CN100436427C - 用作糖原合酶激酶3β抑制剂的氨基苯甲酰胺衍生物 - Google Patents
用作糖原合酶激酶3β抑制剂的氨基苯甲酰胺衍生物 Download PDFInfo
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- CN100436427C CN100436427C CNB028219163A CN02821916A CN100436427C CN 100436427 C CN100436427 C CN 100436427C CN B028219163 A CNB028219163 A CN B028219163A CN 02821916 A CN02821916 A CN 02821916A CN 100436427 C CN100436427 C CN 100436427C
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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Abstract
本发明涉及式(I)化合物,其N-氧化物、可药用加成盐、季铵和立体化学异构体,其中环A为6-元杂环;R1为氢;芳基;甲酰基;C1-6烷基羰基;任选取代的C1-6烷基;C1-6烷氧基羰基;任选取代的C1-6烷氧基C1-6烷基羰基;X为直接键或连接原子或基团;Z为O或S;R2为氢,C1-10烷基,C2-10链烯基,C2-10炔基,碳环或杂环,所述各基团可任选被取代;R3为氢;羟基;卤素;任选取代的C1-6烷基或C2-6链烯基或C2-6炔基;C1-6烷氧基;C1-6烷硫基;C1-6烷氧基羰基;C1-6烷基羰氧基;羧基;氰基;硝基;氨基;单-或二(C1-6烷基)氨基;多卤代C1-6烷基;多卤代C1-6烷氧基;多卤代C1-6烷硫基;R21;R21-C1-6烷基;R21-O-;R21-S-;R21-C(=O)-;R21-S(=O)p-;R7-S=O R7-S(=O)p-NH-;R21-S(=O)p-NH-;R7-C(=O)-;-NHC(=O)H;-C(=O)NHNH2;R7-C(=O)-NH-;R21-C(=O)-NH-;-C(=NH)R7;-C(=NH)R21;R4a或R4b各自独立地代表氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10;条件是-X-R2和/或R3不能为氢;它们的应用;包含它们的药物组合物以及它们的制备方法。
Description
本发明涉及一组新化合物,其作为药品的应用,它们在制备用于治疗通过糖原合酶激酶3(特别是糖原合酶激酶3β)介导的疾病的药物中的应用;制备它们的方法以及包含它们的药物组合物。
WO 00/62778描述了环肽酪氨酸激酶抑制剂。
WO 91/18887涉及具有胃酸分泌抑制特性的二氨基嘧啶衍生物。
US 5,691,364涉及作为抗凝剂的苯甲酰胺衍生物。
WO 98/41512涉及可用作src-家族蛋白激酶抑制剂的取代的2-苯氨基嘧啶化合物。
WO 00/78731公开了作为KDR和/或FGFr激酶抑制剂的5-氰基-2-氨基嘧啶化合物。
WO 99/50250和WO 00/27825涉及抑制HIV的氨基嘧啶衍生物。
WO 95/09853描述了用于***疾病的N-苯基-2-嘧啶胺衍生物。
WO 98/18782涉及用作选择性蛋白酪氨酸激酶抑制剂的2-嘧啶胺衍生物。
EP 0,337,943公开了具有除草性植物生长调节活性的N-苯基-N-嘧啶-2-基衍生物。
EP 0,164,204涉及提高免疫反应的2-氨基嘧啶化合物。
EP 0,233,461涉及具有抗哮喘活性的4,5,6-三取代的2-嘧啶胺化合物。
US 5,516,775涉及2-苯氨基嘧啶化合物作为蛋白激酶C抑制剂的应用。
本发明涉及其结构、药理活性、效力或选择性不同于现有技术的化合物。
本发明涉及式(I)化合物,其N-氧化物,可药用加成盐,季铵及立体化学异构体:
其中:
Z代表O或S;
环A为吡啶基,嘧啶基,吡嗪基或哒嗪基;
R1为氢;芳基;甲酰基;C1-6烷基羰基;C1-6烷基;C1-6烷氧基羰基;被甲酰基,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰氧基取代的C1-6烷基;任选被C1-6烷氧基羰基取代的C1-6烷氧基C1-6烷基羰基;
X为-NR1-;-NH-NH-;-N=N-;-O-;-C(=O)-;-C(=S)-;-O-C(=O)-;-C(=O)-O-;-O-C(=O)-C1-6烷基;-C(=O)-O-C1-6烷基;-O-C1-6烷基-C(=O)-;-C(=O)-C1-6烷基-O-;-O-C(=O)-NR1-;-NR1-C(=O)-O-;-O-C(=O)-C(=O)-;-C(=O)-NR1-;-NR1-C(=O)-;-C(=S)-NR1-,-NR1-C(=S)-;-NR1-C(=O)-NR1-;-NR1-C(=S)-NR1-;-NR1-S(=O)-NR1-;-NR1-S(=O)2-NR1-;-C1-6烷基-C(=O)-NR1-;-O-C1-6烷基-C(=O)-NR1-;-C1-6烷基-O-C(=O)-NR1-;-C1-6烷基-;-O-C1-6烷基-;-C1-6烷基-O-;-NR1-C1-6烷基-;-C1-6烷基-NR1-;-NR1-C1-6烷基-NR1;-NR1-C1-6烷基-C3-7环烷基-;-C2-6链烯基-;-C2-6炔基-;-O-C2-6链烯基-;-C2-6链烯基-O-;-NR1-C2-6链烯基-;-C2-6链烯基-NR1-;-NR1-C2-6链烯基-NR1-;-NR1-C2-6链烯基-C3-7环烷基-;-O-C2-6炔基-;-C2-6炔基-O-;-NR1-C2-6炔基-;-C2-6炔基-NR1-;-NR1-C2-6炔基-NR1-;-NR1-C2-6炔基-C3-7环烷基-;-O-C1-6烷基-O-;-O-C2-6链烯基-O-;-O-C2-6炔基-O-;-CHOH-;-S-;-S(=O)-;-S(=O)2-;-S(=O)-NR1-;-S(=O)2-NR1-;-NR1-S(=O)-;-NR1-S(=O)2-;-S-C1-6烷基-;-C1-6烷基-S-;-S-C2-6链烯基-;-C2-6链烯基-S-;-S-C2-6炔基-;-C2-6炔基-S-;-O-C1-6烷基-S(=O)2-或直接键;
R2为氢,C1-10烷基,C2-10链烯基,C2-10炔基,R20,可能的话,该R2代表的各基团可任选被一个或多个各自独立选自以下的取代基取代:=S;=O;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R5R6N;R5R6N-C1-6烷基;R5R6N-C3-7环烷基;R5R6N-C1-6烷氧基;R5R6N-C(=O)-;R5R6N-C(=S)-;R5R6N-C(=O)-NH-;R5R6N-C(=S)-NH-;R5R6N-S(=O)n-;R5R6N-S(=O)n-NH-;R15-C(=S)-;R15-C(=O)-NH-;R15-O-C(C=O)-NH-;R15-S(=O)n-NH-;R15-O-S(=O)n-NH-;R15-C(=S)-NH-;R15-O-C(=S)-NH-;R17R18N-Y1a-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;
R3为氢;羟基;卤素;C1-6烷基;被氰基,羟基或-C(=O)R7取代的C1-6烷基;C2-6链烯基;被一个或多个卤原子或氰基取代的C2-6链烯基;C2-6炔基;被一个或多个卤原子或氰基取代的C2-6炔基;C1-6烷氧基;C1-6烷硫基;C1-6烷氧基羰基;C1-6烷基羰氧基;羧基;氰基;硝基;氨基;单-或二(C1-6烷基)氨基;多卤代C1-6烷基;多卤代C1-6烷氧基;多卤代C1-6烷硫基;R21;R21-C1-6烷基;R21-O-;R21-S-;R21-C(=O)-;R21-S(=O)p-;R7-S(=O)p-;R7-S(=O)p-NH-;R21-S(=O)p-NH-;R7-C(=O)-;-NHC(=O)H;-C(=O)NHNH2;R7-C(=O)-NH-;R21-C(=O)-NH-;-C(=NH)R7;-C(=NH)R21;
R4a或R4b各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10;
R5和R6各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10,或者
R5和R6可以与它们所连接的氮一起形成3-8元饱和或部分饱和的单杂环,或形成4-8元芳族单杂环,所述杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代,或者所述杂环各自可任选与苯环稠合,其中所述苯环任选被一个或多个选自R12、R13和R14的取代基取代;
R7为C1-6烷基;C1-6烷氧基,氨基,单-或二(C1-6烷基)氨基或多卤代C1-6烷基;
R8为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;该R8代表的各基团可任选被一个或多个选自R12、R13和R14的取代基取代;
R9,R10和R11各自独立地为氢或R8,或者
R9、R10和R11中的任意两个可一起表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的氮原子一起形成3-8元饱和或部分饱和的单杂环或4-8元的芳族单杂环;所述杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
R12、R13和R14各自独立地为氢;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R15R16N-S(=O)-;R15R16N-S(=O)2-R17R18N-Y1-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;氧代,或者
R12、R13和R14中的任意两个可一起表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的原子一起形成3-8元饱和或部分饱和的单碳环或单杂环或形成4-8元的芳族单碳环或单杂环;或者
R12、R13和R14中的任意两个可一起表示-O-(CH2)r-O-,从而与它们所连接的原子一起形成饱和、部分饱和或芳香性的4-8元单碳环或单杂环;
R15为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;所述R15代表的各基团可任选被一个或多个选自R12、R13和R14的取代基取代;或者所述碳环或杂环各自可任选与苯环稠合,并且所述苯环任选被一个或多个选自R12、R13和R14的取代基取代;
R16、R17、R18和R19各自独立地为氢或R15,或者
R17与18,或R15与R19可一起表示C1-6亚烷基或C2-6亚烯基,从而形成3-8元饱和或部分饱和的单杂环或形成4-8元的芳族单杂环;所述各杂环可任选被一个或多个选自R12、R13和R14的取代基取代;或者
R17和R18与R15一起可表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的氮原子一起形成3-8元饱和或部分饱和的单杂环或形成4-8元的芳族单杂环;所述各杂环可任选被一个或多个选自R12、R13和R14的取代基取代;
R20为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;或芳族单环、二环或三环杂环;
R21为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;该R21代表的碳环或杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
Y1a为-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y1或Y2各自独立地为直接键,-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y3或Y4各自独立地为直接键,C1-6亚烷基,C2-6亚烯基或C2-6亚炔基;
n为1或2;
m为1或2;
p为1或2;
r为1-5;
s为1-3;
芳基是指苯基或被一个、两个、三个、四个或五个各自独立选自以下的取代基所取代的苯基:卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基、氰基、硝基、多卤代C1-6烷基和多卤代C1-6烷氧基;
条件是-X-R2和/或R3不能为氢;并且
不包括下列化合物:
4-[(5-氰基-4-苯基-2-嘧啶基)氨基]-N-[2-(二乙基氨基)乙基]-苯甲酰胺;
4-[[4-[6-(1-哌嗪基)-3-吡啶基]-2-嘧啶基]氨基]-苯甲酰胺;
N-甲基-4-[[4-(3-吡啶基)-2-嘧啶基]氨基]-苯甲酰胺;
4-[[4-(3-甲氧基苯基)硫基]-2-嘧啶基]氨基]-N-[2-(1-吡咯烷基)乙基]-苯甲酰胺;
N-[2-(二乙基氨基)乙基]-4-[[4-(3-吡啶基)-2-嘧啶基]氨基]-苯甲酰胺;
4-[(5-氨基-1,4-二氢-4-氧代-2-嘧啶基)氨基]-N,N-二甲基苯甲酰胺;
4-[(5-氨基-1,4-二氢-4-氧代-2-嘧啶基)氨基]-N,N-二乙基-苯甲酰胺;
4-[(5-氨基-1,4-二氢-4-氧代-2-嘧啶基)氨基]-N-甲基-苯甲酰胺;
4-[[5-(4-甲氧基苯基)-2-嘧啶基]氨基]-苯甲酰胺;
4-[[1-氧化-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]-苯甲酰胺;
4-[[3-氧化-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]-苯甲酰胺;
4-[[4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]-苯甲酰胺;
2-[[4-甲基-6-(三氟甲基)-2-嘧啶基]氨基]-苯甲酰胺;
N-(3-氨基丙基)-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-苯甲酰胺;
N-(3-羟基丙基)-3-[[4-[2-[(3-羟基丙基)氨基]-4-吡啶基]-2-嘧啶基]氨基]-苯甲酰胺;
N-(3-氨基丙基)-3-[[4-[2-[(3-羟基丙基)氨基]-4-吡啶基]-2-嘧啶基]氨基]-苯甲酰胺;
3-[[4-[2-[(3-羟基丙基)氨基]-4-吡啶基]-2-嘧啶基]氨基]-N-[2-(1H-咪唑-4-基)乙基]-苯甲酰胺;
4,4’-[(6-甲基-5-硝基-2,4-亚嘧啶基)二亚氨基]双-苯甲酰胺;
4-[[5-氨基-4-(甲基氨基)-2-嘧啶基]氨基]-N,N-二乙基-苯甲酰胺;
N,N-二乙基-4-[[4-(甲基氨基)-5-硝基-2-嘧啶基]氨基]-苯甲酰胺。
本发明也涉及化合物在制备用于预防或治疗通过GSK3介导的疾病的药物中的应用,所述化合物为式(I’)化合物:
其N-氧化物,可药用的加成盐,季铵和立体化学异构体,
其中:
Z代表O或S;
环A为吡啶基,嘧啶基,吡嗪基或哒嗪基;
R1为氢;芳基;甲酰基;C1-6烷基羰基;C1-6烷基;C1-6烷氧基羰基;被甲酰基,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰氧基取代的C1-6烷基;任选被C1-6烷氧基羰基取代的C1-6烷氧基C1-6烷基羰基;
