CN1964970B - Iap的抑制剂 - Google Patents
Iap的抑制剂 Download PDFInfo
- Publication number
- CN1964970B CN1964970B CN2005800186137A CN200580018613A CN1964970B CN 1964970 B CN1964970 B CN 1964970B CN 2005800186137 A CN2005800186137 A CN 2005800186137A CN 200580018613 A CN200580018613 A CN 200580018613A CN 1964970 B CN1964970 B CN 1964970B
- Authority
- CN
- China
- Prior art keywords
- methylamino
- phenyl
- pyrrolidyl
- cyclohexyl
- propionic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000003112 inhibitor Substances 0.000 title description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 70
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 59
- -1 tetrazyl Chemical group 0.000 claims description 57
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 claims 18
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 7
- 150000003851 azoles Chemical class 0.000 claims 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 4
- VTDXVLNCQSBLMT-XZZVZQAVSA-N (2s)-n-[(1s)-1-cyclohexyl-2-oxo-2-[(2s)-2-(3-phenoxyphenyl)pyrrolidin-1-yl]ethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(OC=3C=CC=CC=3)C=CC=2)CCCCC1 VTDXVLNCQSBLMT-XZZVZQAVSA-N 0.000 claims 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- KMEYYKLNJDBCPU-FIKGOQFSSA-N (2s)-2-(methylamino)-n-[(2s)-1-oxo-1-[(2s)-2-(3-phenoxyphenyl)pyrrolidin-1-yl]propan-2-yl]propanamide Chemical compound CN[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C1=CC=CC(OC=2C=CC=CC=2)=C1 KMEYYKLNJDBCPU-FIKGOQFSSA-N 0.000 claims 1
- KVGQXXNSQRRKHI-RJWMVNQGSA-N (2s)-n-[(1s)-1-cyclohexyl-2-oxo-2-[(2s)-2-(2-phenoxyphenyl)pyrrolidin-1-yl]ethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C(=CC=CC=2)OC=2C=CC=CC=2)CCCCC1 KVGQXXNSQRRKHI-RJWMVNQGSA-N 0.000 claims 1
- XMLVJVXHBBMNCZ-XZZVZQAVSA-N (2s)-n-[(1s)-1-cyclohexyl-2-oxo-2-[(2s)-2-(4-phenoxyphenyl)pyrrolidin-1-yl]ethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=CC(OC=3C=CC=CC=3)=CC=2)CCCCC1 XMLVJVXHBBMNCZ-XZZVZQAVSA-N 0.000 claims 1
- LVMGRCRBRDPJCO-LQGLAIQGSA-N (2s)-n-[(1s)-1-cyclopentyl-2-oxo-2-[(2s)-2-(3-phenoxyphenyl)pyrrolidin-1-yl]ethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(OC=3C=CC=CC=3)C=CC=2)CCCC1 LVMGRCRBRDPJCO-LQGLAIQGSA-N 0.000 claims 1
- VOQNQDGSABNMPI-XZZVZQAVSA-N (2s)-n-[(1s)-2-[(2s)-2-(3-benzoylphenyl)pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(C=CC=2)C(=O)C=2C=CC=CC=2)CCCCC1 VOQNQDGSABNMPI-XZZVZQAVSA-N 0.000 claims 1
- ZPDHHIXSFRFHSN-HSQYWUDLSA-N (2s)-n-[(1s)-2-[(2s)-2-(4-benzoyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2SC=C(N=2)C(=O)C=2C=CC=CC=2)CCCCC1 ZPDHHIXSFRFHSN-HSQYWUDLSA-N 0.000 claims 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims 1
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- 125000000217 alkyl group Chemical group 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
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- 229910052760 oxygen Inorganic materials 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- 125000000753 cycloalkyl group Chemical group 0.000 description 28
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
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Classifications
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- 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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- 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
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Abstract
可抑制Smac蛋白与细胞凋亡蛋白抑制剂(IAP)结合的式(I)的新化合物。
Description
本发明涉及可抑制Smac蛋白与细胞凋亡蛋白抑制剂(IAP)结合的新化合物。本发明包括新化合物、新组合物、它们的使用方法及其生产方法,其中所述的化合物通常是在药物学上用作治疗剂,它的作用机理取决于对Smac/IAP相互作用的抑制,特别是用作用于治疗增殖性疾病、包括癌症的治疗剂。
发明背景
程序性细胞死亡在调节细胞数量以及从正常组织中消除受刺激或受损的细胞中起着重要的作用。事实上,大部分细胞类型中所固有的细胞凋亡信号传导机制网络为阻止人类癌症的形成和发展提供了一个重要的屏障。由于最常用的放射和化学疗法均依赖于激活细胞凋亡途径以杀死癌症细胞,因此能够逃避程序性细胞死亡的肿瘤细胞通常会对治疗产生抗药性。
细胞凋亡信号传导网络分为内在的(由死亡受体-配体相互作用所介导)和外在的(由细胞应激和线粒体通透化所介导)。两种途径最终在半胱天冬酶(Caspases)处会合。一旦被激活,半胱天冬酶就会裂解大量与细胞死亡相关的底物,造成细胞的破坏。
肿瘤细胞遗承了大量的策略以规避细胞凋亡。一种最近报道的分子机制涉及IAP(细胞凋亡抑制剂)蛋白家族成员的过度表达。IAP通过直接与半胱天冬酶相互作用并中和半胱天冬酶来阻止细胞凋亡。原型IAP-XIAP和cIAP-具有三种功能结构域,分别为称为BIR1、2和3结构域。BIR3结构域直接与半胱天冬酶9相互作用并抑制其结合和裂解其天然底物半胱天冬酶-3酶原的能力。
有报道指出,促凋亡线粒体蛋白Smac(也称为DIABLO)能够通过与BIR3表面上的蛋白结合袋(Smac结合位点)相结合来中和XIAP和/或cIAP,从而阻止XIAP和/或cIAP与半胱天冬酶9之间的相互作用。本发明涉及可与Smac结合袋相结合从而促进迅速分化的细胞发生细胞凋亡的治疗性分子。所述治疗性分子可用于治疗增殖性疾病,包括癌症。换句话说,Smac类似物可与IAP的BIR3结构域相结合并消除IAP对活化的半胱天冬酶9的抑制作用,从而使半胱天冬酶9可以诱导细胞凋亡。
发明概述
本发明涉及可抑制Smac蛋白与细胞凋亡蛋白抑制剂(IAP)结合的新化合物。本发明包括新化合物、新组合物、它们的使用方法及其生产方法,其中所述的化合物通常是在药物学上用作治疗剂,它的作用机理取决于对Smac/IAP相互作用的抑制,特别是用作用于治疗增殖性疾病、包括癌症的治疗剂。
发明详述
本发明涉及式(I)化合物或其可药用盐:
其中
R1是H;C1-C4烷基;C1-C4链烯基;C1-C4炔基或C3-C10环烷基,它们是未取代的或取代的;
R2是H;C1-C4烷基;C1-C4链烯基;C1-C4炔基或C3-C10环烷基,它们是未取代的或取代的;
R3是H;-CF3;-C2F5;C1-C4烷基;C1-C4链烯基;C1-C4炔基;-CH2-Z或R2和R3与氮一起形成het环;
Z是H;-OH;F;Cl;-CH3;-CF3;-CH2Cl;-CH2F或-CH2OH;
R4是C1-C16直链或支链烷基;C1-C16链烯基;C1-C16炔基;或-C3-C10环烷基;-(CH2)1-6-Z1;-(CH2)0-6-芳基;和-(CH2)0-6-het;其中烷基、环烷基和苯基是未取代的或取代的;
Z1是-N(R8)-C(O)-C1-C10烷基;-N(R8)-C(O)-(CH2)1-6-C3-C7环烷基;-N(R8)-C(O)-(CH2)0-6-苯基;-N(R8)-C(O)-(CH2)1-6-het;-C(O)-N(R9)(R10);-C(O)-O-C1-C10烷基;-C(O)-O-(CH2)1-6-C3-C7环烷基;-C(O)-O-(CH2)0-6-苯基;-C(O)-O-(CH2)1-6-het;-O-C(O)-C1-C10烷基;-O-C(O)-(CH2)1-6-C3-C7环烷基;-O-C(O)-(CH2)0-6-苯基;-O-C(O)-(CH2)1-6-het;其中烷基、环烷基和苯基是未取代的或取代的;
het是含有1-4个选自N、O和S的杂原子的5-7元的杂环或包括至少一个含有1、2或3个选自N、O和S的杂原子的5-7元的杂环的8-12元的稠环系,所述的杂环或稠环系是未取代的或者在碳或氮原子上被取代;R8是H;-CH3;-CF3;-CH2OH或-CH2Cl;
R9和R10彼此独立地是H;C1-C4烷基;C3-C7环烷基;-(CH2)1-6-C3-C7环烷基;-(CH2)0-6-苯基;其中烷基、环烷基和苯基是未取代的或取代的,或R9和R10与氮一起形成het;
R5是H;C1-C10-烷基;芳基;苯基;C3-C7环烷基;-(CH2)1-6-C3-C7环烷基;
-C1-C10烷基-芳基;-(CH2)0-6-C3-C7环烷基-(CH2)0-6-苯基;
-(CH2)0-4CH-((CH2)1-4-苯基)2;-(CH2)0-6-CH(苯基)2;-茚满基;-C(O)-C1-C10烷基;-C(O)-(CH2)1-6-C3-C7-环烷基;-C(O)-(CH2)0-6-苯基;-(CH2)0-6-C(O)-苯基;-(CH2)0-6-het;-C(O)-(CH2)1-6-het;或R5是氨基酸的残基,其中烷基、环烷基、苯基和芳基取代基是未取代的或取代的;
U如结构式II所示:
其中
n=0-5;
X是-CH或N;
Ra和Rb独立地是O、S或N原子或C0-8烷基,其中烷基链中的一个或多个碳原子可被选自O、S或N的杂原子所代替,并且其中烷基是未取代的或取代的;
Rd选自:
(a)-Re-Q-(Rf)p(Rg)q;或
(b)Ar1-D-Ar2;
Rc是H或Rc和Rd可一起形成环烷基或het;其中如果Rd和Rc形成环烷基或het,则R5在C或N原子处连接到所形成的环上;
p和q独立地是0或1;
Re是C1-8烷基或亚烷基,并且Re是未取代的或取代的;
Q是N、O、S、S(O)或S(O)2;
Ar1和Ar2是取代或未取代的芳基或het;
Rf和Rg彼此独立地是H;-C1-C10烷基;C1-C10烷基芳基;-OH;-O-C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-O-(CH2)0-6-芳基;苯基;芳基;苯基-苯基;-(CH2)1-6-het;-O-(CH2)1-6-het;-OR11;-C(O)-R11;-C(O)-N(R11)(R12);-N(R11)(R12);-S-R11;-S(O)-R11;-S(O)2-R11;-S(O)2-NR11R12;-NR11-S(O)2-R12;S-C1-C10烷基;芳基-C1-C4烷基;het-C1-C4-烷基,其中烷基、环烷基、het和芳基是未取代的或取代的;-SO2-C1-C2烷基;-SO2-C1-C2烷基苯基;-O-C1-C4烷基;或Rg和Rf形成选自het或芳基的环;
D是-CO-;-C(O)-C1-7亚烷基或亚芳基;-CF2-;-O-;-S(O)r,其中r是0-2;1,3-二氧杂环戊烷;或C1-7烷基-OH;其中烷基、亚烷基或亚芳基是未取代的或者被一个或多个卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基或-CF3所取代,或者D是-N(Rh),其中Rh是H;C1-7烷基(未取代的或取代的);芳基;-O(C1-7环烷基)(未取代的或取代的);C(O)-C1-C10烷基;C(O)-C0-C10烷基-芳基;C-O-C1-C10烷基;C-O-C0-C10烷基-芳基或SO2-C1-C10-烷基;SO2-(C0-C10-烷基芳基);
R6、R7、R’6和R’7彼此独立地是H;-C1-C10烷基;-C1-C10烷氧基;芳基
-C1-C10烷氧基;-OH;-O-C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-O-(CH2)0-6-芳基;苯基;-(CH2)1-6-het;-O-(CH2)1-6-het;-OR11;-C(O)-R11;
-C(O)-N(R11)(R12);-N(R11)(R12);-S-R11;-S(O)-R11;-S(O)2-R11;
-S(O)2-NR11R12;-NR11-S(O)2-R12;其中烷基、环烷基和芳基是未取代的或取代的;并且R6、R7、R’6和R’7可连接形成环系;
R11和R12独立地是H;C1-C10烷基;-(CH2)0-6-C3-C7环烷基;
-(CH2)0-6-(CH)0-1(芳基)1-2;-C(O)-C1-C10烷基;-C(O)-(CH2)1-6-C3-C7环烷基;
-C(O)-O-(CH2)0-6-芳基;-C(O)-(CH2)0-6-O-芴基;-C(O)-NH-(CH2)0-6-芳基;
