CN114846005B - Shp2抑制剂及其应用 - Google Patents
Shp2抑制剂及其应用 Download PDFInfo
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- CN114846005B CN114846005B CN202180007361.7A CN202180007361A CN114846005B CN 114846005 B CN114846005 B CN 114846005B CN 202180007361 A CN202180007361 A CN 202180007361A CN 114846005 B CN114846005 B CN 114846005B
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- dihydrospiro
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- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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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
- C07D401/14—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 three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
Abstract
本发明涉及一种作为含Src同源区2蛋白质酪氨酸磷酸酶2(SHP2)抑制剂的化合物(如式I所示),及其药物组合物、制备方法,以及其在治疗SHP2介导的疾病中的用途。本发明的化合物通过参与调节细胞增殖、凋亡、迁移、新生血管生成等多个过程而发挥作用。
Description
技术领域
本发明涉及一系列作为含Src同源区2蛋白质酪氨酸磷酸酶2(Srchomologyregion 2-containing protein tyrosine phosphatase 2,SHP2)抑制剂的化合物及其制备方法、药物组合物。本发明还涉及上述化合物或其药物组合物在治疗SHP2介导的疾病中的用途。
背景技术
含Src同源区2蛋白质酪氨酸磷酸酶2(Src homologyregion 2-containingprotein tyrosine phosphatase 2,SHP2)是由一种由PTPN11基因编码的非受体型蛋白质酪氨酸磷酸酶,PTPN11是首个被发现的编码酪氨酸激酶的原癌基因(Chan R J etal.PTPN11 is the first identified proto-oncogene that encodes a tyrosinephosphatase.Blood,2007,109:862-867),其编码的SHP2蛋白包含N端的SHP2结构域(N-SHP2)、C端SHP2结构域(C-SHP2)、蛋白质磷酸酶催化结构域(PTP),两个C端的酪氨酸残基(Y542和Y580)以及一个富含脯氨酸(Pro)的模体。
近年研究主要认为Ras/ERK通路是SHP2发挥作用最重要的一条信号转导通路,其机制(Dance M et al.The molecular functions of Shp2 in the RAS/mitogen-activated protein kinase(ERK1/2)pathway.Cell Signal,2008,20:453-459)大致为:生长因子受体活化后,其酪氨酸残基发生自体磷酸化,为Grb2和SHP2(含有SH2结构域的衔接蛋白)磷酸酪氨酸结合区域SH2提供停靠位点。Grb2与磷酸化的生长因子受体的结合导致SOS蛋白在胞膜的聚集。SOS作为一种鸟嘌呤核苷酸交换因子(guanine nucleotideexchange factor,GEF),可以催化膜结合蛋白Ras从无活性的Ras-GDP转换为有活性的Ras-GTP。Ras-GTP再进一步与下游的信号系统发生联系,激活Ser/Thr激酶Raf1等,进而在调节激酶MEK的作用下使ERK活化,ERK活化后直接作用于细胞质的靶分子或转移到细胞核内调节基因转录,使细胞增殖或分化。这一过程可能还受到SHP2结合蛋白和底物(SHPsubstrate-1,SHPS-1)、Ras-GTP酶活化蛋白(Ras-GAP)以及其他Src成员的影响。
SHP2蛋白不仅调节Ras/ERK信号通路,另有报道其还调节JAK-STAT3、NF-κB、PI3K/Akt、RHO和NFAT等多条信号通路,进而调节细胞增殖、分化、迁移、凋亡等生理学功能。
SHP2被证明与多种疾病相关,Tartaglia等(Tartaglia M et al Mutations inPTPN11,encoding the protein tyrosine phosphatase SHP-2,cause Noonansyndrome.Nat Genet,2001,29:465-468)发现大约50%的努南综合征患者伴有PTPN11的错义突变。另外,研究发现PTPN11突变是JMML以及多种白血病发病的重要原因(Tartaglia Met al.Nat Genet,2003,34:148-150;Loh ML et al.Blood,2004,103:2325-2331;Tartaglia M et al.Br J Haematol,2005,129:333-339;Xu R et al.Blood,2005,106:3142-3149.)。随着对PTPN11/SHP2研究的深入,发现其与肺癌、胃癌、结肠癌、黑色素瘤、甲状腺癌等多种癌症的发生均有的关系(唐春兰等.中国肺癌杂志,2010,13:98-101;HiguchiM et al.Cancer Sci,2004,95:442-447;Bentires-Al j M et al.Cancer Res,2004,64:8816-8820;Martinelli S et al.Cancer Genet Cytogenet,2006,166:124-129.)。
因此,SHP2抑制剂作为潜在的治疗手段得到了越来越多的关注。目前在开发的SHP2抑制剂有多种,诺华开发的TNO155在2017年进入治疗实体瘤的I期临床试验;加科思设计开发的JAB-3068于2018年1月正式获得美国FDA新药临床实验许可;Revolution开发的RMC-4630于2018年下半年进行首次人体临床试验;以及后续进入临床阶段的SHP2靶点分子JAB-3312、BBP-398、RLY-1971和ERAS-601。目前,该靶点在国内外还未见上市品种,因此,开发出能够靶向抑制SHP2活性的小分子药物,为患者提供更加安全有效的SHP2抑制剂具有重要的研究意义。
发明内容
本发明涉及一种作为含Src同源区2蛋白质酪氨酸磷酸酶2(SHP2)抑制剂的化合物,或其药学上可接受的盐、顺反异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物,所述化合物如式(I)所示:
其中,
R1任意地选自氢、氨基、-C(O)-NH2、-C=N、羟基、C1-8烷基、含取代基的C1-8烷基、C1-8烷氧基、含取代基的C1-8烷氧基;
R2任意地选自氢或C1-4烷基;
R3任意地选自氢、卤素、氨基、-C=N、C1-8烷基、含取代基的C1-8烷基、C1-8烷氧基、合取代基的C1-8烷氧基;
R4选自Ra或Rb,其中当R4为Rb时,Rb可以被m个Rc取代;
Ra任意地选自卤素、氨基、酰胺基或磺酰基;
Rb任意地选自C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、C3-8碳环基、C3-8杂环基、C5-8芳基或C5-8杂芳基,所述C3-8杂环基和C5-8杂芳基含有1-3个独立地选自氮、氧和硫的杂原子;
Rc选自氨基、羟基、卤素、C1-3烷基或C1-3烷氧基;
m为0、1、2或3;
Q任意地选自C2-4烷基、C2-4烯基或C2-4炔基,其中C2-4烷基和C2-4烯基可以被卤素、C1-3烷基或C1-3卤代烷基取代;
U任意地选自C(R5)2、O或NR6;
其中,R5和R6独立地选自氢、羟基、卤素;
环A任意地选自C6-10芳基或C5-10杂芳基,所述C5-10杂芳基含有一个或两个N或S杂原子;
Rx任意地选自羟基、卤素、氰基、氨基、含取代基的氨基、磺酰基、C1-8烷基、含取代基的C1-8烷基、C1-8烷氧基、含取代基的C1-8烷氧基、C3-8环烷基或含取代基的C3-8环烷基;
n为0、1、2、3或4。
一些实施方式中,式I中的R1任意地选自氢或含取代基的C1-3烷基。
一些实施方式中,式I中的R1任意地选自氢或羟基取代的甲基。
一些实施方式中,式I中的R2为氢。
一些实施方式中,式I中的R3任意地选自氢、C1-3烷基或氨基。
一些实施方式中,式I中的R3任意地选自氢、甲基或氨基。
一些实施方式中,式I中的R3选自氢。
一些实施方式中,式I中的R4任意地选自酰胺基、甲磺酰基、卤素取代的C1-3烷基、羟基取代的C1-3烷基、C3-6环烷基、甲基取代的C3-6环烷基、苯基、吡啶、嘧啶、咪唑、吡唑、噻唑、噁唑,其中苯基、吡啶、嘧啶、咪唑、吡唑、噻唑、噁唑可以任意地被m个Rc取代。
一些实施方式中,式I中的R4任意地选自-CF3、
一些实施方式中,式I中的Q任意地选自C2烷基、C2烯基或C2炔基,其中C2烷基和C2烯基可以被卤素、C1-3烷基或C1-3卤代烷基取代;
一些实施方式中,式I中的Q选自
一些实施方式中,式I中的U为CH2或O。
一些实施方式中,式I中的环A任意地选自C5-8芳基或C5-6杂芳基,所述C5-6杂芳基含有一个或两个N或S杂原子。
一些实施方式中,式I中的环A选自苯基。
一些实施方式中,式I中的Rx任意地选自羟基、卤素、氰基、C1-3烷基、卤素取代的C1-3烷基或C1-3烷氧基。
一些实施方式中,式I中的Rx选自甲氧基。
一些实施方式中,式I中的n选自0、1或2。
本发明进一步提供了一种化合物或其药学上可接受的盐,其中,所述化合物选自:
1)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(环丙基乙炔基)吡嗪-2-基)甲醇;
2)(3-((S)-1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-((2-甲基环丙基)乙炔基)吡嗪-2-基)甲醇;
3)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(3-甲基丁-1-炔-1-基)吡嗪-2-基)甲醇;
4)(3-((S)-1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-甲基环丙基)乙烯基)吡嗪-2-基)甲醇;
