CN117693505A - 杂芳基衍生物化合物及其用途 - Google Patents
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Classifications
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- 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
- C07D401/12—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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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- 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
- C07D401/14—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
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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
本发明涉及杂芳基衍生物化合物及其用途。本发明的杂芳基衍生物对HER2和EGFR表现出优异的抑制活性,并且因此可以有效地用作HER2和/或EGFR相关疾病的治疗剂。
Description
技术领域
本公开涉及杂芳基衍生物化合物及其医药用途。特别地,本公开涉及具有HER2和/或EGFR抑制活性的杂芳基衍生物化合物。
背景技术
蛋白激酶充当分子开关参与信号转导途径,并且在细胞内通过激酶在靶蛋白的激活和失活状态之间的转变应受到顺利控制。如果在激活和失活状态之间的转变受到异常控制,则细胞内信号转导过度激活或失活以诱导不受控制的细胞分裂和增殖。特别地,蛋白激酶基因的突变、扩增和/或过表达导致的异常激活引起各种肿瘤的发展和进展,或在各种疾病(诸如炎性疾病、退行性脑疾病和自身免疫性疾病)的发展中起至关主要作用。
特别地,HER2(ErbB2),其是ErbB家族的受体酪氨酸激酶,与其他EGFR受体(诸如HER1(EGFR、ErbB1)、HER3(ErbB3)或HER4(ErbB4))形成同二聚体或异二聚体,并且被细胞内酪氨酸残基处的自磷酸化激活,以在正常细胞和癌细胞中的细胞增殖、分化和存活中发挥重要作用(Di Fore PP,et al.,Science.1987;237:178-182)。已知HER2在多种癌(诸如乳腺癌、胃部癌和卵巢癌)中过表达(Hardwick R,et al.,Eur.J Surg Oncol.1997(23):30-35;Korkaya H,et al.,Oncogene.2008;27(47):6120-6130;)。
此外,已知表皮生长因子受体(EGFR),其是另一个ErbB家族,在许多上皮细胞肿瘤(包括非小细胞肺癌(NSCLC)、乳腺癌、胶质瘤、头颈部鳞状细胞癌、结直肠癌、直肠腺癌、头颈癌、胃癌和前列腺癌)是异常激活的,并且EGFR-酪氨酸激酶的激活引起持续细胞增殖、侵袭周围组织、远处转移和血管生成,并增加细胞存活。
作为靶向HER2和EGFR的抗癌药物,存在阿法替尼(afatinib)(GILOTRIF)和曲司珠单抗(trastuzumab)(HERCEPTIN)等,但这些抗癌药物具有治疗后癌症复发或仅一些患者组示出反应性的问题。例如,在曲司珠单抗的情况下,已报道了以下情况:接受常规抗癌治疗的HER2过表达的乳腺癌患者中约11.6%对曲司珠单抗有反应,并且其余88.4%的患者对曲司珠单抗无反应或具有弱反应(Baselga et al.,J.Clin.Oncol.14:737-744(1996))。
如上所述,对能够通过调节HER2和EGFR活性有效用于治疗HER2和EGFR相关疾病的新颖化合物存在不断增加的未满足的需求。
发明内容
技术问题
本公开的目的是提供具有新颖结构的杂芳基衍生物、其光学异构体或其药学上可接受的盐。
本公开的另一目的是提供用于制备杂芳基衍生物化合物的方法。
本公开的仍另一目的是提供杂芳基衍生物化合物的药物用途,并且特别地,用于治疗或预防HER2和/或EGFR相关疾病的药物组合物,该药物组合物包括该杂芳基衍生物化合物作为活性成分,该化合物用于治疗或预防HER2和/或EGFR相关疾病的用途,或用于治疗或预防HER2和/或EGFR相关疾病的方法,该方法包括给药该化合物。
技术方案
为了实现上述目的,本发明人进行了研究努力,并且作为结果,通过确认由以下化学式1表示的杂芳基衍生物化合物抑制HER2和/或EGFR激活的细胞的增殖而完成本发明。
杂芳基衍生物化合物
本发明提供了一种由以下化学式1表示的化合物、其光学异构体或其药学上可接受的盐:
[化学式1]
在以上化学式1中,
X是N或CRX1;
R1是-H、-ORX2或-NRX3RX4;
RX1是-H、-C1-6烷基、-C1-6卤代烷基、-CN或-卤素;
RX2是-H、-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-C1-6烷基-O(C1-6烷基)、-C1-6烷基-O(C1-6烷基)-C1-6氨基烷基、-(CH2)n-环烷基或-(CH2)n-杂环烷基{其中–(CH2)n-环烷基或–(CH2)n-杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-C1-6烷基-O(C1-6烷基)、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH、-卤素或杂环烷基取代};
n是0、1、2、3或4;
RX3和RX4各自独立地是-H或-C1-6烷基,或RX3和RX4彼此连接以与N原子一起形成环,以及W1和W2各自独立地是CH2、NH、O或S{其中杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH、-卤素或杂环烷基取代};
a至d各自独立地是1、2或3;
R2是-H、-C1-6烷基、-C1-6卤代烷基、-CN或-卤素;
L是-NH-、{其中环B是在环中包含N原子的单环或多环,并且所述环B中的至少一个H可以被-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH、=O或-卤素取代};
R3是-CZ1=Z2Z3、-C1-6烷基、-C1-6卤代烷基或环烷基;
Z1是-H、-C1-6烷基、-C1-6氨基烷基、-C1-6羟烷基、-C1-6卤代烷基、-CN或-卤素;
Z2和Z3各自独立地是-H、-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-C1-6烷基-O(C1-6烷基)、-卤素、环烷基、杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基{其中所述环烷基、杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基中的至少一个H可以被-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH、=O或杂环烷基取代};
Y1至Y3各自独立地是N或CRY;
RY是-H、-C1-6烷基、-C1-6氨基烷基、-C1-6羟烷基、-C1-6卤代烷基、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH或-卤素;
R4是-C1-6烷基、-C1-6烷基-O-C1-6烷基、-C1-6卤代烷基、环烷基、杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基{其中所述环烷基、杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基中的至少一个H可以被-C1-6烷基取代};
环A是芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基{其中芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基环中的至少一个H可以被-C1-6烷基、-C1-6氨基烷基、-C1-6羟烷基、-C1-6卤代烷基、-C1-6烯基、-CN、-C(=O)-RA1、-NO2、-NRA2RA3、-ORA4、-S-C1-6烷基、-卤素或杂环烷基取代[此处,杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-卤素或杂环烷基取代],并且芳基或杂芳基环上的取代基可以彼此连接以形成5-6元环烷基或5-6元杂环烷基};
RA1是-H、-C1-6烷基、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NH-(CH2)m-芳基、-OH或-O-C1-6烷基{其中-NH-(CH2)m-芳基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基或-卤素取代};
m是0、1、2、3或4;
RA2和RA3各自独立地是-H、-C1-6烷基、-C(=O)-C1-6烷基、-C(=O)-C1-6烯基、-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-芳基{其中-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-芳基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、=O、-卤素或芳基取代};以及
RA4是-H、-C1-6烷基或-C1-6卤代烷基。
根据本发明的实施方式,由化学式1表示的化合物、其光学异构体或其药学上可接受的盐可以在以下范围内:
X是N或CRX1;
R1是-H、-ORX2或-NRX3RX4;
RX1是-H或-CN;
RX2是-C1-6烷基、-C1-6氨基烷基、-C1-6卤代烷基、-C1-6烷基-O(C1-6烷基)、-C1-6烷基-O(C1-6烷基)-C1-6氨基烷基或-(CH2)n-杂环烷基{其中-(CH2)n-杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6烷基-O(C1-6烷基)或杂环烷基取代};
n是0、1、2、3或4;
RX3和RX4各自独立地是-H或-C1-6烷基,或RX3和RX4彼此连接以与N原子一起形成环,以及W1和W2各自独立地是CH2、NH或O{其中所述环中的至少一个H可以被-卤素或杂环烷基取代};
a至d各自独立地是1或2;
R2是-H或-卤素;
L是-NH-、{其中环B是在环中包含N原子的单环或多环,并且所述环B中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、=O或–卤素取代};
R3是-CZ1=Z2Z3、-C1-6卤代烷基或环烷基;
Z1是-H、-C1-6氨基烷基、-CN或-卤素;
Z2和Z3各自独立地是-H、-C1-6烷基、-C1-6氨基烷基、-C1-6烷基-O(C1-6烷基)、-卤素、-杂环烷基或-C1-6烷基-杂环烷基{其中所述-杂环烷基或-C1-6烷基-杂环烷基中的至少一个H可以被-C1-6烷基或-杂环烷基取代};
Y1至Y3各自独立地是N或CRY;
RY是-H、-C1-6烷基或-卤素;以及
R4是-C1-6烷基、-C1-6烷基-O-C1-6烷基、-C1-6卤代烷基、环烷基或杂环烷基{其中所述环烷基或杂环烷基中的至少一个H可以被-C1-6烷基取代};
环A是芳基、杂芳基、杂环烷基或杂环烯基{其中芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-C1-6烯基、-CN、-C(=O)-RA1、-NO2、-NRA2RA3、-ORA4、-S-C1-6烷基、-卤素或杂环烷基取代[此处,杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-卤素或杂环烷基取代],并且芳基或杂芳基环上的取代基可以彼此连接以形成5-6元环烷基或5-6元杂环烷基};
RA1是-H、-NH-(CH2)m-芳基、-OH或-O-C1-6烷基{其中-NH-(CH2)m-芳基环中的至少一个H可以被-卤素取代};
m是0、1、2、3或4;
RA2和RA3各自独立地是-H、-C1-6烷基、-C(=O)-C1-6烷基、-C(=O)-C1-6烯基、-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-芳基{其中-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-芳基环中的至少一个H可以被=O、-卤素或芳基取代};以及
RA4是-H、-C1-6烷基或-C1-6卤代烷基。
根据本发明的实施方式,由化学式1表示的化合物、其光学异构体或其药学上可接受的盐可以在以下范围内:
X是N或CRX1;
R1是-H、-ORX2或-NRX3RX4;
RX1是-H或-CN;
RX2是-C1-6烷基、-C1-6氨基烷基、-C1-6卤代烷基、-C1-6烷基-O(C1-6烷基)、-C1-6烷基-O(C1-6烷基)-C1-6氨基烷基或-(CH2)n-杂环烷基{其中-(CH2)n-杂环烷基环是4-6元,并且所述-(CH2)n-杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6烷基-O(C1-6烷基)或4-6元杂环烷基取代};
n是0、1、2或3;
RX3和RX4各自独立地是-H或-C1-6烷基,或RX3和RX4彼此连接以与N原子一起形成并且W1和W2各自独立地是CH2或O{其中环中的至少一个H可以被-卤素或4-6元杂环烷基取代};
a至d各自独立地是1或2;以及
R2是-H或-卤素。
根据本发明的实施方式,由化学式1表示的化合物、其光学异构体或其药学上可接受的盐可以在以下范围内:
