JP4504375B2 - Zap−70および/またはsyk阻害剤としての2,4−ジ(ヘテロ)−アリールアミノピリミジン誘導体 - Google Patents
Zap−70および/またはsyk阻害剤としての2,4−ジ(ヘテロ)−アリールアミノピリミジン誘導体 Download PDFInfo
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- JP4504375B2 JP4504375B2 JP2006526583A JP2006526583A JP4504375B2 JP 4504375 B2 JP4504375 B2 JP 4504375B2 JP 2006526583 A JP2006526583 A JP 2006526583A JP 2006526583 A JP2006526583 A JP 2006526583A JP 4504375 B2 JP4504375 B2 JP 4504375B2
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- Prior art keywords
- alkyl
- pyrimidin
- compound
- hydrogen
- alkoxy
- 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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- 102000007624 ZAP-70 Protein-Tyrosine Kinase Human genes 0.000 title claims description 14
- 108010046882 ZAP-70 Protein-Tyrosine Kinase Proteins 0.000 title claims description 14
- 125000005842 heteroatom Chemical group 0.000 title claims description 13
- 239000003112 inhibitor Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 97
- 125000003545 alkoxy group Chemical group 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 42
- -1 terminated with OH Chemical group 0.000 claims description 38
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 19
- 150000003839 salts Chemical group 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 9
- 230000001154 acute effect Effects 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
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- 208000037976 chronic inflammation Diseases 0.000 claims description 3
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 3
- WGABHAUZGHBPON-UHFFFAOYSA-N 2-[[2-(n-amino-3,4-dimethylanilino)pyrimidin-4-yl]amino]-6-methoxybenzenesulfonamide Chemical compound COC1=CC=CC(NC=2N=C(N=CC=2)N(N)C=2C=C(C)C(C)=CC=2)=C1S(N)(=O)=O WGABHAUZGHBPON-UHFFFAOYSA-N 0.000 claims description 2
- UVPYXZGUFFMABH-UHFFFAOYSA-N 6-[[2-[4-methyl-3-(methylamino)anilino]pyrimidin-4-yl]amino]-2,3-dihydro-1,4-benzodioxine-5-sulfonamide Chemical compound C1=C(C)C(NC)=CC(NC=2N=C(NC=3C(=C4OCCOC4=CC=3)S(N)(=O)=O)C=CN=2)=C1 UVPYXZGUFFMABH-UHFFFAOYSA-N 0.000 claims description 2
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- BLXAKGMBJSKQOK-UHFFFAOYSA-N 2-[[2-(4-amino-3-methylanilino)pyrimidin-4-yl]amino]-6-methoxybenzenesulfonamide Chemical compound COC1=CC=CC(NC=2N=C(NC=3C=C(C)C(N)=CC=3)N=CC=2)=C1S(N)(=O)=O BLXAKGMBJSKQOK-UHFFFAOYSA-N 0.000 claims 1
- ZDKZOHJKOZJEBC-UHFFFAOYSA-N 2-[[2-(n-amino-4-ethyl-3-methylanilino)pyrimidin-4-yl]amino]-6-methoxybenzenesulfonamide Chemical compound C1=C(C)C(CC)=CC=C1N(N)C1=NC=CC(NC=2C(=C(OC)C=CC=2)S(N)(=O)=O)=N1 ZDKZOHJKOZJEBC-UHFFFAOYSA-N 0.000 claims 1
- GGIUCRDVNTZACT-UHFFFAOYSA-N 2-methoxy-6-[[2-[4-(methylamino)-3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]benzenesulfonamide Chemical compound C1=C(C(F)(F)F)C(NC)=CC=C1NC1=NC=CC(NC=2C(=C(OC)C=CC=2)S(N)(=O)=O)=N1 GGIUCRDVNTZACT-UHFFFAOYSA-N 0.000 claims 1
- CYHGYGRWYOTQNC-UHFFFAOYSA-N 6-[[2-[4-methyl-3-(methylamino)anilino]pyrimidin-4-yl]amino]-2,3-dihydro-1-benzofuran-7-sulfonamide Chemical compound C1=C(C)C(NC)=CC(NC=2N=C(NC=3C(=C4OCCC4=CC=3)S(N)(=O)=O)C=CN=2)=C1 CYHGYGRWYOTQNC-UHFFFAOYSA-N 0.000 claims 1
- YVUZNTXMWZQKAR-UHFFFAOYSA-N 7-[[2-[4-methyl-3-(methylamino)anilino]pyrimidin-4-yl]amino]-3,4-dihydro-2h-chromene-8-sulfonamide Chemical compound C1=C(C)C(NC)=CC(NC=2N=C(NC=3C(=C4OCCCC4=CC=3)S(N)(=O)=O)C=CN=2)=C1 YVUZNTXMWZQKAR-UHFFFAOYSA-N 0.000 claims 1
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000002955 immunomodulating agent Substances 0.000 claims 1
- 239000003018 immunosuppressive agent Substances 0.000 claims 1
- 229940125721 immunosuppressive agent Drugs 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 148
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
- 235000019439 ethyl acetate Nutrition 0.000 description 57
- 239000000243 solution Substances 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 238000003756 stirring Methods 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
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- 239000012267 brine Substances 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 17
- 238000004587 chromatography analysis Methods 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 239000007858 starting material Substances 0.000 description 16
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 15
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 11
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- 230000005764 inhibitory process Effects 0.000 description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 description 11
- 239000000047 product Substances 0.000 description 11
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- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 10
- 125000003302 alkenyloxy group Chemical group 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
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- 125000001072 heteroaryl group Chemical group 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
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- 125000001424 substituent group Chemical group 0.000 description 6
- RLAYPUDLIZBCKQ-UHFFFAOYSA-N 6-[(2-chloropyrimidin-4-yl)amino]-2,3-dihydro-1,4-benzodioxine-5-sulfonamide Chemical compound C1=CC=2OCCOC=2C(S(=O)(=O)N)=C1NC1=CC=NC(Cl)=N1 RLAYPUDLIZBCKQ-UHFFFAOYSA-N 0.000 description 5
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Description
Zは=CR2−または=N−であり;
R0、R1、R2、R3およびR4の各々は、独立して水素;ヒドロキシ;C1−C8アルキル;C2−C8アルケニル;C3−C8シクロアルキル;C3−C8シクロアルキル−C1−C8アルキル;ヒドロキシC1−C8アルキル;C1−C8アルコキシC1−C8アルキル;ヒドロキシC1−C8アルコキシC1−C8アルキル;環を所望によりヒドロキシ、C1−C8アルコキシ、カルボキシまたはC1−C8アルコキシカルボニルで置換されていてよいアリールC1−C8アルキルであるか;
