6.62 (d, J=8.67 Hz, 2 H), 6.68 (s, 2 H), 7.07 (d, J=9.42 Hz, 1 H), 7.38 (t, J=8.29 Hz, 1 H). MS m/z: C24H36N4O4の計算値:444.27 [M]+, 実測値:445.5 [M+H]+.
142:(S)-5-(2,6-ジメトキシフェニル)-N-(1-((2-ヒドロキシエチル)アミノ)-5-メチル-1-オキソヘキサン-3-イル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド:収率61%;1H NMR (CDCl3 , 300 MHz) δ 0.75 (d, J=6.78 Hz, 3 H), 0.74 (d, J=6.78 Hz, 3 H), 0.96 (d, J=6.40 Hz, 6 H), 1.38-1.50 (m, 1 H), 1.60 - 1.83 (m, 2 H), 2.05 - 2.19 (m, 1 H), 2.45 - 2.68 (m, 3 H), 3.21-3.31 (m, 1 H), 3.47 - 3.62 (m, 2 H), 3.64 (dd, J=7.16, 1.51 Hz, 2 H), 3.74 (s, 6 H), 4.43-4.57 (m, 1 H), 6.62 (d, J=8.29 Hz, 2 H), 6.68 (s, 1 H), 6.88 - 7.11 (m, 2 H), 7.38 (t, J=8.29 Hz, 1 H). MS m/z: C25H38N4O5の計算値:474.38 [M]+, 実測値:475.7 [M+H]+.
143:(S)-N-(1-(ブチルアミノ)-5-メチル-1-オキソヘキサン-3-イル)-5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド:収率71%;1HNMR (CDCl3 , 300 MHz) δ 0.74 (dd, J=6.78, 2.26 Hz, 6 H), 0.87 (t, J=7.16 Hz, 3 H), 0.94 (d, J=6.40 Hz, 6 H), 1.22 - 1.36 (m, 2 H), 1.41 - 1.53 (m, 3 H), 1.60 - 1.81 (m, 2 H), 2.07-2.19 (m, 1 H), 2.54 (d, J=6.03 Hz, 2 H), 3.19 - 3.28 (m, 2 H), 3.63 (d, J=7.16 Hz, 2 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 4.34 - 4.46 (m, 1 H), 6.51 (br. s., 1 H), 6.62 (d, J=8.29 Hz, 2 H), 6.67 (s, 1 H), 7.06 (d, J=8.67 Hz, 1 H), 7.37 (t, J=8.48 Hz, 1 H). MS m/z: C27H42N4O4の計算値:486.65 [M]+, 実測値:487.6 [M+H]+.
150:(S)-3-(5-(2,6-ジメトキシフェニル)-1-イソブチル-4-メチル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率67%;1H NMR (CDCl3 , 300 MHz) δ 0.72 (d, J=6.78 Hz, 6 H), 0.97 (d, J=6.40 Hz, 6 H), 1.46 - 1.55 (m, 1 H), 1.62 - 1.84 (m, 2 H), 1.98 - 2.11 (m, 1 H), 2.08 (s, 3 H), 2.64 - 2.79 (m, 2 H), 3.61 (d, J=7.54 Hz, 2 H), 3.75 (s, 6 H), 4.33-4.49 (m, 1 H), 6.63 (d, J=8.29 Hz, 2 H), 7.30 (d, J=8.29 Hz, 1 H), 7.39 (t, J=8.48 Hz, 1 H). MS m/z: C24H35N3O5の計算値:445.26 [M]+, 実測値:444.7 [M-H]+.
151:(S)-N-(1-(ブチルアミノ)-5-メチル-1-オキソヘキサン-3-イル)-5-(2,6-ジメトキシフェニル)-1-イソブチル-4-メチル-1H-ピラゾール-3-カルボキサミド:収率80%;1H NMR (CDCl3 , 300 MHz) δ 0.72 (dd, J=6.78, 3.39 Hz, 6 H), 0.86 (t, J=7.16 Hz, 3 H), 0.95 (d, J=6.78 Hz, 6 H), 1.24-1.36 (m, 3 H), 1.40 - 1.52 (m, 2 H), 1.60 - 1.69 (m, 1 H), 1.69 - 1.83 (m, 1 H), 1.98 - 2.12 (m, 1 H), 2.08 (s, 3 H), 2.54 (d, J=6.40 Hz, 2 H), 3.15 - 3.33 (m, 2 H), 3.59 (d, J=7.16 Hz, 2 H), 3.74 (s, 6 H), 4.35 - 4.47 (m, 1 H), 6.62 - 6.74 (m, 3 H), 7.04 (d, J=9.04 Hz, 1 H), 7.39 (t, J=8.29 Hz, 1 H). MS m/z: C28H44N4O4の計算値:500.34 [M]+, 実測値:501.8 [M+H]+.
