CN114478403B - 一种含芳香胍基类化合物及其制备方法与应用 - Google Patents
一种含芳香胍基类化合物及其制备方法与应用 Download PDFInfo
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- CN114478403B CN114478403B CN202210185606.1A CN202210185606A CN114478403B CN 114478403 B CN114478403 B CN 114478403B CN 202210185606 A CN202210185606 A CN 202210185606A CN 114478403 B CN114478403 B CN 114478403B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 101
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 title abstract description 7
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
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- -1 aromatic guanidino compound Chemical class 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 7
- YGUFCDOEKKVKJK-UHFFFAOYSA-N 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine Chemical compound NC1(CCN(CC1)C1=CN=C(C(=N1)N)C1=C(C(=CC=C1)Cl)Cl)C YGUFCDOEKKVKJK-UHFFFAOYSA-N 0.000 abstract description 5
- 102000007607 Non-Receptor Type 11 Protein Tyrosine Phosphatase Human genes 0.000 abstract description 3
- 108010032107 Non-Receptor Type 11 Protein Tyrosine Phosphatase Proteins 0.000 abstract description 3
- 229940002612 prodrug Drugs 0.000 abstract description 3
- 239000000651 prodrug Substances 0.000 abstract description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 2
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- 238000006243 chemical reaction Methods 0.000 description 50
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
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- 238000004440 column chromatography Methods 0.000 description 19
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- 239000000203 mixture Substances 0.000 description 10
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- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 7
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- UVYKKFKLOUEFAR-UHFFFAOYSA-N hydron;piperazine-1-carboxamide;chloride Chemical compound Cl.NC(=O)N1CCNCC1 UVYKKFKLOUEFAR-UHFFFAOYSA-N 0.000 description 7
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- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- GTTQRVGVEIXEHQ-UHFFFAOYSA-N 3-chloro-4-iodopyridin-2-amine Chemical compound NC1=NC=CC(I)=C1Cl GTTQRVGVEIXEHQ-UHFFFAOYSA-N 0.000 description 5
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- 101800001401 Activation peptide Proteins 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- CJQWLNNCQIHKHP-UHFFFAOYSA-N Ethyl 3-mercaptopropanoic acid Chemical compound CCOC(=O)CCS CJQWLNNCQIHKHP-UHFFFAOYSA-N 0.000 description 2
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