またはR3およびR4は、それらが結合している窒素および炭素原子と一体となって、さらにN、OおよびSから選択される1個、2個または3個のヘテロ原子を含む、5から10員ヘテロ環式環を形成するか;
またはR1、R2およびR3の各々は、独立して、ハロゲン;ハロ−C1−C8アルキル;C1−C8アルコキシ;C2−8アルケニル−オキシ;C2−8アルキニル−オキシ;ハロ−C1−C8−アルコキシ;シアノ−C1−C8−アルコキシ;ヒドロキシC1−C8アルコキシ;C1−C8アルコキシC1−C8アルコキシ;C1−C8アルコキシC1−C8アルコキシC1−C8アルコキシ;アリール;アリールC1−C8アルコキシ;ヘテロアリール;ヘテロアリール−C1−C4アルキル;5から10員ヘテロ環式環;ニトロ;カルボキシ;C2−C8アルコキシカルボニル;C2−C8アルキルカルボニル;−N(C1−C8−アルキル)C(O)C1−C8アルキル;−N(R10)R11;−CON(R10)R11;−SO2N(R10)R11;または−C1−C4−アルキレン−SO2N(R10)R11であり;ここで、R10およびR11の各々は、独立して水素;OH;C1−C8アルキル;C2−C8アルケニル;C2−C8アルケニルオキシ;ハロ−C2−C8アルケニルオキシ;C3−C8シクロアルキル;C3−C8シクロアルキル−C1−C8アルキル;C1−C8アルコキシC1−C8アルキル;ヒドロキシC1−C8アルコキシC1−C8アルキル;ヒドロキシC1−C8アルキル;(C1−C8アルキル)−カルボニル;所望により環をヒドロキシ、C1−C8アルコキシ、カルボキシまたはC2−C8アルコキシカルボニルで置換されていてよいアリールC1−C8アルキル;または5から10員ヘテロ環式環であるか;
またはR1およびR2は、それらが結合しているC原子と一体となって、アリールもしくは、N、OおよびSから選択される1個または2個のヘテロ原子を含む5から10員ヘテロアリール残基を形成するか;
またはR1およびR2は、それらが結合しているC原子と一体となって、5から15員非芳香属性炭素環式またはヘテロ環式残基(ここで、該ヘテロ環式残基はN、OおよびSから選択される1個から5個のヘテロ原子を含む)を形成し;
(I)R7、R8およびR9の少なくとも1個が:
(i)ハロゲン;または
(ii)テトラヒドロピラン−2−イルメトキシ、テトラヒドロフラン−2−イルメトキシ、チアゾル−2−イルメトキシ、2−(2−オキソ−ピロリジン−1−イル)−エトキシ、3−ピリジルメトキシまたはフェニル;または
(iii)2−ヒドロキシ−エチルアミノ、ピペラジン−1−イル、4−イソプロピル−ピペラジン−1−イル、4−(2−メトキシエチル)−ピペラジン−1−イル、4−フェニル−ピペラジン−1−イルまたは4−アセチル−ピペラジン−1−イル;または
(iv)C1−C8アルキルスルファニル;または
(v)C1−C8アルコキシC1−C8アルコキシC1−C8アルコキシであるか;
または
(II)R7とR8またはR8とR9が、各々、それらが結合している炭素原子と一体となって、:
(a)2個の窒素原子を含む5員ヘテロ環式環(ここで、該ヘテロ環は、ハロゲン、2−ジメチルアミノ−エチルまたは2,2,2−トリフルオロ−エチルにより置換されている);または
(b)1個の窒素原子を含む5または6員ヘテロ環式環;または
(c)5から20員ヘテロ環式残基(ここで、該ヘテロ環式残基は、1個から7個の酸素原子を含む);
を形成し、そして(I)において2個まで、および(II)において1個までのR7、R8およびR9は水素;ヒドロキシ;C1−C8アルキル;C2−C8アルケニル;ハロ−C1−C8アルキル;C1−C8アルコキシ;C3−C8シクロアルキル;C3−C8シクロアルキルC1−C8アルキル;アリールC1−C8アルキル;−Y−R12(ここで、Yは直接結合、O、C1−C8アルキレンまたは−O−(CH2)1−8−であり、そしてR12はN、OおよびSから選択される1個、2個または3個のヘテロ原子を含む置換または非置換5、6または7員ヘテロ環式環である);カルボキシ;(C1−C8アルコキシ)−カルボニル;−N(C1−8アルキル)−CO−NR10R11;−CONR10R11;−N(R10)(R11);−SO2N(R10)R11であるか;またはR7とR8またはR8とR9は、各々、それらが結合している炭素原子と一体となって、N、OおよびSから選択される1個、2個または3個のヘテロ原子を含む5員または6員ヘテロアリール、または、5員または6員炭素環式環を形成するか;
または
(III)R7、R8およびR9の各々は、独立して水素;ヒドロキシ;ハロゲン;C1−C8アルキル;C2−C8アルケニル;ハロ−C1−C8アルキル;C1−C8アルキルスルファニル;C1−C8アルコキシ;C1−C8アルコキシC1−C8アルコキシ;C1−C8アルコキシC1−C8アルコキシC1−C8アルコキシ;C3−C8シクロアルキル;C3−C8シクロアルキルC1−C8アルキル;アリールC1−C8アルキル;−Y−R12(式中、Yは直接結合、O、C1−C8アルキレンまたは−O−(CH2)1−8−であり、そしてR12はN、OおよびSから選択される1個、2個または3個のヘテロ原子を含む置換または非置換5、6または7員ヘテロ環式環である);カルボキシ;(C1−C8アルコキシ)−カルボニル;−N(C1−8アルキル)−CO−NR10R11;−CONR10R11;−N(R10)(R11);−SO2N(R10)R11であるか;またはR7とR8またはR8とR9は、各々、それらが結合している炭素原子と一体となって、N、OおよびSから選択される1個、2個または3個のヘテロ原子を含む5または6員ヘテロアリールまたはヘテロ環式残基、または、5もしくは6員炭素環式環、もしくは1個から7個の酸素原子を含む7から20員ヘテロ環式残基を形成し;そして
(a)R1およびR2は、それらが結合しているC原子と一体となって、5から15員非芳香属性炭素環式またはヘテロ環式残基(ここで、該ヘテロ環式残基はN、OおよびSから選択される1個から5個のヘテロ原子を含む)を形成するか;または
(b)R1およびR2は、一体となって式−C(CH3)=CH−O−、−CH=CH−NH−または−N=C(CH3)−C(CH3)=N−を形成するか;または
(c)R1およびR2は、一体となって、式−CH=N−NH−を形成し、そしてR3は−SO2N(R10)R11であるか;または
(d)R2は
(i)2個から5個のフッ素原子を含むフルオロ−C1−5アルコキシ;または
(ii)C1−C8アルコキシC1−C8アルコキシC1−C8アルコキシ;または
(iii)C2−C8アルケニルオキシ;または
(iv)ハロ−C2−C8アルケニルオキシ;または
(v)ベンジルオキシ;または
(vi)−N(CH3)(R13)(ここで、R13はメチルまたはベンジルである);または
(vii)C1−4アルコキシであるか;または
(B)Zは=N−である。〕
の化合物を提供する。
ハロゲンはF、Cl、Br、またはIであり得る。
好ましくは最大でR1、R2またはR3の1個がCONR10R11またはSO2NR10R11、より好ましくはSO2NR10R11である。
(a)Zが=CR2である;
(b)R0が水素;ハロゲン、例えばCl;非置換C1−C4アルキル、例えばメチルまたはエチル;非置換C1−4アルコキシ、例えばメトキシ;好ましくは水素である;
(c)R1が水素;ハロゲン、例えばClまたはF;OH;C1−C8アルキル、例えばメチルまたはエチル;置換C1−8アルキル、例えば末端をOH置換されているC1−8アルキル;−SO2N(R10)R11;−N(C1−4アルキル)C(O)C1−4アルキル;所望により環N原子(可能であるとき)を置換されていてよい、5または6員ヘテロ環式環;C1−C8アルコキシ、例えばメトキシ;アリール、例えばフェニルであるか;
またはR1が、R2と、かつR1とR2が結合しているC−原子と一体となって、5から10員アリールまたはヘテロアリールであり、後者は1個または2個の窒素原子を含み;
R1およびR2が、それらが結合しているC−原子と一体となって5から15員非芳香族性炭素環式残基を形成するとき、これは、好ましくはシクロペンチルであり得;
R1およびR2が、それらが結合しているC−原子と一体となって5から15員非芳香族性ヘテロ環式残基を形成するとき、この残基は、好ましくは1個から5個のO原子をヘテロ原子として含み;該ヘテロ環式残基は、所望により、例えば4個までの置換基、例えば1個から4個のハロゲン原子、例えばFで置換されていてよく;より好ましくはR1およびR2は、2個のO原子を含む5または6または7員ヘテロ環式残基の一部を形成し、例えばR1およびR2は、一体となって、式−O−(CH2)3−O−、−O−(CH2)2−O−、−O−(CF2)2−O−、−O−CH2−O−または−O−CF2−O−を形成するか、またはR1およびR2は、5個のO原子を含む15員ヘテロ環式残基を形成し、例えばR1およびR2は、一体となって、式−O−((CH2)2−O−)4の残基を形成し;
R2が、上記の(III)(A)(d)(i)に定義した通りであるとき、フルオロ−C1−5アルコキシは好ましくは−O−CF3、−O−CH2−CF3または−O−(CH2)3−CF2−CF3であり;
R2が上記の(III)(A)(d)(ii)に定義した通りであるとき、C1−C8アルコキシC1−C8アルコキシC1−C8アルコキシは好ましくは−O−(CH2)2−O−(CH2)2−O−CH3であり;
R2が上記の(III)(A)(d)(iii)に定義した通りであるとき、C2−C8アルケニルオキシは好ましくはC2−C4アルケニルオキシ、例えばプロプ−2−エニルオキシであり;
R2が上記の(III)(A)(d)(iv)に定義した通りであるとき、ハロ−C2−C8アルケニルオキシは、好ましくは1個から3個のハロゲン原子、例えばClまたはFを含むハロ−C2−C4アルケニルオキシ、より好ましくはハロ−プロプ−2−エニルオキシ、例えば2−クロロプロプ−2−エニルオキシ、2−フルオロプロプ−2−エニルオキシ、1,1,2−トリフルオロプロプ−2−エニルオキシまたは2,3,3−トリフルオロプロプ−2−エニルオキシであり;
(g)R5が水素;ハロゲン;C1−4アルキル;またはCF3であり;
(h)R6が水素であり;
(i)R10およびR11の一方が、独立して、水素またはC1−4アルキルであり、他方が水素;C1−8−アルキル、例えば末端をOH、C3−6−シクロアルキルまたはヘテロ環式環で置換された置換C1−8アルキル;C2−8アルケニル;C3−8シクロアルキル;C1−8アルコキシC1−4アルキル;ヒドロキシC1−8アルコキシC1−8アルキル;または5員ヘテロ環式環である。
(I)(i)R7またはR8がハロゲンであり;ハロゲンがフルオロ、クロロまたはブロモであるか;R7がメトキシであり、R8がフルオロであり、そしてR9が水素であるか;R7がクロロであり、R8がフルオロそしてR9が水素であるか;R7がトリフルオロメチルであり、R8がクロロであり、そしてR9が水素であるか;R7がブロモであり、そしてR8およびR9が各々水素である;
(ii)R7がテトラヒドロピラン−2−イルメトキシ、テトラヒドロフラン−2−イルメトキシ、チアゾル−2−イルメトキシ、2−(2−オキソ−ピロリジン−1−イル)−エトキシ、3−ピリジルメトキシまたはフェニルであり、そして、所望により、R8およびR9は各々水素であるか;R7、R8またはR9がテトラヒドロピラン−2−イルメトキシまたはテトラヒドロフラン−2−イルメトキシである;
(iii)R7が2−ヒドロキシ−エチルアミノであり、そして、所望によりR8がヒドロキシメチルであり、そしてR9が水素であるか;R7がピペラジン−1−イル、4−イソプロピル−ピペラジン−1−イル、4−(2−メトキシエチル)−ピペラジン−1−イル、4−フェニル−ピペラジン−1−イルまたは4−アセチル−ピペラジン−1−イルであり、所望によりR8およびR9が水素である;
(iv)R8がC1−C8アルキルスルファニルであり;C1−C8アルキルスルファニルが例えばメチルスルファニルであり;R7がメトキシであり、R8がメチルスルファニルであり、そしてR9が水素である;
(v)R7がC1−C8アルコキシC1−C8アルコキシC1−C8アルコキシであり;C1−C8アルコキシC1−C8アルコキシC1−C8アルコキシが、例えば2−(2−メトキシ−エトキシ)−エトキシであり;R7が2−(2−メトキシ−エトキシ)−エトキシであり、R8がメトキシまたは水素であり、そしてR9が水素である;
(b)R8およびR9が、一体となって、式−N=CH−CH=CH−の残基であり、そして所望によりR7がメトキシである;
(c)R7とR8またはR8とR9、好ましくはR8とR9が、それらが結合している炭素原子と一体となって下記を形成する:
(i)2個の酸素原子を含む6から9員ヘテロ環式環、より好ましくは各酸素原子が、直接、R7とR8またはR8とR9が結合している芳香環に隣接している、例えばR7とR8またはR8とR9が、一体となって、式−O−(CH2)n−O−(ここで、nは2、3、4または5である)の残基を形成するもの;または
