JP2022547436A - イミダゾピリジン誘導体及びこれを有効成分として含有する薬学的組成物 - Google Patents
イミダゾピリジン誘導体及びこれを有効成分として含有する薬学的組成物 Download PDFInfo
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- JP2022547436A JP2022547436A JP2022513547A JP2022513547A JP2022547436A JP 2022547436 A JP2022547436 A JP 2022547436A JP 2022513547 A JP2022513547 A JP 2022513547A JP 2022513547 A JP2022513547 A JP 2022513547A JP 2022547436 A JP2022547436 A JP 2022547436A
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- Prior art keywords
- imidazo
- dimethyl
- pyrrol
- bromo
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 20
- 239000004480 active ingredient Substances 0.000 title claims abstract description 16
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 title abstract 3
- 230000000694 effects Effects 0.000 claims abstract description 59
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 42
- 201000011510 cancer Diseases 0.000 claims abstract description 40
- 102000001253 Protein Kinase Human genes 0.000 claims abstract description 28
- 108060006633 protein kinase Proteins 0.000 claims abstract description 28
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 26
- 206010022000 influenza Diseases 0.000 claims abstract description 15
- 208000014644 Brain disease Diseases 0.000 claims abstract description 12
- 230000003412 degenerative effect Effects 0.000 claims abstract description 12
- 230000002265 prevention Effects 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 199
- 125000000217 alkyl group Chemical group 0.000 claims description 94
- 125000001072 heteroaryl group Chemical group 0.000 claims description 77
- 125000003118 aryl group Chemical group 0.000 claims description 70
- 125000000623 heterocyclic group Chemical group 0.000 claims description 60
- 125000001424 substituent group Chemical group 0.000 claims description 46
- -1 Benzenesulfonamide (3-((6-bromo-2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-yl) amino)benzenesulfonamide) Chemical compound 0.000 claims description 34
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 31
- 239000000126 substance Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
- 239000012453 solvate Substances 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 15
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- 101001005602 Homo sapiens Mitogen-activated protein kinase kinase kinase 11 Proteins 0.000 claims description 14
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- CMIBWIAICVBURI-ZETCQYMHSA-N tert-butyl (3s)-3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](N)C1 CMIBWIAICVBURI-ZETCQYMHSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 150000004867 thiadiazoles Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003441 thioacyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 150000003918 triazines Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
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Abstract
Description
Arは、C6-C20アリールまたは5~20員環ヘテロアリールであり、
R1、R2、及びR3は、互いに独立的に、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C20アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルコキシアルキル、C1-C6アミノアルキル、C2-C20アルケニル、C2-C20アルキニル、C1-C8アルコキシ、C3-C12シクロアルキル、C4-C12シクロアルキルアルキル、3~12員環ヘテロシクリル、3~12員環ヘテロシクリルアルキル、C6-C20アリール、及び5~20員環ヘテロアリールからなる群より選択され、
前記Ra、Rb、及びRcは、互いに独立的に、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、C1-C20アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルコキシアルキル、C1-C6アミノアルキル、C2-C20アルケニル、C2-C20アルキニル、C1-C8アルコキシ、C3-C12シクロアルキル、C4-C12シクロアルキルアルキル、3~12員環ヘテロシクリル、3~12員環ヘテロシクリルアルキル、C6-C20アリール、及び5~20員環ヘテロアリールからなる群より選択され、
前記lは、0~3の整数であり、mは、0~3の整数であり、
ここで、前記アルキル、ハロアルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、アリール、及びヘテロアリールは、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C10アルキル、C1-C4ハロアルキル、C1-C4ヒドロキシアルキル、C1-C4アルコキシアルキル、C1-C4アミノアルキル、C2-C10アルケニル、C2-C10アルキニル、C1-C4アルコキシ、C3-C10シクロアルキル、C4-C10シクロアルキルアルキル、3~10員環ヘテロシクリル、3~10員環ヘテロシクリルアルキル、C6-C12アリール、及び5~12員環ヘテロアリールからなる群より選択された1つ以上の置換基に置換されることができる。
R1~R3、l、及びmは、前記化学式1の定義と同一であり、
R4は、互いに独立的に水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C10アルキル、C1-C4ハロアルキル、C1-C4ヒドロキシアルキル、C1-C4アルコキシアルキル、C1-C4アミノアルキル、C2-C10アルケニル、C2-C10アルキニル、C1-C4アルコキシ、C3-C10シクロアルキル、C4-C10シクロアルキルアルキル、3~10員環ヘテロシクリル、3~10員環ヘテロシクリルアルキル、C6-C12アリール、及び5~12員環ヘテロアリールからなる群より選択されるか、隣り合った基同士に互いに結合して環を形成でき、