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- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 229910000104 sodium hydride Inorganic materials 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- 230000004960 subcellular localization Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明属于药物化学领域,具体涉及一种含芳香胍基类化合物及其制备方法与应用。含有通式I的一种芳香胍基类化合物及其药学上可接受的盐、对映异构体、非异构体、互变异构体、溶剂化物、多晶型物或前药;本发明基于SHP099为先导化合物,制备出一类芳香胍基的全新化合物,以解决目前SHP2抑制剂结构骨架单一等问题;本发明重要意义在于提供很多修饰位点,为后期结构改造提供基础。同时本发明的实施例证实了化合物对SHP2磷酸酶具有变构抑制作用,为后续开发SHP2磷酸酶抑制剂提供骨架支持。
Description
技术领域
本发明属于药物化学领域,具体涉及一种具有抗肿瘤活性的SHP2抑制剂及其医药用途。
背景技术
SHP2是一个在体内广泛存在的非受体型蛋白酪氨酸磷酸酶,具有两个N末端Src同源性2结构域(N-SH2和C-SH2)、催化结构域(PTP)和C末端尾部。这两个SH2结构域控制SHP2的亚细胞定位和功能调节。作为血小板源性生长因子(PDGF)、表皮生长因子(EGF)、成纤维细胞因子(FGF)、白细胞介素-3(IL-3)、白血病抑制因子(LIF)及α-干扰素(INF-α)等生长因子的下游信号分子,SHP2参与RAS/MAPK通路、PI3K/AKT通路、JAK/STAT通路、JNK通路等在内的多条信号通路。因此,发现和寻找具有较好成药性的SHP2抑制剂逐渐成为工业界和学术界的一大热点研究领域。
发明内容
发明目的
本发明需要解决的技术问题之一是提供一类末端为杂芳香胍基类全新SHP2抑制剂,以解决目前SHP2抑制剂结构骨架单一等问题。解决上述技术问题的方案如下:
技术方案
一种如通式I所示的化合物,及其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药
X为N或CH;
L为键、O或S;
R1、R2和R3分别独立地为氢、卤素、氨基;
R4和R5独立地为氢、C6-C10芳环、C5-C10杂芳环;其中所述的芳环或杂芳环可任选地被一个或多个取代基取代;
或者,R4和R5分别为C(=O)RaRb或C(=O)RcRd。其中,Ra,Rb,Rc和Rd独立地为不存在、氢、C1-C3烷基、C6-C10芳环、C5-C10杂芳环;其中所述的芳环或杂芳环可任选地被一个或多个取代基取代;
所述的化合物,其特征在于所述的化合物为如下结构式中任意一个:
一种药物组合物,其特征在于含有所述的化合物和药学可接受的辅料。
所述的药物组合物,其特征在于药物组合物制成片剂、胶囊剂、注射液或冻干粉剂。
所述的化合物、所述的药物组合物在制备治疗抗肿瘤药物、作为抗肿瘤药物的前药或作为抗肿瘤药物的中间体中应用。
有益效果
本发明首次公开一系列含有胍基结构的SHP2抑制剂,相较于阳性对照SHP099,具有更好的酶抑制活性和抗肿瘤活性,为后续开发抗肿瘤药物提供支持。
具体实施方式
中间体(4-叔丁氧基羰基)哌嗪-1-羧酰亚胺盐酸盐(A1)的合成
将N-Boc-哌嗪(3.00g,16.1mmol,1.0eq.)和吡唑甲眯盐酸盐(0.95eq.)溶于乙腈(20mL)中,加入DIPEA(1.1eq.),室温搅拌过夜,监测反应至原料转化完全,抽滤得化合物A1(2.60g,收率61%)。
中间体6-氯-3-(2,3-二氯丙基)吡嗪-2-氨基叔丁酯(B1)的合成:
步骤一:6-氯-3-(2,3-二氯苯基)吡嗪-2-胺(B1-2)的合成
将化合物B1-1(5.00g,24.0mmol,1.0eq.)、2,3-二氯苯硼酸(1.1eq.)、Pd(dppf)Cl2(5mol%)和K3PO4(2.0eq.)置于200mL单口瓶中,将体系抽真空置换氮气,加入1,4-二氧六环(54mL)和水(6mL)于120℃油浴中反应过夜,监测至原料转化完全。硅藻土过滤,滤液浓缩,加入30mL乙酸乙酯萃取,饱和氯化钠水溶液水洗3次,浓缩,柱层析纯化,得化合物B1-2(5.94g,收率91%)。
步骤二:6-氯-3-(2,3-二氯苯基)吡嗪-2-氨基叔丁酯(B1)的合成
将化合物B1-2(5.30g,19.4mmol)和DMAP(0.05eq.)置于200mL单口瓶中,加入二氯甲烷(50mL),在0℃加入二碳酸二叔丁酯(2.1eq.),加毕,移至室温反应过夜,监测反应完全后,饱和氯化钠水溶液水洗3次(15mL×3),有机相浓缩,柱层析纯化,得化合物B1(7.50g,收率82%)。
中间体(C1)的合成:
步骤一:2-氟-3-氯-4-碘吡啶(C1-2)的合成:
-78℃下,将正丁基锂(38mL,1.25eq.)缓慢滴加到C1-1(10.00g,76.3mmol)的THF(75mL)溶液中。反应1h后缓慢滴加I2的THF(30mL)溶液。反应30min后监测。监测反应完全后,滴加饱和Na2SO3水溶液淬灭,浓缩除THF,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析分离得化合物C1-2(7.76g,收率41%)。
步骤二:3-氯-4-碘-2-吡啶胺(C1-3)的合成
将NH3·H2O(38mL)缓慢滴加到C1-2(7.56g,29.4mmol)的DMSO(38mL)溶液中。加毕,60℃封管反应过夜。监测反应完全后,将反应体系倒入水(200mL)中搅拌30min,抽滤干燥得化合物C1-3(6.79g,收率91%)。
步骤三:3-((5-氯吡嗪-2-基)硫代)丙酸乙酯(C1-5)的合成