(ii)m個の酸素原子と2m個の炭素原子(ここで、mは3、4または5である)を含む、ヘテロ環式環、例えばR7とR8またはR8とR9が、一体となって、式−(O−CH2−CH2)m−1−O−の残基を形成するもの;
R8が水素;ヒドロキシ;C1−4アルコキシ;C1−4アルキル;カルボキシ;所望により、環CまたはN原子を置換されている、5または6員ヘテロ環式環;N(C1−4アルキル)−CO−NR10R11;NR10R11であるか;またはR7またはR9と、かつR7とR8またはR8とR9が各々結合しているC−原子と一体となって、例えば−NH−CH=CH−、−CH=CH−NH−、−NH−N=CH−、−CH=N−NH−、−NH−N=N−または−N=N−NH−で架橋されている、5員ヘテロアリール残基を形成し;
R9が水素;C1−4アルコキシ;NR10R11であるか;またはR8と、かつ、R8およびR9が結合しているC原子と一体となって、例えば−NH−CH=CH−、−CH=CH−NH−、−NH−N=CH−、−CH=N−NH−、−NH−N=N−または−N=N−NH−で架橋されている、5員ヘテロアリールを形成する。
a)式II
の化合物と、式III
の化合物を反応させるか;または
の化合物と、式V
の化合物を反応させ;
そして、得られた式Iの化合物を遊離形でまたは塩形で回収し、そして、必要であれば、遊離形で得られた式Iの化合物を所望の塩形に変換するか、または、その逆を行うことを含む、方法も提供する。
の化合物を、例えば既知の方法を使用して、例えば実施例1に記載の通りに、式IIの化合物に変換することにより、得ることができる。
の化合物を反応させることにより、得ることができる。
の化合物は、新規であり、また本発明の一部を成す。それは、式IIの化合物の製造のための中間体として有用である。
下記略語を用いる:
DMF=ジメチルホルムアミド、DMSO=ジメチルスルホキシド;MS=エレクトロスプレー質量分析により測定した分子イオン(例えばM+H1+);THF=テトラヒドロフラン;TBME=tert−ブチルメチルエーテル。
3,4,5−トリメトキシ−フェニルアミン(10g、54.6mmol)および2−メチルスルファニル−ピリミジン−4−オール(7.76g、54.6mmol)を混合し、150℃で2時間加熱し、そうすると、混合物が融解する。発生したガスを次亜塩素酸ナトリウム溶液に吸収させる。残った残渣をアセトニトリル(300ml)に懸濁させる。POCl3(10.8ml、117mmol)および4N HClのジオキサン(35.2ml、140mmol)溶液を添加し、混合物を90℃で反応が終了するまで加熱する。混合物を酢酸エチルで抽出し、飽和重炭酸ナトリウムおよび塩水で洗浄する。有機層を硫酸ナトリウムで乾燥させ、蒸発させる。残渣をメタノールから結晶化させて、(4−クロロ−ピリミジン−2−イル)−(3,4,5−トリメトキシ−フェニル)−アミンを得る。
窒素雰囲気下、2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−6−イルアミン(5.0g、33.0mmol)を、クロルスルホニルイソシアネート(3.14ml、36.3mmol)のニトロエタン(75ml)溶液に、−55から−49℃の温度で滴下する。冷却浴を外し、混合物を0℃に温め、そこで塩化アルミニウム(5.27g、39.6mmol)を添加する。混合物を120℃で30分加熱すると、透明褐色溶液が形成され、それを室温に冷却し、氷に注ぐ。濾過後、氷水およびジエチルエーテルで洗浄し、沈殿を回収する。
6−アミノ−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−スルホン酸アミド(87mg、0.38mmol)および(4−クロロ−ピリミジン−2−イル)−(3,4,5−トリメトキシ−フェニル)−アミン(112mg、0.38mmol)をジオキサン(1.3ml)に溶解する。混合物を120℃で1時間加熱する。反応混合物を、異なる溶媒混合物を使用したシリカゲルクロマトグラフィーの繰り返しにより精製し、6−[2−(3,4,5−トリメトキシ−フェニルアミノ)−ピリミジン−4−イルアミノ]−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−スルホン酸アミドを得る。
MS(ESI):490[M+H]+
(4−クロロ−ピリミジン−2−イル)−(3,4−ジメトキシ−フェニル)−アミンを、実施例1工程Aに記載の通り、3,4−ジメトキシ−フェニルアミンを3,4,5−トリメトキシ−フェニルアミンの代わりに使用して製造する。
1,3−ベンゾジオキソル−5−アミン(10g、73mmol)の200ml Et2Oおよび100ml THF溶液中に、NEt3(12.3ml、87.6mmol)を添加する。反応混合物を0℃に冷却し、塩化ピバロイル(10.5ml、87.6mmol)のTHF溶液を添加する。1時間、25℃で撹拌後、氷水を添加し、混合物をEtOAcで抽出し、塩水で洗浄し、続いて乾燥させ(Na2SO4)、揮発物を蒸発させ、結晶化(CH2Cl2/ヘキサン)し、それによりN−ベンゾ[1,3]ジオキソル−5−イル−2,2−ジメチル−プロピオンアミドを得る。
5−[2−(3,4−ジメトキシ−フェニルアミノ)−ピリミジン−4−イルアミノ]−ベンゾ[1,3]ジオキソール−4−スルホン酸アミドを、実施例1工程Cに記載の通り、4−クロロ−ピリミジン−2−イル)−(3,4−ジメトキシ−フェニル)−アミンおよび5−アミノ−ベンゾ[1,3]ジオキソール−4−スルホン酸アミドを使用して製造する。
MS(ESI):446.1[M+H]+、444.1[M−H]+。
実施例1、工程Aに記載の通り。
5−アミノ−インダン−4−スルホン酸アミドを、実施例1工程Bに記載の通り、出発物質としてインダン−5−イルアミンを2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−6−イルアミンの代わりに使用して製造する。
(4−クロロ−ピリミジン−2−イル)−(3,4,5−トリメトキシ−フェニル)−アミン(240mg、0.81mmol)および5−アミノ−インダン−4−スルホン酸アミド(190mg、0.89mmol)をイソプロパノール(15ml)に懸濁させる。濃HCl(1.5ml)を添加する。混合物を環流温度で1時間加熱する。反応混合物を酢酸エチル(300ml)および水(100ml)に分配する。NaHCO3を添加して、pHを塩基性とする。層を分離する。有機層をNa2SO4で乾燥させ、蒸発させる。残渣を酢酸エチルから結晶化させ、5−[2−(3,4,5−トリメトキシ−フェニルアミノ)−ピリミジン−4−イルアミノ]−インダン−4−スルホン酸アミドを得る。
MS(ESI):472[(M+H]+
実施例1、工程Aに記載の通り。
フェニル−メタンチオール(12.0ml、100mmol)を、1,2−ジクロロ−ニトロベンゼン(23.0g、120mmol)、Bu4NHSO4(1.0g)、CH2Cl2(250ml)およびNaOH(30%、60ml)の混合物に滴下し、混合物を25℃で16時間撹拌する。水を添加し、有機相を分離し、Na2SO4で乾燥させる。溶媒を除去して、オレンジ色油状物を得、それをAcOH(90%、500ml)に溶解する。Cl2ガスを、完全に消費されるまで溶液を通してバブリングする。溶媒を除去し、残渣をクロマトグラフィーに付す(SiO2、TBME/シクロヘキサン1:4→TBME)。得られた固体を、NH4OHおよびエタノール(1:1、150ml)の混合物に少しずつ添加し、混合物を2時間、25℃で撹拌する。水を添加し、得られた沈殿を濾取する。2−クロロ−6−ニトロ−ベンゼンスルホンアミドを無色固体として単離する。
2−(ジメチル−アミノ)−6−[2−(3,4,5−トリメトキシ−フェニルアミノ)−ピリミジン−4−イルアミノ]−ベンゼンスルホンアミドを、実施例1工程Cに記載の通り、4−クロロ−ピリミジン−2−イル)−(3,4,5−トリメトキシ−フェニル)−アミン(実施例1工程A)および2−アミノ−6−ジメチルアミノ−ベンゼンスルホンアミドを使用して製造する。
MS(ESI):475[M+H+]+
(4−クロロ−ピリミジン−2−イル)−(3,4−ジメトキシ−フェニル)−アミンを、実施例1工程Aに記載の通り、3,4−ジメトキシ−フェニルアミンを3,4,5−トリメトキシ−フェニルアミンの代わりに使用して製造する。
3−アミノ−フェノール(60g、6.55mol)の2N NaOH(1l)溶液に、10℃に冷却し、塩化ピバロイル(68ml、0.55mol)のトルエン(200ml)溶液を1時間以内に添加する。15時間、25℃で撹拌後、混合物を0℃に冷却し、濃HClでpH1に酸性化する。EtOAcで抽出し、水、10%NaHCO3、水および塩水で洗浄し、続いて乾燥させ(Na2SO4)、揮発物を蒸発させ、結晶化(EtOAc/ヘキサン)し、N−(3−ヒドロキシ−フェニル)−2,2−ジメチル−プロピオンアミドを得る。
6−アリルオキシ−2−アミノフェニル−スルホンアミド(38mg、0.166mmol)および4−クロロ−2−(3,4−ジメトキシ−フェニルアミノ)ピリミジン(44.2mg、0.166mmol)の2−プロパノール(5ml)および1N HCl(333μl)溶液を、105分環流する。反応混合物をアンモニア(pH10−11)およびEtOAcに分配する。有機層を乾燥させ(Na2SO4)、濃縮する。エーテル/ヘキサンでの沈殿により、所望の2−アリルオキシ−6−[2−(3,4−ジメトキシ−フェニルアミノ)−ピリミジン−4−イルアミノ]−ベンゼンスルホンアミドを得る。
MS(ESI):458([M+H]+)、456([M−H]+)。
(4−クロロ−ピリミジン−2−イル)−(3,4−ジメトキシ−フェニル)−アミンを、実施例1工程Aに記載の通り、3,4−ジメトキシ−フェニルアミンを3,4,5−トリメトキシ−フェニルアミンの代わりに使用して、製造する。
3−トリフルオロメトキシニトロベンゼン(4.0g、20mmol)のDMSO(60ml)溶液に、トリメチルヒドラジニウムアイオダイド(4.4g、22mmol)を添加し、0℃に冷却する。KOt−Buを少しずつ添加する。4時間、25℃で撹拌後、氷水を添加し、HCl溶液でpHを2−3に調整し、混合物をEtOAcで抽出し、塩水で洗浄し、続いて乾燥させ(Na2SO4)、溶媒を蒸発させる。クロマトグラフィー(シリカゲル、CH2Cl2/ヘキサン=1:1)により、2−ニトロ−6−トリフルオロメトキシ−フェニルアミンを得る。
2−[2−(3,4−ジメトキシ−フェニルアミノ)−ピリミジン−4−イルアミノ]−6−トリフルオロメトキシ−ベンゼンスルホンアミドを、実施例1工程Cに記載の通り、4−クロロ−ピリミジン−2−イル)−(3,4−ジメトキシ−フェニル)−アミンおよび2−アミノ−6−トリフルオロメトキシ−ベンゼンスルホンアミドを使用して製造する。
MS(ESI):486[M+H]+。
2,N−ジメチル−ベンゼン−1,3−ジアミン
SnCl2−二水和物(1117mg、4.95mmol)を、N−ベンジル−N,2−ジメチル−5−ニトロ−アニリン(247mg、0.96mmol)のメタノール(10mL)および濃HCl(1mL)の溶液に添加する。環流下、2.5時間沸騰させた後、揮発物を減圧下蒸発させ、残渣をEtOAcおよび水に分配し、2N NaOHの添加によりpHを約10に調整する。有機層を飽和塩水で洗浄し、乾燥させ(Na2SO4)、蒸発させる。残渣のクロマトグラフィー(シリカゲル、ヘキサン/EtOAc 3:2)により、N3−ベンジル−N3,4−ジメチル−ベンゼン−1,3−ジアミンを得る。
微粉化した2−メトキシ−6−ニトロ−アニリン(14.7g、87.5mmol)の80mLの37%塩酸の機械的に撹拌した溶液に、NaNO2(7,3g、105mmol)の水(25mL)溶液を−5から−10℃で30分以内にに添加する。−10℃での撹拌を30分続け、その後混合物を、−10℃に冷却した、SO2ガスを、30分、室温でバブリングすることによりSO2で飽和させているCuCl(2g)およびCuCl2(2g)のAcOH(100mL)および水(5mL)の溶液に添加し、それにより温度が15℃に上がる。SO2−ガスの注入を、1時間、室温で続ける。沈殿した結晶を濾過により回収し、2−メトキシ−6−ニトロ−ベンゼンスルホニルクロライドを得る。
2−メトキシ−6−ニトロ−ベンゼンスルホニルクロライド(12.8g、50.87mmol)および25%水酸化アンモニウムの混合物を、65℃で、rotavapで回転させる。15分後、得られた溶液の容量を、減圧下の揮発物の蒸発により半分に減少させる。冷却後、沈殿物の濾過による回収により、2−メトキシ−6−ニトロ−ベンゼンスルホンアミドを得る。