-C(O)-(CH2)0-6-芳基;-C(O)-(CH2)1-6-het;-C(S)-C1-C10烷基;
-C(S)-(CH2)1-6-C3-C7环烷基;-C(S)-O-(CH2)0-6-芳基;-C(S)-(CH2)0-6-O-芴基;-C(S)-NH-(CH2)0-6-芳基;-C(S)-(CH2)0-6-芳基;-C(S)-(CH2)1-6-het;其中烷基、环烷基和芳基是未取代的或取代的;或R11和R12是有利于分子跨过细胞膜转运的取代基;或R11和R12与氮原子一起形成het;
其中R11和R12的烷基取代基可以是未取代的或者被一个或多个选自下列的取代基所取代:C1-C10烷基、卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基或-CF3;
R11和R12的取代的环烷基取代基被一个或多个选自下列的取代基所取代:
C1-C10链烯烃;C1-C6烷基;卤素;OH;-O-C1-C6烷基;-S-C1-C6烷基或-CF3;并且
R11和R12的取代的苯基或芳基被一个或多个选自下列的取代基所取代:卤素;羟基;C1-C4烷基;C1-C4烷氧基;硝基;-CN;-O-C(O)-C1-C4烷基和-C(O)-O-C1-C4-芳基。
本发明还涉及式I化合物在治疗增殖性疾病、尤其是依赖于Smac蛋白与细胞凋亡蛋白抑制剂(IAP)的结合的那些疾病中的用途,或其在生产用于治疗所述疾病的药物中的用途、使用式(I)化合物治疗所述疾病的方法、包含式(I)化合物的用于治疗所述疾病的药物制剂、用于治疗所述疾病的式(I)化合物。
上下文中所用的一般术语在本文中具有以下含义,除非另有说明:
“芳基”是含有6-14个碳原子的芳香族基团,其可以是稠合的或非稠合的,并且可以是未取代的或者被一个或多个、优选1或2个取代基所取代,其中取代基如以下所定义。优选的“芳基”是苯基、萘基或茚满基。
“Het”是指杂芳基和杂环以及含有芳香族和非芳香族杂环的稠环。“Het”是含有1-4个选自N、O和S的杂原子的5-7元的杂环或包括至少一个含有1、2或3个选自N、O和S的杂原子的5-7元的杂环的8-12元的稠环系。适当的het取代基包括未取代的和取代的吡咯烷基、四氢呋喃基、四氢硫代呋喃基、哌啶基、哌嗪基、四氢吡喃基、吗啉代、1,3-二氮杂环庚烷、1,4-二氮杂环庚烷、1,4-氧氮杂环庚烷、1,4-氧硫杂环庚烷、呋喃基、噻吩基、吡咯、吡唑、三唑、1,2,3-三唑、四唑基、噁二唑、噻吩,咪唑、吡咯烷、吡咯烷酮、噻唑、噁唑、吡啶、嘧啶、异噁唑基、吡嗪、喹啉、异喹啉、吡啶并吡嗪、吡咯并吡啶、呋喃并吡啶、吲哚、苯并呋喃、苯并硫代呋喃、苯并吲哚、苯并噁唑、吡咯并喹啉等。het取代基是未取代的或者在碳原子上被卤素、尤其是氟或氯、羟基、C1-C4烷基、诸如甲基和乙基、C1-C4烷氧基、尤其是甲氧基和乙氧基、硝基、-O-C(O)-C1-C4烷基或-C(O)-O-C1-C4烷基所取代或者在氮原子上被C1-C4烷基、尤其是甲基或乙基、-O-C(O)-C1-C4烷基或-C(O)-O-C1-C4烷基、诸如甲氧羰基或乙氧羰基所取代。
当两个取代基与共同连接的氮一起是het时,可以理解成所形成的杂环是含氮环,诸如氮杂环丙烷、氮杂环丁烷、吡咯、哌啶、哌嗪、吗啉、吡咯,吡唑、噻唑、噁唑、吡啶、嘧啶,异噁唑基等。
卤素是氟、氯、溴或碘,尤其是氟和氯。
除非另有说明,“烷基”包括直链或支链烷基,诸如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基和支链戊基、正己基和支链己基等。
“环烷基”是指含有3-8个环碳原子的C3-C10环烷基,其可以是例如环丙基、环丁基、环戊基、环己基、环庚基或环辛基。优选的环烷基是环庚基。环烷基可以是未取代的或者被以下所定义的任何一个取代基所取代,优选卤素、羟基或C1-C4烷基诸如甲基。
氨基酸残基包括标准氨基酸诸如丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸的残基。氨基酸残基还包括不常见的和修饰的氨基酸的侧链。不常见的和修饰的氨基酸对于本领域技术人员来说是已知的(参见例如G.B.Fields,Z.Tiam和G Barany;Synthetic Peptides A Users Guide,Universityof Wisconsin Biochemistry Center,第3章,(1992)),并且包括氨基酸诸如4-羟基脯氨酸、5-羟基赖氨酸、锁链素、β-丙氨酸、α、γ-和β-氨基丁酸、高半胱氨酸、高丝氨酸、瓜氨酸、鸟氨酸、2-或3-氨基己二酸、6-氨基己酸、2-或3-氨基异丁酸、2,3-二氨基丙酸、二苯基丙氨酸、羟基脯氨酸等。如果氨基酸残基的侧链含有可衍生化的基团诸如COOH、-OH或氨基,则侧链可通过与该可衍生化的基团反应的取代基来衍生化。例如,酸性氨基酸例如天冬氨酸和谷氨酸或羟基取代的侧链例如丝氨酸或苏氨酸的侧链可衍生化以形成酯,或者氨基侧链可形成酰胺或烷基氨基衍生物。尤其是所述的衍生物可以是有利于跨过细胞膜转运的取代基。另外,氨基酸残基中的任何羧酸基团例如α羧酸基团可按照以上所述的方法衍生化以形成酯或酰胺。
有利于分子跨过细胞膜转运的取代基对于药物化学领域的技术人员来说是已知的(参见例如Gangewar S.,Pauletti G.M.,Wang B.,Siahaan T.J.,Stella V.J.,Borchardt R.T.,Drug Discovery Today,vol.2.p148-155(1997)和Bundgaard H.和Moss J.,Pharmaceutical Research、vol.7,p 885(1990))。通常,所述的取代基是亲脂性取代基。所述的亲脂性取代基包括C6-C30烷基(其是饱和的、单不饱和的、多不饱和的,包括亚甲基中断的多烯)、苯基、被1或2个C1-C8烷基取代的苯基、C5-C9环烷基、被1或2个C1-C8烷基取代的C5-C9环烷基、-X1-苯基、在苯环中被1或2个C1-C8烷基取代的-X1-苯基、X1-C5-C9环烷基或被1或2个C1-C8烷基取代的X1-C5-C9环烷基;其中X1是C1-C24烷基,它是饱和的、单不饱和的或多不饱和的并且是直链或支链的。
未取代的是指氢是唯一的取代基。
以上所定义的芳基、het、烷基、环烷基或杂环基团中的任何一个都可以是未取代的或者独立地被最多四个、优选一、二或三个选自下列的取代基所取代:卤素(诸如Cl或Br);羟基;低级烷基(诸如C1-C3低级烷基);可被本文所定义的取代基中的任何一个所取代的低级烷基;低级链烯基;低级炔基;低级烷酰基;烷氧基(诸如甲氧基);芳基(诸如苯基或苄基);取代的芳基(诸如氟苯基或甲氧基苯基);氨基;单-或二取代的氨基;氨基低级烷基(诸如二甲基氨基);乙酰基氨基;氨基低级烷氧基(诸如乙氧基胺);硝基;氰基;氰基低级烷基;羧基;酯化的羧基(诸如低级烷氧基羰基,例如甲氧基羰基);正丙氧基羰基或异丙氧基羰基;烷酰基;苯甲酰基;氨基甲酰基;N-单-或N,N-二取代的氨基甲酰基;氨基甲酸酯;烷基氨基甲酸酯;脒基;胍;脲;脲基;巯基;磺基;低级烷硫基;磺氨基;磺酰胺;苯磺酰胺;磺酸酯;硫基低级烷基(诸如甲硫基);磺氨基;取代或未取代的磺酰胺(诸如苯磺酰胺);取代或未取代的磺酸酯(诸如氯-苯基磺酸酯);低级烷基亚磺酰基;苯基亚磺酰基;苯基-低级烷基亚磺酰基;烷基苯基亚磺酰基;低级烷烃磺酰基;苯基磺酰基;苯基-低级烷基磺酰基;烷基苯基磺酰基;卤代-低级烷基巯基;卤素-低级烷基磺酰基;诸如尤其是三氟甲磺酰基;膦酰基(-P(=O)(OH)2);羟基-低级烷氧基磷酰基或二-低级烷氧基磷酰基;取代的脲(诸如3-三氟-甲基-苯基脲);烷基氨基甲酸酯或氨基甲酸酯(诸如乙基-N-苯基-氨基甲酸酯)或-NR4R5,其中R4和R5可以相同或不同,并且独立地是H;低级烷基(例如甲基、乙基或丙基);或R4和R5与N原子一起形成含有1-4个氮、氧或硫原子的3-至8-元的杂环(例如哌嗪基、吡嗪基、低级烷基-哌嗪基、吡啶基、吲哚基、噻吩基、噻唑基、N-甲基哌嗪基、苯并噻吩基、吡咯烷基、哌啶-1-基或咪唑啉基),其中所述的杂环可以被本文所定义的任何取代基所取代。
优选以上所述的烷基、环烷基、芳基或het基团可以被卤素、羰基、硫醇、S(O)、S(O2)、-OH、-SH、-OCH3、-SCH3、-CN、-SCN或硝基所取代。
在将复数形式用于化合物、盐、药物制剂、疾病等的情况下,它也指单一的化合物、盐等。
对于本领域技术人员来说显而易见的是,本发明化合物可以以盐的形式、尤其是以酸加成盐或碱加成盐的形式存在。当化合物以盐的形式存在时,所述盐的形式也包括在本发明的范围内。尽管任何盐的形式都可用于化学加工处理、诸如纯化过程,但仅有可药用盐能够用于制药产品。
在适当的情况下,可药用盐包括可药用碱加成盐和酸加成盐,例如金属盐诸如碱金属和碱土金属盐、铵盐、有机胺加成盐、氨基酸加成盐和磺酸盐。酸加成盐包括无机酸加成盐诸如盐酸盐、硫酸盐和磷酸盐以及有机酸加成盐诸如烷基磺酸盐、芳基磺酸盐、乙酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐和乳酸盐。金属盐的例子是碱金属盐、诸如锂盐、钠盐和钾盐、碱土金属盐诸如镁盐和钙盐、铝盐和锌盐。铵盐的例子是铵盐和四甲基铵盐。有机胺加成盐的例子是与吗啉和哌啶所形成的盐。氨基酸加成盐的例子是与甘氨酸、苯丙氨酸、谷氨酸和赖氨酸所形成的盐。磺酸盐包括甲磺酸盐、甲苯磺酸盐和苯磺酸盐。
鉴于游离形式的化合物与它们的盐(包括可用作例如化合物的纯化或鉴别中的中间体的那些盐)、互变体或互变体混合物及其盐之间的密切关系,所以,若无另外说明,在适当且有利的情况下,上下文所提到的任何化合物、尤其是式I化合物均应还理解成是指这些化合物、尤其是式I化合物的相应的互变体、这些化合物、尤其是式I化合物的互变体混合物或这些化合物中任何一种的盐。
任何不对称的碳原子都可以(R)-、(S)-或(R,S)-构型存在,优选以(R)-或(S)-构型存在。如果可能的话,在环上具有饱和键的原子上的取代基以顺式-(=Z-)或反式(=E-)形式存在。因此该化合物可以以异构体混合物或优选以纯异构体、优选以对映体纯的非对映体或纯对映体的形式存在。
本发明的优选实施方案:
在以下优选的实施方案中,一般表述可以被上下文提供的相应的更具体的定义所代替,由此得到本发明的特别优选的实施方案。
优选的是式I化合物或其可药用盐的用途,其中待治疗的疾病是依赖于Smac蛋白与细胞凋亡蛋白抑制剂(IAP)相结合的增殖性疾病。
本发明的一种实施方案涉及式(I)化合物或其可药用盐:
其中
R1是H;C1-C4烷基;C1-C4链烯基;C1-C4炔基或环烷基,它们是未取代的或者被一个或多个选自下列的取代基所取代:卤素、-OH、-SH、-OCH3、-SCH3、-CN、-SCN和硝基;
R2是H;C1-C4烷基;C1-C4链烯基;C1-C4炔基或环烷基,它们是未取代的或者被一个或多个选自下列的取代基所取代:卤素、-OH、-SH、-OCH3、-SCH3、-CN、-SCN和硝基;
R3是H;-CF3;-C2F5;C1-C4烷基;C1-C4链烯基;C1-C4炔基;-CH2-Z或R2和R3与氮一起形成het;
Z是H;-OH;F;Cl;-CH3;-CF3;-CH2Cl;-CH2F或-CH2OH;
R4是C1-C16直链或支链烷基;C1-C16链烯基;C1-C16炔基;或-C3-C16环烷基;-(CH2)1-6-Z1;-(CH2)0-6-苯基;和-(CH2)0-6-het,其中烷基、环烷基和苯基是未取代的或取代的;
Z1是-N(R8)-C(O)-C1-C10烷基;-N(R8)-C(O)-(CH2)1-6-C3-C7环烷基;
-N(R8)-C(O)-(CH2)0-6-苯基;-N(R8)-C(O)-(CH2)1-6-het;-C(O)-N(R9)(R10);
-C(O)-O-C 1-C10烷基;-C(O)-O-(CH2)1-6-C3-C7环烷基;-C(O)-O-(CH2)0-6-苯基;-C(O)-O-(CH2)1-6-het;-O-C(O)-C1-C10烷基;-O-C(O)-(CH2)1-6-C3-C7环烷基;-O-C(O)-(CH2)0-6-苯基;-O-C(O)-(CH2)1-6-het,其中烷基、环烷基和苯基是未取代的或取代的;
het是含有1-4个选自N、O和S的杂原子的5-7元的杂环或包括至少一个含有1、2或3个选自N、O和S的杂原子的5-7元的杂环的8-12元的稠环系,所述的杂环或稠环系是未取代的或者在碳原子上被卤素、羟基、C1-C4烷基、C1-C4烷氧基、硝基、-O-C(O)-C1-C4烷基或-C(O)-O-C1-C4-烷基所取代或者在氮原子上被C1-C4烷基、-O-C(O)-C1-C4烷基或-C(O)-O-C1-C4烷基所取代;
R8是H、-CH3、-CF3、-CH2OH或-CH2Cl;
R9和R10彼此独立地是H;C1-C4烷基;C3-C7环烷基;-(CH2)1-6-C3-C7环烷基;-(CH2)0-6-苯基;其中烷基、环烷基和苯基是未取代的或取代的,或R9和R10与氮一起形成het;
R5是H;C1-C10-烷基;C3-C7环烷基;-(CH2)1-6-C3-C7环烷基;-C1-C10烷基-芳基;-(CH2)0-6-C3-C7环烷基-(CH2)0-6-苯基;-(CH2)0-4CH-((CH2)1-4-苯基)2;-(CH2)0-6-CH(苯基)2;-(CH2)0-6-C(O)苯基-茚满基;芳基-C(O)-C1-C10烷基;-C(O)-(CH2)1-6-C3-C7环烷基;-C(O)-(CH2)0-6-苯基;-(CH2)0-6-het;-C(O)-(CH2)1-6-het;或R5是氨基酸的残基,其中烷基、环烷基、苯基和芳基是未取代的或取代的;
U如结构式II所示:
其中
n=0-5;
X是-CH或N;
Ra和Rb独立地是O、S或N原子或C0-8烷基,其中烷基链中的一个或多个碳原子被选自O、S或N的杂原子所代替,并且其中烷基是未取代的或取代的;
Rd选自:
(a)-Re-Q-(Rf)p(Rg)q;或
(b)Ar1-D-Ar2;
Rc是H或Rd和Rc一起形成环烷基或het;其中如果Rd和Rc形成环烷基或杂环,则R5在C或N原子处连接到所形成的环上;
p和q独立地是0或1;
Re是C1-8烷基或亚烷基,优选亚甲基,Re是未取代的或取代的;
Q是N、O、S、S(O)或S(O)2;
Ar1和Ar2是取代或未取代的芳基或het;
Rf和Rg彼此独立地是H;-C1-C10烷基;C1-C10烷基芳基;-OH;-O-C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-O-(CH2)0-6-芳基;苯基;芳基;苯基-苯基;-(CH2)1-6-het;-O-(CH2)1-6-het;-OR11;-C(O)-R11;-C(O)-N(R11)(R12);-N(R11)(R12);-S-R11;-S(O)-R11;-S(O)2-R11;-S(O)2-NR11R12;-NR11-S(O)2-R12;S-C1-C1-烷基;芳基-C1-C4烷基;het-C1-C4烷基,其中烷基、环烷基、het和芳基是未取代的或取代的;-SO2-C1-C2烷基;-SO2-C1-C2烷基苯基;-O-C1-C4烷基;或Rg和Rf形成选自het或芳基的环;
D是-CO-;-C(O)-C1-7亚烷基或亚芳基;-CF2-;-O-;-S(O)r,其中r是0-2;
1,3-二氧杂环戊烷;或C1-7烷基-OH;其中烷基、亚烷基或亚芳基是未取代的或者被一个或多个卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基或-CF3所取代;或者D是-N(Rh),其中Rh是H;C1-7烷基(未取代的或取代的);芳基;-O(C1-7环烷基)(未取代的或取代的);C(O)-C1-C10烷基;C(O)-C0-C10烷基-芳基;C-O-C1-C10烷基;C-O-C0-C10烷基-芳基或SO2-C1-C10-烷基;SO2-(C0-C10-烷基芳基);
R6、R7、R’6和R’7彼此独立地是H;-C1-C10烷基;-C1-C10烷氧基;芳基-C1-C10烷氧基;-OH;-O-C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-O-(CH2)0-6-芳基;苯基;-(CH2)1-6-het;-O-(CH2)1-6-het;-OR11;-C(O)-R11;-C(O)-N(R11)(R12);-N(R11)(R12);-S-R11;-S(O)-R11;-S(O)2-R11;-S(O)2-NR11R12;-NR11-S(O)2-R12;其中烷基、环烷基和芳基是未取代的或取代的;并且R6、R7、R’6和R’7可连接形成环系;