将3-巯基丙酸乙酯(4.45mL,1.05eq.)缓慢滴加到2,5-二氯吡嗪(5.00g,33.6mmol)和K2CO3(4.64g,1eq.)的DMF(42mL)溶液中。室温反应4h。监测反应完全后,乙酸乙酯稀释,饱和食盐水水洗5次,有机相浓缩,柱层析分离得化合物C1-5(7.78g,收率94%)。
步骤四:5-氯吡嗪-2-硫醇钠(C1-6)的合成
将乙醇钠(2.24g,1.1eq.)分批加入到C1-5(7.38g,30mmol)的THF(100mL)溶液中。室温反应2h。监测反应完全后,加正己烷(100mL)打浆抽滤,固体干燥得化合物C1-6(5.13g,粗品)。
步骤五:(C1)的合成
将化合物C1-3(3.00g,11.8mmol)、化合物C1-6(1.99g,1eq.)、Pd2(dba)3(216.3mg,2mol%)、XantPhos(273.2mg,4mol%)、DIPEA(3.04g,2eq.)置于封管中,氮气保护后加入无水二氧六环(50mL)于105℃反应过夜。监测反应完全后,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析分离得化合物C1(2.33g,收率72%)。
中间体(D1)的合成:
步骤一:3-((3-氨基-5-氯吡嗪-2-基)硫代)丙酸乙酯(D1-2)的合成
将3-巯基丙酸乙酯(1.05eq.)、化合物D1-1(1eq.)、Pd(OAc)2(0.02eq.)、XantPhos(0.04eq.)、DIPEA(2.0eq.)置于封管中,氮气保护后加入无水二氧六环(20mL)于105℃反应过夜。监测反应完全后,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析分离得化合物D1-2(3.62g,收率96%)。
步骤二:3-氨基-5-氯吡嗪-2-硫醇钠(D1-3)的合成
将乙醇钠(1.03g,1.1eq.)缓慢滴加到D1-2(3.6g,13.8mmol)的THF(30mL)溶液中。室温反应过夜。监测反应完全后,加二氯甲烷打浆抽滤,固体干燥得化合物D1-3(3.07g,粗品)。
步骤三:(D1)的合成
将化合物C1-3(2.08g,8.17mmol)、化合物D1-3(1.5g,1eq.)、Pd2(dba)3(74.8mg,8mol%)、XantPhos(92.6mg,16mol%)、DIPEA(2.11g,2.0eq.)置于封管中,氮气保护后加入无水二氧六环(20mL)于105℃反应过夜。监测反应完全后,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析分离得化合物D1(1.37g,收率58%)。
实施例1:(I-1)的合成
步骤一:(I-1-1)的合成
将化合物A1(100mg,0.38mmol,1eq.)、对溴三氟甲苯(1eq.),碘化亚铜(0.1eq.),磷酸钾(6eq.)和N-甲基甘氨酸(0.2eq.)置于单口瓶中,加入2mL乙腈,将体系抽真空置换氮气,将反应瓶置于90℃油浴中反应过夜。监测反应完全后,硅藻土抽滤,旋干溶剂,柱层析纯化,得化合物I-1-1(84.9mg,收率60%)。ESI-MS(m/z):372.1[M+H]+;1H NMR(300MHz,CDCl3):δ7.52(d,J=8.2Hz,2H),6.95(d,J=8.2Hz,2H),3.56-3.47(m,4H),3.45-3.37(m,4H),1.48(s,9H).
步骤二:(I-1-2)的合成
将化合物I-1-1(84.9mg,0.23mmol,1eq.)溶于乙酸乙酯(1mL)中,缓慢加入2M的盐酸乙酸乙酯溶液(1mL),室温反应过夜。监测反应完全后,抽滤,所得固体为化合物I-1-2(92.1mg,粗品)。
步骤三:(I-1-3)的合成
将化合物I-1-2(92.1mg,0.34mmol,1eq.)、化合物B1(1eq.)和碳酸铯(5eq.)溶于2mL二甲基亚砜中,室温反应过夜。监测反应完全后,加入乙酸乙酯30mL,饱和氯化钠水溶液水洗(10mL×5),无水硫酸钠干燥,浓缩,柱层析纯化,得化合物I-1-3(71.3mg,两步收率44%)。ESI-MS(m/z):709.2[M+H]+;1H NMR(300MHz,CDCl3):δ8.19(s,1H),7.57(d,J=8.2Hz,2H),7.49(dd,J=8.0,1.4Hz,1H),7.34(dd,J=7.9,1.4Hz,1H),7.24(dd,J=7.9,7.8Hz,1H),7.06(d,J=8.2Hz,2H),3.83-3.72(m,4H),3.66-3.56(m,4H),1.36(s,18H).
步骤四:(I-1)的合成
将化合物I-1-3(63.5mg,0.09mmol,1eq.)溶于1mL乙酸乙酯中,缓慢加入2M的盐酸乙酸乙酯溶液(1mL),室温反应过夜。监测反应完全后,加水萃取分液,弃去有机相,滴加饱和碳酸钠水溶液调pH至中性,乙酸乙酯萃取有机相,无水硫酸钠干燥,浓缩,所得固体为化合物I-1(33.3mg,收率73%)。1H NMR(300MHz,CDCl3):δ10.59(s,1H),8.68(s,2H),7.68-7.43(m,4H),7.33-7.19(m,7H),4.37(s,2H),3.66(d,J=29.8Hz,8H).
实施例2:(I-2)的合成
参照实施例1的合成方法,得到化合物I-2(46.6mg,收率92%)。1H NMR(300MHz,CDCl3):δ7.54(s,1H),7.53-7.48(m,1H),7.33-7.28(m,2H),7.17-7.01(m,4H),4.33(s,2H),3.7-3.61(m,4H),3.58-3.48(m,4H).
实施例3:(I-3)的合成
参照实施例1的合成方法,得到化合物I-3(9.8mg,收率49%)。1H NMR(300MHz,CDCl3):δ7.63-7.55(m,3H),7.52(dd,J=6.4,3.2Hz,1H),7.36-7.28(m,2H),7.08-6.99(m,2H),4.31(s,2H),3.75-3.65(m,4H),3.62-3.51(m,4H).