nは、0~5の整数であり、
ここで、前記アルキル、ハロアルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、アリール、及びヘテロアリールは、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C10アルキル、C1-C4ハロアルキル、C1-C4ヒドロキシアルキル、C1-C4アルコキシアルキル、C1-C4アミノアルキル、C2-C10アルケニル、C2-C10アルキニル、C1-C4アルコキシ、C3-C10シクロアルキル、C4-C10シクロアルキルアルキル、3~10員環ヘテロシクリル、3~10員環ヘテロシクリルアルキル、C6-C12アリール、及び5~12員環ヘテロアリールからなる群より選択された1つ以上の置換基にさらに置換されることができる。
R1~R4、m、及びnは、前記化学式2の定義と同一であり、
pは、0~2の整数であり、
R5及びR6は、互いに独立的に、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、C1-C20アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルコキシアルキル、C1-C6アミノアルキル、C2-C20アルケニル、C2-C20アルキニル、C1-C8アルコキシ、C3-C12シクロアルキル、C4-C12シクロアルキルアルキル、3~12員環ヘテロシクリル、3~12員環ヘテロシクリルアルキル、C6-C20アリール、及び5~20員環ヘテロアリールからなる群より選択され、
ここで、前記アルキル、ハロアルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、アリール、及びヘテロアリールは、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C10アルキル、C1-C4ハロアルキル、C1-C4ヒドロキシアルキル、C1-C4アルコキシアルキル、C1-C4アミノアルキル、C2-C10アルケニル、C2-C10アルキニル、C1-C4アルコキシ、C3-C10シクロアルキル、C4-C10シクロアルキルアルキル、3~10員環ヘテロシクリル、3~10員環ヘテロシクリルアルキル、C6-C12アリール、及び5~12員環ヘテロアリールからなる群より選択された1つ以上の置換基に置換されることができる。
本発明の化合物等は、一例として次のような合成方法1~3により製造されることができる。
4-morpholinoaniline(1eq)、hexane-2,5-dione(1eq)、MeOH、ceric ammonium nitrate(0.05eq)を混合した後、常温で3時間攪拌させる。反応混合物を減圧下で濃縮した。粗生性物をコラムクロマトグラフィー(silicagel、Hexane/EtOAc)で精製して目的化合物aを得た(74%)。
4-chloropyridin-2-amine(1eq)、N-bromosuccinimide(1.05eq)、acetonitrileを混合した後、常温で12時間攪拌させる。反応混合物を減圧下で濃縮した後、EtOAcで希釈し、1N NaOH、水、brineで洗浄し、Na2SO4で乾燥させた後、濃縮した。粗生性物を再結晶(DCM/Hxane)して目的化合物cを得た(70%)。
前記合成例で収得した化合物b(1eq)と化合物g(1eq)、sodium dithionite(4.09eq)、EtOHを混合した後、2日の間攪拌させる。反応混合物を減圧下で濃縮した後、EtOAcで希釈し、水とbrineで洗浄してNa2SO4で乾燥させた後、濃縮した。粗生性物は、カラムクロマトグラフィー(silicagel column、Hxane/EtOAc)で精製して最終生成物hを得た(60%)。1H NMR (300 MHz, DMSO-d6) δ 1.19 (t, J = 7.3 Hz, 3H), 1.98 (s, 3H), 2.10 (m, 1H), 2.31 (m, 1H), 2.37 (s, 3H), 3.09 (q, J = 7.5 Hz 2H), 3.20 (t, J = 4.4 Hz, 4H), 3.30 (m, 1H), 3.35 (m, 1H), 3.50(m, 1H), 3.68 (m, 1H), 3.75 (d, J= 4.4 Hz, 4H), 5.62 (m, 1H), 5.75 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 7.07 (d, J = 9 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.96 (s, 1H), 12.66 (s, 1H)
前記実施例化合物のキナーゼ阻害活性測定のために、各キナーゼ別プロトコルによって分析を行った。
MLK1キナーゼ蛋白質と化合物を8mM MOPS pH7.0、0.2mM EDTA、2mg/mL casein、10mM Magnesium acetate、及び[γ-33P]-ATPが含有された緩衝液システムに添加した後、前記システムにMg/ATP混合物を添加して反応を開始した。室温で40分間培養した後、0.5%のphosphoric acidを添加して反応を終結させた。10μLの反応混合物をP30フィルタマット(filtermat)に点で打ち、0.425% phosphoric acidに4回、総4分間洗浄した。メタノールで1回洗浄した後、フィルタマットを乾燥させ、閃光計測した。
MLK2キナーゼ蛋白質と化合物を8mM MOPS pH7.0、0.2mM EDTA、0.33mg/mL myelin basic protein、10mM Magnesium acetate、及び[γ-33P]-ATPが含有された緩衝液システムに添加した後、前記システムにMg/ATP混合物を添加して反応を開始した。室温で40分間培養した後、0.5%のphosphoric acidを添加して反応を終結させた。10μLの反応混合物をP30フィルタマットに点で打ち、0.425% phosphoric acidに4回、総4分間洗浄した。メタノールで1回洗浄した後、フィルタマットを乾燥させ、閃光計測した。
MLK3キナーゼ蛋白質と化合物を8mM MOPS pH7.0、0.2mM EDTA、0.33mg/mL myelin basic protein、5mM DTT、10mM Magnesium acetate、及び[γ-33P]-ATPが含有された緩衝液システムに添加した後、前記システムにMg/ATP混合物を添加して反応を開始した。室温で120分間培養した後、0.5%のphosphoric acidを添加して反応を終結させた。10μLの反応混合物をP30フィルタマットに点で打ち、0.425% phosphoric acidに4回、総4分間洗浄した。メタノールで1回洗浄した後、フィルタマットを乾燥させ、閃光計測した。
化合物のMLK3活性抑制関連作用機序を確認するために、人間の乳がん細胞株MDA-MB-231を活用して、実施例7の化合物を3μMの濃度で処理し、MLK3の下位信号伝達蛋白質であるMKK3、p38、paxillinのリン酸化様相をウェスタンブロットで確認して、図1に示した。
化合物の坑癌活性可否を確認するために、人間の乳がん細胞株MDA-MB-231、大腸癌細胞株HT-29、急性骨髄性白血病細胞株U937、慢性骨髄性白血病細胞株K562を活用した。前記細胞株は、10%牛胎児血清が含まれたRPMI-1640培地を活用して培養した。培地は、welgene社製品を、牛胎児血清は、hyclone社製品を使用し、培養培地には、Gibco社の細胞培養用抗生剤1%が含まれるようにして使用した。
化合物の坑癌活性可否を確認するために、急性骨髄性白血病細胞株U937、急性リンパ芽球性白血病細胞株Jurkat、胃癌細胞株AGS、Hs76T、及び人間の肺癌細胞株A549を活用した。前記細胞株は、10%牛胎児血清が含まれたRPMI-1640培地(U937、Jurkat、AGS、A549)またはDMEM(Hs746T)培地を活用して培養した。培地は、welgene社製品を、牛胎児血清は、hyclone社製品を使用し、培養培地には、Gibco社の細胞培養用抗生剤1%が含まれるようにして使用した。
化合物の濃度による坑癌活性可否を確認するために、人間の乳がん細胞株MDA-MB-231及び急性T細胞白血病細胞株Jurkatを活用して、実施例7の化合物を0.1、0.3、1、3、10、30μMの濃度で処理して前記実験例3と同じ方法で坑癌活性を評価し、50%抑制する濃度をエクセルプログラムを活用して計算し、IC50値で表記した。
化合物の濃度による坑癌活性可否を確認するために、人間の胃癌細胞株HS746Tを活用して、実施例の化合物を各々0.1、0.3、1、3、10、30μMの濃度で処理して前記実験例3と同じ方法で坑癌活性を評価し、50%抑制する濃度をエクセルプログラムを活用して計算し、IC50値で表記した。参考として、「N.T.」で表示された部分は、「Not Tested」を意味する。
化合物の癌転移抑制効果を確認するために、人間の乳がん細胞株MDA-MB-231を使用した。ImageLock96-ウェルプレート(Essen BioScience)に15,000細胞/ウェルで24時間培養した後、無血青培地に交替した。96-ウェルWound maker(Essen BioScience)を使用してウェル毎に均一に細胞を掻いて傷(Wound)を形成し、各々1または3μMの濃度で化合物を処理し、12時間毎にIncuCyte softwareを利用してWoundの残っている距離を測定した。全ての実験は、3回繰り返し、図3は、Wound形成以後、60時間経過結果を示した写真である。