154:(S)-5-(2,6-ジメトキシフェニル)-N-(1-(ヘキシルアミノ)-5-メチル-1-オキソヘキサン-3-イル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド:収率64%;1HNMR (CDCl3 , 300 MHz) δ 0.74 (d, J=6.40 Hz, 6 H), 0.85 (t, J=7.35 Hz, 3 H), 0.94 (d, J=6.78 Hz, 6 H), 1.21 - 1.34 (m, 6 H), 1.40 - 1.54 (m, 3 H), 1.61 - 1.82 (m, 2 H), 2.05 - 2.19 (m, 1 H), 2.53 (d, J=6.03 Hz, 2 H), 3.18 - 3.27 (m, 2 H), 3.63 (d, J=7.54 Hz, 2 H), 3.74 (s, 6 H), 4.35 - 4.45 (m, 1 H), 6.54 (br. s., 1 H), 6.62 (d, J=8.29 Hz, 2 H), 6.67 (s, 1 H), 7.09 (d, J=9.04 Hz, 1 H), 7.38 (t, J=8.29 Hz, 1 H). MS m/z: C29H46N4O4の計算値:514.35 [M]+, 実測値:515.6 [M+H]+.
155:(S)-N-(1-((シクロヘキシルメチル)アミノ)-5-メチル-1-オキソヘキサン-3-イル)-5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド:収率71%;1HNMR (CDCl3 , 300 MHz) δ 0.75 (d, J=3.77 Hz, 3 H), 0.72 (d, J=3.39 Hz, 3 H), 0.80 - 0.92 (m, 2 H), 0.94 (d, J=6.40 Hz, 6 H), 1.05 - 1.27 (m, 4 H), 1.38 - 1.54 (m, 3 H), 1.62 - 1.79 (m, 5 H), 2.06-2.19 (m, 1 H), 2.55 (d, J=6.03 Hz, 2 H), 3.01 - 3.16 (m, 2 H), 3.63 (d, J=7.16 Hz, 2 H), 3.72 (s, 3 H), 3.74 (s, 3 H), 4.37-4.47 (m, 1 H), 6.53 - 6.73 (m, 4 H), 7.07 (d, J=8.67 Hz, 1 H), 7.37 (t, J=8.29 Hz, 1 H). MS m/z: C30H46N4O4の計算値:526.35 [M]+, 実測値:527.5 [M+H]+.
156:(S)-5-(2,6-ジメトキシフェニル)-1-イソブチル-N-(5-メチル-1-オキソ-1-(ペンチルアミノ)ヘキサン-3-イル)-1H-ピラゾール-3-カルボキサミド;収率83%;1H NMR (CDCl3 , 300 MHz) δ 0.74 (dd, J=6.78, 1.13 Hz, 6 H), 0.86 (t, J=7.35 Hz, 3 H), 0.94 (d, J=6.40 Hz, 6 H), 1.21 - 1.35 (m, 4H), 1.39 - 1.53 (m, 3 H), 1.62 - 1.83 (m, 2 H), 2.04 - 2.20 (m, 1 H), 2.53 (d, J=6.03 Hz, 2 H), 3.19 - 3.26 (m, 2 H), 3.63 (d, J=7.54 Hz, 2 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 4.34-4.48 (m, 1 H), 6.55 (br. s., 1 H), 6.62 (d, J=8.29 Hz, 2 H), 6.67 (s, 1 H), 7.08 (d, J=8.67 Hz, 1 H), 7.38 (t, J=8.29 Hz, 1 H). MS m/z: C28H44N4O4の計算値:500.67 [M]+, 実測値:501.8 [M+H]+.
158:(S)-5-(2,6-ジメトキシフェニル)-1-イソブチル-N-(5-メチル-1-(4-メチルピペラジン-1-イル)-1-オキソヘキサン-3-イル)-1H-ピラゾール-3-カルボキサミド:収率72%;1HNMR (CDCl3 , 300 MHz) δ 0.74 (d, J=6.78 Hz, 6 H), 0.95 (dd, J=6.40, 1.51 Hz, 6 H), 1.46 - 1.57 (m, 1 H), 1.67 - 1.82 (m, 2 H), 2.05 - 2.20 (m, 1 H), 2.29 (s, 3 H), 2.32 - 2.55 (m, 4 H), 2.89 (dd, J=14.51, 3.96 Hz, 1 H), 3.45 - 3.60 (m, 3 H), 3.63 (d, J=7.54 Hz, 2 H), 3.73 (s, 6 H), 3.68-3.80 (m, 2 H), 4.32 - 4.44 (m, 1 H), 6.62 (d, J=8.29 Hz, 2 H), 6.67 (s, 1 H), 7.18 (d, J=8.67 Hz, 1 H), 7.37 (t, J=8.29 Hz, 1 H). MS m/z: C28H43N5O4の計算値:513.33 [M]+, 実測値:514.5 [M+H]+.
159:(S)-5-(2,6-ジメトキシフェニル)-1-イソブチル-N-(5-メチル-1-オキソ-1-((3-フェニルプロピル)アミノ)ヘキサン-3-イル)-1H-ピラゾール-3-カルボキサミド:収率68%;1H NMR (CDCl3 , 300 MHz) δ 0.73 (dd, J=6.78, 1.13 Hz, 6 H), 0.95 (d, J=6.40 Hz, 6 H), 1.40-1.52 (m, 1 H), 1.61-1.75 (m, 1 H), 1.76 - 1.88 (m, 3 H), 2.05 - 2.18 (m, 1 H), 2.52 (d, J=6.03 Hz, 2 H), 2.62 (t, J=7.15 Hz, 2 H), 3.24 - 3.30 (m, 2 H), 3.62 (d, J=7.16 Hz, 2 H), 3.68 (s, 3 H), 3.73 (s, 3 H), 4.35-4.48 (m, 1 H), 6.61 (dd, J=8.29, 1.51 Hz, 2 H), 6.65-6.71 (m, 1 H), 6.68 (s, 1 H), 7.07 (d, J=9.04 Hz, 1 H), 7.12 - 7.20 (m, 3 H), 7.21 - 7.24 (m, 2 H), 7.37 (t, J=8.48 Hz, 1 H). MS m/z: C32H44N4O4の計算値:548.34 [M]+, 実測値:549.6 [M+H]+.