实施例4:(I-4)的合成
参照实施例1的合成方法,得到化合物I-4(29.9mg,收率53%)。1H NMR(300MHz,CDCl3):δ7.60(s,1H),7.51(dd,J=7.0,2.6Hz,1H),7.36-7.28(m,2H),6.93-6.82(m,4H),4.29(s,2H),3.79(s,3H),3.71-3.62(m,4H),3.59-3.50(m,4H).
实施例5:(I-5)的合成
参照实施例1的合成方法,得到化合物I-5(32.8mg,收率53%)。1H NMR(300MHz,CDCl3):δ7.62(s,1H),7.52(dd,J=7.3,2.5Hz,1H),7.36-7.27(m,2H),7.20(t,J=8.2Hz,1H),6.62-6.54(m,1H),6.53-6.46(m,2H),4.29(s,2H),3.79(s,3H),3.74-3.65(m,4H),3.61-3.52(m,4H).
实施例6:(I-6)的合成
参照实施例1的合成方法,得到化合物I-6(38.2mg,收率76%)。1H NMR(300MHz,CDCl3):δ7.72(d,J=8.6Hz,2H),7.58(s,1H),7.52(dd,J=6.9,2.9Hz,1H),7.36-7.29(m,2H),6.99(d,J=8.5Hz,2H),6.29-6.18(m,1H),4.31(s,1H),3.72-3.62(m,4H),3.61-3.51(m,4H),2.99(d,J=4.8Hz,3H).
实施例7:(I-7)的合成
参照实施例1的合成方法,得到化合物I-7(29.3mg,收率61%)。1H NMR(300MHz,CDCl3):δ8.21-8.15(m,1H),7.71(dd,J=8.9,1.6Hz,1H),7.60(s,1H),7.52(dd,J=6.8,2.7Hz,1H),7.36-7.29(m,2H),7.28-7.22(m,1H),4.31(s,2H),3.80-3.60(m,8H).
实施例9:(I-9)的合成
参照实施例1的合成方法,得到化合物I-9(45.4mg,收率60%)。1H NMR(300MHz,CDCl3):δ8.16(dd,J=5.2,1.9Hz,1H),7.60(s,1H),7.57-7.49(m,2H),7.36-7.27(m,2H),7.02(d,J=8.2Hz,1H),6.81-6.73(m,1H),4.29(s,2H),3.80-3.67(m,8H).
实施例10:(I-10)的合成
参照实施例1的合成方法,得到化合物I-10(35.7mg,收率67%)。1H NMR(300MHz,CDCl3):δ8.29-8.22(m,2H),7.62(s,1H),7.52(dd,J=7.3,2.6Hz,1H),7.36-7.30(m,2H),7.25-7.21(m,2H),4.30(s,2H),3.75-3.67(m,4H),3.64-3.56(m,4H).
实施例11:(I-11)的合成
参照实施例1的合成方法,得到化合物I-11(4.3mg,收率37%)。1H NMR(300MHz,CD3OD):δ8.21(brs,2H),7.61(dd,J=7.8,1.8Hz,1H),7.50-7.28(m,4H),6.96(d,J=5.3Hz,2H),3.77-3.61(m,8H).
实施例12:(I-12)的合成
参照实施例1的合成方法,得到化合物I-12(45.5mg,收率57%)。1H NMR(300MHz,CDCl3):δ8.28(s,1H),8.01(dd,J=2.8,1.4Hz,1H),7.91(d,J=2.8Hz,1H),7.61(s,1H),7.52(dd,J=7.1,2.5Hz,1H),7.44(brs,2H),7.36-7.28(m,2H),4.30(s,2H),3.82-3.76(m,4H),3.76-3.70(m,4H).
实施例13:(I-13)的合成
参照实施例1的合成方法,得到化合物I-13(25.6mg,收率41%)。1H NMR(300MHz,CDCl3):δ8.83(s,1H),8.36(s,2H),7.62(s,1H),7.52(dd,J=7.0,2.6Hz,1H),7.36-7.27(m,2H),4.30(s,2H),3.76-3.68(m,4H),3.67-3.59(m,4H).
实施例14:(I-14)的合成
参照实施例1的合成方法,得到化合物I-14(43.2mg,收率73%)。1H NMR(300MHz,CDCl3):δ7.62(s,1H),7.52(dd,J=7.8,2.4Hz,1H),7.36-7.27(m,2H),6.99(dd,J=11.8,8.4Hz,1H),6.54(dd,J=7.9,2.4Hz,1H),6.42-6.36(m,1H),4.29(s,2H),3.86(s,3H),3.73-3.66(m,4H),3.60-3.53(m,4H).
