JP2016534135A - ピロロピリダジン誘導体を含むタンパク質キナーゼ阻害剤 - Google Patents
ピロロピリダジン誘導体を含むタンパク質キナーゼ阻害剤 Download PDFInfo
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- JP2016534135A JP2016534135A JP2016540797A JP2016540797A JP2016534135A JP 2016534135 A JP2016534135 A JP 2016534135A JP 2016540797 A JP2016540797 A JP 2016540797A JP 2016540797 A JP2016540797 A JP 2016540797A JP 2016534135 A JP2016534135 A JP 2016534135A
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- Prior art keywords
- fluorophenyl
- phenyl
- pyridazin
- oxy
- pyrrolo
- Prior art date
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- YTJAMOLQXDNLJC-UHFFFAOYSA-N N1N=CC=C2N=CC=C21 Chemical class N1N=CC=C2N=CC=C21 YTJAMOLQXDNLJC-UHFFFAOYSA-N 0.000 title abstract description 4
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
- 239000003909 protein kinase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 230000000694 effects Effects 0.000 claims abstract description 15
- 102000001253 Protein Kinase Human genes 0.000 claims abstract description 14
- 108060006633 protein kinase Proteins 0.000 claims abstract description 14
- -1 nitro, cyano, amino Chemical group 0.000 claims description 114
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 34
- FEHLGOYZDFFMND-UHFFFAOYSA-N cyclopropane-1,1-dicarboxamide Chemical compound NC(=O)C1(C(N)=O)CC1 FEHLGOYZDFFMND-UHFFFAOYSA-N 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 16
- ZXNZHVDQMZJUKH-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound O=C1C(C(=O)N)=CC=CN1C1=CC=C(F)C=C1 ZXNZHVDQMZJUKH-UHFFFAOYSA-N 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- IRTLROCMFSDSNF-UHFFFAOYSA-N 2-phenyl-1h-pyrrole Chemical compound C1=CNC(C=2C=CC=CC=2)=C1 IRTLROCMFSDSNF-UHFFFAOYSA-N 0.000 claims description 3
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- BUUWDMLKCDTDLC-UHFFFAOYSA-N CN(C)Cc1cc(F)cc(c1)-c1ccn2nccc(Oc3ccc(NC(=O)C4(CC4)C(=O)Nc4ccc(F)cc4)cc3F)c12 Chemical compound CN(C)Cc1cc(F)cc(c1)-c1ccn2nccc(Oc3ccc(NC(=O)C4(CC4)C(=O)Nc4ccc(F)cc4)cc3F)c12 BUUWDMLKCDTDLC-UHFFFAOYSA-N 0.000 claims description 3
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- WJLMIWRWZVNPHR-UHFFFAOYSA-N N-[3-fluoro-4-[5-(2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]oxyphenyl]-1-(4-fluorophenyl)-2-oxopyridine-3-carboxamide Chemical compound FC=1C=C(C=CC=1OC=1C=2N(N=CC=1)C=CC=2C1=CC(=NC=C1)OC)NC(=O)C=1C(N(C=CC=1)C1=CC=C(C=C1)F)=O WJLMIWRWZVNPHR-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052799 carbon Inorganic materials 0.000 claims description 3
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- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims description 3
- PQKICWZZTXIBMT-UHFFFAOYSA-N 1-N'-[4-[5-(5-amino-2-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yl]oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound Nc1ccc(F)c(c1)-c1ccn2nccc(Oc3ccc(NC(=O)C4(CC4)C(=O)Nc4ccc(F)cc4)cc3F)c12 PQKICWZZTXIBMT-UHFFFAOYSA-N 0.000 claims description 2
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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Abstract
Description
受容体であり、肝臓から分泌され、大食細胞の作用を調節する血清タンパク質であるMSP(macrophage-stimulating protein)の受容体である(非特許文献2)。RONの発現は、乳癌および大腸直腸癌において異常に調節され、特に大腸直腸癌の転移と密接に関連している。例えば、RONに結合するモノクローナル抗体IMC−41A10が細胞転移と腫瘍形成を阻害することが報告されることにより、RON阻害剤が抗癌および癌転移に優れた効能を示すことができるだろう。
R1は、水素、またはハロゲンであり;
R2は、インドリル、フェニル、ピラジニル、ピラゾリル、ピリジニル、ピリミジニル、チアゾリルおよびチエニルからなる群から選択されるアリールまたはヘテロアリールであり、
前記アリールまたはヘテロアリールは、非置換されたり、または、
Ri はヒドロキシ、O−CH2CH2−O−CH3、OCO−NH2、モルホリノ、アミノ、NH(C1−4アルキル)およびN(C1−4アルキル)2からなる群から選択され;
Rii はヒドロキシ、またはC1−4アルコキシであり;
Riii は、ヒドロキシであり;
R3は、
Raは、水素、またはC1−4アルコキシであり;
Rbは、水素、またはハロゲンであり;
Rcは、水素、またはC1−4アルキルである。
前記フェニルは、非置換されたり、または、
Ri はヒドロキシ、O−CH2CH2−O−CH3、OCO−NH2、モルホリノ、アミノ、NH(C1−4アルキル)およびN(C1−4アルキル)2からなる群から選択され、
Rii は、ヒドロキシ、またはC1−4アルコキシであり、
Riii は、ヒドロキシである。
前記ピリジニルは、非置換されたり、または、
Rii は、ヒドロキシである。
前記ピラゾリルは、非置換されたり、または、C1−4アルキル、SO2−(C1−4アルキル)またはピペリジニルで置換される。
前記インドリル、ピラジニル、ピリミジニル、チアゾリルまたはチエニルは非置換される。
1)4−エトキシ−N−(3−フルオロ−4−((5−(3−(ヒドロキシメチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
2)4−エトキシ−N−(3−フルオロ−4−((5−フェニルピロール[1,2−b]ピリダジン−4−イル)−オキシ)フェニル)−1−(4−フルオロフェニル)2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
3)4−エトキシ−N−(3−フルオロ−4−((5−(ピリジン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
4)4−エトキシ−N−(3−フルオロ−4−((5−チアゾール−2−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
5)4−エトキシ−N−(2−フルオロ−4−((ピラジン−2−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
6)4−エトキシ−N−(2−フルオロ−4−((5−(1−メチル−1H−ピラゾール−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
7)4−エトキシ−N−(3−フルオロ−4−((5−ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
8)4−エトキシ−N−(3−フルオロ−4−((5−(ピリミジン−5−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
9)4−エトキシ−N−(3−フルオロ−4−((5−(6−メトキシピリジン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
10)4−エトキシ−N−(3−フルオロ−4−((5−(チオフェン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
11)4−エトキシ−N−(3−フルオロ−4−((5−(4−メトキシフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
12)4−エトキシ−N−(3−フルオロ−4−((5−(2−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
13)N−(4−((5−(3,4−ジメトキシフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
14)4−エトキシ−N−(3−フルオロ−4−((5−(4−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
15)4−エトキシ−N−(3−フルオロ−4−((5−(チオフェン−2−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
16)N−(4−((5−(2−クロロピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
17)N−(4−((5−(1H−ピラゾール−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
18)4−エトキシ−N−(3−フルオロ−4−((5−(1−メチルスルホニル)−1H−ピラゾール−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
19)4−エトキシ−N−(3−フルオロ−4−((5−(2−フルオロピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
20)N−(4−((5−(5−クロロ−2−メトキシピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
21)N−(4−((5−(6−アミノピリジン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