R11和R12独立地是H;C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-(CH2)0-6-(CH)0-1(芳基)1-2;-C(O)-C1-C10烷基;-C(O)-(CH2)1-6-C3-C7环烷基;-C(O)-O-(CH2)0-6-芳基;-C(O)-(CH2)0-6-O-芴基;-C(O)-NH-(CH2)0-6-芳基;-C(O)-(CH2)0-6-芳基;-C(O)-(CH2)1-6-het;-C(S)-C1-C10烷基;-C(S)-(CH2)1-6-C3-C7环烷基;-C(S)-O-(CH2)0-6-芳基;-C(S)-(CH2)0-6-O-芴基;-C(S)-NH-(CH2)0-6-芳基;-C(S)-(CH2)0-6-芳基;-C(S)-(CH2)1-6-het;其中烷基、环烷基和芳基是未取代的或取代的;或R11和R12是有利于分子跨过细胞膜转运的取代基;或R11和R12与氮一起是het;R11和R12的芳基可以是苯基、萘基或茚满基,它是未取代的或取代的;
R11和R12的烷基是未取代的或者被一个或多个选自下列的取代基所取代:C1-C10链烯烃、卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基和-CF3;
R11和R12的环烷基是未取代的或者被一个或多个选自下列的取代基所取代:C1-C10链烯烃、一个或多个卤素、C1-C6烷基、卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基或-CF3;并且
R11和R12的苯基或芳基是未取代的或者被一个或多个选自下列的取代基所取代:卤素、羟基、C1-C4烷基、C1-C4烷氧基、硝基、-CN、-O-C(O)-C1-C4烷基和-C(O)-O-C1-C4-芳基。
本发明的另一种实施方案涉及式(I)化合物在治疗增殖性疾病、尤其是依赖于Smac蛋白与细胞凋亡蛋白抑制剂(IAP)的结合的那些疾病中的用途,或者在生产用于治疗所述疾病的药物中的用途、使用式(I)化合物治疗所述疾病的方法、包含式(I)化合物的用于治疗所述疾病的药物制剂、用于治疗所述疾病的式(I)化合物。
本发明的一种实施方案涉及式(I)化合物及其可药用盐:
其中
R1和R2独立地是H或取代或未取代的C1-C4烷基;
R4是C1-C16直链或支链烷基或C3-C10环烷基,其中烷基或环烷基是未取代的或取代的;
R5是H;C1-C10烷基;C1-C10烷基-芳基;-C(O)-(CH2)0-6-苯基;-(CH2)0-6-C(O)-苯基;芳基;茚满基;萘基,或R5是氨基酸的残基,其中烷基或芳基取代基是未取代的或取代的;
U如结构式II所示:
其中
n=0-5;
X是-CH或N;
Ra和Rb独立地是O、S或N原子或C0-8烷基,其中烷基链中的一个或多个碳原子被选自O、S或N的杂原子所代替,并且其中烷基是未取代的或取代的;
Rd选自
(a)-Re-Q-(Rf)p(Rg)q;或
(b)Ar1-D-Ar2;
Rc是H或Rc和Rd一起形成环烷基或het;其中如果Rd和Rc形成环烷基或杂环,则R5在C或N原子处连接到所形成的环上;
p和q独立地是0或1;
Re是C1-8烷基或亚甲基,它是未取代的或取代的;
Q是N、O、S、S(O)或S(O)2;
Ar1和Ar2是取代或未取代的芳基或het;
Rf和Rg彼此独立地是H或取代或未取代的C0-C10烷基;C1-C10烷基芳基;芳基-C1-C10烷基;het-C1-C10烷基;-C(O)-C1-C4-烷基-苯基;-C(O)-C1-C4-烷基;-SO2-C1-C2烷基;-SO2-C1-C2烷基苯基;-O-C1-C4-烷基;
D是-C(O)-;C1-7亚烷基或亚芳基;-O-或-S(O)r,其中r是0-2;其中烷基、亚烷基或亚芳基是未取代的或者被一个或多个卤素;-OH;-O-C1-C6烷基;-S-C1-C6烷基或-CF3所取代;或者D是NRh,其中Rh是H;C1-7烷基(未取代的或取代的);芳基;-OC1-7环烷基(未取代的或取代的);-CO-C0-10烷基或芳基或SO2-C0-10-烷基或芳基;并且R6、R7、R’6和R’7彼此独立地是H、-C1-C10烷基或-OH、烷氧基或芳基氧基。
在另一种实施方案中,U是完全由碳骨架构成的或者含有一个或多个杂原子诸如O、N、S的二环饱和或不饱和环系,但优选如结构式III所示:
其中
任何的环碳原子均是未取代的或者被以上关于R6、R7、R6’和R7’所定义的取代基中的任何一个所取代;
X是CH或N;
V是O、F2、Cl2、Br2、I2、S、YH、H2、NH或C1-C4烷基;
W是-CH或-N;
n是0-3;并且
m是0-3。
在优选的实施方案中,环原子可以被独立地选自卤素、H、OH、低级烷基或低级烷氧基的取代基所取代,其中烷基或烷氧基是未取代的或者被卤素、OH、低级烷基或低级烷氧基取代。
在另一种实施方案中,式II或III的U与R5一起形成稠环系。
特别优选的是如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H;甲基;乙基;氯甲基;二氯甲基或三氟甲基;
R4是-C1-C4烷基;-C3-C7环烷基;-(CH2)1-6环烷基或-(CH2)0-6芳基。R4尤其是乙基;丙基;异丙基;叔丁基;环戊基或环己基;-CH2-环戊基;-CH2-环己基或-CH2-苯基。
R5是-C1-C4烷基-苯基;-C(O)-C1-C4烷基-苯基;-C1-C4烷基-C(O)-苯基或芳基;R5尤其是苯基甲基、苯基乙基和苯基丙基;茚满基、萘基;-C(O)-CH2-苯基或-CH2-C(O)-苯基;
R6和R7是H或甲基;
U具有式III的结构:
其中
任何的环碳原子均是未取代的或者被以上关于R6、R7、R6’和R7’所定义的取代基中的任何一个所取代;
X是N;
V是O或H2;
W是-N;
n是1;并且
m是1或2。
特别优选的是如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2是H;
R4是C1-C4烷基;C3-C7环烷基;C1-C7环烷基-C1-C7烷基;苯基-C1-C7烷基或芳基。R4尤其是甲基;乙基;丁基;异丙基;叔丁基或环己基;-CH2-环戊基;-CH2-环己基;-CH2-环丙基;苯基或-CH2-苯基;
R5是-C1-C4烷基-苯基;-C(O)-C1-C4烷基-苯基;-C1-C4烷基-C(O)-苯基或芳基。R5尤其是苯基乙基;茚满基、萘基;-C(O)-CH2-苯基;-CH2-C(O)-苯基或(CF3O)苯基乙基;
R6、R’6、R7和R’7是H;
U具有式III的结构,其中
任何的环碳原子均是未取代的或者被以上关于R6、R7、R6’和R7’所定义的取代基中的任何一个所取代;
X是N;
V是O或H2;
W是-N;
n是1;并且
m是1或2。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H;
U具有式II的结构,其中
X是N;
R6、R’6、R7和R’7是H;
n是0;
Rc是H;
Ar1和Ar2是取代或未取代的苯基或het,尤其是四唑基、1,2,3-三唑、吡唑、噁唑、吡咯基、三嗪、嘧啶、咪唑、噁二唑;并且
D是任选地被卤素、尤其是F取代的C1烷基。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基;C3-C7环烷基;C1-C7环烷基-C1-C7烷基;苯基-C1-C7烷基或芳基。R4尤其是甲基、乙基、丁基、异丙基、叔丁基或环己基;-CH2-环戊基;-CH2-环己基;-CH2-环丙基;苯基或-CH2-苯基;
R5是H;
U具有式II的结构,其中
X是N:
R6、R’6、R7和R’7是H;或R6是-C(O)-C1-C4烷基.苯基且R’6、R7和R’7是H;
n是0:
Rc是H:
Ar1和Ar2是取代或未取代的苯基或het,尤其是三嗪、嘧啶、吡啶、噁唑、2,4-二氟苯基-Cl-苯基或氟苯基;并且
D是N(Rh),其中Rh是H、Me、-CHO、-SO2、-C(O)、-CHOH、-CF3或-SO2CH3。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基;C3-C7环烷基;C1-C7环烷基-C1-C7烷基;苯基-C1-C7烷基或芳基。R4尤其是甲基、乙基、丁基、异丙基、叔丁基或环己基;-CH2-环戊基;-CH2-环己基;-CH2-环丙基;苯基或-CH2-苯基;
R5是H;
U具有式II的结构,其中
X是N:
R6、R’6、R7和R’7是H;
n是0:
Rc是H;
Ar1和Ar2是取代或未取代的苯基或het,尤其是嘧啶、吡啶、噁唑、2-甲基噁唑;并且
D是-O-。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H;
U具有式II的结构,其中
X是N:
R6、R’6、R7和R’7是H;
n是0;
Rc是H:
Ar1和Ar2是取代或未取代的苯基或het;并且
D是S、S(O)或S(O)2。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H;
U具有式II的结构,其中
X是N:
R6、R,6、R7和R’7是H;
n是0:
Rc是H;
Ar1和Ar2是取代或未取代的苯基或het,尤其是噁唑、噻唑和噁二唑;
并且D是C(O)或1,3-二氧戊环。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H或苯基C1-C10烷基,诸如苯基乙基;
U具有式II的结构,其中
X是N;
R6、R’6、R7和R’7是H;
n是0;
Rc和Rd是杂环,尤其是吡咯烷;吡咯烷-2-酮或吡咯烷-3-酮。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H、茚满基或苯基;
U具有式II的结构,其中
X是N;
Q是O;
R6、R’6、R7和R’7是H;
n是0;
Re是C1烷基;并且
p和q是0。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H、茚满基或苯基;
U具有式II的结构,其中
X是N;
Q是N;
R6、R’6、R7和R’7是H;
n是0;
Re是C1烷基;并且
Rg是H、C1-C8烷基、甲基、乙基、己基、庚基、辛基或CH2CF3或芳基-C1-C4烷基,尤其是苯基乙基、呋喃基乙基;C3-C7环烷基,尤其是环己基;乙基苯基;-C(O)-C1-C4烷基-苯基;-C(O)-C1-C4烷基;-C1-C4烷基-芳基,尤其是-CH2-苯基;-CH2-噻吩、-CH2-呋喃、-CH2-吡咯烷基、-CH2-咪唑、-CH2-三唑、-CH2-咪唑;
并且Rf是C1-C2烷基;C1-C2烷基苯基;-SO2-C1-C2烷基;-SO2-C1-C2烷基苯基;-O-C1-C4烷基,尤其是O-乙基;苯基-苯基、1,2,3,4-四氢萘和茚满基。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H、茚满基或苯基;
U具有式II的结构,其中
X是N;
Q是N;
R6、R’6、R7和R’7是H;
n是0;
Re是C1烷基;并且
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基:
R5是苯基;
U具有式II的结构,其中
X是N:
Q是O、S、S(O)或S(O)2;
R6、R’6、R7和R’7是H;
n是0;
Re是C1烷基;
q是0;
Rc是H:
并且Rf是C2烷基。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是苯基;
U具有式II的结构,其中
X是N:
Q是N;
R6、R’6、R7和R’7是H;
n是0;
Re是CH;
q是0;
Rc是H;
并且Rf是OC1烷基。
在本发明的一个尤其重要的实施方案中,R3和R4具有式IV所示的立体化学结构,以上所述的可变取代基的定义和优选情况也适用于具有式IV所示的立体化学结构的化合物。
特别优选的是具有式(IV)的立体化学结构的化合物,其中
R1和R3优选是甲基或乙基;
R2是H、甲基、乙基或取代的甲基,尤其是氯甲基、二氯甲基和三氟甲基;优选R2是H或未取代的甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是-C1-C4-烷基-苯基,尤其是苯基甲基、苯基乙基和苯基丙基、茚满基、萘基;并且
R6和R7是H或甲基。
优选的U的立体化学结构如式V所示:
在本发明的一个具体实施方案中,R6、R7、R6’和R7’中的一个或两个是H。如果R6、R7、R6’和R7’中的一个不是H,则它尤其是羟基或苯氧基。
合成方法
缩写词:
CH2Cl2 二氯甲烷
CH3CN 乙腈
DIBAL 二异丁基氢化铝
DIPEA 二异丙基乙基胺
DME 乙二醇二甲醚
DMF N,N二甲基甲酰胺
DTBB 4,4’-二叔丁基联苯
EtOAc 乙酸乙酯
HBTU O-苄基三唑-1-基-N,N,N’,N’-四甲基脲六氟磷酸盐
HOBt 1-羟基苯并三唑
HPLC 高压液相色谱
KOTMS 三甲基硅烷醇钾(potassium trimethysilanoate)
MeOH 甲醇
MgO4 硫酸镁
MnO2 二氧化锰
Na2CO3 碳酸钠
NaHCO3 碳酸氢钠
NaOH 氢氧化钠
Tetrakis (三苯基膦)钯(0)
TFA 三氟乙酸
THF 四氢呋喃
式(I)化合物可按照以下方案1所述的方法制得(用于化合物#9-25、29-31):
用于其中W=N且X和X’独立地选自以上关于R6所定义的取代基的式1化合物的一般合成方案:
KOTMS指三甲基硅烷醇钾。
步骤A
步骤B
步骤C
步骤D
分离非对映体
步骤E
步骤F
步骤G
步骤H
方案1
步骤A:该步骤包括通过标准的碱介导的条件形成氮杂环丙烷环。
步骤B:该步骤包括通过烷基溴与过量胺在碱的存在下反应以形成仲胺。
步骤C:该步骤包括仲胺与氮杂环丙烷甲酯的活性衍生物的偶联以形成酰胺取代的氮杂环丙烷。
步骤D:该步骤包括氮杂环丙烷与悬挂的链烯烃经由热生成的甲亚胺叶立德中间体进行的分子内环加成。
步骤E:该步骤包括通过标准的还原条件用DIBAL-H将酰胺还原成胺。
步骤F:该步骤包括利用标准的钯条件在氢气氛下除去苄基型保护基。
步骤G:该步骤包括利用标准的肽偶联条件将基本骨架与t-Boc保护的天然或非天然氨基酸相偶联,然后用TFA除去t-Boc基团。
步骤H:该步骤包括利用标准的肽偶联条件将前一步骤产生的胺与t-Boc保护的或叔型天然或非天然氨基酸相偶联,然后用TFA除去t-Boc基团,
如果合适的话。然后将产物通过高效液相色谱(HPLC)纯化。
式(I)化合物可按照以下方案2所述的方法制得(用于化合物#26-28):
方案2
式(I)化合物可按照以下方案3所述的方法制得(用于化合物#32-33):
方案3
式(I)化合物可按照以下方案4所述的方法制得(用于化合物#34-35):
方案4
化合物36-38可按照方案4按照类似于制备化合物34-35的方法来制得。
如上所述,本发明化合物可用于治疗增殖性疾病。因此,本发明进一步涉及治疗增殖性疾病的方法,该方法包括向需要所述治疗的哺乳动物、优选人施用治疗有效量的本发明化合物。
增殖性疾病主要是肿瘤疾病(或癌症)(和/或任何转移瘤)。本发明化合物尤其可用于治疗的肿瘤是乳腺癌、泌尿生殖系统癌症、肺癌、胃肠癌、表皮样癌、黑瘤、卵巢癌、胰腺癌、成神经细胞瘤、头和/或颈部癌症或膀胱癌,或者广义上的肾、脑或胃癌;尤其是(i)乳腺肿瘤;表皮样肿瘤,例如表皮样头和/或颈部肿瘤或口腔肿瘤;肺肿瘤,例如小细胞或非小细胞肺肿瘤;胃肠肿瘤,例如结肠直肠肿瘤;或泌尿生殖系统肿瘤,例如前列腺肿瘤(尤其是激素难治性前列腺肿瘤);或(ii)用其它化疗剂难以治疗的增殖性疾病;或(iii)由于多重抗药性而用其它化疗剂难以治疗的肿瘤。
从本发明的广义上说,增殖性疾病还可以是过度增殖性状况,诸如白血病、增生、纤维化(尤其是肺纤维化,但也可以是其它类型的纤维化诸如肾的纤维化)、血管生成、牛皮癣、动脉粥样硬化和血管内的平滑肌增生诸如血管成形术后的狭窄或再狭窄。
当提到肿瘤、肿瘤疾病、癌或癌症时,还另外或额外地暗指在原器官或组织和/或任何其它部位的转移瘤,无论肿瘤和/或转移瘤的部位如何。
本发明化合物具有选择性的毒性,或者对快速增殖的细胞比对正常细胞具有更大的毒性,尤其是在人类癌细胞例如癌性肿瘤中,该化合物具有显著的抗增殖效果并能促进分化,例如促进细胞周期停滞和细胞凋亡。