5)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-环丙基乙烯基)吡嗪-2-基)甲醇;
6)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(3,3,3-三氟丙-1-烯-1-基)吡嗪-2-基)甲醇;
7)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(3-甲基丁-1-烯-1-基)吡嗪-2-基)甲醇;
8)(S)-4-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(羟甲基)吡嗪-2-基)-2-甲基丁-3-烯-2-醇;
9)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(甲磺酰基)乙烯基)吡嗪-2-基)甲醇;
10)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氨基-3-氯吡啶-4-基)乙烯基)吡嗪-2-基)甲醇;
11)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4′-哌啶]-1′-基)-6-(2-(2-甲基噁唑-5-基)乙烯基)吡嗪-2-基)甲醇;
12)(S,Z)-(6-(2-(2-氨基-3-氯吡啶-4-基)乙烯基)-3-(1-氨基-6-甲氧基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)吡嗪-2-基)甲醇;
13)(R,Z)-(6-(2-(2-氨基-3-氯吡啶-4-基)乙烯基)-3-(3-氨基-3H-螺[苯并呋喃-2,4′-哌啶]-1′-基)吡嗪-2-基)甲醇;
14)(S,Z)-1′-(5-(2-(2-氨基-3-氯吡啶-4-基)乙烯基)吡嗪-2-基)-1,3-二氢螺[茚-2,4′-哌啶]-1-胺;
15)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2,3-二氯苯乙烯基)吡嗪-2-基)甲醇;
16)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(吡啶-4-基)乙烯基)吡嗪-2-基)甲醇;
17)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氨基嘧啶-5-基)乙烯基)吡嗪-2-基)甲醇;
18)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(5-氯嘧啶-2-基)乙烯基)吡嗪-2-基)甲醇;
19)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氯-3-氟吡啶-4-基)乙烯基)吡嗪-2-基)甲醇;
20)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(4-氨基-2-氯嘧啶-5-基)乙烯基)吡嗪-2-基)甲醇;
21)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(吡啶-3-基)乙烯基)吡嗪-2-基)甲醇;
22)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-苯乙烯基吡嗪-2-基)甲醇;
23)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(1-甲基-1H-咪唑-5-基)乙烯基)吡嗪-2-基)甲醇;
24)(S,Z)-3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(羟甲基)吡嗪-2-基)丙烯酰胺;
25)(S,E)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-苯乙烯基吡嗪-2-基)甲醇;
26)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(嘧啶-2-基)乙烯基)吡嗪-2-基)甲醇;
27)(S,E)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氨基-3-氯吡啶-4-基)乙烯基)吡嗪-2-基)甲醇;
28)(S,E)-(3-(1-氨基-1,3-二氢螺[茚-2,4′-哌啶]-1′-基)-6-(2-(2-氨基嘧啶-4-基)乙烯基)吡嗪-2-基)甲醇;
29)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(嘧啶-4-基)乙烯基)吡嗪-2-基)甲醇;
30)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(3-氯-2-甲氧基吡啶-4-基)乙烯基)吡嗪-2-基)甲醇;
31)(S,Z)-4-(2-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(羟甲基)吡嗪-2-基)乙烯基)嘧啶-2-醇;
32)(S,Z)-4-(2-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(羟甲基)吡嗪-2-基)乙烯基)-3-氯吡啶-2-醇;
33)(S,Z)-(6-(2-(1H-吡唑-4-基)乙烯基)-3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)吡嗪-2-基)甲醇;
34)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氨基噻唑-5-基)乙烯基)吡嗪-2-基)甲醇;
35)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(噻唑-5-基)乙烯基)吡嗪-2-基)甲醇;
36)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(5-甲基-1H-吡唑-4-基)乙烯基)吡嗪-2-基)甲醇;
37)(S)-4-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(羟甲基)吡嗪-2-基)-2-甲基丁-3-炔-2-醇;
38)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-((甲基磺酰基)乙炔基)吡嗪-2-基)甲醇;
39)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4′-哌啶]-1′-基)-6-(2-(2-氨基-3-氯吡啶-4-基)丙-1-烯-1-基)吡嗪-2-基)甲醇;
40)(S,E)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氨基-3-氯吡啶-4-基)-2-氟乙烯基)吡嗪-2-基)甲醇;或
41)(S,E)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氨基-3-氯吡啶-4-基)-1-氟乙烯基)吡嗪-2-基)甲醇;或
42)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4′-哌啶]-1′-基)-6-(2-(2-氨基-3-氯吡啶-4-基)乙基)吡嗪-2-基)甲醇。
本发明还提供了一种药物组合物,其特征在于,包含治疗有效量的至少一种式(I)所示的化合物和至少一种药学上可接受的辅料。
本发明进一步提供了一种药物组合物,其特征在于,治疗有效量的至少一种式(I)所示的化合物和药学上可接受的辅料的质量百分比为0.0001∶1-10。
本发明提供了结构式(I)所示化合物或药物组合物在制备药物中的应用。
本发明进一步提供了所述应用的优选技术方案:
作为优选,所述应用为制备用于治疗、预防、延迟或阻止癌症,癌症转移,心血管疾病,免疫疾病,纤维化或眼部疾病的药物的应用。
作为优选,所述应用为制备治疗由SHP2介导的疾病的药物中的应用。作为优选,所述疾病是癌症。
作为优选,所述癌症选自Noonan综合征、豹斑综合征、青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合。
作为优选,所述应用为用于制备SHP2抑制剂的应用。
本发明还提供了一种治疗和/或预防由SHP2介导的疾病的方法,包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或药物组合物。
作为优选,在上述方法中,所述SHP2介导的疾病是癌症。
本发明还提供了一种治疗癌症的方法,包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或药物组合物。
作为优选,所述癌症选自Noonan综合征、豹斑综合征、青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合。
作为优选,在上述方法中,所述治疗对象为人类。
除非另有说明,本发明所用术语含义如下:
术语“烷基”包括直连、支链或环状的饱和烷基。例如,烷基包括但不限于甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、环戊基、n-己基、2-己基、2-甲基戊基及环己基等类似基团。类似的,“C1-8烷基”中的“C1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链、支链或环状形式排列的基团。
“烯基”和“炔基”包括直链、支链或环状的烯基和炔基。同样地,“C2-8烯基”和“C2-8炔基”是指含有2、3、4、5、6、7或8个碳原子以直链、支链或环状形式排列的烯基或炔基。
术语“烷氧基”是指前述的直链、支链或环状烷基的氧醚形式。
术语“芳基”是指未取代或取代的包括碳原子的单环或多环芳香基团。优选为6到10元的单环或双环芳香基团。优选为苯基、萘基。最优选为苯基。
术语“杂芳基”是指,从一个母体杂芳环系统的一个碳原子上移走一个氢原子所形成的单价的杂原子基团。杂芳基包括:5-到7-元芳香、单环,包括至少一个选自N、O或S的杂原子,例如,1到4个杂原子,或优选为1到3个杂原子,环上的其他原子为碳;多杂芳基环包括至少一个选自N、O或S的杂原子,例如,1到4个杂原子,或优选为1到3个杂原子,环上的其他原子为碳,且其中至少一个杂原子在芳环上。特别优选的杂芳基基团是C3-10的杂芳基,包括但不限于,吡咯基、呋喃基、噻吩基、吡啶基、吡喃基、吡唑基、嘧啶基、哒嗪基、吡嗪基、咪唑基、噻唑基、恶唑基、异恶唑基、三氮唑基、吲哚基、苯并呋喃基、苯并噻唑基、苯并咪唑基、苯并吡唑基、苯并三氮唑基、咔唑基、喹啉基、异喹啉基、嘌呤基等类似基团。