22)4−エトキシ−N−(3−フルオロ−4−((5−(1−ピペリジン−4−イル)−1H−ピラゾール−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
23)4−エトキシ−N−(3−フルオロ−4−((5−(3−ホルミルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
24)4−エトキシ−N−(3−フルオロ−4−((5−(2−(ピペラジン−1−イル)ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
25)N−(4−((5−(6−アセトアミドピリジン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
26)N−(4−((5−(2−アセチルピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
27)N−(4−((5−(3−アセチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
28)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−4−メトキシ−2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−カルボキサミド、
29)N−(3−フルオロ−4−((5−(3−ヒドロキシメチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
30)4−エトキシ−N−(4−((5−(3−(エチルスルホニル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
31)4−エトキシ−N−(3−フルオロ−4−((5−(3−(メチルスルホニル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
32)4−エトキシ−N−(3−フルオロ−4−((5−(3−スルファモイルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
33)N−(4−((5−(3−アセチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
34)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−4−メトキシ−2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−カルボキサミド、
35)N−(4−((5−(3−(N,N−ジメチルスルファモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
36)N−(4−((5−(3−(N,N−ジメチルスルファモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
37)4−エトキシ−N−(3−フルオロ−4−((5−(4−ニトロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
38)N−(4−((5−(4−アミノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
39)4−エトキシ−N−(3−フルオロ−4−((5−(3−((2−メトキシエトキシ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
40)N−(3−フルオロ−4−((5−(2−メトキシピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
41)N−(4−((5−(3−(ジメチルカルバモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
42)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキシアミド、
43)4−エトキシ−N−(3−フルオロ−4−((5−(3−(2−ヒドロキシプロパン−2−イル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
44)4−エトキシ−N−(3−フルオロ−4−((5−(3−(メチルカルバモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
45)3−(4−(4−(4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド)−2−フルオロフェノキシ)ピロロ[1,2−b]ピリダジン−5−イル)ベンジルカルバメート、
46)4−エトキシ−N−(3−フルオロ−4−((5−(3−(1−ヒドロキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
47)N−(3−フルオロ−4−((5−(3−(1−ヒドロキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
48)N−(3−フルオロ−4−((5−(3−(1−ヒドロキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−4−メトキシ−2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−カルボキサミド、
49)4−エトキシ−N−(3−フルオロ−4−((5−(ピリミジン−5−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
50)4−エトキシ−N−(3−フルオロ−4−((5−(3−モルホリン−4−カルボニル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
51)4−エトキシ−N−(3−フルオロ−4−((5−(2−モルホリノピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
52)4−エトキシ−N−(3−フルオロ−4−((5−(3−ニトロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
53)4−エトキシ−N−(3−フルオロ−4−((5−(3−アミノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
54)4−エトキシ−N−(3−フルオロ−4−((5−(3−(1−メトキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
55)N−(3−フルオロ−4−((5−(3−(1−ヒドロキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
56)N−(4−((5−(3−((ジメチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
57)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
58)4−エトキシ−N−(4−((5−(2−エトキシピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)−オキシ)−3−フルオロフェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
59)4−エトキシ−N−(3−フルオロ−4−((5−(2−メトキシピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
60)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−4−エトキシ−2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−カルボキサミド、
61)N−(4−((5−(2,6−ジメチルピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
62)N−(4−((5−(2−(1−ヒドロキシエチル)ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
63)N−(4−((5−(3−((ジメチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
64)N−(4−((5−(3−アミノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
65)N−(4−((5−(3−アセトアミドフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
66)N−(4−((5−(3−アミノ−4−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
67)N−(4−((5−(3−アミノ−5−シアノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
68)N−(4−((5−(3−((ジメチルアミノ)メチル)フェニル)ピロロ[1,2−bピリダジン−4−イル]オキシ)−3−フルオロフェニル)−1−(4−フルオロフェニル)−6−メチル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
69)N−(4−((5−(3−カルバモイルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
70)N−(4−((5−(3−アミノメチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
71)N−(4−((5−(3−ヒドロキシメチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
72)N−(4−((5−(3−(メチルアミノ)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
73)N−(4−((5−(3−(エチルアミノ)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
74)N−(4−((5−(1H−インドール−6−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
75)N−(4−((5−(2−クロロ−5−((ジメチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
76)N−(4−((5−(5−((ジメチルアミノ)メチル)−2−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
77)N−(4−((5−(3−((ジメチルアミノ)メチル)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
78)N−(4−((5−(3−アミノ−4−メチル)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
79)N−(4−((5−(3−アミノ−2−メチル)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
80)N−(3−フルオロ−4−((5−(3−((メチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
81)N−(4−((5−(3−((エチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
82)N−(4−((5−(3−アミノ−4−メトキシ)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
83)N−(4−((5−(5−アミノ−2−フルオロ)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
84)N−(4−((5−(3−(メチルカルバモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
85)N−(4−((5−(3−シアノメチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、および
86)N−(4−((5−3−アミノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−1−(4−フルオロフェニル)−6−メチル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド 。
ステップ1)エチル4−エトキシ−2−オキソ−1,2−ジヒドロピリジン−3−カルボキシレートの製造