本发明化合物可单独给药或者与其它抗癌剂联合给药,诸如可抑制肿瘤血管生成的化合物,例如蛋白酶抑制剂、表皮生长因子受体激酶抑制剂、血管内皮生长因子受体激酶抑制剂等;细胞毒性药物,诸如抗代谢物、例如嘌呤和嘧啶模拟抗代谢物;抗有丝分裂剂如微管稳定化药物和抗有丝分裂的生物碱;铂配位的络合物;抗肿瘤的抗生素;烷基化剂诸如氮芥和亚硝基脲;内分泌药物诸如肾上腺皮质类固醇、雄激素、抗雄激素、雌激素、抗雌激素、芳香酶抑制剂、促性腺激素释放激素激动剂和生长抑素类似物以及靶向于在肿瘤细胞中被上调的特定代谢途径中过度表达和/或涉及的酶或受体的化合物,例如ATP和GTP磷酸二酯酶抑制剂、组蛋白脱乙酰酶抑制剂、蛋白激酶抑制剂诸如丝氨酸、苏氨酸和酪氨酸激酶抑制剂,例如Abelson蛋白酪氨酸激酶和各种生长因子、它们的受体和激酶抑制剂,诸如表皮生长因子受体激酶抑制剂、血管内皮生长因子受体激酶抑制剂、成纤维细胞生长因子抑制剂、类胰岛素生长因子受体抑制剂和源自血小板的生长因子受体激酶抑制剂等;蛋氨酸氨基肽酶抑制剂、蛋白酶体抑制剂和环加氧酶抑制剂,例如,环加氧酶-1或-2抑制剂。
本发明进一步涉及促进快速增殖的细胞发生细胞凋亡的方法,该方法包括将快速增殖的细胞与促进细胞凋亡有效量的可与XIAP和/或cIAP蛋白的Smac结合位点相结合的非天然存在的化合物接触。优选非天然存在的化合物是本发明的式I或IV化合物。
本发明进一步涉及治疗或抑制骨髓瘤、尤其是多发性骨髓瘤的方法。本文所用的术语“骨髓瘤”涉及由在正常情况下存在于骨髓中的细胞类型所组成的肿瘤。本文所用的术语“多发性骨髓瘤”是指弥散的恶性浆细胞肿瘤,其特征在于多发的骨髓肿瘤病灶以及M成分(一种单克隆免疫球蛋白片断)的分泌,伴有广泛的溶骨性损伤,可导致骨痛、病理性骨折、高钙血症和正常血色素贫血。多发性骨髓瘤无法用常规和高剂量的化疗剂治愈。本发明涉及治疗骨髓瘤、特别是对常规化学疗法具有抗药性的骨髓瘤的方法。
药物组合物
本发明还涉及包含式I化合物的药物组合物、它们在治疗性(从本发明的广义上说也是预防性的)处置或治疗激酶依赖性疾病、尤其是以上所述的优选疾病中的应用、用于所述应用的化合物以及尤其是用于所述应用的药物制剂及其生产。
本发明还涉及在体内可转化成式I化合物本身的式I化合物的前药。因此,所提到的任何式I化合物都应理解成也是指相应的式I化合物的前药,如果合适且有利的话。
本发明的可药用化合物可以以例如药物组合物的形式存在或用于制备药物组合物,所述的药物组合物包含作为活性成分的有效量的式I化合物或其可药用盐或其与一种或多种无机或有机、固体或液体的可药用载体(载体物质)的混合物。
本发明还涉及适于给药于温血动物、尤其是人(或者给药于温血动物、尤其是人的细胞或细胞系,例如淋巴细胞)用于治疗(从本发明的广义上说,也包括预防)对抑制蛋白激酶活性有响应的疾病的药物组合物,所述的药物组合物包含一定量的、优选对于所述抑制有效量的式I化合物或其可药用盐,以及至少一种可药用载体。
本发明的药物组合物是可用于肠道诸如鼻、直肠或口服或非肠道诸如肌内或静脉内给药于温血动物(尤其是人)的药物组合物,所述的组合物包含有效剂量的药物活性成分本身或者还包含显著量的可药用载体。活性成分的剂量取决于温血动物的种类、体重、年龄和个体状况、个体的药动学数据、待治疗的疾病和给药方式。
本发明还涉及治疗对抑制蛋白激酶有响应的疾病和/或增殖性疾病的方法,该方法包括向因上述疾病之一而需要所述治疗的温血动物、例如人施用(针对所述疾病的)预防或尤其是治疗有效量的本发明的式I化合物或其互变体或其可药用盐。
给药于温血动物例如约70kg体重的人的式I化合物或其可药用盐的剂量优选是约3mg-约10g,更优选约10mg-约1.5g,最优选约100mg-约1000mg/人/天,优选分成1-3个例如可以是相同大小的单一剂量。小孩的用量是成人剂量的一半。
药物组合物包含约1%-约95%、优选约20%-约90%的活性成分。本发明的药物组合物可以是例如单位剂量形式,诸如安瓿、小瓶、栓剂、糖衣丸、片剂或胶囊的形式。
本发明的药物组合物按照本领域已知的方式例如通过常规的溶解、冷冻干燥、混合、造粒或成型过程来制得。
联合形式
式I化合物还可有利地与其它抗增殖剂联合施用。所述的抗增殖剂包括但不限于芳香酶抑制剂;抗雌激素;拓扑异构酶I抑制剂;拓扑异构酶II抑制剂;微管活化剂;烷化剂;组蛋白脱酰酶抑制剂;诱导细胞分化过程的化合物;环加氧酶抑制剂;MMP抑制剂;mTOR抑制剂;抗肿瘤抗代谢剂;铂化合物;靶向于/降低蛋白质或脂类激酶活性的化合物和其它抗血管生成化合物;靶向于、降低或抑制蛋白质或脂类磷酸酯酶活性的化合物;戈那瑞林激动剂;抗雄激素;蛋氨酸氨基肽酶抑制剂;二膦酸类;生物响应调节剂;抗增殖抗体;乙酰肝素酶抑制剂;Ras致癌同工型抑制剂;端粒酶抑制剂;蛋白酶体抑制剂;用于治疗血液恶性肿瘤的试剂;靶向于、降低或抑制Flt-3活性的化合物;Hsp90抑制剂;替莫唑胺;和亚叶酸钙(leucovorin)。
本文所用的术语“芳香酶抑制剂”涉及能抑制雌激素生成(即将雄甾烯二酮和睾酮底物分别转化为雌酮和雌二醇)的化合物。该术语包括但不局限于甾类,尤其是阿他美坦、依西美坦和福美坦,和特别是非甾类,尤其是氨鲁米特、罗谷亚胺、吡啶基苯乙哌啶酮、曲洛司坦、睾内酯、酮康唑、伏氯唑、法倔唑、阿那曲唑和来曲唑。依西美坦可以如市售形式如商标为AROMASIN的形式给药。福美坦可以如市售形式如商标为LENTARON的形式给药。法倔唑可以如市售形式如商标为AFEMA的形式给药。阿那曲唑可以如市售形式如商标为ARIMIDEX的形式给药。来曲唑可以如市售形式如商标为FEMARA或FEMAR的形式给药。氨鲁米特可以如市售形式如商标为ORIMETEN的形式给药。本发明中含芳香酶抑制剂化疗剂的联合给药对治疗激素受体阳性肿瘤如乳腺肿瘤特别有效。
本文所用的术语“抗雌激素药”涉及能在雌激素受体水平拮抗雌激素效应的化合物。该术语包括但不局限于他莫昔芬、氟维司群、雷洛昔芬和盐酸雷洛昔芬。他莫昔芬可以如市售形式如商标NOLVADEX的形式给药。盐酸雷洛昔芬可以如市售形式如商标为EVISTA的形式给药。氟维司群可按US4,659,516中公开的内容制得或以如市售形式如商标为FASLODEX的形式给药。本发明中含有抗雌激素药化疗剂的联合给药对治疗雌激素受体阳性肿瘤如乳腺肿瘤特别有效。
本文所用的术语“抗雄激素药”涉及能抑制雄性激素的生物学效应的任何物质,包括但不局限于比卡鲁胺(CASODEX),其可按照US4,636,505中公开的内容配制。
本文所用的术语“戈那瑞林激动剂”包括但不局限于阿巴瑞克、戈舍瑞林和醋酸戈舍瑞林。戈舍瑞林在US4,100,274中公开,可以如市售形式如商标为ZOLADEX的形式给药。阿巴瑞克可按照US5,843,901中公开的内容配制。
本文所用的术语“拓扑异构酶I抑制剂”包括但不局限于托泊替康、伊立替康、9-硝基喜树碱和大分子喜树碱轭合物PNU-166148(WO99/17804中的化合物A1)。伊立替康可以例如市售形式如商标为CAMPTOSAR的形式给药。托泊替康可以如市售形式如商标为HYCAMTIN的形式给药。
本文所用的术语“拓扑异构酶II抑制剂”包括但不局限于蒽环霉素类如阿霉素(包括脂质体剂型,例如CAELYX)、柔红霉素、表柔比星、伊达比星和奈莫柔比星(nemorubicin)、蒽醌米托蒽醌和洛索蒽醌,和鬼臼脂素(podophyllotoxines)依托泊苷和替尼泊苷。依托泊苷可以例如市售形式如商标为ETOPOPHOS的形式给药。替尼泊苷以如市售形式如商标为VM26-BRISTOL的形式给药。阿霉素以如市售形式如商标为ADRIBLASTIN的形式给药。表柔比星以如市售形式如商标为FARMORUBICIN的形式给药。伊达比星以如市售形式如商标为ZAVEDOS的形式给药。米托蒽醌以如市售形式如商标为NOVANTRON的形式给药。
本文所用的术语“微管活化药”涉及微管稳定药、微管去稳定药以及微管蛋白聚合抑制剂,包括但不局限于紫杉烷类如紫杉醇和多西他赛,长春生物碱如长春花碱,特别是硫酸长春花碱、长春新碱,特别是硫酸长春新碱和长春瑞滨、海绵内酯(discodermolide)、秋水仙素(cochicine)和埃博霉素及其衍生物,如埃博霉素B或D或其衍生物。紫杉醇以如市售形式如商标为TAXOL的形式给药。多西他赛以如市售形式如商标为TAXOTERE的形式给药。硫酸长春花碱以例如市售形式如商标为VINBLASTIN R.P.的形式给药。硫酸长春新碱以例如市售形式如商标为FARMISTIN的形式给药。海绵内酯可如US5,010,099中公开的内容得到。还包括公开于WO98/10121、US6,194,181、WO98/25929、WO98/08849、WO99/43653、WO98/22461和WO00/31247中的埃博霉素及其衍生物。特别优选的是埃博霉素A和/或B。
本文所用的术语“烷化剂”包括但不局限于环磷酰胺、异环磷酰胺、苯丙氨酸氮芥或亚硝基脲(BCNU或Gliadel)。环磷酰胺以例如市售形式如商标为CYCLOSTIN的形式给药。异环磷酰胺以例如市售形式如商标为HOLOXAN的形式给药。
术语“组蛋白脱酰酶抑制剂”或“HDAC抑制剂”涉及可抑制组蛋白脱酰酶并且具有抗增殖活性的化合物。它包括公开于WO02/22577中的化合物,尤其是N-羟基-3-[4-[[(2-羟基乙基)[2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺、N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)-乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺及其可药用盐。它进一步尤其包括辛二酰苯胺异羟肟酸(SAHA)。
术语“抗肿瘤抗代谢药剂”包括但不局限于5-氟尿嘧啶或5-FU、卡培他滨、吉西他滨、DNA脱甲基化试剂诸如5-氮杂胞苷和地西他滨(decitabine)、甲氨蝶呤和依达曲沙,以及叶酸拮抗剂诸如培美曲塞(pemetrexed)。卡培他滨以例如市售形式如商标为XELODA的形式给药。吉西他滨以例如市售形式如商标为GEMZAR的形式给药。还包括单克隆抗体曲妥珠单抗(trastuzumab),其可以以例如市售形式如商标为HERCEPTIN的形式给药。
本文所用的术语“铂化合物”包括但不局限于卡铂、顺铂、cisplatinum和奥沙利铂。卡铂以例如市售形式如商标为CARBOPLAT的形式给药。奥沙利铂以例如市售形式如商标为ELOXATIN的形式给药。
本文所用的术语“靶向于/降低蛋白或脂类激酶的活性的化合物以及其它抗血管生成化合物”包括但不限于:蛋白酪氨酸激酶和/或丝氨酸和/或苏氨酸激酶抑制剂或脂类激酶抑制剂,例如:
a)靶向于、降低或抑制成纤维细胞生长因子受体(FGF-Rs)活性的化合物;
b)靶向于、降低或抑制类胰岛素生长因子受体I(IGF-IR)活性的化合物,诸如靶向于、降低或抑制IGF-IR活性的化合物,尤其是可抑制IGF-IR受体的化合物,诸如公开于WO02/092599的那些化合物;
c)靶向于、降低或抑制Trk受体酪氨酸激酶家族的活性的化合物;
d)靶向于、降低或抑制Axl受体酪氨酸激酶家族的活性的化合物;
e)靶向于、降低或抑制c-Met受体的活性的化合物;
f)靶向于、降低或抑制蛋白激酶C(PKC)和丝氨酸/苏氨酸激酶的Raf家族的成员、MEK、SRC、JAK、FAK、PDK的成员和Ras/MAPK家族成员或PI(3)激酶家族或PI(3)-激酶相关性激酶家族和/或细胞周期蛋白依赖性激酶家族(CDK)的成员的活性的化合物,尤其是公开于US5,093,330中的星形孢菌素衍生物,例如米哚妥林(midostaurin);其它化合物的例子包括例如UCN-01、沙芬戈(safingol)、BAY 43-9006、Bryostatin 1、哌立福新(Perifosine);伊莫福新(Ilmofosine);RO318220和RO320432;GO6976;Isis3521;LY333531/LY379196;异喹啉化合物诸如公开于WO00/09495的那些化合物;FTIs;PD184352或QAN697(P13K抑制剂);
g)靶向于、降低或抑制蛋白-酪氨酸激酶的活性的化合物,诸如甲磺酸伊马替尼(GLIVEC/GLEEVEC)或tyrphostin。Tyrphostin优选是低分子量(Mr<1500)的化合物或其可药用盐,尤其是选自苄亚基丙二腈类或S-芳基苯丙二腈类或二取代的喹啉类的化合物,更优选选自下列的任何化合物:Tyrphostin A23/RG-50810;AG 99;Tyrphostin AG 213;Tyrphostin AG1748;Tyrphostin AG 490;Tyrphostin B44;Tyrphostin B44(+)对映体;Tyrphostin AG 555;AG 494;Tyrphostin AG 556、AG957和adaphostin(4-{[(2,5-二羟基苯基)甲基]氨基}-苯甲酸金刚烷基酯;NSC680410、adaphostin);和
h)靶向于、降低或抑制受体酪氨酸激酶的表皮生长因子家族(EGF-R、ErbB2、ErbB3、ErbB4,为均或杂二聚体形式)的活性的化合物,诸如靶向于、降低或抑制表皮生长因子受体家族的活性的化合物,尤其是可抑制EGF受体酪氨酸激酶家族的成员例如EGF受体、ErbB2、ErbB3和ErbB4或与EGF或EGF相关性配体结合的化合物、蛋白质或抗体,尤其是概括性地和具体地公开于以下文献的那些化合物、蛋白质或单克隆抗体:WO97/02266,例如实施例39的化合物;或EP 0 564 409、WO99/03854、EP0520722、EP 0 566 226、EP 0 787 722、EP 0 837 063、US5,747,498、WO98/10767、WO97/30034、WO97/49688、WO97/38983和尤其是WO96/30347(例如称作CP358774的化合物)、WO96/33980(例如化合物ZD1839)和WO95/03283(例如化合物ZM105180);例如公开于WO03/013541的曲妥珠单抗(HERCEPTIN)、西妥昔单抗(cetuximab)、Iressa、Tarceva、CI-1033、EKB-569、GW-2016、E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3或E7.6.3和7H-吡咯并-[2,3-d]嘧啶衍生物。
其它抗血管生成化合物包括具有另外的活性机制,例如与蛋白或脂类激酶抑制作用无关的化合物,例如萨力多胺(THALOMID)和TNP-470。
靶向于、降低或抑制蛋白或脂类磷酸酯酶活性的化合物是例如磷酸酯酶1、磷酸酯酶2A、PTEN或CDC25的抑制剂,例如冈田酸或其衍生物。
可诱导细胞分化过程的化合物是例如视黄酸、α-、γ-或δ-生育酚或α-、γ-或δ-生育三烯酚。
本文所用的术语“环加氧酶抑制剂”包括但不限于例如Cox-2抑制剂、5-烷基取代的2-芳基氨基苯基乙酸和衍生物,诸如塞来考昔(CELEBREX)、罗非考昔(VIOXX)、依托考昔(etoricoxib)、伐地考昔或5-烷基-2-芳基氨基苯基乙酸例如5-甲基-2-(2’-氯-6’-氟苯氨基)苯基乙酸、lumiracoxib。
术语“mTOR抑制剂”涉及可抑制哺乳动物的雷帕霉素靶点(mTOR)并且具有抗增殖活性的化合物,诸如西罗莫司(sirolimus)、依维莫司(everolimus)(CerticanTM)、CCI-779和ABT578。
本文所用的术语“二膦酸类”包括但不限于依替膦酸、氯膦酸、替鲁膦酸、帕米膦酸、阿仑膦酸、依班膦酸、利塞膦酸和唑来膦酸。“依替膦酸”可以以市售的形式例如以商标DIDRONEL市售的形式给药。“氯膦酸”可以以市售的形式例如以商标BONEFOS市售的形式给药。“替鲁膦酸”可以以市售的形式例如以商标SKELID市售的形式给药。“帕米膦酸”可以以市售的形式例如以商标AREDIATM市售的形式给药。“阿仑膦酸”可以以市售的形式例如以商标FOSAMAX市售的形式给药。“依班膦酸”可以以市售的形式例如以商标BONDRANAT市售的形式给药。“利塞膦酸”可以以市售的形式例如以商标ACTONEL市售的形式给药。“唑来膦酸”可以以市售的形式例如以商标ZOMETA市售的形式给药。
本文所用的术语“乙酰肝素酶抑制剂”是指靶向于、降低或抑制硫酸肝素降解的化合物。该术语包括但不限于PI-88。
本文所用的术语“生物学响应修饰剂”是指淋巴因子或干扰素,例如干扰素γ。
本文所用的术语“Ras致癌同工型”,例如H-Ras、K-Ras或N-Ras是指靶向于、降低或抑制Ras的致癌活性的化合物,例如“法尼基转移酶抑制剂”,例如L-744832、DK8G557或R115777(Zarnestra)。
