JP2023516714A - 新規ep4拮抗薬の合成及びその癌及び炎症における使用 - Google Patents
新規ep4拮抗薬の合成及びその癌及び炎症における使用 Download PDFInfo
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- JP2023516714A JP2023516714A JP2022552881A JP2022552881A JP2023516714A JP 2023516714 A JP2023516714 A JP 2023516714A JP 2022552881 A JP2022552881 A JP 2022552881A JP 2022552881 A JP2022552881 A JP 2022552881A JP 2023516714 A JP2023516714 A JP 2023516714A
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Abstract
Description
本願は、出願番号が202010144983.1で、出願日が2020年3月4日である中国特許出願に基づいて提案され、この中国特許出願の優先権を主張し、この中国特許出願の全ての内容をここで参照として援用することにより本願に取り入れる。
本発明は化学及び医学分野に関し、具体的に、本発明はピラゾール誘導体及びその使用に関する。
環Bは
R1は-CH3、-CHF2及び-CF3から選ばれ、
R2はC2-C6アルキル、C3-C6シクロアルキル、フェニル、トリフルオロメチル、ハロゲンで置換されたC2-C6アルキル、ハロゲンで置換されたC3-C6シクロアルキル、ヒドロキシで置換されたC2-C6アルキル、シアノで置換されたC2-C6アルキル、-SF5、-X-R2aから選ばれ、ただし、Xは酸素、硫黄、-CO-、-SO2-、-SO-から選ばれ、R2aはC1-C6アルキル、ハロゲンで置換されたC1-C6アルキルから選ばれ、
R3は水素、ハロゲン、C1-C2アルキル、フッ素で置換されたC1-C2アルキル、フェニルから選ばれ、
R4は水素、ハロゲン、C1-C6アルキル、C1-C6アルコキシ、ハロゲンで置換されたC1-C6アルキル、ハロゲンで置換されたC1-C6アルコキシから選ばれ、
R5は水素、ハロゲンから選ばれ、
R6aとR6bの一方は水素であり、他方はメチルであり、またはR6aとR6bは一緒にシクロブチル環を形成し、
R7は-CH3、-CHF2及び-CF3から選ばれ、
Mは酸素、硫黄、メチレンから選ばれ、
R2はトリフルオロメチルであり、Mは酸素であり、R6aとR6bの一方は水素であり、他方はメチルである場合、環Aは
R2はトリフルオロメチルであり、Mは酸素であり、環Aは
特に明記しない限り、本願の明細書及び特許請求の範囲に記載された基及び用語の定義は、例としての定義、例示的な定義、好ましい定義、表に記載された定義、実施例における具体的な化合物の定義等を含むことができ、互い間に任意に組み合わせることができる。このように組み合わせた基の定義及び化合物構造は、本願の明細書に記載された範囲に属する。
本発明の実施例によれば、本発明に記載の化合物および/またはその組成物は、EP4受容体の活性を効果的に拮抗することができ、より良好な肝代謝安定性および心臓安全性の利点を有し、そして、より良好な薬物動態特性、より高いインビボ曝露量、より低い投与量、より良好なコンプライアンスを有する。EP4関連疾患を治療する薬物の調製には幅広い応用の見通しがある。
BAST:ビス(2-メトキシエチル)アミノ硫黄トリフルオリド
m-CPBA:m-クロロペルオキシ安息香酸
L-selectride:リチウムトリ-sec-ブチルボロヒドリド
Pd(dppf)Cl2:1,1-ビス(ジフェニルホスホニウム)フェロセン塩化パラジウム
DCM:ジクロロメタン
HATU:O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチル尿素ヘキサフルオロホスフェート
DIPEA:ジイソプロピルエチルアミン、即ちN,N-ジイソプロピルエチルアミン
DMF:N,N-ジメチルホルムアミド
N:当量濃度、例えば1Nの塩酸が1mol/Lの塩酸溶液を示す
THF:テトラヒドロフラン
DMA:N,N-ジメチルアセトアミド
DMSO:ジメチルスルホキシド
EA:酢酸エチル
IC50:半分の阻害濃度、最大の阻害効果の半分に達成する濃度を指す。
CHO:Chinese hamster ovary cells、チャイニーズハムスター卵巣細胞
HBSS:Hank’s Balanced Salt Solution、Hankの平衡塩類溶液
BSA:Albumin from bovine serum、ウシ血清アルブミン
HEPES:ヒドロキシエチルピペラジンエタンチオスルホン酸
IBMX:3-isobutyl-1-methyl-7H-xanthine、3-イソブチル-1-メチルキサンチン
FLIPR:Fluorescence Imaging Plate Reader、リアルタイム蛍光イメージング分析システム
EC80:concentration for 80% of maximal effect、最大効果の80%を引き起こす濃度
反対の指示がない限り、本明細書で例示されている化合物は、ChemBioDraw Ultra 13.0を使用して名前と番号を付ける。
メチル(S)-4-(1-(5-クロロ-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)ベンゾエート(中間体A)
methyl (S)-4-(1-(5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxam ido)ethyl)benzoate(中間体A)
LCMS(ESI)m/z:372.5[M+H]+
この実施例は製品の精製実施例であり、この精製過程では、高速液体クロマトグラフィーを使用して精製し、精製条件は以下の通りである。
Welch、Ultimate C18コラム、10μm、21.2mm×250mm。
(S)-4-(1-(3-(ジフルオロメチル)-5-(3-エチルフェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-1)
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-1)
methyl (S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-1B)
LCMS(ESI)m/z:458.1[M+H]+
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-1)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 7.90 (d, 1H), 7.71 (d, 2H), 7.32 (t, 1H), 7.25 (t, 1H), 7.12 (d, 2H), 7.07 (d, 1H), 6.90 (s, 1H), 6.76 (dd, 1H), 4.90 (t, 1H), 3.72 (s, 3H), 2.61 (q, 2H), 1.22 (d, 3H), 1.14 (t, 3H).
LCMS(ESI)m/z:444.1[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-5-(3-エチル-4-フルオロフェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-2)
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-2)
1-fluoro-4-methoxy-2-vinylbenzene(化合物I-2B)
2-ethyl-1-fluoro-4-methoxybenzene(化合物I-2C)
3-ethyl-4-fluorophenol(化合物I-2D)
3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde(化合物I-2E)
LCMS(ESI)m/z:299.1[M+H]+
3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid(化合物I-2F)
LCMS(ESI)m/z:315.1[M+H]+
methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-2G)
LCMS(ESI)m/z:476.2[M+H]+
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-2)
1HNMR (400m Hz, DMSO-d6) δ 12.8 (s, 1H), 8.03 (d, 1H), 7.74 (d, 2H), 7.17 (t, 1H), 7.14-7.10 (m, 3H), 7.01-6.97 (m, 1H), 6.82-6.79 (m, 1H), 4.92 (t, 1H), 3.73 (s, 3H), 2.59 (q, 2H), 1.25 (d, 3H), 1.11 (t, 3H).
LCMS(ESI)m/z:462.2[M+H]+
(S)-4-(1-(5-(3-シクロプロピルフェノキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-3)
(S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-3)
methyl(S)-4-1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-3B)
LCMS(ESI)m/z:470.6[M+H]+
(S)-4-(1-(5-(3-cyclopropylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-3)
1HNMR (400m Hz, DMSO-d6) δ 12.8 (s, 1H), 7.92 (d, 1H), 7.72 (d, 2H), 7.27 (t, 1H), 7.11 (t, 1H), 7.10 (d, 2H), 6.90 (d, 1H), 6.80 (t, 1H), 6.70 (dd, 1H), 4.90 (t, 1H), 3.72 (s, 3H), 1.92-1.98 (m, 1H), 1.23 (d, 3H), 0.96-0.92 (m, 2H), 0.66-0.27 (m, 2H).