但是,在任何情况下,杂芳基和芳基都不会彼此交叉或相互包含。因此,根据以上定义,如果至少一个全碳芳香环与一个杂环基相稠合,得到的是杂芳基,而不是芳基。
“碳环基”指饱和的或不饱和的但不具有芳香性的环状基团。根据其饱和度的特殊水平,分别采用术语“环烷基”、“环烯基”或“环炔基”。有代表性的碳环基基团包括但不限于,环丙烷、环丁烷、环戊烷、环己烷或环己烯等类似基团。
“杂环基”是指饱和的或不饱和的但不具有芳香性的环状基团,而且其中一个或多个碳原子(以及所连接的氢原子)可分别被相同的或不相同的杂原子和相应所连接的氢原子所取代。有代表性的取代碳原子的杂原子包括但不限于N、P、O、S和Si。当需要描述特定的饱和度时,分别采用术语“杂环烷基”或“杂环烯基”。具有代表性的杂环基基团包括但不限于环氧化合物、咪唑烷、吗啉、哌嗪、哌啶、吡唑烷、吡咯烷、奎宁环、四氢呋喃或四氢吡喃等类似基团。含取代基的杂环基也包含被至少一个含氧的(=O)或氧化物(-O-)取代基取代的环系统,如:哌啶-氮-氧化物、吗啉基-氮-氧化物、1-氧代-1-硫吗啉基和1-二氧-1-硫吗啉基。
但是,在任何情况下,杂环烷基和碳环基都不会彼此交叉或相互包含。因此,根据上述定义,如果至少一个全碳环与一个杂环烷基稠合形成一个二-、多-或螺-环,将仍然定义为杂环烷基。
另外,如果一个杂芳基与一个杂环基稠和形成一个二-、多-或螺-环,将定义为杂环基而不是杂芳基。
“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。优选的卤素是指氟、氯和溴。
“卤代基”是指氟代、氯代、溴代或碘代基团。优选的卤代基是指氟代和氯代。
“取代”是指一个基团中的一个或多个氢原子分别被相同的或不同的取代基所取代。具有代表性的取代基包括但不限于卤素、氨基、羟基、氧代基、羰基、氰基、-C(O)NH2、烷基、烷氧基、芳基、环烷基、杂环基、杂芳基。在一些实施例中,取代基包含但不限于卤素、氨基、羟基、氰基、甲基、-CH2OH、-C(O)NH2、-OCH3、三氟甲基。
无论何时,术语“烷基”或“芳基”或者其前缀词根出现在取代基名称中(如芳烷基,或二烷基氨基),均应按前述的“烷基”和“芳基”定义对取代基进行限定性解释。碳原子的指定数量(如C1-6)将独立的表示在一个烷基部分或在一个更大的取代基中的烷基部分(其中烷基作为前缀词根)中的碳原子的数量。
本发明所述“化合物”包括式(I)的化合物,及其所有药学上可接受的形式。这些药学上可接受的形式包括盐、溶剂化物、非共价复合物、螯合物、立体异构体(包括非对映异构体、对映异构体和外消旋体)、顺反异构体、同位素标记的化合物、互变异构体、前体药物、或上述所有形式的任意混合物。
所述“顺反异构体”是存在于某些双键化合物或环状化合物中的一种立体异构现象。由于存在双键或环,这些分子的自由旋转受阻,产生两个物理性质或化学性质均不相同的同分异构体,分别称为顺式(cis)和反式(trans)异构体。
除非另有说明,否则本发明化合物意在包括所有这些可能的顺反异构体,包括顺式构型化合物\反式构型化合物和任意比例的顺反异构体混合物。例如化合物(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氯-3-氟吡啶-4-基)乙烯基)吡嗪-2-基)甲醇,包括化合物19a、化合物19b、以及任意比例的化合物19a和化合物19b的混合物。顺反异构体可以使用常规技术来分离(例如,在Prep-HPLC色谱柱上分离)。
所述“药学上可接受的”是指公知的用于动物的,特别是可用于人体的。
本发明中术语“组合物”包括含有特定数量的特定组分的产品,也包括任何由特定数量的特定组分直接或间接得到的产品。因此,包括本发明中的化合物作为活性组分的药物组合物和制备该化合物的方法都是本发明的内容。
“治疗有效量”是指一个化合物施用于治疗主体时治疗并且预防和/或抑制一种疾病、病情、症状、适应症和/或不适的至少一种临床症状时,足以这种疾病、病情、症状、适应症或不适的治疗产生一定效果的剂量。具体的“有效治疗剂量”可以根据化合物,给药途径、患者年龄、患者体重,所治疗的疾病或不适的类型、症状和严重程度等的不同而变化。在任意可能的情况下,一个合适的剂量对那些在本领域的专业人员可以是显而易见的,也可以是用常规实验方法确定的。
本发明提供的化合物可以以“药学上可接受的盐”的形式存在。药物应用方面,本发明提供的化合物的盐是指无毒的药学上可接受的盐。药学上可接受的盐的形式包括药学上可接受的酸/阴离子或碱/阳离子盐。药学上可接受的酸/阴离子盐一般以碱性氮与无机酸或有机酸质子化的形式存在。典型的有机或无机酸包括盐酸、氢溴酸、氢碘酸、高氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、乙醇酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、α-酮戊二酸、马尿酸、苯甲酸、扁桃酸、甲磺酸、羟乙基磺酸、苯磺酸、草酸、扑酸、2-萘磺酸、对甲苯磺酸、环己胺磺酸、水杨酸、糖精酸或三氟乙酸。药学上可接受的碱/阳离子盐,包括但不限于,铝盐、钙盐、氯普鲁卡因盐、胆碱、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐。
本发明化合物的药物前体包含在本发明的保护范围内。通常,所述药物前体是很容易在体内转化成所需要的化合物的功能性衍生物。因此,本发明提供的治疗方法涉及的术语“给药”包括施用本发明公开的化合物,或虽未明确公开但对主体给药后能够在体内转化为本发明公开的化合物治疗所述的各种疾病。有关选择和制备合适药物前体衍生物的常规方法,已记载在例如《药物前体设计》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。
显然的,一个分子中任何取代基或特定位置的变量的定义,与其他分子中的任何取代基或特定位置的变量的定义是无关的。很容易理解,本发明中的化合物可以根据本学科现有技术选择合适的取代基或取代形式,以提供化学上稳定且容易用本学科现有技术或本发明中所述的方法进行制备合成。
当式(I)所示化合物及其药学上可接受的盐为溶剂化物或多晶型的形式时,本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定,只要该溶剂是药理学上可以接受的。例如,水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。当本发明提供的化合物是酸时,可以从药学上可接受的无毒的碱,包括无机碱和有机碱,制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(ic和ous)、铁、亚铁、锂、镁、锰(ic和ous)、钾、钠、锌之类的盐。特别地,优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺,也包括环胺及含有取代基的胺,如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱,包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N′,N′-二苄乙烯二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸,甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明提供的化合物是碱时,可以从药学上可接受的无毒的酸,包括无机酸和有机酸,制得其相应的盐。这样的酸包括,如,醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、羟乙基磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、乳酸、马来酸、苹果酸、扁桃酸、α-酮戊二酸、马尿酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。较优地,苹果酸、柠檬酸、氢溴酸、盐酸、甲磺酸、马来酸、磷酸、硫酸和酒石酸。更优地,磷酸、盐酸和苹果酸。由于式(I)所示化合物将作为药物应用,所以优选使用基本上纯的形式,例如,至少60%纯度,更适当至少75%的纯度,特别适当至少98%的纯度(%是重量比)。
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐),一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下,最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度,但是本发明的药物组合物包括适于口腔、直肠、局部和肠外(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。
实际上,根据常规的药物混合技术,本发明式(I)所示化合物,或药物前体,或代谢物,或药学上可接受的盐,可以合并用药作为活性组分,与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式,取决于想采用的给药方式,例如,口服或注射(包括静脉注射)。因此,本发明的药物组合物可以采用适于口服给药的独立单位的形式,如包含预先确定剂量的活性组分的胶囊剂,扁囊剂或片剂。进一步地,本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液,或油包水型乳液形式。另外,除了上述提到的常见的剂型,式(I)所示化合物或其药学上可接受的盐,也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下,这种方法包括使活性组分和构成一个或多个必要组分的载体缔合的步骤。一般情况下,所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的的密切混合制得。另外,该产品可以方便地制备成所需要的外观。
因此,本发明的药物组合物包括药学上可接受的载体和式(I)所示化合物,或其药学上可接受的盐。式(I)所示化合物,或其药学上可接受的盐,与其他一种或多种具有治疗活性联合用药的化合物的也包括在本发明的药物组合物中。
本发明采用的药物载体可以是,例如,固体载体、液体载体或气体载体。固体载体的例子,包括,乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸、甘露醇、山梨醇、微晶纤维素、无机盐类、淀粉、预胶化淀粉、糖粉、糊精等。液体载体的例子包括,糖浆、花生油、橄榄油和水。气体载体的例子包括二氧化碳和氮气。制备药物口服制剂时,可以使用任何方便的制药学上的介质。例如,水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂;而载体,如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用,口服制剂首选片剂和胶囊。可选地,片剂包衣可使用标准的水制剂或非水制剂技术。