本文所用的术语“端粒酶抑制剂”是指靶向于、降低或抑制端粒酶的活性的化合物。靶向于、降低或抑制端粒酶的活性的化合物尤其是可抑制端粒酶受体的化合物、例如telomestatin。
本文所用的术语“蛋氨酸氨基肽酶抑制剂”是指靶向于、降低或抑制蛋氨酸氨基肽酶的活性的化合物。靶向于、降低或抑制蛋氨酸氨基肽酶的活性的化合物是例如bengamide或其衍生物。
本文所用的术语“蛋白酶体抑制剂”是指靶向于、降低或抑制蛋白酶体的活性的化合物。靶向于、降低或抑制蛋白酶体的活性的化合物包括例如PS-341和MLN341。
本文所用的术语“基质金属蛋白酶抑制剂”或(“MMP抑制剂”)包括但不限于胶原模拟肽和非模拟肽抑制剂、四环素衍生物例如异羟肟酸模拟肽抑制剂巴马司他及其口服生物可利用的类似物马立马司他(BB-2516)、普啉司他(AG3340)、metastat(NSC 683551)BMS-279251、BAY 12-9566、TAA211、MMI270B或AAJ996。
本文所用的术语“用于治疗血液恶性肿瘤的试剂”包括但不限于类FMS-酪氨酸激酶抑制剂,例如靶向于、降低或抑制Flt-3的活性的化合物;干扰素、1-b-D-阿拉伯呋喃糖基胞嘧啶(ara-c)和bisulfan;和ALK抑制剂,例如靶向于、降低或抑制间变性淋巴瘤激酶的化合物。
术语“靶向于、降低或抑制Flt-3的活性的化合物”特别是可抑制Flt-3的化合物、蛋白质或抗体,例如PKC412、米哚妥林、星形孢菌素衍生物、SU11248和MLN518。
本文所用的术语“HSP90抑制剂”包括但不限于靶向于、降低或抑制HSP90的固有ATP酶活性的化合物;通过遍在蛋白酶体途径降解、靶向于、降低或抑制HSP90的客户(client)蛋白的化合物。靶向于、降低或抑制HSP90的固有ATP酶活性的化合物尤其是可抑制HSP90的ATP酶活性的化合物、蛋白质或抗体,例如17-烯丙基氨基,17-脱甲氧基格尔德霉素(17AAG)、格尔德霉素衍生物;其它格尔德霉素相关化合物;radicicol和HDAC抑制剂。
本文所用的术语“抗增殖性抗体”包括但不限于曲妥珠单抗(HerceptinTM)、曲妥珠单抗-DM1、埃罗替尼(erlotinib)(TarcevaTM)、贝伐单抗(bevacizumab)(AvastinTM)、利妥昔单抗、PRO64553(抗-CD40)和2C4抗体。抗体是指例如完整的单克隆抗体、多克隆抗体、由至少两个完整的抗体形成的多特异性抗体以及抗体片断,只要它们能够显示所需的生物学活性即可。
对于急性骨髓性白血病(AML)的治疗而言,可将式I化合物与标准的白血病治疗联合使用,尤其是与用于治疗AML的治疗联合使用。更确切地说,式I化合物可以与例如法尼基转移酶抑制剂和/或其它用于治疗AML的药物诸如柔红霉素、阿霉素、Ara-C、VP-16、替尼泊苷、米托蒽醌、伊达比星、卡铂和PKC412联合给药。
用代码、类名或商标名确定的活性剂的结构可以得自标准纲要“默克索引(The Merck Index)”的现行版本或得自数据库,例如PatentsInternational(例如,IMS World Publications)。
可以与式I化合物联合使用的上述化合物可按照本领域已知的诸如以上所引用的文献所述的方法进行制备和给药。
式I化合物还可有利地与已知的治疗方法组合使用,例如激素疗法或尤其是放射疗法。
式I化合物尤其可用作放射致敏剂,特别是用于治疗对放射疗法表现出不良敏感性的肿瘤。
“联合形式”是指在一个剂量单位形式中的固定的组合,或用于联合给药的成套的药盒,其中式I化合物和联合伴侣可以独立地在相同的时间给药或在一定时间间隔内、尤其是可以使联合伴侣产生合作的,例如协同的效果的时间间隔内分别给药,或它们的各种组合。
实施例
以下实施例是用于解释说明、而不是进一步限制本发明。
实施例1
N-[1-环己基-2-氧代-2-(6-苯乙基-八氢-吡咯并[2,3-c]吡啶-1-基)-乙基]-2-甲基氨基-丙酰胺(9);
式I的化合物9按照方案5所述的方法制得。
方案5
1-(1-萘-1-基-乙基)-氮杂环丙烷-2-甲酸甲酯(1)
向(S)-(-)-1-(1-萘基)乙基胺(20.8g,120mmol)的乙腈(HPLC级,600mL)溶液中加入K2CO3(52.7g,360mmol)和2,3-二溴丙酸甲酯(30g,120mmol)。将该溶液在室温下搅拌过夜。将溶液蒸发至干,然后加入H2O/EtOAc(1∶1)(600mL),将混合物用EtOAc萃取(4×100mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶2)得到24g(78%)标题化合物,为等分子比率的两种非对映体的混合物。M+H+=256.10。
丁-3-烯基-苯乙基-胺(2)
向2-苯基乙基胺(72mL,570mmol)的溶液中加入K2CO3(82g,570mmol)和4-溴-1-丁烯(25g,185mmol)。将该溶液在室温下搅拌过夜。将溶液蒸发至干并加入H2O/EtOAc(1∶1)(600mL)。将混合物用EtOAc萃取(4×150mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc1∶8)得到20g(62%)标题化合物。M+H+=176.10。1-(1-萘-1-基-乙基)-氮杂环丙烷-2-甲酸丁-3-烯基-苯乙基-酰胺(3)
向1(12.6g,49.75mmol)的THF(200mL)溶液中加入KOTMS(6.38g,49.75mmol)。将混合物在室温下搅拌过夜。将混合物浓缩,将残余物溶于二氯甲烷(200mL)并冷却至0℃。缓慢加入三甲基乙酰氯(5.94g,49.25mmol),将混合物在2小时升温至室温。将混合物冷却至-78℃,加入2(8.63g,49.25mmol),然后在-78℃下继续搅拌1.5小时。加入饱和碳酸氢钠(100mL)并将混合物升温至室温。将混合物用EtOAc萃取(4×100mL),将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶8)得到15g(76%)标题化合物,为等分子比率的两种非对映体的混合物。M+H+=399.37。
1-(1-萘-1-基-乙基)-6-苯乙基-八氢-吡咯并[2,3-c]吡啶-7-酮(4)
将3(15g,58.7mmol)的邻二氯苯(100mL)溶液在250℃下在微波反应器中加热1200秒。将混合物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶1;第二个点)得到5g(33%)标题化合物,为对映体纯的化合物。M+H+399.32。
1-(1-萘-1-基-乙基)-6-苯乙基-八氢-吡咯并[2,3-c]吡啶(5)
向4(4.8g,12mmol)的THF(100mL)溶液中于-78℃下缓慢加入1MDIBAL的甲苯溶液(50mL,50mmol)。将混合物在室温下搅拌1小时,然后用20mL水终止反应。蒸发溶剂,将残余物用100mL 1∶1饱和Rochells盐/15%NaOH稀释并用EtOAc萃取(4×50mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶9)得到2.3g(48%)标题化合物。M+H+=385.26。
6-苯乙基-八氢-吡咯并[2,3-c]吡啶(6)
向5(2.3g,6mmol)的MeOH/CH2Cl2(1∶1;200mL)溶液中加入Pd(OH)2(300mg)。将混合物在50psi.氢气氛下搅拌10小时。将混合物通过硅藻土垫过滤,将滤液浓缩,残余物不经进一步纯化即可直接用于下一步骤。M+H+=231.17。
化合物(7)
向6的二氯甲烷(25mL)溶液中依次加入二异丙基乙基胺(4.17mL,24mmol)、t-Boc-L-环己基甘氨酸(1.54g,6mmol)和0.45 M HOBt/HBTU的DMF溶液(16mL,7.19mmol)。将混合物在室温下搅拌过夜,然后用EtOAc(200mL)稀释,依次用1M柠檬酸水溶液(50mL)、水(50mL)、饱和NaHCO3水溶液(50mL)和盐水洗涤(2×50mL)。将有机层干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶9)得到黄色油。将该黄色油溶于二氯甲烷(20mL),加入TFA(10mL)并将混合物在室温下搅拌3小时。将混合物浓缩,将残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩得到1.75g(79%两步骤)标题化合物,其不经进一步纯化或表征即可用于下一步骤。
化合物(9)
向7(1.75g,4.74mmol)的二氯甲烷(25mL)溶液中依次加入二异丙基乙基胺(3.30mL,19mmol)、t-Boc-N-甲基-L-丙氨酸(0.97g,4.74mmol)和0.45MHOBt/HBTU的DMF溶液(13mL,5.691mmol)。将混合物在室温下搅拌过夜。将混合物用EtOAc(200mL)稀释,依次用1M柠檬酸(50mL)、水(50mL)、饱和NaHCO3水溶液(50mL)和盐水洗涤(2×50mL)。将有机层干燥并真空浓缩。将残余物溶于二氯甲烷(20mL),加入TFA(10mL)并将混合物在室温下搅拌3小时。将混合物浓缩,将残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过HPLC纯化(C-18硅胶,20%CH3CN/H2O的0.5%TFA溶液)得到1g(36%,两步)标题化合物,为TFA盐。M+H+=455.39。
实施例2
(S)-N-((S)-1-环己基-2-{(2S,3R)-2-[(乙基-苯乙基-氨基)-甲基]-3-甲基-吡咯烷-1-基}-2-氧代-乙基)-2-甲基氨基-丙酰胺(23)
丁-3-烯基-((S)-1-苯基-乙基)-胺(A)
向S-(-)-1-苯基乙基胺(15.75g,130mmol)的150mL DMF溶液中于0℃下分成小份加入K2CO3(53.9g,390mmol)。在0℃下搅拌10分钟后,滴加4-溴丁烯(13.5g,100mmol),然后分成小份加入NaI(58.5g,390mmol)。将反应混合物(白色悬浮液)加热至95℃并搅拌过夜/16小时。将溶液冷却至室温,用200mL乙醚稀释,用3×100ml水洗涤。将有机层用Na2SO4干燥并浓缩。将粗产物通过蒸馏纯化(65~70℃,在高真空下)得到无色液体(13.5g,76.7%)。(经NMR和MS数据证实,U-4117-28-23)。
[丁-3-烯基-((S)-1-苯基-乙基)-氨基]-乙酸乙酯(B)
向丁-3-烯基-((S)-1-苯基-乙基)-胺(6.37g,36.4mmol)的150mL DMF溶液中于0℃下分成小份加入K2CO3(10.0g,72.8mmol)。在0℃下搅拌10分钟后,缓慢加入溴乙酸乙酯(8.35g,54.6mmol)。将反应混合物(白色悬浮液)在室温下搅拌过夜/16小时。将溶液用200mL乙醚稀释,用3×100ml水洗涤。将粗产物通过色谱纯化(己烷/CH2Cl2:50/50)得到浅色液体(8.5g,94.5%)。(经NMR和MS数据证实,U-4117-58)。
(2S,3R)-3-丁-3-烯基-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸乙酯(C)
向二异丙基胺(3.6g,35.7mmol)的THF(80mL)溶液中于-40℃下缓慢加入BuLi(14.28mL,35.7mmol,2.5M的己烷溶液)。将溶液温热至0℃并搅拌30分钟以形成LDA溶液。将该LDA溶液冷却至-70℃并将其于-70℃下缓慢加入到[丁-3-烯基-((S)-1-苯基-乙基)-氨基]-乙酸乙酯(7.8g,29.8mmol)的THF(80mL)溶液中。将浅黄色反应溶液在-20℃下搅拌30分钟,变成深黄色溶液,然后冷却至-70℃。向该溶液中于-70℃下滴加**ZnBr2 **(16.76g,74.5mmol)的乙醚(50mL)溶液。在室温下搅拌1.5小时后,将反应溶液冷却至0℃并缓慢加入CuCN(3.47g,38.74mmol)和LiCl(3.29g,77.48mmol)的THF(80mL)溶液。在0℃下搅拌10分钟后,将烯丙基溴(7.26g,60mmol)滴加到该反应溶液中,然后非常缓慢地升温至室温。在室温下搅拌过夜后,通过加入60mL饱和NH4Cl终止反应,然后用3X150mL乙醚萃取。将合并的有机层浓缩。将粗产物通过色谱纯化(己烷/EtOAc:85/15)得到无色液体(7.4g,82.6%)。(经NMR和MS数据证实,U-4117-40-19,U-4117-34-35)。将**ZnBr2 **于使用前在150℃及高真空下干燥1小时**。
(2S,3R)-1-((2E,4Z)-(S)-1,2-二甲基-己-2,4-二烯基)-3-(3-氧代-丙基)吡咯烷-2-甲酸乙酯(D)
将(2S,3R)-3-丁-3-烯基-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸乙酯(1.0g,3.32mmol)溶于EtOH(10mL)和HCl(0.5mL,37%),然后冷却至-70℃。将臭氧气体通过溶液鼓泡约10分钟,或者直至溶液变成非常浅的蓝色。将氮气通过该溶液鼓泡15分钟以除去溶液中过量的臭氧。向冷却的溶液中加入Zn粉(0.43g.6.6mmol)和HCl(0.5mL,37%)并在室温下搅拌20分钟。过滤后,将溶液用50mL CH2Cl2稀释,用饱和NaHCO3(10mL)和2×20ml水洗涤。干燥并浓缩后,得到无色液体(1.0g),其不经进一步纯化即可用于下一步骤的反应。(经NMR和MS数据证实,U-4117-51-30)。
(2S,3R)-3-(3-苯乙基氨基-丙基)-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸乙酯(E)
向(2S,3R)-1-((2E,4Z)-(S)-1,2-二甲基-己-2,4-二烯基)-3-(3-氧代-丙基)吡咯烷-2-甲酸乙酯(1.g,粗品)的EtOH(10mL)溶液中于室温下加入苯乙基胺(0.44g,3.65mmol)。在室温下搅拌30分钟后,一次性加入NaBH3CN(0.3g,4.87mmol)。在室温下搅拌1.5小时后,将反应溶液用50mL乙醚稀释,用20mL盐水洗涤。将乙醚层浓缩,将粗产物通过色谱纯化(CH2Cl2/MeOH:97/3)得到浅色液体(405mg,30.0%)。(经NMR和MS数据证实,U-4117-52-20)。
(3aS,7aS)-6-苯乙基-1-((S)-1-苯基-乙基)-八氢-吡咯并[2,3-c]吡啶-7-酮(F):
将(2S,3R)-3-(3-苯乙基氨基-丙基)-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸乙酯(340mg,0.83mmol)溶于20mL MeOH/KOH/H2O(10mL/5g/5mL)。在80℃下搅拌2小时后,将溶液冷却至0℃,通过加入HCl(37%)中和至pH=5。浓缩后,将粗产物溶于1mL CH2Cl2并通过短硅胶柱过滤,用CH2Cl2/MeOH(93/7)洗脱得到酸形式的浅色玻璃状固体(250mg,78.9%)。(经NMR和MS数据证实,U-4117-60-22)。
向(0.05~0.1M)酸(1当量)的DMF溶液中于室温下加入二异丙基乙基胺(5当量)。在室温下搅拌20分钟后,将(0.05~0.1M)HOBT(1.2当量)和HBTU(1.2当量)的DMF溶液加入到反应混合物中并继续搅拌1.5小时(或者通过TLC监测)。将反应溶液用乙醚稀释(溶液体积的1X5~10倍),用水洗涤(两次,每次为3倍溶液体积)。将合并的有机溶液浓缩。将粗产物用CH2Cl2稀释,用Na2SO4干燥,通过色谱纯化(CH2Cl2/MeOH:97/3)得到纯产物(70~95%的收率)。(经NMR和MS数据证实,U-4117-102)。
合成化合物F的方法:
将(2S,3R)-3-(2-苯乙基氨基-乙基)-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸甲酯(400mg,1.05mmol)和2-羟基吡啶(100mg,1.05mmol)的THF(10mL)溶液在40℃下搅拌24小时。将反应液用50mL乙醚稀释,用2×120mL水洗涤。干燥并浓缩后得到浅色液体(350mg,LC/MS表明仅有纯净的产物),其不经进一步纯化即可用于下一步骤的反应。
(3aR,8aS)-7-苯乙基-1-((S)-1-苯基-乙基)-十氢-吡咯并[2,3-c]氮杂(G)