LCMS(ESI)m/z:456.6[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-5-(3-イソプロピルフェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-4)
(S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-4)
3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde(化合物I-4B)
LCMS(ESI)m/z:295.1[M+H]+
3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxylic acid(化合物I-4C)
LCMS(ESI)m/z:311.1[M+H]+
methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-4D)
LCMS(ESI)m/z:472.2[M+H]+
(S)-4-(1-(3-(difluoromethyl)-5-(3-isopropylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-4)
1HNMR (400m Hz, DMSO-d6) δ 12.7 (s, 1H), 7.89 (d, 1H), 7.70 (d, 2H), 7.32 (t, 1H), 7.12 (t, 1H), 7.10 (s, 1H), 7.06 (d, 2H), 6.99 (s, 1H), 6.72-6.70 (m, 1H), 4.91 (t, 1H), 3.73 (s, 3H), 2.91-2.85 (m, 1H), 1.21 (d, 3H), 1.17 (d, 6H).
LCMS(ESI)m/z:458.3[M+H]+
(S)-4-(1-(5-(3-(1,1-ジフルオロエチル)フェノキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-5)
(S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-5)
2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(化合物I-5B)
3-(1,1-difluoroethyl)phenol(化合物I-5C)
methyl(S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-5D)
LCMS(ESI)m/z:494.6[M+H]+。
(S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-5)
LCMS(ESI)m/z:480.5[M+H]+
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 8.10 (d, 1H), 7.71 (d, 2H), 7.53 (t, 1H), 7.47 (d, 1H), 7.27 (d, 1H), 7.11 (t, 1H), 7.11 (d, 2H), 7.07 (dd, 1H), 4.88 (t, 1H), 3.74 (s, 3H), 1.96 (t, 3H), 1.96 (d, 3H).
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-(2,2,2-トリフルオロエチル)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-6)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-6)
methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-6B)
LCMS(ESI)m/z:458.1[M+H]+
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-6C)
LCMS(ESI)m/z:512.1[M+H]+
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-6)
1HNMR (400m Hz, DMSO-d6) δ 12.7 (s, 1H), 7.95 (d, 1H), 7.73 (d, 2H), 7.43 (t, 1H), 7.22 (d, 1H), 7.13 (t, 1H), 7.12 (d, 2H), 7.10 (s, 1H), 6.97 (dd, 1H), 4.89 (t, 1H), 3.74 (s, 3H), 3.72-3.63 (m, 2H), 1.24 (d, 3H).
LCMS(ESI)m/z:498.5[M+H]+
(S)-4-(1-(5-(3-(1,1-ジフルオロエチル)フェノキシ)-3-(トリフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-7)
(S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-7)
5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid(化合物I-7B)
LCMS(ESI)m/z:229.6[M+H]+
methyl(S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-7C)
LCMS(ESI)m/z:390.5[M+H]+
methyl(S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-7D)
LCMS(ESI)m/z:512.3[M+H]+
(S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-7)
1HNMR (400m Hz, DMSO-d6) δ 12.8 (s, 1H), 8.58 (d, 1H), 7.73 (d, 2H), 7.53 (t, 1H), 7.40 (d, 1H), 7.27 (s, 1H), 7.15 (d, 2H), 7.11 (d, 1H), 4.85 (t, 1H), 3.29 (s, 3H), 1.96 (t, 3H), 1.17 (d, 3H).
LCMS(ESI)m/z:498.3[M+H]+
(S)-4-(1-(5-(3-(1,1-ジフルオロエチル)フェノキシ)-1,3-ジメチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-8)
(S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-8)
5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde(化合物I-8B)
LCMS(ESI)m/z:159.6[M+H]+
5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid(化合物I-8C)
LCMS(ESI)m/z:175.6[M+H]+
methyl(S)-4-(1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-8D)
LCMS(ESI)m/z:336.6[M+H]+
methyl(S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-8E)
LCMS(ESI)m/z:458.5[M+H]+
(S)-4-(1-(5-(3-(1,1-difluoroethyl)phenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-8)
1HNMR (400m Hz, DMSO-d6) δ 12.8 (s, 1H), 7.73 (d, 2H), 7.71 (d, 1H), 7.52 (t, 1H), 7.37 (d, 1H), 7.21 (s, 1H), 7.14 (d, 2H), 7.01 (dd, 1H), 4.91 (t, 1H), 3.59 (s, 3H), 2.27 (s, 3H), 1.96 (t, 3H), 1.22 (d, 3H).
LCMS(ESI)m/z:444.5[M+H]+
(S)-4-(1-(5-(3-エチルフェノキシ)-1,3-ジメチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-9)
(S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-9)
化合物I-9の合成経路は以下の通りである。
methyl(S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-9B)
LCMS(ESI)m/z:422.6[M+H]+
(S)-4-(1-(5-(3-ethylphenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-9)
1HNMR (400m Hz, DMSO-d6) δ 12.6 (s, 1H), 7.72 (d, 2H), 7.50 (d, 1H), 7.31 (t, 1H), 7.12 (d, 2H), 7.04 (d, 1H), 6.85 (s, 1H), 6.71 (dd, 1H), 4.92 (t, 1H), 3.56 (s, 3H), 2.67 (q, 2H), 2.27 (s, 3H), 1.24 (d, 3H), 1.14 (t, 3H).
LCMS(ESI)m/z:408.6[M+H]+
(S)-4-(1-(5-(3-(1,1-ジフルオロエチル)-4-フルオロフェノキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-10)
(S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-10)
methyl(S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-10B)
LC-MS,M/Z(ESI):490.2[M+H]+
methyl(S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-10C)
LC-MS,M/Z(ESI):512.2[M+H]+
(S)-4-(1-(5-(3-(1,1-difluoroethyl)-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-10)
LC-MS,M/Z(ESI):498.1[M+H]+
1 HNMR (400mHz, DMSO-d6) δ12.10 (s, 1H), 8.19 (d, 1H), 7.75 (d, 2H), 7.39 (t, 1H), 7.26 (t, 1H), 7.15 (d, 2H), 7.13 (d, 1H), 7.12 (t, 1H), 4.90 (t, 1H), 3.75 (s, 3H), 2.01 (t, 3H), 1.22 (d, 3H).
(S)-4-(1-(5-(4-クロロ-3-エチルフェノキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-11)
(S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-11)
methyl(S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-11B)
LC-MS,M/Z(ESI):492.3(M+1)。
(S)-4-(1-(5-(4-chloro-3-ethylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-11)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 8.04 (d, 1H), 7.73 (d, 2H), 7.41 (d, 1H), 7.11 (t, 1H), 7.10 (d, 2H), 7.08 (d, 1H), 6.82 (d, 1H), 4.91 (t, 1H), 3.73 (s, 3H), 2.67 (q, 2H), 1.24 (d, 3H),1.11 (t, 3H).