实施例15:(I-15)的合成
参照实施例1的合成方法,得到化合物I-15(30.5mg,收率34%)。1H NMR(400MHz,CDCl3):δ7.61(s,1H),7.52(dd,J=7.0,2.6Hz,1H),7.45(d,J=8.6Hz,1H),7.35-7.28(m,2H),6.58-6.51(m,2H),4.30(s,2H),3.90(s,3H),3.74-3.66(m,4H),3.63-3.54(m,4H).
实施例16:(I-16)的合成
参照实施例1的合成方法,得到化合物I-16(15.0mg,收率41%)。1H NMR(400MHz,CDCl3):δ8.02(d,J=5.6Hz,1H),7.61(s,1H),7.52(dd,J=7.4,2.3Hz,1H),7.36-7.28(m,2H),6.47(dd,J=5.6,1.7Hz,1H),6.26(d,J=1.6Hz,1H),4.29(s,2H),3.92(s,3H),3.74-3.66(m,4H),3.63-3.55(m,4H).
实施例8:(I-8)的合成
步骤一:(E1)的合成
将化合物E1-1(4.45g,21.4mmol,1.0eq.)、2,3-二氯苯硼酸(1.1eq.)、Pd(dppf)Cl2(5mol%)和K3PO4(2.0eq.)置于200mL单口瓶中,将体系抽真空置换氮气,加入1,4-二氧六环(54mL)和水(6mL)于120℃油浴中反应过夜,监测至原料转化完全。硅藻土过滤,滤液浓缩,加入30mL乙酸乙酯萃取,饱和氯化钠水溶液水洗3次,浓缩,柱层析纯化,得化合物E1(3.60g,收率65%)。1H NMR(300MHz,CDCl3):δ8.77-8.65(m,2H),7.60(dd,J=8.0,1.6Hz,1H),7.48(dd,J=7.8,1.7Hz,1H),7.36(t,J=7.8Hz,1H).
步骤二:(I-8)的合成
将化合物I-15-2(1eq.)、化合物E1(100mg,0.39mmol,1eq.)和碳酸铯(5eq.)溶于2mL二甲基亚砜中,室温反应过夜。监测反应完全后,加入乙酸乙酯30mL,饱和氯化钠水溶液水洗(10mL×5),无水硫酸钠干燥,浓缩,柱层析纯化,得化合物I-8(67.2mg,收率36%)。1HNMR(300MHz,DMSO-d6):δ8.39(d,J=1.2Hz,1H),8.32(d,J=1.1Hz,1H),7.60(dd,J=7.9,1.7Hz,1H),7.52-7.44(m,2H),7.40(t,J=7.8Hz,1H),6.69(d,J=1.4Hz,1H),6.64(dd,J=8.3,1.5Hz,1H),3.90(s,3H),3.86-3.75(m,4H),3.72-3.59(m,4H).
实施例17:(I-17)的合成/>
步骤一:(I-17-1)的合成
将化合物A1(200mg,0.76mmol,1eq.)、2-碘苯甲醚(1eq.),碘化亚铜(0.1eq.),碳酸铯(4eq.)和N,N-二甲基乙二胺(0.2eq.)置于单口瓶中,加入2mL 1.4-二氧六环,将体系抽真空置换氮气,将反应瓶置于100℃油浴中反应过夜。监测反应完全后,硅藻土抽滤,旋干溶剂,柱层析纯化,得化合物I-17-1(88.6mg,收率35%)。ESI-MS(m/z):334.2[M+H]+;1H NMR(300MHz,CDCl3):δ7.12-6.84(m,4H),3.81(s,3H),3.55-3.34(m,8H),1.45(s,9H).
步骤二:(I-17-2)的合成
将化合物I-1-1(88.6mg,0.26mmol,1eq.)溶于乙酸乙酯(1mL)中,缓慢加入2M的盐酸乙酸乙酯溶液(1mL),室温反应过夜。监测反应完全后,抽滤,所得固体为化合物I-17-2(84.9mg,粗品)。
步骤三:(I-17-3)的合成
将化合物I-17-2(84.9mg,0.36mmol,1eq.)、化合物B1(1eq.)和碳酸铯(5eq.)溶于2mL二甲基亚砜中,室温反应过夜。监测反应完全后,加入乙酸乙酯30mL,饱和氯化钠水溶液水洗(10mL×5),无水硫酸钠干燥,浓缩,柱层析纯化,得化合物I-17-3(68.2mg,两步收率42%)。ESI-MS(m/z):671.2[M+H]+;1H NMR(300MHz,CDCl3):δ8.17(s,1H),7.47(dd,J=8.0,1.6Hz,1H),7.34(dd,J=7.8,1.6Hz,1H),7.22(t,J=7.9Hz,1H),7.11-7.02(m,1H),7.02-6.88(m,3H),3.83(s,3H),3.79-3.71(m,4H),3.67-3.57(m,4H),1.35(s,18H).