含有本发明化合物或药物组合物的片剂可通过,可选地,可以与一种或多种辅助组分或辅药一起混合、压制或成型制备。活性组分以可以自由流动的形式如粉末或颗粒,与润滑剂、惰性稀释剂、表面活性或分散剂混合,在适当的机器中,通过压制可以制得压制片剂。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物,然后在适当的机器中,通过成型可以制得模制片。较优地,每个片剂含有大约0.01mg到5g的活性组分,每个扁襄剂或胶囊剂含有大约0.1mg到0.5g的活性组分。例如,拟用于人类口服给药的剂型包含约0.1mg到约0.5g的活性组分,与合适且方便计量的辅助材料复合,该辅助材料约占药物组合物总量的5%至99.99%。单位剂型一般包含约0.1mg到约0.5g的有效组分,典型的是0.1mg、0.2mg、0.5mg、1mg、2mg、2.5mg、5mg、10mg、25mg、50mg、100mg、200mg、300mg、400mg或500mg。
本发明提供的适用于胃肠外给药的药物组合物可将活性组分加入水中制备成水溶液或悬浮液。可以包含适当的表面活性剂如十二烷基硫酸钠、聚山梨酯-80(吐温-80)、聚氧乙烯氢化蓖麻油、泊洛沙姆。在甘油、液态聚乙二醇,及其在油中的混合物,也可以制得分散体系。进一步地,防腐剂也可以,包含在本发明的药物组合物中用于防止有害的微生物生长。
本发明提供适用于注射使用的药物组合物,包括无菌水溶液或分散体系。进一步地,上述药物组合物可以制备成可用于即时配制无菌注射液的无菌粉末的形式。无论如何,最终的注射形式必须是无菌的,且为了易于注射,必须是易于流动的。此外,所述药物组合物在制备和储存过程中必须稳定。因此,优选抗微生物如细菌和真菌的污染的保存。载体可以是溶剂或分散介质,例如,水、乙醇、多元醇(如甘油、丙二醇、液态聚乙二醇)、植物油,及其适当的混合物。
本发明提供的药物组合物,可以是适于局部用药的形式,例如,气溶胶、乳剂、软膏、洗液、撒粉,或其他类似的剂型。进一步地,本发明提供的药物组合物可以采用适于经皮给药装置使用的形式。利用本发明式(I)所示化合物,或其药学上可接受的盐,通过常规的加工方法,可以制备这些制剂。作为一个例子,乳剂或软膏剂的制备是通过在上述化合物中加入亲水性材料和水(二者总量约为化合物的5wt%到50wt%),制得具有预期一致性的乳剂或软膏。
本发明提供的药物组合物,可以制成以固体为载体、适用于直肠给药的形式。混合物形成单位剂量的栓剂是最优选的剂型。适当的辅料包括本领域常用的可可脂和其他材料。栓剂可以方便地制备,首先药物组合物与软化或熔化的辅料混合,然后冷却和模具成型而制得。
除了上述提到的载体组分外,上述药学制剂还可以包括,适当的,一种或多种附加的辅料组分,如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂(包括抗氧化剂)等。进一步地,其他的辅药还可以包括调节药物与血液等渗压的促渗剂。包含有式(I)所示化合物,或其药学上可接受的盐的药物组合物,也可以制备成粉剂或浓缩液的形式。
具体实施方式
为使上述内容更清楚、明确,本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式,以使本领域的技术人员能够理解本发明,但不用于限制本发明的保护范围。本发明的具体实施方式中,未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。
除非另有说明,本发明所有的一部分和百分比均按重量计算,所有温度均指摄氏度。
实施例中使用了下列缩略语:
DCM:二氯甲烷;
DIEA:N,N-二异丙基乙胺;
DIBAL-H:二异丁基氢化铝;
DME:乙二醇二甲醚
DMF:N,N-二甲基甲酰胺;
DMSO:二甲基亚砜;
EtOAc:乙酸乙酯;
h、hr或hrs:小时;
LC-MS或LCMS:液相色谱-质谱联用;
MeCN:乙腈;
MeOH:甲醇;
min或mins:分钟;
NEt3:三乙胺;
Prep-HPLC:制备高效液相色谱;
PdCl2(PPh3)2:双三苯基磷二氯化钯;
Pd(PPh3)4:四(三苯基膦)钯;
PE:石油醚;
rt、r.t.或RT:室温;
TFA:三氟乙酸;
THF:四氢呋喃;
Ti(OEt)4:钛酸四乙酯;和
TLC:薄层色谱。
中间体化合物M1的制备:
步骤1:化合物M1-3的制备
氮气保护下,将25.00g化合物M1-1溶解于200mL的DMF中,降温至0℃,分批加入22.70g NaH,0℃保温1hr,然后将54.96g化合物M6-2缓慢滴加到反应液中,滴完后0℃下反应1hr,升温至60℃继续反应1hr。反应液降温至0℃,用500mL冰水淬灭反应,EtOAc(500mL×3)萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得29.00g棕色油状物M1-3。
步骤2:化合物M1-5的制备
将29.00g化合物M1-3溶解于50mL的Ti(OEt)4中,加入34.99g化合物M1-4,然后加热至90℃反应12hrs。TCL检测反应完全,将反应液倒入500mL的冰水中,加入300mL EtOAc搅拌1hr,用EtOAc(300mL×3)萃取,合并有机相,有机相用饱和食盐水(100mL×4)洗涤,无水硫酸钠干燥,减压浓缩得39.00g棕色油状物化合物M1-5粗品。
步骤3:化合物M1-6的制备
氮气保护下,将48.00g化合物M1-5溶解于500mL无水THF中,降温至-20℃,缓慢加入6.73gNaHB4,然后自然升温至RT搅拌2hrs。反应完毕,反应液降温至0℃,用300mL水淬灭,EtOAc(300mL×3)萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得25.40g棕色油状物的化合物M1-6。
步骤4:化合物M1-7的制备
将10.00g化合物M1-6溶解于100mL DCM溶液中,滴加28.04g TFA溶液,然后RT下反应1hr。反应液降温至0℃,用100mL饱和NaHCO3水溶液淬灭,EtOAc∶THF=3∶1(100mL×3)萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得7.64g棕色固体即化合物M1-7粗品,直接用于下一步反应。
1H NMR(500MHz,DMSO-d6)δ7.26-7.21(m,4H),5.80(d,J=10.5Hz,1H),4.43(d,J=10.5Hz,1H),3.17-3.15(m,2H),3.08(d,J=15.5Hz,1H),2.98-2.88(m,2H),2.69(d,J=15.5Hz,1H),2.04-1.99(m,1H),1.80-1.75(m,1H),1.62-1.59(m,1H),1.35(m,1H),1.22(s,9H)。
步骤5:化合物M1-8的制备
将1.29g 3,6-二溴吡嗪-2-甲酸甲酯和1.60g化合物M1-7溶解于20mL四氢呋喃中,滴加1.12g DIEA,60℃搅拌反应12小时。TLC检测反应完全,减压浓缩,加入50mL水,再用EtOAc(50mL×3)萃取,合并有机层,用硫酸钠干燥后脱溶,经柱层析纯化得1.60g化合物M1-8。
步骤6:化合物M1和M2的制备
氮气保护下,将1.00g化合物M1-8溶解于30mL无水二氯甲烷中,温度降至-78℃,滴加DIBAL-H(1M,9.6mL)的正己烷溶液。-78℃搅拌反应1小时。再缓慢升温至-40℃,继续反应2小时。TLC检测原料反应完全,在0℃下,缓慢滴加0.4mL水,再滴加氢氧化钠水溶液(15%,0.4mL),再加入1mL水。升至室温搅拌15分钟。加入硫酸钠干燥,搅拌十分钟后过滤。滤液浓缩,经柱层析纯化得0.40g化合物M1和0.11g化合物M2。
实施例1化合物1的制备:
步骤1:化合物1-1的制备
将100mg化合物M1、42mg三甲基硅炔环丙烷、15mg PdCl2(PPh3)2、22mg PPh3和10mgCuCl溶于DMF(5mL)中,氮气置换后,90℃反应15h。LC-MS及TLC检测反应完全,加入10mL水淬灭,过滤除去不溶物,DCM(10mL×3)萃取,有机相饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,得105mg粗品化合物1-1直接用于下一步反应。
步骤2:化合物1的制备
将105mg化合物1-1溶解于3.0mL二氧六环和0.5mL MeOH中,加入2N HCl(0.55mL,甲醇溶液),RT搅拌反应0.5h。LCMS和TLC检测反应完全,反应液减压浓缩,残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8~9,将固体干燥,固体经制备薄层色谱纯化得10.0mg浅黄色固体即化合物1。
[M+H+]=375.38。
1H NMR(500MHz,DMSO)δ8.13(s,1H),7.30(d,J=7.0Hz,1H),7.21-7.11(m,3H),5.39(t,J=6.0Hz,1H),4.45(d,J=6.0Hz,2H),3.83(s,1H),3.73-3.66(m,2H),3.10-3.00(m,3H),2.58(d,J=15.0Hz,1H),2.02-1.96(m,1H),1.89-1.84(m,1H),1.78-1.73(m,1H),1.61-1.55(m,1H),1.52-1.49(m,1H),0.93-0.89(m,2H),0.77-0.74(m,2H).
经由不同的反应起始原料和合适的试剂,采用与前述实施例1类似的方法制备表1中的化合物。
表1
实施例5化合物5的制备:
步骤1:化合物5的制备
将90mg化合物1溶解于10mL无水甲醇中,室温加入30mg Pd-CaCO3,氢气置换后,室温搅拌3hrs。LC-MS检测反应完全,将反应液过滤,滤液减压浓缩,残余物经制备薄层色谱纯化得63.3mg化合物5。
[M+H+]=377.32。
1H NMR(500MHz,DMSO-d6)δ8.10(s,1H),7.31(d,J=6.5Hz,1H),7.20-7.10(m,3H),6.25(d,J=11.5Hz,1H),5.19(t,J=5.5Hz,1H),5.13(dd,J=11.5Hz,J=10.5Hz,1H),4.53(d,J=5.5Hz,2H),3.85(s,1H),3.64-3.53(m,2H),3.08-2.96(m,3H),2.96-2.87(m,1H),2.59(d,J=15.5Hz,1H),1.94-1.88(m,1H),1.86-1.77(m,2H),1.54-1.51(m,1H),1.14-1.09(m,1H),0.87-0.82(m,2H),0.47-0.44(m,2H).
