CN100480248C - 用作γ-分泌酶抑制剂的丙二酰胺衍生物 - Google Patents
用作γ-分泌酶抑制剂的丙二酰胺衍生物 Download PDFInfo
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- CN100480248C CN100480248C CNB2004800033052A CN200480003305A CN100480248C CN 100480248 C CN100480248 C CN 100480248C CN B2004800033052 A CNB2004800033052 A CN B2004800033052A CN 200480003305 A CN200480003305 A CN 200480003305A CN 100480248 C CN100480248 C CN 100480248C
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- Prior art keywords
- methyl
- fluoro
- oxo
- dihydro
- malonamide
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- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical class NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 title abstract description 5
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- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 239000002253 acid Substances 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims description 185
- 125000004175 fluorobenzyl group Chemical group 0.000 claims description 90
- 239000001257 hydrogen Substances 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- -1 tetralyl Chemical group 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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- NOOLHZQBHCVURF-UHFFFAOYSA-N n-[(3-fluorophenyl)methyl]-2-methyl-n'-(5-methyl-6-oxo-7h-benzo[d][1]benzazepin-7-yl)propanediamide Chemical compound C12=CC=CC=C2C2=CC=CC=C2N(C)C(=O)C1NC(=O)C(C)C(=O)NCC1=CC=CC(F)=C1 NOOLHZQBHCVURF-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
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- 208000024827 Alzheimer disease Diseases 0.000 abstract 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/41—Y being a hydrogen or an acyclic carbon atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及式(IA)或(IB)丙二酰胺衍生物及其可药用的酸加成盐。该化合物是γ-分泌酶抑制剂且相关化合物可用于治疗阿尔茨海默氏病。
Description
本发明涉及式IA或IB的丙二酰胺衍生物及其可药用的酸加成盐,
其中:
R1和R1′相同或不同,为氢、低级烷基、卤素、苄基或低级链烯基;
(R2)1,2,3彼此独立地为氢、羟基、卤素、低级烷基、低级烷氧基或三氟甲基;
R3-是未取代或被一个或两个选自卤素或氰基的取代基取代的苯基或苄基,或者是
-低级烷基,
-两个氢原子,
-(CH2)1,2-S-低级烷基,
-(CH2)1,2-环烷基,
-(CH2)1,2-OH,
-CH2OCH2-苯基,或者是
R4-为低级烷氧基,
-单或二烷基氨基,
-N(CH3)(CH2)1,2-C≡CH,
-或者是未取代或被R5至R10取代的且可通过-N(CH3)(CH2)0,1,2与式IB中的-C(O)-基团连接的单-、双-或三-环基团,
其中,
X是-CH2-、-S(O)2或-C(O)-;
R11是氢或低级烷基;
R12是氢或卤素;
R14是氢、低级烷基、-(CH2)2OH或-(CH2)2CN。
未取代或被R5至R10取代的且可通过-N(CH3)(CH2)0,1,2与式IB中的-C(O)-基团连接的单-、双-或三-环基团可以是下列基团:
(R5)1,2彼此独立地为氢、卤素、低级烷基或-(CH2)1,2OH;
R6为氢、卤素或低级烷氧基;
R7为氢或-CH2OCH3;
R8为氢或卤素;
R9为氢、低级烷氧基、低级烷基或氨基;
(R10)1,2,3彼此独立地为氢、低级烷基、低级烷氧基、低级环烷基、卤素、羟基、=O、氨基、硝基、-CH2CN、-OCH2C6H5,或下列基团
本文所使用的术语“低级烷基”表示含有1-6个碳原子的饱和直链或支链烷基,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、2-丁基、叔丁基等。优选的低级烷基为含有1-4个碳原子的基团。
术语“环烷基”表示含有3-7个碳原子的饱和碳环基团。
术语“卤素”表示氯、碘、氟和溴。
术语“低级烷氧基”表示其中烷基残基定义如上并且通过氧原子连接的基团。
术语“可药用的酸加成盐”包括与无机酸和有机酸如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等的盐。
已发现通式IA和IB化合物是γ-分泌酶(secretase)抑制剂并且相关化合物可用于治疗阿尔茨海默氏病。
阿尔茨海默氏病(AD)是晚年痴呆最常见的原因。在病理学上,AD的特征是淀粉状蛋白脑内沉积形成胞外斑和胞内神经原纤维缠结。淀粉样蛋白斑主要由淀粉样肽(Aβ肽)构成,该淀粉样肽由β-淀粉样蛋白前体(APP)通过一系列蛋白酶剪切步骤而产生。某些形式的APP已经被确认,其中最为丰富的是具有695、751和770个氨基酸长度的蛋白质。它们全都经差别剪接来自于单基因。Aβ肽衍生于APP的相同结构域,但其N-和C-端不同,并且主要的类型具有40和42个氨基酸长度。
Aβ肽通过称作β-和γ-分泌酶的两种蛋白水解酶的连续作用由APP产生。β-分泌酶首先切割APP恰好位于跨膜结构域(TM)外的胞外域,产生含有TM-和细胞质结构域的APP的C-端片段(CTFβ)。CTFβ是γ-分泌酶的底物,γ-分泌酶在TM内的多个邻近位置切割,产生Aβ肽和细胞质片段。大多数Aβ肽的长度为40个氨基酸(Aβ40)。少数在C-端载有2个额外的氨基酸。推测后者是更为致病的淀粉样肽。
β-分泌酶是一种典型的天冬氨酰蛋白酶。γ-分泌酶具有蛋白水解活性,由若干蛋白质构成,其确切组成还未完全了解。但早老素是该活性的主要成分,可以代表一组新的非典型的天冬氨酰蛋白酶,它们切割其底物的TM,并且本身是多起源膜蛋白质。γ-分泌酶的其它主要成分可能是nicastrin和α1与pen-2基因的产物。被证明的γ-分泌酶的底物是APP和Notch受体家族蛋白,然而γ-分泌酶具有宽松的底物特异性,并且还可切割与APP和Notch不相关的膜蛋白质。
γ-分泌酶活性是生成Aβ肽所据对必需的。这一点已通过遗传方法、即切除早老素基因和通过低分子量抑制剂化合物得以证明。根据淀粉状蛋白假说或AD,Aβ肽的产生和沉积是该疾病的根本原因,因此认为γ-分泌酶的选择性和有效抑制剂可用于预防和治疗AD。
因此,本发明的化合物通过阻滞γ-分泌酶活性以及减少或预防多种致淀粉样变性的Aβ肽的形成而用于治疗AD。
大量文献描述了有关γ-分泌酶抑制的现有知识,例如下列出版物:
Nature Reviews/Neuroscience,第3卷,2002年4月/281,
Biochemical Society Transactions(2002),第30卷,第4部分,
Current Topics in Medicinal Chemistry,2002,2,371-383,
Current Medicinal Chemistry,2002,第9卷,第11期,1087-1106,
Drug Development Research,56,211-227,2002,
Drug Discovery Today,第6卷,第9期,2001年5月,459-462,
FEBS Letters,483,(2000),6-10,
Science,第297卷,353-356,2002年7月,和
Journ.of Medicinal Chemistry,第44卷,13期,2001,2039-2060。
本发明的目的是式IA或IB化合物本身、式IA或IB化合物及其可药用盐在制备用于治疗与β-分泌酶抑制相关的药物中的用途、它们的制备、基于本发明的化合物的药物及其生产方法以及式IA或IB化合物在控制或预防阿尔茨海默氏病中的用途。
本发明的另一目的是式IA或IB化合物的所有形式的光学纯对映异构体、外消旋物或非对映异构体混合物。
本发明的实施方案是通式IA或IB的化合物及其可药用的酸加成盐,
其中,
R1和R1′相同或不同,为氢、低级烷基、卤素、苄基、低级链烯基,或者与它们所连接的碳原子一起为低级环烷基;
(R2)1,2,3彼此独立地为氢、卤素、低级烷基、低级烷氧基或三氟甲基;
R3-是未取代或被一个或两个选自卤素或氰基的取代基取代的苯基或苄基,或者是
-低级烷基,
-两个氢原子,
-(CH2)1,2-S-低级烷基,
-(CH2)1,2-环烷基,
-(CH2)1,2-OH,
-CH2OCH2-苯基,或者是
R4-为低级烷氧基,
-单或二烷基氨基,
-N(CH3)(CH2)1,2-C≡CH,
-或者是未取代或被R5至R10取代的且可通过-N(CH3)(CH2)0,1,2与式IB中的-C(O)-基团连接的单-、双-或三-环基团,选自
其中,
(R5)1,2彼此独立地为氢、卤素、低级烷基或-(CH2)1,2OH;
R6为氢、卤素或低级烷氧基;
R7为氢或-CH2OCH3;
R8为氢或卤素;
R9为氢、低级烷氧基、低级烷基或氨基;
(R10)1,2,3彼此独立地为氢、低级烷基、低级烷氧基、低级环烷基、卤素、羟基、=O、氨基、硝基、-CH2CN、-OCH2C6H5,或
其中,
X为-CH2、-S(O)2或-C(O)-;
R11为氢或低级烷基;
R12为氢或卤素;
N-(3,5-二氟-苄基)-N′-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-2-丙基-丙二酰胺,
2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-N′-(2,3,5-三氟-苄基)-丙二酰胺,
N-(4-氯-苄基)-2-甲基-N′-(1-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-丙二酰胺。
(2S-顺式)-N-(3,5-二氟-苄基)-2-甲基-N′-{4-氧代-2-[(2-噻吩-2-基-乙酰氨基)-(2R,S)-甲基]-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-5-基}-丙二酰胺,或
(2S-顺式)-N-(3,5-二氟-苄基)-N′-(2-{[2-(4-氟-苯基)-乙酰氨基]-甲基}-4-氧代-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-5-基)-2,2-二甲基-丙二酰胺。
而且,优选其中至少一个(R2)1,2,3是氟的式IA和IB化合物。
本发明的式IA和IB化合物及其可药用盐可通过本领域已知的方法、例如通过下述方法来制备,该方法包括
a)使式VI化合物
与式VII化合物反应,
得到式IA化合物
其中所述取代基定义同上,或者
b)使式VI化合物
与式VIII化合物反应,
得到式IB化合物
其中所述取代基定义同上,或者
c)使式XI化合物
与式IV化合物反应,
得到式IA化合物
其中取代基定义同上,并且
需要时,将所得化合物转化为可药用的酸加成盐。
式IA和IB化合物可按照下列方案1、2和3来制备:
方案1
在该方案中,R和R′彼此独立地为低级烷基,其它取代基如上所述。
详细描述可见于下文和实施例1-150和159。