160:(S)-N-(1-(ベンジルアミノ)-5-メチル-1-オキソヘキサン-3-イル)-5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド:収率66%;1HNMR (CDCl3 , 300 MHz) δ 0.74 (d, J=6.78 Hz, 6 H), 0.94 (d, J=6.40 Hz, 6 H), 1.37 - 1.52 (m, 1 H), 1.63 - 1.80 (m, 2 H), 2.03 - 2.19 (m, 1 H), 2.60 (d, J=6.40 Hz, 2 H), 3.64 (d, J=7.54 Hz, 2 H), 3.72 (s, 3 H), 3.75 (s, 3 H), 4.37 - 4.51 (m, 3 H), 6.62 (s, 1 H), 6.65 (d, J=6.40 Hz, 2 H), 7.11 (d, J=9.04 Hz, 1 H), 7.17 - 7.25 (m, 6 H), 7.38 (t, J=8.29 Hz, 1 H). MS m/z: C30H40N4O4の計算値:520.30 [M]+, 実測値:521.6 [M+H]+.
161:(S)-5-(2,6-ジメトキシフェニル)-N-(1-(エチルアミノ)-5-メチル-1-オキソヘキサン-3-イル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド:収率69%;1HNMR (CDCl3 , 300 MHz) δ 0.74 (d, J=6.78 Hz, 6 H), 0.95 (d, J=6.40 Hz, 6 H), 1.10 (t, J=7.35 Hz, 3 H), 1.40 - 1.51 (m, 1 H), 1.60 - 1.82 (m, 2 H), 2.08-2.19 (m, 1 H), 2.53 (d, J=6.03 Hz, 2 H), 3.23-3.32 (quin, J=6.78 Hz, 2 H), 3.63 (d, J=7.54 Hz, 2 H), 3.74 (s, 6 H), 4.34 - 4.46 (m, 1 H), 6.50 (br. s., 1 H), 6.62 (d, J=8.67 Hz, 2 H), 6.68 (s, 1 H), 7.07 (d, J=9.04 Hz, 1 H), 7.37 (t, J=8.48 Hz, 1 H). MS m/z: C25H38N4O4の計算値:5458.29 [M]+, 実測値:459.5 [M+H]+.
163:(S)-5-(2,6-ジメトキシフェニル)-N-(1-((4-フルオロフェニル)アミノ)-5-メチル-1-オキソヘキサン-3-イル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド:収率10%;1HNMR (CDCl3 , 300 MHz) δ 0.74 (dd, J=6.78, 1.88 Hz, 6 H), 0.97 (d, J=6.40 Hz, 6 H), 1.46 - 1.55 (m, 1 H), 1.63 - 1.73 (m, 1 H), 1.73 - 1.84 (m, 1 H), 2.06 - 2.18 (m, 1 H), 2.72 (d, J=5.65 Hz, 2 H), 3.63 (d, J=7.54 Hz, 2 H), 3.73 (s, 3 H), 3.75 (s, 3 H), 4.43-4.59 (m, 1 H), 6.62 (dd, J=8.29, 1.51 Hz, 2 H), 6.72 (s, 1 H), 6.97 (t, J=8.85 Hz, 2 H), 7.05 (d, J=8.67 Hz, 1 H), 7.38 (t, J=8.48 Hz, 1 H), 7.58 (dd, J=9.04, 4.90 Hz, 2 H), 9.11 (s, 1 H). MS m/z: C29H37FN4O4の計算値:524.28 [M]+, 実測値:525.6 [M+H]+.
165:(S)-3-(5-(2,6-ジクロロフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド)-5-メチルヘキサン酸:収率71%;1HNMR (CDCl3 , 300 MHz) δ 0.81 (d, J=6.40 Hz, 6 H), 0.98 (dd, J=6.22, 3.20 Hz, 6 H), 1.45 - 1.56 (m, 1 H), 1.65 - 1.82 (m, 2 H), 2.08-2.22 (m, 1 H), 2.73 (d, J=5.27 Hz, 2 H), 3.67 (d, J=7.54 Hz, 2 H), 4.45-4.56 (m, 1 H), 6.81 (s, 1 H), 7.22 - 7.24 (m, 1 H), 7.32 - 7.40 (m, 1 H), 7.43 (s, 1 H), 7.45 (d, J=1.88 Hz, 1 H). MS m/z: C21H27Cl2N3O3の計算値:439.14 [M]+, 実測値:440.3[M+H]+.