向(0.02M)内酰胺(1当量)的THF溶液中于-20℃下缓慢加入LiAlH4(2当量)的THF溶液(0.02M)。在室温下搅拌1.5小时后,将溶液用乙醚稀释(溶液体积的1×5倍),用水洗涤(两次,每次为溶液体积的2倍),干燥并浓缩。将粗产物通过色谱纯化(CH2Cl2/MeOH:97/3)得到产物(收率:70~90%)。(经NMR和MS数据证实,U-4117-104)。
(3aR,8aS)-7-苯乙基-十氢-吡咯并[2,3-c]氮杂(H)
将1000ml圆底烧瓶中的反应物(<1g)和10%Pd碳(20重量%)的MeOH(10mL,含有2滴乙酸)溶液/悬浮液在室温及气囊产生的氢气(在大气压下)下剧烈搅拌4~8小时。通过室内真空脱气10分钟后,将反应混合物过滤除去催化剂并浓缩。将粗产物用CH2Cl2/H2O(8/2,适量)稀释,用10%NH4OH中和至pH=7~8。干燥并浓缩后得到产物(80%~定量收率),其不经进一步纯化即可用于下一步骤的反应。(经NMR和MS数据证实,U-4117-105)。
(S)-N-((S)-1-环己基-2-{(2S,3R)-2-[(乙基-苯乙基-氨基)-甲基]-3-甲基-吡咯烷-1-基}-2-氧代-乙基)-2-甲基氨基-丙酰胺(化合物23):从化合物H按照方案5所述的方法制得。
实施例3
方案6
二苯乙基胺(D)
向苯乙醛(6.0g,50mmol)和2-苯基乙基胺的THF(200mL)溶液中滴加三乙酰氧基-硼氢化钠。将溶液在氮气下于室温下搅拌过夜。将溶液用饱和碳酸氢钠水溶液(200mL)终止反应并用EtOAc(4×100mL)萃取。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;EtOAc/MeOH 9∶1)得到1.25g(11%)化合物D,为澄清的油。M+H+=226.10。二苯乙基-(S)-1-吡咯烷-2-基甲基-胺(E)
向(S)-2-甲酰基-吡咯烷-1-甲酸叔丁酯(1.0g,5.0mmol)和D(1.125g,5.0mmol)的THF(40mL)溶液中滴加三乙酰氧基硼氢化钠。将溶液在氮气下于室温下搅拌过夜。将溶液用饱和碳酸氢钠水溶液(40mL)终止反应。将混合物用EtOAc萃取(4×50mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc4∶1)得到黄色油。将该黄色油溶于二氯甲烷(20mL),加入TFA(10mL)并将混合物在室温下搅拌3小时。将混合物浓缩,将残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩得到1.04g(68%,两步)标题化合物E,其不经进一步纯化或表征即可用于下一步骤。
化合物(F)
向t-Boc-L-环己基甘氨酸(0.868g,3.38mmol)的DMF(20mL)溶液中加入二异丙基乙基胺(1.83mL,16.9mmol)。将混合物在室温下搅拌20分钟。然后加入E、HOBt(516mg,3.82mmol)和HBTU(1.448g,3.82mmol)的DMF(30mL)溶液。将混合物在室温下搅拌过夜,然后用乙醚(200mL)稀释并依次用1M柠檬酸水溶液(50mL)、水(50mL)、饱和NaHCO3水溶液(50mL)和盐水(2×50mL)洗涤。将有机萃取液干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 2∶3)得到黄色油。将该黄色油溶于二氯甲烷(20mL),加入TFA(10mL)并将混合物在室温下搅拌3小时。将混合物浓缩,将残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩得到780mg(52%,两步)标题化合物F,其不经进一步纯化或表征即可用于下一步骤。
化合物26
向t-Boc-N-甲基-L-丙氨酸(354mg,1.75mmol)的DMF(20mL)溶液中加入二异丙基乙基胺(0.938mL,8.75mmol)。将混合物在室温下搅拌20分钟。然后加入F、HOBt(267mg,1.98mmol)和HBTU(751mg,1.98mmol)的DMF(30mL)溶液。将混合物在室温下搅拌3小时,然后用乙醚(200mL)稀释并依次用1M柠檬酸(50mL)、水(50mL)、饱和NaHCO3水溶液(50mL)和盐水(2×50mL)洗涤。将有机萃取液干燥并真空浓缩。将残余物溶于二氯甲烷(20mL)并加入TFA(10mL)。将混合物在室温下搅拌3小时并浓缩。将得到的残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩。将部分残余物通过HPLC纯化(C-18硅胶,30%CH3CN/H2O的0.5%TFA溶液)得到120mg化合物26,为TFA盐。M+H+=533.47。
实施例4
化合物32按照以下方法制得:
方案7
化合物I
将化合物G(122mg,1mmol)和H(226mg,1mmol)溶于5mL DME。向该混合物中加入1mL 2N Na2CO3水溶液和50mg Tetrakis。将形成的混合物脱气5分钟,在90℃下搅拌6小时,冷却至室温并浓缩。将残余物通过快速色谱纯化(乙酸乙酯/己烷)得到琥珀色油状的I(204mg,90%)。该粗产物不经进一步纯化或表征即可直接用于下一步反应。
化合物J
将LAH(38mg)于0℃下加入到I(226mg,1mmol)的5mL THF溶液中。将该混合物的温度升温至室温并继续搅拌过夜。通过Fisher方法终止反应,过滤并浓缩得到无色油状的J(183mg,92%),其不经进一步纯化或表征即可直接用于下一步反应。
化合物K
将化合物J(198mg,1mmol)和MnO2(870mg,10mmol)的15mL氯仿悬浮液搅拌过夜。过滤并浓缩得到无色油状的产物K(192mg,98%)。1H NMR(CDCl3)δ9.96(s,1H),7.72(s,2H),7.47(s,2H),7.15-7.35(m,5H),4.07(s,2H)。
化合物L
将3-氯丙基胺盐酸盐(140mg,1.1mmol)、醛K(196mg,1.0mmol)和碳酸钠(212mg,2mmol)在水(10mL)中的混合物于室温下搅拌过夜。将形成的溶液用乙酸乙酯萃取(3×20mL),分离,用Na2SO4干燥,真空(15Torr)蒸发得到基本上纯净的油状残余物(270mg),其不经进一步纯化即可用于下一步反应。(M+H+272,计算值:272)。
化合物M
将亚胺L(271mg,1mmol)于-78℃下加入到锂粉末(75mg,10mmol)和催化量的DTBB(30mg,0.10mmol;5%mol)在THF(5mL)中的蓝色悬浮液中。将形成的混合物在相同的温度下搅拌2小时。用水(20mL)终止反应,将温度升至20℃。将形成的溶液依次通过用2 M盐酸(3×15mL)和4 M氢氧化钠(3×20mL)酸-碱萃取而进行纯化。将最终的溶液用乙酸乙酯萃取(3×20mL),分离,用Na2SO4干燥,蒸发得到纯化合物M(214mg,90%);(M+H+238,计算值:238)。
化合物O
将化合物M(237mg,1mmol)、化合物N(257mg,1mmol)、HBTU(460mg,1.2mmol)、HOBT(170mg,1.1mmol)、DIPEA(512mg,3mmol)和5mL DMF的混合物搅拌过夜。将混合物用乙醚(25mL)稀释,用水、盐水洗涤,用MgO4干燥,过滤并浓缩。将得到的残余物用2mL CH2Cl2/TFA(1/1)处理,搅拌2小时,浓缩得到浅黄色固体状产物O(320mg,85%);(M+H+377,计算值:377)。
化合物32
将化合物O(376mg,1mmol)、t-Boc-N-甲基丙氨酸P(203mg,1mmol)、HBTU(460mg,1.2mmol)、HOBT(170mg,1.1mmol)、DIPEA(512mg,3mmol)和5mL DMF的混合物搅拌过夜。将混合物用乙醚(25mL)稀释,用水、盐水洗涤,用MgO4干燥,过滤并浓缩。将得到的残余物用2mL CH2Cl2/TFA(1/1)处理,搅拌2小时并真空浓缩。通过柱色谱纯化得到浅黄色固体状化合物32(397mg,86%)。(M+H+462,计算值:462)。
实施例5
(S)-N-{(S)-1-环己基-2-[(S)-2-(茚满-2-基氧基甲基)-吡咯烷-1-基]-2-氧代-乙基}-2-甲基氨基-丙酰胺(34)
(S)-2-甲磺酰基氧基甲基-吡咯烷-1-甲酸叔丁酯,(P)
将火焰干燥的装有(S)-2-羟基甲基-吡咯烷-1-甲酸叔丁酯(1g,5mmol)、二氯甲烷(DCM)(20mL)和三乙基胺(0.70mL,5.2mmol)的烧瓶在N2下冷却至0℃,然后在10分钟内向其中滴加甲磺酰氯(0.38mL,5mmol)的DCM(5mL)溶液。将反应液搅拌1小时。加入DCM(100mL)后,将反应混合物用盐水洗涤,干燥并真空浓缩。将残余物通过SiO2色谱纯化(5%EtOAc/己烷)得到1.38g甲磺酸酯(P),为澄清的无色油:LCMS(ES)280.10(MH+)。(S)-2-(茚满-2-基氧基甲基)-吡咯烷-1-甲酸叔丁酯,(Q)
将氢化钠(60%)(0.6g,14.4mmol)加入到火焰干燥的装有茚满-2-醇(0.965g,7.2mmol)和N,N’-二甲基甲酰胺(DMF)(20mL)的烧瓶中,在N2下冷却至0℃并搅拌30分钟。将(S)-2-甲磺酰基氧基甲基-吡咯烷-1-甲酸叔丁酯(P)(1g,3.6mmol)的DMF(5mL)溶液以使反应混合物的温度保持在0℃的方式滴加到反应混合物中。将反应液在60℃下搅拌1小时,冷却至0℃,用盐水终止反应,用EtOAc稀释,用盐水反复洗涤(6X),干燥并真空浓缩。将残余物通过SiO2色谱纯化(5%EtOAc/己烷)得到0.20g茚满基醚(Q),为澄清的无色油:LCMS(ES)340.17(MNa+)。
(S)-N-{(S)-1-环己基-2-[(S)-2-(茚满-2-基氧基甲基)-吡咯烷-1-基]-2-氧代-乙基}-2-甲基氨基-丙酰胺,(34)
将((S)-1-{(S)-1-环己基-2-[(S)-2-(茚满-2-基氧基甲基)-吡咯烷-1-基]-2-氧代-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(Q)(0.54g,1mmol)溶于DCM(8mL)并用三氟乙酸(4mL)处理45分钟。将反应混合物真空浓缩,通过制备型反相hplc纯化得到澄清树胶状的0.096g甲基胺(34):LCMS(ES)442.26(MH+)。
实施例6
1-溴-3-苯氧基-苯(A)
将二溴苯(3g,12.75mmol)、苯酚(1g,10.6mmol)、氧化亚铜(I)(152mg,1mmol)和碳酸铯(3.46g,10.6mmol)在8mL NMP中的混合物在微波中于195℃下加热20分钟。将该多相混合物通过硅藻土床过滤,将残余物用EtOAc洗涤(1×20mL)。将滤液用1N NaOH(200mL)稀释并用EtOAc萃取(3×100mL)。将有机液合并,用Na2SO4干燥,过滤并减压浓缩得到黄色油状粗产物,将其通过柱色谱纯化(100%己烷)得到无色油状的1-溴-3-苯氧基-苯(1.4g,53%)。LCMS m/z 250(M+1)。
5-(3-苯氧基-苯基)-3,4-二氢-2H-吡咯(B):
向1-溴-3-苯氧基-苯(10.13g,40.6mmol)在无水THF(100mL)中的冷却的溶液(-78℃)中于氮气下加入n-BuLi(1.6M,44.7mmol,27mL)。将混合物搅拌30分钟,然后在氮气下通过套管将其加入到冷的(-780℃)1-(叔丁氧基羰基)-2-吡咯烷酮的无水THF(50mL)溶液中。将形成的混合物升温至室温过夜,然后用水(200mL)终止反应并用EtOAc萃取(3×100mL)。收集有机液,用Na2SO4干燥,过滤并减压浓缩。将残余物溶于CH2Cl2(20mL)并在搅拌下加入TFA(10mL)。将混合物搅拌30分钟,用冰冷的饱和NaHCO3终止反应,用CH2Cl2萃取(3×100mL),将有机液合并,用Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱纯化(20%EtOAc/己烷)得到浅黄色油状的5-(3-苯氧基-苯基)-3,4-二氢-2H-吡咯(6.1g,63%)。LCMS m/z238(M+1)。
(S)-2-(3-苯氧基-苯基)-吡咯烷(C):
向烘箱干燥的圆底烧瓶中加入S,S-EBTHITiF2(100mg,0.3mmol)并用THF(5mL)稀释。将烧瓶密封并用氩气净化。向该黄色溶液中加入苯基硅烷(4.6mL,37.5mmol)、吡咯烷(100μL,1.1mmol)和无水甲醇(100μL,1.1mmol)。将形成的黄色混合物搅拌45分钟,直至持续是绿色。将5-(3-苯氧基-苯基)-3,4-二氢-2H-吡咯(1.2g,5.05mmol)的THF(2mL)溶液加入到催化剂中并将混合物搅拌8小时。用10%HCl(100mL)小心地终止反应,直至停止气体溢出并且pH~2。将混合物用EtOAc(100mL)稀释,除去水层,用3M NaOH(50mL)中和至碱性,然后用EtOAc萃取(3×100mL)。将有机液合并,用Na2SO4干燥,过滤并减压浓缩。将固体残余物通过硅胶柱色谱纯化(100%EtOAc)得到黄色固体状的(S)-2-(3-苯氧基-苯基)-吡咯烷(580mg,48%)。LCMS m/z 240.1(M+1)。
{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基}-氨基甲酸叔丁酯(D):
将(S)-2-(3-苯氧基-苯基)-吡咯烷(1.2g,5.02mmol)加入到Boc-L-α-环己基甘氨酸(1.42g,5.2mmol)、HOBt(1.0g,7.53mmol)和HBTU(2.86g,7.53mmol)的10mL DMF溶液中。加入Hunig碱(3.6ml,20mmol)并将混合物搅拌30分钟。将混合物用盐水(20mL)稀释并用EtOAc萃取(3×10mL)。将有机液合并,用Na2SO4干燥,过滤,减压浓缩,然后通过硅胶柱色谱纯化(20%EtOAc/己烷)得到白色粉末状的{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基}-氨基甲酸叔丁酯(1.65g,66%)。LCMS m/z 479.2(M+1)。
(S)-2-氨基-2-环己基-1-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙酮(E):
向{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基}-氨基甲酸叔丁酯的CH2Cl2(20mL)溶液中加入TFA(10mL)并将混合物搅拌30分钟。将混合物减压浓缩,以定量收率得到(S)-2-氨基-2-环己基-1-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙酮的TFA盐(1.65g)。LCMS m/z379(M+1)。
((S)-1-{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(F):
向Boc-N-甲基-L-丙氨酸(771mg,3.79mmol)、HOBt(700mg,5.17mmol)和HBTU(2.0g,5.17mmol)的DMF(10mL)溶液中加入(S)-2-氨基-2-环己基-1-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙酮和DIPEA(3mL,17.25mmol)。将混合物搅拌30分钟,用盐水(20mL)稀释并用EtOAc萃取(3×10mL)。将有机液合并,用Na2SO4干燥,过滤,减压浓缩,然后通过硅胶柱色谱纯化(50%EtOAc/己烷)得到白色粉末状产物((S)-1-{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(1.3g,84%)。LCMS m/z 564(M+1)。
(S)-N-{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基}-2-甲基氨基-丙酰胺(45):
向((S)-1-{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(450mg,0.79mmol)的CH2Cl2(20mL)溶液中加入TFA(10mL)并搅拌30分钟。将混合物减压浓缩,然后通过反相柱色谱纯化得到TFA盐形式的产物(370mg,82%)。LCMS m/z 464.1(M+1)。