向氢氧化钾或氢氧化钠在溶剂如乙醇中的溶液中加入式II的甲基-丙二酸酯并将混合物回流约4小时。冷却后,浓缩反应混合物并按照常规方法干燥,未经进一步纯化用于下一步骤。向所得的甲基-丙二酸单乙酯(III)的四氢呋喃溶液中加入式IV化合物,例如3,5-二氟苄胺、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐、1-羟基苯并三唑水合物和N,N-二异丙基-乙胺。在室温下将混合物搅拌约18小时。真空浓缩后,加入HCl并萃取混合物,干燥,并按常规方法纯化。向所得式V化合物溶液中加入水和氢氧化锂并将混合物回流约5小时。纯化后,可如下得到式IA化合物:向式VI化合物如N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸的四氢呋喃溶液中加入式VII化合物、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐、1-羟基苯并三唑水合物和N,N-二异丙基-乙胺。在室温下将混合物搅拌约18小时。浓缩、干燥并纯化后,得到式IA化合物。式IB化合物可在与上述相同的条件下使用式VIII化合物来获得。
方案2
式IB-1化合物可如方案1中最后一步所述(VI与VII或VIII→IA或IB)来制备。
式IB-1化合物与如下定义的式IB化合物相同:其中,
R1、R1,、R2和R3定义同上,且其中
R4为-NR15R16,
R15为氢或低级烷基,且
R16为低级烷基、-(CH2)1,2-C≡CH或者是如上所述的未取代或被R5至R10取代-(CH2)0,1,2-单-、二-或三环基。
方案3
取代基定义同上。
详细描述可见于下文和实施例151-158。
向所得甲基-丙二酸单叔丁酯(III-tBu)的四氢呋喃溶液中加入式VII化合物如7-氨基-5-甲基-5H,7H-二苯并[b,d]氮杂-6-酮以及N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐、1-羟基苯并三唑和N,N-二异丙基-乙胺。在室温下搅拌混合物约12小时。纯化后,得到式X化合物,在适宜溶剂如二氯甲烷中用酸如TFA处理,得到式XI化合物。使用式XI和IV化合物,按照上述酰胺偶合方法获得式IA化合物。
某些式IA或IB化合物可转化为相应的酸加成盐,例如含有氨基的化合物。
转化通过用至少一种化学计算量的适宜酸处理来完成,所述酸例如是盐酸、氢溴酸、硫酸、硝酸、磷酸等和有机酸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。具有代表性地,将游离碱溶解在惰性有机溶剂如乙醚、乙酸乙酯、氯仿、乙醇或甲醇等中,将酸加到类似溶剂中。温度保持在0℃至50℃之间。所得盐自发沉淀或者可用弱极性溶剂从溶液中析出。
式IA或IB化合物的酸加成盐可通过使用至少化学计算当量的适宜碱如氢氧化钠或氢氧化钾、碳酸钾、碳酸氢钠、氨等处理而转化为相应的游离碱。
式IA和IB化合物及其可药用酸加成的盐具有重要的药理性质。具体地说,已发现本发明的化合物可抑制γ-分泌酶。
按照下文提供的试验来研究本发明的化合物。
γ-分泌酶测定的描述
试验化合物的活性可在测量适宜底物通过γ-分泌酶活性进行蛋白酶剪切的测定中进行评价。这可以是细胞测定试验,例如其中γ-分泌酶的底物在其细胞质结构域与转录因子融合。细胞用该融合基因和报道基因如萤火虫荧光素酶(其表达通过转录因子而增强)转染。通过γ-分泌酶剪切融合底物将导致报道基因的表达,而该报道基因可在适宜测定中进行监测。γ-分泌酶活性还可在不含细胞的体外测定中进行确定,例如将含有γ-分泌酶复合物的细胞溶解产物与适宜的APP-衍生底物一起培养,该底物被剪切为Aβ肽。通过特异性ELISA测定法来确定所产生的肽的量。来源于神经元的细胞系分泌Aβ肽,其可通过特异性ELISA测定法来测量。用抑制γ-分泌酶的化合物处理导致所分泌的Aβ肽减少,由此提供一种抑制方法。
γ-分泌酶活性的体外测定使用HEK293膜部分作为γ-分泌酶和重组APP底物的来源。重组APP底物由与6xHistidin尾端融合以纯化的人APP的C-端100个氨基酸组成,所述氨基酸在可调节表达载体如pEt15中在大肠杆菌中表达。该重组蛋白符合截短的APP片段,该片段在β-分泌酶切割胞外域后产生并构成γ-分泌酶的底物。测定原理在Li YM等人的PNAS 97(11),6138-6143(2000)中有描述。Hek293细胞进行机械破坏,通过差速离心分离微粒体部分。将膜溶解在清洁剂(0.25%CHAPSO)中并用APP底物培养。通过所述特异性ELISA测定法(Brockhaus M等人,Neuroreport 9(7),1481-1486(1998))来检测由γ-分泌酶切割底物所产生的Aβ肽。
优选的化合物显示IC50<1.0μM。在下表中列出了γ-分泌酶抑制的某些数据:
实施例编号 | 体外IC<sub>50</sub>(μM) | 实施例编号 | 体外IC<sub>50</sub>(μM) |
1 | 0.083 | 128 | 0.052 |
2 | 0.021 | 130 | 0.043 |
12 | 0.05 | 133 | 0.04 |
13 | 0.018 | 134 | 0.03 |
14 | 0.004 | 141 | 0.1 |
16 | 0.25 | 151 | 0.09 |
21 | 0.70 | 152 | 0.08 |
102 | 0.92 | 157 | 0.09 |
103 | 0.72 | 162 | 0.1 |
107 | 0.027 | 165 | 0.045 |
110 | 0.04 | 167 | 0.70 |
113 | 0.003 | 169 | 0.66 |
114 | 0.087 | 171 | 0.11 |
115 | 0.008 | 173 | 0.05 |
116 | 0.011 | 175 | 0.31 |
117 | 0.041 | 176 | 0.1 |
118 | 0.019 | 179 | 0.2 |
123 | 0.015 | 183 | 0.09 |
125 | 0.064 |
式IA或IB化合物及式IA或IB化合物的可药用盐可用作药物,例如以药物制剂的形式。药物制剂可经口服施用,例如以片剂、包衣片剂、锭剂、硬和软明胶胶囊、溶液、乳剂或悬浮液的形式施用。然而,还可经直肠(例如以栓剂形式)或胃肠道外(例如以注射液形式)进行施用。
式IA或IB化合物可用用于生产药物制剂的惰性无机或有机载体进行加工。可使用乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等作为例如用于片剂、包衣片剂、锭剂和硬明胶胶囊的载体。适于软明胶胶囊的载体例如是植物油、蜡、脂肪、半固态及液态多元醇等。然而,当为软明胶胶囊时,根据活性物质的性质,通常不需要载体。适于生产溶液和糖浆剂的载体例如是水、多元醇、甘油或植物油等。适于栓剂的载体例如是天然或硬化油、蜡、脂肪、半液态或液态多元醇等。
此外,药物制剂还可含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可含有其它在治疗上有价值的物质。
与它们的生产方法一样,含有式IA和IB化合物或其可药用盐以及治疗惰性载体的药物同样是本发明的主题,所述方法包括使一种或多种式IA和IB化合物和/或其可药用的酸加成盐,以及如果需要的话,和一种或多种其它在治疗上有价值的物质与一种或多种治疗惰性载体一起制成盖仑给药的形式。
根据本发明,式IA和IB化合物及其可药用盐可用于控制或预防基于γ-分泌酶抑制的疾病,如阿尔茨海默氏病。
剂量可在宽限制内改变,并且当然必须根据每个具体病例中的个体需要进行调整。成人口服施用的剂量为约0.01mg至约1000mg/天的通式I化合物或其相应量的可药用盐。日剂量可作为单剂量或以分次剂量施用,另外,当指明剂量时,同样可超出该上限。
片剂配制(湿法制粒)
项目 组分 mg/片
5mg 25mg 100mg 500mg
1. 式IA或IB化合物 5 25 100 500
2. 无水乳糖DTG 125 105 30 150
3. Sta-Rx1500 6 6 6 30
4. 微晶纤维素 30 30 30 150
5. 硬脂酸镁 1 1 1 1
总计 167 167 167 831
生产方法
1.将第1、2、3和4项混合并用纯水制粒。
2.于50℃干燥颗粒。
3.将颗粒过适宜的研磨设备。
4.加入第5项并混合3分钟;用适宜压片机压片。
胶囊剂的配制
项目 组分 mg/粒胶囊
5mg 25mg 100mg 500mg
1. 式IA或IB化合物 5 25 100 500
2. 含水乳糖 159 123 148 ---
3. 玉米淀粉 25 35 40 70
4. 滑石粉 10 15 10 25
5. 硬脂酸镁 1 2 2 5
总计 200 200 300 600
生产方法
1.在适宜混合器中将第1、2和3项混合30分钟。
2.加入第4和5项并混合3分钟。
3.填充入适宜胶囊。
实施例1
a)2-甲基-丙二酸单乙酯
向6.44g(115mmol)氢氧化钾的200ml乙醇溶液中加入20.0g甲基-丙二酸二乙酯(115mmol)并将混合物回流4小时。冷却后,在旋转蒸发仪上浓缩反应混合物,加入50ml水并用乙醚萃取混合物(两次50ml)。水溶液用4M盐酸酸化并用乙酸乙酯萃取(三次50ml)。将所合并的有机层干燥(MgSO4),减压浓缩,未经进一步纯化即可使用。
MS m/e(%):101.1(M-EtO,100),147.1(M+H+,8)
b)N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸乙酯
向2.92g(20mmol)甲基-丙二酸单乙酯的100ml四氢呋喃溶液中加入2.86g(20mmol)3,5-二氟苄胺、3.83g(20mmol)N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐、2.70g(20mmol)1-羟基苯并三唑水合物和2.58g(20mmol)N,N-二异丙基-乙胺。将混合物在室温下搅拌18小时。真空浓缩后,加入0.5N HCl(50ml)并用二氯甲烷萃取混合物(三次50ml)。所合并的有机层用0.5N NaHCO3水溶液萃取,干燥(MgSO4)并在旋转蒸发仪上蒸发。残余物通过快速色谱法纯化(己烷/乙酸乙酯=3:1),得到4.29g(79%)标题化合物,为白色结晶固体。
MS m/e(%):272.2(M+H+,100)
c)N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸
向4.0g(14.75mmol)N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸乙酯的300ml乙醇溶液中加入15ml水和1.41g(59mmol)氢氧化锂并将混合物回流5小时。真空浓缩后,加入水(50ml)并用二氯甲烷萃取混合物(三次30ml)。水相用8N盐酸酸化并用二氯甲烷萃取(四次30ml)。将第二次萃取的所合并的有机层干燥(MgSO4)并真空蒸发,得到橙色油状物。将混合物溶解在少量乙酸乙酯和己烷中并放置过夜。经过滤收集所得白色晶体,得到11.4g(74.8%)标题化合物。
MS m/e(%):142.1(C6H3F2-CH=NH2 +,100),243.1(M+H+,16)
向0.073g(0.3mmol)N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸的5ml四氢呋喃溶液中加入0.080g(0.3mmol)(3RS)-3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮、0.058g(0.3mmol)N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐、0.040g(0.3mmol)1-羟基苯并三唑水合物和0.039g(0.3mmol)N,N-二异丙基-乙胺。将混合物在室温下搅拌18小时。真空浓缩后,加入0.5N HCl(5ml)并用二氯甲烷萃取混合物(三次5ml)。所合并的有机层用0.5N NaHCO3水溶液萃取,干燥(MgSO4)并在旋转蒸发仪上蒸发。残余物通过快速色谱法纯化(己烷/乙酸乙酯=3:1),得到0.099g(67%)标题化合物的非对映异构体混合物,为白色固体。
MS m/e(%):491.2(M+H+,100)
实施例2
按照实施例1描述的方法,用2-氟-2-甲基-丙二酸二乙酯代替步骤a)中的甲基-丙二酸二乙酯,得到收率类似的标题化合物。
MS m/e(%):509.3(M+H+,100)
实施例3
按照实施例1描述的方法,用2,2-二甲基-丙二酸二乙酯代替步骤a)中的甲基-丙二酸二乙酯,得到收率类似的标题化合物。
MS m/e(%):505.2(M+H+,100)
实施例4
按照实施例1描述的方法,用丙二酸二乙酯代替步骤a)中的甲基-丙二酸二乙酯,得到收率类似的标题化合物。
MS m/e(%):477.2(M+H+,100)
实施例5
按照实施例1描述的方法,用2-氟-2-甲基-丙二酸二乙酯代替步骤a)中的甲基-丙二酸二乙酯并用(3RS)-3-氨基-1-苯基-6,7-二氢-3H-[1,4]二氮杂并[6,7,1-hi]吲哚-4-酮代替步骤d)中的(3RS)-3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮,得到收率类似的标题化合物。
MS m/e(%):521.1(M+H+,100)
实施例6
N-(3,5-二氟-苄基)-2-甲基-N′-{(S)-苯基-[(4-苯基-吗啉-2-基甲基)-氨基甲酰基]-甲基}-丙二酰胺