L是-NH-、 {其中/> 环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、=O或-卤素取代};
V1和V2通过单键、C1烷基、C2烷基或C3烷基连接在一起以形成桥连双环或不存在(空位);以及
e至h各自独立地是1、2或3。
根据本发明的实施方式,由化学式1表示的化合物、其光学异构体或其药学上可接受的盐可以在以下范围内:
R3是-CZ1=Z2Z3、-C1-6卤代烷基或环烷基{其中环烷基环是单环或多环};
Z1是-H、-C1-6氨基烷基、-CN或-卤素;以及
Z2和Z3各自独立地是-H、-C1-6烷基、-C1-6氨基烷基、-C1-6烷基-O(C1-6烷基)、-卤素、-杂环烷基或-C1-6烷基-杂环烷基{其中杂环烷基或-C1-6烷基-杂环烷基环是4-6元,并且所述杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基中的至少一个H可以被-C1-6烷基或4-6元杂环烷基取代}。
根据本发明的实施方式,由化学式1表示的化合物、其光学异构体或其药学上可接受的盐可以在以下范围内:
Y1至Y3各自独立地是N或CRY;
RY是-H、-C1-6烷基或-卤素;以及
R4是-C1-6烷基、-C1-6烷基-O-C1-6烷基、-C1-6卤代烷基、3-7元环烷基或4-6元杂环烷基{其中所述3-7元环烷基或4-6元杂环烷基中的至少一个H可以被-C1-6烷基取代}。
根据本发明的实施方式,由化学式1表示的化合物、其光学异构体或其药学上可接受的盐可以在以下范围内:
环A是苯基、5-10元杂芳基、4-6元杂环烷基或4-6元杂环烯基{其中苯基、5-10元杂芳基、4-6元杂环烷基或4-6元杂环烯基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-C1-6烯基、-CN、-C(=O)-RA1、-NO2、-NRA2RA3、-ORA4、-S-C1-6烷基、-卤素或4-6元杂环烷基取代[此处,4-6元杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-卤素或杂环烷基取代],并且苯基或5-10元杂芳基环上的取代基可以彼此连接以形成5-6元环烷基或5-6元杂环烷基};
RA1是-H、-NH-(CH2)m-苯基、-OH或-O-C1-6烷基{其中-NH-(CH2)m-苯基环中的至少一个H可以被-卤素取代};
m是0、1或2;
RA2和RA3各自独立地是-H、-C1-6烷基、-C(=O)-C1-6烷基、-C(=O)-C1-6烯基、-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-苯基{其中-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-苯基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、=O、-卤素或苯基取代};以及
RA4是-H、-C1-6烷基或-C1-6卤代烷基。
根据本发明的另一种实施方式,由化学式1表示的化合物可以选自由以下描述的表1中列出的化合物组成的组。
在本公开中,除非另有说明,否则术语“烷基”可以指它们所键合的直链或支链非环状、环状或饱和烃。例如,“C1-6烷基”可以表示包含1至6个碳原子的烷基。作为实例,非环状烷基可以包括但不限于甲基、乙基、正丙基、正丁基、异丙基、仲丁基、异丁基、叔丁基等。环状烷基可以与如本文所用的“环烷基”互换使用,并且作为实例,可以包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本公开中,“烷氧基”可以表示作为烷基醚基团的-(O-烷基),其中烷基与上述定义相同。例如,“C1-6烷氧基”可以意指包含C1-6烷基的烷氧基,即-(O-C1-6烷基),并且作为实例,可以包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。
在本公开中,“卤素”可以是F、Cl、Br或I。
如本文所用,“卤代烷基”可以意指具有一个或多个如本文所定义的卤素取代的碳原子的直链或支链烷基(烃)。卤代烷基的实例可以包括但不限于独立地被一个或多个卤素(诸如F、Cl、Br或I)取代的甲基、乙基、丙基、异丙基、异丁基或正丁基。
在本公开中,“羟烷基”可以表示具有被-羟基(-OH)取代的碳原子的直链或支链烷基(烃)。卤代烷基的实例可以包括但不限于独立地被一个或多个卤素(例如-OH)取代的甲基、乙基、丙基、异丙基、异丁基或正丁基。
如本文所用,“氨基烷基”可以意指具有被氨基取代的碳原子的直链或支链烷基(烃)(NR'R”)。此处,R'和R”可以各自独立地选自由氢和C1-6烷基组成的组,并且所选择的R'和R”可以各自独立地被取代或未被取代。
在本公开中,“杂环烷基”可以意指包含1至5个选自N、O和S的杂原子的环,这些原子形成环,并且可以是饱和的或部分不饱和的。此处,当不饱和时,它可以被称为杂环烯烃。除非另有说明,杂环烷基可以是单环或多环,诸如螺环、桥环或稠环。此外,“3至12元杂环烷基”可以表示包含3至12个形成环的原子的杂环烷基。作为实例,杂环烷基可以包括但不限于吡咯烷、哌啶、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、嘧啶-2,4(1H,3H)-二酮、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环(quinuclidine)、莨菪烷(tropane)、2-氮杂螺[3.3]庚烷、(1R,5S)-3-氮杂双环[3.2.1]辛烷、(1s,4s)-2-氮杂双环[2.2.2]辛烷或(1R,4R)-2-氧杂-5-氮杂双环[2.2.2]辛烷等。
在本公开中,“芳烃”可以意指芳香烃环。芳烃可以是单环芳烃或多环芳烃。芳烃中的成环碳数可以是5或更多且30或更少、5或更多且20或更少、或者5或更多且15或更少。芳烃的实例可以包括但不限于苯、萘、芴、蒽、菲、联苯、三联苯、四联苯、五联苯、六联苯、三亚苯、芘、苯并荧蒽、等。在本说明书中,通过从“芳烃”中除去一个氢原子获得的残基称为“芳基”。
在本公开中,“杂芳烃”可以是包含O、N、P、Si和S中的至少一个作为异质元素的环。杂芳烃中的成环碳数可以是2或更多且30或更少,或者2或更多且20或更少。杂芳烃可以是单环杂芳烃或多环杂芳烃。多环杂芳烃可以具有例如双环或三环结构。杂芳烃的实例可以包括噻吩、嘌呤、吡咯、吡唑、咪唑、噻唑、噁唑、异噻唑、噁二唑、三唑、吡啶、联吡啶、三嗪、吖啶基、哒嗪、吡嗪、喹啉、喹唑啉、喹喔啉、吩噁嗪、酞嗪、嘧啶、吡啶并嘧啶、吡啶并吡嗪、吡嗪并吡嗪、异喹啉、吲哚、咔唑、咪唑并哒嗪、咪唑并吡啶、咪唑并嘧啶、吡唑并嘧啶、咪唑并吡嗪或吡唑并吡啶、三唑并吡啶、三唑并嘧啶、N-芳基咔唑、N-杂芳基咔唑、N-烷基咔唑、苯并噁唑、苯并咪唑、苯并噻唑、苯并咔唑、苯并噻吩、二苯并噻吩、噻吩并噻吩、苯并呋喃、菲咯啉、异噁唑、噁二唑、噻二唑、苯并噻唑、四唑、吩噻嗪、二苯并噻咯(dibenzosilole)、二苯并呋喃等,但不限于此。在本公开的实施方式中,杂芳烃还可以包括包含稠合至芳烃环的杂芳烃或稠合至杂环烷基环的环烷基环的双环杂环芳烃。在本说明书中,通过从“杂芳烃”中除去一个氢原子获得的残基称为“杂芳基”。
在本公开中,“环”可以是单环或多环,并且多环可以呈螺环、桥环、稠环等形式。
在本公开中,术语“光学异构体(对映异构体)”意指具有相同化学式或分子式但立体结构不同的本公开的化合物或其盐。这些对映异构体及其混合物中的每一种也包括在本公开的范围内。除非另有说明,否则连接不对称碳原子的直实线键(-)可以包括表示立构中心的绝对构型的楔形实线键或楔形虚线键/>
在本公开中,术语“顺式”是指其中环中两个取代基的结合方向相同的情况,并且术语“反式”是指其中环中两个取代基的结合方向不同的情况。
本公开的化学式1的化合物可以以“药学上可接受的盐”的形式存在。作为盐,由药学上可接受的游离酸形成的酸加成盐是有用的。如本文所用,术语“药学上可接受的盐”意指由化学式1表示的化合物的任何和所有有机或无机酸加成盐,由该盐引起的副作用在具有对患者相对无毒且无害的有效作用的浓度下不降低化合物的有益功效。
酸加成盐通过常规方法制备,例如通过将化合物溶解于过量的水性酸溶液中并使用与水混溶的有机溶剂(诸如甲醇、乙醇、丙酮或乙腈)沉淀盐。可以加热等摩尔量的化合物和水的酸或醇,并且然后可以将混合物蒸发至干,或可以抽滤出沉淀的盐。
此处,可以使用有机酸和无机酸作为游离酸,其中无机酸可以是盐酸、磷酸、硫酸、硝酸等,以及有机酸可以是甲磺酸、对甲苯磺酸、乙酸、三氟乙酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、柠檬酸、乳酸、乙醇酸、葡糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸、氢碘酸等。然而,本公开不限于此。
此外,可以使用碱制备药学上可接受的金属盐。碱金属盐或碱土金属盐例如通过将化合物溶解于过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的化合物盐,以及然后蒸发并干燥滤液而得到。此处,制备钠盐、钾盐或钙盐作为金属盐在药学上是合适的,但本公开不限于此。此外,可以通过使碱金属或碱土金属盐与合适的银盐(例如硝酸银)反应来得到相应的银盐。
除非另有说明,否则本公开的药学上可接受的盐包括可存在于化学式1的化合物中的酸性或碱性基团的盐。例如,药学上可接受的盐可以包括羟基基团的钠盐、钙盐和钾盐等,并且作为氨基基团的其他药学上可接受的盐,可以包括氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、乙酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、甲磺酸盐(methanesulfonate)(甲磺酸盐(mesylate))和对甲苯磺酸盐(甲苯磺酸盐)等,并且可以通过本领域已知的用于制备盐的方法进行制备。
杂芳基衍生物化合物的用途
本发明提供了由以下化学式1表示的化合物、其光学异构体或其药学上可接受的盐的用途:
[化学式1]
其中化学式1与以上所定义的相同。
本发明的由化学式1表示的化合物、其光学异构体或其药学上可接受的盐对各种激酶表现出抑制活性。
根据本发明的实施方式,由化学式1表示的杂芳基衍生物可以对HER2和EGFR激酶表现出优异的抑制活性,从而有效地用于治疗或预防HER2和/或EGFR相关疾病,特别是癌症。特别地,本发明的杂芳基衍生物化合物可以对HER2突变(例如,HER2 L869R、HER2L755S、HER2 T798I、HER2T862A等)和EGFR突变(例如,EGFR G719A、EGFR L861Q、EGFRS768I、EGFR G719A/S768I、EGFR Del19/T790M等)表现出优异的抑制活性,其可有效用于治疗或预防由HER2和/或EGFR诱导的癌。
在本公开中,癌症包括由于抑制HER2和/或EGFR激酶活性而能够表现出治疗或预防功效的任何癌症,并且可以是实体癌或血液学癌症。例如,该癌症可以是选自由以下组成的组中的一种或多种:假黏液瘤、肝内胆管癌、肝母细胞瘤、肝癌、甲状腺癌、结肠癌、睾丸癌、骨髓增生异常综合征、胶质母细胞瘤、口腔癌、唇癌、蕈样肉芽肿、急性髓系白血病、急性淋巴细胞性白血病、基底细胞癌、卵巢上皮癌、卵巢生殖细胞肿瘤、男性乳腺癌、脑癌、垂体腺瘤、多发性骨髓瘤、胆囊癌、胆道癌、结直肠癌、慢性髓细胞性白血病、慢性淋巴细胞白血病、视网膜母细胞瘤、脉络膜黑素瘤、法特壶腹癌(ampulla of vater cancer)、膀胱癌、腹膜癌、甲状旁腺癌、肾上腺癌、鼻腔鼻窦癌(sinonasal cancer)、非小细胞肺癌、舌癌、星形细胞瘤、小细胞肺癌、小儿脑癌、小儿淋巴瘤、小儿白血病、小肠癌、脑膜瘤、食管癌、胶质瘤、肾盂癌、肾癌、心脏癌、十二指肠癌、恶性软组织肿瘤、恶性骨肿瘤、恶性淋巴瘤、恶性间皮瘤、恶性黑素瘤、眼癌、外阴癌、输尿管癌、尿道癌、不明原发部位的癌症、胃部淋巴瘤、胃部癌、胃部类癌瘤、胃肠道间质瘤、维尔姆斯瘤、乳腺癌、肉瘤、阴茎癌、咽癌、妊娠绒毛膜癌、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、转移性骨癌、转移性脑癌、纵隔癌、直肠癌、直肠类癌瘤、阴道癌、脊髓癌、前庭神经鞘瘤、胰腺癌、唾液腺癌、卡波西肉瘤、佩吉特病、扁桃体癌、鳞状细胞癌、肺腺癌、肺癌、肺鳞状细胞癌、皮肤癌、肛门癌、横纹肌肉瘤、喉癌、胸膜癌、血液学癌症和胸腺癌,但是不限于此。癌症不仅包括原发性癌症,还包括转移性癌症。
根据本公开的实施方式,本公开提供了用于治疗或预防HER2和/或EGFR相关疾病的药物组合物,该药物组合物包含由化学式1表示的化合物、其光学异构体或其药学上可接受的盐作为活性成分。特别地,HER2和/或EGFR相关疾病可以是癌症。癌症的类型与上述相同。
除了上述由化学式1表示的化合物、其光学异构体或其药学上可接受的盐之外,本公开的药物组合物可以进一步包括表现出相同或相似药物功效的一种或多种活性成分。
此外,根据本公开的实施方式,提供了用于治疗或预防HER2和/或EGFR相关疾病的方法,该方法包括向有此需要的受试者给药治疗有效量的由化学式1表示的化合物、其光学异构体或其药学上可接受的盐。受试者可以是哺乳动物,包括人。
如本文所用,术语“治疗有效量”是指有效治疗或预防HER2和/或EGFR相关疾病的由化学式1表示的化合物的量。特别地,“治疗有效量”表示足以治疗具有适用于医学治疗的合理益处/风险比的疾病的量,并且有效剂量水平可以根据因素来确定,因素包括受试者类型和严重程度、年龄、性别、疾病的类型、药物活性、药物敏感性、给药时间、给药途径和排泄率、治疗周期、同时使用的药物以及医学领域熟知的其他因素。本公开的药物组合物可以作为单独的治疗剂给药或者可以与其他治疗剂联合给药,并且可以与市售治疗剂序依次或同时给药。此外,本公开的药物组合物可以单剂量或多剂量给药。考虑到所有上述因素,给药能够获得最大效果而没有副作用的最小量是重要的,并且该量可以由本领域技术人员容易地确定。本公开的药物组合物的剂量可以由医学专科医生根据多种因素(诸如患者的病症、年龄、性别、并发症等)来确定。由于本公开的药物组合物的活性成分具有优异的安全性,因此可以以高于确定剂量的剂量使用。