实施例7
(S)-2-(1H-四唑-5-基)-吡咯烷-1-甲酸叔丁酯(A)
向(S)-2-氰基-吡咯烷-1-甲酸叔丁酯(500mg,2.55mmol)的N,N-二甲基-甲酰胺(20mL)溶液中加入叠氮化钠(174mg,2.68mmol)和氯化铵(150mg,2.81mmol)。将溶液在93℃下搅拌过夜。将溶液倒入5%柠檬酸溶液和冰中,然后将混合物用EtOAc萃取。将有机萃取液用盐水洗涤,干燥并真空浓缩。将粗品油不经进一步纯化直接用于下一步骤。M+H+240。
(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-甲酸叔丁酯(B)
向粗品化合物A的N,N-二甲基-甲酰胺(5mL)溶液中加入K2CO3(1.16g,8.4mmol)和苄基溴(665μL,5.6mmol)。将溶液在室温下搅拌1小时。将混合物用EtOAc稀释并用盐水洗涤。将有机层干燥并真空浓缩。将残余物通过快速柱色谱纯化(己烷/EtOAc)得到404mg标题化合物M+H+=330和401mg另一种区域异构体(S)-2-(1-苄基-1H-四唑-5-基)-吡咯烷-1-甲酸叔丁酯(C)。M+H+=330。该两步的合并收率是87%。
2-苄基-5-(S)-吡咯烷-2-基-2H-四唑(D)
向化合物B的DCM(5mL)溶液中加入三乙基硅烷(479μL,3.0mmol)和TFA(5mL)。将溶液在室温下搅拌1小时并真空干燥。将粗品油不经进一步纯化直接用于下一步骤。M+H+=230。
{2-[(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-氨基甲酸叔丁酯(E)
向(S)-叔丁氧基羰基氨基-环己基-乙酸(123.8mg,0.48mmol)的DMA(5mL)溶液中加入HBTU(248.8mg,0.656mmol)、HOBt(88.6mg,0.656mmol)和二异丙基乙基胺(305μL,1.75mmol)。将混合物在室温下搅拌5分钟。将化合物D的DCM(5mL)溶液于0℃下加入到上述混合物中。将反应混合物在室温下搅拌1小时并真空浓缩。将残余物用EtOAc稀释。将有机液用盐水、柠檬酸(5%)、盐水、NaHCO3(饱和)和盐水洗涤。然后将有机层干燥并真空浓缩。将残余物通过快速柱色谱纯化(己烷/EtOAc)得到标题化合物190mg(92%)。M+H+=369。
2-氨基-1-[(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-基]-2-环己基-乙酮;与三氟乙酸所形成的化合物(F)
向化合物E的DCM(4mL)溶液中于0℃下加入TFA(4mL)。将溶液在室温下搅拌1小时并真空干燥。将粗品油不经进一步纯化直接用于下一步骤。M+H+=369。
((S)-1-{2-[(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基氨基甲酰基}-丙基)-甲基-氨基甲酸叔丁酯(G)
向(S)-2-(叔丁氧基羰基-甲基-氨基)-丁酸(53.0mg,0.24mmol)的DMA(2mL)溶液中加入HBTU(125.0mg,0.33mmol)、HOBt(44.6mg,0.33mmol)和二异丙基乙基胺(192μL,1.1mmol)。将混合物在室温下搅拌5分钟。将化合物F的DCM(2mL)溶液于0℃下加入到上述混合物中。将反应混合物在室温下搅拌1小时并真空浓缩。将残余物用EtOAc稀释。将有机液用盐水、柠檬酸(5%)、盐水、NaHCO3(饱和)和盐水洗涤。然后将有机层干燥并真空浓缩。将粗品油不经进一步纯化直接用于下一步骤。M+H+=554。
(S)-N-{2-[(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-2-甲基氨基-丁酰胺;与三氟乙酸所形成的化合物(50)
向化合物G的DCM(2mL)溶液中于0℃下加入TFA(2mL)。将溶液在室温下搅拌1小时并真空干燥。将粗品油通过HPLC纯化得到标题化合物。M+H+=467。
实施例8
2-(苄氧基亚氨基-甲基)-吡咯烷-1-甲酸叔丁酯(A)
向苄基羟基胺(2.64g,16.56mmol)的干燥吡啶(20ml)溶液中加入2-甲酰基-吡咯烷-1-甲酸叔丁酯(3.30g,16.56mmol)。将溶液在室温下搅拌3小时。将反应溶液用水终止反应并用二氯甲烷萃取。将有机层合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;50%至50%乙酸乙酯的己烷溶液)得到4.9g(98%)标题化合物。M+H+-Boc=205.1。
吡咯烷-2-甲醛-O-苄基-肟(B)
将2-(苄氧基亚氨基-甲基)-吡咯烷-1-甲酸叔丁酯(1.50g,4.92mmol)和TFA(10ml)的二氯甲烷(10ml)溶液在室温下搅拌2小时。除去溶剂。粗产物不经进一步纯化即可用于下一步骤。M+H+=205.1。
{(S)-2-[苄氧基亚氨基-甲基-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-氨基甲酸叔丁酯(C)
将boc-L-α-环己基甘氨酸(1.27g,4.92mmol)、1-羟基苯并三唑(0.99g,7.38mmol)、二异丙基乙基胺(2.54g,19.68mmol)和O-苯并三唑-N,N,N,N-四甲基-脲六氟磷酸盐(2.80g,7.38mmol)的二氯甲烷(30ml)溶液在室温下搅拌15分钟。加入吡咯烷-2-甲醛-O-苄基-肟(~1.00g,0.49mmol)的二氯甲烷溶液。将反应溶液在室温下搅拌3小时,然后用饱和NaHCO3水溶液终止反应,用二氯甲烷萃取。将有机层合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;20%至70%乙酸乙酯的己烷溶液)得到1.81g(83%,2步)标题化合物。M+H+=444.2。
1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-甲醛-O-苄基-肟(D)
将{(S)-2-[苄氧基亚氨基-甲基-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-氨基甲酸叔丁酯(1.76g,3.97mmol)和TFA(10ml)的二氯甲烷(20ml)溶液搅拌1小时。真空除去溶剂。残余物不经进一步纯化即可用于下一步骤。M+H+=344.2。
((S)-1-{(S)-2-[2-(苄氧基亚氨基-甲基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(E)
将Boc-L-α-环己基甘氨酸(0.81g,3.87mmol)、1-羟基苯并三唑(0.81g,5.95mmol)、二异丙基乙基胺(2.05g,15.88mmol)和O-苯并三唑-N,N,N,N-四甲基-脲六氟磷酸盐(2.35g,5.95mmol)的二氯甲烷溶液在室温下搅拌15分钟。加入1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-甲醛-O-苄基-肟(~1.40g,3.97mmol)的二氯甲烷溶液。将反应溶液在室温下搅拌3小时,然后用饱和NaHCO3水溶液终止反应并用二氯甲烷萃取。将有机层合并,干燥并真空浓缩。残余物不经进一步纯化即可用于下一步骤。M+H+=529.4。
(S)-N-{2-[2-(苄氧基亚氨基-甲基-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-2-甲基氨基-丙酰胺(8)
将((S)-1-{(S)-2-[2-(苄氧基亚氨基-甲基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(~2.10g,3.97mmol)和TFA(20ml)的二氯甲烷(40ml)溶液搅拌1小时。真空除去溶剂。得到1.36g粗产物。将粗产物(0.66g)通过HPLC纯化(C18硅胶,10%至70%CH3CN/H2O的0.1%TFA溶液)得到0.058g标题化合物,为异构体混合物的TFA盐。M+H+=429.4。
实施例9-78
以下化合物通过与本文所述的相类似的方法利用类似的原料制得:
式I范围内的另外的化合物包括:
实施例195
(S)-N-[(S)-1-环己基-2-((R)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基]-2-甲基氨基-丙酰胺(78)
4,4,N-三甲氧基-N-甲基-丁酰胺(1)
向4,4-二甲氧基-丁酸甲酯(4.99g,30.8mmol)和N,O-二甲基羟基胺HCl(4.65g,47.68mmol)的60mL THF溶液中于-20℃下加入异丙基氯化镁(46mL,92.28mmol,2.0M的THF溶液),将温度保持在-20℃以下。在-10℃下搅拌30分钟后,将反应混合物用50mL水终止反应并用3×80mL EtOAc萃取。将合并的有机层用Na2SO4干燥并通过短硅胶柱过滤。将溶液浓缩得到浅色液体状的4,4,N-三甲氧基-N-甲基-丁酰胺(5.9g,99%)。M/Z=191.0。N-[1-乙-(Z)-亚基-5,5-二甲氧基-2-氧代-戊基]-丙烯酰亚胺酰基(acrylimidoyl)溴(2)
向2,6-二溴吡啶(8.1g,34.03mmol)的80mL乙醚悬浮液中于-70℃下一次性加入BuLi(12.3mL,26.17mmol,2.5 M的己烷溶液)。在-70℃下搅拌5分钟后,将4,4,N-三甲氧基-N-甲基-丁酰胺(5.0g,26.17mmol)加入到该溶液中。在-70℃下搅拌1.5小时后,将反应混合物用120mL水终止反应并用3×130mL EtOAc萃取。将合并的有机层浓缩,通过色谱纯化(己烷/EtOAc:70/30)得到浅黄色液体状的N-[1-乙-(Z)-亚基-5,5-二甲氧基-2-氧代-戊基]-丙烯酰亚胺酰基溴(5.96g,60.5%)。M/Z=288.0。
N-[1-乙-(Z)-亚基-2,5-二氧代-戊基]-丙烯酰亚胺酰基溴(3)
向N-[1-乙-(Z)-亚基-5,5-二甲氧基-2-氧代-戊基]丙烯酰亚胺酰基溴(7.0g,28.9mmol)在丙酮(30mL)和水(1.5mL)中的溶液中于室温下加入Amberlyse-15(20g)。在室温下机械振荡3小时后,将反应混合物过滤。将树脂珠粒用丙酮(含有10%Et3N)洗涤。将合并的有机层浓缩,通过色谱纯化(己烷/EtOAc:70/30)得到浅黄色液体状的N-[1-乙-(Z)-亚基-2,5-二氧代-戊基]-丙烯酰亚胺酰基溴(5.18g,88.1%)。M/Z=421,243.9[M+1]。
2-溴-6-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-吡啶(4)
向N-[1-乙-(Z)-亚基-2,5-二氧代-戊基]-丙烯酰亚胺酰基溴(1.0g,4.1mmol)和R(+)-α-甲基苄基胺(0.5g,4.1mmol)的17mL CH2Cl2溶液中于-70℃下加入乙酸(0.6mL)和三乙酰氧基硼氢化钠(1.74g,8.2mmol)。在-70℃下搅拌40分钟后,除去干冰浴,将反应溶液升温至室温。在室温下搅拌过夜后,将反应混合物用20mL水终止反应并用3×30mL CH2Cl2.萃取。将合并的有机层浓缩,通过色谱纯化(己烷/EtOAc:70/30)得到浅黄色液体状的2-溴-6-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-吡啶(0.86g,62.9%)。M/Z=332.7[M+1]。
(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(5)
向2-溴-6-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-吡啶(86.5mg,2.57mmol)、2-氟-甲基苯胺(64.7mg,5.14mmol)和2-(二-环己基膦)-联苯(38.5mg,0.13mmol)的20mL甲苯溶液中于室温下加入Pd2(dba)3(117.6mg,0.13mmol)。将反应混合物在80℃下搅拌2小时,然后冷却至室温。将反应混合物通过硅藻土过滤,将滤液用50mL EtOAc稀释并用2×50mL水洗涤。将合并的有机层浓缩,通过色谱纯化(CH2Cl2/MeOH:97/3)得到浅色固体状的(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(870mg,90.3%)。M/Z=376.0[M+1]。(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(6)
在含有300mg Pd/C的500mL圆底烧瓶中,将(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(500mg,1.33mmol)溶于10mL MeOH。将反应混合物在气囊产生的H2气(1atm)下搅拌24小时。真空脱气后,将反应混合物过滤以除去催化剂。将粗产物通过反相HPLC纯化得到黄色油状的(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(200mg,55.4%)。M/Z=272.07[M+1]。
[(S)-1-环己基-2-((S)-2-{1-[(E)-(Z)-N-(2-氟-苯基)-N-甲基-1-imioxo-丙烯基亚氨基]-烯丙基}-吡咯烷-1-基)-2-氧代-乙基]-氨基甲酸叔丁酯(7)
向Boc-L-a-环己基甘氨酸(204mg,0.79mmol)的5mL DMF溶液中于室温下缓慢加入二异丙基乙基胺(0.58mL,3.3mmol)。在室温下搅拌20分钟后,将HOBT(116mg,0.86mmol)和HBTU(325mg,0.86mmol)的DMF(5mL)溶液加入到反应混合物中,然后将溶液转移到另一个含有(Z)-N-(2-氟-苯基)-N-甲基-N′-[(S)-1-吡咯烷-2-基-丙-2-烯-(E)-亚基]-丙烯脒(180mg,0.66mmol)的烧瓶中。搅拌1小时后,将反应溶液用EtOAc(50mL)稀释并用水洗涤(3×20mL)。将合并的有机层浓缩。将粗产物用CH2Cl2(10mL)稀释并用Na2SO4干燥,通过色谱纯化(CH2Cl2/MeOH:97/3)得到浅色树胶状的[(S)-1-环己基-2-((S)-2-{1-[(E)-(Z)-N-(2-氟-苯基)-N-甲基-1-imioxo-丙烯基亚氨基]-烯丙基}-吡咯烷-1-基)-2-氧代-乙基]-氨基甲酸叔丁酯(320mg,94.5%)。N/Z=511.14[M+1]。
(Z)-N′-[1-[(S)-1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-N-(2-氟-苯基)-N-甲基-丙烯脒(8)
向[(S)-1-环己基-2-((S)-2-{1-[(E)-(Z)-N-(2-氟-苯基)-N-甲基-1-imioxo-丙烯基亚氨基]-烯丙基}-吡咯烷-1-基)-2-氧代-乙基]-氨基甲酸叔丁酯(320mg,0.63mmol)的CH2Cl2(3mL)溶液中于-20℃下缓慢加入TFA(5mL,预冷却至-20℃)。在0℃下搅拌30分钟后,将反应混合物浓缩以除去大部分的TFA。将残余物溶于20mL CH2Cl2,用10%NH4OH中和至pH=8。将溶液用Na2SO4干燥,浓缩得到浅色树胶状(Z)-N′-[1-[(S)-1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-N-(2-氟-苯基)-N-甲基-丙烯脒(260mg,定量),其不经进一步纯化即可用于下一步骤的反应。
M/Z=411.2[M+1]。
{(S)-1-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基氨基甲酰基]-乙基}-甲基-氨基甲酸叔丁酯(9)
向Boc-N-甲基-L-a-丙氨酸(155mg,0.76mmol)的5mL DMF溶液中于室温下缓慢加入二异丙基乙基胺(0.58mL,3.3mmol)。在室温下搅拌20分钟后,将HOBT(111mg,0.82mmol)和HBTU(311mg,0.82mmol)的DMF(5mL)溶液加入到反应混合物中,然后将该溶液转移到另一个含有(Z)-N′-[1-[(S)-1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-N-(2-氟-苯基)-N-甲基-丙烯脒(260mg,0.63mmol)的烧瓶中。搅拌1小时后,将反应溶液用EtOAc(50mL)稀释,用水洗涤(3×20mL)。将合并的有机层浓缩。将粗产物用CH2Cl2(10mL)稀释并用Na2SO4干燥,然后通过色谱纯化(CH2Cl2/MeOH:97/3)得到浅色树胶状的{(S)-1-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基氨基甲酰基]-乙基}-甲基-氨基甲酸叔丁酯(300mg,79.5%)。M/Z=596.2[M+1]。