按照实施例1描述的方法,用(2S)-2-氨基-2-苯基-N-((2RS)-4-苯基-吗啉-2-基甲基)-乙酰胺代替步骤d)中的(3RS)-3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮,得到收率类似的标题化合物。
MS m/e(%):551.2(M+H+,100)
实施例7
(2S)-2-[2-(RS)-(3,5-二氟-苄基氨基甲酰基)-丙酰基氨基]-苯基-乙酸叔丁酯
MS m/e(%):377.3(M+H+,100)
实施例8
(2RS)-N-[(1S)-1-(环己基-甲基-氨基甲酰基)-1-苯基-甲基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例1描述的方法,用(2S)-2-氨基-N-环己基-N-甲基-2-苯基-乙酰胺代替步骤d)中的(3RS)-3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮,得到收率类似的标题化合物。
MS m/e(%):472.3(M+H+,100)
实施例9
(2S)-2-[(2RS)-2-(3,5-二氟-苄基氨基甲酰基)-丙酰基氨基]-3-苯基-丙酸叔丁酯
MS m/e(%):391.2(M+H+,100)
实施例10
(2S)-2-[(2RS)-2-(3,5-二氟-苄基氨基甲酰基)-2-氟-丙酰基氨基]-2-苯基-乙酸叔丁酯
按照实施例1描述的方法,用2-氟-2-甲基-丙二酸二乙酯代替步骤a)中的甲基-丙二酸二乙酯并用(S)-苯基甘氨酸叔丁酯代替步骤d)中的(3RS)-3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮,得到收率类似的标题化合物。
MS m/e(%):473.1(M+Na+,100),451.0(M+H+,29)
实施例11
N-(3,5-二氟-苄基)-2-氟-2-甲基-N′-(2-氧代-1,2,3,4-四氢-喹啉-3-基)-丙二酰胺
按照实施例1描述的方法,用2-氟-2-甲基-丙二酸二乙酯代替步骤a)中的甲基-丙二酸二乙酯并用(RS)-3-氨基-3,4-二氢-1H-喹啉-2-酮代替步骤d)中的(3RS)-3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮,得到收率类似的标题化合物。
MS m/e(%):406.4(M+H+,100)
实施例12
向0.94g(3.38mmol)(S)-(2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-氨基甲酸叔丁酯溶于20ml四氢呋喃中的-78℃溶液中加入3.4ml双(三甲基甲硅烷基)氨基化锂(1N四氢呋喃溶液)。将反应混合物-78℃下搅拌30分钟并放置到室温。缓慢加入甲基碘并继续搅拌2小时。反应混合物用乙酸乙酯稀释,用饱和NaHSO4溶液洗涤并分离。水相用乙酸乙酯萃取两次(2×50ml)。所合并的有机层用水(2×100ml)、盐水(1×100ml)洗涤,用MgSO4干燥,过滤并蒸发。残余物通过色谱法纯化(庚烷/乙酸乙酯=7:3),得到0.855g(87%)产物,为淡黄色固体。
MS m/e(%):292.2(M+H+,100)
向0.087g(1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-氨基甲酸叔丁酯的1ml二甲基甲酰胺溶液中加入0.138g碳酸钾和0.062g苄基溴。反应混合物于室温振摇16小时。真空蒸发溶剂并将残余物溶解在乙酸乙酯中,用水洗涤。有机层用MgSO4干燥,过滤并蒸发。残余物通过色谱法纯化(庚烷/乙酸乙酯=2:1),得到0.10g(87%)淡黄色泡沫产物。
MS m/e(%):382.3(M+H+,100)
向0.086g(5-苄基-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-氨基甲酸叔丁酯的1ml二氯甲烷溶液中加入1ml三氟乙酸。将反应混合物在室温下搅拌2-3小时,同时通过LC-MS监测反应进程。反应结束后,蒸发溶剂和过量的三氟乙酸并将残余物在高真空下干燥1小时。将所得泡沫物溶解在1ml四氢呋喃中,并在其中加入0.060g N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸、0.043g N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐、0.030g 1-羟基苯并三唑水合物和0.087g N,N-二异丙基-乙胺。在室温下搅拌混合物18小时后,加入0.5N HCl(1ml)并用二氯甲烷(2ml)萃取混合物,有机层用0.5N NaHCO3水溶液萃取,干燥(MgSO4)并在旋转蒸发仪上蒸发。残余物用庚烷/EtOAc=4:1结晶,得到0.057g(50%)标题化合物的差向异构体混合物,为白色固体。
MS m/e(%):507.3(M+H+,100)
实施例13
向0.087g(1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-氨基甲酸叔丁酯的1ml二氯甲烷溶液中加入0.064g苯磺酰氯和0.052g吡啶。反应混合物在室温下搅拌16小时。通过加入1M HCl(1ml)终止反应并用二氯甲烷萃取。有机层用饱和NaHCO3洗涤,干燥(MgSO4)并在旋转蒸发仪上蒸发,得到0.113g(95%)淡黄色泡沫产物。
MS m/e(%):432.3(M+H+,100)
按照实施例12c)描述的方法,用(5-苯磺酰基-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-氨基甲酸叔丁酯代替(5-苄基-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-氨基甲酸叔-丁基酯,得到收率类似的标题化合物。
MS m/e(%):557.2(M+H+,100)
实施例14
向0.087g(1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-氨基甲酸叔丁酯的1ml二氯甲烷溶液中加入0.051g苯甲酰氯和0.061g三乙胺。反应混合物在室温下搅拌16小时。通过加入1M HCl(1ml)终止反应并用二氯甲烷萃取。有机层用饱和NaHCO3洗涤,干燥(MgSO4)并在旋转蒸发仪上蒸发,得到0.125g(97%)淡黄色泡沫产物。
MS m/e(%):396.3(M+H+,100)
按照实施例12c)描述的方法,用(5-苯磺酰基-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-氨基甲酸叔丁酯代替(5-苄基-1-甲基-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-氨基甲酸叔-丁基酯,得到收率类似的标题化合物。
MS m/e(%):521.3(M+H+,100)
实施例15
N-(7-氯-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例1描述的方法,用(3RS)-3-氨基-1,3-二氢-7-氯-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮代替步骤d)中的(3RS)-3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮,得到收率类似的标题化合物。
MS m/e(%):525.3(M+H+,100)
实施例16
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
a)[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-氨基
甲酸叔丁酯
将叔丁氧羰基-L-色氨酸(3.00g,9.9mmol)和1,2,3,4-四氢异喹啉(1.31g,9.9mmol)悬浮在THF(20ml)。在0℃下,加入羟基苯并三唑(1.33g,9.9mmol)、二异丙基乙胺(1.27g,9.9mmol)和EDC(N-3-二甲基氨基丙基-N′-乙基碳二亚胺盐酸盐,1.89g,9.9mmol)。室温下将反应混合物搅拌过夜。蒸发溶剂,残余物溶解在乙酸乙酯中,用水洗涤并干燥(Na2SO4)。蒸发溶剂后,经色谱法纯化残余物(硅胶,MeOH,CH2Cl2),得到标题化合物,MS:m/e=420.5(M+H+),(2.90g,70%)。
b)2-氨基-1-(3,4-二氢-1H-异喹啉-2-基)-3-(1H-吲哚-3-基)-丙-1-酮
将[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-氨基甲酸叔丁酯(2.90g,6.91mmol)溶解在CH2Cl2(10ml)中。加入三氟乙酸(10ml)并将混合物在室温下搅拌90分钟,直到HPLC分析表明起始材料完全消耗。蒸发溶剂,残余物溶解在乙酸乙酯中,洗涤(水)并干燥(Na2SO4)。溶剂蒸发后,经色谱法纯化残余物(硅胶,MeOH,CH2Cl2)得到标题化合物,MS:m/e=320.4(M+H+),(1.73g,69%)。
c)N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲
基)-2-氧代-乙基]-2-甲基-丙二酰胺
将2-氨基-1-(3,4-二氢-1H-异喹啉-2-基)-3-(1H-吲哚-3-基)-丙-1-酮(57mg,0.18mmol)置于一次性聚丙烯管并溶解在DMF(1ml)中。加入TBTU(O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓-四氟硼酸盐,65mg,0.2mmol)和N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(49mg,0.2mmol),并将混合物于室温振摇过夜。经自动制备型HPLC(YMC CombiPrep C18柱50×20mm,溶剂梯度为6分钟内在0.1%TFA(水溶液)中的5-95%CH3CN,λ=230nm,流速40ml/min)从反应混合物中分离出标题化合物,MS:m/e=545.3(M+H+)。
实施例17
N-[1-苄基-2-(3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由叔丁氧羰基-L-苯丙氨酸制备标题化合物,MS:m/e=506.3(M+H+)。
实施例18
N-[苄氧基甲基-2-(3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由N-(叔丁氧羰基)-O-苄基-L-丝氨酸制备标题化合物,MS:m/e=536.4(M+H+)。
实施例19
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-2-氧代-1-(S)苯基-乙基]-2-甲基-丙二酰胺
按照实施例16类似的方法,由N-α-(叔丁氧羰基)-L-苯基甘氨酸制备标题化合物,MS:m/e=492.3(M+H+)。
实施例20
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-2-氧代-1-(R)-苯基-乙基]-2-甲基-丙二酰胺
按照实施例16类似的方法,由N-α-(叔丁氧羰基)-D-苯基甘氨酸制备标题化合物,MS:m/e=492.3(M+H+)。
实施例21
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-羟基甲基-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例16类似的方法,由叔丁氧羰基-L-丝氨酸制备标题化合物,MS:m/e=446.3(M+H+)。
实施例22
N-[1-(4-氯-苄基)-2-(3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由N-α-(叔丁氧羰基)-对-氯-L-苯丙氨酸制备标题化合物,MS:m/e=540.4(M+)。
实施例23
N-[1-苯并[b]噻吩-3-基甲基-2-(3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由N-α-(叔丁氧羰基)-L-苯并噻吩基丙氨酸制备标题化合物,MS:m/e=562.4(M+H+)。
实施例24
N-[1-(3,4-二氯-苄基)-2-(3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由N-α-(叔丁氧羰基)-间,对-二氯-L-苯丙氨酸制备标题化合物,MS:m/e=574.3(M+)。
实施例25
N-[1-环己基甲基-2-(3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由N-α-(叔丁氧羰基)-L-环己基丙氨酸制备标题化合物,MS:m/e=511.6(M+H+)。
实施例26
N-(3,5-二氟-苄基)-N′-[1-(3,4-二氢-1H-异喹啉-2-羰基)-3-甲硫基-丙基]-2-甲基-丙二酰胺
按照实施例16类似的方法,由叔丁氧羰基-L-蛋氨酸制备标题化合物,MS:m/e=490.4(M+H+)。
实施例27
N-(3,5-二氟-苄基)-N′-[1-(3,4-二氢-1H-异喹啉-2-羰基)-戊基]-2-甲基-丙二酰胺
按照实施例16类似的方法,由N-α-叔丁氧羰基-L-2-氨基己酸制备标题化合物,MS:m/e=472.3(M+H+)。