LC-MS,M/Z(ESI):478.3(M+1)
(S)-4-(1-(3-(ジフルオロメチル)-5-(3-エチル-5-フルオロフェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-12)
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-12)
1-fluoro-3-methoxy-5-vinylbenzene(化合物I-12B)
1-ethyl-3-fluoro-5-methoxybenzene(化合物I-12C)
3-ethyl-5-fluorophenol(化合物I-12D)
methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-12E)
LC-MS,M/Z(ESI):476.2(M+1)。
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-5-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-12)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 8.10 (d, 1H), 7.74 (d, 2H), 7.16 (d, 2H), 7.11 (t, 1H), 6.93 (d, 1H), 6.72 (s, 1H), 6.69 (d, 1H), 4.92 (t, 1H), 3.73 (s, 3H), 2.58-2.54 (m, 2H), 1.25 (d, 3H), 1.13 (t, 3H).
LC-MS,M/Z(ESI):462.1(M+1)
4-((1S)-1-(3-(ジフルオロメチル)-5-(3-(1-フルオロエチル)フェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-13)
4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-13)
3-vinylphenol(化合物I-13B)
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-13C)
LC-MS,M/Z(ESI):456.2(M+1)。
methyl4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-13D)
LC-MS,M/Z(ESI):476.3(M+1)
4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-fluoroethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-13)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 8.03 (d, 1H), 7.72 (d, 2H), 7.45 (t, 1H), 7.25 (t, 1H), 7.11 (d, 2H), 6.98 (t, 1H), 6.94 (t, 1H), 5.78 (dd, 1H),4.89 (m, 1H), 3.73 (s, 3H), 3.60 (s, 1H), 1.55 (dd, 3H), 1.24 (d, 3H).
LC-MS,M/Z(ESI):462.3(M+1)
(S)-4-(1-(5-(3-(2,2-ジフルオロエチル)フェノキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-14)
(S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-14)
methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-formylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-14B)
LC-MS,M/Z(ESI):458.3[M+H]+。
methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-(2,2-difluorovinyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-14C)
LC-MS,M/Z(ESI):492.4[M+H]+。
methyl(S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-14D)
LC-MS,M/Z(ESI):494.4[M+H]+。
(S)-4-(1-(5-(3-(2,2-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-14)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 7.95 (d, 1H), 7.74 (d, 2H), 7.39 (t, 1H), 7.25 (t, 1H), 7.16 (d, 2H), 7.13 (d, 1H), 7.04 (d, 1H), 6.91 (t, 1H), 6.34 (dt, 1H), 4.91 (t, 1H), 3.71 (s, 3H), 3.22 (q, 2H), 1.22 (d, 3H).
LC-MS,M/Z(ESI):480.4[M+H]+
4-((1S)-1-(3-(ジフルオロメチル)-1-メチル-5-(3-(1,1,1-トリフルオロプロパン-2-イル)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-15)
4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-15)
3-(1,1,1-trifluoropropan-2-yl)phenol(化合物I-15B)
3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carbaldehyde(化合物I-15C)
LC-MS,M/Z(ESI):349.2[M+H]+。
3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxylic acid(化合物I-15D)
LC-MS,M/Z(ESI):365.1[M+H]+。
methyl4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-15E)
LC-MS,M/Z(ESI):526.3[M+H]+。
4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(1,1,1-trifluoropropan-2-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-15)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 7.97 (dd, 1H), 7.73 (d, 2H), 7.43 (dd, 1H), 7.28 (d, 1H), 7.25 (t, 1H), 7.13 (d, 2H), 7.11 (d, 1H), 6.99 (t, 1H), 4.90 (t, 1H), 3.89-3.85 (m, 1H), 3.73 (s, 3H), 1.41 (d, 3H), 1.21 (t, 3H).
LC-MS,M/Z(ESI):512.3[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-5-(3-エチル-4,5-ジフルオロエチル)フェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-16)
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-16)
1-(benzyloxy)-2,3-difluoro-5-methoxybenzene(化合物I-16B)
2,3-difluoro-5-methoxyphenol(化合物I-16C)
2,3-difluoro-5-methoxyphenyl trifluoromethanesulfonate(化合物I-16D)
1,2-difluoro-5-methoxy-3-vinylbenzene(化合物I-16E)
1-ethyl-2,3-difluoro-5-methoxybenzene(化合物I-16F)
3-ethyl-4,5-difluorophenol(化合物I-16G)
methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-16H)
LC-MS,M/Z(ESI):494.4[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4,5-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-16)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 8.15 (d, 1H), 7.76 (d, 2H), 7.24 (t, 1H), 7.18 (d, 2H), 7.01 (t, 1H), 6.80 (d, 1H), 4.94 (t, 1H), 3.74 (s, 3H), 2.62 (q, 2H), 1.27 (d, 3H), 1.11 (t, 3H).
LC-MS,M/Z(ESI):480.4[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-5-(3-エチル-4-メチルフェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-17)
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-17)
methyl(S)-4-(1-(5-(3-bromo-4-methylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-17B)
LC-MS,M/Z(ESI):522.3[M+H]+。
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-methyl-3-vinylphenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-17C)
LC-MS,M/Z(ESI):470.3[M+H]+。
methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-17D)
LC-MS,M/Z(ESI):472.3[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-methylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-17)
1HNMR (400m Hz, DMSO-d6) δ12.7 (s, 1H), 7.90 (d, 1H), 7.69 (d, 2H), 7.25 (t, 1H), 7.13 (d, 1H), 7.11 (d, 2H), 6.85 (d, 1H), 6.64 (dd, 1H), 4.93 (t, 1H), 3.71 (s, 3H), 2.55 (q, 2H), 2.23 (s, 3H), 1.24 (d, 3H), 1.07 (t, 3H).
LC-MS,M/Z(ESI):458.3[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-5-(4-エチルフェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-18)
(S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl) benzoic acid(化合物I-18)
methyl(S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-18B)
LC-MS,M/Z(ESI):458.3[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-5-(4-ethylphenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-18)
1HNMR (400mHz, DMSO-d6) δ12.7 (s, 1H), 7.95 (d, 1H), 7.71 (d, 2H), 7.24 (d, 2H), 7.21 (t, 1H), 7.11 (d, 2H), 6.92 (d, 2H), 4.91 (t, 1H), 3.72 (s, 3H), 2.62 (q, 2H), 1.24 (d, 3H), 1.19 (t, 3H).
LC-MS,M/Z(ESI):444.3[M+H]+
(S)-4-(1-(5-(4-(1,1-ジフルオロエチル)フェノキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-19)
(S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-19)
5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde(化合物I-19B)
LC-MS,M/Z(ESI):295.1[M+H]+。
5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid(化合物I-19C)
LC-MS,M/Z(ESI):311.1[M+H]+。
methyl(S)-4-(1-(5-(4-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-19D)
LC-MS,M/Z(ESI):472.2[M+H]+。
methyl(S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-19E)
LC-MS,M/Z(ESI):494.5[M+H]+。
(S)-4-(1-(5-(4-(1,1-difluoroethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-19)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 8.11 (d, 1H), 7.71 (d, 2H), 7.60 (d, 2H), 7.25 (t, 1H), 7.12 (d, 2H), 7.08 (d, 2H), 4.90 (t, 1H), 3.73 (s, 3H), 2.01 (t, 3H), 1.23 (d, 3H).
LC-MS,M/Z(ESI):480.5[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3,4,5-トリフルオロフェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-20)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-20)
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-20B)
LC-MS,M/Z(ESI):484.1[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3,4,5-trifluorophenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-20)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.24 (d, 1H), 7.78 (d, 2H), 7.24 (d, 2H), 7.22 (t, 1H), 7.09 (d, 1H), 7.02 (d, 1H), 4.96 (t, 1H), 3.73 (s, 3H), 1.30 (d, 3H).