化合物の非アルコール性脂肪性肝疾患の症状抑制可否を確認するために、人間肝癌細胞株HepG2をATCC社から購買して使用した。前記細胞株は、Gibco社のFBS(Fetal Bovine Serum) 10%、penicillin 100U/mL、streptomycin 100μg/mLを添加したDMEM(Dulbecco’s modification of Eagle’s medium)を使用して、5% CO2、37℃環境で培養した。
相対的発現抑制程度(%)=100-相対的発現程度(%)=100-[(実験群-非誘導群)/(陰性対照群-非誘導群)x100(%)]
化合物の非アルコール性脂肪肝炎予防及び治療効果を確認するために、人間肝癌細胞株HepG2をATCCから購買して使用した。前記細胞株は、Gibco社のFBS(Fetal Bovine Serum) 10%、penicillin 100U/mL、streptomycin 100μg/mLを添加したDMEM(Dulbecco’s modification of Eagle’s medium)を使用して、5% CO2、37℃環境で培養した。
化合物の非アルコール性脂肪性肝疾患に対する効果を確認するために、6週齢のC57BL/6Jマウスにメチオニンとコリン欠乏(MCD)食餌を給与した非アルコール性脂肪肝炎動物モデルを使用した。正常食餌群は、正常食餌(Chow)を自律給与し、MCD群は、MCD食餌を8週間の自律給与を介して非アルコール性脂肪肝炎モデルに誘導されるようにした(Molecules 2014、19、8189-8211)。動物は、23±2℃の温度と55±5%の相対湿度で維持される換気が良い環境条件で飼育された。一日に約12時間の間、蛍光灯照明を提供し、周1回、寝藁を交替した。
本発明による実施例化合物のLRRK2野生型とLRRK2の突然変異(G2019S)キナーゼに対する活性抑制効果を確認するために、BL21由来の大腸菌バクテリア(E.coli)を24-ウェルプレートで成長期(log phase)まで培養させた後、LRRK2野生型またはLRRK2突然変異(G2019S)がタグされたT7ファージを使用してMOI(Multiplicity of infection)を0.4で感染させた。その後、32℃で90~150分間、大腸菌バクテリアを攪拌して溶解がなされ得るようにした。大腸菌バクテリアの溶解物を遠心分離し(6,000xg)、ろ過して(0.2μm)得られたタグされたT7ファージをHEK293細胞に形質感染させ、DNAがタグされたキナーゼ蛋白質(LRRK2 or LRRK2 G2019S)を収得した。
本発明による実施例化合物のLRRK2キナーゼのリン酸化抑制効果を確認するために、LRRK2発現細胞朱として知られているNIH-3T3細胞株を使用し、Gibco社のFBS 10%とPenicillin/Streptomycin 1%とを添加したDMEM培地を使用して、5% CO2、37℃環境で培養した。
本発明による実施例化合物の神経損傷に対する保護効果を確認するために、妊娠15日になった白ネズミ(Rat)から胎児を分離した後、大脳皮質部位を摘出して一次大脳皮質神経細胞として使用した。12-ウェルプレートに2×105細胞数に分周して24時間の間培養した後、Gibco社のNeurobasal培地に交替した後、培養した。in vitro 11日目にInvitrogen社のLipofectamineとOpti-MEMとを使用してLRRK2 G22019Sを形質転換(transfection)し、6時間後、実施例化合物または比較化合物を0.01、0.1,1μM濃度で処理した。その後、4% PFAを処理して細胞を固定させた後、abcam社のGFP抗体を使用して免疫染色して神経突起を観察した。神経突起の長さ変化を介して各化合物の神経損傷に対する保護効果を評価した。前記実験の結果を図8に示した。
化合物のインフルエンザ活性抑制効果を確認するために、96-ウェルプレートに十分に育ったMDCK細胞株をリン酸緩衝食塩水(phosphate-buffered saline、PBS)で洗浄した後、50-100プラーク形成単位(plaque forming units、PFU)のインフルエンザウイルスをウェル毎に接種した。1時間ぐらいウイルスが細胞に感染されるように35℃で放置した。培養液を除去し、リン酸緩衝食塩水で洗浄した後、各実施例化合物が様々な濃度で希釈された2μg/ml TPCK-trypsin包含のMEM培養液をウェル毎に添加した。感染後、3日目になる日、MTT(Sigma)を使用して細胞活性を評価した[Jang YJ et.al.,(2014).Antiviral Res 107:66-75.].540nmと690nm波長での吸光度を測定して、50%細胞毒性濃度(CC50)と50%有効濃度(EC50)とを計算した。
化合物のインフルエンザ活性抑制効果を確認するために、24-ウェルプレートに十分に育った人間肺癌細胞株であるA549細胞株をリン酸緩衝食塩水(phosphate-buffered saline、PBS)で洗浄した後、各ウェル毎に14,000プラーク形成単位(plaque forming units、PFU)のインフルエンザウイルス(A/PR8)を接種した。細胞にウイルスが感染されるように1時間の間35℃で培養した。培養液を除去し、リン酸緩衝食塩水で洗浄した後、各実施例化合物が11,33、100μM濃度で希釈された0.1μg/ml TPCK-trypsin包含RPMI培養液を各ウェル毎に添加して35℃で培養した。
動物モデルで化合物のインフルエンザ活性抑制効果を確認するために、mouse-adaptationされたPR8(以下、「maPR8」という)ウイルスを感染させたマウスモデルを使用した。前記モデルは、鼻腔経路を介して3MLD50(aマウス半数致死量)の力価に該当するウイルスを7週齢のBalb/cマウスに感染させて確立した。治療効果を観察するために、ウイルス感染の一日前に(day 0)実施例4化合物を腹腔投与した。動物実験が進行される期間の間、実験群(実施例4化合物)を1日1回、10mg/kg/dayの濃度で9日間毎日投与した。グループ当たり3匹のマウスを使用し、抗ウイルスの効能は、体重の測定を方法とし、実験開始時点を基準に体重の減少が30%以上進行された個体は安楽死をさせた(化学研究院の動物実験委員会規定に基づく)[Shin JS et.al.,(2017)J Microbiol.55:979-983]。
Claims (16)
- 下記の化学式1で表示される化合物またはこれの立体異性体、溶媒和物、水和物、または薬学的に許容される塩:
Arは、C6-C20アリールまたは5~20員環ヘテロアリールであり、
R1、R2、及びR3は、互いに独立的に、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C20アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルコキシアルキル、C1-C6アミノアルキル、C2-C20アルケニル、C2-C20アルキニル、C1-C8アルコキシ、C3-C12シクロアルキル、C4-C12シクロアルキルアルキル、3~12員環ヘテロシクリル、3~12員環ヘテロシクリルアルキル、C6-C20アリール、及び5~20員環ヘテロアリールからなる群より選択され、
前記Ra、Rb、及びRcは、互いに独立的に、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、C1-C20アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルコキシアルキル、C1-C6アミノアルキル、C2-C20アルケニル、C2-C20アルキニル、C1-C8アルコキシ、C3-C12シクロアルキル、C4-C12シクロアルキルアルキル、3~12員環ヘテロシクリル、3~12員環ヘテロシクリルアルキル、C6-C20アリール、及び5~20員環ヘテロアリールからなる群より選択され、
前記lは、0~3の整数であり、mは、0~3の整数であり、
ここで、前記アルキル、ハロアルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、アリール、及びヘテロアリールは、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C10アルキル、C1-C4ハロアルキル、C1-C4ヒドロキシアルキル、C1-C4アルコキシアルキル、C1-C4アミノアルキル、C2-C10アルケニル、C2-C10アルキニル、C1-C4アルコキシ、C3-C10シクロアルキル、C4-C10シクロアルキルアルキル、3~10員環ヘテロシクリル、3~10員環ヘテロシクリルアルキル、C6-C12アリール、及び5~12員環ヘテロアリールからなる群より選択された1つ以上の置換基に置換されることができる。 - 下記の化学式2で表示される請求項1に記載の化合物またはこれの立体異性体、溶媒和物、水和物、または薬学的に許容される塩:
R1~R3、l、及びmは、前記化学式1の定義と同一であり、R4は、互いに独立的に水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C10アルキル、C1-C4ハロアルキル、C1-C4ヒドロキシアルキル、C1-C4アルコキシアルキル、C1-C4アミノアルキル、C2-C10アルケニル、C2-C10アルキニル、C1-C4アルコキシ、C3-C10シクロアルキル、C4-C10シクロアルキルアルキル、3~10員環ヘテロシクリル、3~10員環ヘテロシクリルアルキル、C6-C12アリール、及び5~12員環ヘテロアリールからなる群より選択されるか、隣り合った基同士に互いに結合して環を形成でき、