X为-NR1-;-NH-NH-;-N=N-;-O-;-C(=O)-;-C(=S)-;-O-C(=O)-;-C(=O)-O-;-O-C(=O)-C1-6烷基;-C(=O)-O-C1-6烷基;-O-C1-6烷基-C(=O)-;-C(=O)-C1-6烷基-O-;-O-C(=O)-NR1-;-NR1-C(=O)-O-;-O-C(=O)-C(=O)-;-C(=O)-NR1-;-NR1-C(=O)-;-C(=S)-NR1-,-NR1-C(=S)-;-NR1-C(=O)-NR1-;-NR1-C(=S)-NR1-;-NR1-S(=O)-NR1-;-NR1-S(=O)2-NR1-;-C1-6烷基-C(=O)-NR1-;-O-C1-6烷基-C(=O)-NR1-;-C1-6烷基-O-C(=O)-NR1-;-C1-6烷基-;-O-C1-6烷基-;-C1-6烷基-O-;-NR1-C1-6烷基-;-C1-6烷基-NR1-;-NR1-C1-6烷基-NR1;-NR1-C1-6烷基-C3-7环烷基-;-C2-6链烯基-;-C2-6炔基-;-O-C2-6链烯基-;-C2-6链烯基-O-;-NR1-C2-6链烯基-;-C2-6链烯基-NR1-;-NR1-C2-6链烯基-NR1-;-NR1-C2-6链烯基-C3-7环烷基-;-O-C2-6炔基-;-C2-6炔基-O-;-NR1-C2-6炔基-;-C2-6炔基-NR1-;-NR1-C2-6炔基-NR1-;-NR1-C2-6炔基-C3-7环烷基-;-O-C1-6烷基-O-;-O-C2-6链烯基-O-;-O-C2-6炔基-O-;-CHOH-;-S-;-S(=O)-;-S(=O)2-;-S(=O)-NR1-;-S(=O)2-NR1-;-NR1-S(=O)-;-NR1-S(=O)2-;-S-C1-6烷基-;-C1-6烷基-S-;-S-C2-6链烯基-;-C2-6链烯基-S-;-S-C2-6炔基-;-C2-6炔基-S-;-O-C1-6烷基-S(=O)2-或直接键;
R2为氢,C1-10烷基,C2-10链烯基,C2-10炔基,R20,可能的话,该R2表示的各基团可任选被一个或多个各自独立选自以下的取代基取代:=S;=O;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R5R6N;R5R6N-C1-6烷基;R5R6N-C3-7环烷基;R5R6N-C1-6烷氧基;R5R6N-C(=O)-;R5R6N-C(=S)-;R5R6N-C(=O)-NH-;R5R6N-C(=S)-NH-;R5R6N-S(=O)n-;R5R6N-S(=O)n-NH-;R15-C(=S)-;R15-C(=O)-NH-;R15-O-C(C=O)-NH-;R15-S(=O)n-NH-;R15-O-S(=O)n-NH-;R15-C(=S)-NH-;R15-O-C(=S)-NH-;R17R18N-Y1a-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;
R3为氢;羟基;卤素;C1-6烷基;被氰基,羟基或-C(=O)R7取代的C1-6烷基;C2-6链烯基;被一个或多个卤原子或氰基取代的C2-6链烯基;C2-6炔基;被一个或多个卤原子或氰基取代的C2-6炔基;C1-6烷氧基;C1-6烷硫基;C1-6烷氧基羰基;C1-6烷基羰氧基;羧基;氰基;硝基;氨基;单-或二(C1-6烷基)氨基;多卤代C1-6烷基;多卤代C1-6烷氧基;多卤代C1-6烷硫基;R21;R21-C1-6烷基;R21-O-;R21-S-;R21-C(=O)-;R21-S(=O)p-;R7-S(=O)p-;R7-S(=O)p-NH-;R21-S(=O)p-NH-;R7-C(=O)-;-NHC(=O)H;-C(=O)NHNH2;R7-C(=O)-NH-;R21-C(=O)-NH-;-C(=NH)R7;-C(=NH)R21;
R4a或R4b各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10;
R5和R6各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10,或者
R5和R6可以与它们所连接的氮一起形成3-8元饱和或部分饱和的单杂环,或形成4-8元芳族单杂环,所述各杂环可任选被一个或多个选自R12、R13和R14的取代基取代,或者所述杂环各自可任选与苯环稠合,其中所述苯环任选被一个或多个选自R12、R13和R14的取代基取代;
R7为C1-6烷基;C1-6烷氧基,氨基,单-或二(C1-6烷基)氨基或多卤代C1-6烷基;
R8为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;该R8代表的各基团可任选被一个或多个选自R12、R13和R14的取代基取代;
R9,R10和R11各自独立地为氢或R8,或者
R9、R10和R11中的任意两个可一起表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的氮原子一起形成3-8元饱和或部分饱和的单杂环或4-8元的芳族单杂环;所述杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
R12、R13和R14各自独立地为氢;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R15R16N-S(=O)-;R15R16N-S(=O)2-R17R18N-Y1-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;氧代,或者
R12、R13和R14中的任意两个可一起表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的原子一起形成3-8元饱和或部分饱和的单碳环或单杂环或形成4-8元的芳族单碳环或单杂环;或者
R12、R13和R14中的任意两个可一起表示-O-(CH2)r-O-,从而与它们所连接的原子一起形成饱和、部分饱和或芳香性的4-8元单碳环或单杂环;
R15为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;所述R15代表的各基团可任选被一个或多个选自R12、R13和R14的取代基取代;或者所述碳环或杂环各自可任选与苯环稠合,并且所述苯环任选被一个或多个选自R12、R13和R14的取代基取代;
R16、R17、R18和R19各自独立地为氢或R15,或者
R17与R18,或R15与R19可一起表示C1-6亚烷基或C2-6亚烯基,从而形成3-8元饱和或部分饱和的单杂环或形成4-8元的芳族单杂环;所述各杂环可任选被一个或多个选自R12、R13和R14的取代基取代;
R17和R18与R15一起可表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的氮原子一起形成3-8元饱和或部分饱和的单杂环或形成4-8元的芳族单杂环;所述各杂环可任选被一个或多个选自R12、R13和R14的取代基取代;
R20为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;或芳族单环、二环或三环杂环;
R21为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;该R21代表的碳环或杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
Y1a为-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y1或Y2各自独立地为直接键,-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y3或Y4各自独立地为直接键,C1-6亚烷基,C2-6亚烯基或C2-6亚炔基;
n为1或2;
m为1或2;
p为1或2;
r为1-5;
s为1-3;
芳基是指苯基或被一个、两个、三个、四个或五个各自独立选自以下的取代基所取代的苯基:卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基、氰基、硝基、多卤代C1-6烷基和多卤代C1-6烷氧基;
条件是-X-R2和/或R3不为氢。
本文中使用的作为基团或基团一部分的C1-3烷基是指具有1-3个碳原子的直链或支链饱和烃基,例如甲基、乙基、丙基、1-甲基乙基;作为基团或基团一部分的C1-4烷基是指具有1-4个碳原子的直链或支链饱和烃基,譬如C1-3烷基所定义的基团以及丁基;作为基团或基团一部分的C1-6烷基是指具有1-6个碳原子的直链或支链饱和烃基,譬如C1-4烷基所定义的基团以及戊基、己基、2-甲基丁基等;作为基团或基团一部分的C1-10烷基是指具有1-10个碳原子的直链或支链饱和烃基,譬如C1-6烷基所定义的基团以及庚基、辛基、壬基、癸基等;作为基团或基团一部分的C1-6亚烷基是指具有1-6个碳原子的直链或支链的二价饱和烃基,例如亚甲基、1,2-亚乙基(1,2-ethanediyl)或1,2-乙叉(1,2-ethylidene),1,3-亚丙基(1,3-propanediyl)或1,3-丙叉(1,3-propylidene),1,4-亚丁基(1,4-butanediyl)或1,4-丁叉(1,4-butylidene)等;C2-6链烯基是指具有2-6个碳原子和一条双键的直链和支链烃基,例如乙烯基,丙烯基,丁烯基,戊烯基,己烯基等;C2-10链烯基是指具有2-10个碳原子和一条双键的直链和支链烃基,譬如C2-6链烯基所定义的基团以及庚烯基、辛烯基、壬烯基、癸烯基等;C2-6亚烯基是指含有一条或多条双键且具有2-6个碳原子的二价直链与支链烃基,例如亚乙烯基,亚丙烯基,亚丁烯基,亚戊烯基,亚己烯基等;C2-6炔基是指具有2-6个碳原子和一条叁键的直链和支链烃基,如乙炔基,丙炔基,丁炔基,戊炔基,己炔基等;C2-10炔基是指具有2-10个碳原子和一条叁键的直链和支链烃基,如C2-6炔基所定义的基团以及庚炔基、辛炔基、壬炔基、癸炔基等;C2-6亚炔基是指含有一条双键且具有2-6个碳原子的二价直链与支链烃基,例如亚乙炔基,亚丙炔基,亚丁炔基,亚戊炔基,亚己炔基等;C3-6环烷基是环丙基、环丁基、环戊基、环己基的通称;C3-7环烷基是环丙基、环丁基、环戊基、环己基和环庚基的通称;饱和的单环、二环或三环碳环表示由1、2或3个环组成的环状***,该环系仅由碳原子组成,并且这种环系只含有单键;部分饱和的单环、二环或三环碳环表示由1、2或3个环组成的环状***,该环系仅由碳原子组成并且包括至少一个双键,但该环系不是芳族环系;芳香性的单环、二环或三环表示由1、2或3个环组成的芳族环状***,该环系仅由碳原子组成;术语芳香性是本领域技术人员公知的,表示4n’+2电子的环共轭体系,亦即具有6个、10个、14个等个数π-电子(Hückel规则;n’为1、2、3等);饱和的单环、二环或三环杂环表示由1、2或3个环组成的包含至少-个选自O、N或S的杂原子的环状***,该环系只含有单键;部分饱和的单环、二环或三环杂环表示由1、2或3个环组成的包含至少一个选自O、N或S的杂原子和至少一条双键的环状***,但该环系不能为芳族环系;芳族单环、二环或三环杂环表示由1、2或3个环组成的包含至少一个O、N或S的杂原子的芳族环状***。
饱和的单环、二环或三环碳环的具体实例为环丙基,环丁基,环戊基,环己基,环庚基,环辛基,二环[4.2.0]辛基,环壬基,环癸基,十氢萘基,十四氢蒽基。
部分饱和的单环、二环或三环碳环的具体实例为环丙烯基,环丁烯基,环戊烯基,环己烯基,环庚烯基,环辛烯基,二环[4.2.0]辛烯基,环壬烯基,环癸烯基,八氢萘基,1,2,3,4-四氢萘基,1,2,3,4,4a,9,9a,10-八氢蒽基。
芳香性的单环、二环或三环碳环的具体实例为苯基,萘基,蒽基。
饱和的单环、二环或三环杂环的具体实例为四氢呋喃基,吡咯烷基,二氧戊环基,咪唑烷基,噻唑烷基,四氢噻吩基,二氢噁唑基,异噻唑烷基,异噁唑烷基,噁二唑烷基,***烷基,噻二唑烷基,吡唑烷基,哌啶基,六氢嘧啶基,六氢吡嗪基,二噁烷基,吗啉基,二噻烷基,硫代吗啉基,哌嗪基,三噻烷基,十氢喹啉基,八氢吲哚基。
部分饱和的单环、二环或三环杂环的具体实例为吡咯啉基,咪唑啉基,吡唑啉基,2,3-二氢苯并呋喃基,1,3-苯并间二氧杂环戊烯基,2,3-二氢-1,4-苯并噁英基,2,3-二氢吲哚基等。
芳族单环、二环或三环杂环的具体实例为氮杂环丁二烯基,氧杂环丙烯基(oxethylidenyl),吡咯基,呋喃基,噻吩基,咪唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,吡唑基,***基,噻二唑基,噁二唑基,四唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,三嗪基,吡喃基,苯并呋喃基,异苯并呋喃基,苯并噻吩基,异苯并噻吩基,吲嗪基,吲哚基,异吲哚基,苯并噁唑基,苯并咪唑基,吲唑基,苯并异噁唑基,苯并异噻唑基,苯并吡唑基,苯并噁二唑基,苯并噻二唑基,苯并***基,嘌呤基,喹啉基,异喹啉基,邻二氮杂萘基,喹嗪基,酞嗪基,喹喔啉基,喹唑啉基,萘啶基,喋啶基,苯并吡喃基,吡咯并吡啶基,噻吩并吡啶基,呋喃并吡啶基,异噻唑并吡啶基,噻唑并吡啶基,异噁唑并吡啶基,噁唑并吡啶基,吡唑并吡啶基,咪唑并吡啶基,吡咯并吡嗪基,噻吩并吡嗪基,呋喃并吡嗪基,异噻唑并吡嗪基,噻唑并吡嗪基,异噁唑并吡嗪基,噁唑并吡嗪基,吡唑并吡嗪基,咪唑并吡嗪基,吡咯并嘧啶基,噻吩并嘧啶基,呋喃并嘧啶基,异噻唑并嘧啶基,噻唑并嘧啶基,异噁唑并嘧啶基,噁唑并嘧啶基,吡唑并嘧啶基,咪唑并嘧啶基,吡咯并哒嗪基,噻吩并哒嗪基,呋喃并哒嗪基,异噻唑并哒嗪基,噻唑并哒嗪基,异噁唑并哒嗪基,噁唑并哒嗪基,吡唑并哒嗪基,咪唑并哒嗪基,噁二唑并吡啶基,噻二唑并吡啶基,***并吡啶基,噁二唑并吡嗪基,噻二唑并吡嗪基,***并吡嗪基,噁二唑并嘧啶基,噻二唑并嘧啶基,***并嘧啶基,噁二唑并哒嗪基,噻二唑并哒嗪基,***并哒嗪基,咪唑并噁唑基,咪唑并噻唑基,咪唑并咪唑基,异噁唑并三嗪基,异噻唑并三嗪基,吡唑并三嗪基,噁唑并三嗪基,噻唑并三嗪基,咪唑并三嗪基,噁二唑并三嗪基,噻二唑并三嗪基,***并三嗪基,咔唑基,吖啶基,吩嗪基,吩噻嗪基,吩噁嗪基。
前文中使用的术语(=O)当连接在碳原子时形成羰基部分,当连接在硫原子上时形成亚砜基团,当两个该术语连接在硫原子上时则形成砜部分。
术语卤(代)是指氟、氯、溴和碘的通称。正如本发明上下文中所用,作为基团或基团一部分的多卤代甲基是指单-或多卤代的甲基,特别是具有一个或多个氟原子的甲基,例如二氟甲基或三氟甲基;作为基团或基团一部分的多卤代C1-6烷基被定义为单-或多卤代的C1-6烷基,例如卤代甲基中描述的基团,1,1-二氟-乙基等。在多卤代甲基或多卤代C1-6烷基的定义范围内,当有一个以上的卤原子连接在烷基上时,它们可以相同或不同。
在例如R2,R5,R6,R8或R15定义中使用的术语杂环包括所述杂环的所有可能的异构形式,例如吡咯基也包括2H-吡咯基。
如果没有另加说明,上述碳环可以通过任何适当的环碳原子连接在式(I)或(I’)分子的剩余部分上。例如,当部分饱和的二环为1,2,3,4-四氢萘基时,它可以是1,2,3,4-四氢萘-1-基,1,2,3,4-四氢萘-2-基等。
如果没有另外说明,上述杂环可以通过任何适当的环碳原子或杂原子连接在式(I)或(I’)分子的剩余部分上。例如,当芳族单杂环为咪唑基时,它可以是1-咪唑基,2-咪唑基,4-咪唑基等等。
当任何变量(例如R5、R6等)在任何部分出现超过一次时,各自的定义是独立的。
从取代基引出的进入到环状***的线表示该键可连接在任何适宜的环原子上。
对于治疗应用而言,式(I)或(I’)化合物的盐是指其中抗衡离子为药学上可接受的那些盐。但药学上不能接受的酸和碱的盐也能够找到用途,例如用于制备或纯化可药用化合物。所有这些盐,无论是可药用的还是非药用的,都包括在本发明的范围内。
上述可药用加成盐包括式(I)或(I’)化合物能够生成的具有治疗活性的无毒酸加成盐。这种酸加成盐易通过用适当酸处理碱形式的式(I)或(I’)化合物而获得,其中所述酸例如为无机酸类,譬如氢卤酸(像盐酸、氢溴酸等);硫酸;硝酸;磷酸等;或有机酸类,如乙酸、丙酸、羟基乙酸、2-羟基丙酸、2-氧代丙酸、草酸、丙二酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、2-羟基-1,2,3-丙烷三羧酸、甲磺酸、乙烷磺酸、苯磺酸、4-甲基苯磺酸、环己烷氨磺酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸等酸。反之,通过用碱处理,也可以将这种盐形式转化成游离碱形式。
通过用合适的有机与无机碱处理,也可以将含有酸性质子的式(I)或(I’)化合物转化成其具有治疗活性、无毒的金属或胺加成盐形式。适当的碱盐形式包括例如铵盐,碱及碱土金属盐类,例如锂、钠、钾、镁、钙盐等,与有机碱例如脂族和芳族的伯、仲和叔胺类,如甲胺、乙胺、丙胺、异丙胺、四种丁胺异构体、二甲胺、二乙胺、二乙醇胺、二丙胺、二异丙基胺、二-正丁基胺、吡咯烷、哌啶、吗啉、三甲胺、三乙胺、三丙基胺、奎宁、吡啶、喹啉和异喹啉、苄星青霉素G、N-甲基-D-葡萄糖胺、2-氨基-2-(羟甲基)-1,3-丙烷二醇、哈胺(hybramine)所形成的盐类,以及与氨基酸例如精氨酸、赖氨酸等形成的盐类。反之,所述盐形式可通过用酸处理而转化为游离酸形式。
术语加成盐一词也包括式(I)或(I’)化合物所能形成的水合物和溶剂加合物形式。这类形式的实例为水合物、乙醇化物等。