N−[1−ジメチルアミノ−メチリデン]−2−ニトロ−6−メトキシ−ベンゼンスルホンアミド(956mg、3.33mmol)のジクロロメタン(50mL)溶液に、BBr3(0.64mL、6.64mmol)を室温で撹拌しながら添加する。30分撹拌後、混合物をCH2Cl2で希釈し、飽和塩水で2回抽出する。有機相のNa2SO4での乾燥、溶媒の蒸発、残渣へのヘキサンの添加、および濾過により、N−(1−ジメチルアミノ−メチリデン)−2−ニトロ−6−ヒドロキシ−ベンゼンスルホンアミドを得る。
a)N−(3−メトキシ−フェニル)−2,2−ジメチル−プロピオンアミド
氷冷した20g(162mmol)3−メトキシ−フェニルアミンの400ml ジエチルエーテルの溶液に、24.9ml(178mmol)トリエチルアミンを、および、ゆっくり30分以内に23.9ml(195mmol)塩化ピバロイルを添加する。発熱反応のため、温度は冷却しているにもかかわらず、15℃に上昇する。温度を室温まで上げ、1時間後、反応混合物を氷に注ぎ、酢酸エチルで抽出し、2回水および1回塩水で洗浄し、Na2SO4で乾燥させ、蒸発させて粗生成物を得て、それをCH2Cl2/ヘキサンからの2回の結晶化により精製して、N−(3−メトキシ−フェニル)−2,2−ジメチル−プロピオンアミドを得る。
15g(72mmol)化合物a)の300ml THF溶液に、アルゴン下、−60℃で112.5ml(180mmol)n−BuLi(ヘキサン中1.6M)を添加する。反応混合物を0から+5℃に温め、2時間撹拌する。反応混合物を再び−60℃に冷却し、37.1ml(579mmol)SO2のジエチルエーテル溶液を添加する。反応混合物を0から+5℃に温め、30分撹拌する。反応混合物を濾過して、2−(2,2−ジメチル−プロピオニルアミノ)−6−メトキシベンゼンスルフィン酸リチウム塩を固体残渣として得る。濾液はまた生成物を含み、それを蒸発させ、残渣を酢酸エチルに溶解し、2回水で洗浄し、Na2SO4で乾燥させ、蒸発させてさらに生成物を得る。
21g(75mmol)化合物b)の400ml 水中の懸濁液に、0−5℃で31.05g(378mmol)酢酸ナトリウムを、および一度に21.34g(189mmol)ヒドロキシルアミン−オルトスルホン酸を添加する。反応混合物を室温で撹拌し続ける。結晶が、反応混合物中に形成される。1時間後、結晶を濾過して、N−(3−メトキシ−2−スルファモイル−フェニル)−2,2−ジメチル−プロピオンアミドを得た。濾液を蒸発させ、酢酸エチルに溶解し、2回水および1回塩水で洗浄し、Na2SO4で乾燥させ、蒸発させる。残渣をシリカクロマトグラフィーにより精製し、シクロヘキサン:酢酸エチル4:6で溶出して、さらなる生成物を得る。
11g(33mmol)化合物c)の100ml 1,2−ジメトキシエタン溶液に、100ml 6N HClを添加し、90℃で3.5時間撹拌する。反応混合物を氷に注ぎ、酢酸エチルで抽出する。有機層を2回水および1回塩水で洗浄する。1N NaOHを水性相に添加し、pH=13とする。この塩基性水性相を酢酸エチルで抽出し、それを2回水および1回塩水で洗浄する。有機層をNa2SO4で乾燥させ、蒸発させて2−アミノ−6−メトキシ−ベンゼン−スルホンアミドを得る。
6g NaH(鉱油中60%、145mmol)の50ml ジメトキシエタン溶液に、アルゴン下、10分以内に、18.4g(121mmol)2−メチル−5−ニトロ−フェニルアミンを添加する。20分後、15ml(242mmol)ヨウ化メチルを添加する。温度を28℃に上げる。3時間、室温で撹拌後、さらに7.5ml(121mmol)ヨウ化メチルを添加する。24時間後、50mlの水をゆっくり添加し、反応混合物を1lのCH2Cl2および1lの水に分配する。有機層をNa2SO4で乾燥させ、蒸発させる。粗生成物をシリカゲルクロマトグラフィーで精製し、酢酸エチル/シクロヘキサン1:3で溶出して、溶出の順番でジメチル−(2−メチル−5−ニトロ−フェニル)−アミンを含む油状残渣(それは廃棄する)、次いで、所望のメチル−(2−メチル−5−ニトロ−フェニル)−アミンを得る。
3.44g(21mmol)化合物e)の60ml メタノール溶液に、50mg 10%パラジウム炭および注意深く1.18g NaBH4を添加する。15分後、反応混合物を濾過し、濾液を500ml CH2Cl2および500ml 水に分配する。有機層をNa2SO4で乾燥させ、蒸発させる。粗生成物をシリカゲルクロマトグラフィーにより精製し、酢酸エチル/シクロヘキサン1:1で溶出して、4,N3−ジメチル−ベンゼン−1,3−ジアミンを得る。
7.57g(37mmol)化合物d)および16.73g(112mmol)2,4−ジクロロピリミジンの80ml N−メチルピロリドン溶液に、ジオキサン中4Mの43ml HClを添加する。反応混合物を5.5時間、60℃で撹拌する。反応混合物を1.5l 酢酸エチルおよび1l 水に分配する。水性層をNaHCO3の添加によりわずかに塩基性のpHに調整する。有機層を2回水で洗浄し、Na2SO4で乾燥させ、蒸発させる。粗生成物をシリカゲルクロマトグラフィーで精製し、酢酸エチルで溶出する。生成物含フラクションの蒸発中に、生成物が結晶化し始める。結晶を濾取して、2−(2−クロロ−ピリミジン−4−イルアミノ)−6−メトキシ−ベンゼンスルホンアミドを得る。
a)N−(2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−6−イル)−2,2−ジメチル−プロピオンアミド
22.5g(149mmol)2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−6−イルアミンおよび25ml(179mmol)トリエチルアミンの1l ジエチルエーテル溶液に、12℃で10分以内に、250ml ジエチルエーテルに溶解させた20ml(164mmol)塩化ピバロイルを添加する。温度を12−16℃の間に保つ。反応混合物を室温で1時間する。次いでそれを2回300ml 水、2回150ml 1N HClおよび2回塩水で洗浄し、Na2SO4で乾燥させ、80mlの容量まで一部蒸発させる。これにより懸濁液となる。ヘキサンを添加し、固体を濾過して、N−(2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−6−イル)−2,2−ジメチル−プロピオンアミドを得る。
21.45g(91mmol)化合物a)の400ml THF溶液に、アルゴン下、−50℃で143ml(228mmol)n−BuLi(ヘキサン中1.6M)を添加する。温度は−5℃に上昇し、反応混合物を次いで3時間、0から3℃で撹拌する。加圧ビンからの36g(562mmol)のSO2をエーテルに−30℃で溶解し、この溶液を上記反応混合物に−50℃で添加する。反応混合物を室温に温める。次いで1.3lのジエチルエーテルを添加し、混合物を濾過する。固体残渣を乾燥させて、24.2gの6−(2,2−ジメチル−プロピオニル−アミノ)−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−スルフィン酸リチウム塩を得る。
5g(16mmol)化合物b)の30ml 水溶液に、9℃で、6.7g(82mmol)酢酸ナトリウムおよび4.63g(41mmol)ヒドロキシルアミン−オルトスルホン酸を添加する。温度は、氷浴冷却にもかかわらず、24℃に上がる。反応混合物を酢酸エチルで抽出し、有機相を水、10%水性NaHCO3溶液および塩水で洗浄し、Na2SO4で乾燥させ、蒸発させて2,2−ジメチル−N−(5−スルファモイル−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−6−イル)−プロピオンアミドを得る。
7.09g(22.5mmol)化合物c)の70ml 1,2−ジメトキシエタン溶液に、70ml 6N HClを添加し、90℃で2時間撹拌する。反応混合物を600mlのCH2Cl2および500mlの水に分配する。水性層をNaHCO3の添加によりわずかに塩基性のpHに調整する。有機層をNa2SO4で乾燥させ、蒸発させる。残渣は出発物質であることが示される。水性層を、2×500ml 酢酸エチルでさらに徹底的に抽出する。有機層をNa2SO4で乾燥させ、蒸発させ、酢酸エチルから結晶化させ、6−アミノ−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−スルホン酸アミドを得る。結晶化の繰り返しと、溶離剤としてメタノールを使用したSephadex LH-20でのクロマトグラフィーの組み合わせにより、さらに所望の生成物を単離する。
5.98g(26mmol)化合物d)および15.5g(103mmol)2,4−ジクロロピリミジンの120ml イソプロパノール溶液に、12ml 濃HClを添加する。反応混合物を2.25時間、60℃で撹拌する。反応混合物を1l 酢酸エチルおよび1l 水に分配する。水性層をNaHCO3の添加によりわずかに塩基性のpHに調整する。有機層をNa2SO4で乾燥させ、150mlまで一部蒸発させ、結晶化して、6−(2−クロロ−ピリミジン−4−イルアミノ)−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−スルホン酸アミドを得る。
ZAP−70およびLck(リンパ性T細胞タンパク質チロシンキナーゼ)は、Upstate Biotechnology, Lake Placid, NYから市販されている。
本発明のある種の化合物は、Syk阻害活性を、解離増強ランタニド蛍光免疫アッセイ(dissociation-enhanced lanthanide fluoroimmunoassay)(DELFIA)技術に基づいた異種Sykキナーゼアッセイで測定する。この方法は、記載の通り(Braunwalder AF, Yarwood DR, Sills MA, Lipson KE. Measurement of the protein tyrosine kinase activity of c-src using time-resolved fluorometry of europium chelates. Anal.Biochem. 1996;238(2):159-64)、ユーロピウムキレート標識抗ホスホチロシン抗体を使用し、Sykからマイクロタイタープレート上に被覆した重合化グルタミン酸−チロシン(Glu、Tyr)基質へのリン酸移動を検出する。次いで、リン酸化の量を時間分解、解離増強蛍光により定量する。簡単に言うと、100μlのポリ(Glu、Tyr)(4:1;リン酸緩衝化食塩水、PBS中、2μg/ml)をELISAプレートで、一晩、室温でコーティングさせる。ポリ(Glu、Tyr)溶液を除去し、250μlの1%ウシ血清アルブミンのPBS溶液を1時間、室温で添加する。プレートを次いで3回350μlの洗浄緩衝液(25mM Tris−HCl、pH7.4、0.03%Tween-20含有)で洗浄する。キナーゼ反応を1時間、室温で、30μlの阻害剤の連続希釈と30μlのSykキナーゼ(20ng/ml)およびATP(1μM)をキナーゼ緩衝液(20mM Tris、pH7.5、10μM Na3VO4、1mM DTT、10mM MnCl2、2mM MgCl2、0.01%ウシ血清アルブミン、0.05%Tween 20)中で混合することにより行う。プレートを上記の通り4回洗浄後、60μl DELFIAユーロピウムN1標識抗ホスホチロシン抗体PY20(Advant/Wallac)を添加し(50mM Tris−HCl、pH7.4、150mM NaCl、20μM Titriplex V、0.2%ウシ血清アルブミン、0.05%Tween-20中、100ng/ml)、1時間、室温でインキュベートする。プレートを8回洗浄し、60μl 増強溶液(Wallac)を添加する。蛍光を615nm(Victor 2;Wallac)で測定する。高対照値(100%シグナル)を試験サンプルの非存在下、低対照値(背景)を試験サンプルおよびATPの非存在下、得る。低対照を全ての値から引く。試験化合物存在下で得られる阻害を、高対照の阻害のパーセントとして計算する。50%阻害をもたらす試験化合物濃度(IC50)を、用量応答曲線から決定する。このアッセイにおいて、本発明の活性化合物は、100nMから10μMの範囲のIC50値を有する。
ALKチロシンキナーゼ活性の阻害を、既知の方法を使用して、例えば、J. Wood et al. Cancer Res. 60, 2178-2189(2000)に記載のVEGF−Rキナーゼアッセイに準じた、ALKの組み換えキナーゼドメインの使用により測定する。
IC50=[(ABS試験−ABS開始)/(ABS対照−ABS開始)]×100。
これらの実験におけるIC50値を、阻害剤なしの対照を使用して得られたより50%少ない細胞数をもたらす当該試験化合物の濃度として示す。本発明の化合物は、約0.01から1μMの範囲のIC50で阻害活性を示す。