nは、0~5の整数であり、
ここで、前記アルキル、ハロアルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、アリール、及びヘテロアリールは、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C10アルキル、C1-C4ハロアルキル、C1-C4ヒドロキシアルキル、C1-C4アルコキシアルキル、C1-C4アミノアルキル、C2-C10アルケニル、C2-C10アルキニル、C1-C4アルコキシ、C3-C10シクロアルキル、C4-C10シクロアルキルアルキル、3~10員環ヘテロシクリル、3~10員環ヘテロシクリルアルキル、C6-C12アリール、及び5~12員環ヘテロアリールからなる群より選択された1つ以上の置換基にさらに置換されることができる。 - 下記の化学式5で表示される請求項2に記載の化合物またはこれの立体異性体、溶媒和物、水和物、または薬学的に許容される塩:
pは、0~2の整数であり、
R5及びR6は、互いに独立的に、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、C1-C20アルキル、C1-C6ハロアルキル、C1-C6ヒドロキシアルキル、C1-C6アルコキシアルキル、C1-C6アミノアルキル、C2-C20アルケニル、C2-C20アルキニル、C1-C8アルコキシ、C3-C12シクロアルキル、C4-C12シクロアルキルアルキル、3~12員環ヘテロシクリル、3~12員環ヘテロシクリルアルキル、C6-C20アリール、及び5~20員環ヘテロアリールからなる群より選択され、
ここで、前記アルキル、ハロアルキル、ヒドロキシアルキル、アルコキシアルキル、アミノアルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、アリール、及びヘテロアリールは、各々水素、ハロゲン、ヒドロキシ、シアノ、ニトロ、-SRa、-S(=O)Ra、-S(=O)2Ra、-NRbRc、-CO2Rb、-CO-NRbRc、C1-C10アルキル、C1-C4ハロアルキル、C1-C4ヒドロキシアルキル、C1-C4アルコキシアルキル、C1-C4アミノアルキル、C2-C10アルケニル、C2-C10アルキニル、C1-C4アルコキシ、C3-C10シクロアルキル、C4-C10シクロアルキルアルキル、3~10員環ヘテロシクリル、3~10員環ヘテロシクリルアルキル、C6-C12アリール、及び5~12員環ヘテロアリールからなる群より選択された1つ以上の置換基に置換されることができる。 - 前記化学式1で表示される化合物は、下記化合物等で構成された群より選択される請求項1に記載の化合物またはこれの立体異性体、溶媒和物、水和物、または薬学的に許容される塩:
1)(S)-6-ブロモ-2-(2,5-ジメチル-1-(4-モルホリノフェニル)-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-3H -イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-2-(2,5-dimethyl-1-(4-morpholinophenyl)-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b] pyridine-7-amine);
2)(S)-6-ブロモ-2-(2,5-ジメチル-1-(3-モルホリノフェニル)-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-2-(2,5-dimethyl-1-(3-morpholinophenyl)-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-amine);
3)(S)-6-ブロモ-2-(2,5-ジメチル-1-(3-(2-モルホリノエトキシ)フェニル)-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-2-(2,5-dimethyl-1-(3-(2-morpholinoethoxy)phenyl)-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-1H-imidazo[4,5-b]pyridine-7-amine);
4)(S)-6-ブロモ-2-(2,5-ジメチル-1-(4-(2-モルホリノエトキシ)フェニル)-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-2-(2,5-dimethyl-1-(4-(2-morpholinoethoxy)phenyl)-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-1H-imidazo[4,5-b]pyridine-7-amine);
5)(S)-(4-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)(モルホリノ)メタノン((S)-(4-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)(morpholino)methanone);
6)(S)-(3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)(モルホリノ)メタノン((S)-(3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)(morpholino)methanone);
7)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)メタンスルホンアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)methanesulfonamide);
8)N-(4-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-3-メチルフェニル)メタンスルホンアミド(N-(4-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-3-methylphenyl)methanesulfonamide);
9)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-2-メチルフェニル)メタンスルホンアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)methanesulfonamide);
10)(S)-6-ブロモ-2-(2,5-ジメチル-1-(4-(モルホリノスルホニル)フェニル)-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-2-(2,5-dimethyl-1-(4-(morpholinosulfonyl)phenyl)-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-amine);
11)(S)-6-ブロモ-2-(2,5-ジメチル-1-(3-(モルホリノスルホニル)フェニル)-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-2-(2,5-dimethyl-1-(3-(morpholinosulfonyl)phenyl)-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-amine);
12)(S)-N-(3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)メタンスルホンアミド((S)-N-(3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)methanesulfonamide);
13)(S)-6-ブロモ-2-(1-(2,6-ジクロロフェニル)-2,5-ジメチル-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-2-(1-(2,6-dichlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-amine);
14)6-ブロモ-2-(1-(2,5-ジクロロフェニル)-2,5-ジメチル-1H-ピロール-3-イル)-N-((S)-1-(エチルスルホニル)ピロリジン-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン(6-bromo-2-(1-(2,5-dichlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-N-((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-amine);
15)(S)-6-ブロモ-2-(1-(3,4-ジクロロフェニル)-2,5-ジメチル-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-2-(1-(3,4-dichlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-amine);