经由不同的反应起始原料和合适的试剂,采用与前述实施例5类似的方法制备表2中的化合物。
表2
实施例10化合物10的制备:
步骤1:化合物10-1的制备
将1.85g化合物M1、552mg三甲基硅炔、132mg PdCl2(PPh3)2和36mg CuI溶于THF(66mL)和NEt3(11mL)中,氮气置换后,室温反应4小时。LC-MS及TLC检测反应完全,加入200mL水淬灭,乙酸乙酯(100mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,得1.9g粗品10-1直接用于下一步反应。
步骤2:化合物10-2的制备
将1.9g粗品化合物10-1溶解于20mL的无水甲醇和20mL的THF中。在氮气保护下,加入1.0g碳酸钾,室温下搅拌0.5小时。LC-MS及TLC检测反应完全,将反应液过滤后,真空浓缩,拌硅胶,经柱层析纯化得1.0g黄色固体化合物10-2。
步骤3:化合物10-3的制备
将120mg化合物10-2、254mg 3-氯-4-碘吡啶-2-胺、9.6mg PdCl2(PPh3)2和2.6mgCuI溶于THF(4mL)和NEt3(0.8mL)溶液中,氮气置换后,室温反应2小时。LC-MS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得100mg黄色固体化合物10-3。
步骤4:化合物10-4的制备
将100mg化合物10-3溶解于10mL无水甲醇中,室温加入30mg Pd-CaCO3,氢气置换后,40℃搅拌反应4hrs。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得70mg化合物10-4。
步骤5:化合物10的制备
将60mg化合物10-4溶解于2.5mL二氧六环和0.5mL MeOH中,加入2N HCl(0.5mL,甲醇溶液),RT搅拌反应0.5hrs。LCMS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得13.0mg白色固体即化合物10。
[M+H+]=463.34。
1H NMR(500MHz,DMSO-d6)δ7.85(s,1H),7.78(d,J=5.0Hz,1H),7.30(d,J=7.0Hz,1H),7.18-7.12(m,3H),6.76(d,J=12.0Hz,1H),6.63(d,J=12.5Hz,1H),6.45(d,J=5.5Hz,1H),6.31(s,2H),4.84(t,J=5.5Hz,1H),4.44(d,J=5.0Hz,2H),3.83(s,1H),3.71-3.64(m,2H),3.08-2.99(m,3H),2.58(d,J=15.5Hz,1H),1.88-1.82(m,1H),1.77-1.71(m,1H),1.51-1.48(m,1H),1.10-1.07(m,1H).
经由不同的反应起始原料和合适的试剂,采用与前述实施例10类似的方法制备表3中的化合物。
表3
实施例15化合物15的制备:
步骤1:化合物15-1的制备
将120mg化合物10-2、89.6mg 2,3-二氯-3-碘吡啶、9.6mg PdCl2(PPh3)2和2.6mgCuI溶于THF(4mL)和NEt3(0.8mL)溶液中,氮气置换后,室温反应2小时。LCMS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水反洗,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得120mg黄色固体化合物15-1。
步骤2:化合物15-2的制备
将120mg化合物15-1溶解于10mL无水甲醇中,室温加入40mg Pd-CaCO3,氢气置换后,40℃搅拌,每隔2小时更换催化剂,反复六次。LCMS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得60mg化合物15-2。
步骤3:化合物15的制备
将60mg化合物15-2溶解于2.5mL二氧六环和0.5mL MeOH中,加入2N HCl(0.5mL,甲醇溶液),RT搅拌反应0.5h。LCMS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得27.4mg黄色固体即化合物15(纯度:99%)。
[M+H+]=481.24。
1H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.58(dd,J=7.5,1.5Hz,1H),7.36(dd,J=8.0,1.5Hz,1H),7.31-7.25(m,2H),7.19-7.11(m,3H),6.79(d,J=12.5,1H),6.75(d,J=12.0,1H),4.67(t,J=5.5Hz,1H),4.39(d,J=5.5Hz,2H),3.82(s,1H),3.70-3.61(m,2H),3.09-2.96(m,3H),2.57(d,J=15.5Hz,1H),1.87-1.81(m,1H),1.76-1.71(m,1H),1.51-1.47(m,1H),1.10-1.07(m,1H).
实施例16化合物16(化合物16a和16b的混合物)的制备:
步骤1:化合物16-1的制备
将100mg化合物10-2、93mg化合物4-碘吡啶、8mg PdCl2(PPh3)2、2.2mg CuI和95mgNEt3溶于THF(2mL)中,氮气置换后,室温反应2小时。LC-MS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得70mg黄色固体化合物16-1。
步骤2:化合物16-2(化合物16-2a和16-2b的混合物)的制备
将70mg化合物16-1溶解于5mL无水甲醇中,室温加入20mg Pd-CaCO3,氢气置换后,35℃搅拌反应1.5hrs。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经高效液相制备纯化得20mg化合物16-2a和16-2b的混合物。
步骤3:化合物16(化合物16a和16b的混合物)的制备
将20mg化合物16-2溶解于1.5mL二氧六环和1mL MeOH中,加入2N HCl(0.2mL,甲醇溶液),RT搅拌反应0.5hrs。LCMS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,二氯甲烷(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得7.4mg黄色固体即化合物16(化合物16a和16b的混合物)。
[M+H+]=414.36。
化合物16b反式构型:1H NMR(500MHz,DMSO-d6)δ8.56(d,J=4.5Hz,2H),8.28(s,1H),7.58(d,J=4.5Hz,2H),7.60(d,J=16.0Hz,1H),7.53(d,J=16.0Hz,1H),7.32-7.14(m,4H),5.32(t,J=5.5Hz,1H),4.58(d,J=5.5Hz,2H),3.87(s,1H),3.74-3.71(m,2H),3.12-3.01(m,3H),2.64-2.60(m,1H),1.93-1.74(m,2H),1.55-1.50(m,1H),1.15-1.10(m,1H).
化合物16a顺式构型:1H NMR(500MHz,DMSO-d6)δ8.50(d,J=4.5Hz,2H),8.00(s,1H),7.49(d,J=4.5Hz,2H),7.32-7.14(m,4H),6.75(d,J=13.0Hz,1H),6.67(d,J=13.0Hz,1H),5.10(t,J=5.5Hz,1H),4.58(d,J=5.5Hz,2H),3.85(s,1H),3.74-3.71(m,2H),3.12-3.01(m,3H),2.64-2.60(m,1H),1.93-1.74(m,2H),1.55-1.50(m,1H),1.15-1.10(m,1H).
实施例17化合物17的制备:
步骤1:化合物17-1的制备
将80mg化合物10-2、48mg 2-氨基-5-碘嘧啶、12.8mg PdCl2(PPh3)2、1.7mg CuI和37mg NEt3溶于DMF(3mL)中,氮气置换后,80℃反应2小时。LCMS及TLC检测反应完全,加入30mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水反洗,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得60mg黄色固体化合物17-1。
步骤2:化合物17-2的制备
将60mg化合物17-1溶解于6mL无水甲醇中,室温加入30mg Pd-CaCO3,氢气置换后,40℃搅拌2小时,更换催化剂,氢气置换后40℃搅拌再搅拌3小时,LCMS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得40mg化合物17-2。
步骤3:化合物17的制备
将40mg化合物17-2溶解于1.5mL二氧六环和0.3mL MeOH中,加入2N HCl(0.6mL,甲醇溶液),RT搅拌反应0.5hrs。LCMS和TLC检测反应完全,反应液减压浓缩,残余物加入H2O(2.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后真空浓缩,经Prep-HPLC(FA)制备得4.3mg黄色固体,即化合物17(甲酸盐)。
[M+H+]=430.34。
1H NMR(500MHz,DMSO-d6)δ8.64(s,2H),8.31(s,2H),8.10(s,1H),7.37-7.31(m,1H),7.24-7.13(m,3H),6.82(s,2H),6.45(d,J=13.0Hz,1H),6.39(d,J=12.5Hz,1H),4.52(s,2H),3.94(s,1H),3.72-3.66(m,2H),3.10-3.03(m,3H),2.66(d,J=15.5Hz,1H),1.92-1.77(m,2H),1.53-1.50(m,1H),1.21-1.18(m,1H).
实施例18化合物18的制备:
步骤1:化合物18-1的制备
将100mg化合物10-2、60mg 2-碘-5-氯嘧啶、8.0mg PdCl2(PPh3)2和2.2mg CuI溶于DMF(4mL)和NEt3(46mg)溶液中,氮气置换后,70℃反应2小时。LCMS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得60mg黄色固体化合物18-1。
步骤2:化合物18-2的制备
将60mg化合物18-1溶解于10mL无水甲醇中,室温加入30mg Pd-CaCO3,氢气置换后,室温搅拌反应3hrs。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得20mg化合物18-2。
步骤3:化合物18的制备
将20mg化合物18-2溶解于2.5mL二氧六环和0.5mL MeOH中,加入2N HCl(0.5mL,甲醇溶液),RT搅拌反应0.5hrs。LCMS和TLC检测反应完全,反应液减压浓缩,残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得3.0mg黄色固体即化合物18。
[M+H+]=449.33。
1H NMR(500MHz,DMSO-d6)δ8.91(s,2H),8.39(s,1H),7.94(d,J=10.5Hz,1H),7.54(d,J=10.5Hz,1H),7.19(d,J=7.0Hz,1H),7.20-7.14(m,3H),5.41(t,J=6.0Hz,1H),4.58(d,J=6.0Hz,2H),3.86(s,1H),3.81-3.73(m,2H),3.18-3.11(m,2H),3.08(d,J=15.5Hz,1H),2.64(d,J=15.5Hz,1H),1.92-1.88(m,1H),1.81-1.76(m,1H),1.55-1.52(m,1H),1.15-1.11(m,1H).