本発明の化合物は、T細胞阻害活性を示す。より具体的に、本発明の化合物は、例えば下記試験法により証明されるように、例えば水性溶液中でT細胞活性化および/または増殖を防止する。2方向MLRを標準法に従い行う(J. Immunol. Methods, 1973, 2, 279およびMeo T. et al., Immunological Methods, New York, Academic Press, 1979, 227-39)。簡単に言うと、CBAおよびBALB/cマウスの脾臓細胞(各種類から1.6×105細胞/平底組織培養マイクロタイタープレートウェル、合計3.2×105)を10%FCS、100U/mlペニシリン、100μg/mlストレプトマイシン(Gibco BRL, Basel, Switzerland)、50μM 2−メルカプトエタノール(Fluka, Buchs, Switzerland)および連続希釈した化合物を含むRPMI培地中インキュベートする。試験化合物あたり、デュプリケートの73倍希釈工程を行う。インキュベーション4日後、1μCi 3H−チミジンを添加する。細胞をさらに5時間のインキュベーション時間の後に回収し、取り込まれた3H−チミジンを標準法により測定する。MLRの背景値(低対照)は、BALB/c細胞単独の増殖でる。低対照を全ての値から引く。サンプルのいずれも存在しない高対照を100%増殖と取る。サンプルによる阻害パーセントを計算し、50%阻害(IC50値)に必要な濃度を決定する。このアッセイにおいて、本発明の化合物は、10nMから10μM、好ましくは10nMから100nMの範囲のIC50値を有する。実施例24の化合物は、40nMのIC50値を示す。
DA(RT1n)心臓を、標準移植法に従い、麻酔したLewisレシピエントラットの腹に異所性に移植する。移植片機能を、腹壁を介した心拍の触診によりモニターする。心拍が停止したとき、拒絶反応が完了したと見なす。式Iの化合物を、1から30mg/kg bidで経口投与することにより処置した動物において、移植片生存の増加が得られる。
(1)医薬として使用するための、式Iの化合物またはその薬学的に許容される塩;
(2)ZAP−70またはALK阻害剤として使用するための、例えば前記で明示の特定の適応症のいずれかに使用するための、式Iの化合物またはその薬学的に許容される塩;
(3)式Iの化合物またはその薬学的に許容される塩を、1個またはそれ以上の薬学的に許容される希釈剤または担体と共に含む、例えば前記で明示の適応症のいずれかに使用するための、医薬組成物;
(4)処置を必要とする対象における、前記で明示の特定の適応症のいずれかを処置するための方法であり、該患者に有効量の式Iの化合物またはその薬学的に許容される塩を投与することを含む、方法;
(5)ZAP−70またはALK活性化が役割を演ずるかまたは関与する疾患または状態;例えば上記の通りのものの処置または予防のための医薬の製造のための、式Iの化合物またはその薬学的に許容される塩の使用。
(i)アロマターゼ阻害剤、例えばステロイド、とりわけエクセメスタンおよびホルメスタンおよび、特に、非ステロイド、とりわけアミノグルテチミド、ボロゾール、ファドロゾール、アナストロゾールおよび、非常にとりわけ、レトロゾール;
(ii)抗エストロゲン、例えばタモキシフェン、フルヴェストラント、ラロキシフェンおよび塩酸ラロキシフェン;
(iii)トポイソメラーゼI阻害剤、例えばトポテカン、イリノテカン、9−ニトロカンプトテシンおよびPNU−166148に接合した巨大分子カンプトテシン(WO99/17804の化合物A1);
(iv)トポイソメラーゼII阻害剤、例えばアントラサイクリン類ドキソルビシン(リポソーム製剤、例えばCAELYX(登録商標)を含む)、エピルビシン、イダルビシンおよびネモルビシン、アントラキノン類ミトキサントロンおよびロソキサントロン、およびポドフィロトキシン類エトポシドおよびテニポシド;
(v)微小管活性化剤、例えばタキサン類パクリタキセルおよびドセタキセル、ビンカアルカロイド類、例えば、ビンブラスチン、とりわけ硫酸ビンブラスチン、ビンクリスチン、とりわけ硫酸ビンクリスチン、およびビノレルビン、ディスコデルモライドおよびエポチロン類、例えばエポチロンBおよびD;
(vi)アルキル化剤、例えばシクロホスファミド、イフォスファミドおよびメルファラン;
(vii)ヒストンデアセチラーゼ阻害剤;
(viii)ファルネシルトランスフェラーゼ阻害剤;
(ix)COX−2阻害剤、例えばセレコキシブ(Celebrex(登録商標))、ロフェコキシブ(Vioxx(登録商標))およびルミラコキシブ(COX189);
(x)MMP阻害剤;
(xi)mTOR阻害剤;
(xii)抗新生物代謝拮抗剤、例えば5−フルオロウラシル、テガフール、カペシタビン、クラドリビン、シタラビン、リン酸フルダラビン、フルオロウリジン、ゲムシタビン、6−メルカプトプリン、ヒドロキシウレア、メトトレキサート、エダトレキサートおよびこのような化合物の塩、およびさらにZD1694(RALTITREXEDTM)、LY231514(ALIMTATM)、LY264618(LOMOTREXOLTM)およびOGT719;
(xiii)白金化合物、例えばカルボプラチン、シスプラチンおよびオキサリプラチン;
(xiv)タンパク質キナーゼ活性を減少させる化合物およびさらなる抗血管形成化合物、例えば(i)血管内皮細胞増殖因子(VEGF)上皮細胞増殖因子(EGF)、c−Src、タンパク質キナーゼC、血小板由来増殖因子(PDGF)、Bcr−Ablチロシンキナーゼ、c−kit、Flt−3およびインシュリン様増殖因子I受容体(IGF−IR)およびサイクリン依存性キナーゼ(CDK)の活性を減少させる薬剤;(ii)イマチニブ、ミドスタウリン、IressaTM(ZD1839)、CGP75166、バタラニブ、ZD6474、GW2016、CHIR−200131、CEP−7055/CEP−5214、CP−547632およびKRN−633;(iii)サリドマイド(THALOMID)、セレコキシブ(Celebrex)、SU5416およびZD6126;
(xv)ゴナドレリンアゴニスト、例えばアバレリックス、ゴセレリンおよびゴセレリンアセテート;
(xvi)抗アンドロゲン、例えばビカルタミド(CASODEX(登録商標));
(xvii)ベンガミド;
(xviii)ビスホスホネート、例えばエチドロン酸、クロドロン酸、チルドロン酸、パミドロン酸、アレンドロン酸、イバンドロン酸、リセドロン酸およびゾレドロン酸;
(xix)抗増殖性抗体、例えばトラスツマブ(Herceptin(登録商標))、トラスツマブ−DM1、エルロチニブ(Tarceva(登録商標))、ベバシズマブ(Avastin(登録商標))、リツキシマブ(Rituxan(登録商標))、PRO64553(抗−CD40)および2C4抗体;
(xx)テモゾロミド(TEMODAL(登録商標))。
(6)治療的有効量のa)式Iの化合物またはその薬学的に許容される塩、およびb)第二医薬物質(該第二医薬物質は例えば前記で明示の特定の適応症のいずれかに使用するためのものである)を、例えば同時にまたは連続して併用投与することを含む、上記で定義の方法;
(7)治療的有効量のZAP−70またはALKキナーゼ阻害剤、例えば式Iの化合物またはその薬学的に許容される塩、および第二医薬物質(該第二医薬物質は例えば上記の通りである)を含む、組み合わせ。
Claims (11)
- 遊離形または塩形の、式I
Zは=CR2 −であり;
R0 は水素であり;
R1 およびR2 はそれらが結合している炭素原子と一体となって5から15員非芳香族性炭素環式またはヘテロ環式基(ここで、該ヘテロ環式基はN、OおよびSから選択される1から5個のヘテロ原子を含む)を形成するか;
またはR 1 は水素であり、そしてR 2 はC 1−4 アルコキシであり;
R3 は−SO 2 NH 2 であり;
R 4 およびR 6 はそれぞれ水素であり;
R 5 は水素、ハロゲン、C 1−C 4 アルキルまたはCF 3 であり;
R 7、R8およびR9 の1個はNR 10 R 11 であり、残りの2個のうち1個は水素、ハロゲン、COOH、CF 3 またはC1−C 4 アルキルであり、そして残りの1個は水素であり;そして
R 10 およびR 11 の一方は水素またはC 1−4 アルキルであり、そして他方は水素、C 1−8 アルキル、末端をOH、C 3−6 シクロアルキルまたはヘテロ環式環で置換されたC 1−8 アルキル、C 2−8 アルケニル、C 3−8 シクロアルキル、C 1−8 アルコキシC 1−4 アルキル、ヒドロキシC 1−8 アルコキシC 1−8 アルキル、または5員ヘテロ環式環である。]
で示される化合物。 - R 1 およびR 2 が一体となって式−O−(CH 2 ) n −O−(ここで、nは2、3、4または5である)の基を形成する、請求項1に記載の化合物。
- Zが=CR 2 であり;
R 0 、R 4 、R 5 、R 6 およびR 9 がそれぞれ水素であり;
R 3 がSO 2 NH 2 であり;
R 1 が水素であり、そしてR 2 がメトキシであるか;
またはR 1 およびR 2 が一体となって−O−CH 2 −CH 2 −O−を形成し;
R 7 がNHCH 3 であり;そして
R 8 がCH 3 である
請求項1に記載の化合物。 - 6−{2−[3−(2−メトキシ−エチルアミノ)−4−メチル−フェニルアミノ]−ピリミジン−4−イルアミノ}−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−スルホン酸アミド;
2−メトキシ−6−[2−(4−アミノ−3−メチル−フェニルアミノ)−ピリミジン−4−イルアミノ]−ベンゼンスルホンアミド;
2−メトキシ−6−[2−(4−エチル−3−メチル−アミノ−フェニルアミノ)−ピリミジン−4−イルアミノ]−ベンゼンスルホンアミド;
2−メトキシ−6−[2−(4−メチルアミノ−3−トリフルオロメチル−フェニルアミノ)−ピリミジン−4−イルアミノ]−ベンゼンスルホンアミド;
2−メトキシ−6−[2−(4−メチル−3−メチル−アミノ−フェニルアミノ)−ピリミジン−4−イルアミノ]−ベンゼンスルホンアミド;
6−[2−(4−メチル−3−メチルアミノ−フェニルアミノ)−ピリミジン−4−イルアミノ]−2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−5−スルホン酸アミド;
6−[2−(4−メチル−3−メチルアミノ−フェニルアミノ)−ピリミジン−4−イルアミノ]−2,3−ジヒドロ−ベンゾフラン−7−スルホン酸アミド;または
7−[2−(4−メチル−3−メチルアミノ−フェニルアミノ)−ピリミジン−4−イルアミノ]−クロマン−8−スルホン酸アミド;
もしくはこれらの塩である、請求項1に記載の化合物。 - 医薬として使用するための、請求項1から4のいずれかに記載の化合物。
- 請求項1から5のいずれかに記載の化合物を1個またはそれ以上の薬学的に許容される希釈剤または担体と共に含む、医薬組成物。
- ZAP−70および/またはSykが役割を演ずる障害または疾患の処置または予防、または急性または慢性炎症性障害または疾患もしくは自己免疫性疾患の処置または予防に使用するための医薬組成物の製造における、請求項1から5のいずれかに記載の化合物の使用。
- 障害または疾患が腫瘍から選択される、請求項7に記載の使用。
- 請求項1に記載の化合物と、免疫抑制剤、免疫調節剤、抗炎症剤、抗新生物剤および抗感染剤から選択される第二医薬物質を含む、組み合わせ剤。
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PCT/EP2004/010348 WO2005026158A1 (en) | 2003-09-16 | 2004-09-15 | 2,4 di (hetero) -arylamino-pyrimidine derivatives as zap-70 and/or syk inhibitors |
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Families Citing this family (132)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
GB0206215D0 (en) * | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
ATE451104T1 (de) | 2002-07-29 | 2009-12-15 | Rigel Pharmaceuticals Inc | Verfahren zur behandlung oder pruvention von autoimmunkrankheiten mit 2,4-pyrimidindiamin- verbindungen |
GB0305929D0 (en) * | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