16)6-ブロモ-2-(1-(2-クロロフェニル)-2,5-ジメチル-1H-ピロール-3-イル)-N-((S)-1-(エチルスルホニル)ピロリジン-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン(6-bromo-2-(1-(2-chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-N-((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-amine);
17)3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-クロロベンゼンスルホンアミド(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-chlorobenzenesulfonamide);
18)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-メチルベンゼンスルホンアミド((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-methylbenzenesulfonamide);
19)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-エチルベンゼンスルホンアミド((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-ethylbenzenesulfonamide);
20)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)ベンズアミド((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)benzamide);
21)(S)-6-ブロモ-N-(1-(エチルスルホニル)ピロリジン-3-イル)-2-(1-(3-(2-メトキシエトキシ)フェニル)-2,5-ジメチル-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-2-(1-(3-(2-methoxyethoxy)phenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-amine);
22)(S)-6-ブロモ-N-(1-(エチルスルホニル)ピロリジン-3-イル)-2-(1-(4-(2-メトキシエトキシ)フェニル)-2,5-ジメチル-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-2-(1-(4-(2-methoxyethoxy)phenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-amine);
23)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)ベンゼンスルホンアミド((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)benzenesulfonamide);
24)(S)-4-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)ベンゼンスルホンアミド((S)-4-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)benzenesulfonamide);
25)(S)-6-ブロモ-2-(2,5-ジメチル-1-フェニル-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-bromo-2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-amine);
26)3-((6-ブロモ-2-(1-(2,6-ジクロロフェニル)-2,5-ジメチル-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(1-(2,6-dichlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
27)3-((6-ブロモ-2-(2,5-ジメチル-1-(4-(モルホリン-4-カルボニル)フェニル)-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
28)3-((6-ブロモ-2-(2,5-ジメチル-1-(3-(モルホリン-4-カルボニル)フェニル)-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(3-(morpholine-4-carbonyl)phenyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
29)3-((6-ブロモ-2-(2,5-ジメチル-1-(4-(モルホリノスルホニル)フェニル)-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(4-(morpholinosulfonyl)phenyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
30)3-((6-ブロモ-2-(2,5-ジメチル-1-(3-(モルホリノスルホニル)フェニル)-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(3-(morpholinosulfonyl)phenyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
31)3-((6-ブロモ-2-(1-(2-クロロフェニル)-2,5-ジメチル-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(1-(2-chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
32)3-((6-ブロモ-2-(2,5-ジメチル-1-(2-メチル-4-(メチルスルホンアミド)フェニル)-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(2-methyl-4-(methylsulfonamido)phenyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
33)3-((6-ブロモ-2-(2,5-ジメチル-1-(2-メチル-5-(メチルスルホンアミド)フェニル)-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(2-methyl-5-(methylsulfonamido)phenyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
34)3-((6-ブロモ-2-(2,5-ジメチル-1-(2-メチル-3-(メチルスルホンアミド)フェニル)-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(2-methyl-3-(methylsulfonamido)phenyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
35)3-((6-ブロモ-2-(1-(2,5-ジクロロフェニル)-2,5-ジメチル-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(1-(2,5-dichlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
36)3-(3-(6-ブロモ-7-((3-スルファモイルフェニル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-クロロベンゼンスルホンアミド(3-(3-(6-bromo-7-((3-sulfamoylphenyl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrole-1-yl)-4-chlorobenzenesulfonamide);
37)3-((6-ブロモ-2-(2,5-ジメチル-1-(3-モルホリノフェニル)-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(3-morpholinophenyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
38)3-((6-ブロモ-2-(2,5-ジメチル-1-(3-(2-モルホリノエトキシ)フェニル)-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(3-(2-morpholinoethoxy)phenyl)-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
39)3-((6-ブロモ-2-(2,5-ジメチル-1-(4-(2-モルホリノエトキシ)フェニル)-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(4-(2-morpholinoethoxy)phenyl)-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