前文中使用的术语“季铵”是指式(I)或(I’)化合物能够形成的季铵盐,即通过式(I)或(I’)化合物的碱性氮与合适的季铵化剂如任选取代的烷基卤、芳基卤或芳基烷基卤(例如碘甲烷或苄基碘)反应形成的季铵盐。也可以使用具有良好离去基团的其它反应物,例如三氟甲磺酸烷基酯,甲磺酸烷基酯,和对-甲苯磺酸烷基酯。季铵具有带正电荷的氮。可药用的抗衡离子包括氯、溴、碘、三氟乙酸根和乙酸根。所选择的抗衡离子可以利用离子交换树脂引入。
应当理解,某些式(I)或(I’)化合物和它们的N-氧化物、加成盐、季铵和立体化学异构体可能包含一个或多个手性中心,并能以立体化学异构体形式存在。
前文中使用的术语“立体化学异构体”定义为式(I)或(I’)化合物以及它们的N-氧化物、加成盐、季铵或生理性官能衍生物可能具有的所有可能的立体异构体。除非另有说明或指示,化合物的化学名称表示所有可能的立体化学异构体的混合物,所述混合物包含基本分子结构的所有非对映体与对映体,以及基本上无其它异构体的式(I)或(I’)化合物和它们的N-氧化物,盐,溶剂化物或季铵的各单一异构体,亦即其它异构体的含量低于10%,优选低于5%,特别是低于2%,且最优选低于1%。具体讲,立体生成中心可能具有R-或S-构型;二价环状(部分)饱和基团上的取代基可能具有顺式-或反式-构型。包含双键的化合物在所述双键上可以具有E或Z-立体化学。显然,式(I)或(I’)化合物的立体化学异构体意欲包括在本发明的范围之内。
本发明化合物的N-氧化物形式意欲包括其中一个或数个叔氮原子被氧化成所谓的N-氧化物的式(I)化合物。
某些式(I)或(I’)化合物也可以其互变异构体形式(例如酮-烯醇互变体)存在。此类形式虽未在上式中明确指出,但被认为包括在本发明范围之内。
下文中凡使用术语“式(I)化合物”或“式(I)或(I’)化合物”时,均还包括它们的N-氧化物,它们的盐,它们的季铵和它们的立体化学异构体。其中特别重要的是立体化学纯的式(I)或(I’)化合物。
特定化合物是这些上述式(I)或(I’)化合物,即要求化合物的分子质量最高为1000u,特别是最高为800u,更特别的是最高为700u(u表示统一的原子质量单位,等于1.66x10-27kg)。
同样也特别重要的化合物为这些上述式(I)或(I’)化合物,它们的N-氧化物、可药用的加成盐、季铵和其立体化学异构体,其中:
Z代表O或S;
环A为吡啶基,嘧啶基,吡嗪基或哒嗪基;
R1为氢;芳基;甲酰基;C1-6烷基羰基;C1-6烷基;C1-6烷氧基羰基;被甲酰基,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰氧基取代的C1-6烷基;任选被C1-6烷氧基羰基取代的C1-6烷氧基C1-6烷基羰基;
X为-NR1-;-NH-NH-;-N=N-;-O-;-C(=O)-;-C(=S)-;-O-C(=O)-;-C(=O)-O-;-O-C(=O)-C1-6烷基;-C(=O)-O-C1-6烷基;-O-C1-6烷基-C(=O)-;-C(=O)-C1-6烷基-O-;-O-C(=O)-NR1-;-NR1-C(=O)-O-;-O-C(=O)-C(=O)-;-C(=O)-NR1-;-NR1-C(=O)-;-C(=S)-NR1-,-NR1-C(=S)-;-NR1-C(=O)-NR1-;-NR1-C(=S)-NR1-;-NR1-S(=O)-NR1-;-NR1-S(=O)2-NR1-;-C1-6烷基-C(=O)-NR1-;-O-C1-6烷基-C(=O)-NR1-;-C1-6烷基-O-C(=O)-NR1;-C1-6烷基-;-O-C1-6烷基-;-C1-6烷基-O-;-NR1-C1-6烷基-;-C1-6烷基-NR1-;-NR1-C1-6烷基-NR1-;-NR1-C1-6烷基-C3-7环烷基-;-C2-6链烯基-;-C2-6炔基-;-O-C2-6链烯基-;-C2-6链烯基-O-;-NR1-C2-6链烯基-;-C2-6链烯基-NR1-;-NR1-C2-6链烯基-NR1-;-NR1-C2-6链烯基-C3-7环烷基-;-O-C2-6炔基-;-C2-6炔基-O-;-NR1-C2-6炔基-;-C2-6炔基-NR1-;-NR1-C2-6炔基-NR1-;-NR1-C2-6炔基-C3-7环烷基-;-O-C1-6烷基-O-;-O-C2-6链烯基-O-;-O-C2-6炔基-O-;-CHOH-;-S-;-S(=O)-;-S(=O)2-;-S(=O)-NR1-;-S(=O)2-NR1-;-NR1-S(=O)-;-NR1-S(=O)2-;-S-C1-6烷基-;-C1-6烷基-S-;-S-C2-6链烯基-;-C2-6链烯基-S-;-S-C2-6炔基-;-C2-6炔基-S-;-O-C1-6烷基-S(=O)2-或直接键;
R2为氢,C1-10烷基,C2-10链烯基,C2-10炔基,R20,可能的话,该R2表示的各基团可任选被一个或多个各自独立选自以下的取代基取代:=S;=O;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R5R6N;R5R6N-C1-6烷基;R5R6N-C3-7环烷基;R5R6N-C1-6烷氧基;R5R6N-C(=O)-;R5R6N-C(=S)-;R5R6N-C(=O)-NH-;R5R6N-C(=S)-NH-;R5R6N-S(=O)n-;R5R6N-S(=O)n-NH-;R15-C(=S)-;R15-C(=O)-NH-;R15-O-C(C=O)-NH-;R15-S(=O)n-NH-;R15-O-S(=O)n-NH-;R15-C(=S)-NH-;R15-O-C(=S)-NH-;R17R18N-Y1a-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;
R3为氢;羟基;卤素;C1-6烷基;被氰基,羟基或-C(=O)R7取代的C1-6烷基;C2-6链烯基;被一个或多个卤原子或氰基取代的C2-6链烯基;C2-6炔基;被一个或多个卤原子或氰基取代的C2-6炔基;C1-6烷氧基;C1-6烷硫基;C1-6烷氧基羰基;C1-6烷基羰氧基;羧基;氰基;硝基;氨基;单-或二(C1-6烷基)氨基;多卤代C1-6烷基;多卤代C1-6烷氧基;多卤代C1-6烷硫基;R21;R21-C1-6烷基;R21-O-;R21-S-;R21-C(=O)-;R21-S(=O)p-;R7-S(=O)p-;R7-S(=O)p-NH-;R21-S(=O)p-NH-;R7-C(=O)-;-NHC(=O)H;-C(=O)NHNH2;R7-C(=O)-NH-;R21-C(=O)-NH-;-C(=NH)R7;-C(=NH)R21;
R4a或R4b各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10;
R5和R6各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10;
R7为C1-6烷基;C1-6烷氧基,氨基,单-或二(C1-6烷基)氨基或多卤代C1-6烷基;
R8为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;该R8表示的各基团可任选被一个或多个选自R12、R13和R14的取代基取代;
R9,R10和R11各自独立地为氢或R8;
R12、R13和R14各自独立地为氢;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R15R16N-S(=O)-;R15R16N-S(=O)2-R17R18N-Y1-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;氧代;
R15为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;该R15表示的各基团可任选被一个或多个选自R12、R13和R14的取代基取代;
R16、R17、R18和R19各自独立地为氢或R15;
R20为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;或芳族单环、二环或三环杂环;
R21为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;该R21代表的碳环或杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
Y1a为-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y1或Y2各自独立地为直接键,-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y3或Y4各自独立地为直接键,C1-6亚烷基,C2-6亚烯基或C2-6亚炔基;
n为1或2;
m为1或2;
p为1或2;
r为1-5;
s为1-3;
芳基是指苯基或被一个、两个、三个、四个或五个各自独立选自以
下的取代基取代的苯基:卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基、氰基、硝基、多卤代C1-6烷基和多卤代C1-6烷氧基;
条件是-X-R2和/或R3不为氢;并且
不包括下列化合物:
4-[(5-氰基-4-苯基-2-嘧啶基)氨基]-N-[2-(二乙基氨基)乙基]-苯甲酰胺;
4-[[4-[6-(1-哌嗪基)-3-吡啶基]-2-嘧啶基]氨基]-苯甲酰胺;
N-甲基-4-[[4-(3-吡啶基)-2-嘧啶基]氨基]-苯甲酰胺;
4-[[4-(3-甲氧基苯基)硫基]-2-嘧啶基]氨基]-N-[2-(1-吡咯烷基)乙基]-苯甲酰胺;
N-[2-(二乙基氨基)乙基]-4-[[4-(3-吡啶基)-2-嘧啶基]氨基]-苯甲酰胺;
4-[(5-氨基-1,4-二氢-4-氧代-2-嘧啶基)氨基]-N,N-二甲基苯甲酰胺;
4-[(5-氨基-1,4-二氢-4-氧代-2-嘧啶基)氨基]-N,N-二乙基-苯甲酰胺;
4-[(5-氨基-1,4-二氢-4-氧代-2-嘧啶基)氨基]-N-甲基-苯甲酰胺;
4-[[5-(4-甲氧基苯基)-2-嘧啶基]氨基]-苯甲酰胺;
4-[[1-氧化-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]-苯甲酰胺;
4-[[3-氧化-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]-苯甲酰胺;
4-[[4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]-苯甲酰胺;
2-[[4-甲基-6-(三氟甲基)-2-嘧啶基]氨基]-苯甲酰胺;
N-(3-氨基丙基)-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-苯甲酰胺;
N-(3-羟基丙基)-3-[[4-[2-[(3-羟基丙基)氨基]-4-吡啶基]-2-嘧啶基]氨基]-苯甲酰胺;
N-(3-氨基丙基)-3-[[4-[2-[(3-羟基丙基)氨基]-4-吡啶基]-2-嘧啶基]氨基]-苯甲酰胺;
3-[[4-[2-[(3-羟基丙基)氨基]-4-吡啶基]-2-嘧啶基]氨基]-N-[2-(1H-咪唑-4-基)乙基]-苯甲酰胺;
4,4’-[(6-甲基-5-硝基-2,4-亚嘧啶基)二亚氨基]双-苯甲酰胺;
4-[[5-氨基-4-(甲基氨基)-2-嘧啶基]氨基]-N,N-二乙基-苯甲酰胺;
N,N-二乙基-4-[[4-(甲基氨基)-5-硝基-2-嘧啶基]氨基]-苯甲酰胺。
进一步重要的化合物为这些上述式(I)或(I’)化合物,其中:
Z代表0;
环A为嘧啶基;
R1为氢;
X为-NR1-;-O-;-O-C1-6烷基-;-NR1-C1-6烷基-或直接键;
R2为氢,C1-10烷基,R20,可能的话,该R2代表的各基团可任选被一个或多个各自独立选自R15;氰基;R15-O-;R5R6N-C(=O)-的取代基取代;
R3为氢;卤素;氰基;硝基;氨基;R21-C1-6烷基;
R4a或R4b各自独立地为氢或R8;
R5和R6为氢;
R8为C1-6烷基;
R12,R13和R14为R15;
R15为C1-6烷基;芳香性的单环、二环或三环碳环;芳族单环、二环或三环杂环;被芳族单环、二环或三环碳环取代的C1-6烷基;
R20为芳香性单环、二环或三环碳环;
R21为芳香性单环、二环或三环碳环;
s为1或2;
条件是-X-R2和/或R3不能为氢;并且
不包括下列化合物:
4-[(5-氨基-1,4-二氢-4-氧代-2-嘧啶基)氨基]-N,N-二甲基苯甲酰胺;
4-[(5-氨基-1,4-二氢-4-氧代-2-嘧啶基)氨基]-N,N-二乙基-苯甲酰胺;
4-[(5-氨基-1,4-二氢-4-氧代-2-嘧啶基)氨基]-N-甲基-苯甲酰胺;
4-[[1-氧化-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]-苯甲酰胺;
4-[[3-氧化-4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]-苯甲酰胺;
4-[[4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]-苯甲酰胺;
4-[[5-氨基-4-(甲基氨基)-2-嘧啶基]氨基]-N,N-二乙基-苯甲酰胺;
N,N-二乙基-4-[[4-(甲基氨基)-5-硝基-2-嘧啶基]氨基]-苯甲酰胺。
更进一步特别重要的化合物为这些上述式(I)或(I’)化合物,条件是所述化合物不能为:
a)
其中R2为氢,三氟甲基,C1-4烷基;R3为氢,C1-4烷基,羟基C1-4烷基,氨基,C1-4烷基羰基,或其中苯基可任选取代的苯基C1-4烷基,或者R2为NR2’R2”(其中R2’和R2”各自独立地代表氢或C1-4烷基或任选取代的苯基);饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环,条件是当R2为饱和的单环、二环或三环杂环或部分饱和的单环、二环或三环杂环或芳族单环、二环或三环杂环时,则存在至少一个N原子,且R2经氮原子与嘧啶环结合;R1为氢或C1-4烷基,且s如上定义;
b)
其中R1为氢,C1-4烷基或任选取代的苯基;R1’为氢或C1-4烷基;R2为任选取代的苯基;R3为氢,C1-4烷基,羟基C1-4烷基,氨基,C1-4烷基羰基,或其中苯基可任选被取代的苯基C1-4烷基,且s如上定义;
c)
其中R4a和R4b各自独立地如上定义;R2为C1-10烷基,C2-10链烯基,C2-10炔基,饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;该R2代表的各基团可任选被取代;R1为氢或C1-6烷基;R3和s如上定义;
d)
其中R1如上定义;R4a和R4b各自独立地为氢或甲基;X为直接键,-C1-6烷基-,-NR1-,-NH-NH-,-N=N-,-O-,-C(=O)-,-CHOH-,-S-,-S(=O)-,-S(=O)2-,-NR1-C1-4烷基-,-S-C1-4烷基-;R2为C1-10烷基,C2-10链烯基,C2-10炔基,C3-7环烷基,苯基,吡啶基,嘧啶基,吡嗪基,哒嗪基,该R2代表的基团可任选被取代;R3a代表氢,羟基,卤素,C1-6烷基,C3-7环烷基,任选被一个或多个卤原子或氰基取代的C2-6链烯基,任选被一个或多个卤原子取代的C2-6炔基,被氰基或-C(=O)R7取代的C1-6烷基,C1-6烷氧基,C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,多卤代甲基,多卤代甲氧基,多卤代甲硫基,-S(=O)pR7,-NH-S(=O)pR7,-C(=O)R7,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R7,-C(=NH)R7或芳基;R3b为羟基,氰基,羧基,卤素,氰基C1-6烷基,羟基C1-6烷基,氨基羰基,单-或二(C1-4烷基)氨基羰基,C1-6烷氧基,C1-6烷硫基,C1-6烷基-S(=O)p,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰氧基,C2-6链烯基,C2-6炔基,多卤代C1-6烷基,咪唑基,噻唑基,噁唑基,吡唑基,异噻唑基,异噁唑基,***基,任选被亚氨基,5-元杂芳环取代的四唑基,咪唑烷基,吡唑烷基,噻唑烷基,异噻唑烷基,噁唑烷基,任选被羟基取代的异噁唑烷基,异噁唑烷酮,或下式基团:
其中A2为O,CH2或直接键;
A3为CH2或NH;
A4为CH2或直接键;或者A3-A4代表-CH=CH;
Rx为氢或C1-4烷基羰基.