PL1656372T3 (pl) | 2003-07-30 | 2013-08-30 | Rigel Pharmaceuticals Inc | Związki 2,4-pirymidynodiaminy do stosowania w leczeniu lub zapobieganiu chorobom autoimmunologicznym |
CA2533320A1 (en) * | 2003-08-15 | 2006-02-24 | Novartis Ag | 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
GB0321710D0 (en) * | 2003-09-16 | 2003-10-15 | Novartis Ag | Organic compounds |
BRPI0606318B8 (pt) | 2005-01-19 | 2021-05-25 | Rigel Pharmaceuticals Inc | composto, composição, e, uso de um composto |
EP1856075A1 (en) * | 2005-01-25 | 2007-11-21 | Epix Delaware, Inc. | Substituted arylamine compounds and their use as 5-ht6 modulators |
WO2006129100A1 (en) * | 2005-06-03 | 2006-12-07 | Glaxo Group Limited | Novel compounds |
US20070203161A1 (en) | 2006-02-24 | 2007-08-30 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
WO2006133426A2 (en) | 2005-06-08 | 2006-12-14 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
GB0517329D0 (en) * | 2005-08-25 | 2005-10-05 | Merck Sharp & Dohme | Stimulation of neurogenesis |
US7528143B2 (en) * | 2005-11-01 | 2009-05-05 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
US8133900B2 (en) | 2005-11-01 | 2012-03-13 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
US8604042B2 (en) | 2005-11-01 | 2013-12-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
WO2007120339A1 (en) * | 2005-12-19 | 2007-10-25 | Genentech, Inc. | Pyrimidine kinase inhibitors |
WO2007085540A1 (en) * | 2006-01-27 | 2007-08-02 | Glaxo Group Limited | 1h-indaz0l-4-yl-2 , 4-pyrimidinediamine derivatives |
WO2007089768A2 (en) * | 2006-01-30 | 2007-08-09 | Exelixis, Inc. | 4-aryl-2-amino-pyrimidines or 4-aryl-2-aminoalkyl-pyrimidines as jak-2 modulators and pharmaceutical compositions containing them |
SI1984357T1 (sl) | 2006-02-17 | 2014-02-28 | Rigel Pharmaceuticals, Inc. | Spojine 2,4-pirimidindiamina za zdravljenje ali preventivo avtoimunih bolezni |
ES2622493T3 (es) | 2006-02-24 | 2017-07-06 | Rigel Pharmaceuticals, Inc. | Composiciones y métodos para la inhibición de la ruta de JAK |
US8168383B2 (en) | 2006-04-14 | 2012-05-01 | Cell Signaling Technology, Inc. | Gene defects and mutant ALK kinase in human solid tumors |
ES2637592T3 (es) | 2006-04-14 | 2017-10-13 | Cell Signaling Technology, Inc. | Defectos de genes y quinasa ALK mutante en tumores sólidos humanos |
EP2222647B1 (en) | 2006-10-23 | 2015-08-05 | Cephalon, Inc. | Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors |
SI2091918T1 (sl) | 2006-12-08 | 2015-01-30 | Irm Llc | Spojine in sestavki kot inhibitorji protein-kinaze |
CN101563327A (zh) * | 2006-12-19 | 2009-10-21 | 健泰科生物技术公司 | 嘧啶类激酶抑制剂 |
PE20081636A1 (es) | 2007-01-26 | 2009-01-10 | Smithkline Beecham Corp | Inhibidores de antranilamida para aurora quinasa |
TW200840581A (en) * | 2007-02-28 | 2008-10-16 | Astrazeneca Ab | Novel pyrimidine derivatives |
PL2154967T3 (pl) * | 2007-04-16 | 2014-08-29 | Hutchison Medipharma Entpr Ltd | Pochodne pirymidyny |
TWI389893B (zh) * | 2007-07-06 | 2013-03-21 | Astellas Pharma Inc | 二(芳胺基)芳基化合物 |
KR101174201B1 (ko) | 2007-08-28 | 2012-08-16 | 아이알엠 엘엘씨 | 키나제 억제제로서의 2-비페닐아미노-4-아미노피리미딘 유도체 |
SI2252300T1 (sl) | 2008-02-22 | 2017-04-26 | Rigel Pharmaceuticals, Inc. | Uporaba 2,4-pirimidindiaminov za zdravljenje ateroskleroze |
CA2717529A1 (en) * | 2008-03-11 | 2009-09-17 | Cellzome Limited | Sulfonamides as zap-70 inhibitors |
WO2009127642A2 (en) * | 2008-04-15 | 2009-10-22 | Cellzome Limited | Use of lrrk2 inhibitors for neurodegenerative diseases |
NZ589315A (en) | 2008-04-16 | 2012-11-30 | Portola Pharm Inc | 2,6-diamino-pyrimidin-5-yl-carboxamides as Spleen tryosine kinase (syk) or Janus kinase (JAK) inhibitors |
US8138339B2 (en) | 2008-04-16 | 2012-03-20 | Portola Pharmaceuticals, Inc. | Inhibitors of protein kinases |
US7829574B2 (en) | 2008-05-09 | 2010-11-09 | Hutchison Medipharma Enterprises Limited | Substituted quinazoline compounds and their use in treating angiogenesis-related diseases |
HUE035029T2 (en) | 2008-05-21 | 2018-03-28 | Ariad Pharma Inc | Kinase inhibitor phosphorus derivatives |
US9273077B2 (en) | 2008-05-21 | 2016-03-01 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
EP2331526A2 (en) * | 2008-06-25 | 2011-06-15 | Irm Llc | Pyrimidine derivatives as kinase inhibitors |
US8445505B2 (en) | 2008-06-25 | 2013-05-21 | Irm Llc | Pyrimidine derivatives as kinase inhibitors |
UY31929A (es) | 2008-06-25 | 2010-01-05 | Irm Llc | Compuestos y composiciones como inhibidores de cinasa |
SG10201510696RA (en) | 2008-06-27 | 2016-01-28 | Celgene Avilomics Res Inc | Heteroaryl compounds and uses thereof |
US11351168B1 (en) | 2008-06-27 | 2022-06-07 | Celgene Car Llc | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
US8338439B2 (en) * | 2008-06-27 | 2012-12-25 | Celgene Avilomics Research, Inc. | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
US8426430B2 (en) | 2008-06-30 | 2013-04-23 | Hutchison Medipharma Enterprises Limited | Quinazoline derivatives |
TW201008933A (en) | 2008-08-29 | 2010-03-01 | Hutchison Medipharma Entpr Ltd | Pyrimidine compounds |
NZ621143A (en) * | 2008-09-05 | 2016-08-26 | Celgene Avilomics Res Inc | Algorithm for designing irreversible inhibitors |
ES2659725T3 (es) | 2009-05-05 | 2018-03-19 | Dana-Farber Cancer Institute, Inc. | Inhibidores de EGFR y procedimiento de tratamiento de trastornos |
WO2010142766A2 (en) * | 2009-06-10 | 2010-12-16 | Cellzome Limited | Pyrimidine derivatives as zap-70 inhibitors |
US20120165332A1 (en) * | 2009-06-18 | 2012-06-28 | Cellzome Limited | Sulfonamides and sulfamides as zap-70 inhibitors |
IN2012DN02534A (ja) | 2009-09-16 | 2015-08-28 | Avila Therapeutics Inc | |
AU2010339456A1 (en) | 2009-12-30 | 2012-07-05 | Celgene Avilomics Research, Inc. | Ligand-directed covalent modification of protein |