(S)-N-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基]-2-甲基氨基-丙酰胺(78)
向{(S)-1-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基氨基甲酰基]-乙基}-甲基-氨基甲酸叔丁酯(300mg,0.50mmol)的CH2Cl2(1mL)溶液中于-20℃下缓慢加入TFA(5mL,预冷却至-20℃)。在0℃下搅拌30分钟后,将反应混合物浓缩,通过制备型HPLC纯化(柱:Waters Sunfire prep C18 30×100mm;流动相:恒溶剂条件,CH3CN 28%/H2O 72%,含0.1%TFA;流速:45mL/min)得到(S)-N-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基]-2-甲基氨基-丙酰胺(206mg,67.0%),为白色固体状的TFA盐。(HRMass M/Z=496.3069[M+1])。
为了测定本发明化合物与BIR3肽结合袋结合的能力,采用ELISA和基于细胞的试验。
Elisa
将化合物与GST-BIR3融合蛋白和生物素化的SMAC肽(AVPFAQK)一起在涂覆有链霉抗生物素的96孔板中培养。对于XIAP BIR3 Smac Elisa,采用含有来自XIAP的氨基酸248-358的GST-BIR3融合蛋白。对于CIAP1BIR3 Smac Elisa,采用含有来自CIAP1的氨基酸259-364的GST-BIR3融合蛋白。培养30分钟后,将各孔充分洗涤。通过ELISA试验检测剩余的GST-BIR3融合蛋白,该试验包括,首先与山羊抗-GST抗体一起培养,然后进行洗涤并与同碱性磷酸酶结合的抗-山羊抗体一起培养。将信号用Attophos(Promega)放大并用Cytoflour Ex 450nm/40和Em 580nm读取信号。IC50相当于置换一半GST-BIR3信号的化合物浓度。对于非生物素结合的Smac的IC50是400nM。在所述的ELISA试验中,表1所列的化合物的IC50值为0.005-10μM。
细胞增殖试验
化合物在体外抑制肿瘤细胞生长的能力用AQueousNon-Radioactive Cell Proliferation Assay(Promega)进行测定。该试验由新的四唑鎓化合物[3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H-四唑鎓,内盐;MTS]和电子偶合试剂(吩嗪硫酸甲酯)PMS组成。MTS被细胞生物还原成甲产物,在490nm测定其吸光度。MTS向水溶性田产物的转化由具有代谢活性的细胞内的脱氢酶来完成。由490nm的吸光度所测得的甲产物的量与培养物内活细胞的数量成正比。在所述的细胞试验中,表1所列的化合物的IC50值为0.005-50μM。
实施例196
包含式(I)化合物的片剂1
利用常规方法制得具有下列组成的片剂,所述的片剂包含作为活性成分的50mg前述实施例9-194所述的式(I)化合物中的任一种化合物:
组成: | |
活性成分 | 50mg |
小麦淀粉 | 60mg |
乳糖 | 50mg |
胶态二氧化硅 | 5mg |
滑石 | 9mg |
硬脂酸镁 | 1mg |
总量 | 175mg |
生产:将活性成分与一部分小麦淀粉、乳糖和胶态二氧化硅相混合,然后将混合物过筛。将另一部分小麦淀粉与5.倍量的水在水浴中混合以形成糊剂,然后将首先制得的混合物与该糊剂捏合,直至形成弱可塑性物质。
将干燥颗粒通过筛孔尺寸为3mm的筛网,与剩余的玉米淀粉、硬脂酸镁和滑石的预先过筛的混合物(1mm筛网)相混合并压片以形成略微双凸的片剂。
实施例197
包含式(I)化合物的片剂2
按照标准方法制得具有下列组成的片剂,所述的片剂包含作为活性成分的100mg实施例9-194的式(I)化合物中的任一种化合物:
组成: | |
活性成分 | 100mg |
结晶乳糖 | 240mg |
微晶纤维素(Avicel) | 80mg |
PVPPXL | 20mg |
气相法二氧化硅(Aerosil) | 2mg |
硬脂酸镁 | 5mg |
总量 | 447mg |
生产:将活性成分与载体物质相混合,然后通过压片机(Korsch EKO,Stempeldurchmesser 10mm)压片。
实施例198
胶囊
按照标准方法制得具有下列组成的胶囊,所述的胶囊包含作为活性成分的100mg实施例9-194给出的式(I)化合物中的任一种化合物:
组成: | |
活性成分 | 100mg |
微晶纤维素(Avicel) | 200mg |
PVPPXL | 15mg |
气相法二氧化硅(Aerosil) | 2mg |
硬脂酸镁 | 1.5mg |
总量 | 318.5mg |
生产通过混合各成分、然后将其填充到1号硬明胶胶囊中来完成。
Claims (4)
1.式IVa化合物或其可药用盐:
其中
R1是H或C1-C4烷基;
R2是H或C1-C4烷基;
R3是C1-C4烷基;
R4是环己基、环戊基或C1-C4烷基;
R5是H;
U如结构式V所示:
其中
n=0;
X是N;
Rc是H;
Rd是Ar1-D-Ar2,其中D是-CH2-、-CF2-、-O-、-C(O)-、-S-、-S(O)-、-S(O)2-、1,3-二氧杂环戊烷或N(Rh)-,其中Rh是H、任选地被OH取代的C1-C7烷基、CF3、-C(O)H或-SO2CH3,并且Ar1和Ar2是取代或未取代的芳基或het,其中所述het可被甲基取代并且选自吡啶基、嘧啶基、四唑基、三唑基、吡唑基、唑基、噻唑基、二唑基、吡咯基或三嗪基,并且所述的芳基是可被一个或两个卤素取代的苯基;
R6、R7、R′6和R′7均是H。
2.权利要求1所述的化合物或其可药用盐,其中Ar1是吡啶基或噻唑基;Ar2是可被一个或两个卤素取代的苯基。
3.权利要求1或2所述的化合物或其可药用盐,其中D是-CH2-、-CF2-、-O-或-C(O)-。
4.权利要求1所述的化合物,其选自
N-[(1S)-1-环己基-2-[(2S)-2-[6-[(2-氟苯基)甲基氨基]-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[2-(苯基甲基)-2H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丁酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-咪唑-4-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[6-(苯基甲基)吡嗪基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[4-(苯基甲基)-1,3,5-三嗪-2-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[2-[(4-氟苯基)甲基氨基]-4-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-吡咯-3-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2-[(2S)-2-(4-苯甲酰基-2-噻唑基)-1-吡咯烷基]-1-环己基-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[4-(苯基甲基)-2-唑基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2-[(2S)-2-(4-苯甲酰基-5-甲基-2-唑基)-1-吡咯烷基]-1-环己基-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-吡唑-4-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-1,2,3-三唑-4-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[2-氟-5-(甲基-2-吡啶基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(甲基-2-嘧啶基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(甲基-2-吡啶基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[6-(甲基-2-吡啶基氨基)-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[6-[(2,4-二氟苯基)甲基氨基]-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2-[(2S)-2-[6-[(3-氯苯基)甲基氨基]-2-吡啶基]-1-吡咯烷基]-1-环己基-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[6-[(4-氟苯基)甲基氨基]-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[6-(甲基苯基氨基)-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[2-[(2-氟苯基)甲基氨基]-4-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[2-[(2-氟苯基)甲基氨基]-4-嘧啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-[苯基(三氟甲基)氨基]苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-[(2-羟基乙基)苯基氨基]苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(甲酰基苯基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-[(甲基磺酰基)苯基氨基]苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环戊基-2-[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2,2-二甲基-1-[[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]羰基]丙基]-2-(甲基氨基)-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-3-甲基-1-[[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]羰基]丁基]-(2S)-丙酰胺,
2-(甲基氨基)-N-[(1S)-1-[[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]羰基]丙基]-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-1-甲基-2-[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯基氨基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(3-吡啶基氧基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(2-苯氧基-4-嘧啶基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(2-苯氧基-4-吡啶基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(5-苯氧基-3-吡啶基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(6-苯氧基-2-吡啶基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2,2-二甲基-1-[[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]羰基]丙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环戊基-2-氧代-2-[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-3-甲基-1-[[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]羰基]丁基]-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-1-甲基-2-氧代-2-[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]乙基]-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-2-甲基-1-[[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]羰基]丙基]-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(2-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(4-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(2-苯基-1,3-二氧杂环戊烷-2-基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2-[(2S)-2-(3-苯甲酰基苯基)-1-吡咯烷基]-1-环己基-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(二氟苯基甲基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯基亚磺酰基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯基磺酰基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丁酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[2-(苯基甲基)-2H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丁酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[2-(苯基甲基)-2H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯硫基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-2-甲基-1-[[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]羰基]丙基]-(2S)-丙酰胺;和
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯基甲基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
或其可药用盐。
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