此外,根据本公开的实施方式,本公开提供了由化学式1表示的化合物、其光学异构体或其药学上可接受的盐用于在制备治疗或预防HER2和/或EGFR相关疾病的药物中的用途。用于制备药物的由化学式1表示的化合物可以与可接受的佐剂、稀释剂、载体等混合,并且可以通过与其他活性剂制备为复合制剂而具有活性成分的协同效应。
本公开的用途、组合物和治疗方法中提及的事项等同地适用,除非到它们彼此不一致的程度。
有益效果
本公开的杂芳基衍生物化合物对HER2和/或EGFR表现出优异的抑制活性,并且因此可以有效地用于治疗或预防HER2和/或EGFR相关疾病。
最佳模式
在下文中,将通过实施例和实验实施例详细描述本发明。然而,仅提供以下实施例和实验实施例用于说明本发明,并且本发明的范围不限于这些实施例。
<分析和纯化条件>
1.HPLC分析条件
(a)仪器:Waters e2695
柱:Xbridge C18,4.6x 150mm,5μm,40℃
流动相:20%->95%乙腈/H2O+0.1% TFA
分析时间:10分钟,流速:1mL/min
UV检测器:254nm
(b)仪器:Waters e2695
柱:YMC-Pack ODS-AM,150x 4.6mm,3μm,12nm,40℃
流动相:10%->90%乙腈/H2O+0.1% TFA
分析时间:20分钟,流速:1mL/min
UV检测器:254nm
2.LC-MS分析条件
仪器:Waters ACQUITY UPLC
柱:BEH C18,50x 2.1mm,5μm,40℃
流动相:乙腈/H2O+0.1% TFA
流速:0.6mL/min
UV检测器:254nm
3.MPLC分析条件
仪器:Rf+
UV检测器:254nm
4.制备型HPLC纯化条件(A)
仪器:ACCQPrep HP125
柱:Prep Shield RP18,250x 19mm,10μm
流动相:乙腈/0.1% TFA H2O
流速:25mL/min
UV检测器:254nm
5.制备型HPLC纯化条件(B)
仪器:ACCQPrep HP125
柱:Prep Shield RP18,250x 19mm,10μm
流动相:乙腈/0.1% FA H2O
流速:25mL/min
UV检测器:254nm
6.1H NMR
仪器:Bruker AscendTM400(400MHz)
实验中使用的商业试剂在没有进一步纯化的情况下使用。本发明中,室温意指15~25℃的温度。使用旋转蒸发器进行减压浓缩或溶剂蒸馏除去。
制备实施例1.制备N-(2,6-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)乙酰胺
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将2,6-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(1.0当量)和乙酸酐(2.81当量)溶解于乙酸(15.4当量)中,添加DMAP(0.02当量),并将混合物在室温下搅拌1小时。将反应混合物浓缩,得到为乳白色固体的目标化合物,其无需进一步纯化用于下一反应(产率:100%,MS(ESI):m/z298[M+1]+)。
实施例1.制备N-(3'-((6-((1-丙烯酰基哌啶-4-基)氧基)-7-甲氧基喹唑啉-4-
基)氨基)-2,4-二氟-4'-甲氧基-[1,1'-联苯]-3-基)乙酰胺
[步骤-1]制备4-((4-氯-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯
将4-氯-7-甲氧基喹唑啉-6-醇(1.0当量)、4-羟基哌啶-1-甲酸叔丁酯(2.0当量)和三苯基膦(1.5当量)溶解于DCM中。然后,在5℃下缓慢添加DTBAD(1.5当量),随后在室温下搅拌16小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为白色固体的目标化合物(产率:52%,MS(ESI):m/z394[M+1]+)。
[步骤-2]制备4-((4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)
哌啶-1-甲酸叔丁酯
将上述步骤-1中得到的4-((4-氯-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯(1.0当量)和5-溴-2-甲氧基苯胺(1.2当量)溶解于仲BuOH中。向反应混合物中添加溶解于二噁烷中的4.0M HCl,并在80℃下搅拌2小时。将反应混合物冷却至室温,并且然后添加乙醚以产生固体。将固体通过过滤器过滤,得到为乳白色固体的目标化合物(产率:96%,MS(ESI):m/z 559[M+1]+)。
[步骤-3]制备N-(5-溴-2-甲氧基苯基)-7-甲氧基-6-(哌啶-4-基氧基)喹唑啉-4-
胺
将上述步骤-2中得到的4-((4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯(1.0当量)溶解于DCM中,并且然后添加三氟乙酸(50当量)并在室温下搅拌1小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为淡黄色固体的目标化合物(产率:97%,MS(ESI):m/z 459[M+1]+)。
[步骤-4]制备1-(4-((4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧
基)哌啶-1-基)丙-2-烯-1-酮
将上述步骤-3中得到的N-(5-溴-2-甲氧基苯基)-7-甲氧基-6-(哌啶-4-基氧基)喹唑啉-4-胺(1.0当量)和饱和NaHCO3水性溶液(5.0当量)溶解于THF中,并且然后在0℃下添加丙烯酰氯(1.0当量)并搅拌1小时。将反应混合物浓缩,向其中添加水,并用DCM萃取有机物质。通过使用MgSO4除去剩余的水来浓缩收集的有机层。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为白色固体的目标化合物(产率:60%,MS(ESI):m/z 513[M+1]+)。
[步骤-5]制备N-(3'-((6-((1-丙烯酰基哌啶-4-基)氧基)-7-甲氧基喹唑啉-4-
基)氨基)-2,4-二氟-4'-甲氧基-[1,1'-联苯]-3-基)乙酰胺
将上述步骤-4中得到的1-(4-((4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮(1.0当量)、制备实施例1中得到的N-(2,6-二氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)乙酰胺(2.3当量)和K3PO4(3.5当量)溶解于二噁烷:水(5:1)中。使用氮气使反应混合物脱气,并在80℃下添加Xphos Pd G2(0.1当量),随后在100℃下搅拌30分钟。将反应产物通过硅藻土过滤器过滤,并浓缩。将反应混合物通过制备型HPLC纯化,得到为黄色固体的目标化合物(产率:96%,MS(ESI):m/z604[M+1]+)。
制备实施例2至231的化合物
以与上述实施例1类似的方式制备根据本发明的实施例2至231的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表1中。
[表1]
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24 PPI23172001KR
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实施例231.制备4-(3-((6-((1-丙烯酰基哌啶-4-基)氧基)-7-甲氧基喹唑啉-4-
基)氨基)-4-甲氧基苯基)-N-(3-氟苯乙基)噻吩-2-甲酰胺
[步骤-1]制备4-(4-甲氧基-3-硝基苯基)噻吩-2-甲酸甲酯
将4-溴-1-甲氧基-2-硝基苯(1.0当量)、(5-(甲氧基羰基)噻吩-3-基)硼酸(2.0当量)和K3PO4(2.2当量)溶解于1,4-二噁烷(0.1M)和水(0.5M)中,并使用氮气脱气。然后,在80℃下添加Xphos Pd G2(0.13当量),并将混合物在100℃下搅拌1小时。将反应混合物通过硅藻土过滤器过滤,并浓缩。将反应混合物通过MPLC(DCM/MeOH)纯化,得到为黄色固体的目标化合物(产率:100%,MS(ESI):m/z 294[M+1]+)。
[步骤-2]制备4-(4-甲氧基-3-硝基苯基)噻吩-2-甲酸
将上述步骤-1中得到的4-(4-甲氧基-3-硝基苯基)噻吩-2-甲酸甲酯(1.0当量)溶解于THF(0.05M)和MeOH(0.05M)中,并进一步添加溶解于蒸馏水中的5M KOH(1.2当量)并在60℃下搅拌2小时。将反应产物在50℃下真空干燥,得到为白色固体的目标化合物(产率:100%,MS(ESI):m/z 280[M+1]+)。
[步骤-3]制备4-(3-氨基-4-甲氧基苯基)噻吩-2-甲酸
在0℃下将上述步骤-2中得到的4-(4-甲氧基-3-硝基苯基)噻吩-2-甲酸(1.0当量)溶解于THF(0.3M)中,并且然后添加乙酸(20当量)和锌(10当量)。将反应混合物在室温下搅拌2小时。将混合物通过硅藻土过滤器过滤并浓缩。在0℃下通过添加饱和NaHCO3水性溶液中和浓缩物,用DCM萃取有机物质,并通过使用Na2SO4除去剩余的水来浓缩收集的有机层。将浓缩物通过制备型HPLC纯化,得到为黄色固体的目标化合物(产率:84%,MS(ESI):m/z 250[M+1]+)。
[步骤-4]制备4-(3-((6-((1-(叔丁氧基羰基)哌啶-4-基)氧基)-7-甲氧基喹唑
啉-4-基)氨基)-4-甲氧基苯基)噻吩-2-甲酸
将上述步骤-3中得到的4-(3-氨基-4-甲氧基苯基)噻吩-2-甲酸(1.2当量)和4-((4-氯-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯(1.0当量)溶解于仲BuOH(0.1M)中。然后,进一步添加溶解于1,4-二噁烷中的4M HCl(0.2当量),并在80℃下搅拌2小时,并且然后浓缩。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:100%,MS(ESI):m/z 607[M+1]+)。
[步骤-5]制备4-((4-((5-(5-((3-氟苯乙基)氨基甲酰基)噻吩-3-基)-2-甲氧基
苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯
将上述步骤-4中得到的4-(3-((6-((1-(叔丁氧基羰基)哌啶-4-基)氧基)-7-甲氧基喹唑啉-4-基)氨基)-4-甲氧基苯基)噻吩-2-甲酸(1.0当量)和2-(3-氟苯基)乙烷-1-胺(1.0当量)溶解于乙腈(0.1M)中。然后,添加HATU(2.0当量)和DIPEA(3.0当量),并在室温下搅拌5小时,并且然后浓缩。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:100%,MS(ESI):m/z 728[M+1]+)。
[步骤-6]制备N-(3-氟苯乙基)-4-(4-甲氧基-3-((7-甲氧基-6-(哌啶-4-基氧基)
喹唑啉-4-基)氨基)苯基)噻吩-2-甲酰胺
将上述步骤-5中得到的4-((4-((5-(5-((3-氟苯乙基)氨基甲酰基)噻吩-3-基)-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯(1.0当量)溶解于DCM(0.1M)中。然后,添加TFA(10当量)并将反应混合物在室温下搅拌1小时,并且然后浓缩。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:95%,MS(ESI):m/z 628[M+1]+)。
[步骤-7]制备4-(3-((6-((1-丙烯酰基哌啶-4-基)氧基)-7-甲氧基喹唑啉-4-基)
氨基)-4-甲氧基苯基)-N-(3-氟苯乙基)噻吩-2-甲酰胺
将上述步骤-6中得到的N-(3-氟苯乙基)-4-(4-甲氧基-3-((7-甲氧基-6-(哌啶-4-基氧基)喹唑啉-4-基)氨基)苯基)噻吩-2-甲酰胺(1.0当量)和饱和NaHCO3水性溶液(5.0当量)溶解于THF(0.1M)中。然后,在0℃下添加丙烯酰氯(1.0当量),并将反应混合物搅拌10分钟,并且然后浓缩。将反应混合物通过制备型HPLC纯化,得到为淡黄色固体的目标化合物(产率:13%,MS(ESI):m/z 682[M+1]+)。
制备实施例232至235的化合物
以与上述实施例231类似的方式制备根据本发明的实施例232至235的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表2中。
[表2]
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实施例236.制备(R)-N-(3'-((6-((1-丙烯酰基氮杂环丁烷-3-基)氧基)-7-甲氧
基喹唑啉-4-基)氨基)-4'-甲氧基-[1,1'-联苯]-3-基)-2-氧亚基-4-苯基噁唑烷-3-甲酰
胺
[步骤-1]制备3-((4-((3'-氨基-4-甲氧基-[1,1'-联苯]-3-基)氨基)-7-甲氧基
喹唑啉-6-基)氧基)氮杂环丁烷-1-甲酸叔丁酯
将3-((4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)氮杂环丁烷-1-甲酸叔丁酯(1.0当量)、(3-氨基苯基)硼酸(3.0当量)和K3PO4(2.0当量)溶解于1,4-二噁烷:蒸馏水=5:1(v/v)(0.1M)中,然后用氮气脱气,并在100℃下在氮气下搅拌3分钟。然后,在100℃下添加Xphos Pd G2(0.13当量),并将反应混合物搅拌1小时并且然后浓缩。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为淡黄色固体的目标化合物(产率:63%,MS(ESI):m/z 544[M+1]+)。