LC-MS,M/Z(ESI):470.1[M+H]+
(S)-4-(1-(5-(3-アセチル-4-フルオロフェノキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-21)
(S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-21)
methyl(S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-21B)
LC-MS,M/Z(ESI):490.2[M+H]+
(S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-21)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.18 (d, 1H), 7.72 (d, 2H), 7.38-7.32 (m, 2H), 7.29-7.24 (m, 1H), 7.26 (t, 1H), 7.16 (d, 2H), 4.91 (t, 1H), 3.73 (s, 3H), 2.54 (d,3H), 1.24 (d, 3H).
LC-MS,M/Z(ESI):476.1[M+H]+
4-((1S)-1-(3-(ジフルオロメチル)-5-(3-(1-ヒドロキシエチル)フェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-22)
4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-22)
methyl(S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-22B)
LC-MS,M/Z(ESI):472.3[M+H]+
(S)-4-(1-(5-(3-acetylphenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-22C)
LC-MS,M/Z(ESI):458.3[M+H]+。
4-((1S)-1-(3-(difluoromethyl)-5-(3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-22)
LC-MS,M/Z(ESI):460.3[M+H]+。
1HNMR (400mHz, DMSO-d6) δ12.7 (s, 1H), 7.92 (d, 1H), 7.73 (d, 2H), 7.36 (t, 1H), 7.26 (t, 1H), 7.18 (d, 1H), 7.13 (d, 2H), 7.11 (t, 1H), 6.83 (dd, 1H), 5.26 (d, 1H), 4.92 (t, 1H), 4.71 (s, 1H), 3.72 (s, 3H), 1.28 (dd, 3H), 1.22 (d, 3H).
LC-MS,M/Z(ESI):478.1[M+H]+
4-((1S)-1-(3-(ジフルオロメチル)-5-(4-フルオロ-3-(1-ヒドロキシエチル)フェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-23)
4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-23)
methyl(S)-4-(1-(5-(3-acetyl-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-23B)
LC-MS,M/Z(ESI):490.2[M+H]+
methyl4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-23C)
LC-MS,M/Z(ESI):492.1[M+H]+。
4-((1S)-1-(3-(difluoromethyl)-5-(4-fluoro-3-(1-hydroxyethyl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-23)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.02 (d, 1H), 7.74 (d, 2H), 7.25 (t, 1H), 7.21-7.10 (m, 4H), 6.90-6.81 (m, 1H), 4.96-4.86 (m, 2H), 3.72 (s, 3H), 3.67 (s,1H), 1.28 (d, 3H), 1.24 (d, 3H).
LC-MS,M/Z(ESI):478.1[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-5-(4-フルオロ-3-(2-ヒドロキシプロパン-2-イル)フェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-24)
(S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropan-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-24)
4-fluoro-3-(2-hydroxypropan-2-yl)phenol(化合物I-24B)
methyl(S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropan-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-24C)
LC-MS,M/Z(ESI):506.3[M+1]+。
(S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(2-hydroxypropan-2-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-24)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 7.96 (d, 1H), 7.73 (d, 2H), 7.33 (t, 1H), 7.26 (t, 1H), 7.17 (d, 2H), 7.14 (t, 1H), 6.85 (t, 1H), 4.92 (t, 1H), 3.73 (s, 3H), 3.72 (s, 1H), 1.44 (s, 6H), 1.25 (d, 3H).
LC-MS,M/Z(ESI):492.3[M+1]+
(S)-4-(1-(5-(3-(シアノメチル)フェノキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-25)
(S)-4-(1-(5-(3-(cyanomethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-25)
(S)-4-(1-(5-(3-(cyanomethyl)phenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-25)
1HNMR (400mHz, CDCl3) δ12.7 (s, 1H), 7.93 (d, 2H), 7.38 (t, 1H), 7.25 (t, 1H), 7.19 (d, 1H), 7.16 (d, 2H), 6.94 (s, 1H), 6.82 (t, 1H), 6.35 (d, 1H), 5.18 (t, 1H), 3.73 (s, 2H), 3.70 (s, 3H), 1.41 (d, 3H).
LC-MS,M/Z(ESI):455.5[M+H]+
(S)-4-(1-(5-([1,1’-ジフェニル]-4-イルオキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-26)
(S)-4-(1-(5-([1,1’-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-26)
methyl(S)-4-(1-(5-([1,1’-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-26B)
LC-MS,M/Z(ESI):506.4[M+H]+
(S)-4-(1-(5-([1,1’-biphenyl]-4-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-26)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.08 (d, 1H), 7.71 (d, 2H), 7.69 (d, 2H), 7.63 (d, 2H), 7.48 (t, 2H), 7.38 (t, 1H), 7.26 (t, 1H), 7.15 (d, 2H), 7.12 (d, 2H), 4.92 (t, 1H), 3.76 (s, 3H), 1.25 (d, 3H).
LC-MS,M/Z(ESI):492.4[M+H]+
(S)-4-(1-(5-([1,1’-ジフェニル]-3-イルオキシ)-3-(ジフルオロメチル)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-27)
(S)-4-(1-(5-([1,1’-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-27)
methyl(S)-4-(1-(5-([1,1’-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-27B)
LC-MS,M/Z(ESI):506.4[M+H]+
(S)-4-(1-(5-([1,1’-biphenyl]-3-yloxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-27)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.07 (d, 1H), 7.68 (d, 2H), 7.62 (d, 2H), 7.50-7.44 (m, 4H), 7.41 (d, 1H), 7.31 (s, 1H), 7.25-6.96 (m, 4H), 4.89 (t, 1H), 3.77 (s, 3H), 1.19 (d, 3H).
LC-MS,M/Z(ESI):492.4[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-(ペンタフルオロ-λ6-スルファニル)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-28)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ6-sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-28)
3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ6-sulfanyl)phenoxy)-1H-pyrazole-4-carbaldehyde(化合物I-28B)
LC-MS,M/Z(ESI):379.1[M+H]+。
3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ6-sulfanyl)phenoxy)-1H-pyrazole-4-carboxylic acid(化合物I-28C)
LC-MS,M/Z(ESI):395.1[M+H]+。
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ6-sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-28D)
LC-MS,M/Z(ESI):556.1[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(pentafluoro-λ6-sulfanyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-28)
1HNMR (400m Hz, DMSO-d6) δ12.7 (s, 1H), 8.18 (d, 1H), 7.74 (d, 2H), 7.73 (d, 1H), 7.71 (d, 1H), 7.65 (t, 1H), 7.26 (d, 1H), 7.23 (t, 1H), 7.21 (d, 2H), 4.89 (t, 1H), 3.78 (s, 3H), 1.11 (d, 3H).
LC-MS,M/Z(ESI):542.1[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-((トリフルオロメチル)チオ)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-29)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-29)
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-29B)
LC-MS,M/Z(ESI):530.2[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-((trifluoromethyl)thio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-29)
1HNMR (400 mHz, DMSO-d6) δ12.8 (s, 1H), 8.16 (d, 1H), 7.74 (d, 2H), 7.57 (t, 2H), 7.39 (s, 1H), 7.22-6.69 (m, 4H), 4.91-4.84 (m, 1H), 3.74 (s, 3H), 1.21 (d, 3H).