1H NMR(400MHz,DMSO−d6)δ11.61(bs,1H), 7.46(d,J=7.6Hz,1H),6.21(d,J=7.6Hz, 1H),4.14(m,4H),1.22(m,6H)
MS:212[M+H]+
1H NMR(400MHz,DMSO−d6)δ7.95(d,J=7.6
Hz,1H),7.48(m,2H),7.35(m,2H),6.58(d, J=8Hz,1H),4.28(q,J=6.8Hz,2H),1.32(t, J=6.8Hz,3H)
MS:276[M+H]−
1H NMR(400MHz,DMSO−d6)δ7.98(d,J=8Hz, 1H),7.56−7.41(m, 5H),6.60(d,J=7.6Hz, 1H),4.30(q,J=7.2Hz,2H),1.34(t,J=
7.2Hz,3H)
MS:260[M+H]+
ステップ1)メチル4−メトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキシレートの製造
1H NMR(400MHz,DMSO−d6)δ13.89(bs,1H),
8.02(d,J=7.6Hz,1H),7.53−7.48(m,2H),
7.40−7.34(m,2H),6.63(d,J=8Hz,1H),4.02
(s,3H)
MS:264[M+H]+
1H NMR(400MHz,DMSO−d6)δ7.96(d,J=7.8
Hz,1H),7.55−7.45(m,5H),6.58(d,J=7.8Hz,1H),3.99(s,3H)
MS:246[M+H]+
ステップ1)メチル1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキシレートの製造
1H NMR(400MHz,DMSO−d6)δ8.12(dd,J=6.8 and 2.0Hz,1H),7.95(dd,J=6.8 and 2.0Hz
,1H),7.50(d,J=4.8Hz,1H),7.48(J=5.2Hz,1H),7.36(t,J=8.8Hz,2H),6.41(t,J=6.8Hz,2H),3.75(s,1H)
MS:248[M+H]+
1H NMR(400MHz,DMSO−d6)δ14.23(s,1H),
8.49(dd,J=6.8 and 2.0Hz),8.21(dd,J=6.8 and 2.0Hz),7.63(d,J=4.8Hz,1H),7.61(J=
5.2Hz,1H),7.42(t,J=8.8Hz,2H),6.79(t,J=7.2Hz,2H)
MS:234[M+H]+
ステップ1)4−(2−フルオロ−4−ニトロフェノキシ)ピロロ[1,2−b]ピリダジンの製造
1H NMR(400MHz,CDCl3)δ8.16−8.11(m,2H),
7.91(d,J=5.2Hz,1H),7.82−7.81(m,1H),
7.41−7.35(m,1H),6.86−6.84(m,1H),6.67−6.32(m,1H),5.84(t,J=4.8Hz,1H)
1H NMR(400MHz,CDCl3)δ8.20−8.12(m,2H),
7.91(d,J=5.6Hz,1H),7.75(d,J=2.8Hz,1H)
,7.38−7.34(m,1H),6.98(d,J=2.8Hz,1H),
5.85−5.84(m,1H)
1H NMR(400MHz,DMSO−d6)δ7.99(d,J=5.6
Hz,1H),7.90(d,J=3.2Hz,1H),7.08(t,J=
9.2Hz,1H),6.92(d,J=2.8Hz,1H),6.56−
6.52(m,1H),6.46−6.44(m,1H),5.75(d,J=
5.2Hz,1H),5.53(s,2H)
1H NMR(400MHz,DMSO−d6)δ10.61(s,1H),
8.01−8.00(m,1H),7.95−7.90(m,2H),7.86
(d,J=8.0Hz,1H),7.51−7.42(m,3H),7.39−
7.34(m,2H),7.01(d,J=2.8Hz,1H),6.51(d,
J=8.0Hz,1H),5.86(d,J=5.2Hz,1H),4.26
(q,J=6.8Hz,2H),1.30(t,J=6.8Hz,3H)
1H NMR(400MHz,CDCl3)δ11.59(s,1H),7.90
(dd,J=12.8 and 2.4Hz,1H),7.82(d,J=5.2
Hz,1H),7.80(d,J=2.8Hz,1H),7.64(s,1H),
7.58−7.56(m,1H),7.50(d,J=8.0Hz,1H),
7.37−7.32(m,3H),7.25−7.21(m,4H),7.03
(t,J=8.8Hz,1H),6.89(d,J=2.8Hz,1H),
6.35(d,J=8.0Hz,1H),5.70(d,J=5.2Hz,1H),4.69(s,2H),4.35(q,J=7.2Hz,2H),1.58
(t,J=7.2Hz,3H)
8.01−7.99(m,2H),7.92−7.84(m,2H),7.64−7.54(m,3H),7.47−7.33(m,7 H),7.24−7.21
(m,1H),6.98(d,J=2.8Hz,1H),6.51(d,J=
8.0Hz,1H),4.25(q,J=7.2Hz,2H),1.29(t,J
=7.2Hz,3H)
MS:579[M+H]+
8.83(s,1H),8.42(d,J=3.6Hz,1H),8.06−
7.99(m,3H),7.92−7.85(m,2H),7.46−7.34
(m,7H),7.09(d,J=2.4Hz,1H),6.51(d,J=
8.0Hz,1H),5.89(d,J=4.8Hz,1H),4.25(q,J=6.8Hz,2H),1.29(t,J=6.8Hz,2H)
MS:580[M+H]+
8.08(d,J=5.6Hz,1H),8.01(d,J=2.8Hz,1H),7.97−7.94(m,1H),7.86(d,J=8.0Hz,1H),
7.80(d,J=3.2Hz,1H),7.62(d,J=3.2Hz,1H),7.52−7.44(m,4H),7.41−7.34(m,3H),6.52(d,J=8.0Hz,1H),6.05(d,J=5.2Hz,1H),
4.26(q,J=6.8Hz,2H),1.30(t,J=6.8Hz,3H)
MS:586[M+H]+
9.04(s,1H),8.65−8.64(m,1H),8.44−8.43
(m,1H),8.12−8.08(m,2H),7.92(d,J=13.6
Hz,1H),7.85(d,J=8.0Hz,1H),7.54−7.44
(m,4H),7.38−7.34(m,2H),7.29−7.28(m,
1H),6.51(d,J=8.0Hz,1H),6.03(d,J=5.2Hz,1H),4.25(q,J=6.8Hz,2H),1.29(t,J=6.8
Hz,3H)
MS:581[M+H]+
7.95−7.85(m,5H),7.69(s,1H),7.50−7.45
(m,4H),7.39−7.35(m,2H),6.95(d,J=2.8Hz,1H),6.52(d,J=8.0Hz,1H),5.74(d,J=5.2
Hz,1H),4.26(q,J=6.8Hz,2H),3.82(s,3H),1.30(t,J=6.8Hz,3H)
MS:583[M+H]+
8.52−8.50(m,2H),8.09−8.06(m,2H),7.94−7.93(m,1H),7.86(d,J=8.0Hz,1H),7.64−
7.62(m,2H),7.49−7.44(m,4H),7.39−7.34
(m,2H),7.16(d,J=2.8Hz,1H),6.51(d,J=
8.0Hz,1H),5.96(d,J=5.2Hz,1H),4.25(q,
J=7.2Hz,2H),1.30(t,J=7.2Hz,3H)
MS:580[M+H]+
9.04(d,J=2.8Hz,3H),8.11(t,J=3.2Hz,2H),7.93−7.90(m,1H),7.86(d,J=7.6Hz,1H),
7.53−7.44(m,4H),7.39−7.34(m,2H),7.21
(d,J=2.8Hz,1H),6.51(d,J=8.0Hz,1H),
5.96(d,J=5.2Hz,1H),4.25(q,J=6.8Hz,2H),1.30(t,J=7.2Hz,3H)
MS:581[M+H]+
8.38(d,J=2.4Hz,1H),8.02−8.00(m,2H),
7.94−7.88(m,2H),7.85(d,J=8.0Hz,1H),
7.47−7.44(m,4H),7.38−7.34(m,2H),7.01−6.99(m,1H),6.82(d,J=8.4Hz,1H),6.51(d,J=8.0Hz,1H),5.83(d,J=5.6Hz,1H),4.26
(q,J=6.8Hz,2H),3.84(s,3H),1.29(t,J=
6.8Hz,3H)
MS:610[M+H]+
7.96−7.92(m,1H),7.79(d,J=5.6Hz,1H),
7.76(d,J=2.8Hz,1H),7.50(d,J=8.0Hz,
1H),7.44−7.42(m,2H),7.37−7.34(m,2H),
7.30−7.21(m,4H),7.09(t,J=8.4Hz,1H),
6.91(d,J=2.8Hz,1H),6.36(d,J=8.0Hz,
1H),5.67−5.65(m,1H),4.36(q,J=4.0Hz,
2H),1.58(t,J=8.0Hz,3H)
MS:585[M+H]+
7.93−7.89(m,1H),7.80−7.77(m,2H),7.58−7.55(m,2H),7.50(d,J=8.0Hz,1H),7.37−
7.34(m,2H),7.25−7.21(m,2H),7.05(t,J=
8.0Hz,1H),6.91−6.88(m,2H),6.84(d,J=
4.0Hz,1H),6.77(s,1H),6.36(d,J=8.0Hz,
1H),5.64(d,J=4.0Hz,1H),4.36(q,J=8.0
Hz,2H),3.81(s,3H),1.58(t,J=8.0Hz,3H)
MS:609[M+H]+
7.88(dd,J=12.4 and 2.4Hz,1H),7.83
(d,J=5.2Hz,1H),7.81(d,J=2.8Hz,1H),
7.55−7.49(m,2H),7.37−7.33(m,2H),7.26−7.19(m,4H),7.13−7.02(m,3H),6.89−6.88
(m,1H),6.35(d,J=8.0Hz,1H),5.67(d,J=5.2Hz,1H),4.35(q,J=7.2Hz,2H),1.58(t,
J=7.2Hz,3H)
MS:597[M+H]+
7.96−7.92(m,1H),7.80−7.78(m,2H),7.51
(d,J=8.0Hz,1H),7.37−7.34(m,2H),7.25−
7.21(m,4H),7.18−7.15(m,1H),7.04(t,J=
8.8Hz,1H),6.89−6.86(m,2H),6.37−6.35
(m,1H),5.63(d,J=5.2Hz,1H),4.36(q,J=
6.8Hz,2H),3.89(s,3H),3.83(s,3H),1.58
(t,J=6.8Hz,3H)
MS:639[M+H]+
7.92(dd,J=12.4 and 2.4Hz,1H),7.81
(d,J=5.6Hz,1H),7.78(d,J=2.8Hz,1H),
7.60−7.56(m,2H),7.50(d,J=7.6Hz,1H),
7.37−7.33(m,2H),7.26−7.21(m,3H),7.06−
7.00(m,3H),6.83(d,J=2.8Hz,1H),6.35
(d,J=8.0Hz,1H),5.66(d,J=5.2Hz,1H),
4.35(q,J=6.8Hz,2H),1.58(t,J=6.8Hz,3H)
MS:597[M+H]+
7.96−7.92(m,1H),7.80(d,J=5.2Hz,1H),
7.74(d,J=2.8Hz,1H),7.52(d,J=8.0Hz,
1H),7.38−7.35(m,2H),7.30(d,J=3.6Hz,
1H),7.24−7.19(m,4H),7.13(t,J=8.8Hz,
1H),7.01(t,J=4.4Hz,1H),6.94(d,J=2.4
Hz,1H),6.37(d,J=7.6Hz,1H),5.68(d,J=
5.2Hz,1H),4.37(q,J=6.8Hz,2H),1.59(t,
J=6.8Hz,3H)
MS:585[M+H]+
8.30(d,J=5.2Hz,1H),8.00−7.96(m,1H),
7.91(d,J=5.2Hz,1H),7.83(d,J=2.8Hz,
1H),7.61(s,1H),7.51(t,J=7.6Hz,2H),
7.38−7.35(m,2H),7.30(s,1H),7.25−7.22
(m,2H,7.08(t,J=8.8Hz,1H),6.95(d,J=2.8Hz,1H),6.38(d,J=8.0Hz,1H),5.81(d,J=
5.2Hz,1H),4.37(q,J=7.2Hz,2H),1.59(t,J=7.2Hz,3H)
MS:614[M+H]+
7.97−7.93(m,1H),7.89(s,2H),7.78−7.76
(m,2H),7.52(d,J=7.6Hz,1H),7.38−7.35
(m,2H),7.30−7.22(m,4H),7.11(t,J=8.8