实施例19化合物19(化合物19a和19b的混合物)的制备:
步骤1:化合物19-1的制备
将100mg化合物10-2、71mg 2-氯-3-氟-4-碘吡啶、8.0mg PdCl2(PPh3)2和2.2mgCuI溶于THF(5mL)和NEt3(0.1mL)溶液中,氮气置换后,室温反应10分钟。LC-MS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(10ml×2)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品经柱层析纯化得81mg黄色固体化合物19-1。
步骤2:化合物19-2(化合物19-2a和19-2b的混合物)的制备
将81mg化合物19-1溶解于10mL无水甲醇中,室温加入25mg Pd-CaCO3,氢气置换后,40℃搅拌反应2hrs。LC-MS及TLC检测反应一半,终止反应,将反应液过滤,滤液减压浓缩,残余物经Prep-HPLC纯化得12mg化合物19-2a和19-2b的混合物。
[M+H+]=568.13。
步骤3:化合物19(化合物19a和19b的混合物)的制备
将12mg化合物19-2溶解于1.0mL二氧六环和0.5mL MeOH中,加入2N HCl(0.1mL,甲醇溶液),RT搅拌反应1.0hrs。LCMS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(1.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,析出固体,过滤,滤饼用DCM溶解,无水硫酸钠干燥,旋干得4.4mg黄色固体,即化合物19(化合物19a和19b的混合物)。
[M+H+]=466.28。
实施例20化合物20的制备:
步骤1:化合物20-1的制备
将100mg化合物10-2、116mg 4-氨基-2-氯-5-碘嘧啶、8mg PdCl2(PPh3)2和2.2mgCuI溶于THF(2mL)和NEt3(0.127mL)溶液中,氮气置换后,室温反应2小时。LCMS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得52mg黄色固体化合物20-1。
步骤2:化合物20-2的制备
将52mg化合物20-1溶解于5mL无水甲醇中,室温加入30mg Pd-CaCO3,氢气置换后,50℃搅拌反应1.5hrs,LCMS及TLC检测产物生成,过滤,回收原料,继续加入15mg Pd-CaCO3,氢气置换后,50℃搅拌反应5hrs。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经制备薄层色谱纯化得15mg化合物20-2。
步骤3:化合物20的制备
将15mg化合物20-2溶解于1.5mL二氧六环和1mL MeOH溶液中,加入2N HCl(0.6mL,甲醇溶液),RT搅拌反应0.5hrs。LCMS和TLC检测反应完全,反应液减压浓缩,残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,二氯甲烷(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得3.8mg黄色固体化合物20。
[M+H+]=464.29。
实施例21化合物21的制备:
步骤1:化合物21-1的制备
将100mg化合物10-2、56mg 3-碘吡啶、8.0mg PdCl2(PPh3)2和2.2mg CuI溶于THF(4mL)和NEt3(0.8mL)溶液中,氮气置换后,室温反应1小时。LCMS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水反洗,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得100mg黄色固体化合物21-1。
步骤2:化合物21-2的制备
将100mg化合物21-1溶解于10mL无水甲醇中,室温加入35mg Pd-CaCO3,氢气置换后,40℃搅拌12hrs。LCMS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得57mg化合物21-2。
步骤3:化合物21的制备
将57mg化合物21-2溶解于2.5mL二氧六环和0.5mL MeOH溶液中,加入2N HCl(0.5mL,甲醇溶液),RT搅拌反应0.5hrs。LCMS和TLC检测反应完全,反应液减压浓缩,残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得11.0mg黄色固体,即化合物21(纯度:97.9%)。
[M+H+]=414.32。
1H NMR(500MHz,DMSO-d6)δ8.60(d,J=1.7Hz,1H),8.47(dd,J=5.0,1.5Hz,1H),8.11-8.07(m,1H),8.00(s,1H),7.35-7.28(m,2H),7.19-7.12(m,3H),6.71(s,2H),5.00(t,J=5.5Hz,1H),4.47(d,J=5.5Hz,2H),3.84(s,1H),3.73-3.66(m,2H),3.11-3.06(m,2H),3.03(d,J=15.5Hz,1H),2.59(d,J=15.5Hz,1H),1.91-1.85(m,1H),1.80-1.74(m,1H),1.53-1.50(m,1H),1.15-1.09(m,1H).
实施例22化合物22的制备:
步骤1:化合物22-1的制备
将80mg化合物10-2、37mg化合物碘苯、12.8mg PdCl2(PPh3)2、1.7mg CuI和37mgNEt3溶于DMF(3mL)中,氮气置换后,80℃反应2小时。LC-MS及TLC检测反应完全,加入30mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水反洗,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得80mg黄色固体化合物22-1。
步骤2:化合物22-2的制备
将80mg化合物22-1溶解于8mL无水甲醇中,室温加入40mg Pd-CaCO3,氢气置换后,40℃搅拌16小时,LCMS检测反应结束,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得70mg化合物22-2。
步骤3:化合物22的制备
将70mg化合物22-2溶解于2.5mL二氧六环和0.5mL MeOH中,加入2N HCl(1.0mL,甲醇溶液),RT搅拌反应0.5hrs。LCMS检测反应完全,反应液减压浓缩,残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后真空浓缩,经Prep-HPLC(FA)制备得2.6mg黄色固体,即化合物22(甲酸盐)。
[M+H+]=413.43。
1H NMR(500MHz,DMSO-d6)δ8.31(s,1H),7.91(s,1H),7.48-7.40(m,2H),7.35-7.24(m,3H),7.19-7.17(m,3H),6.77(d,J=12.6Hz,1H),6.58(d,J=12.5Hz,1H),4.49(s,2H),3.90(s,1H),3.68-3.60(m,2H),3.07-2.98(m,3H),2.63(d,J=15.0Hz,1H),1.91-1.83(m,1H),1.81-1.73(m,1H),1.52-1.49(m,1H),1.15-1.13(m,1H).
实施例23化合物23的制备:
步骤1:化合物23-1的制备
将100mg化合物10-2、57mg化合物4-碘-1-甲基咪唑、16mg PdCl2(PPh3)2、2.2mgCuI和46mgEt3N溶于DMF(4mL)中,氮气置换后,80℃反应2小时。LC-MS及TLC检测反应完全,加入30mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得50mg黄色固体化合物23-1。
步骤2:化合物23-2的制备
将50mg化合物23-1溶解于5mL无水甲醇中,室温加入25mg Pd-CaCO3,氢气置换后,40℃搅拌反应4hrs。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得20mg化合物23-2。
步骤3:化合物23的制备
将20mg化合物23-2溶解于1.0mL二氧六环和0.2mL MeOH中,加入2N HCl(0.3mL,甲醇溶液),RT搅拌反应0.5hrs。LC-MS和TLC检测反应完全,反应液减压浓缩,残余物加入H2O(1.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得9.1mg白色固体,即化合物23。
[M+H+]=417.34。
1H NMR(500MHz,DMSO-d6)δ8.60(s,1H),8.52(s,1H),7.59(s,1H),7.31(d,J=7.0Hz,1H),7.20-7.11(m,3H),6.51(d,J=13.0Hz,1H),6.30(d,J=13.0Hz,1H),5.48(t,J=5.5Hz,1H),4.65(d,J=5.3Hz,2H),3.85(s,1H),3.66(s,3H),3.58-3.51(m,2H),3.09-2.95(m,3H),2.60(d,J=15.5Hz,1H),1.95-1.90(m,1H),1.85-1.77(m,1H),1.55-1.52(m,1H),1.15-1.10(m,1H).
实施例24化合物24的制备:
步骤1:化合物24-1的制备
将200mg化合物M1、168mg丙炔酰胺、28mg PdCl2(PPh3)2和11mg CuI溶于DMF(3mL)与NEt3(3mL)中,氮气置换后,80℃反应1.5小时。LC-MS及TLC检测反应完全,加入10mL乙酸乙酯,滤掉不溶物,20mL水分散滤液,饱和食盐水洗涤有机相,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得76mg类白色固体化合物24-1。
步骤2:化合物24-2的制备
将76mg化合物24-1溶解于4mL无水甲醇中,室温加入10mg Pd-CaCO3,氢气置换后,室温搅拌反应2hrs。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经高效液相色谱纯化得28mg化合物24-2。
步骤3:化合物24的制备
将28mg化合物24-2溶解于2.5mL二氧六环和0.5mL MeOH中,加入2N HCl(0.5mL,甲醇溶液),RT搅拌反应1hrs。LC-MS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(1.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,二氯甲烷(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得2.7mg黄色固体,即化合物24。
[M+H+]=380.30。
1H NMR(500MHz,DMSO-d6)δ8.88(s,1H),8.54(s,1H),7.30(d,J=6.5Hz,1H),7.23-7.07(m,4H),6.67(d,J=13.5Hz,1H),5.95(d,J=13.5Hz,1H),5.28(t,J=5.5Hz,1H),4.54(d,J=5.5Hz,2H),3.84(s,1H),3.78-3.64(m,2H),3.33-3.08(m,2H),3.05(d,J=15.5Hz,1H),2.61(d,J=15.5Hz,1H),1.92-1.85(m,1H),1.79-1.75(m,1H),1.53-1.51(m,1H),1.13-1.11(m,1H).