LC-MS,M/Z(ESI):516.2[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-(メチルチオ)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-30)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-30)
3-(methylthio)phenol(化合物I-30B)
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-30C)
LC-MS,M/Z(ESI):476.5[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylthio)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-30)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.03 (d, 1H), 7.74 (d, 2H), 7.34 (t, 2H), 7.14 (d, 2H), 7.11 (t, 1H), 6.97 (t, 1H), 6.70 (d, 1H), 4.91 (t, 1H), 3.73 (s, 3H), 2.45 (s, 3H), 1.24 (d, 3H).
LC-MS,M/Z(ESI):462.5[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-(メチルスルホニル)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-31)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(methylsulfonyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-31)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.21 (d, 1H), 7.77 (d, 2H), 7.75 (d, 1H), 7.70 (t, 1H), 7.59 (t, 1H),7.37 (d, 1H), 7.25 (t, 1H), 7.15 (d, 2H), 4.87 (t, 1H), 3.77 (s, 3H), 3.19 (s, 3H), 1.19 (d, 3H).
LC-MS,M/Z(ESI):494.1[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-(メチルスルフィニル)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-32)
4-((1S)-1-(3-(difluoromethyl)-1-methyl-5-(3-(methylsulfinyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-32)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.15 (d, 1H), 7.73 (d, 2H), 7.61 (d, 1H), 7.50 (t, 1H), 7.36 (s, 1H), 7.25 (t, 1H), 7.15 (d, 1H), 7.13 (d, 2H), 4.87 (t, 1H), 3.75 (s, 3H), 2.69 (s, 3H), 1.20 (d, 3H).
LC-MS,M/Z(ESI):478.2[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-(2,2,2-トリフルオロエトキシ)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-33)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-33)
1-(benzyloxy)-3-(2,2,2-trifluoroethoxy)benzene(化合物I-33B)
3-(2,2,2-trifluoroethoxy)phenol(化合物I-33C)
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-33D)
LC-MS,M/Z(ESI):528.2[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(2,2,2-trifluoroethoxy)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-33)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.02 (d, 1H), 7.74 (d, 2H), 7.38 (t, 1H), 7.16 (t, 1H), 7.14 (d, 2H), 6.93 (d, 1H), 6.76 (t, 1H), 6.65 (d, 1H), 4.92 (t, 1H), 4.78 (dd, 2H), 3.72 (s, 3H), 1.25 (d, 3H).
LC-MS,M/Z(ESI):514.2[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-5-(2,4-ジフルオロフェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-34)
(S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-34)
methyl(S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-34B)
LC-MS,M/Z(ESI):466.1[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-5-(2,4-difluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-34)
1HNMR (400mHz, DMSO-d6) δ12.7 (s, 1H), 8.28 (d, 1H), 7.78 (d, 2H), 7.45 (t, 1H), 7.21 (d, 2H), 7.17 (t, 1H), 7.04 (d, 1H), 7.02 (d, 1H), 4.88 (t, 1H), 3.76 (s, 3H), 1.26 (d, 3H).
LC-MS, M/Z(ESI):452.1[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-((3-(トリフルオロメチル)フェニル)チオ)-1H-ピラゾール-4-カルボキサミド)エチル)ベンゾエート(化合物I-35)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-35)
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-35B)
LC-MS,M/Z(ESI):514.2(M+1)。
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((3-(trifluoromethyl)phenyl)thio)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-35)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 8.68 (d, 1H), 7.79 (d, 2H), 7.63 (d, 1H), 7.58 (t, 2H), 7.39 (d, 2H), 7.27 (t, 1H), 7.14 (t, 1H), 5.10-5.03 (m, 1H), 3.89 (s, 3H), 1.38 (d, 3H).
LC-MS,M/Z(ESI):500.2(M+1)
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(4-(トリフルオロメチル)ベンジル)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-36)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-36)
(4-(trifluoromethyl)benzyl)zinc(II) bromide(化合物I-36B)
methyl (S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-36C)
LC-MS,M/Z(ESI):496.3[M+1]+。
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-36)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.47 (d, 1H), 7.86 (d, 2H), 7.62 (d, 2H), 7.41 (d, 2H), 7.33 (d, 2H), 7.23 (t, 1H), 5.12 (t, 1H),4.37 (dd, 2H), 3.77 (s, 3H), 1.41 (s, 3H).
LC-MS,M/Z(ESI):482.3[M+1]+
(S)-5-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-(トリフルオロメチル)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)チオフェン-2-カルボン酸(化合物I-37)
(S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylic acid(化合物I-37)
(R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide(化合物I-37B)
(R)-N-((S)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide(化合物I-37C)
LC-MS,M/Z(ESI):310.2[M+H]+。
(S)-1-(5-bromothiophen-2-yl)ethan-1-amine hydrochloride(化合物I-37D)
(S)-N-(1-(5-bromothiophen-2-yl)ethyl)-3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamide(化合物I-37E)
LC-MS,M/Z(ESI):524.2[M+H]+。
methyl(S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylate(化合物I-37F)
LC-MS,M/Z(ESI):504.5[M+H]+。
(S)-5-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)thiophene-2-carboxylic acid(化合物I-37)
1HNMR (400mHz, DMSO-d6) δ12.7 (s, 1H), 8.32 (d, 1H), 7.62 (t, 1H), 7.54 (t, 1H), 7.42 (d, 2H), 7.28 (t, 1H), 7.23 (t, 1H), 6.75 (d, 1H), 5.51-5.04 (m, 1H), 3.76 (s, 3H), 1.27 (d, 3H).
LC-MS,M/Z(ESI):490.5[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-(トリフルオロメチル)フェノキシ)-1H-ピラゾール-4-カルボキサミド)エチル)-2,6-ジフルオロ安息香酸(化合物I-38)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoic acid(化合物I-38)
tert-butyl (S)-(1-(3,5-difluorophenyl)ethyl)carbamate(化合物I-38B)
(S)-4-(1-((tert-butoxycarbonyl)amino)ethyl)-2,6-difluorobenzoic acid(化合物I-38C)
methyl(S)-4-(1-aminoethyl)-2,6-difluorobenzoate(化合物I-38D)
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoate(化合物I-38E)
LC-MS,M/Z(ESI):534.3[M+H]+。
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)-2,6-difluorobenzoic acid(化合物I-38)
1HNMR (400mHz, DMSO-d6) δ12.8 (s, 1H), 8.12 (d, 1H), 7.61 (t, 1H), 7.56 (t, 1H), 7.45 (s, 1H), 7.27 (t, 1H), 7.25 (t, 1H), 6.62 (d, 2H),4.76 (t, 1H), 3.76 (s, 3H), 1.13 (d, 3H).
LC-MS,M/Z(ESI):520.3[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-5-(3-エチル-4-フルオロフェノキシ)-1-メチル-1H-ピラゾール-4-カルボキサミド)エチル)-2-メチル安息香酸(化合物I-39)
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoic acid(化合物I-39)
methyl4-formyl-2-methylbenzoate(化合物I-39B)
methyl(S,E)-4-(((tert-butylsulfinyl)imino)methyl)-2-methylbenzoate(化合物I-39C)
methyl4-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-2-methylbenzoate(化合物I-39D)
methyl(S)-4-(1-aminoethyl)-2-methylbenzoate(化合物I-39E)
methyl(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoate(化合物I-39F)
(S)-4-(1-(3-(difluoromethyl)-5-(3-ethyl-4-fluorophenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)-2-methylbenzoic acid(化合物I-39)
1HNMR (400 MHz, DMSO) δ 7.94 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 7.6, 6.4 Hz, 2H), 6.99 ? 6.94 (m, 2H), 6.89 (d, J = 8.2 Hz, 1H), 6.80 ? 6.75 (m, 1H), 4.84 ? 4.79 (m, 1H), 3.69 (s, 3H), 2.36 (s, 3H), 2.53 (dd, J = 14.8, 7.4 Hz, 2H) 1.19 (d, J = 7.0 Hz, 3H), 1.06 (t, J = 7.6 Hz, 3H).