e)
其中R1如上定义;R4a和R4b各自独立地为氢或甲基;R2为苯基,吡啶基,嘧啶基,吡嗪基,哒嗪基,该R2代表的基团可任选被取代;R3a代表氢,羟基,卤素,C1-6烷基,C3-7环烷基,任选被一个或多个卤原子取代的C2-6链烯基,任选被一个或多个卤原子取代的C2-6炔基,被氰基或-C(=O)R7取代的C1-6烷基,C1-6烷氧基,C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,多卤代甲基,多卤代甲氧基,多卤代甲硫基,-S(=O)pR7,-NH-S(=O)pR7,-C(=O)R7,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R7,-C(=NH)R7或芳基;R3b为羟基,氰基,羧基,卤素,氰基C1-6烷基,羟基C1-6烷基,氨基羰基,单-或二(C1-4烷基)氨基羰基,C1-6烷氧基,C1-6烷硫基,C1-6烷基-S(=O)p,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰氧基,C2-6链烯基,C2-6炔基,多卤代C1-6烷基,咪唑基,噻唑基,噁唑基,吡唑基,异噻唑基,异噁唑基,***基,任选被亚氨基,5-元杂芳环取代的四唑基,咪唑烷基,吡唑烷基,噻唑烷基,异噻唑烷基,噁唑烷基,任选被羟基取代的异噁唑烷基,异噁唑烷酮,或下式基团:
其中A2为O,CH2或直接键;
A3为CH2或NH;
A4为CH2或直接键;或者A3-A4代表-CH=CH;
Rx为氢或C1-4烷基羰基.
f)
其中R1如上定义;R4a和R4b各自独立地为氢或甲基;R2为苯基,吡啶基,嘧啶基,吡嗪基,哒嗪基,该R2代表的基团在对位(较之NR1连接基)被取代,并任选在邻位或间位(较之NR1连接基)被取代;R3a为羟基,卤素,C3-7环烷基,任选被一个或多个卤原子取代的C2-6链烯基,任选被一个或多个卤原子取代的C2-6炔基,被氰基或-C(=O)R7取代的C1-6烷基,C1-6烷氧基,C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,多卤代甲基,多卤代甲氧基,多卤代甲硫基,-S(=O)pR7,-NH-S(=O)pR7,-C(=O)R7,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R7,-C(=NH)R7或芳基;R3b为氢,卤素,C1-6烷基,多卤代C1-6烷基,氨基,单-或二(C1-4烷基)氨基,任选取代的吡咯烷基,哌啶基,吗啉基,R7-C(=O)-NH-;
g)
其中R1如上定义;R4a和R4b各自独立地为氢或甲基;R2为C1-10烷基,C2-10链烯基,C2-10炔基,C3-7环烷基,苯基,吡啶基,嘧啶基,吡嗪基,哒嗪基,所述基团可任选被取代;X为直接键,-C1-6烷基-,-NR1,-NH-NH-,-N=N-,-O-,-C(=O)-,-CHOH-,-S-,-S(=O)p-,-O-C1-4烷基-,-NR1-C1-4烷基-,-S-C1-4烷基-;R3a代表羟基,卤素,C3-7环烷基,任选被一个或多个卤原子取代的C2-6链烯基,任选被一个或多个卤原子取代的C2-6炔基,被氰基或-C(=O)R7取代的C1-6烷基,C1-6烷氧基,C1-6烷氧基羰基,羧基,氰基,硝基,氨基,单-或二(C1-6烷基)氨基,多卤代甲基,多卤代甲氧基,多卤代甲硫基,-S(=O)pR7,-NH-S(=O)pR7,-C(=O)R7,-NHC(=O)H,-C(=O)NHNH2,-NHC(=O)R7,-C(=NH)R7或芳基;R3b为氢,卤素,C1-6烷基,多卤代C1-6烷基,氨基,单-或二(C1-4烷基)氨基,任选取代的吡咯烷基,哌啶基,吗啉基,R7-C(=O)-NH-;
h)
其中R1如上定义;R3a为氢或C1-4烷基;R3b为氢,氨基,单-或二(C1-4烷基)氨基,任选取代的吡咯烷基,哌啶基,吗啉基,R7-C(=O)-NH-;X为直接键,-C1-10烷基-,-NR1-,-NH-NH-,-N=N-,-O-,-C(=O)-,-CHOH-,-S-,-S(=O)p-,-O-C1-4烷基-,-NR1-C1-4烷基-,-S-C1-4烷基-;R2为C1-10烷基,C2-10链烯基,C2-10炔基,C3-7环烷基,2,3-二氢化茚基,吲哚基,苯基,吡啶基,嘧啶基,吡嗪基,哒嗪基,该R2代表的基团可任选被取代;
i)
其中R1如上定义;R2为苯基或吡啶基,该R2代表的各基团可任选被以下基团取代:羟基,卤素,C1-6烷基,C1-6烷氧基,氰基,氨基羰基,硝基,氨基,三卤代甲基,三卤代甲氧基或被氰基或氨基羰基取代的C1-6烷基;R3a为氢或C1-4烷基;R3b为氢,氨基,单-或二(C1-4烷基)氨基,任选取代的吡咯烷基,哌啶基,吗啉基,R7-C(=O)-NH-;
j)
其中R1为氢或C1-6烷基;R4a和R4b各自独立地为氢;任选取代的C1-6烷基;任选取代的C2-6链烯基,任选取代的C2-6炔基,任选取代的芳香性单环、二环或三环碳环,或任选取代的芳族单环、二环或三环杂环,X-R2如上定义;
k)
其中R4a和R4b各自独立地为氢,C1-6烷基,苯基,萘基,被苯基或萘基取代的C1-6烷基,其中苯基或萘基可任选被卤素、C1-6烷基、C1-6烷氧基、硝基或羧基取代;R1为氢;任选被卤素取代的苯基;C1-6烷基;C1-6烷氧基;硝基;或羧基;X为-O-,-NH-,-N-C1-6烷基,-S-,-OCH2-;R2为任选被卤素、C1-6烷基、C1-6烷氧基、硝基或羧基取代的苯基;环A为嘧啶基,吡啶基,吡嗪基;s和R3如上定义;
l)
其中R4a和R4b各自独立地为氢或C1-3烷基;R2为2-吡啶基,3-吡啶基,4-吡啶基,2-甲基-3-吡啶基,4-甲基-3-吡啶基,2-呋喃基,5-甲基-2-呋喃基,2,5-二甲基-3-呋喃基,2-噻吩基,3-噻吩基,5-甲基-2-噻吩基,2-吩噻嗪基,4-吡嗪基,2-苯并呋喃基,N-氧化-2-吡啶基,N-氧化-3-吡啶基,N-氧化-4-吡啶基,1H-吲哚-2-基,1H-吲哚-3-基,1-甲基-1H-吡咯-2-基,4-喹啉基,碘化1-甲基-吡啶翁-4-基;R1为氢或C1-3烷基;R3为氢或C1-3烷基;s如上定义;
m)
其中Z、R4a和R4b如上定义;R2为任选被含3-7个原子的饱和杂环取代的吡啶基;R3为氢;卤素;C1-6烷基;被氰基、羟基或-C(=O)R7取代的C1-6烷基;C2-6链烯基;被一个或多个卤原子或氰基取代的C2-6链烯基;C2-6炔基;被一个或多个卤原子或氰基取代的C2-6炔基;C1-6烷氧基;C1-6烷硫基;C1-6烷氧基羰基;C1-6烷基羰氧基;多卤代C1-6烷基;多卤代C1-6烷氧基;多卤代C1-6烷硫基;R21-C1-6烷基;R7-S(=O)p-;R7-S(=O)p-NH-;R7-C(=O)-;R7-C(=O)-NH-;-C(=NH)R7;其中R7代表C1-6烷基,C1-6烷氧基或多卤代C1-6烷基;
n)
其中R2为3位被取代的4-吡啶基;n为2或3;R4a’为羟基,氨基,咪唑基或二(C1-3烷基)氨基;
o)
其中R4a和R4b各自独立地为氢或C1-4烷基;R3为氢,C1-3烷基,多卤代C1-3烷基,卤素,或多卤代C1-3烷氧基;-X-R2为C1-4烷基,C1-4烷氧基,C1-4烷硫基,C1-4烷基-S(=O)p-,多卤代C1-4烷氧基,任选被多至三个选自卤素或C1-4烷基或多卤代C1-4烷基或C1-4烷氧基取代的苯基,2-呋喃基,2-噻吩基,3-噻吩基,任选被多至三个选自C1-4烷基,多卤代C2-4链烯基,C1-4烷氧基C1-4烷基,C1-4烷氧基C1-4烷氧基,多卤代C1-4烷硫基取代的C3-6环烷基;或者当R3为氰基时X-R2为氢;
p)
其中R1如上定义;-X-R2为吡啶基,嘧啶基,噻唑基,吡嗪基,哒嗪基,咪唑基,苯基,所述各环任选被一个或多个选自以下的取代基取代:卤素,氰基,氨基羰基,-C(=O)-O-R2’,-C(=O)-R2’,-S(=O)2’-NR2’R2”,NR2’R2”,-O-R2’或任选被氟取代的C1-6烷基,其中R2’和R2”各自独立地代表氢或任选被单-或二(C1-6烷基)氨基取代的C1-6烷基;或者-X-R2为氢,羟基,C1-6烷基,C1-6烷氧基;R3a和R3b各自独立地为吡啶基,嘧啶基,噻唑基,吡嗪基,哒嗪基,咪唑基,苯基,该R3a和R3b代表的各环可任选被一个或多个选自以下的取代基取代:卤素,氰基,氨基羰基,-C(=O)-O-R3’,-C(=O)-R3’,-S(=O)2-NR3’R3”,NR3’R3”,-O-R3’或任选被氟取代的C1-6烷基,其中R3’和R3”各自独立地代表氢或任选被单-或二(C1-6烷基)氨基取代的C1-6烷基;或者R3a和R3b为氢,羟基,C1-6烷基,C1-6烷氧基;
q)
其中n为2或3;R1为氢或C1-3烷基;s为1或2;-X-R2为氢,C1-3烷基,2-吡啶基,3-吡啶基,4-吡啶基,2-甲基-3-吡啶基,6-甲基-3-吡啶基,2-呋喃基,5-甲基-2-呋喃基,2,5-二甲基-3-呋喃基,2-噻吩基,3-噻吩基,5-甲基-2-噻吩基,2-吩噻嗪基,2-吡嗪基,2-苯并呋喃基,N-氧化-2-吡啶基,N-氧化-3-吡啶基,N-氧化-4-吡啶基,1H-吲哚-2-基,1H-吲哚-3-基,1-甲基-1H-吡咯-2-基,4-喹啉基,4-吡啶基甲基碘;二甲氨基苯基;R3为氢,C1-3烷基,2-吡啶基,3-吡啶基,4-吡啶基,2-甲基-3-吡啶基,6-甲基-3-吡啶基,2-呋喃基,5-甲基-2-呋喃基,2,5-二甲基-3-呋喃基,2-噻吩基,3-噻吩基,5-甲基-2-噻吩基,2-吩噻嗪基,2-吡嗪基,2-苯并呋喃基,N-氧化-2-吡啶基,N-氧化-3-吡啶基,N-氧化-4-吡啶基,1H-吲哚-2-基,1H-吲哚-3-基,1-甲基-1H-吡咯-2-基,4-喹啉基,4-吡啶基甲基碘,二甲氨基苯基。
进一步优选的化合物为这些式(I)或(I’)化合物,其中可能的话使用一个或多个以下限制:
a)X为直接键和R2为氢;
b)R2和R3不为氢;
c)R3为氢;
d)X不为直接键;
e)片断-C(=Z)NR4aR4b位于相对于NR1连接基的间位;
f)R3当位于相对于NR1连接基的间位时不为氰基;
g)X不能为NR1或S;
h)X不能为直接键以及R2不能为氢;
i)当X为NR1时,则R4a和/或R4b不能为氢;
j)环A为吡啶基,嘧啶基或哒嗪基。
同样还优选这些式(I)或(I’)化合物,其中所述化合物为下式化合物:
同样也优选这些式(I)或(I’)化合物,其中所述化合物为下式化合物:
同样也优选这些式(a-1)化合物,其中使用一个或(可能的话)多个以下限制:
(a)X不为直接键,S或C1-6烷基;
(b)当X为NR1时,R2不为任选取代的苯基;
(c)R3为氢;
(d)R3不为氢,氰基或C1-4烷基;
(e)R2不为任选取代的苯基;
(f)-X-R2不为氢,羟基,C1-6烷基,C1-6烷氧基,C1-4烷硫基,C1-4烷基-S(=O)p-,多卤代C1-4烷基,多卤代C1-4烷氧基;
(g)当R4a为氢时,R4b不为-(CH2)n-N(C1-3烷基)2,其中n为2或3;
(h)X-R2和R3不为氢;
(i)R2为R20。
同样也优选这些式(a-2)化合物,其中使用下述限制:
(a)X-R2和R3不为氢。
特别优选的化合物为这些式(a-1)化合物,其中:
R1为氢;芳基;甲酰基;C1-6烷基羰基;C1-6烷基;C1-6烷氧基羰基;被甲酰基,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰氧基取代的C1-6烷基;任选被C1-6烷氧基羰基取代的C1-6烷氧基C1-6烷基羰基;
X为-NR1-;-NH-NH-;-N=N-;-C(=O)-;-C(=S)-;-O-C(=O)-;-C(=O)-O-;-O-C(=O)-C1-6烷基;-C(=O)-O-C1-6烷基;-O-C1-6烷基-C(=O)-;-C(=O)-C1-6烷基-O-;-O-C(=O)-NR1-;-NR1-C(=O)-O-;-O-C(=O)-C(=O)-;-C(=O)-NR1-;-NR1-C(=O)-;-C(=S)-NR1-,-NR1-C(=S)-;-NR1-C(=O)-NR1-;-NR1-C(=S)-NR1-;-NR1-S(=O)-NR1-;-NR1-S(=O)2-NR1-;-C1-6烷基-C(=O)-NR1-;-O-C1-6烷基-C(=O)-NR1-;-C1-6烷基-O-C(=O)-NR1-;-C1-6烷基-;-O-C1-6烷基-;-C1-6烷基-O-;-NR1-C1-6烷基-;-C1-6烷基-NR1-;-NR1-C1-6烷基-NR1;-NR1-C1-6烷基-C3-7环烷基-;-C2-6链烯基-;-C2-6炔基-;-O-C2-6链烯基-;-C2-6链烯基-O-;-NR1-C2-6链烯基-;-C2-6链烯基-NR1-;-NR1-C2-6链烯基-NR1-;-NR1-C2-6链烯基-C3-7环烷基-;-O-C2-6炔基-;-C2-6炔基-O-;-NR1-C2-6炔基-;-C2-6炔基-NR1-;-NR1-C2-6炔基-NR1-;-NR1-C2-6炔基-C3-7环烷基-;-O-C1-6烷基-O-;-O-C2-6链烯基-O-;-O-C2-6炔基-O-;-CHOH-;-S(=O)-;-S(=O)2-;-S(=O)-NR1-;-S(=O)2-NR1-;-NR1-S(=O)-;-NR1-S(=O)2-;-S-C1-6烷基-;-C1-6烷基-S-;-S-C2-6链烯基-;-C2-6链烯基-S-;-S-C2-6炔基-;-C2-6炔基-S-;-O-C1-6烷基-S(=O)2-;
R2为氢,C1-10烷基,C2-10链烯基,C2-10炔基,R20,可能的话,该R2表示的各基团可任选被一个或多个各自独立选自以下的取代基取代:=S;=O;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R5R6N;R5R6N-C1-6烷基;R5R6N-C3-7环烷基;R5R6N-C1-6烷氧基;R5R6N-C(=O)-;R5R6N-C(=S)-;R5R6N-C(=O)-NH-;R5R6N-C(=S)-NH-;R5R6N-S(=O)n-;R5R6N-S(=O)n-NH-;R15-C(=S)-;R15-C(=O)-NH-;R15-O-C(C=O)-NH-;R15-S(=O)n-NH-;R15-O-S(=O)n-NH-;R15-C(=S)-NH-;R15-O-C(=S)-NH-;R17R18N-Y1a-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;
R3为羟基;卤素;被氰基,羟基或-C(=O)R7取代的C1-6烷基;C2-6链烯基;被一个或多个卤原子或氰基取代的C2-6链烯基;C2-6炔基;被一个或多个卤原子或氰基取代的C2-6炔基;C1-6烷氧基;C1-6烷硫基;C1-6烷氧基羰基;C1-6烷基羰氧基;羧基;氰基;硝基;氨基;单-或二(C1-6烷基)氨基;多卤代C1-6烷基;多卤代C1-6烷氧基;多卤代C1-6烷硫基;R21;R21-C1-6烷基;R21-O-;R21-S-;R21-C(=O)-;R21-S(=O)p-;R7-S(=O)p-;R7-S(=O)p-NH-;R21-S(=O)p-NH-;R7-C(=O)-;-NHC(=O)H;-C(=O)NHNH2;R7-C(=O)-NH-;R21-C(=O)-NH-;-C(=NH)R7;-C(=NH)R21;