40)3-((6-ブロモ-2-(2,5-ジメチル-1-(4-モルホリノフェニル)-1H-ピロール-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(4-morpholinophenyl)-1H-pyrrol-3-yl)-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
41)3-((2-(1-(ベンゾ[d][1,3]ジオキソール-5-イル)-2,5-ジメチル-1H-ピロール-3-イル)-6-ブロモ-3H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((2-(1-(benzo[d][1,3]dioxole-5-yl)-2,5-dimethyl-1H-pyrrol-3-yl)-6-bromo-3H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
42)3-((6-ブロモ-2-(1-(3-(2-メトキシエトキシ)フェニル)-2,5-ジメチル-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(1-(3-(2-methoxyethoxy)phenyl)-2,5-dimethyl-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
43)3-((6-ブロモ-2-(2,5-ジメチル-1-フェニル-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
44)3-(3-(7-(ベンゾ[d][1,3]ジオキソール-5-イル-アミノ)-6-ブロモ-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)ベンゼンスルホンアミド(3-(3-(7-(benzo[d][1,3]dioxole-5-yl-amino)-6-bromo-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)benzenesulfonamide);
45)2-(1-(ベンゾ[d][1,3]ジオキソール-5-イル)-2,5-ジメチル-1H-ピロール-3-イル)-6-ブロモ-N-(4-(2-メトキシエトキシ)フェニル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン(2-(1-(benzo[d][1,3]dioxole-5-yl)-2,5-dimethyl-1H-pyrrol-3-yl)-6-bromo-N-(4-(2-methoxyethoxy)phenyl)-3H-imidazo[4,5-b]pyridine-7-amine);
46)3-(3-(6-ブロモ-7-((4-(2-メトキシエトキシ)フェニル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)ベンゼンスルホンアミド(3-(3-(6-bromo-7-((4-(2-methoxyethoxy)phenyl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)benzenesulfonamide);
47)3-((6-ブロモ-2-(2,5-ジメチル-1-(ピリジン-3-イル)-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(pyridine-3-yl)-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
48)3-((6-ブロモ-2-(2,5-ジメチル-1-(ピリジン-4-イルメチル)-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(pyridine-4-ylmethyl)-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
49)(S)-2-(1-(ベンゾ[d][1,3]ジオキソール-5-イル)-2,5-ジメチル-1H-ピロール-3-イル)-6-ブロモ-N-(1-(エチルスルホニル)ピロリジン-3-イル)-3H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-2-(1-(benzo[d][1,3]dioxole-5-yl)-2,5-dimethyl-1H-pyrrol-3-yl)-6-bromo-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-3H-imidazo[4,5-b]pyridine-7-amine);
50)N-(3-(3-(7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)メタンスルホンアミド (N-(3-(3-(7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)methanesulfonamide);
51)N-(3-(3-(6-クロロ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)メタンスルホンアミド(N-(3-(3-(6-chloro-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)methanesulfonamide);
52)(S)-6-クロロ-2-(2,5-ジメチル-1-(4-(2-モルホリノエトキシ)フェニル)-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-6-chloro-2-(2,5-dimethyl-1-(4-(2-morpholinoethoxy)phenyl)-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-1H-imidazo[4,5-b]pyridine-7-amine);
53)(S)-2-(2,5-ジメチル-1-(4-(2-モルホリノエトキシ)フェニル)-1H-ピロール-3-イル)-N-(1-(エチルスルホニル)ピロリジン-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-アミン((S)-2-(2,5-dimethyl-1-(4-(2-morpholinoethoxy)phenyl)-1H-pyrrol-3-yl)-N-(1-(ethylsulfonyl)pyrrolidine-3-yl)-1H-imidazo[4,5-b]pyridine-7-amine);
54)(S)-(3-(3-(6-クロロ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)(モルホリノ)メタノン((S)-(3-(3-(6-chloro-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)(morpholino)methanone);
55)(S)-(3-(3-(7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)(モルホリノ)メタノン((S)-(3-(3-(7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)(morpholino)methanone);
56)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(ジエチルアミノ)エチル)ベンズアミド((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(diethylamino)ethyl)benzamide);
57)(S)-4-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(ジエチルアミノ)エチル)ベンズアミド((S)-4-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(diethylamino)ethyl)benzamide);
58)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)安息香酸((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)benzoic acid);
59)(S)-4-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)安息香酸((S)-4-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)benzoic acid);
60)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-((ジメチルアミノ)メチル)ベンズアミド((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-((dimethylamino)methyl)benzamide);
61)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(ジメチルアミノ)エチル)-N-メチルベンズアミド((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide);