实施例28
N-(3,5-二氟-苄基)-N′-[1-(3,4-二氢-1H-异喹啉-2-羰基)-3,3-二甲基-丁基]-2-甲基-丙二酰胺
按照实施例16类似的方法,由叔丁氧羰基-L-新戊基甘氨酸制备标题化合物,MS:m/e=486.4(M+H+)。
实施例29
N-(3,5-二氟-苄基)-N′-[1-(3,4-二氢-1H-异喹啉-2-羰基)-丙基]-2-甲基-丙二酰胺
按照实施例16类似的方法,由叔丁氧羰基-L-2-氨基丁酸制备标题化合物,MS:m/e=444.4(M+H+)。
实施例30
N-[1-(2-氰基-苄基)-2-(3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由N-α-(叔丁氧羰基)-邻-氰基-L-苯丙氨酸制备标题化合物,MS:m/e=531.4(M+H+)。
实施例31
N-(3,5-二氟-苄基)-N′-[1-(3,4-二氢-1H-异喹啉-2-羰基)-2-甲基-丁基]-2-甲基-丙二酰胺
按照实施例16类似的方法,由叔丁氧羰基-L-异亮氨酸制备标题化合物,MS:m/e=472.4(M+H+)。
实施例32
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-(6-甲氧基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-2-甲基-丙二酰胺
a)2-[2-(3,5-二氟-苄基氨基甲酰基)-丙酰基氨基]-3-(1H-吲哚-3-基)-丙酸叔
丁酯
将N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(3.00g,12.3mmol)、L-色氨酸-叔丁酯盐酸盐(3.66g,12.3mmol)、TBTU(O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓-四氟硼酸盐,3.96g,12.3mmol)和三乙胺(3.74g,3.70mmol)溶解在DMF(15ml)中并在室温下搅拌5小时。反应混合物倾入水中,用乙酸乙酯萃取产物混合物。有机层干燥(Na2SO4)。溶剂蒸发后,经色谱法纯化残余物(硅胶,MeOH,CH2Cl2),得到标题化合物,MS:m/e=486.4(M+H+),(6.45g,定量)。
b)2-[2-(3,5-二氟-苄基氨基甲酰基)-丙酰基氨基]-3-(1H-吲哚-3-基)-丙酸
将2-[2-(3,5-二氟-苄基氨基甲酰基)-丙酰基氨基]-3-(1H-吲哚-3-基)-丙酸叔丁酯(5.99g,12.3mmol)溶解在二氯甲烷(15ml)中,并在0℃下加入三氟乙酸(15ml)。将混合物在室温下搅拌过夜,直到起始材料全部被耗尽(分析HPLC)。蒸去挥发性物质,残余物溶于乙酸乙酯并用水洗涤。干燥有机层(Na2SO4)。蒸发溶剂后,经色谱法纯化残余物(硅胶,MeOH,CH2Cl2),得到标题化合物,MS:m/e=429.4(M+H+),(3.5g,66%)。
c)N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-(6-甲氧基-3,4-二氢-1H-
异喹啉-2-基)-2-氧代-乙基]-2-甲基-丙二酰胺
将2-[2-(3,5-二氟-苄基氨基甲酰基)-丙酰基氨基]-3-(1H-吲哚-3-基)-丙酸(64mg,0.15mmol)置于一次性聚丙烯管中并溶解在DMF(1ml)中。加入TPTU(O-[2-氧代-1(2H)-吡啶基]-N,N,N′,N′-四甲基脲鎓-四氟硼酸盐,49mg,0.165mmol)和6-甲氧基-1,2,3,4-四氢-异喹啉(24mg,0.15mmol),并将混合物于室温振摇过夜。经自动制备型HPLC(YMC CombiPrep C18柱50×20mm,溶剂梯度为6分钟内在0.1%TFA(水溶液)中的5-95%CH3CN,λ=230nm,流速40ml/min)从反应混合物中分离出标题化合物,MS:m/e=575.3(M+H+)。
实施例33
N-{1-苄基-2-[1-(2,5-二甲基-2H-吡唑-3-基)-3,4-二氢-1H-异喹啉-2-基]-2-氧代-乙基}-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和(RS)-1-(2,5-二甲基-2H-吡唑-3-基)-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=600.3(M+H+)。
实施例34
N-[1-苄基-2-(5-苄氧基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和5-苄氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=612.3(M+H+)。
实施例35
N-[2-(8-氯-3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由8-氯-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=579.3(M+H+)。
实施例36
N-[1-苄基-2-(6-甲氧基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和6-甲氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=536.4(M+H+)。
实施例37
N-(3,5-二氟-苄基)-N′-[2-(7,8-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由7,8-二甲氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=605.3(M+H+)。
实施例38
N-[1-苄基-2-氧代-2-(1-吡嗪-2-基-3,4-二氢-1H-异喹啉-2-基)-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和(RS)-1-吡嗪-2-基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=584.4(M+H+)。
实施例39
N-[1-苄基-2-(4-甲基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和4-甲基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=520.3(M+H+)。
实施例40
N-(3,5-二氟-苄基)-N′-[2-(1,3-二氢-异吲哚-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由异二氢吲哚制备标题化合物,MS:m/e=531.3(M+H+)。
实施例41
N-(3,5-二氟-苄基)-N′-[2-(6,9-二氢-7H-[1,3]间二氧杂环戊烯并[4,5-h]异喹啉-8-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由6,7,8,9-四氢-[1,3]间二氧杂环戊烯并[4,5-h]异喹啉制备标题化合物,MS:m/e=589.5(M+H+)。
实施例42
N-[1-苄基-2-氧代-2-(1-吡啶-2-基-3,4-二氢-1H-异喹啉-2-基)-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和1,2,3,4-四氢-1-(2-吡啶基)异喹啉制备标题化合物,MS:m/e=583.4(M+H+)。
实施例43
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-(4-甲基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由4-甲基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=559.4(M+H+)。
实施例44
N-[2-(9-氮杂-三环[6.2.2.02,7]十二碳-2,4,6-三烯-9-基)-1-苄基-2-氧代-乙基]-N’-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和9-氮杂-三环[6.2.2.02,7]十二碳-2,4,6-三烯制备标题化合物,MS:m/e=532.4(M+H+)。
实施例45
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-氧代-2-(6,7,8-三甲氧基-3,4-二氢-1H-异喹啉-2-基)-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由6,7,8-三甲氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=635.4(M+H+)。
实施例46
N-{1-苄基-2-[7-(4-甲基-哌嗪-1-磺酰基)-3,4-二氢-1H-异喹啉-2-基]-2-氧代-乙基}-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和7-(4-甲基-哌嗪-1-磺酰基)-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=668.5(M+H+)。
实施例47
N-[1-苄基-2-氧代-2-(1,3,4,9-四氢-b-咔啉-2-基)-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和1,2,3,4-四氢-β-咔啉制备标题化合物,MS:m/e=545.3(M+H+)。
实施例48
N-[1-苄基-2-(5-氯-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和5-氯-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=540.4(M+)。
实施例49
N-(3,5-二氟-苄基)-N′-[2-(4,4-二氟-哌啶-1-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由4,4-二氟哌啶制备标题化合物,MS:m/e=533.4(M+H+)。
实施例50
N-[1-苄基-2-(7,8-二氢-5H-[1,3]间二氧杂环戊烯并[4,5-g]异喹啉-6-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和5,6,7,8-四氢-1,3-间二氧杂环戊烯并(4,5-G)异喹啉制备标题化合物,MS:m/e=550.3(M+H+)。
实施例51
N-[1-苄基-2-氧代-2-(1-嘧啶-5-基-3,4-二氢-1H-异喹啉-2-基)-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和1-嘧啶-5-基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=584.4(M+H+)。
实施例52
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-(3-甲基-哌啶-1-基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由3-甲基哌啶制备标题化合物,MS:m/e=511.4(M+H+)。
实施例53
N-[1-苄基-2-(6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和6,7-二甲氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=566.3(M+H+)。
实施例54
N-[1-苄基-2-(八氢-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和反式-十氢异喹啉制备标题化合物,MS:m/e=512.3(M+H+)。
实施例55
N-[1-苄基-2-(1,3-二氢-异吲哚-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和异二氢吲哚制备标题化合物,MS:m/e=492.4(M+H+)。
实施例56
N-(3,5-二氟-苄基)-N′-[2-(3,6-二氢-2H-吡啶-1-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由1,2,3,6-四氢吡啶制备标题化合物,MS:m/e=494.6(M+H+)。
实施例57
N-[1-苄基-2-(6,9-二氢-7H-[1,3]间二氧杂环戊烯并[4,5-h]异喹啉-8-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和6,7,8,9-四氢-[1,3]间二氧杂环戊烯并[4,5-h]异喹啉制备标题化合物,MS:m/e=550.3(M+H+)。
实施例58
N-[1-苄基-2-氧代-2-(6,7,8-三甲氧基-3,4-二氢-1H-异喹啉-2-基)-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和6,7,8-三甲氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=596.3(M+H+)。