Hz,1H),6.89(d,J=2.4Hz,1H),6.37(d,J=
8.0Hz,1H),5.64(d,J=5.6Hz,1H),4.37(q,
J=6.8Hz,2H),1.59(t,J=6.8Hz,3H)
MS:569[M+H]+
8.14(m,2H),7.98−7.94(m,1H),7.83(d,J=
5.6Hz,1H),7.77(d,J=2.8Hz,1H),7.52(d,
J=7.6Hz,1H),7.38−7.35(m,2H),7.33−7.30
(m,1H),7.25−7.22(m,2H),7.12(t,J=8.8
Hz,1H),6.87(d,J=2.8Hz,1H),6.37(d,J=
7.6Hz,1H),5.73−5.72(m,1H),4.37(q,J=
7.2Hz,2H),3.31(s,3H),1.59(t,J=6.8Hz,
3H)
MS:647[M+H]+
8.13(d,J=5.2Hz,1H),7.98−7.95(m,1H),
7.90(d,J=5.6Hz,1H),7.83(d,J=2.8Hz,
1H),7.52(d,J=7.6Hz,1H),7.46(d,J=5.2)
Hz,1H),7.38−7.35(m,2H),7.30−7.19(m,
4H,7.07(t,J=8.4Hz,1H),6.96(d,J=3.2Hz,1H),6.37(d,J=8.0Hz,1H),5.81(d,J=5.6
Hz,1H),4.37(q,J=6.8Hz,2H),1.58(t,J=
3.6Hz,3H)
MS:598[M+H]+
7.98(s,1H),7.94−7.91(m,1H),7.87(d,J=
5.2Hz,1H),7.81(d,J=2.8Hz,1H),7.51(d,J=8.0Hz,1H),7.41(s,1H),7.37−7.34(m,
2H),7.24−7.22(m,3H),7.00(t,J=8.8Hz,
1H),6.94(d,J=3.2Hz,1H),6.37(d,J=8.0
Hz,1H),5.73(d,J=5.2Hz,1H),4.36(q,J=
6.8Hz,2H),3.88(s,3H),1.58(t,J=6.8Hz,
3H)
MS:644[M+H]+
8.14(d,J=2.0Hz,1H),7.96−7.86(m,4H),
7.61−7.58(m,1H),7.48−7.44(m,4H),7.37
(t,J=8.8Hz,2H),6.89(d,J=2.8Hz,1H),
6.52(d,J=8.0Hz,1H),6.43(d,J=8.4Hz,
1H),5.85(s,1H),5.76−5.75(m,2H),4.25
(q,J=6.8Hz,2H),1.29(t,J=6.8Hz,3H)
MS:595[M+H]+
7.97−7.94(m,1H),7.79−7.71(m,4H),7.52
(d,J=7.6Hz,1H),7.38−7.35(m,2H),7.26−
7.21(m,3H),7.10(t,J=8.4Hz,1H),6.85(d,J=2.8Hz,1H),6.37(d,J=8.0Hz,1H),5.65
(d,J=5.2Hz,1H),4.37(q,J=6.8Hz,2H),
4.23−4.18(m,1H),3.24−3.21(m,2H),2.80−2.74(m,2H),2.19−2.15(m,2H),1.91−1.97
(m,2H),1.59(t,J=6.8Hz,3H)
MS:652[M+H]+
10.02(s,1H),8.16−8.15(m,1H),7.95−7.91(m,2H),7.86(d,J=5.2Hz,1H),7.83(d,J=
2.8Hz,1H),7.76−7.74(m,1H),7.53−7.48
(m,2H),7.38−7.34(m,2H),7.24−7.22(m,3
H),7.06(t,J=8.8Hz,1H),6.93(d,J=3.2Hz,1H),6.37(d,J=7.6Hz,1H),5.73(d,J=5.6
Hz,1H),4.37(q,J=7.2Hz,2H),1.59(t,J=
7.2Hz,3H)
MS:607[M+H]+
8.15(d,J=4.0Hz,1H),7.99−7.95(m,1H),
7.86−7.80(m,2H),7.51(d,J=8.0Hz,1H),
7.37−7.34(m,2H),7.25−7.21(m,3H),7.06−
7.01(m,2H),6.95−6.91(m,2H),6.36(d,J=
8.0Hz,1H),5.73(d,J=8.0Hz,1H),4.36(q,
J=7.2Hz,2H),3.51(t,J=4.8Hz,4H),2.93
(t,J=5.2Hz,4H),2.18(s,1H),1.58(t,J=
7.2Hz,3H)
MS:665[M+H]+
8.51−8.50(m,1H),8.36(s,1H),8.20(d,J=
8.4Hz,1H),7.99−7.90(m,2H),7.85−7.81
(m,2H),7.50(d,J=7.6Hz,1H),7.37−7.34
(m,2H),7.24−7.22(m,3H),7.03(t,J=8.8
Hz,1H),6.86(d,J=2.8Hz,1H),6.36(d,J=
8.0Hz,1H),5.69(d,J=5.6Hz,1H),4.36(q,
J=7.2Hz,2H),2.17(s,3H),1.59(t,J=6.
8Hz,3H)
MS:637[M+H]+
8.61(d,J=4.8Hz,1H),8.33(s,1H),7.99−
7.95(m,1H),7.91(d,J=5.2Hz,1H),7.84(d,J=2.8Hz,1H),7.78−7.76(m,1H),7.52(d,J=8.0Hz,1H),7.38−7.35(m,2H),7.30−7.22
(m,3H),7.13(t,J=8.8Hz,1H),7.01(d,J=
2.8Hz,1H),6.37(d,J=8.0Hz,1H),5.80(d,
J=5.2Hz,1H),4.36(q,J=7.2Hz,2H),2.73
(s,3H),1.59(t,J=6.8Hz,3H)
MS:622[M+H]+
8.27−8.26(m,1H),7.96−7.92(m,1H),7.86−7.82(m,4H),7.51(d,J=7.8Hz,1H),7.44(t,J=7.7Hz,1H),7.37−7.32(m,2H),7.24−7.22
(m,3H),7.06(t,J=8.7Hz,1H),6.93(d,J=2.8Hz,1H),6.37(d,J=7.9Hz,1H),5.71(d,J=
5.0Hz,1H),4.37(q,J=7.0Hz,2H),2.58(s,
3H),1.59(t,J=7.0Hz,3H)
MS:621[M+H]+
(d,J=6.0Hz,2H),8.01−7.97(m,1H),7.89
(d,J=5.4Hz,1H),7.83(d,J=2.9Hz,1H),
7.60−7.52(m,6H),7.39−7.37(m,2H),7.31−
7.28(m,1H),7.06(t,J=8.7Hz,1H),6.96
(d,J=2.9Hz,1H),6.41(d,J=7.9Hz,1H),
5.78(d,J=5.3Hz,1H),4.12(s,3H)
MS:548[M+H]+
8.73−8.71(m,1H),7.93−7.89(m,1H),7.84−7.80(m,2H),7.65−7.61(m,2H),7.59−7.57
(m,1H),7.41−7.25(m,7H),7.08(t,J=8.4
Hz,1H),6.90(d,J=2.4Hz,1H),6.61(t,J=
6.8Hz,1H),5.71(d,J=5.6Hz,1H),4.70(s,
2H)
MS:565[M+H]+
(t,1H),7.92−7.81(m,4H),7.75−7.73(m,
1H),7.52−7.48(m,2H),7.36−7.33(m,2H),
7.29−7.20(m,3H),7.10(t,1H),6.92(d,J=
2.8Hz,1H),6.34(d,J=8.0Hz,1H),5.74−
5.73(m,1H),4.38−4.33(q,2H),3.04−2.99
(q,2H),1.58(t,J=7.2Hz,3H),1.16(t,J=
7.6Hz,3H)
MS:671[M+H]+
(t,1H),7.92−7.81(m,4H),7.77(m,1H),
7.67(m,1H),7.53−7.47(m,2H),7.36−7.33
(m,2H),7.29−7.20(m,3H),7.10(t,1H),
6.92(d,J=3.6Hz,1H),6.33(d,J=7.6Hz,
1H),5.75−5.74(q,1H),4.38−4.33(q,2H),
2.94(s,3H),1.58(t,J=7.2Hz,3H)
MS:657[M+H]+
(t,1H),7.88−7.81(m,4H),7.78−7.75(m,
1H),7.49−7.45(m,2H),7.36−7.33(m,2H),
7.26−7.20(m,3H),7.02(t,1H),6.91(d,J=
2.8Hz,1H),6.33(d,J=8.0Hz,1H),5.79(d,
J=5.2Hz,1H),4.37−4.35(q,2H),2.52(d,J=
5.2Hz,3H),1.58(t,J=6.8Hz,3H)
MS:658[M+H]+
−8.26(m,1H),7.96−7.92(m,1H),7.86−7.82(m,4H),7.51(d,J=7.8Hz,1H),7.44(t,J=
7.7Hz,1H),7.37−7.32(m,2H),7.24−7.22
(m,3H),7.06(t,J=8.7Hz,1H),6.93(d,J=
2.8Hz,1H),6.37(d,J=7.9Hz,1H),5.71(d,
J=5.0Hz,1H),4.37(q,J=7.0Hz,2H),2.58(s,3H),1.59(t,J=7.0Hz,3H)
MS:548[M+H]+
(d,J=6.0Hz,2H),8.01−7.97(m,1H),7.89
(d,J=5.4Hz,1H),7.83(d,J=2.9Hz,1H),
7.60−7.52(m,6H),7.39−7.37(m,2H),7.31−7.28(m,1H),7.06(t,J=8.7Hz,1H),6.96
(d,J=2.9Hz,1H),6.41(d,J=7.9Hz,1H),
5.78(d,J=5.3Hz,1H),4.12(s,3H)
MS:621[M+H]+
(t,1H),7.93−7.81(m,4H),7.73−7.67(m,
1H),7.50−7.46(m,2H),7.36−7.33(m,2H),
7.26−7.23(m,2H),7.08(t,1H),6.91(d,J=
2.8Hz,1H),6.34(d,J=7.6Hz,1H),5.74(d,J=6.4Hz,1H),4.37−4.35(q,2H),2.52(d,J=
5.2Hz,3H),1.58(t,J=6.8Hz,3H)
MS:672[M+H]+
8.09(t,1H),7.91−7.81(m,4H),7.63−7.61
(m,1H),7.51−7.47(m,2H),7.37−7.33(m,
2H),7.26−7.20(m,2H),7.08(t,1H),6.90
(d,J=3.2Hz,1H),6.34(d,J=7.6Hz,1H),
5.73(d,J=3.6Hz,1H),4.38−4.33(q,2H),
2.60(s,6H),1.58(t,J=6.8Hz,3H)
MS:686[M+H]+
−8.19(m,2H),7.91−7.93(m,1H),7.89(d,J
=5.6Hz,1H),7.83(d,J=2.8Hz,1H),7.79−
7.77(m,2H),7.51(d,J=7.6Hz,1H),7.37−
7.34(m,2H),7.28−7.21(m,3H),7.05(t,J=
8.4Hz,1H),6.94(d,J=2.8Hz,1H),6.36(d,
J=8.0Hz,1H),5.75(d,J=5.2Hz,1H),4.39−
4.34(q,2H),1.59(d,J=6.8Hz,3H)
MS:624[M+H]+
7.92−7.88(m,1H),7.77−7.75(m,2H),7.50
(d,J= 8.0Hz,1H),7.45−7.43(m,2H),7.23
−7.21(m,2H)7.37−7.34(m,2H),7.04(t,J=
8.4Hz,2H),6.81(d,J=2.4Hz,1H),6.68
(d,J=8.4Hz,1H),6.36(d,J=8.0Hz,1H),
5.61(d,J=5.2Hz,1H),5.4(br,2H),4.37−
4.35(q,2H),1.59(d,J=6.8Hz,3H)
MS:594[M+H]+
7.93−7.90(dd,2H),7.81(d,J=5.2Hz,1H),
7.79(d,J=2.8Hz,1H),7.69−7.63(m,3H),7.51−7.46(m,2H),7.37−7.30(m,3H),7.24−
7.21(m,2H)7.04(t,1H),6.88(d,J=2.8Hz,1H),6.36(d,J=8.0Hz,1H),5.61(d,J=5.2Hz,1H),4.57(s,2H),4.37−4.35(q,2H),3.56−3.53(m,2H),3.47−3.34(m,2H),1.59(d,J=6.8Hz,3H)
MS:667[M+H]+
8.09(d,J= 5.2Hz,1H),7.86(d,J= 5.2Hz,
1H),7.80(d,J= 2.8Hz,1H),7.55(d,J=7.