62)(S)-4-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(ジメチルアミノ)エチル)ベンズアミド((S)-4-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(dimethylamino)ethyl)benzamide);
63)(S)-4-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(ジメチルアミノ)エチル)-N-メチルベンズアミド((S)-4-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide);
64)(S)-N-(3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)-2-(ジメチルアミノ)アセトアミド((S)-N-(3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-2-(dimethylamino)acetamide);
65)(S)-N-(3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)-2-(4-メチルピペラジン-1-イル)アセトアミド((S)-N-(3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-2-(4-methylpiperazine-1-yl)acetamide);
66)(S)-N-(3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)-2-モルホリノアセトアミド((S)-N-(3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-2-morpholinoacetamide);
67)(S)-(4-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)(4-メチルピペラジン-1-イル)メタノン((S)-(4-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)(4-methylpiperazine-1-yl)methanone);
68)(S)-(3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)フェニル)(4-メチルピペラジン-1-イル)メタノン((S)-(3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)phenyl)(4-methylpiperazine-1-yl)methanone);
69)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-モルホリノエチル)ベンズアミド((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-morpholinoethyl)benzamide);
70)(S)-4-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-モルホリノエチル)ベンズアミド((S)-4-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-morpholinoethyl)benzamide);
71)(S)-3-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(4-メチルピペラジン-1-イル)エチル)ベンズアミド((S)-3-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(4-methylpiperazine-1-yl)ethyl)benzamide);
72)(S)-4-(3-(6-ブロモ-7-((1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(4-メチルピペラジン-1-イル)エチル)ベンズアミド((S)-4-(3-(6-bromo-7-((1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(4-methylpiperazine-1-yl)ethyl)benzamide);
73)N-(4-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-3-メチルフェニル)-2-(ジメチルアミノ)アセトアミド( N-(4-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-3-methylphenyl)-2-(dimethylamino)acetamide);
74)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)-2-(ジメチルアミノ)アセトアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)-2-(dimethylamino)acetamide);
75)N-(4-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-3-メチルフェニル)-2-(4-メチルピペラジン-1-イル)アセトアミド(N-(4-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-3-methylphenyl)-2-(4-methylpiperazine-1-yl)acetamide);
76)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)-2-(4-メチルピペラジン-1-イル)アセトアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)-2-(4-methylpiperazine-1-yl)acetamide);
77)N-(4-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-3-メチルフェニル)-2-モルホリノアセトアミド(N-(4-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-3-methylphenyl)-2-morpholinoacetamide);
78)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)-2-モルホリノアセトアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)-2-morpholinoacetamide);
79)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-2-メチルフェニル)-3-(ジメチルアミノ)プロパンアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-3-(dimethylamino)propanamide);
80)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)-3-(ジメチルアミノ)プロパンアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)-3-(dimethylamino)propanamide);
81)(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-2-メチルフェニル)(4-メチルピペラジン-1-イル)メタノン((3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)(4-methylpiperazine-1-yl)methanone);
82)3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(ジメチルアミノ)エチル)-2-メチルベンズアミド(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(dimethylamino)ethyl)-2-methylbenzamide);
83)(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-2-メチルフェニル)(モルホリノ)メタノン((3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)(morpholino)methanone);
84)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-2-メチルフェニル)-2-(ジメチルアミノ)アセトアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-2-(dimethylamino)acetamide);
85)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-2-メチルフェニル)-2-モルホリノアセトアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-2-morpholinoacetamide);