步骤四:(I-17)的合成
将化合物I-17-3(68.2mg,0.10mmol,1eq.)溶于1mL乙酸乙酯中,缓慢加入2M的盐酸乙酸乙酯溶液(1mL),室温反应过夜。监测反应完全后,加水萃取分液,弃去有机相,滴加饱和碳酸钠水溶液调pH至中性,乙酸乙酯萃取有机相,无水硫酸钠干燥,浓缩,所得固体为化合物I-17(37.8mg,收率84%)。1H NMR(300MHz,CDCl3):δ7.54-7.46(m,2H),7.34-7.27(m,2H),7.22-7.08(m,2H),6.99-6.87(m,2H),4.29(s,2H),3.85(s,3H),3.59(brs,4H),3.52(brs,4H).
实施例18:(I-18)的合成
参照实施例17的合成方法,得到化合物I-18(61.7mg,收率72%)。1H NMR(300MHz,CDCl3)δ7.58-7.47(m,2H),7.33-7.28(m,3H),6.93(dd,J=5.0,0.8Hz,1H),6.89(d,J=2.5Hz,1H),4.33(s,2H),3.71-3.61(m,4H),3.61-3.52(m,4H).
实施例19:(I-19)的合成
参照实施例17的合成方法,得到化合物I-19(31.3mg,收率66%)。1H NMR(300MHz,CDCl3):δ7.60(s,1H),7.52(dd,J=7.0,2.7Hz,1H),7.36-7.29(m,2H),6.87-6.80(m,2H),6.43(dd,J=3.0,1.8Hz,1H),4.30(s,2H),3.74-3.56(m,8H).
实施例20:(I-20)的合成/>
步骤一:(I-20-1)的合成
将化合物A1(400mg,1.51mmol,1eq.)、2-氯嘧啶(1eq.)溶于5mL 1.4-二氧六环,加入氢化钠(3eq.,60%分散于液状石蜡),室温搅拌30分钟。将反应瓶置于100℃油浴中反应过夜。监测反应完全后,旋干溶剂,加入乙酸乙酯10mL×3萃取,合并有机相,无水硫酸钠干燥,浓缩,柱层析纯化,得化合物I-20-1(161.8mg,收率35%)。ESI-MS(m/z):306.2[M+H]+;1HNMR(300MHz,CDCl3):δ8.45(d,J=4.8Hz,2H),7.49(brs,2H),6.67(t,J=4.8Hz,1H),3.77-3.35(m,8H),1.45(s,9H).
步骤二:(I-20-2)的合成
将化合物I-20-1(155.3mg,0.51mmol,1eq.)溶于乙酸乙酯(1mL)中,缓慢加入2M的盐酸乙酸乙酯溶液(1mL),室温反应过夜。监测反应完全后,抽滤,所得固体为化合物I-20-2(167.2mg,粗品)。
步骤三:(I-20-3)的合成
将化合物I-20-2(167.2mg,0.81mmol,1eq.)、化合物B1(1eq.)和碳酸铯(5eq.)溶于4mL二甲基亚砜中,室温反应过夜。监测反应完全后,加入乙酸乙酯30mL,饱和氯化钠水溶液水洗(10mL×5),无水硫酸钠干燥,浓缩,柱层析纯化,得化合物I-20-3(26.0mg,两步收率8%)。ESI-MS(m/z):643.2[M+H]+;1H NMR(300MHz,CDCl3):δ8.51(d,J=4.9Hz,2H),8.18(s,1H),7.48(dd,J=7.8,1.5Hz,1H),7.35(dd,J=7.7,1.8Hz,2H),7.26-7.19(m,2H),6.78(t,J=4.7Hz,1H),3.95-3.86(m,4H),3.85-3.78(m,4H),1.36(s,18H).
步骤四:(I-20)的合成
将化合物I-20-3(26.0mg,0.06mmol,1eq.)溶于1mL乙酸乙酯中,缓慢加入2M的盐酸乙酸乙酯溶液(1mL),室温反应过夜。监测反应完全后,加水萃取分液,弃去有机相,滴加饱和碳酸钠水溶液调pH至中性,乙酸乙酯萃取有机相,无水硫酸钠干燥,浓缩,所得固体为化合物I-20(12.6mg,收率53%)。1H NMR(300MHz,CDCl3):δ8.48(d,J=4.8Hz,2H),7.59(s,1H),7.51(dd,J=7.2,2.4Hz,1H),7.36-7.29(m,2H),6.71(t,J=4.8Hz,1H),4.31(s,2H),3.89-3.80(m,4H),3.78-3.69(m,4H).