LC-MS,M/Z(ESI):476.3[M+H]+。
4-(1-(3-(ジフルオロメチル)-1-メチル-5-(3-(トリフルオロメチル)フェノキシ)-1H-ピラゾール-4-カルボキサミド)シクロブチル)安息香酸(化合物I-40)
4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoic acid(化合物I-40)
N-cyclobutylidene-2-methylpropane-2-sulfinamide(化合物I-40B)
N-(1-(4-bromophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide(化合物I-40C)
LC-MS,M/Z(ESI):330.0[M+H]+。
methyl4-(1-((tert-butylsulfinyl)amino)cyclobutyl)benzoate(化合物I-40D)
methyl4-(1-aminocyclobutyl)benzoate(化合物I-40E)
LC-MS,M/Z(ESI):206.5[M+H]+。
methyl4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoate(化合物I-40F)
LC-MS,M/Z(ESI):524.5[M+H]+。
4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazole-4-carboxamido)cyclobutyl)benzoic acid(化合物I-40)
1HNMR (400mHz, DMSO-d6) δ12.7 (s, 1H), 8.52 (s, 1H), 7.74 (d, 2H), 7.68 (d, 1H), 7.62 (d, 1H), 7.50 (s, 1H), 7.34 (t, 1H), 7.25 (d, 2H), 7.18 (t, 1H), 3.78 (s, 3H), 2.33-2.28 (m, 2H), 2.16-2.13 (m, 2H), 1.70-1.65 (m, 1H), 1.59-1.54 (m, 1H).
LC-MS,M/Z(ESI):510.5[M+H]+
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-((5-メチルチオフェン3-イル)オキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-41)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-methylthiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-41)
methyl3-((3-(difluoromethyl)-4-formyl-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate(化合物I-41B)
LC-MS,M/Z(ESI):331.4(M+1)。
3-(difluoromethyl)-5-((2-(methoxycarbonyl)-5-methylthiophen-3-yl)oxy)-1-methyl-1H-pyrazole-4-carboxylic acid(化合物I-41C)
LC-MS,M/Z(ESI):347.4(M+1)。
methyl(S)-3-((3-(difluoromethyl)-4-((1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylate(化合物I-41D)
LC-MS,M/Z(ESI):508.6(M+1)。
(S)-3-((4-((1-(4-carboxyphenyl)ethyl)carbamoyl)-3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)oxy)-5-methylthiophene-2-carboxylic acid(化合物I-41E)
LC-MS,M/Z(ESI):480.3(M+1)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-methylthiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-41)
1HNMR (400m Hz, CDCl3) δ12.8 (s, 1H), 7.99 (d, 2H), 7.20 (t, 1H), 7.20 (d, 2H), 6.51 (s, 1H), 6.39 (d, 1H), 6.20 (s, 1H), 5.22 (t, 1H), 3.75 (s, 3H), 2.45 (s, 3H), 1.43 (d, 3H)。
LC-MS,M/Z(ESI):436.1(M+1)
(S)-4-(1-(3-(ジフルオロメチル)-1-メチル-5-((3-(トリフルオロメチル)チオフェン3-イル)オキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-42)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-42)
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-42B)
LC-MS,M/Z(ESI):504.2(M+1)。
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-42)
1HNMR (400m Hz, DMSO-d6) δ12.8 (s, 1H), 8.20 (d, 1H), 7.79 (d, 2H), 7.67 (s, 1H), 7.25 (d, 2H), 7.23 (d, 1H), 7.09 (t, 1H), 4.99-4.92 (m, 1H), 3.77 (s, 3H), 1.29 (d, 3H).
LC-MS,M/Z(ESI):490.2(M+1)
(S)-4-(1-(1-メチル-3-(トリフルオロメチル)-5-((5-(トリフルオロメチル)チオフェン3-イル)オキシ)-1H-ピラゾール-4-カルボキサミド)エチル)安息香酸(化合物I-43)
(S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-43)
5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid(化合物I-43B)
LC-MS,M/Z(ESI):229.6(M+1)。
methyl(S)-4-(1-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-43C)
LC-MS,M/Z(ESI):390.5(M+1)。
methyl(S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(化合物I-43D)
LC-MS,M/Z(ESI):522.1(M+1)。
(S)-4-(1-(1-methyl-3-(trifluoromethyl)-5-((5-(trifluoromethyl)thiophen-3-yl)oxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-43)
LC-MS,M/Z(ESI):508.1(M+1)
テスト例1:EP4拮抗作用測定実験
対照化合物、実施例1-43で調製された化合物のEP4に対する拮抗作用をそれぞれテストするが、ヒトEP4受容体の高発現で安定的にトランスフェクトされた細胞株で測定される。
対照化合物、実施例1-43で調製された化合物のEP4カルシウムフラックスに対する阻害効果をそれぞれテストしたが、ヒトEP4受容体を過剰発現する293細胞で測定される。