6Hz,1H),7.37(d,J= 4.0Hz,1H),7.35−7.34
(m,2H)7.27−7.20(m,3H),7.18(t,1H),7.01(s,1H),6.93(d,J=2.8Hz,1H),6.40(d,J=
8.0Hz,1H),5.75(d,J=5.2Hz,1H),4.11
(s,3H),3.92(s,3H),3.56−3.53(m,2H),3.7
−3.34(m,2H),1.59(d,J=6.8Hz,3H)
MS:596[M+H]+
7.95−7.91(m,1H),7.83−7.79(m,2H),7.68−7.64(m,2H),7.51(d,J=7.8Hz,1H),7.39−
7.33(m,3H),7.28−7.21(m,4H),7.03(t,J=
8.7Hz,1H),6.88(d,J=2.8Hz,1H),6.36
(d,J=7.9Hz,1H),5.69(d,J=5.3Hz,1H),
4.36(q,J=7.0Hz,2H),3.10(s,3H),2.92(s,3H),1.58(t,J=7.0Hz,3H)
MS:650[M+H]+
8.54(d,J=5.4Hz,2H),8.23(s,1H),7.89
(d,J=5.4Hz,1H),7.85(d,J=2.9Hz,1H),
7.77−7.73(m,1H),7.57(d,J=6.0Hz,2H),
7.46−7.41(m,2H),7.23−7.21(m,1H),7.14−7.12(m,1H),7.09−7.03(m,2H),6.97(d,J=
2.9Hz,1H),5.77(d,J=5.3Hz,1H),1.81
(q,J=5.2Hz,2H),1.62(q,J=4.6Hz,2H)
MS:526[M+H]+
7.94−7.89(m,1H),7.82−7.78(m,3H),7.52−7.48(m,2H),7.39−7.33(m,4H),7.25−7.21
(m,3H),7.07−6.98(m,2H),6.90(d,J=2.8Hz,1H),6.35(d,J=8.0Hz,1H),5.67(d,J=
5.2Hz,1H),4.35(q,J=7.2Hz,2H),1.57
(t,J=7.2Hz,3H),1.54(s,6H)
MS:637[M+H]+
7.99(d,J=4.8Hz,1H),7.97−7.96(m,1H),
7.84(d,J=5.2Hz,1H),7.81(d,J=2.8Hz,1H),7.77−7.69(m,2H),7.50(d,J=7.6Hz,1H),
7.41(t,J=7.6Hz,1H),7.36−7.33(m,2H),
7.25−7.21(m,3H),7.03(t,J=8.8Hz,1H),
6.91(d,J=3.2Hz,1H),6.35(d,J=8.0Hz,
1H),6.2(br,1H),5.71(d,J=5.2Hz,1H),
4.38−4.33(q,2H),2.95(d,J=5.2Hz,3H),
1.58(t,J=6.8Hz,3H)
MS:636[M+H]+
7.91(d,J=2.4Hz,1H),7.88(d,J=2.4Hz,1H),7.82(d,J= 5.2Hz,1H),7.79(d,J= 2.8Hz,
1H),7.68(s,1H),7.61−7.59(m,1H),7.50(d,J=8.0Hz,1H),7.37−7.32(m,3H),7.26−
7.20(m,4H),7.05(t,J=8.8Hz,1H),6.89
(d,J=2.8Hz,1H),6.36(d,J=7.6Hz,1H),
5.69(d,J=5.6Hz,1H),5.09(s,2H),4.48(br,2H),4.38−4.35(q,2H),1.59(d,J=6.8Hz,
3H)
MS:652[M+H]+
7.93−7.89(m,1H),7.82−7.79(m,2H),7.67(s,1H),7.56−7.53(m,1H),7.49(d,J=7.8Hz,1H),7.37−7.31(m,3H),7.25−7.21(m,4H),7.04(t,J=8.7Hz,1H),6.89(d,J=2.8Hz,
1H),6.35(d,J=7.9Hz,1H),5.69−5.68(m,
1H),4.89(q,J=6.4Hz,1H),1.57(t,J=7.0Hz,3H),1.45(d,J=6.4Hz,3H)
MS:623[M+H]+
−8.73(m,1H),7.94−7.91(m,1H),7.85−7.82(m,2H),7.69(s,1H),7.64−7.55(m,2H),
7.43−7.26(m,7H),7.11(t,J=8.6Hz,1H),
6.92(d,J=2.7Hz,1H),6.62(t,J=6.8Hz,1H),5.72(d,J=5.3Hz,1H),4.92(q,J=6.2Hz,
1H),1.48(q,J=6.4Hz,3H)
MS:579[M+H]+
−7.91(m,1H),7.83−7.79(m,2H),7.66(s,
1H),7.58−7.49(m,5H),7.37−7.31(m,3H),
7.24−7.18(m,2H),7.04(t,J=8.7Hz,1H,
6.91−6.88(m,1H),6.39(d,J=7.8Hz,1H),
5.70(d,J=5.3Hz,1H),4.87(q,J=6.4Hz,1H),4.10(s,3H),1.49−1.43(m,3H)
MS:591[M+H]+
9.04(d,J=2.8Hz,3H),8.11(t,J=3.2Hz,
2H),7.93−7.90(m,1H),7.86(d,J=7.6Hz,
1H),7.53−7.44(m,4H),7.39−7.34(m,2H),
7.21(d,J=2.8Hz,1H),6.51(d,J=8.0Hz,
1H),5.96(d,J=5.2Hz,1H),4.25(q,J=6.8Hz,2H),1.30(t,J=7.2Hz,3H)
MS:678[M+H]+
7.94(d,J=2.4Hz,1H),7.83(s,1H),7.65(m,2H),7.50(d,J=8.0Hz,1H),7.40−7.15(m,7H),6.04(t,J=8.8Hz,1H),6.86(d,J=2.8Hz,
1H),6.35(d,J=7.6Hz,1H),5.68(d,J=5.2Hz,1H),4.36(q,J=7.3Hz,2H),1.58(t,J=
7.3Hz,3H)
MS:692[M+H]+
8.15(d,J=5.2Hz,1H),7.99(d,J=2.4Hz,
1H),7.96(d,J= 2.4Hz,1H),7.85(d,J=5.6
Hz,1H),7.80(d,J=2.4Hz,1H),7.51(d,J=
8Hz,1H),7.37−7.34(m,2H),7.26−7.21(m,
2H),7.05−7.00(m,2H),6.96−6.94(m,2H),
6.36(d,J=8.0Hz,1H),5.73(d,J=5.6Hz,
1H),4.39−4.34(q,2H),3.75(t,J=4.8Hz,
4H),3.47(t,J=5.2Hz,4H),1.59(d,J=6.8Hz,3H)
MS:665[M+H]+
8.49(d,J=2.0Hz,1H),8.09−8.07(m,4H),
7.94−7.89(m,1H),7.85(d,J=8.0Hz,1H),
7.66(t,J=8.0Hz,1H),7.48−7.43(m,4H),
7.39−7.34(m,2H),7.17(d,J=3.2Hz,1H),
6.51(d,J=8.0Hz,1H),5.95(d,J=5.6Hz,
1H),4.25(q,J=7.2Hz,2H),1.30(t,J=7.2Hz,3H)
MS:624[M+H]+
7.96(d,J=5.6Hz,1H),7.96(d,J=2.8Hz,
1H),7.89(dd,J=11.6 and 2.0Hz,1H),
7.85(d,J=8.0Hz,1H),7.48−7.43(m,4H),
7.69−7.34(m,2H),6.97(t,J=8.0Hz,1H),
6.86(d,J=2.8Hz,1H),6.82−6.74(m,2H),
6.51(d,J=8.0Hz,1H),6.45−6.43(m,2H),
5.78(d,J=4.8Hz,1H),4.94(s,2H),4.25
(q,J=7.2Hz,2H),1.30(t,J=7.2Hz,3H)
MS:594[M+H]+
8.01(d,J=4.8Hz,1H),7.90(m,2H),7.70−
7.30(m,9H),7.16(d,J=8.0Hz,1H),6.99(d,J=2.8Hz,1H),6.52(d,J=8.0Hz,1H),5.84
(d,J=4.8Hz,1H),4.28(q,J=7.1Hz,2H),
3.28(m,1H),2.99(s,3H),1.27(m,6H)
MS:637[M+H]+
8.14(s,1H),7.83−7.81(m,2H),7.72−7.68
(m,1H),7.66(s,1H),7.53(d,J=7.6Hz,1H),