US8247436B2 (en) | 2010-03-19 | 2012-08-21 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
WO2012019132A2 (en) | 2010-08-06 | 2012-02-09 | Cell Signaling Technology, Inc. | Anaplastic lymphoma kinase in kidney cancer |
CN103096716B (zh) | 2010-08-10 | 2016-03-02 | 西建阿维拉米斯研究公司 | Btk抑制剂的苯磺酸盐 |
WO2012061303A1 (en) | 2010-11-01 | 2012-05-10 | Avila Therapeutics, Inc. | Heteroaryl compounds and uses thereof |
BR112013010564B1 (pt) | 2010-11-01 | 2021-09-21 | Celgene Car Llc | Compostos heterocíclicos e composições compreendendo os mesmos |
WO2012060847A1 (en) | 2010-11-07 | 2012-05-10 | Targegen, Inc. | Compositions and methods for treating myelofibrosis |
WO2012064706A1 (en) | 2010-11-10 | 2012-05-18 | Avila Therapeutics, Inc. | Mutant-selective egfr inhibitors and uses thereof |
EP2489663A1 (en) | 2011-02-16 | 2012-08-22 | Almirall, S.A. | Compounds as syk kinase inhibitors |
JP5931933B2 (ja) | 2011-02-25 | 2016-06-08 | 武田薬品工業株式会社 | N−置換オキサジノプテリジンおよびオキサジノプテリジノン |
US9249124B2 (en) | 2011-03-30 | 2016-02-02 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Aurora kinase inhibitors and methods of making and using thereof |
JP5999177B2 (ja) | 2011-05-04 | 2016-09-28 | アリアド・ファーマシューティカルズ・インコーポレイテッド | Egfr発動性がんの細胞増殖阻害用化合物 |
CN103619172A (zh) | 2011-05-10 | 2014-03-05 | 默沙东公司 | 作为syk抑制剂的氨基嘧啶 |
EP2706852B1 (en) | 2011-05-10 | 2018-08-22 | Merck Sharp & Dohme Corp. | Bipyridylaminopyridines as syk inhibitors |
US9120785B2 (en) | 2011-05-10 | 2015-09-01 | Merck Sharp & Dohme Corp. | Pyridyl aminopyridines as Syk inhibitors |
EP2763975B1 (en) | 2011-10-05 | 2016-04-06 | Merck Sharp & Dohme Corp. | 3-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors |
US9216173B2 (en) | 2011-10-05 | 2015-12-22 | Merck Sharp & Dohme Corp. | 2-Pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors |
EP2763974B1 (en) | 2011-10-05 | 2016-09-14 | Merck Sharp & Dohme Corp. | Phenyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors |
TW201325593A (zh) | 2011-10-28 | 2013-07-01 | Celgene Avilomics Res Inc | 治療布魯頓(bruton’s)酪胺酸激酶疾病或病症之方法 |
MX363551B (es) | 2011-11-23 | 2019-03-27 | Portola Pharmaceuticals Inc Star | Compuestos derivados de pirazina como inhibidores de cinasa. |
WO2013126132A1 (en) * | 2012-02-21 | 2013-08-29 | Merck Patent Gmbh | Cyclic diaminopyrimidine derivatives |
SG11201405692UA (en) | 2012-03-15 | 2014-10-30 | Celgene Avilomics Res Inc | Salts of an epidermal growth factor receptor kinase inhibitor |
WO2013138495A1 (en) | 2012-03-15 | 2013-09-19 | Celgene Avilomics Research, Inc. | Solid forms of an epidermal growth factor receptor kinase inhibitor |
AR090650A1 (es) | 2012-04-12 | 2014-11-26 | Alcon Res Ltd | Tratamiento para respuestas inflamatorias inducidas por microbios en el ojo |
AU2013204563B2 (en) | 2012-05-05 | 2016-05-19 | Takeda Pharmaceutical Company Limited | Compounds for inhibiting cell proliferation in EGFR-driven cancers |
US9242984B2 (en) | 2012-06-20 | 2016-01-26 | Merck Sharp & Dohme Corp. | Pyrazolyl derivatives as Syk inhibitors |
WO2013192128A1 (en) | 2012-06-20 | 2013-12-27 | Merck Sharp & Dohme Corp. | Imidazolyl analogs as syk inhibitors |
EP2863916B1 (en) | 2012-06-22 | 2018-07-18 | Merck Sharp & Dohme Corp. | Substituted pyridine spleen tyrosine kinase (syk) inhibitors |
WO2013192088A1 (en) | 2012-06-22 | 2013-12-27 | Merck Sharp & Dohme Corp. | SUBSTITUTED DIAZINE AND TRIAZINE SPLEEN TYROSINE KINASE (Syk) INHIBITORS |
EP2884982B1 (en) | 2012-08-20 | 2017-09-20 | Merck Sharp & Dohme Corp. | SUBSTITUTED PHENYL SPLEEN TYROSINE KINASE (Syk) INHIBITORS |
EP2900665B1 (en) | 2012-09-28 | 2018-01-03 | Merck Sharp & Dohme Corp. | Triazolyl derivatives as syk inhibitors |
DK2914296T4 (da) | 2012-11-01 | 2022-01-03 | Infinity Pharmaceuticals Inc | Behandling af cancere under anvendelse af PI3-kinase-isoform-modulatorer |
EP2931281B1 (en) | 2012-12-12 | 2018-01-17 | Merck Sharp & Dohme Corp. | Amino-pyrimidine-containing spleen tyrosine kinase inhibitors |
EP2934525B1 (en) | 2012-12-21 | 2019-05-08 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors |
WO2014100748A1 (en) | 2012-12-21 | 2014-06-26 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
WO2014124230A2 (en) | 2013-02-08 | 2014-08-14 | Celgene Avilomics Research, Inc. | Erk inhibitors and uses thereof |
CA2900097A1 (en) | 2013-02-22 | 2014-08-28 | F. Hoffmann-La Roche Ag | Methods of treating cancer and preventing drug resistance |
NZ629037A (en) | 2013-03-15 | 2017-04-28 | Infinity Pharmaceuticals Inc | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
US10150742B2 (en) | 2013-03-15 | 2018-12-11 | President And Fellows Of Harvard College | Substituted heterocyclic compounds for treating or preventing viral infections |
US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
US9499534B2 (en) | 2013-04-26 | 2016-11-22 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors |
US9745295B2 (en) | 2013-04-26 | 2017-08-29 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors |
AU2014273946B2 (en) | 2013-05-30 | 2020-03-12 | Infinity Pharmaceuticals, Inc. | Treatment of cancers using PI3 kinase isoform modulators |
US9492471B2 (en) | 2013-08-27 | 2016-11-15 | Celgene Avilomics Research, Inc. | Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase |
US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
PL3052485T3 (pl) | 2013-10-04 | 2022-02-28 | Infinity Pharmaceuticals, Inc. | Związki heterocykliczne i ich zastosowania |
ES2968371T3 (es) | 2013-10-10 | 2024-05-09 | Eastern Virginia Medical School | Derivados de 4-((2-hidroxi-3-metoxibencil)amino) bencenosulfonamida como inhibidores de la 12-lipoxigenasa |