实施例59
N-(1-苄基-2-氧代-2-哌啶-1-基-乙基)-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和哌啶制备标题化合物,MS:m/e=458.3(M+H+)。
实施例60
N-(3,5-二氟-苄基)-N′-[2-(4-氟-哌啶-1-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由4-氟哌啶制备标题化合物,MS:m/e=515.4(M+H+),。
实施例61
N-(3,5-二氟-苄基)-N′-[2-(6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由6,7-二甲氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=605.3(M+H+)。
实施例62
N-(3,5-二氟-苄基)-N′-[2-(2,5-二氢-吡咯-1-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由1-异丙基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=481.4(M+H+)。
实施例63
N-[1-苄基-2-(1-异丙基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和异丙基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=548.4(M+H+)。
实施例64
N-[1-苄基-2-(3,6-二氢-2H-吡啶-1-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和8-氯-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=456.4(M+H+)。
实施例65
N-[1-苄基-2-(8-氯-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和8-氯-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=540.4(M+H+)。
实施例66
N-[1-苄基-2-(1-氰基甲基-6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和1-氰基甲基-6,7-二甲氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=605.4(M+H+)。
实施例67
N-[1-苄基-2-(7-溴-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和7-溴-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=586.3(M+H+)。
实施例68
N-[2-(6,7-二乙氧基-3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-N-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由6,7-二乙氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=633.4(M+H+)。
实施例69N-[2-(4-氨基-1,3-二氢-异吲哚-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由2,3-二氢-1H-异吲哚-4-基胺制备标题化合物,MS:m/e=546.4(M+H+)。
实施例70
N-[2-(5-氯-3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由8-氯-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=579.3(M+)。
实施例71
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-氧代-2-吡咯烷-1-基-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由吡咯烷制备标题化合物,MS:m/e=483.3(M+H+)。
实施例72
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-(2-甲氧基甲基-吡咯烷-1-基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由2-甲氧基甲基-吡咯烷制备标题化合物,MS:m/e=527.3(M+H+)。
实施例73
N-[2-(7,8-二氯-3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由7,8-二氯-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=613.3(M+H+)。
实施例74
N-[1-(苄基-甲基-氨基甲酰基)-2-苯基-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和苄基-甲基-胺制备标题化合物,MS:m/e=494.4(M+H+)。
实施例75
N-[2-氮杂环庚-1-基-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由氮杂环庚烷制备标题化合物,MS:m/e=511.4(M+H+)。
实施例76
N-(3,5-二氟-苄基)-N′-[1-二甲基氨基甲酰基-2-(1H-吲哚-3-基)-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由二甲胺制备标题化合物,MS:m/e=457.5(M+H+)。
实施例77
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-(7-硝基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由7-硝基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=590.4(M+H+)。
实施例78
N-[1-苄基-2-(1-环丙基-6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和1-环丙基-6,7-二甲氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=606.5(M+H+)。
实施例79
N-[2-(7-氯-3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由7-氯-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=579.3(M+H+)。
实施例80
N-(1-苄基-2-氧代-2-吡咯烷-1-基-乙基)-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和吡咯烷制备标题化合物,MS:m/e=444.4(M+H+)。
实施例81
N-[1-苄基-2-(7,8-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和7,8-二甲氧基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=566.4(M+H+)。
实施例82
N-(3,5-二氟-苄基)-N′-[1-(呋喃-2-基甲基-甲基-氨基甲酰基)-2-(1H-吲哚-3-基)-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由呋喃-2-基甲基-甲基-胺制备标题化合物,MS:m/e=523.3(M+H+)。
实施例83
N-[2-(7-溴-3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由7-溴-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=625.3(M+H+)。
实施例84
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-(1-甲基-3,4-二氢-1H-异喹啉-2-基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由1-甲基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=559.4(M+H+)。
实施例85
N-(3,5-二氟-苄基)-N′-[2-(1-羟基-2,2a,4,5-四氢-1H-3-氮杂-苊-3-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由1,2,2a,3,4,5-六氢-3-氮杂-苊-1-醇制备标题化合物,MS:m/e=587.4(M+H+)。
实施例86
N-(3,5-二氟-苄基)-2-甲基-N′-[1-(甲基-丙-2-炔基-氨基甲酰基)-2-苯基-乙基]-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和甲基炔丙基胺制备标题化合物,MS:m/e=442.3(M+H+)。
实施例87
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-(2-甲氧基甲基-吡咯烷-1-基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由2-甲氧基甲基-吡咯烷制备标题化合物,MS:m/e=527.4(M+H+)。
实施例88
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-氧代-2-哌啶-1-基-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由哌啶制备标题化合物,MS:m/e=497.4(M+H+)。
实施例89
N-[1-苄基-2-(6-甲氧基-1,3,4,9-四氢-b-咔啉-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和8-甲氧基-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚制备标题化合物,MS:m/e=575.5(M+H+)。
实施例90
N-(3,5-二氟-苄基)-N′-[2-(4-羟基-3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由4-羟基-1,2,3,4-四氢-异喹啉制备标题化合物,MS:m/e=561.5(M+H+)。
实施例91
N-[1-苄基-2-(6-氟-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和6-氟-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚制备标题化合物,MS:m/e=563.4(M+H+)。
实施例92
N-(3,5-二氟-苄基)-N′-[1-(乙基-甲基-氨基甲酰基)-2-(1H-吲哚-3-基)-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由乙基甲基胺制备标题化合物,MS:m/e=471.3(M+H+)。
实施例93
N-(3,5-二氟-苄基)-N′-[1-(1H-吲哚-3-基甲基)-2-(2-甲基-哌啶-1-基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由2-甲基哌啶制备标题化合物,MS:m/e=511.5(M+H+)。
实施例94
N-(3,5-二氟-苄基)-N′-(1-{[2-(3,4-二甲氧基-苯基)-乙基]-甲基-氨基甲酰基}-2-苯基-乙基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和N-甲基高藜芦基胺制备标题化合物,MS:m/e=568.4(M+H+)。
实施例95
N-[2-氮杂环丁-1-基-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由氮杂环丁烷制备标题化合物,MS:m/e=469.3(M+H+)。
实施例96
N-(3,5-二氟-苄基)-N′-[1-([1,3]二氧戊环-2-基甲基-甲基-氨基甲酰基)-2-(1H-吲哚-3-基)-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由2-甲基氨基甲基-1,3-二氧戊环制备标题化合物,MS:m/e=529.4(M+H+)。
实施例97