[步骤-2]制备3-((7-甲氧基-4-((4-甲氧基-3'-(((4-硝基苯氧基)羰基)氨基)-
[1,1'-联苯]-3-基)氨基)喹唑啉-6-基)氧基)氮杂环丁烷-1-甲酸叔丁酯
将上述步骤-1中得到的3-((4-((3'-氨基-4-甲氧基-[1,1'-联苯]-3-基)氨基)-7-甲氧基喹唑啉-6-基)氧基)氮杂环丁烷-1-甲酸叔丁酯(1.0当量)溶解于DCM(0.1M)中,并且然后添加吡啶(3.0当量)。将反应混合物冷却至0℃,然后添加氯甲酸4-硝基苯酯(1.5当量)并在室温下搅拌2小时。得到的为棕色固体的目标化合物无需进一步纯化用于下一反应(产率:100%,MS(ESI):m/z709[M+1]+)。
[步骤-3]制备(R)-3-((7-甲氧基-4-((4-甲氧基-3'-(2-氧亚基-4-苯基噁唑烷-
3-甲酰胺基)-[1,1'-联苯]-3-基)氨基)喹唑啉-6-基)氧基)氮杂环丁烷-1-甲酸叔丁酯
将(R)-4-苯基噁唑烷-2-酮(2.2当量)溶解于DMF(0.1M)中,然后添加NaH(2.2当量),并将混合物在室温下搅拌20分钟。向上述步骤-2中得到的3-((7-甲氧基-4-((4-甲氧基-3'-(((4-硝基苯氧基)羰基)氨基)-[1,1'-联苯]-3-基)氨基)喹唑啉-6-基)氧基)氮杂环丁烷-1-甲酸叔丁酯中添加反应混合物,并在室温下搅拌15分钟。用饱和NaHCO3和EA从反应混合物中萃取有机物质,并通过使用MgSO4除去剩余的水来浓缩收集的有机层。得到的为棕色固体的目标化合物无需进一步纯化用于下一反应(产率:100%,MS(ESI):m/z 733[M+1]+)。
[步骤-4]制备(R)-N-(3'-((6-(氮杂环丁烷-3-基氧基)-7-甲氧基喹唑啉-4-基)
氨基)-4'-甲氧基-[1,1'-联苯]-3-基)-2-氧亚基-4-苯基噁唑烷-3-甲酰胺
将上述步骤-3中得到的(R)-3-((7-甲氧基-4-((4-甲氧基-3'-(2-氧亚基-4-苯基噁唑烷-3-甲酰胺基)-[1,1'-联苯]-3-基)氨基)喹唑啉-6-基)氧基)氮杂环丁烷-1-甲酸叔丁酯(1.0当量)溶解于DCM:TFA(10:1v/v)(0.1M)溶液中,并在室温下搅拌2小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:38%,MS(ESI):m/z 633[M+1]+)。
[步骤-5]制备(R)-N-(3'-((6-((1-丙烯酰基氮杂环丁烷-3-基)氧基)-7-甲氧基
喹唑啉-4-基)氨基)-4'-甲氧基-[1,1'-联苯]-3-基)-2-氧亚基-4-苯基噁唑烷-3-甲酰胺
将上述步骤-4中得到的(R)-N-(3'-((6-(氮杂环丁烷-3-基氧基)-7-甲氧基喹唑啉-4-基)氨基)-4'-甲氧基-[1,1'-联苯]-3-基)-2-氧亚基-4-苯基噁唑烷-3-甲酰胺(1.0当量)溶解于THF(0.1M)中,并冷却至0℃。向混合物中添加1MNaHCO3溶液(2.0当量),并添加丙烯酰氯(1.2当量)并在0℃下搅拌30分钟。将饱和NaHCO3水性溶液添加到反应混合物中,然后用EA萃取有机物质,并通过使用MgSO4除去剩余的水来浓缩收集的有机层。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为白色固体的目标化合物(产率:49%,MS(ESI):m/z 687[M+1]+)。
制备实施例237的化合物
以与上述实施例236类似的方式制备根据本发明的实施例237的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表3中。
[表3]
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实施例238.制备1-(4-((7-乙氧基-4-((5-(呋喃-2-基)-2-甲氧基苯基)氨基)喹
唑啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
[步骤-1]制备3,4-二羟基苯甲酸甲酯
将3,4-二羟基苯甲酸(1.0当量)和亚硫酰氯(1.0当量)添加到甲醇(0.5M)中。将混合物在70℃下加热2小时并且然后浓缩。将残余物用乙酸乙酯稀释,并将残余物用饱和NaHCO3溶液和盐水洗涤。通过使用MgSO4除去剩余的水来浓缩收集的有机层。得到的为白色固体的目标化合物无需进一步纯化用于下一反应(产率:98%)。
[步骤-2]制备4-乙氧基-3-羟基苯甲酸甲酯
将上述步骤-1中得到的3,4-二羟基苯甲酸甲酯(1.0当量)和K2CO3(1.0当量)添加到DMF(0.2M)中。将混合物在0℃下搅拌20分钟,并滴加碘乙烷(4.0当量)。添加完成后,将混合物在0℃下搅拌另外12小时。通过LC-MS确认期望产物。使混合物通过硅藻土过滤器并减压除去DMF。将残余物再溶解于乙酸乙酯中并用1M HCl洗涤。通过使用MgSO4除去剩余的水来浓缩收集的有机层。得到的为白色固体的目标化合物无需进一步纯化用于下一反应(产率:37%,MS(ESI):m/z 197[M+1]+)。
[步骤-3]制备3-(苄氧基)-4-乙氧基苯甲酸甲酯
将上述步骤-2中得到的4-乙氧基-3-羟基苯甲酸甲酯、K2CO3(1.5当量)和苄基溴(1.1当量)添加到DMF(0.2M)中。将混合物在100℃下加热12小时。将混合物冷却至室温,添加水,并用乙酸乙酯萃取有机物质。通过使用MgSO4除去剩余的水来浓缩收集的有机层。得到的为白色固体的目标化合物无需进一步纯化用于下一反应(产率:91%,MS(ESI):m/z287[M+1]+)。
[步骤-4]制备5-(苄氧基)-4-乙氧基-2-硝基苯甲酸甲酯
将上述步骤-3中得到的3-(苄氧基)-4-乙氧基苯甲酸甲酯(1.0当量)溶解于极少量的乙酸中。向该溶液中添加浓硝酸(2.9当量,70%)。在50℃下搅拌混合物1小时后,倒入冰水以形成固体,并且所得固体用水洗涤,并真空干燥,得到为黄色固体的目标化合物(产率:92%)。
[步骤-5]制备2-氨基-4-乙氧基-5-羟基苯甲酸甲酯
将上述步骤-4中得到的5-(苄氧基)-4-乙氧基-2-硝基苯甲酸甲酯(1.0当量)溶解于甲醇(0.1M)中,并且然后添加Pd/C(10%纯度,0.05当量)。将混合物在氢气下在室温下搅拌1小时。将混合物通过硅藻土过滤器过滤,然后用甲醇洗涤,并浓缩滤液。得到的为白色固体的目标化合物无需进一步纯化用于下一反应(产率:100%,MS(ESI):m/z 212[M+1]+)。
[步骤-6]制备7-乙氧基喹唑啉-4,6-二醇
将上述步骤-5中得到的2-氨基-4-乙氧基-5-羟基苯甲酸甲酯(1.0当量)和乙酸甲脒(2.0当量)溶解于2-甲氧基乙醇(0.1M)中,并将混合物在120℃下搅拌1小时。将溶剂浓缩、用水洗涤并干燥。得到的为浅棕色固体的目标化合物无需进一步纯化用于下一反应(产率:77%,MS(ESI):m/z 207[M+1]+)。
[步骤-7]制备7-乙氧基-4-羟基喹唑啉-6-基乙酸酯
将吡啶(2.5当量)添加到上述步骤-6中得到的7-乙氧基喹唑啉-4,6-二醇(1.0当量)和乙酸酐(1.1当量)中,并将混合物在120℃下加热4小时。将冰水添加到反应混合物中,随后过滤以得到固体,并将得到的固体真空干燥。得到的为浅棕色固体的目标化合物无需进一步纯化用于下一反应(产率:91%,MS(ESI):m/z 249[M+1]+)。
[步骤-8]制备4-氯-7-乙氧基喹唑啉-6-基乙酸酯
将上述步骤-7中得到的7-乙氧基-4-羟基喹唑啉-6-基乙酸酯(1.0当量)和亚硫酰氯(20.0当量)溶解于DMF(0.3M)中,并在120℃下加热2小时。减压除去过量的亚硫酰氯,并且将反应混合物使用MPLC(DCM:MeOH)纯化,得到为白色固体的目标化合物(产率:47%,MS(ESI):m/z 267[M+1]+)。
[步骤-9]制备4-氯-7-乙氧基喹唑啉-6-醇
将上述步骤-8中得到的4-氯-7-乙氧基喹唑啉-6-基乙酸酯(1.0当量)和氨溶液(65当量,在水中28%)溶解于MeOH(0.1M)中,并在室温下搅拌1小时。将反应混合物浓缩,然后添加乙醚以得到固体,并将得到的固体过滤。将得到的固体在60℃下真空干燥,得到为白色固体的目标化合物(产率:52%,MS(ESI):m/z 225[M+1]+)。
[步骤-10]制备4-((4-氯-7-乙氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯
将上述步骤-9中得到的4-氯-7-乙氧基喹唑啉-6-醇(1.0当量)、4-羟基哌啶-1-甲酸叔丁酯(2.0当量)和三苯基膦(1.5当量)溶解于DCM(0.1M)中。然后,在0℃下添加DTBAD(1.5当量),随后在室温下搅拌3小时。将反应混合物浓缩并通过MPLC纯化,得到为白色固体的目标化合物(产率:73%,MS(ESI):m/z 408[M+1]+)。
[步骤-11]制备4-((4-((5-溴-2-甲氧基苯基)氨基)-7-乙氧基喹唑啉-6-基)氧
基)哌啶-1-甲酸叔丁酯
将上述步骤-10中得到的4-((4-氯-7-乙氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯(1.0当量)和5-溴-2-甲氧基苯胺(1.2当量)溶解于仲BuOH(0.1M)中,然后添加溶解于二噁烷中的4M HCl(0.2当量)并在100℃下搅拌1小时。将乙醚添加到混合物中以产生固体,并将得到的固体过滤并用乙醚洗涤。得到的为白色固体的目标化合物无需进一步纯化用于下一反应(产率:94%,MS(ESI):m/z 574[M+1]+)。
[步骤-12]制备N-(5-溴-2-甲氧基苯基)-7-乙氧基-6-(哌啶-4-基氧基)喹唑啉-
4-胺
将上述步骤-11中得到的4-((4-((5-溴-2-甲氧基苯基)氨基)-7-乙氧基喹唑啉-6-基)氧基)哌啶-1-甲酸叔丁酯(1.0当量)溶解于DCM(0.1M)中,并且然后添加TFA(10当量)并在室温下搅拌1小时。将反应混合物真空浓缩,并使用MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:94%,MS(ESI):m/z 474[M+1]+)。
[步骤-13]制备7-乙氧基-N-(5-(呋喃-2-基)-2-甲氧基苯基)-6-(哌啶-4-基氧
基)喹唑啉-4-胺
将上述步骤-12中得到的N-(5-溴-2-甲氧基苯基)-7-乙氧基-6-(哌啶-4-基氧基)喹唑啉-4-胺(1.0当量)、呋喃-2-基硼酸(2.2当量)和K3PO4(2.0当量)溶解于二噁烷(0.1M)和水(0.5M)中,然后将混合物用氮气脱气,在80℃下添加Xphos Pd G2(0.13当量),并将混合物在90℃下搅拌20分钟。将混合物通过硅藻土过滤器过滤,并浓缩滤液,得到为棕色固体的目标化合物,其无需进一步纯化用于下一反应(MS(ESI):m/z 461[M+1]+)。
[步骤-14]制备1-(4-((7-乙氧基-4-((5-(呋喃-2-基)-2-甲氧基苯基)氨基)喹唑
啉-6-基)氧基)哌啶-1-基)丙-2-烯-1-酮
将上述步骤-13中得到的7-乙氧基-N-(5-(呋喃-2-基)-2-甲氧基苯基)-6-(哌啶-4-基氧基)喹唑啉-4-胺(1.0当量)和饱和NaHCO3水性溶液(5.0当量)溶解于THF(0.1M)中,并且然后在0℃下添加丙烯酰氯(1.0当量)并搅拌10分钟。将反应混合物浓缩并使用制备型HPLC纯化,得到为黄色固体的目标化合物(产率:22%,MS(ESI):m/z 515[M+1]+)。
制备实施例239的化合物
以与上述实施例238类似的方式制备根据本发明的实施例239的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表4中。
[表4]
制备实施例2.制备2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-2-基)苯胺
[步骤-1]制备1-甲基吡咯烷-3-基甲磺酸酯
在0℃下将1-甲基吡咯烷-3-醇(1.0当量)溶解于DCM(1.0M)中,然后添加DIPEA(1.2当量)和甲磺酰氯(1.1当量)。将反应混合物在0℃下搅拌1小时并且然后在室温下搅拌16小时。通过TLC确认反应后,将水添加到反应混合物中,并用DCM萃取有机物质。通过使用Na2SO4除去剩余的水来浓缩收集的有机层。得到的为棕色固体的目标化合物无需进一步纯化用于下一反应(产率:80%)。
[步骤-2]制备3-(4-溴-2-硝基苯氧基)-1-甲基吡咯烷
将上述步骤-1中得到的1-甲基吡咯烷-3-基甲磺酸酯(1.0当量)、4-溴-2-硝基苯酚(1.5当量)和K2CO3(2.0当量)溶解于DMF(0.6M)中,并在100℃下搅拌16小时。将水添加到反应混合物中,并用乙酸乙酯萃取有机物质。通过使用Na2SO4除去剩余的水来浓缩收集的有机层。将反应混合物通过MPLC(己烷:EA)纯化,得到为棕色固体的目标化合物(产率:80%,MS(ESI):m/z 301[M+1]+)。
[步骤-3]制备5-溴-2-((1-甲基吡咯烷-3-基)氧基)苯胺
在0℃下将步骤-2中得到的3-(4-溴-2-硝基苯氧基)-1-甲基吡咯烷(1.0当量)溶解于THF(0.3M)中,并且然后添加乙酸(20当量)和锌(10当量)。将反应混合物在室温下搅拌2小时。将混合物用甲醇稀释,通过硅藻土过滤器过滤,并浓缩。在0℃下通过添加饱和NaHCO3水性溶液中和浓缩物,并且然后用DCM萃取有机物质。通过使用Na2SO4除去剩余的水来浓缩收集的有机层。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:77%,MS(ESI):m/z 271[M+1]+)。
[步骤-4]制备2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-2-基)苯胺
将上述步骤-3中得到的5-溴-2-((1-甲基吡咯烷-3-基)氧基)苯胺(1.0当量)、4,4,5,5-四甲基-2-(噻吩-2-基)-1,3,2-二氧杂环戊硼烷(2.0当量)和K3PO4(2.0当量)溶解于二噁烷(0.1M)和水(0.5M)中。使用氮气使反应混合物脱气,并在80℃下将Xphos Pd G2(0.13当量)添加到混合物中,随后在100℃下搅拌1小时。将混合物通过硅藻土过滤器过滤,并浓缩滤液。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为棕色固体的目标化合物(产率:64%,MS(ESI):m/z 275[M+1]+)。