WO2015061204A1 (en) | 2013-10-21 | 2015-04-30 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US9415049B2 (en) | 2013-12-20 | 2016-08-16 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
US9822107B2 (en) | 2013-12-20 | 2017-11-21 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors |
WO2015095444A1 (en) | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors |
US9783531B2 (en) | 2013-12-20 | 2017-10-10 | Merck Sharp & Dohme Corp. | Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors |
WO2015106012A1 (en) | 2014-01-09 | 2015-07-16 | Takeda Pharmaceutical Company Limited | Azaindole derivatives |
US9775839B2 (en) | 2014-03-13 | 2017-10-03 | Merck Sharp & Dohme Corp. | 2-pyrazine carboxamides as spleen tyrosine kinase inhibitors |
SG11201607705XA (en) | 2014-03-19 | 2016-10-28 | Infinity Pharmaceuticals Inc | Heterocyclic compounds for use in the treatment of pi3k-gamma mediated disorders |
US20150320754A1 (en) | 2014-04-16 | 2015-11-12 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US10005760B2 (en) | 2014-08-13 | 2018-06-26 | Celgene Car Llc | Forms and compositions of an ERK inhibitor |
US9708348B2 (en) | 2014-10-03 | 2017-07-18 | Infinity Pharmaceuticals, Inc. | Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof |
CN106146525B (zh) * | 2015-04-10 | 2018-11-02 | 山东轩竹医药科技有限公司 | 三并环类间变性淋巴瘤激酶抑制剂 |
CN105664178B (zh) * | 2015-09-24 | 2019-08-20 | 洪健 | Syk作为肝纤维化/硬化治疗靶点的应用 |
US10919914B2 (en) | 2016-06-08 | 2021-02-16 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
SG10201912456RA (en) | 2016-06-24 | 2020-02-27 | Infinity Pharmaceuticals Inc | Combination therapies |
AR111760A1 (es) | 2017-05-19 | 2019-08-14 | Novartis Ag | Compuestos y composiciones para el tratamiento de tumores sólidos mediante administración intratumoral |
EP3706735A1 (en) | 2017-11-06 | 2020-09-16 | Snap Bio, Inc. | Pim kinase inhibitor compositions, methods, and uses thereof |
WO2019154091A1 (zh) * | 2018-02-07 | 2019-08-15 | 深圳市塔吉瑞生物医药有限公司 | 取代的二氨基嘧啶化合物 |
KR102063155B1 (ko) | 2018-04-11 | 2020-01-08 | 한국과학기술연구원 | 우수한 카이네이즈 저해 활성을 보이는 다양한 치환기를 갖는 피리미딘 유도체 |
CN114364798A (zh) | 2019-03-21 | 2022-04-15 | 欧恩科斯欧公司 | 用于治疗癌症的Dbait分子与激酶抑制剂的组合 |
CA3137472A1 (en) | 2019-04-25 | 2020-10-29 | Bayer Aktiengesellschaft | Acyl sulfonamides for treating cancer |
WO2020253862A1 (zh) * | 2019-06-21 | 2020-12-24 | 上海翰森生物医药科技有限公司 | 含氮芳基磷氧化物类衍生物、其制备方法和应用 |
CA3145864A1 (en) | 2019-07-03 | 2021-01-07 | Sumitomo Dainippon Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof |
WO2021089791A1 (en) | 2019-11-08 | 2021-05-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the treatment of cancers that have acquired resistance to kinase inhibitors |
WO2021098883A1 (zh) * | 2019-11-21 | 2021-05-27 | 浙江同源康医药股份有限公司 | 用作egfr激酶抑制剂的化合物及其应用 |
CN111423419B (zh) * | 2020-01-17 | 2021-12-17 | 温州医科大学 | 一种小分子化合物cyy-260及其在制备抗肿瘤药物中的应用 |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
US20230090742A1 (en) * | 2020-01-30 | 2023-03-23 | Sumitomo Pharma Oncology, Inc. | Aminopyrimidinylaminobenzonitrile derivatives as nek2 inhibitors |
CN111484484B (zh) * | 2020-04-13 | 2021-11-23 | 沈阳药科大学 | 含芳杂环的2,4-二芳氨基嘧啶衍生物及其制备与应用 |
CN115697996A (zh) * | 2020-06-08 | 2023-02-03 | 南京红云生物科技有限公司 | 烯基嘧啶类化合物、其制备方法与应用 |
WO2022017434A1 (zh) * | 2020-07-23 | 2022-01-27 | 上海赛岚生物科技有限公司 | 一类具有激酶抑制活性的化合物 |
WO2023011610A1 (zh) * | 2021-08-06 | 2023-02-09 | 南京红云生物科技有限公司 | 苯并二噁烷类化合物、其制备方法与应用 |
CN117736198A (zh) * | 2022-09-21 | 2024-03-22 | 科辉智药生物科技(深圳)有限公司 | 大环含氮冠醚化合物及其作为蛋白激酶抑制剂的应用 |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9523675D0 (en) * | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
GB9619284D0 (en) * | 1996-09-16 | 1996-10-30 | Celltech Therapeutics Ltd | Chemical compounds |
GB9622363D0 (en) * | 1996-10-28 | 1997-01-08 | Celltech Therapeutics Ltd | Chemical compounds |
GB9705361D0 (en) | 1997-03-14 | 1997-04-30 | Celltech Therapeutics Ltd | Chemical compounds |
GB9721069D0 (en) | 1997-10-03 | 1997-12-03 | Pharmacia & Upjohn Spa | Polymeric derivatives of camptothecin |
AU5438299A (en) * | 1998-08-29 | 2000-03-21 | Astrazeneca Ab | Pyrimidine compounds |
GB9828511D0 (en) * | 1998-12-24 | 1999-02-17 | Zeneca Ltd | Chemical compounds |
ATE396978T1 (de) | 1999-10-07 | 2008-06-15 | Amgen Inc | Triazin-kinase-hemmer |
HUP0301117A3 (en) * | 2000-02-17 | 2004-01-28 | Amgen Inc Thousand Oaks | Imidazole derivatives kinase inhibitors, their use, process for their preparation and pharmaceutical compositions containing them |
GB0004887D0 (en) * | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
GB0004890D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
GB0019632D0 (en) | 2000-08-09 | 2000-09-27 | Novartis Ag | Organic compounds |
US20020132823A1 (en) | 2001-01-17 | 2002-09-19 | Jiahuai Han | Assay method |
US6939874B2 (en) * | 2001-08-22 | 2005-09-06 | Amgen Inc. | Substituted pyrimidinyl derivatives and methods of use |
WO2003030909A1 (en) * | 2001-09-25 | 2003-04-17 | Bayer Pharmaceuticals Corporation | 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer |
TWI329105B (en) * | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
GB0206215D0 (en) * | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
UA80767C2 (en) * | 2002-12-20 | 2007-10-25 | Pfizer Prod Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
JP4634367B2 (ja) * | 2003-02-20 | 2011-02-16 | スミスクライン ビーチャム コーポレーション | ピリミジン化合物 |
GB0305929D0 (en) * | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
GB0321710D0 (en) * | 2003-09-16 | 2003-10-15 | Novartis Ag | Organic compounds |
CN100584832C (zh) * | 2003-09-18 | 2010-01-27 | 诺瓦提斯公司 | 可用于治疗增殖性病症的2,4-二(苯基氨基)嘧啶类 |
US7557207B2 (en) | 2004-11-24 | 2009-07-07 | Rigel Pharmaceuticals, Inc. | Spiro 2,4-pyrimidinediamine compounds and their uses |
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