R4a或R4b各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10;
R5和R6各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10,或者
R5和R6可以与它们所连接的氮一起形成3-8元饱和或部分饱和的单杂环,或形成4-8元芳族单杂环,所述杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代,或者所述杂环各自可任选与苯环稠合,其中所述苯环任选被一个或多个选自R12、R13和R14的取代基取代;
R7为C1-6烷基;C1-6烷氧基,氨基,单-或二(C1-6烷基)氨基或多卤代C1-6烷基;
R8为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;
R9,R10和R11各自独立地为氢或R8,或者
R9、R10和R11中的任意两个可一起表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的氮原子一起形成3-8元饱和或部分饱和的单杂环或4-8元的芳族单杂环;所述杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
R12、R13和R14各自独立地为氢;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R15R16N-S(=O)-;R15R16N-S(=O)2-;R17R18N-Y1-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;氧代,或者
R12、R13和R14中的任意两个可一起表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的原子一起形成3-8元饱和或部分饱和的单碳环或单杂环或形成4-8元的芳族单碳环或单杂环;或者
R12、R13和R14中的任意两个可一起表示-O-(CH2)r-O-,从而与它们所连接的原子一起形成饱和、部分饱和或芳香性的4-8元单碳环或单杂环;
R15为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;所述R15代表的各基团可任选被一个或多个选自R12、R13和R14的取代基取代;或者所述碳环或杂环各自可任选与苯环稠合,并且所述苯环任选被一个或多个选自R12、R13和R14的取代基取代;
R16、R17、R18和R19各自独立地为氢或R15,或者
R17与R18,或R15与R19可一起表示C1-6亚烷基或C2-6亚烯基,从而形成3-8元饱和或部分饱和的单杂环或形成4-8元的芳族单杂环;所述各杂环可任选被一个或多个选自R12、R13和R14的取代基取代;或者
R17和R18与R15一起可表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的氮原子一起形成3-8元饱和或部分饱和的单杂环或形成4-8元的芳族单杂环;所述各杂环可任选被一个或多个选自R12、R13和R14的取代基取代;
R20为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;或芳族单环、二环或三环杂环;
R21为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;该R21代表的碳环或杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
Y1a为-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y1或Y2各自独立地为直接键,-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y3或Y4各自独立地为直接键,C1-6亚烷基,C2-6亚烯基或C2-6亚炔基;
n为1或2;
m为1或2;
p为1或2;
r为1-5;
s为1-3;
芳基是指苯基或被一个、两个、三个、四个或五个各自独立选自以下的取代基所取代的苯基:卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基、氰基、硝基、多卤代C1-6烷基和多卤代C1-6烷氧基;
条件是不包括下列化合物:
4-[[5-氨基-4-(甲基氨基)-2-嘧啶基]氨基]-N,N-二乙基-苯甲酰胺;和
N,N-二乙基-4-[[4-(甲基氨基)-5-硝基-2-嘧啶基]氨基]-苯甲酰胺。
进一步特别优选的化合物为这些式(a-2)的化合物,其中:
R1为氢;芳基;甲酰基;C1-6烷基羰基;C1-6烷基;C1-6烷氧基羰基;被甲酰基,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰氧基取代的C1-6烷基;任选被C1-6烷氧基羰基取代的C1-6烷氧基C1-6烷基羰基;
X为-NR1-;-NH-NH-;-N=N-;-O-;-C(=O)-;-C(=S)-;-O-C(=O)-;-C(=O)-O-;-O-C(=O)-C1-6烷基;-C(=O)-O-C1-6烷基;-O-C1-6烷基-C(=O)-;-C(=O)-C1-6烷基-O-;-O-C(=O)-NR1-;-NR1-C(=O)-O-;-O-C(=O)-C(=O)-;-C(=O)-NR1-;-NR1-C(=O)-;-C(=S)-NR1-,-NR1-C(=S)-;-NR1-C(=O)-NR1-;-NR1-C(=S)-NR1-;-NR1-S(=O)-NR1-;-NR1-S(=O)2-NR1-;-C1-6烷基-C(=O)-NR1-;-O-C1-6烷基-C(=O)-NR1-;-C1-6烷基-O-C(=O)-NR1-;-C1-6烷基-;-O-C1-6烷基-;-C1-6烷基-O-;-NR1-C1-6烷基-;-C1-6烷基-NR1-;-NR1-C1-6烷基-NR1-;-NR1-C1-6烷基-C3-7环烷基-;-C2-6链烯基-;-C2-6炔基-;-O-C2-6链烯基-;-C2-6链烯基-O-;-NR1-C2-6链烯基-;-C2-6链烯基-NR1-;-NR1-C2-6链烯基-NR1-;-NR1-C2-6链烯基-C3-7环烷基-;-O-C2-6炔基-;-C2-6炔基-O-;-NR1-C2-6炔基-;-C2-6炔基-NR1-;-NR1-C2-6炔基-NR1-;-NR1-C2-6炔基-C3-7环烷基-;-O-C1-6烷基-O-;-O-C2-6链烯基-O-;-O-C2-6炔基-O-;-CHOH-;-S(=O)-;-S(=O)2-;-S(=O)-NR1-;-S(=O)2-NR1-;-NR1-S(=O)-;-NR1-S(=O)2-;-S-C1-6烷基-;-C1-6烷基-S-;-S-C2-6链烯基-;-C2-6链烯基-S-;-S-C2-6炔基-;-C2-6炔基-S-;-O-C1-6烷基-S(=O)2-;
R2为氢,C1-10烷基,C2-10链烯基,C2-10炔基,R20,可能的话,该R2表示的各基团可任选被一个或多个各自独立选自以下的取代基取代:=S;=O;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R5R6N;R5R6N-C1-6烷基;R5R6N-C3-7环烷基;R5R6N-C1-6烷氧基;R5R6N-C(=O)-;R5R6N-C(=S)-;R5R6N-C(=O)-NH-;R5R6N-C(=S)-NH-;R5R6N-S(=O)n-;R5R6N-S(=O)n-NH-;R15-C(=S)-;R15-C(=O)-NH-;R15-O-C(C=O)-NH-;R15-S(=O)n-NH-;R15-O-S(=O)n-NH-;R15-C(=S)-NH-;R15-O-C(=S)-NH-;R17R18N-Y1a-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;
R3为羟基;卤素;被氰基,羟基或-C(=O)R7取代的C1-6烷基;C2-6链烯基;被一个或多个卤原子或氰基取代的C2-6链烯基;C2-6炔基;被一个或多个卤原子或氰基取代的C2-6炔基;C1-6烷氧基;C1-6烷硫基;C1-6烷氧基羰基;C1-6烷基羰氧基;羧基;氰基;硝基;氨基;单-或二(C1-6烷基)氨基;多卤代C1-6烷基;多卤代C1-6烷氧基;多卤代C1-6烷硫基;R21;R21-C1-6烷基;R21-O-;R21-S-;R21-C(=O)-;R21-S(=O)p-;R7-S(=O)p-;R7-S(=O)p-NH-;R21-S(=O)p-NH-;R7-C(=O)-;-NHC(=O)H;-C(=O)NHNH2;R7-C(=O)-NH-;R21-C(=O)-NH-;-C(=NH)R7;-C(=NH)R21;
R4a或R4b各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10;
R5和R6各自独立地为氢,R8,-Y1-NR9-Y2-NR10R11,-Y1-NR9-Y1-R8,-Y1-NR9R10,或者
R5和R6可以与它们所连接的氮一起形成3-8元饱和或部分饱和的单杂环,或形成4-8元芳族单杂环,所述杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代,或者所述杂环各自可任选与苯环稠合,其中所述苯环任选被一个或多个选自R12、R13和R14的取代基取代;
R7为C1-6烷基;C1-6烷氧基,氨基,单-或二(C1-6烷基)氨基或多卤代C1-6烷基;
R8为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;
R9,R10和R11各自独立地为氢或R8,或者
R9、R10和R11中的任意两个可一起表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的氮原子一起形成3-8元饱和或部分饱和的单杂环或4-8元的芳族单杂环;所述杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
R12、R13和R14各自独立地为氢;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R15R16N-S(=O)-;R15R16N-S(=O)2-;R17R18N-Y1-;R17R18N-Y2-NR16-Y1-;R15-Y2-NR19-Y1-;H-Y2-NR19-Y1-;氧代,或者
R12、R13和R14中的任意两个可一起表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的原子一起形成3-8元饱和或部分饱和的单碳环或单杂环或形成4-8元的芳族单碳环或单杂环;或者
R12、R13和R14中的任意两个可一起表示-O-(CH2)r-O-,从而与它们所连接的原子一起形成饱和、部分饱和或芳香性的4-8元单碳环或单杂环;
R15为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;该R15代表的各基团可任选被一个或多个选自R12、R13和R14的取代基取代;或者所述碳环或杂环各自可任选与苯环稠合,并且所述苯环任选被一个或多个选自R12、R13和R14的取代基取代;
R16、R17、R18和R19各自独立地为氢或R15,或者
R17与R18,或R15与R19可一起表示C1-6亚烷基或C2-6亚烯基,从而形成3-8元饱和或部分饱和的单杂环或形成4-8元的芳族单杂环;所述各杂环可任选被一个或多个选自R12、R13和R14的取代基取代;或者
R17和R18与R15一起可表示C1-6亚烷基或C2-6亚烯基,从而与它们所连接的氮原于一起形成3-8元饱和或部分饱和的单杂环或形成4-8元的芳族单杂环;所述各杂环可任选被一个或多个选自R12、R13和R14的取代基取代;
R20为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;或芳族单环、二环或三环杂环;
R21为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;该R21代表的碳环或杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
Y1a为-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y1或Y2各自独立地为直接键,-Y3-S(=O)-Y4-;-Y3-S(=O)2-Y4-;-Y3-C(=O)-Y4-;-Y3-C(=S)-Y4-;-Y3-O-Y4-;-Y3-S-Y4-;-Y3-O-C(=O)-Y4-或-Y3-C(=O)-O-Y4-;
Y3或Y4各自独立地为直接键,C1-6亚烷基,C2-6亚烯基或C2-6亚炔基;
n为1或2;
m为1或2;
p为1或2;
r为1-5;
s为1-3;
芳基是指苯基或被一个、两个、三个、四个或五个各自独立选自以下的取代基取代的苯基:卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基、氰基、硝基、多卤代C1-6烷基和多卤代C1-6烷氧基。
同样也优选这些式(a-1)或(a-2)的化合物,其中
R1为氢;芳基;甲酰基;C1-6烷基羰基;C1-6烷基;C1-6烷氧基羰基;被甲酰基,C1-6烷基羰基,C1-6烷氧基羰基,C1-6烷基羰氧基取代的C1-6烷基;任选被C1-6烷氧基羰基取代的C1-6烷氧基C1-6烷基羰基;
X为-NR1-;-C(=O)-;-O-C(=O)-;-C(=O)-O-;-O-C(=O)-C1-6烷基;-C(=O)-O-C1-6烷基;-O-C1-6烷基-C(=O)-;-C(=O)-C1-6烷基-O-;-O-C(=O)-NR1-;-NR1-C(=O)-O-;-C(=O)-NR1-;-NR1-C(=O)-;-C1-6烷基-;-O-C1-6烷基-;-C1-6烷基-O-;-NR1-C1-6烷基-;-C1-6烷基-NR1-;-NR1-C1-6烷基-NR1;-C2-6链烯基-;-C2-6炔基-;-O-C2-6链烯基-;-C2- 6链烯基-O-;-NR1-C2-6链烯基-;-C2-6链烯基-NR1-;-NR1-C2-6链烯基-NR1-;-O-C2-6炔基-;-C2-6炔基-O-;-NR1-C2-6炔基-;-C2-6炔基-NR1-;-NR1-C2-6炔基-NR1-;-O-C1-6烷基-O-;-O-C2-6链烯基-O-;-O-C2-6炔基-O-;-CHOH-;-S(=O)-;-S(=O)2-;-S(=O)-NR1-;-S(=O)2-NR1-;-NR1-S(=O)-;-NR1-S(=O)2-;-S-C1-6烷基-;-C1-6烷基-S-;-S-C2-6链烯基-;-C2-6链烯基-S-;-S-C2-6炔基-;-C2-6炔基-S-;
R2为氢,C1-10烷基,C2-10链烯基,C2-10炔基,R20,可能的话,该R2表示的各基团可任选被一个或多个各自独立选自以下的取代基取代:=O;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R5R6N;R5R6N-C1-6烷基;R5R6N-C1-6烷氧基;R5R6N-C(=O)-;R5R6N-S(=O)n-;R5R6N-S(=O)n-NH-;R15-C(=O)-NH-;