实施例240.制备1-(3-((7-甲氧基-4-((2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-2-基)苯基)氨基)喹唑啉-6-基)氧基)氮杂环丁烷-1-基)丙-2-烯-1-酮
[步骤-1]制备7-甲氧基-4-((2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-2-基)苯
基)氨基)喹唑啉-6-醇
将制备实施例2中得到的2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-2-基)苯胺(1.2当量)和4-氯-7-甲氧基喹唑啉-6-醇(1.0当量)溶解于仲BuOH(0.1M)中,并且添加溶解于1,4-二噁烷中的4M HCl(0.2当量),然后在100℃下搅拌16小时。将乙醚添加到混合物中,并将所得固体过滤并用乙醚洗涤,得到为黄色固体的目标化合物(产率:84%,MS(ESI):m/z449[M+1]+)。
[步骤-2]制备3-((7-甲氧基-4-((2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-2-
基)苯基)氨基)喹唑啉-6-基)氧基)氮杂环丁烷-1-甲酸叔丁酯
将上述步骤-1中得到的7-甲氧基-4-((2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-2-基)苯基)氨基)喹唑啉-6-醇(1.0当量)、3-(甲苯磺酰基氧基)氮杂环丁烷-1-甲酸叔丁酯(1.2当量)和K2CO3(2.0当量)溶解于DMF(0.1M)中,并将混合物在100℃下搅拌16小时。将溶液冷却至室温,并通过添加DCM和盐水来萃取有机物质。通过使用Na2SO4除去剩余的水来浓缩收集的有机层。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:33%,MS(ESI):m/z 604[M+1]+)。
[步骤-3]制备6-(氮杂环丁烷-3-基氧基)-7-甲氧基-N-(2-((1-甲基吡咯烷-3-
基)氧基)-5-(噻吩-2-基)苯基)喹唑啉-4-胺
将上述步骤-2中得到的3-((7-甲氧基-4-((2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-2-基)苯基)氨基)喹唑啉-6-基)氧基)氮杂环丁烷-1-甲酸叔丁酯(1.0当量)溶解于DCM(0.2M)中,并且然后添加TFA(50.0当量)并在室温下搅拌1小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:92%,MS(ESI):m/z 504[M+1]+)。
[步骤-4]制备1-(3-((7-甲氧基-4-((2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-
2-基)苯基)氨基)喹唑啉-6-基)氧基)氮杂环丁烷-1-基)丙-2-烯-1-酮
将上述步骤-3得到的6-(氮杂环丁烷-3-基氧基)-7-甲氧基-N-(2-((1-甲基吡咯烷-3-基)氧基)-5-(噻吩-2-基)苯基)喹唑啉-4-胺(1.0当量)和饱和NaHCO3水性溶液(5.0当量)溶解于THF(0.1M)中,并且然后在0℃下添加丙烯酰氯(1.0当量)并搅拌30分钟。将反应混合物浓缩并使用制备型HPLC纯化,得到为黄色固体的目标化合物(产率:30%,MS(ESI):m/z 558[M+1]+)。
制备实施例241至261的化合物
以与上述实施例240类似的方式制备根据本发明的实施例241至261的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表5中。
[表5]
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实施例262.制备1-(4-((4-((5-(呋喃-2-基)-2-甲氧基苯基)氨基)-7-(2-甲氧基乙氧基)喹唑啉-6-基)氨基)哌啶-1-基)丙-2-烯-1-酮
[步骤-1]制备7-(2-甲氧基乙氧基)-6-硝基喹唑啉-4(1H)-酮
将2-甲氧基乙醇(1.0当量)溶解于无水THF(1.5M)中,并在氮气下冷却至0℃,然后添加NaH(0.68当量),并将混合物在室温下搅拌1小时。向反应混合物中添加7-氟-6-硝基喹唑啉-4(1H)-酮(0.3当量)并在75℃下搅拌12小时。用饱和NaHCO3水性溶液将反应混合物调节至pH 7,并用氯仿萃取有机物质。通过使用MgSO4除去剩余的水来浓缩收集的有机层。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为白色固体的目标化合物(产率:54%,MS(ESI):m/z 266[M+1]+)。
[步骤-2]制备4-氯-7-(2-甲氧基乙氧基)-6-硝基喹唑啉
向上述步骤-1中得到的7-(2-甲氧基乙氧基)-6-硝基喹唑啉-4(1H)-酮(1.0当量)中添加SOCl2(0.4M)和DMF(0.2当量)并在120℃下搅拌2小时。将反应混合物减压浓缩,得到为黄色固体的目标化合物,其无需进一步纯化用于下一反应(产率:70%,MS(ESI):m/z 284[M+1]+)。
[步骤-3]制备N-(5-溴-2-甲氧基苯基)-7-(2-甲氧基乙氧基)-6-硝基喹唑啉-4-
胺
将上述步骤-2中得到的4-氯-7-(2-甲氧基乙氧基)-6-硝基喹唑啉(1.0当量)溶解于异丙醇(0.2M)中,然后添加5-溴-2-甲氧基苯胺(1.0当量)并在60℃下搅拌2小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为淡黄色固体的目标化合物(产率:80%,MS(ESI):m/z 450[M+1]+)。
[步骤-4]制备N4-(5-溴-2-甲氧基苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺
将上述步骤-3中得到的N-(5-溴-2-甲氧基苯基)-7-(2-甲氧基乙氧基)-6-硝基喹唑啉-4-胺(1.0当量)溶解于EA(0.2M)中,并添加二水合氯化锡(II)(5.0当量)并在60℃下搅拌3小时。将反应混合物冷却至室温,然后向其中添加氨水,并浓缩混合物。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为白色固体的目标化合物(产率:86%,MS(ESI):m/z 420[M+1]+)。
[步骤-5]制备4-((4-((5-溴-2-甲氧基苯基)氨基)-7-(2-甲氧基乙氧基)喹唑啉-
6-基)氨基)哌啶-1-甲酸叔丁酯
将上述步骤-4中得到的N4-(5-溴-2-甲氧基苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺(1.0当量)溶解于AcOH(0.2M)中,并添加4-氧亚基哌啶-1-甲酸叔丁酯(2.0当量)。将混合物在室温下搅拌2小时,然后添加三乙酰氧基硼氢化钠(1.2当量),并将混合物在室温下搅拌12小时。将饱和NaHCO3水性溶液添加到反应混合物中,然后用EA萃取有机物质,并通过使用MgSO4除去剩余的水来浓缩收集的有机层。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为淡黄色固体的目标化合物(产率:58%,MS(ESI):m/z 603[M+1]+)。
[步骤-6]制备N4-(5-溴-2-甲氧基苯基)-7-(2-甲氧基乙氧基)-N6-(哌啶-4-基)喹
唑啉-4,6-二胺
将上述步骤-5中得到的4-((4-((5-溴-2-甲氧基苯基)氨基)-7-(2-甲氧基乙氧基)喹唑啉-6-基)氨基)哌啶-1-甲酸叔丁酯(1.0当量)溶解于DCM:TFA(10:1v/v)(0.2M)中,并在室温下搅拌2小时。将反应混合物减压浓缩并通过MPLC(DCM:MeOH)纯化,得到为淡黄色固体的目标化合物(产率:99%,MS(ESI):m/z 503[M+1]+)。
[步骤-7]制备N4-(5-(呋喃-2-基)-2-甲氧基苯基)-7-(2-甲氧基乙氧基)-N6-(哌
啶-4-基)喹唑啉-4,6-二胺
将上述步骤-6中得到的N4-(5-溴-2-甲氧基苯基)-7-(2-甲氧基乙氧基)-N6-(哌啶-4-基)喹唑啉-4,6-二胺(1.0当量)、呋喃-2-基硼酸(2.2当量)和K3PO4(3.0当量)溶解于1,4-二噁烷:蒸馏水=5:1(v/v)(0.2M)中,并用氮脱气。将反应混合物在氮气下在100℃下加热5分钟,并添加Xphos Pd G2(0.1当量)并搅拌1小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为白色固体的目标化合物(产率:98%,MS(ESI):m/z 490[M+1]+)。
[步骤-8]制备1-(4-((4-((5-(呋喃-2-基)-2-甲氧基苯基)氨基)-7-(2-甲氧基乙
氧基)喹唑啉-6-基)氨基)哌啶-1-基)丙-2-烯-1-酮
将上述步骤-7中得到的N4-(5-(呋喃-2-基)-2-甲氧基苯基)-7-(2-甲氧基乙氧基)-N6-(哌啶-4-基)喹唑啉-4,6-二胺(1.0当量)溶解于THF(0.1M)中,然后冷却至0℃,并添加1M NaHCO3水性溶液(1.5当量)和丙烯酰氯(1.0当量),随后在0℃下搅拌30分钟。将反应混合物浓缩并使用制备型HPLC纯化,得到为黄色固体的目标化合物(产率:40%,MS(ESI):m/z 544[M+1]+)。
制备实施例263至286的化合物
以与上述实施例262类似的方式制备实施例263至286的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表6中。
[表6]
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实施例287.制备N-(4-((5-([1,2,4]三唑并[1,5-a]吡啶-7-基)-2-甲氧基苯基)
氨基)-7-甲氧基喹唑啉-6-基)丙烯酰胺
[步骤-1]制备7-甲氧基-6-硝基喹唑啉-4(3H)-酮
将7-氟-6-硝基喹唑啉-4(3H)-酮(1.0当量)和甲醇钠(2.0当量)溶解于MeOH(0.2M)中,并将混合物在70℃下搅拌2小时。向混合物中添加1NHCl以得到固体,并将得到的固体过滤。得到的为白色固体的目标化合物无需进一步纯化用于下一反应(产率:78%,MS(ESI):m/z 222[M+1]+)。
[步骤-2]制备4-氯-7-甲氧基-6-硝基喹唑啉
在氮气下,向上述步骤-1中得到的7-甲氧基-6-硝基喹唑啉-4(3H)-酮(1.0当量)中添加亚硫酰氯(30.0当量)和DMF(1滴)。将混合物在100℃下搅拌4小时,并且然后浓缩。得到的为透明油的目标化合物无需进一步纯化用于下一反应(产率:92%,MS(ESI):m/z 240[M+1]+)。
[步骤-3]制备N-(5-([1,2,4]三唑并[1,5-a]吡啶-7-基)-2-甲氧基苯基)-7-甲氧
基-6-硝基喹唑啉-4-胺
将上述步骤-2中得到的4-氯-7-甲氧基-6-硝基喹唑啉(3.0当量)和5-([1,2,4]三唑并[1,5-a]吡啶-7-基)-2-甲氧基苯胺(1.0当量)溶解于仲BuOH(0.1M)中,并添加溶解于1,4-二噁烷中的4M HCl(0.2当量)并在80℃下搅拌2小时。将乙醚添加到反应混合物中以形成固体,并将形成的固体过滤并用乙醚洗涤。得到的为白色固体的目标化合物无需进一步纯化用于下一反应(产率:39%,MS(ESI):m/z 444[M+1]+)。
[步骤-4]制备N4-(5-([1,2,4]三唑并[1,5-a]吡啶-7-基)-2-甲氧基苯基)-7-甲
氧基喹唑啉-4,6-二胺
将上述步骤-3中得到的N-(5-([1,2,4]三唑并[1,5-a]吡啶-7-基)-2-甲氧基苯基)-7-甲氧基-6-硝基喹唑啉-4-胺(1.0当量)和二水合氯化锡(II)(5.0当量)溶解于乙酸乙酯(0.1M)中,并将混合物在55℃下搅拌1小时。通过LC-MS确认期望产物。将混合物通过硅藻土过滤器过滤并浓缩,得到为白色固体的目标化合物,其无需进一步纯化用于下一反应(MS(ESI):m/z 414[M+1]+)。
[步骤-5]制备N-(4-((5-([1,2,4]三唑并[1,5-a]吡啶-7-基)-2-甲氧基苯基)氨
基)-7-甲氧基喹唑啉-6-基)丙烯酰胺
将上述步骤-4中得到的N4-(5-([1,2,4]三唑并[1,5-a]吡啶-7-基)-2-甲氧基苯基)-7-甲氧基喹唑啉-4,6-二胺(1.0当量)和DIPEA(2.5当量)溶解于DMF(0.1M)中,并且然后在0℃下添加丙烯酰氯(1.0当量)并在0℃下搅拌20分钟。将反应混合物真空浓缩并使用制备型HPLC纯化,得到为白色固体的目标化合物(产率:15%,MS(ESI):m/z 468[M+1]+)。
制备实施例288至296的化合物
以与上述实施例287类似的方式制备根据本发明的实施例288至296的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表7中。
[表7]
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实施例297.制备1-(4-((4-((2',4'-二氟-4-甲氧基-[1,1'-联苯]-3-基)氨基)-
7-(二氟甲氧基)喹唑啉-6-基)氨基)哌啶-1-基)丙-2-烯-1-酮
[步骤-1]制备N-(5-溴-2-甲氧基苯基)-7-氟-6-硝基喹唑啉-4-胺
将4-氯-7-氟-6-硝基喹唑啉(1.0当量)和5-溴-2-甲氧基苯胺(1.0当量)溶解于异丙醇(0.2M)中,并在50℃下搅拌10分钟。添加乙醚以产生固体化合物,并且过滤所得固体,得到为黄色固体的目标化合物(产率:72%,MS(ESI):m/z 393[M+1]+)。
[步骤-2]制备4-((5-溴-2-甲氧基苯基)氨基)-6-硝基喹唑啉-7-醇