166:(S)-N-(1-(ブチルアミノ)-5-メチル-1-オキソヘキサン-3-イル)-5-(2,6-ジクロロフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド:収率85%;1HNMR (CDCl3 , 300 MHz) δ 0.81 (d, J=6.40 Hz, 6 H), 0.87 (t, J=7.35 Hz, 3 H), 0.96 (dd, J=6.40, 2.26 Hz, 6 H), 1.23 - 1.37 (m, 2 H), 1.40 - 1.51 (m, 3 H), 1.64 - 1.79 (m, 2 H), 2.12-2.23 (m, 1 H), 2.48 - 2.62 (m, 2 H), 3.24 (q, J=6.66 Hz, 2 H), 3.66 (d, J=7.54 Hz, 2 H), 4.35 - 4.48 (m, 1 H), 6.31 (br. s., 1 H), 6.78 (s, 1 H), 7.19 (d, J=9.04 Hz, 1 H), 7.32 - 7.40 (m, 1 H), 7.41 - 7.49 (m, 2 H). MS m/z: C25H36Cl2N4O2の計算値:494.22 [M]+, 実測値:495.4 [M+H]+.
169:(S)-2-シクロヘキシル-2-(5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド)酢酸:収率94%;1H NMR (CDCl3 , 300 MHz) δ 0.76 (d, J=6.78 Hz, 3 H), 0.74 (d, J=6.78 Hz, 3 H), 1.09 - 1.39 (m, 6 H), 1.63 - 1.91 (m, 5 H), 1.99 - 2.19 (m, 2 H), 3.69 (dd, J=7.16, 3.01 Hz, 2 H), 3.73 (s, 3 H), 3.75 (s, 3 H), 4.55-4.64 (m, 1 H), 6.62 (d, J=8.67 Hz, 2 H), 6.72 (s, 1 H), 7.38 (t, J=8.48 Hz, 1 H), 7.43 (d, J=8.67 Hz, 1 H). MS m/z: C24H33N3O5の計算値:443.24 [M]+, 実測値:442.7 [M-H]+.
170:(S)-N-(2-(ブチルアミノ)-1-シクロヘキシル-2-オキソエチル)-5-(2,6-ジメトキシフェニル)-1-イソブチル-1H-ピラゾール-3-カルボキサミド:収率65%;1HNMR (CDCl3 , 300 MHz) δ 0.75 (t, J=6.78 Hz, 6 H), 0.91 (t, J=7.35 Hz, 3 H), 1.02 - 1.19 (m, 3 H), 1.20 - 1.40 (m, 5 H), 1.44 - 1.54 (m, 2 H), 1.68 - 1.90 (m, 4 H), 1.93 - 2.08 (m, 1 H), 2.10-2.21 (m, 1 H), 3.19 - 3.34 (m, 2 H), 3.58 - 3.67 (m, 2 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 4.29-4.36 (m, 1 H), 6.06 - 6.10 (m, 1 H), 6.62 (d, J=8.67 Hz, 2 H), 6.68 (s, 1 H), 7.29 - 7.42 (m, 2 H). MS m/z: C28H42N4O4の計算値:498.32 [M]+, 実測値:499.9 [M+H]+.
表1
上記化合物を、アペリンアゴニストとしてのそのin vitro活性について、その内容全体が参照により本明細書に組み込まれる非特許文献23により説明される方法を用いて調査した。非特許文献23に記載の方法および陽性対照としてアペリン-13を使用し、次の番号を有する化合物は、<10μMのアゴニスト活性(EC50)を有していた:34、56、65、67、70、71、77、79、81、82、86、93、95、103、118、126、127、129、130、132、133、134、136、137、138、140、141、142、143、153、154、155、156、157、161、162、163、164、167、168、169、171、172、173、174、175、176、181、182、183、184、185、186、187、188、189、191、198、204、205、212、213、214、215、217、218、219、220、225、226、228、229、231、232、233、234、235、236、238、239、240、241、242、245、247、249、251、252、253、256、257、258、259、263および265。3回の実行に基づき、化合物番号198は53nMの平均活性を有していた。
(化合物の活性を低下させるin vivo血圧)
Claims (15)
- 式Iで表される化合物:
式中、
R1は式:
で表され、
各Aは独立してC1-8アルコキシ、C1-8アルコキシ-アリール、ハロゲン、またはO(CH2)xCO2R7であり;
nは1、2、3、または4であり;
第1のAは、構造式に描かれたピラゾールとの連結点に対してオルソ位で置換され、
R2は、置換C5-12アリール、置換若しくは未置換のC3-8アルキル、置換若しくは未置換のC2-8アルキル-置換C5-12アリール、置換若しくは未置換のC2-8アルキル-置換または未置換のC3-8シクロアルキル、または置換若しくは未置換のC3-8シクロアルキルであり;
R3は、存在せず、;
R4は、C2-8アルキル、C2-8アルケニル、C3-8シクロアルキル、C2-8アルキル-C5-12アリール、C1-8アルキル-C3-8シクロアルキル、C1-8アルキル-5〜7員環のヘテロアリール、(CH2)xNR7R8、または、C5-12アリールはC1-8アルキレンリンカーとメタまたはパラで置換されている、C1-8アルキル-置換C5-12アリールであり、;
R5は、置換若しくは未置換のC1-8アルキル、C5-12アリール、C1-8アルキル-C5-12アリール、C1-8アルキル-C3-8シクロアルキル、C1-8アルキル-5〜7員環のヘテロアリール、C3-8シクロアルキル、(CH2)xNR7R8、(CH2)xNHCOR7、(CH2)xNHCO2R7、(CH2)xCONR7R8、(CH2)xCONR7(CH2)yCO2R9、(CH2)xCONR7(CH2)yCONR7R8、(CH2)xCONR7(CH2)yR9、(CH2)xCOR7、(CH2)xCO2R7、CHR7COR9、CHR7CONHCHR8COR9、または、CONR7R8;
またはR4およびR5は一緒になって4〜8員環を作り、該4〜8員環は、O、NまたはSから選択される1つ以上のヘテロ原子で置換されていてもよく、そして、さらに、1つ以上のC1-8アルコキシ、C1-8アルキル、H、イソオキサゾ―ルまたはヒドロキシルで置換されていても良く、;
R6はHであり;
R7およびR8は、独立して、置換若しくは未置換のアリール、置換若しくは未
置換のC1-8アルキル、置換若しくは未置換のC3-8シクロアルキル、またはHであり;
または
R7およびR8は一緒になって、置換若しくは未置換の3〜8員環を作り、該3〜8員環は、O、NまたはSから選択される1つ以上のヘテロ原子を含み;