抑制率(%)=100-(テスト組-EP4完全拮抗薬組)/(DMSO組-EP4完全拮抗薬組)*100
組換えヒトEP4受容体膜タンパク質(ヒトEP4受容体を過剰発現する293細胞から調製)を使用して、対照化合物、実施例1-43で調製された化合物の放射性リガンドEP4との結合作用をテストする。測定対象化合物とPGE2をDMSO溶媒の中で10mMのストック溶液として調製し、次に、バッファー(50mM HBSS,0.1% BSA,500mM NaCl)を使用して8濃度ポイントの4×作業溶液を段階希釈する。1μLの化合物の作業溶液、DMSO、PGE2作業溶液を測定プレートにそれぞれ加え、100μLのEP4受容体膜タンパク質(20μg/ウェル)と100μL放射性リガンド[3H]-PGE2(PerkinElmer,Cat:NET428250UC,Lot:2469552)(最終濃度1.5nM)を加え、密封し、室温で1時間インキュベートする。室温で、Unifilter-96GF/Cフィルタープレート(Perkin Elmer)を0.5%のBSA、50μL/ウェルに少なくとも30分浸す。結合が完了した後、Perkin Elmer Filtermate Harvesterを使用して反応混合物をGF/Cプレートでろ過して、次に、フィルタープレートを洗浄し、50℃でフィルタープレートを1時間乾燥する。乾燥後、Perkin Elmer Unifilter-96シーリングテープを使用してフィルタープレートウェルの底部を密封し、50μLのMicroScintTM-20 cocktail(Perkin Elmer)を加え、フィルタープレートの頂部を密封する。Perkin Elmer MicroBeta2 Readerを使用してフィルターでキャプチャされた3Hカウントを読み取る。
抑制率(%)=100-(テスト組-PGE2組)/(DMSO組-PGE2組)*100
本実験では、対照化合物、実施例1-43で調製された化合物の薬物動態パラメータをマウス、ラット及びイヌの個体でそれぞれテストする。
本実験では、CT-26マウス結腸癌腫瘍モデルにおける対照化合物、実施例1-43で調製された放射線療法を組み合わせた化合物の抗腫瘍作用をテストする。
腫瘍体積(tumor volume、TV)=1/2×a×b2、ここで、a、bはそれぞれ腫瘍の測定された長さと幅である。
相対腫瘍抑制率TGI(%)=(TWc-TWt/TWc)×100%、ここで、TWcは溶媒対照組の平均腫瘍重量であり、TWtは治療組の平均腫瘍重量である。
[付記1]
式Vで示される化合物または式Vで示される化合物の互変異性体、立体異性体、水和物、溶媒和物、塩またはプロドラッグである、化合物。
環Bは
R1は-CH3、-CHF2及び-CF3から選ばれ、
R2はC2-C6アルキル、C3-C6シクロアルキル、フェニル、トリフルオロメチル、ハロゲンで置換されたC2-C6アルキル、ハロゲンで置換されたC3-C6シクロアルキル、ヒドロキシで置換されたC2-C6アルキル、シアノで置換されたC2-C6アルキル、-SF5、-X-R2aから選ばれ、ただし、Xは酸素、硫黄、-CO-、-SO2-、-SO-から選ばれ、R2aはC1-C6アルキル、ハロゲンで置換されたC1-C6アルキルから選ばれ、
R3は水素、ハロゲン、C1-C2アルキル、フッ素で置換されたC1-C2アルキル、フェニルから選ばれ、
R4は水素、ハロゲン、C1-C6アルキル、C1-C6アルコキシ、ハロゲンで置換されたC1-C6アルキル、ハロゲンで置換されたC1-C6アルコキシから選ばれ、
R5は水素、ハロゲンから選ばれ、
R6aとR6bの一方は水素であり、他方はメチルであり、またはR6aとR6bは一緒にシクロブチル環を形成し、
R7は-CH3、-CHF2及び-CF3から選ばれ、
Mは酸素、硫黄、メチレンから選ばれ、
R2はトリフルオロメチルであり、Mは酸素であり、R6aとR6bの一方は水素であり、他方はメチルである場合、環Aは
R2はトリフルオロメチルであり、Mは酸素であり、環Aは
式IIIで示される化合物または式IIIで示される化合物の互変異性体、立体異性体、水和物、溶媒和物、塩またはプロドラッグである、付記1に記載の化合物。
(ただし、R1は-CH3、-CHF2及び-CF3から選ばれ、
R7は-CH3、-CHF2及び-CF3から選ばれ、
Mは酸素、硫黄、メチレンから選ばれる。)
式IIで示される化合物または式IIで示される化合物の互変異性体、立体異性体、水和物、溶媒和物、塩またはプロドラッグである、付記1に記載の化合物。
R2はエチル、プロピル、イソプロピル、n-ブチル、イソブチル、tert-ブチル、フルオロエチル、フルオロプロピル、フルオロイソプロピル、フルオロブチル、フルオロイソブチル、ヒドロキシエチル、ヒドロキシイソプロピル、シアノメチル、シアノエチル、フェニル、-SF5、-X-R2aから選ばれ、ただし、Xは酸素、硫黄、-CO-から選ばれ、R2aはメチル、エチル、フルオロメチル、フルオロエチルから選ばれ、
R3は水素、フッ素、塩素、メチル、エチル、フルオロメチル、フルオロエチル、フェニルから選ばれ、
R4は水素、フッ素、塩素、メチル、エチル、フルオロメチル、フルオロエチルから選ばれ、
R5は水素、フッ素、塩素から選ばれ、
Mは酸素、硫黄、メチレンから選ばれる。)
化合物であって、前記化合物は、式Iで示される化合物または式Iで示される化合物の互変異性体、立体異性体、水和物、溶媒和物、塩またはプロドラッグである、化合物。
(ただし、R1は-CH3、-CHF2及び-CF3から選ばれ、
R2はC2-C6アルキル、C3-C6シクロアルキル、ハロゲンで置換されたC2-C6アルキル、ハロゲンで置換されたC3-C6シクロアルキルから選ばれ、
R3は水素、ハロゲン、C1-C2アルキル、フッ素で置換されたC1-C2アルキルから選ばれ、
R4は水素、ハロゲン、C1-C6アルキル、C1-C6アルコキシ、ハロゲンで置換されたC1-C6アルキル、ハロゲンで置換されたC1-C6アルコキシから選ばれる。)
R2はC2-C3アルキル、C3-C6シクロアルキル、フッ素で置換されたC2-C3アルキル、フッ素で置換されたC3-C6シクロアルキルから選ばれ、好ましくは、R2は-CH2CH3、-CH(CH3)2、シクロプロピル、-CF2CH3及び-CH2CF3から選ばれ、
R3は水素、フッ素、及び塩素から選ばれ、
R4は水素、フッ素、塩素、C1-C4アルキル、C1-C4アルコキシ、フッ素または塩素で置換されたC1-C4アルキル、フッ素または塩素で置換されたC1-C4アルコキシから選ばれ、好ましくは、R4は水素、フッ素、塩素から選ばれる、付記4に記載の化合物。
薬学的に許容できる賦形剤及び付記1~6のいずれかに記載の化合物を含むことを特徴とする医薬組成物。
EP4関連疾患を治療または予防するための薬物の調製における付記1~6のいずれかに記載の化合物または付記7に記載の医薬組成物の使用。
炎症性疾患、疼痛、癌症、代謝性疾患、泌尿器系疾患から選ばれる少なくとも1つを治療または予防するための薬物の調製における付記1~6のいずれかに記載の化合物または付記7に記載の医薬組成物の使用。
前記炎症性疾患は関節炎、関節リウマチから選ばれる付記9に記載の使用。
前記疼痛は変形性関節症疼痛、子宮内膜症による疼痛から選ばれる付記9に記載の使用。
前記薬物は放射線療法および/または抗体療法と組み合わせて投与され、前記抗体療法はCTLA4抗体療法、PDL1抗体療法及びPD1抗体療法の1つまたはそれらの組み合わせから選ばれる付記9に記載の使用。
前記癌症は固形癌から選ばれ、好ましくは、乳腺癌、子宮頸癌、結腸直腸癌、子宮内膜癌、神経膠芽細胞腫、頭頸癌、腎臓癌、肝臓癌、肺癌、髄芽細胞腫、卵巣癌、膵臓癌、前立腺癌、皮膚癌及び尿路癌から選ばれる付記9に記載の使用。