将上述步骤-1中得到的N-(5-溴-2-甲氧基苯基)-7-氟-6-硝基喹唑啉-4-胺(1.0当量)溶解于1,4-二噁烷中,然后添加50% NaOH水性溶液(12.5当量)并在110℃下搅拌4小时。通过添加10%硫酸水性溶液酸化混合物,并用EA萃取有机物质。通过使用Na2SO4除去剩余的水来浓缩收集的有机层。得到的为黄色固体的目标化合物无需进一步纯化用于下一反应(产率:74%,MS(ESI):m/z 391[M+1]+)。
[步骤-3]制备N-(5-溴-2-甲氧基苯基)-7-(二氟甲氧基)-6-硝基喹唑啉-4-胺
将上述步骤-2中得到的4-((5-溴-2-甲氧基苯基)氨基)-6-硝基喹唑啉-7-醇(1.0当量)、2-氯-2,2-二氟-1-苯基乙烷-1-酮(2.0当量)和K2CO3(2.0当量)溶解于ACN:H2O(5:1)中,并将混合物在80℃下搅拌16小时。向其中添加水,并用EA萃取有机物质。通过使用Na2SO4除去剩余的水来浓缩收集的有机层。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:37%,MS(ESI):m/z 441[M+1]+)。
[步骤-4]制备N4-(5-溴-2-甲氧基苯基)-7-(二氟甲氧基)喹唑啉-4,6-二胺
将上述步骤-3中得到的N-(5-溴-2-甲氧基苯基)-7-(二氟甲氧基)-6-硝基喹唑啉-4-胺(1.0当量)和二水合氯化锡(II)(5.0当量)溶解于乙酸乙酯(0.1M)中,并将混合物在60℃下搅拌2小时。将氨的水性溶液添加到反应混合物中并浓缩,然后使用MPLC(DCM:MeOH)纯化浓缩物,得到为黄色固体的目标化合物(产率:49%,MS(ESI):m/z 411[M+1]+)。
[步骤-5]制备4-((4-((5-溴-2-甲氧基苯基)氨基)-7-(二氟甲氧基)喹唑啉-6-
基)氨基)哌啶-1-甲酸叔丁酯
将上述步骤-4中得到的N4-(5-溴-2-甲氧基苯基)-7-(二氟甲氧基)喹唑啉-4,6-二胺(1.0当量)和4-氧亚基哌啶-1-甲酸叔丁酯(3.0当量)溶解于乙酸(0.1M)中,并在室温下搅拌2小时。添加三乙酰氧基硼氢化钠(3.0当量)并将混合物在室温下搅拌16小时。向混合物中添加2M NaOH水性溶液并用DCM萃取有机物质。通过使用MgSO4除去剩余的水来浓缩收集的有机层。得到的为黄色固体的目标化合物无需进一步纯化用于下一反应(产率:100%,MS(ESI):m/z 594[M+1]+)。
[步骤-6]制备N4-(5-溴-2-甲氧基苯基)-7-(二氟甲氧基)-N6-(哌啶-4-基)喹唑
啉-4,6-二胺
将上述步骤-5中得到的4-((4-((5-溴-2-甲氧基苯基)氨基)-7-(二氟甲氧基)喹唑啉-6-基)氨基)哌啶-1-甲酸叔丁酯(1.0当量)溶解于DCM中,然后添加TFA (50.0当量),并将混合物在室温下搅拌1小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:97%,MS(ESI):m/z 494[M+1]+)。
[步骤-7]制备1-(4-((4-((5-溴-2-甲氧基苯基)氨基)-7-(二氟甲氧基)喹唑啉-
6-基)氨基)哌啶-1-基)丙-2-烯-1-酮
将上述步骤-6中得到的N4-(5-溴-2-甲氧基苯基)-7-(二氟甲氧基)-N6-(哌啶-4-基)喹唑啉-4,6-二胺(1.0当量)和饱和NaHCO3水性溶液(5.0当量)溶解于THF中,并且然后在0℃下添加丙烯酰氯(1.0当量)并搅拌10分钟。将反应混合物浓缩,得到为棕色固体的目标化合物,其无需进一步纯化用于下一反应(产率:100%,MS(ESI):m/z 548[M+1]+)。
[步骤-8]制备1-(4-((4-((2',4'-二氟-4-甲氧基-[1,1'-联苯]-3-基)氨基)-7-
(二氟甲氧基)喹唑啉-6-基)氨基)哌啶-1-基)丙-2-烯-1-酮
将上述步骤-7中得到的1-(4-((4-((5-溴-2-甲氧基苯基)氨基)-7-(二氟甲氧基)喹唑啉-6-基)氨基)哌啶-1-基)丙-2-烯-1-酮(1.0当量)、(2,4-二氟苯基)硼酸(2.2当量)和K3PO4(2.0当量)溶解于1,4-二噁烷:水(5:1)中。使用氮气使反应混合物脱气,并在100℃下添加Xphos Pd G2(0.1当量),随后在100℃下搅拌10分钟。将混合物通过硅藻土过滤器过滤,并浓缩滤液。将反应混合物通过制备型HPLC纯化,得到为黄色固体的目标化合物(产率:7%,MS(ESI):m/z 582[M+1]+)。
制备实施例298至303的化合物
以与上述实施例297类似的方式制备根据本发明的实施例298至303的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表8中。
[表8]
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实施例304.制备(R,E)-N-(4-((2',4'-二氟-4-甲氧基-[1,1'-联苯]-3-基)氨
基)-7-甲氧基喹唑啉-6-基)-2-氟-3-(1-甲基吡咯烷-2-基)丙烯酰胺
[步骤-1]制备N-(5-溴-2-甲氧基苯基)-7-甲氧基-6-硝基喹唑啉-4-胺
将4-氯-7-甲氧基-6-硝基喹唑啉(1.0当量)和5-溴-2-甲氧基苯胺(1.0当量)溶解于仲BuOH(0.2M)中,并且然后添加溶解于1,4-二噁烷中的4M HCl(0.2当量)并在90℃下搅拌2小时。将乙醚添加到反应混合物中,并将所得固体过滤并用乙醚洗涤,得到为黄色固体的目标化合物(产率:99%,MS(ESI):m/z 406[M+1]+)。
[步骤-2]制备N4-(5-溴-2-甲氧基苯基)-7-甲氧基喹唑啉-4,6-二胺
将上述步骤1中得到的N-(5-溴-2-甲氧基苯基)-7-甲氧基-6-硝基喹唑啉-4-胺(1.0当量)和二水合氯化锡(II)(5.0当量)溶解于乙酸乙酯(0.1M)中,并将混合物在60℃下搅拌1小时。将混合物通过硅藻土过滤器过滤,并且浓缩滤液后得到的为棕色固体的目标化合物无需进一步纯化用于下一反应(MS(ESI):m/z 376[M+1]+)。
[步骤-3]制备(2-((4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)氨
基)-1-氟-2-氧亚基乙基)膦酸二乙酯
将2-(二乙氧基磷酰基)-2-氟乙酸(2.0当量)溶解于DMF(0.5M)中,并且然后添加HATU(3.0当量)并在50℃下搅拌1小时。向反应混合物中添加上述步骤2中得到的N4-(5-溴-2-甲氧基苯基)-7-甲氧基喹唑啉-4,6-二胺(1.0当量)和DIPEA(3.0当量)并在50℃下搅拌1小时。将通过添加冰水得到的固体过滤并用蒸馏水洗涤,得到为黄色固体的目标化合物(产率:30%,MS(ESI):m/z 572[M+1]+)。
[步骤-4]制备(R,E)-2-(3-((4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-
6-基)氨基)-2-氟-3-氧亚基丙-1-烯-1-基)吡咯烷-1-甲酸叔丁酯
向上述步骤-3中得到的(2-((4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-1-氟-2-氧亚基乙基)膦酸二乙酯(1.0当量)中添加溶解于乙醇(0.02M)和蒸馏水(0.2M)中的NaOH(8.0当量),并搅拌30分钟。在0℃下向反应混合物中添加(R)-2-甲酰基吡咯烷-1-甲酸叔丁酯(2.0当量)并在室温下搅拌30分钟。将水添加到反应混合物中,并用EA萃取有机物质。通过使用Na2SO4除去剩余的水来浓缩收集的有机层。得到的为黄色固体的目标化合物无需进一步纯化用于下一反应(产率:91%,MS(ESI):m/z 616[M+1]+)。
[步骤-5]制备(R,E)-N-(4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-
基)-2-氟-3-(吡咯烷-2-基)丙烯酰胺
将上述步骤-4中得到的(R,E)-2-(3-((4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-2-氟-3-氧亚基丙-1-烯-1-基)吡咯烷-1-甲酸叔丁酯(1.0当量)溶解于DCM(0.1M)中,并添加TFA(10.0当量)并在室温下搅拌1小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:97%,MS(ESI):m/z 516[M+1]+)。
[步骤-6]制备(R,E)-N-(4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-
基)-2-氟-3-(1-甲基吡咯烷-2-基)丙烯酰胺
将上述步骤5中得到的(R,E)-N-(4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)-2-氟-3-(吡咯烷-2-基)丙烯酰胺(1.0当量)溶解于DCE(0.1M)中,并添加溶解于蒸馏水中的37%甲醛(5.0当量)并在室温下搅拌1小时。然后,添加NaBH(OAc)3(7.0当量)并将混合物在80℃下搅拌1小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:56%,MS(ESI):m/z 530[M+1]+)。
[步骤-7]制备(R,E)-N-(4-((2',4'-二氟-4-甲氧基-[1,1'-联苯]-3-基)氨基)-
7-甲氧基喹唑啉-6-基)-2-氟-3-(1-甲基吡咯烷-2-基)丙烯酰胺
将上述步骤6中得到的(R,E)-N-(4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)-2-氟-3-(1-甲基吡咯烷-2-基)丙烯酰胺(1.0当量)、(2,4-二氟苯基)硼酸(2.2当量)和K3PO4(2.0当量)溶解于1,4-二噁烷(0.1M)和水(0.5M)中。使用氮气使反应混合物脱气,并在80℃下添加Xphos Pd G2(0.13当量),随后在90℃下搅拌10分钟。将反应混合物浓缩并通过制备型HPLC纯化,得到为淡黄色固体的目标化合物(产率:22%,MS(ESI):m/z 564[M+1]+)。
制备实施例305至313的化合物
以与上述实施例304类似的方式制备实施例305至313的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表9中。
[表9]
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实施例314.(E)-N-(4-((5-(呋喃-2-基)-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-
6-基)-4-(4-甲基哌嗪-1-基)丁-2-烯酰胺
[步骤-1]制备N-(5-(呋喃-2-基)-2-甲氧基苯基)-7-甲氧基-6-硝基喹唑啉-4-胺
将4-氯-7-甲氧基-6-硝基喹唑啉(1.0当量)和5-(呋喃-2-基)-2-甲氧基苯胺(1.1当量)溶解于异丙醇(0.1M)中,并在80℃下搅拌2小时。将反应混合物冷却至室温,然后过滤所得到的固体并用乙醚洗涤。得到的为黄色固体的目标化合物无需进一步纯化用于下一反应(产率:96%,MS(ESI):m/z 393[M+1]+)。
[步骤-2]制备N4-(5-(呋喃-2-基)-2-甲氧基苯基)-7-甲氧基喹唑啉-4,6-二胺
将上述步骤-1中得到的N-(5-(呋喃-2-基)-2-甲氧基苯基)-7-甲氧基-6-硝基喹唑啉-4-胺(1.0当量)溶解于EA(0.1M)中,并添加二水合氯化锡(II)(6.0当量)并在60℃下搅拌3小时。将反应混合物冷却至室温,并添加氨水直至反应溶液变成白色。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为白色固体的目标化合物(产率:68%,MS(ESI):m/z363[M+1]+)。
[步骤-3]制备(E)-4-溴-N-(4-((5-(呋喃-2-基)-2-甲氧基苯基)氨基)-7-甲氧基
喹唑啉-6-基)丁-2-烯酰胺
将上述步骤-2中得到的N4-(5-(呋喃-2-基)-2-甲氧基苯基)-7-甲氧基喹唑啉-4,6-二胺(1.0当量)、(E)-4-溴丁-2-烯酸(2.0当量)、DIPEA(4.5当量)和HATU(3.0当量)溶解于DMF(0.2M)中,并将混合物在40℃下搅拌16小时。将水和盐水添加到混合物中,用DCM萃取有机物质,并通过使用Na2SO4除去剩余的水来浓缩收集的有机层。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:7%,MS(ESI):m/z 510[M+1]+)。
[步骤-4]制备(E)-N-(4-((5-(呋喃-2-基)-2-甲氧基苯基)氨基)-7-甲氧基喹唑
啉-6-基)-4-(4-甲基哌嗪-1-基)丁-2-烯酰胺
将上述步骤-3得到的(E)-4-溴-N-(4-((5-(呋喃-2-基)-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)丁-2-烯酰胺溶解于DMF(0.1M)中,然后添加K2CO3(2.3当量)、KI(1.8当量)和1-甲基哌嗪(4.0当量)并在40℃下搅拌1小时。将水和盐水添加到混合物中,用DCM萃取有机物质,并通过使用MgSO4除去剩余的水来浓缩收集的有机层。将反应混合物通过制备型HPLC纯化,得到为白色固体的目标化合物(产率:19%,MS(ESI):m/z 529[M+1]+)。
制备实施例315至319的化合物
以与上述实施例314类似的方式制备实施例315至319的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表10中。
[表10]
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实施例320.制备(E)-N-(5-氯-4-((2',4'-二氟-4-甲氧基-[1,1'-联苯]-3-基)氨