各R9はC1-8アルコキシ、C1-8アルキル、H、ヘテロアリールまたはヒドロキシルであり;
各xは独立して1、2、3または4であり;
各yは独立して1、2、または3であり;
Zは=Oであり、=は二重結合を表わし、
置換は、C1-8アルキル、ハロゲン、C1-8ハロアルキル、C1-8アルコキシ、ヒドロキシル、カルボニル、CO2R9、C5-12アリール、5〜7員環のヘテロアリール、C3-8シクロアルキル、C1-8アルキル-C5-12アリール、C1-8アルキル-5〜7員環のヘテロアリール、C1-8アルキル-C3-8シクロアルキル、NO2、N3、NH2、N(CH3)2、SO(1-3)HまたはSHの1つ以上によって置換されることを意味している、
化合物。 - 請求項1に記載の化合物であって、式中
nは4であり;
各Aは独立してC1-4アルコキシ、C1-4アルコキシアリール、またはハロゲンであり;
R2はC3-8アルキルまたはC3-8シクロアルキルであり;
R4はC2-8アルキル、C2-8アルキル(アリール)、またはC1-8アルキル(C3-8シクロアルキル)であり;
R5は(CH2)xNHCOR7、(CH2)xNHCO2R7、(CH2)xCONR7R8、(CH2)xCONR7(CH2)yCO2R9、(CH2)xCONR7(CH2)yCONR7R8、(CH2)xCONR7(CH2)yR9、(CH2)xCOR7、(CH2)xCO2R7、CHR7COR9、CHR7CONHCHR8COR9またはCONR7R8であり;
R9はC1-8アルキル、H、またはオキサゾールであり;
xは独立して1、2、3または4であり;ならびに
yは独立して1、2または3である、化合物。 - 請求項2に記載の化合物であって、
nは4であり;
各Aは独立してC1アルコキシ、C1アルコキシ(アリール)、またはハロゲンであり;
R2はC4アルキルまたはC6シクロアルキルであり;
R4はC2-4アルキル、C2-8アルキル(アリール)、またはC1-8アルキル(C3-8シクロアルキル)であり;
R5は(CH2)xNHCOR7、(CH2)xNHCO2R7、(CH2)xCONR7R8、(CH2)xCONR7(CH2)yCO2R9、(CH2)xCONR7(CH2)yCONR7R8、(CH2)xCONR7(CH2)yR9、(CH2)xCOR7、(CH2)xCO2R7、CHR7COR9、CHR7CONHCHR8COR9、またはCONR7R8であり;
R8はC1-4アルキルまたはHであり;
R9はC1-8アルキル、H、またはオキサゾールであり;
xは独立して1、2、3または4であり;ならびに
yは独立して1、2または3である、化合物。 - 請求項3に記載の化合物であって、
nは4であり;
各Aは独立してC1アルコキシ、C1アルコキシアリール、またはフッ素であり;
R2はC4アルキルまたはC6シクロアルキルであり;
R4はC2-4アルキル、C2-4アルキルアリール、またはC1-4アルキル(C5-8シクロアルキル)であり;
R5は(CH2)xNHCOR7、(CH2)xNHCO2R7、(CH2)xCONR7R8、(CH2)xCONR7(CH2)yCO2R9、(CH2)xCONR7(CH2)yCONR7R8、(CH2)xCONR7(CH2)yR9、(CH2)xCOR7、(CH2)xCO2R7、CHR7COR9、CHR7CONHCHR8COR9、またはCONR7R8であり;
R8はC1-4アルキルまたはHであり;
R9はC1-8アルキル、H、またはオキサゾールであり;
xは独立して1、2、3または4であり;ならびに
yは独立して1、2または3である、化合物。 - 請求項4に記載の化合物であって、
nは4であり;
各Aは独立してC1アルコキシ、C1アルコキシアリール、またはフッ素であり;
R2はC4アルキルまたはC6シクロアルキルであり;
R4はC2-4アルキル、C2-4アルキル(アリール)、C1-4アルキル(シクロアルキル)であり;
R5は(CH2)xNHCOR7、(CH2)xNHCO2R7、(CH2)xCONR7R8、(CH2)xCONR7(CH2)yCO2R9、(CH2)xCONR7(CH2)yCONR7R8、(CH2)xCONR7(CH2)yR9、(CH2)xCOR7、(CH2)xCO2R7、CHR7COR9、CHR7CONHCHR8COR9、またはCONR7R8であり;
R8はHであり;
R9はC1-8アルキル、H、またはオキサゾールであり;
xは独立して1、2、3または4であり;ならびに
yは独立して1、2または3である、化合物。 - 請求項1に記載の化合物であって、
nは2であり;
各Aは独立してC1-4アルコキシ、C1-4アルコキシアリールであり;
R2はC3-8アルキルまたはC3-8シクロアルキルであり;
R4はC2-8アルキル、C2-8アルキル(アリール)、C1-8アルキル(C3-8シクロアルキル)であり;
R5は(CH2)xNHCOR7、(CH2)xNHCO2R7、(CH2)xCONR7R8、(CH2)xCONR7(CH2)yCO2R9、(CH2)xCONR7(CH2)yCONR7R8、(CH2)xCONR7(CH2)yR9、(CH2)xCOR7、(CH2)xCO2R7、CHR7COR9、CHR7CONHCHR8COR9、またはCONR7R8であり;
R9はC1-8アルキル、H、またはオキサゾールであり;
xは独立して1、2、3または4であり;ならびに
yは独立して1、2または3である、化合物。 - 請求項6に記載の化合物であって、
nは2であり;
各Aは独立してC1アルコキシ、またはC1アルコキシアリールであり;
R2はC4アルキルまたはC6シクロアルキルであり;
R4はC2-8アルキル、C2-8アルキルアリール、C1-8アルキル(C3-8シクロアルキル)であり;
R5は(CH2)xNHCOR7、(CH2)xNHCO2R7、(CH2)xCONR7R8、(CH2)xCONR7(CH2)yCO2R9、(CH2)xCONR7(CH2)yCONR7R8、(CH2)xCONR7(CH2)yR9、(CH2)xCOR7、(CH2)xCO2R7、CHR7COR9、CHR7CONHCHR8COR9、またはCONR7R8であり;
R8はC1-4アルキルまたはHであり;
R9はC1-8アルキル、H、またはオキサゾールであり;
xは独立して1、2、3または4であり;
yは独立して1、2または3である、化合物。 - 請求項7に記載の化合物であって、
nは2であり;
各Aは独立してC1アルコキシ、C1アルコキシアリールであり;
R2はC4アルキルまたはC6シクロアルキルであり;
R4はC2-4アルキル、C2-4アルキル(アリール)、またはC1-4アルキル(C5-8シクロアルキル)であり;
R5は(CH2)xNHCOR7、(CH2)xNHCO2R7、(CH2)xCONR7R8、(CH2)xCONR7(CH2)yCO2R9、(CH2)xCONR7(CH2)yCONR7R8、(CH2)xCONR7(CH2)yR9、(CH2)xCOR7、(CH2)xCO2R7、CHR7COR9、CHR7CONHCHR8COR9、またはCONR7R8であり;
R8はC1-4アルキルまたはHであり;
R9はC1-8アルキル、H、またはオキサゾールであり;
xは独立して1、2、3または4であり;ならびに
yは独立して1、2または3である、化合物。 - 請求項8に記載の化合物であって、
nは2であり;
各Aは独立してC1アルコキシ、C1アルコキシアリールであり;