N-(3,5-二氟-苄基)-N′-[2-(4-羟甲基-哌啶-1-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺
按照实施例32类似的方法,由4-羟甲基哌啶制备标题化合物,MS:m/e=527.3(M+H+)。
实施例98
N-[1-苄基-2-(8-氟-1,3,4,5-四氢-吡啶并[4,3-b]吲哚-2-基)-2-氧代-乙基]-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例32类似的方法,由L-苯丙氨酸叔丁酯盐酸盐和8-氟-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚制备标题化合物,MS:m/e=563.4(M+H+)。
实施例99
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-丙基-丙二酰胺
a)N-(3,5-二氟-苄基)-2-丙基-丙酰胺酸:类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1),由丙基-丙二酸二乙酯来制备。
b)N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲 基)-2-氧代-乙基]-2-丙基-丙二酰胺,MS:m/e=573.4(M+H+):类似于N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺(实施例16),由N-(3,5-二氟-苄基)-2-丙基-丙酰胺酸来制备。
实施例100
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-异丙基-丙二酰胺
a)N-(3,5-二氟-苄基)-2-异丙基-丙酰胺酸:类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1),由异丙基-丙二酸二乙酯来制备。
b)N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲 基)-2-氧代-乙基1-2-异丙基-丙二酰胺,MS:m/e=573.3(M+H+):类似于N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺(实施例16),由N-(3,5-二氟-苄基)-2-异丙基-丙酰胺酸来制备。
实施例101
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-乙基-丙二酰胺
a)N-(3,5-二氟-苄基)-2-乙基-丙酰胺酸:类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1),由二乙基乙基-丙二酸来制备。
b)N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲 基)-2-氧代-乙基]-2-乙基-丙二酰胺,MS:m/e=559.4(M+H+):类似于N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺(实施例16),由N-(3,5-二氟-苄基)-2-乙基-丙酰胺酸来制备。
实施例102
2-烯丙基-N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-丙二酰胺
a)N-(3,5-二氟-苄基)-2-烯丙基-丙酰胺酸:类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1),由烯丙基-丙二酸二乙酯来制备。
b)N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲 基)-2-氧代-乙基]-2-烯丙基-丙二酰胺,MS:m/e=571.4(M+H+):类似于N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺(实施例16),由N-(3,5-二氟-苄基)-2-烯丙基-丙酰胺酸来制备。
实施例103
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-氟-2-甲基-丙二酰胺
a)N-(3,5-二氟-苄基)-2-氟-2-甲基-丙酰胺酸:类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1),由2-氟-2-甲基-丙二酸二乙酯来制备。
b)N-(3.5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲 基)-2-氧代-乙基]-2-氟-2-甲基-丙二酰胺,MS:m/e=563.4(M+H+):类似于N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺(实施例16),由N-(3,5-二氟-苄基)-2-氟-2-甲基-丙酰胺酸。
实施例104
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-丙二酰胺
a)N-(3,5-二氟-苄基)-丙酰胺酸:类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1),由丙二酸二乙酯来制备。
b)N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲 基)-2-氧代-乙基]-丙二酰胺,MS:m/e=531.3(M+H+):类似于N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺(实施例16),由N-(3,5-二氟-苄基)-丙酰胺酸来制备。
实施例105
N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2,2-二甲基-丙二酰胺
a)N-(3,5-二氟-苄基)-2,2-二甲基-丙酰胺酸:类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1),由2,2-二甲基-丙二酸二乙酯来制备。
b)N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲 基)-2-氧代-乙基]-2,2-二甲基-丙二酰胺,MS:m/e=559.3(M+H+):类似于N-(3,5-二氟-苄基)-N′-[2-(3,4-二氢-1H-异喹啉-2-基)-1-(1H-吲哚-3-基甲基)-2-氧代-乙基]-2-甲基-丙二酰胺(实施例16),由N-(3,5-二氟-苄基)-2,2-二甲基-丙酰胺酸来制备。
实施例106
N-(7-氯-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
实施例107
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和N-(3,5-二氟-苄基)-2-丙基-丙酰胺酸制备标题化合物,MS:m/e=519.3(M+H+)。
实施例108
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和N-(3,5-二氟-苄基)-2-叔丁基-丙酰胺酸制备标题化合物,MS:m/e=533.3(M+H+)。
实施例109
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和N-(3,5-二氟-苄基)-2-异丙基-丙酰胺酸制备标题化合物,MS:m/e=519.3(M+H+)。
实施例110
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和N-(3,5-二氟-苄基)-2-乙基-丙酰胺酸制备标题化合物,MS:m/e=505.3(M+H+)。
实施例111
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和N-(3,5-二氟-苄基)-2-氟-丙酰胺酸制备标题化合物,MS:m/e=495.3(M+H+)。
实施例112
实施例113
按照实施例16类似的方法,由7-氨基-5-甲基-5H,7H-二苯并[b,d]氮杂-6-酮和N-(3,5-二氟-苄基)-2-氟-2-甲基-丙酰胺酸制备标题化合物,MS:m/e=482.3(M+H+)。
实施例114
实施例115
实施例116
按照实施例16类似的方法,由7-氨基-5-甲基-5H,7H-二苯并[b,d]氮杂-6-酮和N-(3,5-二氟-苄基)-2-氟-丙酰胺酸制备标题化合物,MS:m/e=468.2(M+H+)。
实施例117
N-(3,5-二氟-苄基)-2,2-二甲基-N′-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-丙二酰胺
实施例118
实施例119
2-苄基-N-(3,5-二氟-苄基)-N′-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-丙二酰胺
实施例120
按照实施例16类似的方法,由7-氨基-5-甲基-5H,7H-二苯并[b,d]氮杂-6-酮和N-(3,5-二氟-苄基)-2-叔丁基-丙酰胺酸制备标题化合物,MS:m/e=506.3(M+Ht)。
实施例121
实施例122
a)N-(4-甲氧基-苄基)-2-甲基-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例123
a)N-苄基-2-甲基-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例124
a)N-(3,4-二甲氧基-苄基)-2-甲基-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例125
a)N-(4-氟-苄基)-2-甲基-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
按照实施例16类似的方法,由7-氨基-5-甲基-5H,7H-二苯并[b,d]氮杂-6-酮和N-(4-氟-苄基)-2-甲基-丙酰胺酸制备标题化合物,MS:m/e=446.2(M+H+)。
实施例126
a)2-甲基-N-(3-甲基-苄基)-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例127
a)2-甲基-N-(4-甲基-苄基)-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例128
a)2-甲基-N-(4-氯-苄基)-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例129
a)2-甲基-N-(3,5-二氯-苄基)-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例130
a)2-甲基-N-(3-氟-苄基)-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
b)N-(3-氟-苄基)-2-甲基-N′-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂
-7-基)-丙二酰胺
按照实施例16类似的方法,由7-氨基-5-甲基-5H,7H-二苯并[b,d]氮杂-6-酮和2-甲基-N-(3-氟-苄基)-丙酰胺酸制备标题化合物,MS:m/e=446.2(M+H+)。
实施例131
a)2-甲基-N-(3,5-二甲氧基-苄基)-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例132
2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-N′-(3-三氟甲基-苄基)-丙二酰胺
a)2-甲基-N-(3-三氟甲基-苄基)-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例133
a)2-甲基-N-(2,5-二氟-苄基)-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
b)N-(2,5-二氟-苄基)-2-甲基-N′-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮
杂
-7-基)-丙二酰胺
实施例134
a)2-甲基-N-(2,3,5-三氟-苄基)-丙酰胺酸
类似于N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(实施例1)制备标题化合物。
实施例135
N-(4-甲氧基-苄基)-2-甲基-N′-(1-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-丙二酰胺
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(4-甲氧基-苄基)-丙酰胺酸制备标题化合物,MS:m/e=485.4(M+H+)。
实施例136
N-苄基-2-甲基-N′-(1-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-丙二酰胺
实施例137