基)喹唑啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺
[步骤-1]制备4-(1H-苯并[d][1,2,3]三唑-1-基)-5-氯喹唑啉-6-胺
将6-氨基-5-氯喹唑啉-4(3H)-酮(1.0当量)和BOP(1.5当量)溶解于乙腈(0.1M)中,然后添加DBU(2.0当量)并在室温下搅拌1小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:100%,MS(ESI):m/z 296[M+1]+)。
[步骤-2]制备N4-(5-溴-2-甲氧基苯基)-5-氯喹唑啉-4,6-二胺
将上述步骤-1中得到的4-(1H-苯并[d][1,2,3]三唑-1-基)-5-氯喹唑啉-6-胺(1.0当量)和5-溴-2-甲氧基苯胺(1.2当量)溶解于异丙醇中,并在90℃下搅拌10分钟,并且然后添加对甲苯磺酸一水合物(0.1当量)并在90℃下搅拌1小时。将反应混合物冷却至室温并添加水以形成固体。将所得固体通过过滤器过滤,得到为黄色固体的目标化合物(产率:39%,MS(ESI):m/z 379[M+1]+)。
[步骤-3]制备(E)-N-(4-((5-溴-2-甲氧基苯基)氨基)-5-氯喹唑啉-6-基)-4-(二
甲基氨基)丁-2-烯酰胺
将上述步骤-2中得到的N4-(5-溴-2-甲氧基苯基)-5-氯喹唑啉-4,6-二胺(1.0当量)溶解于NMP(0.1M)中,然后在氮气下添加(E)-4-(二甲基氨基)丁-2-烯酰氯(1.0当量)并在室温下搅拌1小时。将反应混合物浓缩并通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:44%,MS(ESI):m/z490[M+1]+)。
[步骤-4]制备(E)-N-(5-氯-4-((2',4'-二氟-4-甲氧基-[1,1'-联苯]-3-基)氨
基)喹唑啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺
将上述步骤-3中得到的(E)-N-(4-((5-溴-2-甲氧基苯基)氨基)-5-氯喹唑啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺(1.0当量)、(2,4-二氟苯基)硼酸(2.2当量)和K3PO4(2.0当量)溶解于二噁烷:水(5:1,0.1M)中。使用氮气使反应混合物脱气,并在80℃下添加XphosPd G2(0.13当量),随后在90℃下搅拌10分钟。将反应混合物通过硅藻土过滤器过滤,浓缩,并通过制备型HPLC纯化,得到为黄色固体的目标化合物(产率:8%,MS(ESI):m/z 524[M+1]+)。
制备实施例321的化合物
以与上述实施例320类似的方式制备根据本发明的实施例321的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表11中。
[表11]
实施例322.制备1-(2-(4-((2',4'-二氟-4-甲氧基-[1,1'-联苯]-3-基)氨基)-7-
甲氧基喹唑啉-6-基)-2,6-二氮杂螺[3.5]壬烷-6-基)丙-2-烯-1-酮
[步骤-1]制备5-氟-4-甲氧基-2-硝基苯甲腈
将1-溴-5-氟-4-甲氧基-2-硝基苯(1.0当量)和CuCN(1.5当量)溶解于DMF(0.2M)中,并在180℃下搅拌2小时。向反应混合物中添加冰水以产生固体,并过滤形成的固体,得到为黄色固体的目标化合物(产率:90%)。
[步骤-2]制备2-(5-氰基-2-甲氧基-4-硝基苯基)-2,6-二氮杂螺[3.5]壬烷-6-甲
酸叔丁酯
将上述步骤-1中得到的5-氟-4-甲氧基-2-硝基苯甲腈(1当量)、2,6-二氮杂螺[3.5]壬烷-6-甲酸叔丁酯(1.0当量)和DIPEA(4.0当量)溶解于DMSO(0.1M)中,并在120℃下搅拌1小时。向反应混合物中添加水以形成固体化合物,并将固体化合物通过过滤器过滤,得到为黄色固体的目标化合物(产率:51%,MS(ESI):m/z 347[M+1]+)。
[步骤-3]制备2-(4-氨基-5-氰基-2-甲氧基苯基)-2,6-二氮杂螺[3.5]壬烷-6-甲
酸叔丁酯
将上述步骤-2中得到的2-(5-氰基-2-甲氧基-4-硝基苯基)-2,6-二氮杂螺[3.5]壬烷-6-甲酸叔丁酯(1.0当量)溶解于MeOH(0.1M)中,然后添加Pd/C(10%纯度,0.1当量),并将反应混合物在氢气下在室温下搅拌1小时。将搅拌的混合物通过硅藻土过滤,并浓缩滤液。得到的为黄色固体的目标化合物无需进一步纯化用于下一反应(产率:98%,MS(ESI):m/z 373[M+1]+)。
[步骤-4]制备(Z)-2-(5-氰基-4-(((二甲基氨基)亚甲基)氨基)-2-甲氧基苯基)-
2,6-二氮杂螺[3.5]壬烷-6-甲酸叔丁酯
将上述步骤-3中得到的2-(4-氨基-5-氰基-2-甲氧基苯基)-2,6-二氮杂螺[3.5]壬烷-6-甲酸叔丁酯(1当量)和N,N-二甲基甲酰胺二甲基缩醛(5.0当量)溶解于甲苯(0.1M)中,并将混合物在100℃下搅拌1小时并且然后浓缩。将反应混合物通过MPLC(DCM:MeOH)纯化,得到为黄色固体的目标化合物(产率:81%,MS(ESI):m/z 428[M+1]+)。
[步骤-5]制备2-(4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)-2,6-
二氮杂螺[3.5]壬烷-6-甲酸叔丁酯
将上述步骤-4中得到的(Z)-2-(5-氰基-4-(((二甲基氨基)亚甲基)氨基)-2-甲氧基苯基)-2,6-二氮杂螺[3.5]壬烷-6-甲酸叔丁酯(1.0当量)和5-溴-2-甲氧基苯胺(1.1当量)溶解于乙酸(0.1M)中,并在120℃下搅拌1小时。将混合物冷却至室温后,将饱和NaHCO3水性溶液添加到反应混合物中至pH为8,并用DCM萃取有机层。通过使用MgSO4除去剩余的水来浓缩收集的有机层。得到的为棕色固体的目标化合物无需进一步纯化用于下一反应(产率:30%,MS(ESI):m/z 584[M+1]+)。
[步骤-6]制备N-(5-溴-2-甲氧基苯基)-7-甲氧基-6-(2,6-二氮杂螺[3.5]壬烷-
2-基)喹唑啉-4-胺
将上述步骤-5中得到的2-(4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)-2,6-二氮杂螺[3.5]壬烷-6-甲酸叔丁酯(1.0当量)溶解于DCM中并添加过量的TFA。将反应混合物在室温下搅拌1小时。将期望产物通过LC-MS确认,浓缩,并通过MPLC(DCM:MeOH)纯化,得到为白色固体的目标化合物(产率:100%,MS(ESI):m/z 484[M+1]+)。
[步骤-7]制备1-(2-(4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)-2,
6-二氮杂螺[3.5]壬烷-6-基)丙-2-烯-1-酮
将上述步骤-6中得到的N-(5-溴-2-甲氧基苯基)-7-甲氧基-6-(2,6-二氮杂螺[3.5]壬烷-2-基)喹唑啉-4-胺(1.0当量)和饱和NaHCO3水性溶液(5.0当量)溶解于THF(0.1M)中,并且然后在0℃下添加丙烯酰氯(1.0当量)并搅拌30分钟。将反应混合物浓缩,添加水,并用DCM萃取有机层。通过使用MgSO4除去剩余的水来浓缩收集的有机层。得到的为白色固体的目标化合物无需进一步纯化用于下一反应(产率:42%,MS(ESI):m/z 538[M+1]+)。
[步骤-8]制备1-(2-(4-((2',4'-二氟-4-甲氧基-[1,1'-联苯]-3-基)氨基)-7-甲
氧基喹唑啉-6-基)-2,6-二氮杂螺[3.5]壬烷-6-基)丙-2-烯-1-酮
将上述步骤-7中得到的1-(2-(4-((5-溴-2-甲氧基苯基)氨基)-7-甲氧基喹唑啉-6-基)-2,6-二氮杂螺[3.5]壬烷-6-基)丙-2-烯-1-酮(1.0当量)、(2,4-二氟苯基)硼酸(1.1当量)和K3PO4(2.5当量)溶解于二噁烷:水(5:1,0.006M)中。使用氮气使反应混合物脱气,并在80℃下将Xphos Pd G2(0.1当量)添加到混合物中,随后在100℃下搅拌1小时。将混合物通过硅藻土过滤,并且将滤液浓缩并使用制备型HPLC纯化,得到为黄色固体的目标化合物(产率:64%,MS(ESI):m/z 572[M+1]+)。
制备实施例323至330的化合物
以与上述实施例322类似的方式制备实施例323至330的化合物。各个实施例的化学结构、化合物名称、1H NMR、MS、HPLC数据和产率总结于下表12中。
[表12]
/>
/>
(*:其中最后一列中的数值的右侧标记的“*”意指NMR纯度)
<实验实施例1>HER2、EGFR酶抑制活性的评价
HER2和EGFR的生化激酶测定由Reaction Biology Corp(圣地亚哥(San Diego),USA)进行。在HER2和EGFR酶的ATP(10μM)的条件下,将化合物从10μM稀释3倍,并确定10个剂量的IC50值。其结果示出于下表13中。
[表13]
实施例编号 | HER2 | EGFR |
68 | A | A |
80 | A | - |
90 | A | - |
157 | A | - |
304 | A | A |
305 | A | A |
306 | A | A |
(A:GI50≤50nM,B:50<GI50≤100nM,C:100<GI50≤500nM,D:500nM<GI50)
<实验实施例2>SK-BR-3、BT-474、N-87和HaCaT细胞增殖抑制活性的评价
为了评价根据本发明的化合物对HER2和EGFR激酶的细胞增殖抑制活性,使用HER2过表达细胞系(SK-BR-3、BT-474和N-87)和EGFR表达细胞系(HaCaT)进行以下方法。
补充有10% FBS的McCOY'S 5A用于SK-BR-3细胞,补充有20% FBS的RPMI-1640培养基用于BT-474癌细胞,并且补充有10% FBS的RPMI-1640培养基用于N-87癌细胞。补充有10% FBS的DMEM用于HaCaT细胞。
对于SK-BR-3细胞,在用实施例的化合物处理之前48小时,将5000个细胞等分到白色透明底部96孔板(Corning)的每个孔中。对于BT-474细胞,在用实施例的化合物处理之前48小时,将5000个细胞等分到白色透明底部96孔板(Corning)的每个孔中。对于N-87细胞,在用实施例的化合物处理之前24小时,将5000个细胞等分到白色透明底部96孔板(Corning)的每个孔中。对于HaCaT细胞,在用实施例的化合物处理之前24小时,将3000个细胞等分到白色透明底部96孔板(Corning)的每个孔中。对于SK-BR-3细胞和BT-474细胞,将实施例的化合物在二甲基亚砜中稀释(三倍稀释,总共11个浓度),并各自以1μl的量注射至0.2nM至10μM的最终浓度。对于N-87细胞,将实施例的化合物在二甲基亚砜中稀释(五倍稀释,总共11个浓度),并各自以0.5μl的量注射至0.5pM至5μM的最终浓度。对于HaCaT细胞,将实施例的化合物在二甲基亚砜中稀释(三倍稀释,总共11个浓度),并各自以0.5μl的量注射至0.8nM至45μM的最终浓度。对于活细胞的测量,在用实施例的化合物处理后一定时间段后(SK-BR-3:120小时,BT-474:120小时,N-87:72小时,以及HaCaT:72小时)使用CellTiter-Glo细胞活力试剂(Promega)将细胞在室温下储存10分钟,并使用读取器(SynergyNeo,Biotek)测量其发光强度。每个测试重复三次。
将结果值计算为与对照组的那些结果值相比的细胞生长率(%)。使用GraphPadPrism version 5.0程序创建图形,并计算GI50值。其结果示出于下表14中。
[表14]
/>
/>
/>
/>
/>
(A:GI50≤150nM,B:150<GI50≤1000nM,C:1000nM<GI50)
<实验实施例3>转导的Ba/F3细胞增殖抑制活性的评价
对于Ba/F3细胞,使用补充有10% FBS和5ng/ml IL-3(R&D Systems)的RPMI-1640。通过向相同培养基中添加1μg/ml嘌呤霉素(Invitrogen)来培养转导的Ba/F3细胞。
在用实施例的化合物处理之前24小时,将3000至5000个细胞等分到白色透明底部96孔板(Corning)的每个孔中。将实施例的化合物在二甲基亚砜中稀释(三倍稀释,总共12个浓度),并各自以1μl的量注射至0.2nM至5μM的最终浓度。对于活细胞的测量,在用实施例的化合物处理后72小时使用CellTiter-Glo发光法细胞活力试剂(Promega)将细胞在室温下储存10分钟,并使用读取器(SynergyNeo,Biotek)测量其发光强度。每个测试重复三次。将结果值计算为与对照组的那些结果值相比的细胞生长率(%)。使用GraphPad Prismversion 8.3.0程序创建图形,并计算GI50值。
下表15示出了评价表达HER2罕见或不常见且耐药突变的L869R、L756S、T798I和T862A以及表达EGFR罕见或不常见且耐药突变的G719A、L861Q、S768I、G719A/S768I和Del19/T790M的Ba/F3细胞增殖抑制活性的结果。
[表15]
(A:GI50≤50nM,B:50nM<GI50≤100nM,C:100nM<GI50≤500nM,D:500nM<GI50)。
Claims (14)
1.一种由以下化学式1表示的化合物、其光学异构体或其药学上可接受的盐:
[化学式1]
在以上化学式1中,
X是N或CRX1;
R1是-H、-ORX2或-NRX3RX4;
RX1是-H、-C1-6烷基、-C1-6卤代烷基、-CN或-卤素;
RX2是-H、-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、
-C1-6烷基-O(C1-6烷基)、-C1-6烷基-O(C1-6烷基)-C1-6氨基烷基、-(CH2)n-环烷基或-(CH2)n-杂环烷基{其中–(CH2)n-环烷基或–(CH2)n-杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-C1-6烷基-O(C1-6烷基)、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH、-卤素或杂环烷基取代};