R2はC4アルキルまたはC6シクロアルキルであり;
R4はC2-4アルキル、C2-4アルキルアリール、C1-4アルキル(C5-8シクロアルキル)であり;
R5は(CH2)xNHCOR7、(CH2)xNHCO2R7、(CH2)xCONR7R8、(CH2)xCONR7(CH2)yCO2R9、(CH2)xCONR7(CH2)yCONR7R8、(CH2)xCONR7(CH2)yR9、(CH2)xCOR7、(CH2)xCO2R7、CHR7COR9、CHR7CONHCHR8COR9、またはCONR7R8、であり;
R8はHであり;
R9はC1-8アルキル、H、またはオキサゾールであり;
xは独立して1、2、3または4であり;ならびに
yは独立して1、2または3である、化合物。 - R4がC1-8アルキル-5〜7員環のヘテロアリールであり、該C1-8アルキルヘテロアリールがC1-8アルキルテトラゾールである、請求項1に記載の化合物。
- (2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-4-メチルペンタン酸、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサン酸、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル]ホルムアミド} -5-メチルヘキサンアミド、
(3R)-3-{[5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサン酸、
2-(2-シクロヘキシル-2-{[5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル]ホルムアミド}アセトアミド)酢酸、
2-[(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル]ホルムアミド} -5-メチルヘキサンアミド]酢酸、
(3S)-3-{[1-シクロヘキシル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサン酸、
2-[(3S)-3-{[1-シクロヘキシル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド} -5-メチルヘキサンアミド]酢酸、
(3S)-3-({5-[2-(ベンジルオキシ)-6-メトキシフェニル]-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル}ホルムアミド)-5-メチルヘキサン酸、
(3S)-3-{[1-(4-フルオロフェニル)-5-[2-メトキシ-6-(2-メトキシ-2-オキソエトキシ)フェニル]-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサン酸、
2-シクロヘキシル-2-{[1-シクロヘキシル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}酢酸、
(3S)-3-{[1-(シクロヘキシルメチル)-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド} -5-メチルヘキサン酸、
メチル2-[(3S)-3-{[1-シクロヘキシル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド]アセテート、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサン酸、
(3S)-3-({5-[2-(ベンジルオキシ)-6-メトキシフェニル]-1-シクロヘキシル-1H-ピラゾール-3-イル}ホルムアミド)-5-メチルヘキサン酸、
メチル2-[(3S)-3-({5-[2-(ベンジルオキシ)-6-メトキシフェニル]-1-シクロヘキシル-1H-ピラゾール-3-イル}ホルムアミド)-5-メチルヘキサンアミド]アセテート、
2-[(3S)-3-({5-[2-(ベンジルオキシ)-6-メトキシフェニル]-1-シクロヘキシル-1H-ピラゾール-3-イル}ホルムアミド)-5-メチルヘキサンアミド]酢酸、
メチル2-[(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド]アセテート、
(3S)-N-ベンジル-3-({5-[2-(ベンジルオキシ)-6-メトキシフェニル]-1-シクロヘキシル-1H-ピラゾール-3-イル}ホルムアミド)-5-メチルヘキサンアミド、
(3S)-3-({5-[2-(ベンジルオキシ)-6-メトキシフェニル]-1-シクロヘキシル-1H-ピラゾール-3-イル}ホルムアミド)-N-ブチル-5-メチルヘキサンアミド、
(3S)-3-({5-[2-(ベンジルオキシ)-6-メトキシフェニル]-1-シクロヘキシル-1H-ピラゾール-3-イル}ホルムアミド)-5-メチル-N-(1,3-オキサゾール)-2-イルメチル)ヘキサンアミド、
(3S)-3-({5-[2-(ベンジルオキシ)-6-メトキシフェニル]-1-シクロヘキシル-1H-ピラゾール-3-イル}ホルムアミド)-N-[(ジメチルカルバモイル)メチル]-5-メチルヘキサンアミド、
メチル2-[(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド]アセテート、
エチル3-[(3S)-3-({5-[2-(ベンジルオキシ)-6-メトキシフェニル]-1-シクロヘキシル-1H-ピラゾール-3-イル}ホルムアミド)-5-メチルヘキサンアミド]プロパノエート、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチル-N-(1,3-オキサゾール-2-イルメチル)ヘキサンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド} -N、5-ジメチルヘキサンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド} -N-(2-ヒドロキシエチル)-5-メチルヘキサンアミド、
(3S)-N-ブチル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド、
(3R)-N-ブチル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-ヘキシル-5-メチルヘキサンアミド、
(3S)-N-(シクロヘキシルメチル)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチル-N-ペンチルヘキサンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチル-N-プロピルヘキサンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-エチル-5-メチルヘキサンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチル-N-(プロパン-2-イル)ヘキサンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-(4-フルオロフェニル)-5-メチルヘキサンアミド、