实施例21:(I-21)的合成
步骤一:(I-21-1)的合成
将吡啶-4-羧酸(200mg,0.76mmol,1eq.)溶于2mL二氯甲烷中,在0℃滴加草酰氯(2eq.),1小时后,监测原料反应完全,旋干溶剂,加入碳酸钾(3eq.),将化合物A1(1eq.)溶于2mL乙腈中,加入反应体系。室温反应过夜。监测反应完全后,旋干溶剂,乙酸乙酯萃取(10mL×3),饱和氯化钠水溶液水洗(10mL×3),无水硫酸钠干燥,浓缩,柱层析纯化,得化合物I-21-1(89.7mg,收率35%)。ESI-MS(m/z):333.2[M+H]+;1H NMR(300MHz,CDCl3):δ8.69(d,J=4.4Hz,2H),7.99-7.96(m,2H),3.76-3.66(m,4H),3.61-3.54(m,5H),1.49(s,9H).
步骤二:(I-21-2)的合成
将化合物I-21-1(89.7mg,0.27mmol,1eq.)溶于乙酸乙酯(1mL)中,缓慢加入2M的盐酸乙酸乙酯溶液(1mL),室温反应过夜。监测反应完全后,抽滤,所得固体为化合物I-21-2(95.7mg,粗品)。
步骤三:(I-21-3)的合成
将化合物I-21-2(95.7mg,0.41mmol,1eq.)、化合物B1(1eq.)和碳酸铯(5eq.)溶于2mL二甲基亚砜中,室温反应过夜。监测反应完全后,加入乙酸乙酯30mL,饱和氯化钠水溶液水洗(10mL×5),无水硫酸钠干燥,浓缩,柱层析纯化,得化合物I-21-3(52.8mg,两步收率30%)。ESI-MS(m/z):670.2[M+H]+;1H NMR(300MHz,CDCl3):δ8.72(brs,2H),8.20(s,1H),8.04(d,J=5.1Hz,2H),7.50(dd,J=7.9,1.6Hz,1H),7.35(dd,J=7.7,1.5Hz,1H),7.24(t,J=7.8Hz,1H),3.98-3.83(m,8H),1.37(s,18H).
步骤四:(I-21)的合成
将化合物I-21-3(52.8mg,0.11mmol,1eq.)溶于1mL乙酸乙酯中,缓慢加入2M的盐酸乙酸乙酯溶液(1mL),室温反应过夜。监测反应完全后,加水萃取分液,弃去有机相,滴加饱和碳酸钠水溶液调pH至中性,乙酸乙酯萃取有机相,无水硫酸钠干燥,浓缩,所得固体为化合物I-21(26.8mg,收率79%)。1H NMR(300MHz,CDCl3):δ8.72(d,J=5.3Hz,2H),8.05-8.00(m,2H),7.60(s,1H),7.53(dd,J=6.8,2.9Hz,1H),7.36-7.28(m,2H),4.33(s,2H),3.96-3.85(m,4H),3.84-3.76(m,4H).
实施例22:(I-22)的合成
将中间体I-11-2(150.0mg,0.48mmol)和中间体C1(1eq.)溶于N-甲基吡咯烷酮(1mL)中,加入DIPEA(1.5mL),将反应瓶移至95℃油浴中反应过夜。监测反应完全后,乙酸乙酯萃取(5mL×3),饱和氯化钠水溶液水洗(5mL×3),无水硫酸钠干燥,浓缩,柱层析纯化,得化合物I-22(24.7mg,收率12%)。1H NMR(300MHz,DMSO-d6):δ8.49(d,J=1.2Hz,1H),8.33(d,J=1.3Hz,1H),8.21(d,J=5.9Hz,2H),7.66(d,J=5.4Hz,1H),6.74-6.68(m,2H),6.36(s,2H),5.95(brs,2H),5.82(d,J=5.4Hz,1H),3.77-3.68(m,4H),3.59-3.50(m,4H).
实施例23:(I-23)的合成
将中间体I-11-2(150.0mg,0.48mmol)、中间体D1(1eq.)和碳酸钾(2eq.)溶于N-甲基吡咯烷酮(1mL)中,将反应瓶移至95℃油浴中反应过夜。监测反应完全后,乙酸乙酯萃取(5mL×3),饱和氯化钠水溶液水洗(5mL×3),无水硫酸钠干燥,浓缩,柱层析纯化,得化合物I-23(67.5mg,收率31%)。1H NMR(300MHz,DMSO-d6):δ8.28-8.17(m,2H),7.69-7.62(m,2H),6.78-6.67(m,2H),6.25(d,J=12.6Hz,4H),6.06(s,2H),5.74(d,J=5.4Hz,1H),3.69-3.57(m,4H),3.56-3.47(m,4H).