前記代謝性疾患は糖尿病であり、前記泌尿器系疾患は過活動膀胱から選ばれる付記9に記載の使用。
EP4関連疾患を治療または予防するための方法であって、患者に付記1~6のいずれかに記載の化合物または付記7に記載の医薬組成物を投与することを含むことを特徴とする方法。
疾患を治療するための方法であって、患者に付記1~6のいずれかに記載の化合物または付記7に記載の医薬組成物を投与することを含み、前記疾患は炎症性疾患、疼痛、癌症、代謝性疾患、泌尿器系疾患から選ばれることを特徴とする方法。
前記炎症性疾患は関節炎、関節リウマチから選ばれる、付記16に記載の方法。
前記疼痛は変形性関節症疼痛、子宮内膜症による疼痛から選ばれる、付記16に記載の方法。
前記癌症は固形癌から選ばれ、好ましくは、乳腺癌、子宮頸癌、結腸直腸癌、子宮内膜癌、神経膠芽細胞腫、頭頸癌、腎臓癌、肝臓癌、肺癌、髄芽細胞腫、卵巣癌、膵臓癌、前立腺癌、皮膚癌及び尿路癌から選ばれる、付記16に記載の方法。
前記化合物または医薬組成物を放射線療法および/または抗体療法と組み合わせて投与し、前記抗体療法はCTLA4抗体療法、PDL1抗体療法及びPD1抗体療法の1つまたはそれらの組み合わせから選ばれる、付記16に記載の方法。
前記代謝性疾患は糖尿病であり、前記泌尿器系疾患は過活動膀胱から選ばれる、付記16に記載の方法。
Claims (21)
- 式Vで示される化合物または式Vで示される化合物の互変異性体、立体異性体、水和物、溶媒和物、塩またはプロドラッグである、化合物。
環Bは
R1は-CH3、-CHF2及び-CF3から選ばれ、
R2はC2-C6アルキル、C3-C6シクロアルキル、フェニル、トリフルオロメチル、ハロゲンで置換されたC2-C6アルキル、ハロゲンで置換されたC3-C6シクロアルキル、ヒドロキシで置換されたC2-C6アルキル、シアノで置換されたC2-C6アルキル、-SF5、-X-R2aから選ばれ、ただし、Xは酸素、硫黄、-CO-、-SO2-、-SO-から選ばれ、R2aはC1-C6アルキル、ハロゲンで置換されたC1-C6アルキルから選ばれ、
R3は水素、ハロゲン、C1-C2アルキル、フッ素で置換されたC1-C2アルキル、フェニルから選ばれ、
R4は水素、ハロゲン、C1-C6アルキル、C1-C6アルコキシ、ハロゲンで置換されたC1-C6アルキル、ハロゲンで置換されたC1-C6アルコキシから選ばれ、
R5は水素、ハロゲンから選ばれ、
R6aとR6bの一方は水素であり、他方はメチルであり、またはR6aとR6bは一緒にシクロブチル環を形成し、
R7は-CH3、-CHF2及び-CF3から選ばれ、
Mは酸素、硫黄、メチレンから選ばれ、
R2はトリフルオロメチルであり、Mは酸素であり、R6aとR6bの一方は水素であり、他方はメチルである場合、環Aは
R2はトリフルオロメチルであり、Mは酸素であり、環Aは
- 式IIで示される化合物または式IIで示される化合物の互変異性体、立体異性体、水和物、溶媒和物、塩またはプロドラッグである、請求項1に記載の化合物。
R2はエチル、プロピル、イソプロピル、n-ブチル、イソブチル、tert-ブチル、フルオロエチル、フルオロプロピル、フルオロイソプロピル、フルオロブチル、フルオロイソブチル、ヒドロキシエチル、ヒドロキシイソプロピル、シアノメチル、シアノエチル、フェニル、-SF5、-X-R2aから選ばれ、ただし、Xは酸素、硫黄、-CO-から選ばれ、R2aはメチル、エチル、フルオロメチル、フルオロエチルから選ばれ、
R3は水素、フッ素、塩素、メチル、エチル、フルオロメチル、フルオロエチル、フェニルから選ばれ、
R4は水素、フッ素、塩素、メチル、エチル、フルオロメチル、フルオロエチルから選ばれ、
R5は水素、フッ素、塩素から選ばれ、
Mは酸素、硫黄、メチレンから選ばれる。) - 化合物であって、前記化合物は、式Iで示される化合物または式Iで示される化合物の互変異性体、立体異性体、水和物、溶媒和物、塩またはプロドラッグである、化合物。
(ただし、R1は-CH3、-CHF2及び-CF3から選ばれ、
R2はC2-C6アルキル、C3-C6シクロアルキル、ハロゲンで置換されたC2-C6アルキル、ハロゲンで置換されたC3-C6シクロアルキルから選ばれ、
R3は水素、ハロゲン、C1-C2アルキル、フッ素で置換されたC1-C2アルキルから選ばれ、
R4は水素、ハロゲン、C1-C6アルキル、C1-C6アルコキシ、ハロゲンで置換されたC1-C6アルキル、ハロゲンで置換されたC1-C6アルコキシから選ばれる。) - R2はC2-C3アルキル、C3-C6シクロアルキル、フッ素で置換されたC2-C3アルキル、フッ素で置換されたC3-C6シクロアルキルから選ばれ、好ましくは、R2は-CH2CH3、-CH(CH3)2、シクロプロピル、-CF2CH3及び-CH2CF3から選ばれ、
R3は水素、フッ素、及び塩素から選ばれ、
R4は水素、フッ素、塩素、C1-C4アルキル、C1-C4アルコキシ、フッ素または塩素で置換されたC1-C4アルキル、フッ素または塩素で置換されたC1-C4アルコキシから選ばれ、好ましくは、R4は水素、フッ素、塩素から選ばれる、請求項4に記載の化合物。 - 薬学的に許容できる賦形剤及び請求項1~6のいずれかに記載の化合物を含むことを特徴とする医薬組成物。
- EP4関連疾患を治療または予防するための薬物の調製における請求項1~6のいずれかに記載の化合物または請求項7に記載の医薬組成物の使用。
- 炎症性疾患、疼痛、癌症、代謝性疾患、泌尿器系疾患から選ばれる少なくとも1つを治療または予防するための薬物の調製における請求項1~6のいずれかに記載の化合物または請求項7に記載の医薬組成物の使用。
- 前記炎症性疾患は関節炎、関節リウマチから選ばれる請求項9に記載の使用。
- 前記疼痛は変形性関節症疼痛、子宮内膜症による疼痛から選ばれる請求項9に記載の使用。
- 前記薬物は放射線療法および/または抗体療法と組み合わせて投与され、前記抗体療法はCTLA4抗体療法、PDL1抗体療法及びPD1抗体療法の1つまたはそれらの組み合わせから選ばれる請求項9に記載の使用。
- 前記癌症は固形癌から選ばれ、好ましくは、乳腺癌、子宮頸癌、結腸直腸癌、子宮内膜癌、神経膠芽細胞腫、頭頸癌、腎臓癌、肝臓癌、肺癌、髄芽細胞腫、卵巣癌、膵臓癌、前立腺癌、皮膚癌及び尿路癌から選ばれる請求項9に記載の使用。
- 前記代謝性疾患は糖尿病であり、前記泌尿器系疾患は過活動膀胱から選ばれる請求項9に記載の使用。
- EP4関連疾患を治療または予防するための方法であって、患者に請求項1~6のいずれかに記載の化合物または請求項7に記載の医薬組成物を投与することを含むことを特徴とする方法。
- 疾患を治療するための方法であって、患者に請求項1~6のいずれかに記載の化合物または請求項7に記載の医薬組成物を投与することを含み、前記疾患は炎症性疾患、疼痛、癌症、代謝性疾患、泌尿器系疾患から選ばれることを特徴とする方法。
- 前記炎症性疾患は関節炎、関節リウマチから選ばれる、請求項16に記載の方法。
- 前記疼痛は変形性関節症疼痛、子宮内膜症による疼痛から選ばれる、請求項16に記載の方法。
- 前記癌症は固形癌から選ばれ、好ましくは、乳腺癌、子宮頸癌、結腸直腸癌、子宮内膜癌、神経膠芽細胞腫、頭頸癌、腎臓癌、肝臓癌、肺癌、髄芽細胞腫、卵巣癌、膵臓癌、前立腺癌、皮膚癌及び尿路癌から選ばれる、請求項16に記載の方法。
- 前記化合物または医薬組成物を放射線療法および/または抗体療法と組み合わせて投与し、前記抗体療法はCTLA4抗体療法、PDL1抗体療法及びPD1抗体療法の1つまたはそれらの組み合わせから選ばれる、請求項16に記載の方法。
- 前記代謝性疾患は糖尿病であり、前記泌尿器系疾患は過活動膀胱から選ばれる、請求項16に記載の方法。
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