メチル(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサノエート、
(3S)-3-{[5-(3,5-ジフルオロ-2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサン酸、
(3S)-N-ブチル-3-{[5-(3,5-ジフルオロ-2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド、
(2S)-2-シクロヘキシル-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}酢酸、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N、5-ジメチル-N-プロピルヘキサンアミド、
(3S)-N-シクロプロピル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド、
(3S)-N-シクロブチル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド} -5-メチルヘキサンアミド、
2-[(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド]酢酸、
(3S)-N-(カルバモイルメチル)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチル-N-[(メチルカルバモイル)メチル]ヘキサンアミド、
(3S)-3-{[1-(シクロプロピルメチル)-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサン酸、
(3S)-3-{[1-シクロペンチル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサン酸、
メチル2-[(3S)-3-{[1-(シクロプロピルメチル)-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド]アセテート、
メチル2-[(3S)-3-{[1-シクロペンチル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド]アセテート、
(3S)-N-シクロペンチル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド、
メチル2-[(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-プロピル-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド]アセテート、
メチル2-[(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2,2-ジメチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-メチルヘキサンアミド]アセテート、
メチル2-[(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-4-メチルペンタンアミド]アセテート、
メチル2-[(2S)-2-{[1-シクロヘキシル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド} -4-メチルペンタンアミド]アセテート、
エチル3-[(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-4-メチルペンタンアミド]プロパノエート、
メチル2-[(2S)-3-シクロヘキシル-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}プロパンアミド]アセテート、
(2S)-3-シクロヘキシル-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}プロパン酸、
メチル2-[(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-3-フェニルプロパンアミド]アセテート、
メチル2-[(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}ヘキサンアミド]アセテート、
メチル2-[(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-4-フェニルブタンアミド]アセテート、
(3S)-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}ペンタン酸、
メチル2-[(3S)-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}ペンタンアミド]アセテート、
メチル2-[(2S)-3-シクロヘキシル-2-{[5-(2,5-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}プロパンアミド]アセテート、
メチル2-[(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N、5-ジメチルヘキサンアミド]アセテート、
メチル2-[(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N、4-ジメチルペンタンアミド]アセテート、
2-[(3S)-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}ペンタンアミド]酢酸、
(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-4-フェニル-N-プロピルブタンアミド、
5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-N-[(2S)-1-オキソ-4-フェニル-1-(ピロリジン-1-イル)ブタン-2-イル]-1H-ピラゾール-3-カルボキサミド、
メチル2-[(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド} -N-メチル-4-フェニルブタンアミド]アセテート、
(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-(2-メトキシエチル)-4-フェニルブタンアミド、
(3S)-N-シクロブチル-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}ペンタンアミド、
(3S)-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}ペンタンアミド、
(3S)-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-(2-ヒドロキシブチル)ペンタンアミド、
(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-(2-ヒドロキシブチル)-4-フェニルブタンアミド、
(2S)-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-(2-オキソブチル)-4-フェニルブタンアミド、