R3为羟基;卤素;被氰基,羟基或-C(=O)R7取代的C1-6烷基;C2-6链烯基;被一个或多个卤原子或氰基取代的C2-6链烯基;C2-6炔基;被一个或多个卤原子或氰基取代的C2-6炔基;C1-6烷氧基;C1-6烷硫基;C1-6烷氧基羰基;C1-6烷基羰氧基;羧基;氰基;硝基;氨基;单-或二(C1-6烷基)氨基;多卤代C1-6烷基;多卤代C1-6烷氧基;多卤代C1-6烷硫基;R21;R21-C1-6烷基;R21-O-;R21-S-;R21-C(=O)-;R21-S(=O)p-;R7-S(=O)p-;R7-C(=O)-;-NHC(=O)H;-C(=O)NHNH2;R7-C(=O)-NH-;R21-C(=O)-NH-;-C(=NH)R7;-C(=NH)R21;
R4a或R4b各自独立地为氢或R8;
R5和R6各自独立地为氢或R8;
R7为C1-6烷基;C1-6烷氧基,氨基,单-或二(C1-6烷基)氨基或多卤代C1-6烷基;
R8为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;
R12、R13和R14各自独立地为氢;R15;羟基;卤素;硝基;氰基;R15-O-;SH;R15-S-;甲酰基;羧基;R15-C(=O)-;R15-O-C(=O)-;R15-C(=O)-O-;R15-O-C(=O)-O-;-SO3H;R15-S(=O)-;R15-S(=O)2-;R15R16N-S(=O)-;R15R16N-S(=O)2-;
R15为C1-6烷基;C2-6链烯基;C2-6炔基;饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;被饱和的单环、二环或三环碳环或被部分饱和的单环、二环或三环碳环或被芳香性的单环、二环或三环碳环或被饱和的单环、二环或三环杂环或被部分饱和的单环、二环或三环杂环或被芳族单环、二环或三环杂环取代的C1-6烷基;该R15代表的各基团可任选被一个或多个选自R12、R13和R14的取代基取代;
R16为氢或R15;
R20为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;或芳族单环、二环或三环杂环;
R21为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环;该R21代表的碳环或杂环各自可任选被一个或多个选自R12、R13和R14的取代基取代;
n为1或2;
m为1或2;
p为1或2;
s为1-3;
芳基是指苯基或被一个、两个、三个、四个或五个各自独立选自以下的取代基所取代的苯基:卤素、C1-6烷基、C3-7环烷基、C1-6烷氧基、氰基、硝基、多卤代C1-6烷基和多卤代C1-6烷氧基;
并且适宜的条件是不包括下列化合物:
4-[[5-氨基-4-(甲基氨基)-2-嘧啶基]氨基]-N,N-二乙基-苯甲酰胺;
N,N-二乙基-4-[[4-(甲基氨基)-5-硝基-2-嘧啶基]氨基]-苯甲酰胺。
同样也优选这些上述式(a-1)或(a-2)的化合物,其中R2不为氢或C1-6烷基。
另一组优选的式(I)或(I’)化合物为具有下式的化合物:
其中R1,R2,R3,R4a,R4b和X如式(I)化合物所定义,但其中-X-R2和R3二者不为氢。
特别优选式(a-3)化合物,其中使用一个或(可能的话)多个下列限制:
(a)X不为直接键,S或C1-6烷基;
(b)当X为NR1时,R2不为任选取代的苯基;
(c)R3为氢;
(d)R3不为氢,氰基或C1-4烷基;
(e)R2不为任选取代的苯基;
(f)-X-R2不为氢,羟基,C1-6烷基,C1-6烷氧基,C1-4烷硫基,C1-4烷基-S(=O)p-,多卤代C1-4烷基,多卤代C1-4烷氧基;
(g)当R4a为氢时,R4b不为-(CH2)n-N(C1-3烷基)2,其中n为2或3。
特别优选的式(I)或(I’)化合物为选自以下的化合物:
4-[[5-溴-4-(苯基甲氧基)-2-嘧啶基]氨基]-苯甲酰胺(化合物22);
3-[[5-溴-4-(苯基甲氧基)-2-嘧啶基]氨基]-苯甲酰胺(化合物4);
4-[[5-氰基-4-(苯基甲氧基)-2-嘧啶基]氨基]-苯甲酰胺(化合物23);
3-[[5-氰基-4-(苯基甲氧基)-2-嘧啶基]氨基]-苯甲酰胺(化合物9);
其N-氧化物,可药用加成盐,季铵和立体化学异构体。
进一步优选的式(I)或(I’)化合物为选自以下的化合物:
N,N-二甲基-4-[4-(2,4,6-三甲基苯基氨基)-嘧啶-2-基氨基]-苯甲酰胺;
N-甲基-4-[4-(2,4,6-三甲基苯基氨基)-嘧啶-2-基氨基]-苯甲酰胺;
N-异丙基-4-[4-(2,4,6-三甲基苯基氨基)-嘧啶-2-基氨基]-苯甲酰胺;
3-(4-苄氧基-嘧啶-2-基氨基)-苯甲酰胺;
3-(4-羟基-嘧啶-2-基氨基)-苯甲酰胺;
3-(5-溴-4-羟基-嘧啶-2-基氨基)-苯甲酰胺;
其N-氧化物,可药用加成盐,季铵和立体化学异构体。
式(I)化合物可以按下所述制备:在适当溶剂例如N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、二氯甲烷、二甘醇二甲醚、四氢呋喃、水、醇(譬如乙醇、异丙醇)等存在下,并任选在适当酸例如盐酸,或适当碱例如碳酸钠、N,N-二乙基乙胺或N,N-二异丙基乙胺的存在下,使式(II)中间体与式(III)中间体反应,其中W1代表适当离去基团,例如卤原子(如氯、溴),或C1-6烷基-S-。
式(I)化合物的制备也可以按下所述进行,即任选在适当溶剂如CH3OCH2CH2OH的存在下,使式(IV)中间体[其中W2代表适当离去基团,例如卤原子,像氯、溴等]与式(V)中间体反应。
在适当溶剂例如四氢呋喃或醇类(譬如甲醇、乙醇等)的存在下,使其中W3代表合适离去基团例如卤原子(像氯、溴等)或C1-6烷氧基的式(VI)中间体与式(VII)中间体反应,可以制备其中Z为O的式(I)化合物,即式(I-a)所示化合物。
在适当溶剂例如水、二甲亚砜或醇类(譬如甲醇、乙醇等)存在下,并任选存在适当碱例如碳酸钾的情形下,使式(VIII)中间体与合适的氧化剂例如H2O2或NaBO3反应,可以制备其中Z为O且R4a和R4b为氢的式(I)化合物,即式(I-a-1)所示化合物。
在这一部分及下面的制备中,反应产物可以从反应介质中分离出来,如有必要,可以按照本领域公知的方法如萃取、结晶、蒸馏、研制和层析进一步纯化。
式(I)化合物可进一步按照本领域公知的基团转化反应通过式(I)化合物的相互转化制得。
利用本领域已知的将三价氮转化成其N-氧化物形式的方法,可以将式(I)化合物转化为相应的N-氧化物形式。所述N-氧化反应一般是通过式(I)起始物质与适当的有机或无机过氧化物反应来进行。合适的无机过氧化物包括例如过氧化氢,碱金属或碱土金属的过氧化物如过氧化钠、过氧化钾;合适的有机过氧化物可包括过氧酸,例如过苯甲酸或卤代过苯甲酸,例如3-氯过苯甲酸,过氧链烷酸如过乙酸,烷基过氧化氢如叔丁基过氧化氢。适宜的溶剂例如为水、低级醇如乙醇等,烃类如甲苯,酮如2-丁酮,卤代烃如二氯甲烷,以及此等溶剂的混合物。
任选在适当催化剂例如四(三苯膦)钯和合适的溶剂如N,N-二甲基乙酰胺或N,N-二甲基甲酰胺存在下,通过与适宜的氰基引入剂如***或CuCN反应,可以将其中R3为卤素,或者其中R2被卤素取代的式(I)化合物转化成其中R3为氰基或其中R2被氰基取代的式(I)化合物。在适当酸如盐酸存在下,通过与HCOOH反应,其中R3为氰基或其中R2被氰基取代的式(I)化合物可进一步转化成其中R3为氨基羰基或其中R2被氨基羰基取代的式(I)化合物。其中R3为氰基或其中R2被氰基取代的式(I)化合物也可以在氯化铵和N,N-二甲基乙酰乙酰胺存在下与叠氮化钠反应,而进一步转化为其中R3为四唑基或其中R2被四唑基取代的式(I)化合物。
在适当溶剂例如1,4-二噁烷的存在下,通过与硫化钠反应,也可以将其中R2被卤素取代的式(I)化合物转化成其中R2被巯基取代的式(I)化合物。
在适当溶剂如二甲亚砜存在下,通过与式碱金属+-S-C1-6烷基,例如Na+-S-C1-6烷基的试剂反应,也可以将其中R2被卤素取代的式(I)化合物转化成其中R2被C1-6烷硫基取代的式(I)化合物。后一化合物通过在适当溶剂如醇(像乙醇)存在下与合适的氧化剂如过氧化物(譬如3-氯过苯甲酸)反应,可以进一步转化为其中R2被C1-6烷基-S(=O)-取代的式(I)化合物。
在适当溶剂例如醇类(譬如甲醇)存在下,通过与醇盐例如LiOC1-6烷基反应,也可以将其中R3为卤素或其中R2被卤素取代的式(I)化合物转化成其中R3为C1-6烷氧基或其中R2被C1-6烷氧基取代的式(I)化合物。
通过在适当的反应惰性溶剂例如二甲亚砜中与合适的羧酸盐如乙酸钠反应,进而用合适的碱(譬如吡啶)和乙酰氯处理所得反应产物,可以将其中R3为卤素或其中R2被卤素取代的式(I)化合物转化成其中R3为羟基或其中R2被羟基取代的式(I)化合物。
在适当碱例如氢氧化钠、碳酸钾、氢化钠和适当溶剂如1,4-二噁烷、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺的存在下,通过与H-L反应,可以将中R3为卤素或其中R2被卤素取代的式(I)化合物转化为这些式(I)化合物,其中R3为饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环,或其中R2被饱和的单环、二环或三环碳环;部分饱和的单环、二环或三环碳环;芳香性的单环、二环或三环碳环;饱和的单环、二环或三环杂环;部分饱和的单环、二环或三环杂环;芳族单环、二环或三环杂环所取代,所述取代基由-L表示。
在适当溶剂如环丁砜存在下,通过与合适的氟化物盐如氟化钾反应,可以将其中R3为氯或其中R2被氯取代的式(I)化合物转化为其中R3为氟或其中R2被氟取代的式(I)化合物。
在适当溶剂如N,N-二甲基乙酰胺或N,N-二甲基甲酰胺存在下,并任选在适当碱如N,N-二异丙基乙胺的存在下,通过与H-X-R2反应,可以将其中-X-R2为氢和其中R3取代基位于NR1连接基的间位并且为卤素的式(I)化合物转化为这些式(I)化合物,其中所述R3取代基被X-R2置换,其中当R2为氢时X不为直接键。
在适当脱烷基化剂(如三溴硼烷)和适当溶剂如二氯甲烷存在下,对其中R2被C1-4烷氧基C1-6烷基取代的式(I)化合物进行脱烷基化,从而转化成其中R2被羟基C1-6烷基取代的式(I)化合物。
任选在适当酸如盐酸存在下,以及在有适当溶剂如醇(例如甲醇)、四氢呋喃、N,N-二异丙基乙烷存在下,通过与适宜的试剂如氨、NH2(C1-6烷基),AlCH3[N(C1-6烷基)2]Cl反应,可以将其中R3或X-R2为C1-6烷氧基羰基,或其中R2被C1-6烷氧基羰基取代的式(I)化合物转化为这些式(I)化合物,其中R3或X-R2为氨基羰基,或其中R2被氨基羰基或单-或二(C1-6烷基)氨基羰基取代。
在适当溶剂如四氢呋喃、水、乙腈、氯仿存在下,并任选在适宜碱如N,N-二乙基乙胺存在下,通过与适当卤化剂例如Br2或1-(氯甲基)-4-氟-1,4-二氮杂二环(diazoniabicyclo)[2.2.2]辛烷双[四氟硼酸盐]反应,可以将其中R3为氢或其中R2是未取代的式(I)化合物转化为其中R3为卤素或其中R2被卤素取代的化合物。
其中R3或-X-R2为C1-6烷氧基羰基或其中R2被C1-6烷氧基羰基取代的式(I)化合物,通过与合适的还原剂如LiAlH4反应,而可以转化为其中R3或-X-R2为羟甲基或其中R2被羟甲基取代的式(I)化合物。
在适当催化剂例如钯-碳,和适当溶剂如醇(例如甲醇、乙醇等)或N,N-二甲基乙酰胺存在下,通过与适当还原剂如H2反应,可以将其中-X-R2代表-O-CH2-(任选取代)苯基的式(I)化合物转化为其中-X-R2代表OH的式(I)化合物。
在适当碱如碳酸钾和适当溶剂如N,N-二甲基乙酰胺存在下,通过与W1-X1-R2反应,其中W1代表适当离去基团,例如卤原子(如氯),并且其中的-O-X1代表X定义内的那些连接基,它们通过O原子与苯环相连(在所述定义中,X1代表连接基的一部分,但其中的O原子不包括在内),可以将其中-X-R2代表OH的式(I)化合物转化为其中-X-R2代表-O-X1-R2的式(I)化合物。
在适当催化剂例如钯-碳、适当催化毒物(例如噻吩溶液)和适当溶剂例如醇类(像甲醇、乙醇等)存在下,通过与适宜的还原剂如H2反应,可以将其中R3为硝基,或其中R2被硝基取代的式(I)化合物转化为其中R3为氨基或其中R2被氨基取代的式(I)化合物。
在适当溶剂例如N,N-二甲基乙酰胺和适当碱如N,N-二乙基乙胺存在下,通过与W1-S(=O)2-NR5R6反应,其中W1代表适当离去基团,例如卤原子(如氯),可以将其中R2被NH2取代的式(I)化合物转化为其中R2被-NH-S(=O)2-NR5R6取代的式(I)化合物。
在本发明中,一些式(I)化合物和某些中间体可能包含不对称碳原子。所述化合物与所述中间体的纯立体化学异构体可以利用本领域已知的方法获得。例如,非对映体可以利用物理方法例如选择性结晶或色谱技术譬如逆流分配、液相色谱等方法分离。对映体可以按下所述由外消旋混合物获得,即首先用适当拆分剂例如手性酸将所述外消旋混合物转化成非对映盐或化合物的混合物;然后通过例如选择性结晶或色谱技术例如液相色谱等方法物理分离所述非对映盐或化合物的混合物;最后将这种分离出来的非对映盐或化合物转化为相应的对映体。这种纯立体化学异构体也可以采用适当中间体和起始原料的纯立体化学异构体制得,但要求中间的反应应立体专一性发生。
分离式(I)化合物及其中间体的对映体用的另一种可选择方法是液相色谱法,特别是使用手性固定相的液相色谱法。
一些中间体与起始原料是已知化合物,并且可以从市场上购得或者可以按本领域公知的方法制备,参见WO 99/50250,WO 00/27825或EP 0,834,507中的描述。
在适当溶剂如乙腈或二噁烷存在下,并在合适的碱如N,N-二异丙基乙胺的存在下,使其中W1如上定义的式(IX)中间体与式(X)中间体反应,可以制得式(III)中间体。
在适当溶剂例如CH3OCH2CH2OH的存在下,使式(V)中间体与其中W4代表适当离去基团(例如卤素,像氯等)的式(XI)中间体反应,可以制备式(VI)中间体。
在适当盐例如碳酸钾和CuI的存在下,使式(XI)中间体与式(XII)中间体反应,可以制得其中R1为氢的式(VI)中间体,该中间体用式(VI-a)表示。
式(XII)中间体可通过其中R1为氢的式(V)中间体[即式(V-a)所示中间体]与甲酸反应制备。
在适当还原剂例如H2、适当催化剂例如钯-碳、以及适当溶剂如醇类(譬如乙醇等)存在下,通过还原式(XIII)中间体,可以制备其中X-R2为OH的式(VI)化合物,该中间体用式(VI-b)表示。
在适当溶剂例如二噁烷和***、以及适当酸例如盐酸的存在下,通过式(III)中间体与式(XIV)中间体反应,可以制备式(VIII)中间体。
在氢化钠、以及适当溶剂如四氢呋喃的存在下,通过式(XV)中间体与式(XVI)中间体反应,可以制得式(VIII)中间体,该中间体用式(VIII-a)表示。
式(I)或(I’)化合物能够抑制糖原合酶激酶3(GSK3),特别是糖原合酶激酶3β(GSK3β)。它们是选择性的糖原合酶激酶3抑制剂。具有特异性抑制作用的化合物是优越的治疗剂,凭借其特异性它们具有更高效力和较低毒性之特点。GSK3的同义词为tau蛋白激酶I(TPKI),FA(因子A)激酶,激酶FA和ATP-柠檬酸裂解激酶(ACLK)。