实施例25化合物25的制备:
步骤1:化合物25-1的制备
将200mg化合物M1、90mg反式-BETA-苯乙烯硼酸,23.4mg Pd(PPh3)4和172mgNa2CO3溶于DME(6.8mL)与H2O(1.7mL)中,氮气置换后,100℃反应1小时。LC-MS及TLC检测反应完全,加入20mL水淬灭,二氯甲烷(10mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品经柱层析纯化得160mg黄色固体化合物25-1。
步骤2:化合物25的制备
将15mg化合物25-1溶解于0.6mL二氧六环和0.1mL MeOH中,加入2N HCl(0.2mL,甲醇溶液),RT搅拌反应0.5hrs。LC-MS和TLC检测反应完全,反应液减压浓缩,残余物加入H2O(1.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得3.0mg淡黄色固体,即化合物25。
[M+H+]=413.42。
1H NMR(500MHz,DMSO-d6)δ8.25(s,1H),7.63(d,J=7.5Hz,2H),7.57(d,J=16.0Hz,1H),7.42-7.38(m,2H),7.32-7.28(m,3H),7.19-7.15(m,3H),5.27(t,J=5.5Hz,1H),4.57(d,J=5.5Hz,2H),3.87(s,1H),3.71-3.58(m,2H),3.12-3.02(m,3H),2.61(d,J=15.5Hz,1H),1.94-1.87(m,1H),1.84-1.78(m,1H),1.55-1.52(m,1H),1.16-1.13(m,1H).
实施例26化合物26的制备:
步骤1:化合物26-1的制备
将100mg化合物10-2、94mg化合物2-碘嘧啶、8mg PdCl2(PPh3)2和2.2mg CuI溶于THF(2mL)和NEt3(0.127mL)溶液中,氮气置换后,室温反应2小时。LC-MS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(15mL×3)萃取,有机相饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,粗品经制备薄层色谱纯化得68mg黄色固体化合物26-1。
步骤2:化合物26-2的制备
将68mg化合物26-1溶解于5mL无水甲醇中,室温加入20mg Pd-CaCO3,氢气置换后,35℃搅拌反应1.5hrs。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经制备薄层色谱纯化得20mg化合物26-2。
步骤3:化合物26的制备
将20mg化合物26-2溶解于1.5mL二氧六环和1mL MeOH中,加入2N HCl(0.5mL,甲醇溶液),RT搅拌反应0.5hrs。LC-MS和TLC检测反应完全,反应液减压浓缩,残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后减压浓缩,经制备薄层色谱纯化得5.0mg黄色固体化合物26。
[M+H+]=415.40。
实施例27化合物27的制备:
步骤1:化合物27-1的制备
将40mg LiAlH4溶解于3mL THF中,氮气保护下,冰浴中,将溶有200mg化合物10-3的3mL THF溶液缓慢滴加入反应液中,加完后室温搅拌反应1hrs。LC-MS检测反应有50%产品信号,冰浴下,缓慢加饱和氯化铵水溶液淬灭,再用乙酸乙酯萃取,有机相干燥后真空浓缩,残余物经高压液相色谱制备得50mg化合物27-1。
步骤2:化合物27的制备
将50mg化合物27-1溶解于2mL二氧六环和0.4mL MeOH中,加入2N HCl(0.4mL,甲醇溶液),RT搅拌反应0.5hrs。LC-MS和TLC检测反应完全,反应液减压浓缩,残余物加入H2O(2.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(2mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得12.5mg黄色固体即化合物27。
[M+H+]=463.27。
1H NMR(500MHz,DMSO-d6)δ8.25(s,1H),7.88(s,1H),7.73(d,J=16.0Hz,1H),7.48(d,J=16.0Hz,1H),7.32(d,J=6.5Hz,1H),7.18-7.15(m,3H),7.01(d,J=5.5Hz,1H),6.32(s,2H),5.40(t,J=5.5Hz,1H),4.58(d,J=5.5Hz,2H),3.86(s,1H),3.82-3.75(m,2H),3.16-3.09(m,2H),3.06(d,J=15.5Hz,1H),2.63(d,J=15.5Hz,1H),1.93-1.88(m,1H),1.82-1.77(m,1H),1.55-1.52(m,1H),1.15-1.12(m,1H).
实施例28化合物28的制备:
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步骤1:化合物28-1的制备
将100mg化合物10-2、101mg化合物2-氨基-4-碘嘧啶、24mg PdCl2(PPh3)2和43mgCuI溶于THF(3mL)与NEt3(0.09mL)溶液中,氮气置换后,室温反应1.5小时。LC-MS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(15mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得67mg黄色固体化合物28-1。
步骤2:化合物28-2的制备
将67mg化合物28-1溶解于10mL无水甲醇中,室温加入40mg Pd-CaCO3,氢气置换后,室温搅拌反应3hrs。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得8mg化合物28-2。
步骤3:化合物28的制备
将8mg化合物28-2溶解于2.5mL二氧六环和0.5mL MeOH中,加入2N HCl(0.5mL,甲醇溶液),RT搅拌反应1hr。LC-MS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(1.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,二氯甲烷(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得1.8mg黄色固体,即化合物28。
[M+H+]=430.31。
1H NMR(500MHz,DMSO-d6)δ8.29(s,1H),8.24(d,J=5.0Hz,1H),7.72(d,J=15.5Hz,1H),7.36-7.26(m,2H),7.20-7.15(m,3H),6.72(d,J=5.0Hz,1H),6.68(s,1H),6.56(s,2H),5.33(t,J=5.5Hz,1H),4.57(d,J=6.0Hz,2H),3.86(s,1H),3.82-3.69(m,2H),3.16-3.09(m,2H),3.03(d,J=15.5Hz,1H),2.58(d,J=15.5Hz,1H),1.93-1.88(m,1H),1.81-1.77(m,1H),1.55-1.52(m,1H),1.15-1.12(m,1H).
经由不同的反应起始原料和合适的试剂,采用与前述实施例28类似的方法制备表4中的化合物。
表4
实施例30化合物30(化合物30a和30b的混合物)的制备:
步骤1:化合物30-1的制备
将200mg化合物2-氟-3-氯-4-碘吡啶加入2mL二甲基亚砜溶液中,将84mg甲醇钠溶于2mL无水甲醇,后将上述溶液混合,70℃反应3小时。LC-MS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(10mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,经柱层析纯化,得130mg白色固体化合物30-1。
步骤2:化合物30-2的制备
将74mg化合物30-1、120mg化合物10-2、9.6mg PdCl2(PPh3)2、2.6mg CuI和56mgEt3N依次加入DMF(4mL)中,氮气置换后,80℃反应3小时。LC-MS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(10mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,粗品经制备薄层色谱纯化得120mg黄色固体化合物30-2。
步骤3:化合物30-3(化合物30-3a和30-3b的混合物)的制备
将120mg化合物30-2溶解于10mL无水甲醇中,室温加入10mg Pd/C,氢气置换后,室温搅拌反应20min。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得20mg化合物30-3(化合物30-3a和30-3b的混合物)。
步骤4:化合物30(化合物30a和30b的混合物)的制备
将20mg化合物30-3溶解于2.5mL二氧六环和0.5mL MeOH中,加入2N HCl(0.5mL,甲醇溶液),RT搅拌反应0.5hrs。LC-MS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(2.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(3mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得8.7mg黄色固体,即化合物30(化合物30a和30b的混合物)。
[M+H+]=478.29。
经由不同的反应起始原料和合适的试剂,采用与前述实施例30类似的方法制备表5中的化合物。
表5
实施例33化合物33的制备:
步骤1:化合物33-1的制备
将150mg化合物10-2、133mg 4-碘吡唑、12mg PdCl2(PPh3)2和3mg CuI溶于DMF(2mL)溶液,加入Et3N(69mg),氮气置换后,90℃反应2小时。LC-MS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(5mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,柱层析纯化(DCM∶MeOH=15∶1),得140mg化合物33-1。
步骤2:化合物33-2的制备
将70mg化合物33-1溶解于10mL无水甲醇中,室温加入10mg Pd/C,氢气置换后,室温搅拌反应20min。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经柱层析纯化得23mg化合物33-2。
步骤3:化合物33的制备
将23mg化合物33-2溶解于2.5mL二氧六环和0.5mL MeOH中,加入2N HCl(0.2mL,甲醇溶液),RT搅拌反应0.5h。LCMS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,有固体析出,过滤,二氯甲烷溶解固体,经制备薄层色谱纯化得1.0mg类白色固体,即化合物33。
[M+H+]=403.33。
经由不同的反应起始原料和合适的试剂,采用与前述实施例33类似的方法制备表6中的化合物。
表6
实施例37化合物37的制备:
步骤1:化合物37-1的制备
将100mg化合物M1、63mg 2-甲基-4-三甲基甲硅烷基-3-丁炔-2-醇、7mg PdCl2(PPh3)2和4mg CuI溶于DMF(2mL)溶液,加入NEt3(103mg),氮气置换后,100℃反应24小时。LC-MS及TLC检测反应完全,加入10mL水淬灭,乙酸乙酯(5mL×3)萃取,饱和食盐水洗涤,无水硫酸钠干燥,真空浓缩,柱层析纯化(DCM∶MeOH=15∶1),得77mg化合物37-1。
步骤2:化合物37的制备
将30mg化合物37-1溶解于2.5mL二氧六环和0.5mL MeOH溶液中,加入2N HCl(0.2mL,甲醇溶液),RT搅拌反应0.5h。LCMS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(3.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,有固体析出,过滤,二氯甲烷溶解固体,经制备薄层色谱纯化得2.0mg类白色固体,即化合物37。
[M+H+]=393.34。
1H NMR(500MHz,DMSO)δ8.15(s,1H),7.32(d,J=7.0Hz,1H),7.21-7.16(m,3H),5.56(s,1H),5.45(t,J=5.0Hz,1H),4.47(d,J=4.0Hz,2H),3.88(s,1H),3.75-3.71(m,2H),3.13-3.02(m,3H),2.63(d,J=15.5Hz,1H),1.90-1.85(m,1H),1.79-1.75(m,1H),1.53-1.50(m,1H),1.47(s,6H),1.15-1.13(m,1H).