对照例
按照CN113248449A中的实施例17所描述的方法,制备如下对照例。
体外SHP2酶水平活性测试
对上述实施例中化合物的SHP2酶水平活性进行测试,具体操作如下:
化合物配制
化合物溶解在100%DMSO中,配制成30mM储存液,于-20度冰箱避光保存。
SHP2反应过程
(1)配制1×ReactionBuffer。
(2)化合物浓度梯度的配制:受试化合物测试起始浓度为30μM,3倍稀释,10个浓度,单孔测试。在384source板中稀释成100倍终浓度的100%DMSO溶液,用Precision 3倍稀释化合物,10个浓度。使用分液器Echo 550向目的板384板中转移250nL 100倍终浓度的化合物。正对照加入250nL DMSO,负对照加入250nL 1mM SHP099。
(3)用1×ReactionBuffer配制5倍终浓度的激活肽溶液,分别加入5μL到反应板中,1000rpm离心1min。
(4)用1×ReactionBuffer配制2.5倍终浓度的酶溶液,分别加入10μL到反应板中,1000rpm离心1min,室温孵育60分钟。
(5)用1×ReactionBuffer配制2.5倍终浓度的底物溶液,分别加入10μL到反应板中,1000rpm离心1min,室温孵育20分钟。
(6)用EnSight读取Ex355/Em460荧光数值
数据分析
计算公式
其中:RFU:样品的荧光值;Mean(NC):含10μM SHP099的对照孔荧光值均值;Mean(PC):阳性对照孔荧光值均值。
拟合量效曲线
以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。
计算公式是Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
A<100nM,100nM≤B≤1000nM,C>1000nM
实验结论:以上数据显示,本发明实施例对SHP2磷酸酶具有变构抑制作用,且多个实施例显著优于阳性对照SHP099和实施例17。
化合物体外抗增殖活性
1、实验步骤
(1)将NCI-H358细胞从液氮罐中取出,立刻置于37℃恒温水浴锅中,摇晃使其融化,再将细胞倒入培养瓶中,加入培养液(含10%胎牛血清)稀释。将稀释后的培养基转入离心管中,1000r/min离心5分钟,舍弃上清液,再加入新鲜的培养基吹打混匀,移入培养瓶中培置于5%CO2、37℃培养箱中培养。待细胞贴壁快铺满瓶底时开始进行传代,加入少量新鲜的培养基(含10%胎牛血清)终止消化,倒掉培养瓶中的液体,PBS洗两遍,加入新鲜培养基吹打混匀,均分到两个培养瓶中继续培养。
(2)取对数期细胞,倒掉旧培养基,加入胰蛋白酶溶液消化3分钟,加入含10%胎牛血清的新鲜培养基终止消化,将溶液转移至离心管,1000r/min离心5分钟,舍弃上清液。加入培养基将其配制成细胞悬浊液,进行细胞计数。计数完成后,按照每孔5000个细胞密度将细胞植于96孔板中。将铺好细胞的96孔板置于37℃、5%CO2培养箱中继续培养24h。
(3)用培养基将药物梯度稀释为90μmol/L,30μmol/L,10μmol/L,3.3μmol/L,1.1μmol/L(SHP099);30μmol/L,10μmol/L,3.3μmol/L,1.1μmol/L,0.33μmol/L(待测化合物)。随后将它们加入到96孔板中,每孔100μL,每个浓度设置三个复孔。对照组加入相应浓度的含溶媒的培养基,调零孔加入相同体积的空白培养基,置于5%CO2、37℃培养箱孵育48h。每孔加入20μL CCK8试剂,混合均匀后,于5%CO2、37℃培养箱避光培养1h。随后将96孔板放入酶标仪中检测,于450nm处测定吸光度。
2、数据处理
3、绘制曲线并计算药物对细胞的抑制率及IC50。
OD值为酶标仪各孔读数-空白培养基OD值
抑制率=1-[加药孔平均OD值/(空白对照平均OD值)]×100%
IC50由GraphPad Prism 7拟合得出。
4、实验结果
化合物对非小细胞肺癌细胞株NCI-H358细胞的抑制活性如下:
化合物编号 | IC50(μM) | 化合物编号 | IC50(μM) |
I-1 | 7.8 | I-14 | 11.3 |
I-2 | 11.7 | I-15 | 6.9 |
I-3 | 8.1 | I-18 | 6.7 |
I-4 | 2.2 | SHP099 | 35.4 |
I-5 | 1.5 | 实施例17 | 8.2 |
I-11 | 19.7 |
实验结论:以上数据显示,本发明实施例化合物对NCI-H358细胞的增殖具有良好的抑制作用。相比较SHP099和实施例17而言,本发明多个实施例具备新颖的结构和更优越的体外抗增殖活性。
Claims (4)
1.一种化合物及其药学上可接受的盐,其特征在于,所述的化合物为如下结构式中任意一个:
2.一种药物组合物,其特征在于含有如权利要求1所述的化合物和药学可接受的辅料。
3.如权利要求2所述的药物组合物,其特征在于药物组合物制成片剂、胶囊剂、注射液或冻干粉剂。
4.如权利要求1所述的化合物或权利要求2-3任意一项所述的药物组合物在制备治疗抗肿瘤药物中应用。
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