7.45−7.42(m,2H),7.34(t,J=7.6Hz,1H),
7.19−7.16(m,1H),7.12−7.04(m,3H),7.53
(d,J=2.8Hz,1H),5.68(d,J=5.2Hz,1H),
4.89(q,J=6.4Hz,1H),2.35(t,J=8.0Hz,
1H),1.78(q,J=5.2Hz,2H),1.60(q,J=4.4Hz,2H),1.46(d,J=6.4Hz,3H)
MS:569[M+H]+
7.94−7.90(m,1H),7.81−7.78(m,2H),7.61
(s,1H),7.55−7.52(m,1H),7.50(d,J=8.0Hz,1H),7.36−7.30(m,3H),7.25−7.18(m,4H),7.05(t,J=8.8Hz,1H),6.89(d,J=2.8Hz,
1H),6.35(d,J=8.0Hz,1H),5.67−5.66(m,
1H),4.35(q,J=6.8Hz,2H),3.45(s,2H),
2.18(s,6H),1.57(t,J=7.2Hz,3H)
MS:636[M+H]+
8.76−8.74(m,1H),8.56(s,2H),7.99−7.95
(m,1H),7.89(d,J=5.6Hz,1H),7.84(d,J=
3.2Hz,1H),7.65−7.63(m,1H),7.57(d,J=
6.0Hz,2H),7.42−7.33(m,4H),7.29−7.25
(m,1H),7.13−7.09(m,1H),6.96(d,J=2.8Hz,1H),6.63(t,J=7.2Hz,1H),5.79−5.78(m,
1H)
MS:536[M+H]+
8.07(d,J=5.6Hz,1H),7.94(dd,J=12.4 and
2.4Hz,1H),7.86(d,J=5.2Hz,1H),7.80
(d,J=2.8Hz,1H),7.50(d,J=8.0Hz,1H),
7.37−7.33(m,2H),7.29−7.26(m,1H),7.25−7.21(m,2H),7.18(dd,J=5.2 and 1.6Hz,
1H),7.07(t,J=8.8Hz,1H),6.98(d,J=1.2Hz,1H),6.93(d,J=3.2Hz,1H),6.35(d,J=
8.0Hz,1H),5.75(dd,J=5.6 and 1.2Hz,
1H),4.35(q,J=7.2Hz,2H),4.33(q,J=7.2Hz,2H),1.58(t,J=7.2Hz,3H),1.38(t,J=
7.2Hz,3H)
MS:624[M+H]+
8.10(d,J=5.2Hz,1H),7.94(dd,J=2.4 and 12.4Hz,1H),7.86(d,J=5.2Hz,1H),7.81
(d,J=3.2Hz,1H),7.51(d,J=7.6Hz,1H),
7.38−7.34(m,2H),7.29−7.21(m,2H),7.19
(dd,J=1.2 and5.6Hz,1H),7.07(t,J=8.8
Hz,1H),7.02(m,1H),6.93(d,J=3.2Hz,
1H),6.36(d,J=7.6Hz,1H),5.75(d,J=5.2Hz,1H),4.36(q,J=7.2Hz,1H),3.93(s,3H),
1.58(t,J=7.2Hz,3H)
MS: 610[M+H]+
8.53(d,J=6.0Hz,2H),8.00−7.95(m,1H),
7.88(d,J=5.6Hz,1H),7.83(d,J=2.8Hz,
1H),7.58−7.54(m,3H),7.37−7.34(m,3H),
7.30−7.22(m,2H),7.08−7.04(m,1H),6.95
(d,J=2.8Hz,1H),6.40(d,J=8.0Hz1H),
5.79−5.77(m,1H),4.10(s,3H)
MS: 566[M+H]+
7.98(dd,J=12.8 and 2.4Hz,1H),7.88
(d,J=5.2Hz,1H),7.81(d,J=2.4Hz,1H),
7.52(d,J=7.6Hz,1H),7.38−7.34(m,2H),
7.28−7.22(m,5H),7.06(t,J=8.8Hz,1H),
6.93(d,J=2.8Hz,1H),6.38(d,J=8.0Hz,
1H),5.78(d,J=5.2Hz,1H),4.36(q,J=7.2Hz,2H),2.53(s,6H),1.59(t,J=7.2Hz,3H)
MS:608[M+H]+
8.46(d,J=5.2Hz,1H),7.98−7.95(m,1H),
7.89(d,J=5.6Hz,1H),7.83(d,J=2.8Hz,
1H),7.57(s,1H),7.51(d,J=7.6Hz,1H),
7.48−7.47(m,1H),7.38−7.34(m,2H),7.30−7.22(m,3H),7.08−7.03(m,1H),6.97(d,J=
2.8Hz,1H),6.37(d,J=8.0Hz,1H),5.78
(d,J=5.2Hz,1H),4.87(q,J=6.4Hz,1H),
4.37(q,J=6.8Hz,2H),1.59(t,J=6.8Hz,
3H),1.44(d,J=4.8Hz,3H)
MS:624[M+H]+
8.10(s,1H),7.82−7.80(m,2H),7.73−7.70
(m,1H),7.60(s,1H),7.53(d,J=6.8Hz,1H)
,7.46−7.42(m,2H),7.33−7.29(m,1H),7.20−7.17(m,2H),7.14−7.04(m,3H),6.91(d,J=2.8Hz,1H),5.65(d,J=5.6Hz,1H),3.42
(s,2H),2.18(s,6H),1.82−1.79(m,2H),
1.69−1.60(m,2H)
MS:624[M+H]+
8.24(s,1H),7.81−7.79(m,2H),7.73−7.70
(m,1H),7.49−7.42(m,2H),7.18−7.15(m,1H),7.13−7.01(m,6H),6.88(d,J=2.8Hz,1H)
,6.59−6.57(m,1H),5.66(d,J=5.2Hz,1H),
1.79−1.76(m,2H),1.69−1.58(m,2H)
MS:540[M+H]+
8.43(s,1H),7.82−7.78(m,2H),7.70−7.67
(m,1H),7.61(s,1H),7.47−7.41(m,3H),7.39−7.37(m,1H),7.29−7.24(m,2H),7.14−7.12(m,1H),7.09−7.01(m,3H),6.86(d,J=2.8Hz,1H),5.68(d,J=5.2Hz,1H),2.15(s,3H),
1.76−1.73(m,2H),1.69−1.57(m,2H)
MS:582[M+H]+
8.18(s,1H),7.81−7.77(m,2H),7.74−7.70
(m,1H),7.45−7.42(m,2H),7.19−7.16(m,
1H),7.12−7.00(m,4H),6.94(d,J=8.4Hz,
2H),6.83(d,J=2.8Hz,1H),5.66(d,J=5.2
Hz,1H),3.75(s,2H),1.79−1.75(m,2H),
1.65−1.58(m,2H)
MS:558[M+H]+
8.36(s,1H),7.87−7.80(m,2H),7.68−7.63
(m,3H),7.55−7.54(m,1H),7.48−7.43(m,3H),7.31(s,1H),7.19(s,1H),7.08−7.03(m,
2H),6.86−6.81(m,2H),5.75(d,J=5.6Hz,
1H),1.78−1.69(m,2H),1.65−1.55(m,2H)
MS:565[M+H]+
8.63(d,J=7.6Hz,1H),7.92(dd,J=12.4 and 2.4Hz,1H),7.81(d,J=5.2Hz,1H),7.79(d,J=2.8Hz,1H),7.61(s,1H),7.53(d,J=7.6Hz,1H),7.33−7.29(m,3H),7.26−7.19(m,4H),
7.08(t,J=8.4Hz,1H),6.90(d,J=2.8Hz,1H),6.51(d,J=7.6Hz,1H),5.67(dd,J=5.2Hz,
1H),3.45(s,2H),2.18(s,6H),2.13(s,3H)
MS:589[M+H]+
8.75(s,1H),7.83−7.81(m,2H),7.78−7.66
(m,4H),7.46−7.39(m,3H),7.18−7.16(m,1H),7.07−6.99(m,3H),6.89(d,J=2.8Hz,1H)
,6.24(s,1H),5.79(s,1H),5.68(d,J=5.2Hz,1H),1.73−1.70(m,2H),1.61−1.58(m,2H)
MS:568[M+H]+