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(3,4-二甲氧基-苄基)-丙酰胺酸制备标题化合物,MS:m/e=515.3(M+H+)。
实施例138
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(4-氟-苄基)-丙酰胺酸制备标题化合物,MS:m/e=473.2(M+H+)。
实施例139
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(4-甲基-苄基)-丙酰胺酸制备标题化合物,MS:m/e=468.2(M+H+)。
实施例140
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(3-甲基-苄基)-丙酰胺酸制备标题化合物,MS:m/e=468.2(M+H+)。
实施例141
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(4-氯-苄基)-丙酰胺酸制备标题化合物,MS:m/e=489.3(M+H+)。
实施例142
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(3,5-二氯-苄基)-丙酰胺酸制备标题化合物,MS:m/e=523.3(M+H+)。
实施例143
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(3-氟-苄基)-丙酰胺酸制备标题化合物,MS:m/e=473.2(M+H+)。
实施例144
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(3,5-二甲氧基-苄基)-丙酰胺酸制备标题化合物,MS:m/e=515.3(M+H+)。
实施例145
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(3-三氟甲基-苄基)-丙酰胺酸制备标题化合物,MS:m/e=523.4(M+H+)。
实施例146
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(2,5-二氟-苄基)-丙酰胺酸制备标题化合物,MS:m/e=491.3(M+H+)。
实施例147
按照实施例16类似的方法,由3-氨基-1,3-二氢-1-甲基-5-苯基-2H-1,4-苯并二氮杂-2-酮和2-甲基-N-(2,3,5-三氟-苄基)-丙酰胺酸制备标题化合物,MS:m/e=509.3(M+Ht)。
实施例148
N-{[(2-苄基-苯基)-甲基-氨基甲酰基]-甲基}-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由2-氨基-2′-苄基-N-甲基乙酰苯胺制备标题化合物,MS:m/e=480.3(M+H+)。
实施例149
N-{[(4-氯-2-苯硫基-苯基)-甲基-氨基甲酰基]-甲基}-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由2-氨基-4′-氯-N-甲基-2′-(苯硫基)乙酰苯胺制备标题化合物,MS:m/e=533.4(M+H+)。
实施例150
N-{[(2-苯甲酰基-4-氯-苯基)-甲基-氨基甲酰基]-甲基}-N′-(3,5-二氟-苄基)-2-甲基-丙二酰胺
按照实施例16类似的方法,由2-氨基-2′-苯甲酰基-4′-氯-N-甲基乙酰苯胺制备标题化合物,MS:m/e=528.4(M+H+)。
实施例151
向冷却(0℃)的2-甲基-丙二酸单叔丁酯(1.01g,5.79mmol)和7-氨基-5-甲基-5H,7H-二苯并[b,d]氮杂-6-酮(1.15g,4.83mmol)的THF(8ml)溶液中加入羟基苯并三唑(652mg,4.83mmol)、二异丙基乙胺(624mg,4.83mmol)和N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(925mg,4.83mmol),并将混合物在室温下搅拌过夜。蒸发溶剂,残余物溶解在乙酸乙酯中,用水洗涤并干燥(Na2SO4)。溶剂蒸发后丙二酰胺,MS经色谱法纯化残余物(硅胶,MeOH,CH2Cl2),得到标题化合物,MS:m/e=395.3(M+H+),(920mg,48%)。
将TFA(3ml)加入2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-丙酰胺酸叔丁酯(920mg,2.33mmol)的二氯甲烷(3ml)溶液中并将混合物在室温下搅拌过夜。然后将混合物溶解在另外的二氯甲烷中,用水洗涤并干燥(Na2SO4)。溶剂蒸发后,经色谱法纯化残余物(硅胶,MeOH,CH2Cl2),得到标题化合物,MS:m/e=339.3(M+H+),(580mg,73%)
将2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-丙酰胺酸(20mg,0.059mmol)和2-氟苄胺(7.4mg,0.059mmol)置于一次性聚丙烯管中并溶解在DMF(2ml)中。加入TPTU(2-(2-吡啶酮-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐,19mg,0.065mmol),并将混合物在室温下振摇过夜。经自动制备型HPLC(YMC CombiPrep C18柱50×20mm,溶剂梯度为6分钟内在0.1%TFA(水溶液)中的5-95%CH3CN,λ=230nm,流速40ml/min)从反应混合物中分离出标题化合物,MS:m/e=446.2(M+H+)。
实施例152
按照实施例151类似的方法,由2-氯苄胺制备标题化合物,MS:m/e=462.2(M+H+)。
实施例153
按照实施例151类似的方法,由2-甲基苄胺制备标题化合物,MS:m/e=442.3(M+H+)。
实施例154
按照实施例151类似的方法,2-甲氧基苄胺由制备标题化合物,MS:m/e=458.3(M+H+)。
实施例155
按照实施例151类似的方法,由2-三氟甲基苄胺制备标题化合物,MS:m/e=496.3(M+H+)。
实施例156
按照实施例151类似的方法,由3-甲氧基苄胺制备标题化合物,MS:m/e=458.3(M+H+)。
实施例157
按照实施例151类似的方法,由3-氯苄胺制备标题化合物,MS:m/e=462.2(M+H+)。
实施例158
按照实施例151类似的方法,由4-三氟苄胺制备标题化合物,MS:m/e=496.3(M+H+)。
实施例159
实施例160
在用Fmoc-酰胺连接剂p-[(R,S)-a-1-(9H-芴-9-基)甲氧基甲酰氨基-2,4-二甲氧基苄基]苯氧基乙酸官能化的二苯甲胺聚苯乙烯树脂上进行固相合成。官能化树脂(300mg,0.6mmol/g负荷)用20%哌啶/DMF(10ml,10分钟)处理,然后洗涤(DMF/异丙醇交替洗涤3次)。将(2S-顺式)-5-(9H-芴-9-基)甲氧羰基氨基-4-氧代-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-2-甲酸(127mg,0.27mmol)、O-(1,2-二氢-2-氧代吡啶基-1-基)-N,N,N′,N′-四甲基脲鎓四氟硼酸盐(TPTU)(80mg,0.41mmol)、二异丙基乙胺(140μl,1.22mmol)和DMF(5ml)加入树脂中。混合物振摇1小时(水合茚三酮试验:阴性),过滤树脂并如上洗涤。N-(3,5-二氟-苄基)-2-甲基-丙酰胺酸(131mg,0.54mmo1)、TPTU(160mg,0.54mmo1)、二异丙基乙胺(280μl,1.62mmol)和DMF(5ml)加入树脂并如上偶联。用90%TFA水溶液(5ml)从树脂上裂解产物1小时。滤液减压浓缩并通过制备型RP(C18)HPLC纯化。收集所需要的级分并冷冻干燥:30mg,MS:471.2(MH+(60%)),493.1(MNa+(100),426.3(MH+-CONH2);
实施例161
将(2S-顺式)-N-(2-氨基甲酰基-4-氧代-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-5-基)-N′-(3,5-二氟-苄基)-(2R,S)-甲基-丙二酰胺(18.5mg,0.04mmol)、甲氧羰基氨磺酰基-三乙基氢氧化铵(Burgess试剂)(19mg,0.08mmol)在THF(1.5ml)中的混合物在70℃和氩环境下振摇30小时。将反应混合物减压浓缩并加入乙酸乙酯。有机相用水洗涤,干燥(Na2SO4),过滤并减压浓缩。通过制备型RP(C18)HPLC纯化:10mg,MS:530.1(MH+(100%)),552.1(MNa+(30));
实施例162
(2S-顺式)-N-(3,5-二氟-苄基)-2-甲基-N′-{4-氧代-2-[(2-噻吩-2-基-乙酰氨基)-(2R,S)-甲基]-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-5-基}-丙二酰胺
将9-Fmoc-氨基呫吨-3-基氧基-甲基树脂(Sieber酰胺树脂;Calbiochem-Novabiochem AG)(5g,0.52mmol/g负荷)用20%哌啶/DMF(50ml,10分钟)处理,然后洗涤(DMF/异丙醇交替洗涤3次)。将(2S-顺式)-5-(9H-芴-9-基)甲氧羰基氨基-4-氧代-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-2-甲酸(1.83g,3.9mmol)、TPTU(1.2g,3.9mmol)、二异丙基乙胺(3ml,17.6mmol)和DMF(10ml)加入树脂中。偶联进行1小时(水合茚三酮试验:阴性),树脂过滤并如上洗涤。除去Fmoc基团,然后采用在12ml二氯甲烷中的t-Boc酸酐(5.7g,26mmol)和二异丙基乙胺(2.2.ml,13mmol)进行t-Boc基团胺保护。洗涤且干燥后的树脂在室温下用在15ml二氯甲烷中的三氟乙酸酐(1.8ml,13mmol)和吡啶(2.1ml,26mmol)处理16小时。收集滤液并洗涤树脂(CH2Cl2,2×10ml)。所合并的有机级分用5% NaHCO3洗涤,干燥(MgSO4),过滤并减压浓缩,得到油状粗品,通过快速色谱法(乙酸乙酯-正己烷1:3)纯化:0.71g;MS:328.3(MH+(20%));228.2(MH+-Boc(100))。
将(2S-顺式)-(2-氰基-4-氧代-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-5-基)-氨基甲酸叔丁酯(0.59g,1.80mmol)在80ml乙酸中经披钯炭(10%,0.22g)氢化1小时。过滤混合物(Decalite),冷冻干燥滤液:0.33g白色固体。将一部分该冷冻干燥物(0.16g,0.48mmol)溶解在8ml DMF中并在TPTU(0.43g,1.45mmol)、二异丙基乙胺(0.84ml,5mmol)存在下与噻吩-2-乙酸(0.21g,1.45mmol)偶联1小时。将反应混合物减压浓缩,残余物溶解在乙酸乙酯中并相继用1N NaHCO3、0.2N KHSO4和水洗涤,将有机相干燥(MgSO4),过滤并减压浓缩,通过快速色谱法(乙酸乙酯-正己烷3:1)纯化:白色泡沫物,125mg;MS:456.3(MH+(60%))。
c)(2S-顺式)-N-(3,5-二氟-苄基)-2-甲基-N′-{4-氧代-2-{(2-噻吩-2-基-乙酰氨 基)-(2R,S)-甲基}-1,2,4,5,6,7-六氢-氮杂 并[3,2,1-hi]吲哚-5-基}-丙二酰胺
将(2S-顺式)-{4-氧代-2-[(2-噻吩-2-基-乙酰氨基)-甲基]-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-5-基}-氨基甲酸叔丁酯在室温下用4M HCl/1,4-二噁烷(3ml)处理1小时,将反应混合物减压浓缩并从乙腈中另外浓缩两次。将盐酸盐(约20mg)溶解在1ml DMF中并将溶液pH调至8。加入在0.5mlDMF中的丙二酸衍生物(41mg,0.17mmol)、TPTU(50mg,0.17mmol)、二异丙基乙胺(87μl,0.51mmol),将反应混合物振摇1小时。反应混合物用乙酸酸化,浓缩至较小体积并直接通过制备型RP(C18)HPLC纯化:14.5mg,MS:581.1(MH+(100%));
实施例163
(2S-顺式)-N-(3,5-二氟-苄基)-N′-(2-{[2-(4-氟-苯基)-乙酰氨基]-甲基}-4-氧代-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-5-基)-(2R,S)-甲基-丙二酰胺
按照实施例162描述的方法,用4-氟苯乙酸代替噻吩-2-乙酸,得到收率类似的标题化合物:15.8mg,MS:593.2(MH+(100%));
实施例164
(2S-顺式)-N-(3,5-二氟-苄基)-2,2-二甲基-N′-{4-氧代-2-[(2-噻吩-2-基-乙酰氨基)-甲基]-l,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-5-基}-丙二酰胺
按照实施例162描述的方法,用丙二酸衍生物N-(3,5-二氟苄基)-2,2-二甲基-丙酰胺酸代替衍生物N-(3,5-二氟苄基)-2-甲基-丙酰胺酸,得到收率类似的标题化合物:15.0mg,MS:595.1(MH+(100%));