86)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-2-メチルフェニル)-3-(ジメチルアミノ)プロパンアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-3-(dimethylamino)propanamide);
87)N-(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-2-メチルフェニル)-2-(4-メチルピペラジン-1-イル)アセトアミド(N-(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl)-2-(4-methylpiperazine-1-yl)acetamide);
88)N-(3-(3-(6-ブロモ-7-((3-スルファモイルフェニル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)-2-モルホリノアセトアミド(N-(3-(3-(6-bromo-7-((3-sulfamoylphenyl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)-2-morpholinoacetamide);
89)N-(3-(3-(6-ブロモ-7-((3-スルファモイルフェニル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)-2-(4-メチルピペラジン-1-イル)アセトアミド(N-(3-(3-(6-bromo-7-((3-sulfamoylphenyl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)-2-(4-methylpiperazine-1-yl)acetamide);
90)N-(3-(3-(6-ブロモ-7-((3-スルファモイルフェニル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)-2-(ジメチルアミノ)アセトアミド(N-(3-(3-(6-bromo-7-((3-sulfamoylphenyl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)-2-(dimethylamino)acetamide);
91)(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)(モルホリノ)メタノン((3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)(morpholino)methanone);
92)(3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-4-メチルフェニル)(4-メチルピペラジン-1-イル)メタノン((3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-4-methylphenyl)(4-methylpiperazine-1-yl)methanone);
93)3-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(ジメチルアミノ)エチル)-4-メチルベンズアミド(3-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(dimethylamino)ethyl)-4-methylbenzamide);
94)3-((6-ブロモ-2-(2,5-ジメチル-1-(2-メチル-5-(モルホリン-4-カルボニル)フェニル)-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(2-methyl-5-(morpholine-4-carbonyl)phenyl)-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
95)3-((6-ブロモ-2-(2,5-ジメチル-1-(2-メチル-5-(4-メチルピペラジン-1-カルボニル)フェニル)-1H-ピロール-3-イル)-1H-イミダゾ[4,5-b]ピリジン-7-イル)アミノ)ベンゼンスルホンアミド(3-((6-bromo-2-(2,5-dimethyl-1-(2-methyl-5-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrrol-3-yl)-1H-imidazo[4,5-b]pyridine-7-yl)amino)benzenesulfonamide);
96)3-(3-(6-ブロモ-7-((3-スルファモイルフェニル)アミノ)-1H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-N-(2-(ジメチルアミノ)エチル)-4-メチルベンズアミド(3-(3-(6-bromo-7-((3-sulfamoylphenyl)amino)-1H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-N-(2-(dimethylamino)ethyl)-4-methylbenzamide);
97)(4-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-3-メチルフェニル)(4-メチルピペラジン-1-イル)メタノン((4-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-3-methylphenyl)(4-methylpiperazine-1-yl)methanone);
98)(4-(3-(6-ブロモ-7-(((S)-1-(エチルスルホニル)ピロリジン-3-イル)アミノ)-3H-イミダゾ[4,5-b]ピリジン-2-イル)-2,5-ジメチル-1H-ピロール-1-イル)-3-メチルフェニル)(モルホリノ)メタノン((4-(3-(6-bromo-7-(((S)-1-(ethylsulfonyl)pyrrolidine-3-yl)amino)-3H-imidazo[4,5-b]pyridine-2-yl)-2,5-dimethyl-1H-pyrrol-1-yl)-3-methylphenyl)(morpholino)methanone)。 - 請求項1に記載の化学式1で表示される化合物またはこれの立体異性体、溶媒和物、水和物、または薬学的に許容される塩を有効成分として含有する癌疾患の予防または治療用薬学的組成物。
- 前記化合物は、蛋白質キナーゼ活性を抑制することを特徴とする請求項7に記載の薬学的組成物。
- 前記蛋白質キナーゼは、MLK1、MLK2、MLK3、MLK4、DLK、LZK、ZAK、及びLRRK2からなる群より選択される1種以上であることを特徴とする請求項8に記載の薬学的組成物。
- 前記癌は、偽粘液腫、肝内胆管癌、肝芽腫、肝癌、甲状腺癌、結腸癌、精巣癌、骨髄異形成症候群、膠芽腫、口腔癌、口唇癌、菌状息肉症、急性骨髄性白血病、急性リンパ性白血病、基底細胞癌、上皮性卵巣がん、胚細胞腫瘍、男性乳がん、脳腫瘍、下垂体腺腫、多発性骨髄腫、胆嚢癌、胆管癌、大腸癌、慢性骨髄性白血病、慢性リンパ性白血病、網膜芽細胞腫、脈絡膜悪性黒色腫、びまん性大細胞型B細胞リンパ腫、ファーター膨大部がん、膀胱癌、腹膜癌、副甲状腺癌、副腎癌、副鼻腔癌、非小細胞肺癌、非ホジキンリンパ腫、舌癌、星細胞腫、小細胞肺癌、小児脳腫瘍、小児リンパ種、小児白血病、小腸癌、髄膜腫、食道癌、神経膠腫、神経芽細胞腫、腎盂癌、腎細胞癌、心臓腫瘍、十二指腸癌、悪性軟部腫瘍、悪性骨腫瘍、悪性リンパ種、悪性中皮腫、悪性黒色腫、眼腫瘍、外陰癌、尿管癌、尿道癌、原発不明癌、胃悪性リンパ腫、胃癌、胃カルチノイド腫瘍、消化管間質腫瘍、ウィルムス腫瘍、乳がん、肉腫、陰茎癌、咽頭癌、妊娠性絨毛性疾患、子宮頸部腺癌、子宮内膜癌、子宮肉腫、前立腺がん、転移性骨腫瘍、転移性脳腫瘍、縦隔腫瘍、直腸癌、神経内分泌腫瘍、膣癌、脊髄腫瘍、聴神経鞘腫、膵贓癌、唾液腺癌、カポジ肉腫、パジェット病、扁桃腺癌、扁平上皮癌、肺腺がん、肺癌、肺扁平上皮癌、皮膚癌、肛門癌、横紋筋肉腫、喉頭癌、胸膜腫瘍、及び胸腺癌からなる群より選択される1種以上であることを特徴とする請求項7に記載の薬学的組成物。
- 請求項1に記載の化学式1で表示される化合物またはこれの立体異性体、溶媒和物、水和物、または薬学的に許容される塩を有効成分として含有する退行性脳疾患の予防または治療用薬学的組成物。
- 前記退行性脳疾患は、アルツハイマー疾患、ダウン症候群、パーキンソン病、ルーゲーリック病、痴呆、ハンチントン病、多発性硬化症、筋萎縮性側索硬化症、中風、脳卒中、及び軽度認知障害からなる群より選択される1種以上であることを特徴とする請求項11に記載の薬学的組成物。
- 請求項1に記載の化学式1で表示される化合物またはこれの立体異性体、溶媒和物、水和物、または薬学的に許容される塩を有効成分として含有する非アルコール性脂肪性肝疾患の予防または治療用薬学的組成物。
- 前記非アルコール性脂肪性肝疾患は、非アルコール性脂肪肝、非アルコール性脂肪肝炎、肝硬変、及び肝癌からなる群より選択される1種以上であることを特徴とする請求項13に記載の薬学的組成物。
- 請求項1に記載の化学式1で表示される化合物またはこれの立体異性体、溶媒和物、水和物、または薬学的に許容される塩を有効成分として含有するインフルエンザ疾患の予防または治療用薬学的組成物。
- 前記インフルエンザは、A型インフルエンザまたはB型インフルエンザであることを特徴とする請求項15に記載の薬学的組成物。
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