n是0、1、2、3或4;
RX3和RX4各自独立地是-H或-C1-6烷基,或RX3和RX4彼此连接以与N原子一起形成环,以及W1和W2各自独立地是CH2、NH、O或S{其中杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH、-卤素或杂环烷基取代};
a至d各自独立地是1、2或3;
R2是-H、-C1-6烷基、-C1-6卤代烷基、-CN或-卤素;
L是-NH-、{其中环B是在环中包含N原子的单环或多环,并且所述环B中的至少一个H可以被-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH、=O或-卤素取代};
R3是-CZ1=Z2Z3、-C1-6烷基、-C1-6卤代烷基或环烷基;
Z1是-H、-C1-6烷基、-C1-6氨基烷基、-C1-6羟烷基、-C1-6卤代烷基、-CN或-卤素;
Z2和Z3各自独立地是-H、-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-C1-6烷基-O(C1-6烷基)、-卤素、环烷基、杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基{其中所述环烷基、杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基中的至少一个H可以被-C1-6烷基、-C1-6羟烷基、-C1-6氨基烷基、-C1-6卤代烷基、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH、=O或杂环烷基取代};
Y1至Y3各自独立地是N或CRY;
RY是-H、-C1-6烷基、-C1-6氨基烷基、-C1-6羟烷基、-C1-6卤代烷基、-CN、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NO2、-OH或-卤素;
R4是-C1-6烷基、-C1-6烷基-O-C1-6烷基、-C1-6卤代烷基、环烷基、杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基{其中所述环烷基、杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基中的至少一个H可以被-C1-6烷基取代};
环A是芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基{其中芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基环中的至少一个H可以被-C1-6烷基、-C1-6氨基烷基、-C1-6羟烷基、-C1-6卤代烷基、-C1-6烯基、-CN、-C(=O)-RA1、-NO2、-NRA2RA3、-ORA4、-S-C1-6烷基、-卤素或杂环烷基取代[此处,杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-卤素或杂环烷基取代],并且芳基或杂芳基环上的取代基可以彼此连接以形成5-6元环烷基或5-6元杂环烷基};
RA1是-H、-C1-6烷基、-NH2、-NH-C1-6烷基、-N(C1-6烷基)(C1-6烷基)、-NH-(CH2)m-芳基、-OH或-O-C1-6烷基{其中-NH-(CH2)m-芳基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基或-卤素取代};
m是0、1、2、3或4;
RA2和RA3各自独立地是-H、-C1-6烷基、-C(=O)-C1-6烷基、-C(=O)-C1-6烯基、-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-芳基{其中-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-芳基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、=O、-卤素或芳基取代};以及
RA4是-H、-C1-6烷基或-C1-6卤代烷基。
2.根据权利要求1所述的由化学式1表示的化合物、其光学异构体或其药学上可接受的盐,其中,
X是N或CRX1;
R1是-H、-ORX2或-NRX3RX4;
RX1是-H或–CN;
RX2是-C1-6烷基、-C1-6氨基烷基、-C1-6卤代烷基、-C1-6烷基-O(C1-6烷基)、-C1-6烷基-O(C1-6烷基)-C1-6氨基烷基或-(CH2)n-杂环烷基{其中-(CH2)n-杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6烷基-O(C1-6烷基)或杂环烷基取代};
n是0、1、2、3或4;
RX3和RX4各自独立地是-H或-C1-6烷基,或RX3和RX4彼此连接以与N原子一起形成环,以及W1和W2各自独立地是CH2、NH或O{其中所述环中的至少一个H可以被-卤素或杂环烷基取代};
a至d各自独立地是1或2;
R2是-H或-卤素;
{其中环B是在环中包含N原子的单环或多环,并且所述环B中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、=O或–卤素取代};
R3是-CZ1=Z2Z3、-C1-6卤代烷基或环烷基;
Z1是-H、-C1-6氨基烷基、-CN或-卤素;
Z2和Z3各自独立地是-H、-C1-6烷基、-C1-6氨基烷基、-C1-6烷基-O(C1-6烷基)、-卤素、-杂环烷基或-C1-6烷基-杂环烷基{其中所述-杂环烷基或-C1-6烷基-杂环烷基中的至少一个H可以被-C1-6烷基或-杂环烷基取代};
Y1至Y3各自独立地是N或CRY;
RY是-H、-C1-6烷基或-卤素;
R4是-C1-6烷基、-C1-6烷基-O-C1-6烷基、-C1-6卤代烷基、环烷基或杂环烷基{其中所述环烷基或杂环烷基中的至少一个H可以被-C1-6烷基取代};
环A是芳基、杂芳基、杂环烷基或杂环烯基{其中芳基、杂芳基、环烷基、环烯基、杂环烷基或杂环烯基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-C1-6烯基、-CN、-C(=O)-RA1、-NO2、-NRA2RA3、-ORA4、-S-C1-6烷基、-卤素或杂环烷基取代[此处,杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-卤素或杂环烷基取代],并且芳基或杂芳基环上的取代基可以彼此连接以形成5-6元环烷基或5-6元杂环烷基};
RA1是-H、-NH-(CH2)m-芳基、-OH或-O-C1-6烷基{其中-NH-(CH2)m-芳基环中的至少一个H可以被-卤素取代};
m是0、1、2、3或4;
RA2和RA3各自独立地是-H、-C1-6烷基、-C(=O)-C1-6烷基、-C(=O)-C1-6烯基、-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-芳基{其中-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-芳基环中的至少一个H可以被=O、-卤素或芳基取代};以及
RA4是-H、-C1-6烷基或-C1-6卤代烷基。
3.根据权利要求1所述的由化学式1表示的化合物、其光学异构体或其药学上可接受的盐,其中,
X是N或CRX1;
R1是-H、-ORX2或-NRX3RX4;
RX1是-H或–CN;
RX2是-C1-6烷基、-C1-6氨基烷基、-C1-6卤代烷基、-C1-6烷基-O(C1-6烷基)、-C1-6烷基-O(C1-6烷基)-C1-6氨基烷基或-(CH2)n-杂环烷基{其中-(CH2)n-杂环烷基环是4-6元,并且所述-(CH2)n-杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6烷基-O(C1-6烷基)或4-6元杂环烷基取代};
n是0、1、2或3;
RX3和RX4各自独立地是-H或-C1-6烷基,或RX3和RX4彼此连接以与N原子一起形成并且W1和W2各自独立地是CH2或O{其中环中的至少一个H可以被-卤素或4-6元杂环烷基取代};
a至d各自独立地是1或2;以及
R2是-H或-卤素。
4.根据权利要求1所述的由化学式1表示的化合物、其光学异构体或其药学上可接受的盐,其中,
L是-NH-、 {其中/> 环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、=O或-卤素取代};
V1和V2通过单键、C1烷基、C2烷基或C3烷基连接在一起以形成桥连双环或不存在(空位);以及
e至h各自独立地是1、2或3。
5.根据权利要求1所述的由化学式1表示的化合物、其光学异构体或其药学上可接受的盐,其中,
R3是-CZ1=Z2Z3、-C1-6卤代烷基或环烷基{其中环烷基环是单环或多环};
Z1是-H、-C1-6氨基烷基、-CN或-卤素;
Z2和Z3各自独立地是-H、-C1-6烷基、-C1-6氨基烷基、-C1-6烷基-O(C1-6烷基)、-卤素、-杂环烷基或-C1-6烷基-杂环烷基{其中杂环烷基或-C1-6烷基-杂环烷基环是4-6元,并且所述杂环烷基、-C1-6烷基-环烷基或-C1-6烷基-杂环烷基中的至少一个H可以被-C1-6烷基或4-6元杂环烷基取代}。
6.根据权利要求1所述的由化学式1表示的化合物、其光学异构体或其药学上可接受的盐,其中,
Y1至Y3各自独立地是N或CRY;
RY是-H、-C1-6烷基或-卤素;以及
R4是-C1-6烷基、-C1-6烷基-O-C1-6烷基、-C1-6卤代烷基、3-7元环烷基或4-6元杂环烷基{其中所述3-7元环烷基或4-6元杂环烷基中的至少一个H可以被-C1-6烷基取代}。
7.根据权利要求1所述的由化学式1表示的化合物、其光学异构体或其药学上可接受的盐,其中,
环A是苯基、5-10元杂芳基、4-6元杂环烷基或4-6元杂环烯基{其中苯基、5-10元杂芳基、4-6元杂环烷基或4-6元杂环烯基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-C1-6烯基、-CN、-C(=O)-RA1、
-NO2、-NRA2RA3、-ORA4、-S-C1-6烷基、-卤素或4-6元杂环烷基取代[此处,4-6元杂环烷基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、-卤素或杂环烷基取代],并且苯基或5-10元杂芳基环上的取代基可以彼此连接以形成5-6元环烷基或5-6元杂环烷基};
RA1是-H、-NH-(CH2)m-苯基、-OH或-O-C1-6烷基{其中-NH-(CH2)m-苯基环中的至少一个H可以被-卤素取代};
m是0、1或2;
RA2和RA3各自独立地是-H、-C1-6烷基、-C(=O)-C1-6烷基、-C(=O)-C1-6烯基、-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-苯基{其中-C(=O)-环烷基、-C(=O)-杂环烷基或-C(=O)-苯基环中的至少一个H可以被-C1-6烷基、-C1-6卤代烷基、=O、-卤素或苯基取代};以及
RA4是-H、-C1-6烷基或-C1-6卤代烷基。
8.根据权利要求1所述的化合物、其光学异构体或其药学上可接受的盐,其中,
由以上化学式1表示的化合物选自由以下化合物组成的组:
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9.一种用于预防或治疗癌症的药物组合物,包括根据权利要求1至8中任一项所述的化合物、其光学异构体或其药学上可接受的盐作为活性成分。
10.根据权利要求9所述的药物组合物,其中,
所述药物组合物抑制HER2和/或EGFR。
11.根据权利要求10所述的药物组合物,其中,
所述药物组合物抑制选自由HER2 L869R、HER2 L755S、HER2T798I、HER2 T862A、EGFRG719A、EGFR L861Q、EGFR S768I、EGFRG719A/S768I和EGFR Del19/T790M组成的组中的至少一种。
12.根据权利要求9所述的药物组合物,其中,
所述癌症是选自由以下组成的组中的一种或多种:假黏液瘤、肝内胆管癌、肝母细胞瘤、肝癌、甲状腺癌、结肠癌、睾丸癌、骨髓增生异常综合征、胶质母细胞瘤、口腔癌、唇癌、蕈样肉芽肿、急性髓系白血病、急性淋巴细胞性白血病、基底细胞癌、卵巢上皮癌、卵巢生殖细胞肿瘤、男性乳腺癌、脑癌、垂体腺瘤、多发性骨髓瘤、胆囊癌、胆道癌、结直肠癌、慢性髓细胞性白血病、慢性淋巴细胞白血病、视网膜母细胞瘤、脉络膜黑素瘤、法特壶腹癌、膀胱癌、腹膜癌、甲状旁腺癌、肾上腺癌、鼻腔鼻窦癌、非小细胞肺癌、舌癌、星形细胞瘤、小细胞肺癌、小儿脑癌、小儿淋巴瘤、小儿白血病、小肠癌、脑膜瘤、食管癌、胶质瘤、肾盂癌、肾癌、心脏癌、十二指肠癌、恶性软组织肿瘤、恶性骨肿瘤、恶性淋巴瘤、恶性间皮瘤、恶性黑素瘤、眼癌、外阴癌、输尿管癌、尿道癌、不明原发部位的癌症、胃部淋巴瘤、胃部癌、胃部类癌瘤、胃肠道间质瘤、维尔姆斯瘤、乳腺癌、肉瘤、阴茎癌、咽癌、妊娠绒毛膜癌、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、转移性骨癌、转移性脑癌、纵隔癌、直肠癌、直肠类癌瘤、阴道癌、脊髓癌、前庭神经鞘瘤、胰腺癌、唾液腺癌、卡波西肉瘤、佩吉特病、扁桃体癌、鳞状细胞癌、肺腺癌、肺癌、肺鳞状细胞癌、皮肤癌、肛门癌、横纹肌肉瘤、喉癌、胸膜癌、血液学癌症和胸腺癌。
13.根据权利要求1至8中任一项所述的化合物、其光学异构体或其药学上可接受的盐用于在制备治疗或预防癌症的药物中的用途。
14.一种用于治疗或预防癌症的方法,包括向有此需要的受试者给药治疗有效量的根据权利要求1至8中任一项所述的化合物、其光学异构体或其药学上可接受的盐。
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