经由不同的反应起始原料和合适的试剂,采用与前述实施例37类似的方法制备表7中的化合物。
表7
经由不同的反应起始原料和合适的试剂,采用与前述实施例类似的方法制备表8中的化合物。
表8
实施例42化合物42的制备:
步骤1:化合物42-1的制备
将20mg化合物10-3溶解于3mL无水甲醇中,室温加入5mg Pd/C,氢气置换后,常温搅拌反应16hrs。LC-MS及TLC检测反应完全,将反应液过滤,滤液减压浓缩,残余物经制备薄层色谱纯化得13mg化合物42-1。
步骤2:化合物42的制备
将13mg化合物42-1溶解于0.6mL二氧六环和0.1mL MeOH中,加入2N HCl(0.2mL,甲醇溶液),RT搅拌反应0.5h。LCMS和TLC检测反应完全,反应液减压浓缩。残余物加入H2O(1.0mL)溶解,用饱和NaHCO3调节溶液至pH=8,乙酸乙酯(1mL×3)萃取,有机相干燥后真空浓缩,经制备薄层色谱纯化得3.6mg白色固体即化合物42。
[M+H+]=465.30。
药理试验
实施例A:SHP2变构抑制酶活测定
SHP2通过双-酪氨酰-磷酰化的肽与其Src同源2(SH2)结构域的结合而变构活化。该在后的活化步骤导致SHP2的自动抑制界面的释放,这又使该SHP2蛋白酪氨酸磷酸酶(PTP)活化并可用于底物识别和反应催化。在迅速荧光测定版式中使用替代物DiFMUP监测SHP2的催化活性。
试验步骤:
(1)化合物配制:
用100%DMSO将本发明化合物(10mM储液)稀释成合适倍数,本发明化合物最终测试浓度为10μM、3.3333μM、1.1111μM、0.3704μM、0.1235μM、0.0412μM、0.0137μM、0.0046μM、0.0015μM、0.00μM;
(2)准备酶反应工作液:
在室温下在96孔黑色聚苯乙烯板(平底、低凸缘、非结合表面)(Perki Elmer,Cat#6005270)中,使用50μL的最终反应体积和以下测定缓冲条件进行SHP2酶活检测:60mMHEPES,75mM NaCl,75mM KCl,0.05%BRIJ-35,1mM EDTA,5mM DTT。
(3)酶催化反应及数据监测:
取本发明化合物加到对应的96孔板中,设置不加化合物和酶只加缓冲液的做为空白试验孔。将SHP2 Activating Peptide(IRS1_pY1172(dPEG8)pY1222)置于冰上融化,每孔加入25μM,然后取0.2ng SHP2蛋白样品加到对应孔板中,室温孵育1小时。加入替代底物DiFMUP(Invitrogen,Cat#D6567)加入反应,室温反应2小时后。采用分别使用340nm和450nm的激发波长和发射波长的酶标仪(Envision,Perki Elmer)监测荧光信号。
(4)数据分析:
计算公式:
抑制率%=[1-(Conversion_sample-Conversion_min)/(Conversion_max-Conversion_min)]×100%
其中:Conversion_sample是样品的转化率读数;Conversion_min是空白对照孔均值,代表没有酶活孔的转化率读数;Conversion_max是阳性对照孔比值均值,代表没有化合物抑制孔的转化率读数。采用分析软件GraphPad Prism的log(inhibitor)vs response-Variable slope拟合量效曲线,并计算化合物对酶活性的IC50值。
部分实施例的IC50数据如表9所示。
表9
本发明的化合物对SHP2蛋白具有变构抑制作用。
实施例B:细胞增殖试验
使用体外细胞试验评估本发明的化合物对白血病细胞MV-4-11细胞增殖的影响。试验中所用的检测方法是CELL TITER-GLO(CTG)发光法,该法可通过对ATP进行定量测定来检测活细胞数目。因为ATP参与生物体内多种酶促反应,是活细胞新陈代谢的一个指标,其含量直接反应了细胞的数量及细胞状态,实验过程中向细胞培养基加入CellTiter-GloTM试剂,测量发光值,发光值与ATP量成正比,而ATP又和活细胞数正相关,因此可通过检测ATP含量考察细胞活力。
试验步骤:
(1)细胞铺板:
取一瓶对数生长期的MV-4-11细胞,消化重悬细胞后计数,调整细胞密度后接种到96孔板中,每孔接种4000个细胞,孔板置于37℃、5%CO2的培养箱中培养24hrs后加入本发明化合物进行处理;
(2)细胞化合物处理:
配取适量本发明化合物进行细胞处理,化合物终浓度从高至低依次为1000nM、333.3nM、111.1nM、37.04nM、12.35nM、4.115nM、1.372nM、0.4572nM、0.1524nM、0nM,孔板放入37℃,5%CO2培养箱培养120hrs。只加培养基不加细胞孔设为调零组;化合物浓度为0nM组为空白组。
(3)CTG检测:
细胞培养120hrs后每孔加入50μL的Luminescent Cell ViabilityAssay溶液,轻轻震荡2mins,室温继续孵育10mins,在多功能酶标仪上读取各孔的检测数值。/>
(4)数据分析:
根据发光值读数计算抑制率,
抑制率%=(1-(给药组值-调零组值)/(空白组值-调零组值)*100
GraphPad Prism的log(inhibitor)vs.response-Variable slope拟合量效曲线并计算化合物抑制细胞增殖的IC50。
实验数据如表10所示。
表10
本发明的化合物对MV-4-11细胞的增殖具有良好的抑制作用。
虽然本发明已通过其实施方式进行了全面的描述,但是值得注意的是,各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。
Claims (8)
1.一种化合物,或其药学上可接受的盐,其特征在于,所述化合物是:
5)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-环丙基乙烯基)吡嗪-2-基)甲醇;
10)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氨基-3-氯吡啶-4-基)乙烯基)吡嗪-2-基)甲醇;
15)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2,3-二氯苯乙烯基)吡嗪-2-基)甲醇;
17)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氨基嘧啶-5-基)乙烯基)吡嗪-2-基)甲醇;
19)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(2-氯-3-氟吡啶-4-基)乙烯基)吡嗪-2-基)甲醇;
22)(S,Z)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-苯乙烯基吡嗪-2-基)甲醇;
30)(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(2-(3-氯-2-甲氧基吡啶-4-基)乙烯基)吡嗪-2-基)甲醇;或
33)(S,Z)-(6-(2-(1H-吡唑-4-基)乙烯基)-3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)吡嗪-2-基)甲醇。
2.一种药物组合物,其特征在于,包含治疗有效量的至少一种权利要求1所述的化合物和至少一种药学上可接受的辅料。
3.根据权利要求2所述的药物组合物,其特征在于,所述的化合物和药学上可接受的辅料的质量百分比为0.0001:1-10。
4.权利要求1所述的化合物或权利要求2或3所述的药物组合物在制备药物中的应用;所述的药物用作SHP2抑制剂。
5.根据权利要求4所述的应用,其特征在于,所述药物用于治疗、预防、延迟或阻止癌症,癌症转移,心血管疾病,免疫疾病,纤维化或眼部疾病。
6.权利要求1所述的化合物或权利要求2或3所述的药物组合物在制备治疗由SHP2介导的疾病的药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述疾病是癌症。
8.根据权利要求5或7所述的应用,其特征在于,所述癌症选自Noonan综合征、豹斑综合征、青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合。
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