糖原合酶激酶3(GSK3)存在两种同种型,即GSK3α和GSK3β,是脯氨酸指导的丝氨酸/苏氨酸激酶,最初鉴定为能磷酸化糖原合成酶的酶。但现已证明GSK 3在体外能磷酸化多种蛋白质,如糖原合成酶,磷酸酶抑制剂I-2,依赖于cAMP蛋白激酶的II型亚单位,磷酸酶-1的G亚单位,ATP柠檬酸裂解酶,乙酰辅酶A羧酸酶,髓鞘碱性蛋白,微管相关蛋白,神经丝蛋白,N-CAM细胞粘连分子,神经生长因子受体,c-Jun转录因子,JunD转录因子,c-Myb转录因子,c-Myc转录因子,L-Myc转录因子,腺瘤性结肠息肉病肿瘤抑制蛋白,tau蛋白和β-连环蛋白。
上述可以被GSK3磷酸化的蛋白质多样性暗示GSK3与细胞中的多种代谢与调节过程有关。
因此,GSK3抑制剂可用于预防或治疗通过GSK3活性介导的疾病,例如双相性精神障碍(特别是躁狂性抑郁症),糖尿病,阿尔茨海默氏病,白血球减少症,FTDP-17(与帕金森病有关的额-颞叶性痴呆症),皮质基底性变性,进行性核上麻痹,多发性***萎缩,皮克病(Pick’s disease),C型尼-皮病(Niemann Pick’s disease type C),拳击员痴呆,唯缠结性痴呆(dementia with tangles only),缠结与钙化性痴呆,唐氏综合症(Downsyndrome),肌强直性营养不良,Guam-帕金森神经机能障碍-痴呆复症(Parkinsonism-dementia complex of Guam),获得性免疫缺陷综合征相关性痴呆(aids related dementia),脑炎后帕金森综合症,缠结性朊病毒病(prion diseases with tangles),亚急性致硬化性全脑炎,额叶变性(FLD),嗜银性颗粒病,亚急性硬化性全脑炎(subacute sclerotizingpanencephalitis)(SSPE)(中枢神经***病毒感染的后期并发症),炎性疾病,癌症,皮肤病如脱发,神经元损伤,精神***症,疼痛,特别是神经病性疼痛。GSK3抑制剂也可以用于抑制***的能动性,因而可用作雄性避孕剂。特别是,本发明的化合物可用于预防或治疗阿尔茨海默氏病。糖尿病、尤其是2型糖尿病(非胰岛素依赖性糖尿病)。
阿尔茨海默氏病的主要神经病理学特征是神经元损失、淀粉样纤维沉积和对绞螺旋细丝(PHF)或神经原纤维缠结(NFT)。神经纤维缠结的形成可能是异常磷酸化tau蛋白聚集的结果。这种异常磷酸化动摇了神经元的细胞骨架,从而导致轴索转运减慢,功能化不足,最后致使神经元死亡。神经原纤维缠结的密度已经证明与阿尔茨海默氏病的持续时间与严重程度有关。降低tau磷酸化的程度可能会产生神经保护作用,可以预防或治疗阿尔茨海默氏病,或者可以减缓疾病的进展。如上所述,GSK3磷酸化tau蛋白。因此,对GSK3具有抑制活性的化合物可用于预防或治疗阿尔茨海默氏病。
胰岛素调节贮藏多糖糖原的合成。糖原合成中的限速步骤受酶糖原合酶的催化。据认为糖原合酶受磷酸化作用抑制,并且胰岛素在这种酶的磷酸化过程中通过产生净减少而刺激糖原合酶。因此,为了激活糖原合酶,胰岛素必须或激活磷酸化酶或抑制激酶,或者同时产生这两种作用。
据信,糖原合酶是糖原合酶激酶3的底物,并且胰岛素不激活GSK3,从而能促进糖原合酶的去磷酸化作用。
GSK3除在胰岛素诱导的糖原合成中起作用外,GSK3还对胰岛素抗性也其作用。据信GSK3依赖性胰岛素受体底物-1的磷酸化作用对胰岛素抗性产生影响。
因此,抑制GSK3的结果是糖原的沉积增多,伴随产生低血糖,从而模拟了胰岛素的低血糖作用。对GSK3的抑制提供了另一种控制非胰岛素糖尿病和肥胖症中常见胰岛素抗性的疗法。GSK3抑制剂因而提供了一种治疗1型和2型糖尿病的新药征。
已经指出,GSK3抑制剂,特别是GSK3β抑制剂,也可用于预防或治疗疼痛,特别是神经病性疼痛。在轴突(axotomy)或慢性缩窄性损伤之后,神经元细胞通过编程性细胞死亡途径死亡,形态学变化与痛觉过敏和/或异常性疼痛的发作有关。
编程性细胞死亡的诱因可能是由于神经营养因子的供给减少而引起的,因为给药神经营养蛋白必然改变神经元损失的时程。GSK,尤其是GSK3β,已经证明与编程性细胞死亡级联反应的启动有关,并且去除营养因子会激发GSK3β编程性细胞死亡途径。鉴于上文所述,GSK3β抑制剂可能会减弱神经病性疼痛的信号,甚至能预防神经病性疼痛的程度。
鉴于它们的GSK3抑制特性,特别是它们的GSK3β抑制特性,式(I)或(I’)化合物,它们的N-氧化物,可药用的加成盐,季铵及其立体化学异构体,可用于预防或治疗GSK3介导的疾病,特别是GSK3β介导的疾病,如双相性精神障碍(特别是躁狂性抑郁症),糖尿病,阿尔茨海默氏病,白血球减少症,FTDP-17(与帕金森病有关的额-颞叶性痴呆症),皮质基底性变性,进行性核上麻痹,多发性***萎缩,皮克病,C型尼-皮病,拳击员痴呆,唯缠结性痴呆(dementia with tanglesonly),缠结与钙化性痴呆,唐氏综合症,肌强直性营养不良,Guam-帕金森神经机能障碍-痴呆复症,获得性免疫缺陷综合征相关性痴呆,脑炎后帕金森综合症,缠结性朊病毒病(prion diseases with tangles),亚急性致硬化性全脑炎,额叶变性(FLD),嗜银性颗粒病,亚急性硬化性全脑炎(subacute sclerotizing panencephalitis)(SSPE)(中枢神经***病毒感染的后期并发症),炎性疾病,癌症,皮肤病如脱发,神经元损伤,精神***症,疼痛,特别是神经病性疼痛。本发明化合物也可用作雄性避孕剂。概括地讲,本发明化合物可用于对患有GSK3,尤其是GSK3β介导的疾病的温血动物的治疗,或者它们可用于预防温血动物罹患GSK3,尤其是GSK3β介导的疾病。更具体讲,本发明化合物可用于治疗患有阿尔茨海默氏病,糖尿病,尤其是2型糖尿病,癌症,炎性疾病或双相性精神障碍的温血动物。
鉴于上述药理性质,式(I)化合物或其任何亚组,它们的N-氧化物,可药用的加成盐,季铵及其立体化学异构体,可用作药物。具体讲,本发明化合物可用于制备用于治疗或预防经由GSK3,尤其是GSK3β介导的疾病的药物。更具体讲,本发明化合物可用于制备治疗或预防阿尔茨海默氏病、糖尿病(尤其是2型糖尿病)、癌症、炎性疾病或双相性精神障碍用的药物。
鉴于式(I)或(I’)化合物的用途,本发明提供了治疗包括人在内的哺乳动物或预防包括人在内的哺乳动物罹患由GSK3,特别是GSK3β介导的疾病的的方法,更具体讲,提供了治疗或预防阿尔茨海默氏病、糖尿病(尤其是2型糖尿病)、癌症、炎性疾病或双相性精神障碍的方法。所述方法包括对包括人在内的温血动物给药(优选口服给药)有效量的式(I)或(I’)化合物,其N-氧化物、可药用的加成盐、季铵或可能的立体化学异构体。
本发明也提供了用于预防或治疗由GSK3(尤其是GSK3β)介导的疾病的组合物,其包括治疗有效量的式(I)或(I’)化合物和可药用的载体。
本发明的化合物或其任何亚组可配制成适合给药目的用的不同药剂形式。作为适宜的组合物,可提及常用于全身性给药的所有组合物。为制备本发明的药物组合物,将作为活性成分的有效量的特定化合物(任选为加成盐形式)与药学上可接受的载体(根据给药需要的制剂形式,可使用各种不同形式的载体)致密混合在一起。这些药物组合物宜为特别适合口服、直肠、经皮或非肠道注射给药需要的单位剂型。例如在制备口服剂型的组合物时,可以使用任何常用的药物介质,例如对于口服液体制剂如混悬剂、糖浆剂、酏剂、乳剂和溶液剂,可以使用水、二醇类、油、醇等;或当制备粉剂、丸剂、胶囊剂和片剂时可以使用固体载体,例如淀粉、蔗糖、高岭土、稀释剂、润滑剂、粘合剂、崩解剂等。由于易于给药,片剂和胶凝剂是最适宜的口服单位剂型,这种情况下显然要使用固态药用载体。对于非肠道给药组合物,载体通常包括无菌水(至少为大部分),但为了例如增加溶解性,也可能包括其它成分。注射溶液例如可用包括盐水溶液、葡萄糖溶液或盐水与葡萄糖溶液的混合液的载体制备。也可以制备可注射的混悬剂,其中可以使用合适的液体载体、悬浮剂等组分。同样也包括在临用前可以转化成液体形式制剂的固体形式制剂。在适合经皮给药的组合物中,载体任选包括促渗剂和/或合适的湿润剂,任选混有占很小比例具有各种性质的适当添加剂,这些添加剂不会对皮肤造成明显的伤害作用。所述添加剂可能有利于皮肤给药且/或有助于制备所期望的组合物。这些组合物可以通过各种方式给药,例如以透皮贴剂、点施剂(spot-on)或软膏剂给药。本发明化合物也可以通过吸入或吹入方式给药,这可以采用本领域中适合这种给药方式用的方法与制剂完成。因此,一般来讲,本发明化合物可以以溶液、混悬液或干粉形式给药于肺部。针对通过口或鼻的吸入或吹入给药溶液、混悬液或干粉而研制的任何***都适于给药本发明化合物。
将前述药物组合物配制成易于给药和均化剂量的单位剂量形式特别有利。本文所用的单位剂量形式是指适于作为单位剂量的物理分离单位,每一单位含有经计算能产生所需治疗效果的预定量的活性成分以及需要的药物载体。此类单位剂量形式的实例有片剂(包括刻痕片或包衣片)、胶囊剂、丸剂、散剂包、糯米纸囊剂、栓剂、可注射的溶液或混悬液等,以及其独立的多剂量形式。
本发明化合物为口服活性化合物,因而优选口服给药。
本领域技术人员悉知,精确的剂量、治疗有效量和给药次数根据所用的具体式(I)或(I’)化合物、受治疗的具体病症,所治疗疾病的严重程度、具体患者的年龄、体重、性别、疾病程度和一般健康状况以及患者个体可能给用的其它药物而定。此外,显而易见的是所述有效日剂量根据受治疗者的反应和/或开药本发明化合物的医生的评价而可增减。
当用作用于预防或治疗阿尔茨海默氏病的药物时,式(I)或(I’)的化合物可以与治疗阿尔茨海默氏病用的其它常见药物联用,例如加兰他敏、donepezil、rivastigmine或他可林。因此,本发明还涉及式(I)或(I’)化合物与能预防或治疗阿尔茨海默氏病的其它药剂的并用药物。所述并用药物可以药品形式使用。本发明也涉及一种含有(a)式(I)或(I’)的化合物,和(b)能够预防或治疗阿尔茨海默氏病的其它药剂作为联合制剂的制品,所述联合制剂用于同时、分别或相继地用于预防或治疗阿尔茨海默氏病。不同的药物可以与可药用载体一起复合在单一制剂中。
当用作用于预防或治疗2型糖尿病的药物时,式(I)或(I’)的化合物可以与治疗2型糖尿病用的其它常见药物联用,这类药物例如有格列本脲、氯磺丙脲、格列齐特、格列吡嗪、格列喹酮、甲磺丁脲、二甲双胍、阿卡波糖、米各尼醇、nateglinide、瑞格列奈、格列帕脲、格列美脲、优降糖、妥拉磺脲、罗格列酮、rosgilitazone、吡格列酮、isaglitazone。因此,本发明还涉及式(I)或(I’)化合物与能预防或治疗2型糖尿病的其它药剂的并用药物。所述并用药物可以药品形式使用。本发明也涉及一种含有(a)式(I)或(I’)的化合物,和(b)能够预防或治疗2型糖尿病的其它药剂作为联合制剂的制品,所述联合制剂用于同时、分别或相继地用于预防或治疗2型糖尿病。不同的药物可以与可药用载体一起复合在单一制剂中。
当用作用于预防或治疗癌症的药物时,式(I)或(I’)的化合物可以与治疗癌症用的其它常见药物联用,这类药物例如有铂配合物例如顺铂或卡铂;紫杉烷化合物例如紫杉醇(paclitaxel)或紫杉特尔;喜树碱化合物例如伊立替康或托泊替堪;抗肿瘤长春碱类例如长春碱、长春新碱或长春瑞滨;抗肿瘤核苷衍生物例如5-氟脲嘧啶、吉西他滨(gemcitabine)或截达瘤(capecitabine);氮芥或亚硝基脲类烷化剂例如环磷酰胺、丁酸氮芥、卡莫司汀或洛莫司汀;抗肿瘤蒽衍生物例如柔红霉素、多柔比星或伊达柔霉素;HER2抗体例如trastzumab;抗肿瘤鬼臼毒衍生物例如依托泊甙或替尼泊甙;和抗***剂包括***受体拮抗剂或选择性***受体调节剂,优选他莫昔芬,或托米芬、着洛西芬,faslodex和那洛西芬;芳香酶抑制剂如依西马丁、anastrozole、来曲唑和伏罗唑;分化剂如retinoids,维生素D和DNA甲基转移酶抑制剂例如阿扎胞苷;激酶抑制剂例如flavoperidol和甲磺酸imatinib或法尼基转移酶抑制剂例如R115777。
因此,本发明还涉及式(I)或(I’)化合物与能预防或治疗癌症的其它药剂的并用药物。所述并用药物可以药品形式使用。本发明也涉及一种含有(a)式(I)或(I’)的化合物,和(b)能够预防或治疗癌症的其它药剂作为联合制剂的制品,所述联合制剂用于同时、分别或相继地用于预防或治疗癌症。不同的药物可以与可药用载体一起复合在单一制剂中。
当用作用于预防或治疗双相性精神障碍的药物时,式(I)或(I’)的化合物可以与治疗双相性精神障碍用的其它常见药物联用,这类药物例如有非典型的抗精神病药,抗癫痫药、苯并二氮卓类,锂盐,例如奥氮平、利培酮、卡马西平、丙戊酸、托佩马特。
因此,本发明还涉及式(I)或(I’)化合物与能预防或治疗双相性精神障碍的其它药剂的并用药物。所述并用药物可以药品形式使用。本发明也涉及一种含有(a)式(I)或(I’)的化合物,和(b)能够预防或治疗双相性精神障碍的其它药剂作为联合制剂的制品,所述联合制剂用于同时、分别或相继地用于预防或治疗双相性精神障碍。不同的药物可以与可药用载体一起复合在单一制剂中。
当用作用于预防或治疗炎性疾病的药物时,式(I)或(I’)的化合物可以与治疗炎性疾病用的其它常见药物联用,这类药物例如有甾族类药物、环氧合酶-2抑制剂,非甾体抗炎药、TNF-α抗体,例如乙酰水杨酸、丁苯乙肟、双氯高灭酸钾、双氯高灭酸钠、酮洛酸、氨基丁三醇,甲苯酰吡酸,布洛芬,萘普生,萘普生钠、噻洛芬酸、氟比洛芬、甲灭酸、尼氟酸、甲氯灭酸、吲哚美辛、丙谷炎痛、酮洛芬、那布米酮、扑热息痛、吡罗昔康、替诺昔康、尼美舒利、fenylbutazon、曲马多、二丙酸倍氯米松、倍他米松、倍氯米松、布地缩松、氟地松、莫米他松、***、氢化可的松、甲***、***、强的松、去炎松、celecoxib、rofecoxib、infliximab、leflunomide、来氟米特、CPH82、甲氨喋呤、柳氮磺胺吡啶。
因此,本发明还涉及式(I)或(I’)化合物与能预防或治疗炎性疾病的其它药剂的并用药物。所述并用药物可以药品形式使用。本发明也涉及一种含有(a)式(I)或(I’)的化合物,和(b)能够预防或治疗炎性疾病的其它药剂作为联合制剂的制品,所述联合制剂用于同时、分别或相继地用于预防或治疗炎性疾病。不同的药物可以与可药用载体一起复合在单一制剂中。
实验部分
下文中,“DMF”表示N,N-二甲基甲酰胺,“THF”表示四氢呋喃,“DMSO”表示二甲亚砜,“TFA”表示三氟乙酸。
A.中间体化合物的制备
实施例A 1
a)反应在氩气氛围中进行。向2,4-二氯嘧啶(0.0664mol)/1,4-二噁烷(100ml)中加入2,4,6-三甲基苯胺(0.0678mol)。加入N,N-二(1-甲基乙基)乙胺(N,N-二异丙基乙胺)(0.0830mol)。搅拌回流反应混合物4天,然后蒸发溶剂。将残留物溶于CH2Cl2,用饱和NaHCO3溶液洗涤,然后干燥(Na2SO4),过滤,蒸发溶剂,得17.1g固体残渣。将该固体溶于CH2Cl2:己烷(1∶1,150ml),浓缩所形成的溶液到100ml,然后过滤。残留物通过KP-Sil柱色谱纯化(洗脱剂:CH2Cl2)。收集所需馏分,蒸发溶剂。将低极性馏分在CH2Cl2中搅拌3小时,随后过滤,得0.44g 4-氯-N-(2,4,6-三甲基苯基)-2-嘧啶胺。第二个馏分用乙腈重结晶,滤出,干燥,得2-氯-N-(2,4,6-三甲基苯基)-4-嘧啶胺(中间体1)(mp.182-183℃).