8.70(s,1H),7.79−7.77(m,2H),7.58−7.43
(m,5H),7.31−7.27(m,1H),7.20−7.18(m,1H),7.11−7.09(m,1H),7.05−6.94(m,3H),
6.84(d,J=2.8Hz,1H),5.72(d,J=5.2Hz,
1H),3.93(s,2H),3.13(q,J=7.2Hz,2H),
1.39−1.32(m,4H)
MS:554[M+H]+
8.34(s,1H),7.80−7.79(m,2H),7.68−7.63
(m,2H),7.56(d,J=7.6Hz,1H),7.45−7.40
(m,2H),7.33(t,J=7.6Hz,1H),7.24−7.12
(m,2H),7.08−7.01(m,3H),6.88(d,J=2.8Hz,1H),5.67(d,J=5.6Hz,1H),4.68(s,2H),
1.74−1.71(m,2H),1.61−1.52(m,2H)
MS:555[M+H]+
8.23(s,1H),7.80−7.79(m,2H),7.73−7.69
(m,1H),7.46−7.41(m,2H),7.19−7.15(m,2H),7.12−6.99(m,4H),6.95−6.94(m,1H),
6.91(d,J=2.8Hz,1H),6.53−6.51(m,1H),
5.63(d,J=5.2Hz,1H),2.81(s,3H),1.78
−1.75(m,2H),1.60−1.57(m,2H)
MS:554[M+H]+
(s,1H),7.80−7.79(m,2H),7.73−7.69(m,
1H),7.45−7.41(m,2H),7.18−7.03(m,5H),
7.00−6.97(m,1H),6.94−6.93(m,1H),6.90
d,J=2.8Hz,1H),6.52−6.50(m,1H),5.64−
5.62(m,1H),3.13(q,J=7.2Hz,2H),1.78−
1.75(m,2H),1.60−1.57(m,2H),1.21(t,J=
2.4,3H)
MS:568[M+H]+
8.28−8.23(m,2H),7.81−7.77(m,2H),7.68−7.64(m,2H),7.60(d,J=8.0Hz,1H),7.44−
7.39(m,3H),7.14(t,J=2.8Hz,1H),7.07−
6.99(m,4H),6.92(d,J=2.8Hz,1H),6.52−
6.51(m,1H),5.60(d,J=0.8Hz,1H),1.72−
1.69(m,2H),1.56−1.52(m,2H)
MS:564[M+H]+
8.07(s,1H),7.84(d,J=5.6Hz,1H),7.80
(d,J=2.8Hz,1H),7.73(dd,J=2.4,12Hz,
1H),7.51(t,1H),7.48(s,1H),7.42−7.46
(m,2H),7.19−7.21(m,2H),7.13(t,1H),
7.04−7.09(m,2H),6.89(d,J=2.8Hz,1H),
5.69(dd,J=0.8,5.2Hz,1H),3.38(s,2H),
2.27(s,6H),1.89(t,2H),4.60(t,2H)
MS:616[M+H]+
8.64(s,1H),7.83(d,J=5.6Hz,1H),7.80
(d,J=2.8Hz,1H),7.71(dd,J=2.4,12Hz
,1H),7.42−7.45(m,2H),7.36(s,1H),7.26−7.29(m,1H),7.19−7.22(m,1H),7.01−7.11
(m,3H),6.95(dd,J=1.2,9.2Hz,1H),6.88
(d,J=2.8Hz,1H),5.70(d,J=5.2Hz 1H),
3.58(s,2H),2.33(s,6H),1.74−1.77(m,2H),1.60−1.63(m,2H)
MS:600[M+H]+
8.71(s,1H),7.81−7.84(m,2H),7.68(dd,J=2,12Hz,1H),7.41(m,1H),7.41−7.48(m,3H),7.18(m,2H),7.00−7.10(m,3H),6.90−6.91(m,1H),5.67(d,J=5.2Hz,1H),3.58(s,2H),2.27(s,6H),1.75(t,2H),1.63(t,2H)
MS:600[M+H]+
8.45(s,1H),7.79−7.68(m,3H),7.44−7.40
(m,2H),7.16−6.99(m,6H),6.86(d,J=2.8Hz
,1H),6.18−6.16(m,1H),5.63(d,J=5.2Hz,
1H),2.17(s,3H),1.78−1.71(m,2H),1.60−
1.53(m,2H)
MS:554[M+H]+
8.69(s,1H),7.79−7.78(m,2H),7.62−7.58
(m,2H),7.47−7.40(m,2H),7.12−7.10(m,1H),7.03−6.92(m,3H),6.83(d,J=7.6Hz,1H),6.71(d,J=2.4Hz,1H),6.62(d,J=8.0Hz,
1H),5.58(d,J=5.2Hz,1H),2.09(s,3H),
1.71−1.68(m,2H),1.59−1.56(m,2H)
MS:554[M+H]+
8.37(s,1H),7.83(d,J=5.2Hz,1H),7.81
(d,J=2.8Hz,1H),7.68(dd,J=2.4Hz and 12.4Hz,1H),7.52−7.58(m,2H),7.40−7.47
(m,2H),7.32(t,1H),7.16−7.21(m,3H),
7.07(q,3H),6.90(d,J=2.4Hz,1H),5.70(d,J=5.2Hz,1H),3.79(s,2H),2.37(s,3H),
1.77−1.96(m,2H),1.69(s,1H),1.59−1.63
(m,2H)
MS:568[M+H]+
8.47(s,1H),7.82(d,J=5.2Hz,1H),7.80(d,J=2.8Hz,1H),7.69(dd,J=2.4Hz and
12.4Hz,1H),7.60(s,1H),7.54−7.56(m,1H),7.42−7.47(m,2H),7.32(t,1H),7.24(s,1H),7.17−7.19(m,1H),7.02−7.10(m,3H),
6.90(d,J=2.8Hz,1H),5.67(d,J=5.2Hz,
1H),3.85(s,2H),2.68(q,2H),1.75−1.78
(m,2H),1.59−1.62(m,2H),1.41(s,1H)
MS:582[M+H]+
(s,1H),7.78−7.77(m,2H),7.72−7.68(m,
2H),7.44−7.40(m,2H),7.16−6.99(m,6H),
6.83(d,J=2.8Hz,1H),6.78(d,J=8.4Hz,
1H),3.84(s,5H),1.76−1.73(m,2H),1.59−
1.56(m,2H)
MS:570[M+H]+
1H),7.80(d,J=2.4Hz,1H),7.75−7.71(m,
1H),7.56−7.52(m,2H),7.33−7.29(m,1H),
7.19−7.15(m,1H),7.07−7.03(m,2H),6.88−6.85(m,1H),6.83−6.80(m,2H),6.64−6.60
(m,1H),5.69(d,J=0.8Hz,1H)
MS:558[M+H]+
(s,1H),7.83−7.80(m,2H),7.70−7.64(m,
5H),7.46−7.41(m,2H),7.17−7.15(m,1H),
7.04−6.99(m,3H),6.89(d,J=2.8Hz,1H),6.31(d,J=4.8Hz,1H),5.68(d,J=5.2Hz,1H),
2.96(s,3H),1.75−1.72(m,2H),1.68−1.60
(m,2H)
MS:582[M+H]+
(s,1H),7.84−7.81(m,2H),7.72−7.68(m,
1H),7.60−7.57(m,2H),7.46−7.41(m,2H),
7.35(t,J=7.6Hz,1H),7.18−7.15(m,2H),
7.12−7.07(m,1H),7.06−7.00(m,2H),6.89
(d,J=2.8Hz,1H),5.71(d,J=5.2Hz,1H),
3.74(s,2H),1.75−1.72(m,2H),1.61−1.58
(m,2H)
MS:564[M+H]+
8.65(d,J=7.6Hz,1H),7.94(dd,J=12.4 and 2.4Hz,1H),7.82(d,J=5.6Hz,1H),7.79(d,J=2.8Hz,1H),7.35−7.24(m,5H),7.17−7.11
(m,1H),7.09−7.03(m,3H),6.89(d,J=2.
8Hz,1H),6.61−6.58(m,1H),6.52(d,J=7.