(3S)-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド} -N-(2-オキソブチル)ペンタンアミド、
メチル2-[(3S)-3-{1-[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル] -N-メチルホルムアミド} -5-メチルヘキサンアミド]アセテート、
(3S)-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド} -N-(2-メトキシエチル)ペンタンアミド、
メチル2-[(3S)-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド} -N-メチルペンタンアミド]アセテート、
(2S)-N-シクロブチル-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-4-フェニルブタンアミド、
メチル2-[(3S)-6-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}ヘキサンアミド]アセテート、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-(2-ヒドロキシブチル)-5-(ピペリジン-1-イル)ペンタンアミド。
(3S)-N-シクロブチル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-(ピペリジン-1-イル)ペンタンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド} -N-(2-メトキシエチル)-5-(ピペリジン-1-イル)ペンタンアミド、
(3S)-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-5-(ピペリジン-1-イル)ペンタン酸、
(3S)-3-{[1-シクロペンチル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-(ピペリジン-1-イル)ペンタン酸、
(3S)-N-シクロブチル-3-{[1-シクロペンチル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}-5-(ピペリジン-1-イル)ペンタンアミド、
(2S)-4-シクロヘキシル-2-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-(2-メトキシエチル)-N-メチルブタンアミド、
(3R)-3-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル]ホルムアミド}プロパン酸、
メチル2-(3-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(4-フルオロフェニル)-1H-ピラゾール-3-イル]ホルムアミド}プロパンアミド)アセタート、
(3S)-5-シクロヘキシル-3-{[5-(2,6-ジメトキシフェニル)-1-(2-メチルプロピル)-1H-ピラゾール-3-イル]ホルムアミド}-N-[(2R)-2-ヒドロキシブチル]ペンタンアミド、
(3R)-N-シクロブチル-3-{[1-シクロペンチル-5-(2,6-ジメトキシフェニル)-1H-ピラゾール-3-イル]ホルムアミド}ペンタ-4-エナミド、または、
N-[(2S)-4-シクロヘキシル-1-(1H-1,2,3,4-テトラゾール-5-イル)ブタン-2-イル]-5-(2,6-ジメトキシフェニル)-1-( 2-メチルプロピル)-1H-ピラゾール-3-カルボキサミド、
からなる群から選ばれる化合物
またはその薬学的に許容される塩。 - 少なくとも1つの薬学的に許容される賦形剤および治療有効量の請求項1〜11に記載の化合物を含む、血圧の低下、喘息、心筋症、糖尿病、脂質異常症、高血圧症、炎症、肝疾患、代謝性疾患、神経変性疾患、肥満症、子癇前症、または腎機能障害の治療のための医薬組成物。
- 該高血圧症が、肺動脈高血圧症であり;該肝疾患が、アルコール性肝疾患、毒物誘発性肝疾患またはウイルス誘発性肝疾患であり;腎機能障害が、多発性嚢胞腎疾患であり;または、静脈関連障害が血管腫、静脈不全、うっ血または血栓症である請求項12に記載の医薬組成物。
- 静脈関連障害;またはHIV関連神経変性であるアペリン受容体(APJ)関連障害の治療に使用するための請求項1記載の化合物。
- アペリン受容体(APJ)関連障害が、喘息、心筋症、糖尿病、脂質異常症、高血圧症、炎症、肝疾患、代謝性疾患、神経変性疾患、肥満症、子癇前症、または腎機能障害;高血圧症が、肺動脈高血圧症であり;肝疾患が、アルコール性肝疾患、毒物誘発性肝疾患またはウイルス誘発性肝疾患であり;腎機能障害が、多発性嚢胞腎疾患であり;または、静脈関連障害が血管腫、静脈不全、うっ血または血栓症であり、所望により、α-遮断剤、アンジオテンシン変換酵素(ACE)阻害剤、アンジオテンシン受容体遮断剤(ARB)、β-遮断剤、カルシウムチャネル遮断剤、またはアペリン受容体関連の障害の治療のための利尿薬をさらに含む、アペリン受容体(APJ)関連障害の治療のための請求項14記載の化合物。
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CN106459004A (zh) | 2017-02-22 |
US11401244B2 (en) | 2022-08-02 |
CA2949559C (en) | 2023-08-29 |
US20160207889A1 (en) | 2016-07-21 |
KR20170012305A (ko) | 2017-02-02 |
CA2949559A1 (en) | 2015-12-10 |
RU2016144329A3 (ja) | 2018-11-23 |
US10377718B2 (en) | 2019-08-13 |
ZA201607850B (en) | 2018-05-30 |
PE20170664A1 (es) | 2017-06-10 |
MA39999A (fr) | 2015-12-10 |
JP2017523126A (ja) | 2017-08-17 |
RU2016144329A (ru) | 2018-07-11 |
AU2015269247A1 (en) | 2016-12-01 |
KR102509043B1 (ko) | 2023-03-09 |
US20190315693A1 (en) | 2019-10-17 |
WO2015188073A1 (en) | 2015-12-10 |
AU2015269247B2 (en) | 2019-10-24 |
BR112016028119A2 (pt) | 2017-08-22 |
MX2016014890A (es) | 2017-05-01 |
CN106459004B (zh) | 2020-09-15 |
IL248988A0 (en) | 2017-01-31 |
RU2705800C2 (ru) | 2019-11-12 |
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