实施例165
(2S-顺式)-N-(3,5-二氟-苄基)-N′-(2-{[2-(4-氟-苯基)-乙酰氨基]-甲基}-4-氧代-1,2,4,5,6,7-六氢-氮杂并[3,2,1-hi]吲哚-5-基)-2,2-二甲基-丙二酰胺
按照实施例162描述的方法,用4-氟苯乙酸代替噻吩-2-乙酸并用丙二酸衍生物N-(3,5-二氟苄基)-2,2-二甲基-丙酰胺酸代替N-(3,5-二氟苄基)-2-甲基-丙酰胺酸,得到收率类似的标题化合物:5.4mg,MS:607.1(MH+(100%));
实施例166
向冷却(0℃)的2-甲基-丙二酸单叔丁酯(1.01g,5.79mmol)和7-氨基-5-甲基-5H,7H-二苯并[b,d]氮杂-6-酮(1.15g,4.83mmol)的THF(8ml)溶液中加入羟基苯并三唑(652mg,4.83mmol)、二异丙基乙胺(624mg,4.83mmol)和N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(925mg,4.83mmol),并将该混合物在室温下搅拌过夜.蒸发溶剂,残余物溶解在乙酸乙酯中,用水洗涤并干燥(Na2SO4)。溶剂蒸发后,经色谱法(硅胶,MeOH,CH2Cl2)纯化残余物,得到标题化合物,MS:m/e=395.3(M+H+),(920mg,48%)。
将TFA(3ml)加入2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-丙酰胺酸叔丁酯(920mg,2.33mmol)的二氯甲烷(3ml)溶液中并将该混合物在室温下搅拌过夜。然后将该混合物溶解在另外的二氯甲烷中,用水洗涤并干燥(Na2SO4)。溶剂蒸发后,经色谱法(硅胶,MeOH,CH2Cl2)纯化残余物,得到标题化合物,MS:m/e=339.3(M+H+),(580mg,73%)。
将2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-丙酰胺酸(20mg,0.059mmol)和苯胺(6mg,0.059mmol)置于一次性聚丙烯管中并溶解在DMF(2ml)中。加入TPTU(2-(2-吡啶酮-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐,19mg,0.065mmol),并将混合物在室温下振摇过夜。经自动制备型HPLC(YMC CombiPrep C18柱50×20mm,溶剂梯度为6分钟内在0.1%TFA(水溶液)中的5-95%CH3CN,λ=230nm,流速40ml/min)从反应混合物中分离出标题化合物,MS:m/e=414.2(M+H+)。
实施例167
2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-N′-苯乙基-丙二酰胺
按照实施例166类似的方法,由2-苯乙胺制备标题化合物,MS:m/e=442.3(M+H+)。
实施例168
N-[2-(4-氟-苯基)-乙基]-2-甲基-N′-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-丙二酰胺
按照实施例166类似的方法,由4-氟苯乙胺制备标题化合物,MS:m/e=460.3(M+Ht)。
实施例169
按照实施例166类似的方法,由4-氯苯乙胺制备标题化合物,MS:m/e=476.2(M+H+)。
实施例170
按照实施例166类似的方法,由3-氟苯乙胺制备标题化合物,MS:m/e=460.3(M+H+)。
实施例171
2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-N′-吡啶-3-基甲基-丙二酰胺
按照实施例166类似的方法,由3-氨基甲基吡啶制备标题化合物,MS:m/e=429.3(M+H+)。
实施例172
按照实施例166类似的方法,由2-氨基甲基吡啶制备标题化合物,MS:m/e=429.3(M+H+)。
实施例173
按照实施例166类似的方法,由2-氨基甲基呋喃制备标题化合物,MS:m/e=418.3(M+H+)。
实施例174
按照实施例166类似的方法,由4-氨基甲基吡啶制备标题化合物,MS:m/e=429.3(M+H+)。
实施例175
按照实施例166类似的方法,由5-甲基糠基胺制备标题化合物,MS:m/e=432.3(M+H+)。
实施例176
按照实施例166类似的方法,由3-氨基甲基苯并噻吩制备标题化合物,MS:m/e=484.3(M+H+)。
实施例177
按照实施例166类似的方法,由(R)-(+)-1-苯乙胺制备标题化合物,MS:m/e=442.3(M+H+)。
实施例178
2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-N′-(2-羟乙基)-丙二酰胺
按照实施例166类似的方法,由N-苄基乙醇胺制备标题化合物,MS:m/e=472.3(M+H+)。
实施例179
按照实施例166类似的方法,由N-甲基苄胺制备标题化合物,MS:m/e=442.3(M+H+)。
实施例180
2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-N′-苄基-N′-(2-氰基乙基)-丙二酰胺
按照实施例166类似的方法,由N-苄基-氨基乙腈制备标题化合物,MS:m/e=481.3(M+H+)。
实施例181
按照实施例166类似的方法,由1,2,3,4-四氢-萘-1-基-胺制备标题化合物,MS:m/e=468.3(M+H+)。
实施例182
按照实施例166类似的方法,由1-氨基二氢化茚制备标题化合物,MS:m/e=454.3(M+Ht)。
实施例183
按照实施例166类似的方法,由4,6-二氟-1-氨基二氢化茚制备标题化合物,MS:m/e=490.3(M+H+)。
实施例184
按照实施例166类似的方法,由2-氨基-1-二氢茚醇制备标题化合物,MS:m/e=470.4(M+H+)。
实施例185
按照实施例166类似的方法,由2-氨基二氢化茚制备标题化合物,MS:m/e=454.3(M+H+)。
实施例186
按照实施例166类似的方法,由C-(2,2-二氟-1-苯基-环丙基)-甲胺制备标题化合物,MS:m/e=504.3(M+H+)。
实施例187
按照实施例166类似的方法,由(RS)-2,2-二甲基-[1,3]二氧戊环-4-基甲胺制备标题化合物,MS:m/e=450.3(M-H+)。
实施例188
2-甲基-N-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-N′-(四氢-呋喃-2-基甲基)-丙二酰胺
按照实施例166类似的方法,由(RS)-四氢-呋喃-2-基甲胺制备标题化合物,MS:m/e=420.2(M-H+)。
Claims (18)
1.通式IA或IB的化合物或其可药用的酸加成盐
其中:
R1和R1′ 相同或不同,为氢、C1-6烷基、卤素、苄基或不包括C1链烯基在内的C1-6链烯基;
(R2)1,2,3 彼此独立地为氢、羟基、卤素、C1-6烷基、C1-6烷氧基或三氟甲基;
R3 -是未取代或被一个或两个选自卤素或氰基的取代基取代的苯基或苄基,或者是
-C1-6烷基,
-两个氢原子,
-(CH2)1,2-S-C1-6烷基,
-(CH2)1,2-C3-7环烷基,
-(CH2)1,2-OH,
-CH2OCH2-苯基,或者是
R4 -为C1-6烷氧基,
-单或二烷基氨基,
-N(CH3)(CH2)1,2-C≡CH,
-或者是未取代或被R5至R10取代的且可通过-N(CH3)(CH2)0,1,2与式IB中的-C(O)-基团连接的单-、双-或三-环基团,选自
其中,
R5为氢、卤素、C1-6烷基或-(CH2)1,2OH;
(R5)1,2彼此独立地为氢、卤素、C1-6烷基或-(CH2)1,2OH;
R6为氢、卤素或C1-6烷氧基;
R7为氢或-CH2OCH3;
R8为氢或卤素;
R9为氢、C1-6烷氧基、C1-6烷基或氨基;
(R9)1,2彼此独立地为氢、C1-6烷氧基、C1-6烷基或氨基;
(R10)1,2,3彼此独立地为氢、C1-6烷基、C1-6烷氧基、C3-7环烷基、卤素、羟基、=O、氨基、硝基、-CH2CN、-OCH2C6H5,或
其中,
X是-CH2-、-S(O)2或-C(O)-;
R11是氢或C1-6烷基;
R12是氢或卤素;
R14 是氢、C1-6烷基、-(CH2)2OH或-(CH2)2CN。
2.通式IA或IB的化合物或其可药用的酸加成盐,
或
其中:
R1和R1′ 相同或不同,为氢、C1-6烷基、卤素、苄基或不包括C1链烯基在内的C1-6链烯基;
(R2)1,2,3 彼此独立地为氢、卤素、C1-6烷基、C1-6烷氧基或三氟甲基;
R3 -是未取代或被一个或两个选自卤素或氰基的取代基取代的苯基或苄基,或者是
-C1-6烷基,
-两个氢原子,
-(CH2)1,2-S-C1-6烷基,
-(CH2)1,2-C3-7环烷基,
-(CH2)1,2-OH,
-CH2OCH2-苯基,或者是
R4 -为C1-6烷氧基,
-单或二烷基氨基,
-N(CH3)(CH2)1,2-C≡CH,
-或者是未取代或被R5至R10取代的且可通过-N(CH3)(CH2)0,1,2
与式IB中的-C(O)-基团连接的单-、双-或三-环基团,选自
其中,
R5为氢、卤素、C1-6烷基或-(CH2)1,2OH;
(R5)1,2彼此独立地为氢、卤素、C1-6烷基或-(CH2)1,2OH;
R6为氢、卤素或C1-6烷氧基;
R7为氢或-CH2OCH3;
R8为氢或卤素;
R9为氢、C1-6烷氧基、C1-6烷基或氨基;
(R9)1,2彼此独立地为氢、C1-6烷氧基、C1-6烷基或氨基;
(R10)1,2,3彼此独立地为氢、C1-6烷基、C1-6烷氧基、C3-7环烷基、卤素、羟基、=O、氨基、硝基、-CH2CN、-OCH2C6H5,或
可以是下列环状基团之一
其中,
X是-CH2、-S(O)2或-C(O)-;
R11是氢或C1-6烷基;
R12是氢或卤素;
3.权利要求2的化合物或其可药用的酸加成盐,其中所述化合物为式IA化合物。
5.权利要求4的化合物或其可药用的酸加成盐,其中该化合物为:
N-(3,5-二氟-苄基)-2-乙基-N′-(5-甲基-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂-7-基)-丙二酰胺,
9.权利要求8的化合物或其可药用的酸加成盐,其中该化合物为:
14.权利要求1或2的化合物或其可药用的酸加成盐,其中所述化合物为式IB化合物。
15.权利要求1或2的式IA或IB化合物或其可药用的酸加成盐,其中至少一个(R2)1,2,3为氟。
17.用于治疗阿尔茨海默氏病的药物,含有一种或多种权利要求1-15中任一项的化合物或其可药用的酸加成盐和可药用赋形剂。
18.权利要求1-15中任一项的化合物或其可药用的酸加成盐在制备用于治疗阿尔茨海默氏病的药物中的用途。
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EP03002190 | 2003-02-04 |
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EP1592684B1 (en) | 2008-07-30 |
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ATE402934T1 (de) | 2008-08-15 |
CO5580761A2 (es) | 2005-11-30 |
CN1745076A (zh) | 2006-03-08 |
HRP20050663A2 (en) | 2006-12-31 |
JP2006516556A (ja) | 2006-07-06 |
JP4662914B2 (ja) | 2011-03-30 |
AU2004210036A1 (en) | 2004-08-19 |
WO2004069826A1 (en) | 2004-08-19 |
IL169691A (en) | 2011-03-31 |
NZ541324A (en) | 2008-10-31 |
CA2514267A1 (en) | 2004-08-19 |
EP1592684A1 (en) | 2005-11-09 |
ES2311795T3 (es) | 2009-02-16 |
MXPA05008172A (es) | 2005-10-05 |
IL169691A0 (en) | 2007-07-04 |
RU2330849C2 (ru) | 2008-08-10 |
CL2004000174A1 (es) | 2005-01-14 |
KR100810810B1 (ko) | 2008-03-06 |
ZA200506212B (en) | 2006-05-31 |
US20040220222A1 (en) | 2004-11-04 |
RU2005127666A (ru) | 2006-04-27 |
AR042996A1 (es) | 2005-07-13 |
PL378405A1 (pl) | 2006-04-03 |
KR20050105452A (ko) | 2005-11-04 |
BRPI0407262A (pt) | 2006-01-31 |
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