6Hz,1H),5.70(dd,J=5.2Hz,1H),3.87(brs,2H),2.14(s,3H)
MS:564[M+H]+
本発明に係る化合物のc−MET阻害効果を以下のように確認した。
Claims (14)
- 下記一般式(1)で表される化合物、またはその薬学的に許容可能な塩:
R1は、水素、またはハロゲンであり;
R2は、インドリル、フェニル、ピラジニル、ピラゾリル、ピリジニル、ピリミジニル、チアゾリルおよびチエニルからなる群から選択されるアリールまたはヘテロアリールであり、
前記アリールまたはヘテロアリールは、非置換されたり、または、
Riは、ヒドロキシ、O−CH2CH2−O−CH3、OCO−NH2、モルホリノ、アミノ、NH(C1−4アルキル)およびN(C1−4アルキル)2からなる群から選択され;
Riiはヒドロキシ、またはC1−4アルコキシであり;
Riiiは、ヒドロキシであり;
R3は、
Raは、水素、またはC1−4アルコキシであり;
Rbは、水素、またはハロゲンであり;
Rcは、水素、またはC1−4アルキルである。 - R1は、水素またはフルオロであることを特徴とする、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- R2のアリールまたはヘテロアリールの置換基は、
- R2はフェニルであり、
前記フェニルは非置換されたり、または、
Riはヒドロキシ、O−CH2CH2−O−CH3、OCO−NH2、モルホリノ、アミノ、NH(C1−4アルキル)およびN(C1−4アルキル)2からなる群から選択され、
Riiはヒドロキシ、またはC1−4アルコキシであり、
Riiiはヒドロキシであることを特徴とする、請求項1に記載の化合物、またはその薬学的に許容可能な塩。 - R2は、ピリジニルであり、
前記ピリジニルは非置換されたり、または、
Riiはヒドロキシであることを特徴とする請求項1に記載の化合物、またはその薬学的に許容可能な塩。 - R2は、ピラゾリルであり、
前記ピラゾリルは非置換されたり、またはC1−4アルキル、SO2−(C1−4アルキル)またはピペリジニルで置換されたことを特徴とする、請求項1に記載の化合物、またはその薬学的に許容可能な塩。 - R2は、インドリル、ピラジニル、ピリミジニル、チアゾリルまたはチエニルであり、
前記インドリル、ピラジニル、ピリミジニル、チアゾリルまたはチエニルは非置換されたことを特徴とする、請求項1に記載の化合物、またはその薬学的に許容可能な塩。 - Raは、水素、メトキシ、またはエトキシであることを特徴とする請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- Rbは水素、またはフルオロであることを特徴とする、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- Rcは水素、またはメチルであることを特徴とする、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- 前記一般式(1)で表される化合物は、
1)4−エトキシ−N−(3−フルオロ−4−((5−(3−(ヒドロキシメチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
2)4−エトキシ−N−(3−フルオロ−4−((5−フェニルピロール[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
3)4−エトキシ−N−(3−フルオロ−4−((5−(ピリジン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
4)4−エトキシ−N−(3−フルオロ−4−((5−チアゾール−2−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
5)4−エトキシ−N−(2−フルオロ−4−((ピラジン−2−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
6)4−エトキシ−N−(2−フルオロ−4−((5−(1−メチル−1H−ピラゾール−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
7)4−エトキシ−N−(3−フルオロ−4−((5−ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
8)4−エトキシ−N−(3−フルオロ−4−((5−(ピリミジン−5−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
9)4−エトキシ−N−(3−フルオロ−4−((5−(6−メトキシピリジン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
10)4−エトキシ−N−(3−フルオロ−4−((5−(チオフェン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
11)4−エトキシ−N−(3−フルオロ−4−((5−(4−メトキシフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
12)4−エトキシ−N−(3−フルオロ−4−((5−(2−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
13)N−(4−((5−(3,4−ジメトキシフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
14)4−エトキシ−N−(3−フルオロ−4−((5−(4−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
15)4−エトキシ−N−(3−フルオロ−4−((5−(チオフェン−2−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
16)N−(4−((5−(2−クロロピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
17)N−(4−((5−(1H−ピラゾール−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
18)4−エトキシ−N−(3−フルオロ−4−((5−(1−メチルスルホニル)−1H−ピラゾール−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
19)4−エトキシ−N−(3−フルオロ−4−((5−(2−フルオロピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
20)N−(4−((5−(5−クロロ−2−メトキシピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
21)N−(4−((5−(6−アミノピリジン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
22)4−エトキシ−N−(3−フルオロ−4−((5−(1−ピペリジン−4−イル)−1H−ピラゾール−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
23)4−エトキシ−N−(3−フルオロ−4−((5−(3−ホルミルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
24)4−エトキシ−N−(3−フルオロ−4−((5−(2−(ピペラジン−1−イル)ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
25)N−(4−((5−(6−アセトアミドピリジン−3−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
26)N−(4−((5−(2−アセチルピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
27)N−(4−((5−(3−アセチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
28)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−4−メトキシ−2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−カルボキサミド、
29)N−(3−フルオロ−4−((5−(3−ヒドロキシメチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
30)4−エトキシ−N−(4−((5−(3−(エチルスルホニル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
31)4−エトキシ−N−(3−フルオロ−4−((5−(3−(メチルスルホニル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
32)4−エトキシ−N−(3−フルオロ−4−((5−(3−スルファモイルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
33)N−(4−((5−(3−アセチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
34)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−4−メトキシ−2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−カルボキサミド、
35)N−(4−((5−(3−(N,N−ジメチルスルファモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
36)N−(4−((5−(3−(N,N−ジメチルスルファモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
37)4−エトキシ−N−(3−フルオロ−4−((5−(4−ニトロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
38)N−(4−((5−(4−アミノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
39)4−エトキシ−N−(3−フルオロ−4−((5−(3−((2−メトキシエトキシ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
40)N−(3−フルオロ−4−((5−(2−メトキシピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
41)N−(4−((5−(3−(ジメチルカルバモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
42)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキシアミド、
43)4−エトキシ−N−(3−フルオロ−4−((5−(3−(2−ヒドロキシプロパン−2−イル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
44)4−エトキシ−N−(3−フルオロ−4−((5−(3−(メチルカルバモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
45)3−(4−(4−(4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド)−2−フルオロフェノキシ)ピロロ[1,2−b]ピリダジン−5−イル)ベンジルカルバメート、
46)4−エトキシ−N−(3−フルオロ−4−((5−(3−(1−ヒドロキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
47)N−(3−フルオロ−4−((5−(3−(1−ヒドロキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
48)N−(3−フルオロ−4−((5−(3−(1−ヒドロキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−4−メトキシ−2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−カルボキサミド、
49)4−エトキシ−N−(3−フルオロ−4−((5−(ピリミジン−5−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
50)4−エトキシ−N−(3−フルオロ−4−((5−(3−モルホリン−4−カルボニル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
51)4−エトキシ−N−(3−フルオロ−4−((5−(2−モルホリノピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
52)4−エトキシ−N−(3−フルオロ−4−((5−(3−ニトロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
53)4−エトキシ−N−(3−フルオロ−4−((5−(3−アミノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
54)4−エトキシ−N−(3−フルオロ−4−((5−(3−(1−メトキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
55)N−(3−フルオロ−4−((5−(3−(1−ヒドロキシエチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
56)N−(4−((5−(3−((ジメチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
57)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
58)4−エトキシ−N−(4−((5−(2−エトキシピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)−オキシ)−3−フルオロフェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
59)4−エトキシ−N−(3−フルオロ−4−((5−(2−メトキシピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
60)N−(3−フルオロ−4−((5−(ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−4−エトキシ−2−オキソ−1−フェニル−1,2−ジヒドロピリジン−3−カルボキサミド、
61)N−(4−((5−(2,6−ジメチルピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
62)N−(4−((5−(2−(1−ヒドロキシエチル)ピリジン−4−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
63)N−(4−((5−(3−((ジメチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
64)N−(4−((5−(3−アミノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
65)N−(4−((5−(3−アセトアミドフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
66)N−(4−((5−(3−アミノ−4−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
67)N−(4−((5−(3−アミノ−5−シアノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
68)N−(4−((5−(3−((ジメチルアミノ)メチル)フェニル)ピロロ[1,2−bピリダジン−4−イル]オキシ)−3−フルオロフェニル)−1−(4−フルオロフェニル)−6−メチル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミド、
69)N−(4−((5−(3−カルバモイルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
70)N−(4−((5−(3−アミノメチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
71)N−(4−((5−(3−ヒドロキシメチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
72)N−(4−((5−(3−(メチルアミノ)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
73)N−(4−((5−(3−(エチルアミノ)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
74)N−(4−((5−(1H−インドール−6−イル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
75)N−(4−((5−(2−クロロ−5−((ジメチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
76)N−(4−((5−(5−((ジメチルアミノ)メチル)−2−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
77)N−(4−((5−(3−((ジメチルアミノ)メチル)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
78)N−(4−((5−(3−アミノ−4−メチル)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
79)N−(4−((5−(3−アミノ−2−メチル)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
80)N−(3−フルオロ−4−((5−(3−((メチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)フェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
81)N−(4−((5−(3−((エチルアミノ)メチル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
82)N−(4−((5−(3−アミノ−4−メトキシ)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
83)N−(4−((5−(5−アミノ−2−フルオロ)−5−フルオロフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
84)N−(4−((5−(3−(メチルカルバモイル)フェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、
85)N−(4−((5−(3−シアノメチルフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−N−(4−フルオロフェニル)シクロプロパン−1,1−ジカルボキサミド、および
86)N−(4−((5−3−アミノフェニル)ピロロ[1,2−b]ピリダジン−4−イル)オキシ)−3−フルオロフェニル)−1−(4−フルオロフェニル)−6−メチル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミドからなる群から選択されることを特徴とする、請求項1に記載の化合物、またはその薬学的に許容可能な塩。 - 請求項1〜11のいずれか1項に記載の化合物、またはその薬学的に許容可能な塩を有効成分として含む薬学的組成物。
- 前記薬学的組成物は、薬学的に許容される担体、希釈剤または賦形剤をさらに含むことを特徴とする、請求項12に記載の薬学的組成物。
- 請求項1〜11のいずれか1項に記載の化合物、またはその薬学的に許容可能な塩を有効成分として含む組成物を使用してタンパク質キナーゼの活性を阻害する方法。
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