b)搅拌中间体1(1.06mol)和5.4N HCl/2-丙醇(1.15mol)在水(4000ml)中的混合物,在30分钟内温热到40-45℃。在40-50℃下加入氨基苄腈(1.29mol)。搅拌回流反应混合物3.5小时,然后冷却到室温。加入EtOAc(1000ml),分批加NaHCO3碱化混合物。然后加入EtOAc(1000ml),剧烈搅拌混合物10分钟。整体过滤得到沉淀物(I)和滤液(I)。分出滤液(I)层。有机层用盐水洗涤,干燥(MgSO4),过滤,蒸发溶剂。将残留物在乙醇(300ml)中搅拌,过滤,干燥(真空,40℃),得到50mg馏分1。在EtOAc(1000ml)中搅拌沉淀(I),滤出,干燥(真空,40℃)。在乙醇(400ml)中搅拌该馏分,滤出,干燥(真空,40℃)。得到248mg馏分2。合并馏分1与2,在沸腾乙醇(2000ml,p.a.)中搅拌45分钟,然后在搅拌下任其冷却过夜。滤出沉淀物,用乙醇洗涤,干燥(真空,40℃,24小时),得到271mg 4-[[4-[(2,4,6-三甲基苯基)氨基]-2-嘧啶基]氨基]苄腈(中间体2)(mp 217.1-218.2℃)。
实施例A2
a)中间体3的制备:
在油浴中于125-135℃加热化合物8(按照B4制备)(0.0162mol)与POCl3(25ml),搅拌12分钟。将样品倒入冰上,搅拌,过滤。在200mmHg下室温干燥所产生的固体3天,得4.86g中间体3(黄色固体,97%)。
b)中间体4的制备:
在氩气氛围中搅拌NaH(0.00808mol)、THF(0.00808mol)与苯甲醇(0.00808mol)5分钟。加入中间体3(0.00646mol),回流样品过夜。蒸发样品。再加入THF、水和CH3CN。搅拌混合物60分钟,然后过滤,得2.49g固体。在200mmHg下65℃干燥该固体3天,然后于80℃、0.2mmHg下干燥1天。取0.26g样品通过快速柱色谱纯化(CH2Cl2),然后在0.2mmHg下80℃干燥16小时,得到0.23g中间体4(88%)(mp.156-157℃)。
B.最终化合物的制备
实施例B1
a)化合物1的制备:
60℃搅拌由2-氯-5-硝基-N-(苯基甲基)-4-嘧啶胺(0.012mol)、3-氨基苯甲酰胺(0.012mol)和Et3N(0.012mol)在DMF(50ml)中形成的溶液共2小时。然后冷却混合物到室温,加入甲醇(10ml)。搅拌混合物10分钟,滤出产生的固体,洗涤并干燥,得3.3g化合物1(77%)。
b)化合物2的制备:
在氩气氛围中回流4,5-二氨基-6-甲基-2(1H)-嘧啶硫酮(0.0704mol)、3-氨基苯甲酰胺(0.106mol)和(CH3OCH2CH2)2O(20ml)3小时,然后在室温下搅拌过夜。加热样品到回流状态,过滤,用热(CH3OCH2CH2)2O(2x)洗涤,之后过滤,得15.25g化合物2。
c)化合物3的制备:
向中间体1(0.000242mol)与4-氨基-N-甲基-苯甲酰胺(0.000242mol)的混合物中加入由MeOH(4ml)、H2O(4ml)和HCl/2-丙醇(0.2m)组成的混合物。60℃搅拌反应混合物过夜。分离所需化合物,通过RP C-18高效液相色谱纯化(洗脱剂:(含0.5%NH4OAc的H2O/CH3CN 90/10)/CH3OH/CH3CN 70/15/15;0/50/50;0/0/100)。收集所需馏分,蒸发溶剂,得0.017g化合物3。
实施例B2
化合物4的制备:
在16-17℃的水浴中,向中间体4(0.00378mol)和K2CO3(1.22g)以及DMSO(17.5ml)中逐滴加入30%H2O2(7.3ml)。另外加入20mlDMSO,搅拌并温热反应物到室温共4小时。再加入DMSO(20ml)用于减少泡沫,搅拌混合物1小时。加入水,过滤试样得2.56g固体。将该固体分配到CHCl3与水之间,搅拌过夜,然后过滤,得1.11g白色固体,蒸发滤液得到0.17g。滤液固体用甲醇重结晶。在0.2mmHg下80℃干燥样品16小时,得0.08g化合物4(mp.:216-217℃)。
实施例B3
a)化合物5的制备:
用3-(1-甲基-1H-咪唑-2-基)苯胺(0.0127mol)和N-乙基-N-(1-甲基乙基)-2-丙胺(0.0127mol)处理0.0127mol化合物6:
(按照B1a制备)在DMF(80ml)中的混合物。60℃搅拌反应混合物4小时,然后冷却到室温,得化合物5(100%)。
b)化合物7的制备:
在噻吩溶液(2ml)和另加的DMF(20ml)存在下,利用Pd/C,10%(2g)为催化剂50℃氢化(H166-080)0.0127mol化合物5在DMF(80ml)中的混合物。在吸收3当量H2后,滤除催化剂,洗涤,减压蒸发滤液,得化合物7(100%)。
实施例B4
化合物8的制备:
氩气氛下,向化合物2(按照B1b制备)(0.0663mol)、DMSO(800ml)和Et3N(0.0729mol)形成的溶液通N2 0.5小时。加入Br2(0.0729mol)。室温搅拌反应过夜。逐滴加入水(11)。过滤得17.5g固体。将样品在MeOH(11)中回流60分钟,然后冷却,过滤,在200mmHg下80℃干燥3天,得11.51g化合物8(55%)。
实施例B5
化合物9的制备:
氩气氛下,在高压容器中加入化合物4(按照B2制备)(0.00226mol)、CuCN(0.03383mol)和DMF(27ml)。混合物于110-120℃搅拌2天。过滤混合物,蒸发溶剂2天。超声处理混合物,在10%MeOH:CH2Cl2(250ml)中搅拌。样品经柱色谱纯化,以10%MeOH:CH2Cl2洗脱,得0.05g固体。样品再用Gilson prep HPLC纯化(0.1%TFA/H2O和0.1%TFA/CH3CN梯度),冻干,然后在0.2mmHg下80℃干燥16小时,得0.02g化合物9(mp.:260-261℃)。
表1-3列出按照上述实施例之一制备的式(I)化合物。
表1
表2
表3
C.药理实施例
本发明化合物的药理活性用下述试验测试。
GSK3β测定于25℃在100μl反应体积的25mM Tris(pH 7.4)中进行,其中含有10mM MgCl2、1mM DTT、0.1mg/ml BSA、5%甘油并含有19nM GSK3β、5μM生物素磷酸化CREB肽、1μM ATP、2nM ATP-33P和适当量的式(I)或(I’)受试化合物。1小时后,加入70μl Stop混合物(1mM ATP,18mg/ml链霉抗生物素蛋白包被的PVT SPA微珠pH11.0)终止反应。将与磷酸化CREB肽连接的微珠静置30分钟,利用微量滴定板闪烁仪计数微珠的放射活性,并与对照试验(不存在试验化合物)得到的结果加以比较,以求出GSK3β抑制百分数。根据不同量试验化合物存在下进行上述GSK3β测定获得的剂量反应曲线,计算IC50值,即50%抑制GSK3β的试验化合物的浓度(M)。
表4列出在上述试验中获得的本发明化合物的pIC50值(-log IC50(M))。
表4
化合物序号 | pIC<sub>50</sub> |
17 | 5.85 |
1 | 6.74 |
22 | 7.19 |
4 | 7.28 |
23 | 7.66 |
9 | 7.74 |
Claims (19)
1.下式化合物
或其可药用加成盐,其中:
R1为氢;
X为-NR1-;-O-;-O-C1-6烷基-;-NR1-C1-6烷基-;或直接键;
R2为氢或R20,其中R20,可能的话,任选被一个或多个各自独立选自以下的取代基取代:R15;羟基;卤素;硝基;氰基;R15-O-;R5R6N;
R5R6N-C1-6烷基;R5R6N-C1-6烷氧基;R5R6N-C(=O)-;
R3为氢;卤素;C1-6烷基;C1-6烷氧基;氰基;硝基;氨基;单-或二(C1-6烷基)氨基;多卤代C1-6烷基;多卤代C1-6烷氧基;
R4a或R4b各自独立地为氢或R8;
R5和R6各自独立地为氢或R8;
R8为C1-6烷基;
R15为C1-6烷基,苯基;咪唑基;被苯基取代的C1-6烷基;其中该R15代表的各基团任选被C1-6烷基取代;
R20为苯基;
条件是-X-R2和/或R3不是氢。
2.如权利要求1中所述的化合物,其中X不为NR1。
3.根据权利要求1的化合物,其中:
R1为氢;
X为-NR1-;-O-;-O-C1-6烷基-;-NR1-C1-6烷基-或直接键;
R2为氢或R20,其中R20,可能的话,任选被一个或多个各自独立选自R15;
氰基;R15-O-;R5R6N-C(=O)-的取代基取代;
R3为氢;卤素;氰基;硝基;氨基;
R5和R6为氢;
R15为C1-6烷基,苯基;咪唑基;被苯基取代的C1-6烷基;其中该R15代表的各基团任选被C1-6烷基取代;
R20为苯基。
4.根据权利要求1或2的化合物,其中X-R2和R3不是氢。
5.根据权利要求3的化合物,其中X-R2和R3不是氢。
6.根据权利要求1或2的化合物,其中R2不是氢。
7.根据权利要求3的化合物,其中R2不是氢。
8.根据权利要求4的化合物,其中R2不是氢。
9.根据权利要求5的化合物,其中R2不是氢。
10.如权利要求1所述的化合物,其中所述化合物为:
3-[[5-溴-4-(苯基甲氧基)-2-嘧啶基]氨基]-苯甲酰胺;
3-[[5-氰基-4-(苯基甲氧基)-2-嘧啶基]氨基]-苯甲酰胺;
或其可药用加成盐。
11.如权利要求1所述的化合物,其中所述化合物为3-(4-苄氧基-嘧啶-2-基氨基)-苯甲酰胺或其可药用加成盐。
12.化合物,其中该化合物是
4-[[5-溴-4-(苯基甲氧基)-2-嘧啶基]氨基]-苯甲酰胺;
4-[[5-氰基-4-(苯基甲氧基)-2-嘧啶基]氨基]-苯甲酰胺。
13.前述权利要求任一项所述的化合物在制备用于预防或治疗通过糖原合酶激酶3介导的疾病的药物中的应用。
14.权利要求13所述的化合物在制备用于预防或治疗下述疾病的药物中的应用:双相性精神障碍,糖尿病,阿尔茨海默氏病,白血球减少症,与帕金森病有关的额-颞叶性痴呆症,皮质基底性变性,进行性核上麻痹,多发性***萎缩,皮克病,C型尼-皮病,拳击员痴呆,唯缠结性痴呆,缠结与钙化性痴呆,唐氏综合症,肌强直性营养不良,关岛-帕金森神经机能障碍-痴呆复症,获得性免疫缺陷综合征相关性痴呆,脑炎后帕金森综合症,缠结性朊病毒病,亚急性致硬化性全脑炎,额叶变性,嗜银性颗粒病,亚急性硬化性全脑炎,炎性疾病,癌症,皮肤病,神经元损伤,精神***症,疼痛。
15.权利要求14所述的应用,其中所述药物用于预防或治疗躁狂性抑郁症。
16.如权利要求14所述的应用,其中所述药物用于预防或治疗阿尔茨海默氏病、糖尿病、癌症、炎性疾病或双相性精神障碍。
17.药物组合物,其包括可药用载体和作为活性成分的治疗有效量的权利要求1-12中任一项所述的化合物。
18.制备权利要求17所述药物组合物的方法,其特征在于将治疗有效量的权利要求1-12任一项所述的化合物与可药用载体致密混合。
19.制备权利要求1所述化合物的方法,其特征在于:
a)在适当溶剂存在下,并任选在合适的酸或合适的碱存在下,使式(II)中间体与式(III)中间体反应,
其中W1代表适当离去基团,且R1,R2,R3,R4a,R4b和X如权利要求1中定义;
b)任选在适当溶剂存在下,使式(IV)中间体与式(V)中间体反应:
其中W2代表适当离去基团,且R1,R2,R3,R4a,R4b和X如权利要求1中定义;
c)在适当溶剂存在下,使式(VI)中间体与式(VII)中间体反应:
其中W3代表合适离去基团,且R1,R2,R3,R4a,R4b和X如权利要求1中定义;
d)在适当溶剂存在下,并任选在有合适的碱存在下,使式(VIII)中间体与合适的氧化剂反应:
其中R1,R2,R3和X如权利要求1中定义。
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- 2002-10-29 EA EA200400616A patent/EA007063B1/ru not_active IP Right Cessation
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- 2002-10-29 AT AT02802307T patent/ATE389638T1/de active
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2004
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5516775A (en) * | 1992-08-31 | 1996-05-14 | Ciba-Geigy Corporation | Further use of pyrimidine derivatives |
US6048866A (en) * | 1997-03-14 | 2000-04-11 | Celltech Therapeutics, Limited | Substituted 2-anilinopryimidines useful as protein kinase inhibitors |
CN1312807A (zh) * | 1998-06-19 | 2001-09-12 | 希龙公司 | 糖元合成酶激酶3的抑制剂 |
Also Published As
Publication number | Publication date |
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EP1442024B1 (en) | 2008-03-19 |
CA2463823A1 (en) | 2003-05-08 |
CN1703405A (zh) | 2005-11-30 |
US20060063789A1 (en) | 2006-03-23 |
EP1442024A1 (en) | 2004-08-04 |
ES2303565T3 (es) | 2008-08-16 |
NZ531854A (en) | 2006-03-31 |
DE60225709D1 (de) | 2008-04-30 |
ATE389638T1 (de) | 2008-04-15 |
IL161663A0 (en) | 2004-09-27 |
AU2002363177B2 (en) | 2008-09-18 |
DK1442024T3 (da) | 2008-06-30 |
EA200400616A1 (ru) | 2004-08-26 |
NO326889B1 (no) | 2009-03-16 |
WO2003037877A1 (en) | 2003-05-08 |
HUP0402245A2 (hu) | 2005-02-28 |
DE60225709T2 (de) | 2009-05-07 |
BR0213790A (pt) | 2004-12-07 |
NO20042253L (no) | 2004-06-01 |
PL368920A1 (en) | 2005-04-04 |
HUP0402245A3 (en) | 2010-03-29 |
PT1442024E (pt) | 2008-06-12 |
EA007063B1 (ru) | 2006-06-30 |
MXPA04004176A (es) | 2004-09-06 |
JP2005507420A (ja) | 2005-03-17 |
KR20040062557A (ko) | 2004-07-07 |
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