CN116283800A - 氧代喹唑啉类化合物及其应用 - Google Patents
氧代喹唑啉类化合物及其应用 Download PDFInfo
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- CN116283800A CN116283800A CN202310545934.2A CN202310545934A CN116283800A CN 116283800 A CN116283800 A CN 116283800A CN 202310545934 A CN202310545934 A CN 202310545934A CN 116283800 A CN116283800 A CN 116283800A
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- compound
- alkyl
- group
- alkyl group
- cancer
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- -1 Oxo quinazoline compound Chemical class 0.000 title description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 102100034187 S-methyl-5'-thioadenosine phosphorylase Human genes 0.000 claims abstract description 18
- 101710136206 S-methyl-5'-thioadenosine phosphorylase Proteins 0.000 claims abstract description 17
- 230000007812 deficiency Effects 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000035475 disorder Diseases 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims abstract description 6
- 230000002265 prevention Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
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- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
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- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
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- 238000006467 substitution reaction Methods 0.000 claims description 2
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- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
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- 239000000243 solution Substances 0.000 description 26
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
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- 102000007357 Methionine adenosyltransferase Human genes 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
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- 239000012074 organic phase Substances 0.000 description 7
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- 238000001816 cooling Methods 0.000 description 6
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 4
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 4
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
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- 238000001914 filtration Methods 0.000 description 4
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- 229920006395 saturated elastomer Polymers 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102100026115 S-adenosylmethionine synthase isoform type-1 Human genes 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
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- 125000005843 halogen group Chemical group 0.000 description 3
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
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- 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
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—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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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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Abstract
本发明提供了一系列含2‑氧代喹唑啉类化合物,所述化合物被证明对MAT2A酶具有较好活性,因此可以用于预防和/或治疗由MTAP缺失导致的疾病、病症和病况。此外,该系列化合物制备方法简单,易于实施,因此具有一定的应用前景
Description
技术领域
本发明属于医药技术领域,具体涉及2-氧代喹唑啉类化合物及其在制备预防和/或治疗因MTAP缺失导致的疾病、病症和病况的药物中的用途。
背景技术
蛋氨酸腺苷转移酶(MAT)又称S-腺苷甲硫氨酸合成酶,是催化蛋氨酸和ATP合成S-腺苷甲硫氨酸(SAM或AdoMet)的细胞酶,被认为是蛋氨酸循环的限速步骤。在肝脏中,蛋氨酸循环有个额外的功能,主要是在高蛋氨酸或高蛋白饮食后,用以迅速清除血液中过高的蛋氨酸,最后通过同型半胱氨酸、半胱氨酸、胱硫醚、谷胱甘肽被转运到其它器官。MTAP(甲硫腺苷磷酸化酶)是一种广泛表达于正常组织的酶,催化MAT转化为腺嘌呤和5-甲硫核糖-1-磷酸。腺嘌呤被回收生成单磷酸腺苷,5-甲基硫核糖-1-磷酸转化为蛋氨酸和甲酸盐。由于这种补救途径,当嘌呤从头合成被阻断时,MAT可作为替代嘌呤的来源。
MAT酶主要有三个亚型,MAT1A、MAT2A与MAT2B。MAT1A主要存在于正常肝细胞中,而MAT2A则广泛分布于肝外细胞。这两个亚型在催化效率及调控方式上存在差异。MAT2B不具有催化合成SAM的能力,而是作为MAT2A的调节亚基,与MAT2A形成复合物后,调节MAT2A的催化活性。
MAT2A在包括红细胞、脑、胎儿肝脏、肾、胰腺组织在内的所有组织中均存在表达,但在成人肝脏组织中含量较少。人肝癌和结肠癌中MAT2A和MAT2B表达增加,人胃癌和他莫昔芬耐药性乳腺癌细胞中也报道了MAT2A表达增加。较高的MAT2A和MAT2B表达导致癌细胞生长、迁移和侵袭。总的来说,较低的MAT2A和MAT2B表达会导致细胞凋亡增加,细胞生长、迁移和转移减少。
一些MTAP缺失的癌细胞对MAT2A的抑制特别敏感。MTAP缺失不仅存在于组织培养细胞中,还存在于原发性白血病、胶质瘤、黑色素 瘤、胰腺癌、非小细胞肺癌(NSCLC)、膀胱癌、星形细胞瘤、骨肉瘤、头颈癌、粘液样软骨肉瘤、卵巢癌、子宫内膜癌、乳腺癌、软组织肉瘤、非霍奇金淋巴瘤和间皮瘤。因此,开发有效的MAT2A抑制剂可改善因MTAP缺失导致癌症患者的生活质量。
发明内容
本发明提供如下式I所示的化合物,其互变异构体、立体异构体,或其药学上可接受的盐:
其中,R1选自H、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟基C1-6烷基、OH、CN、NH2、3-10元含N杂环基、-N(C1-6烷基)2或-NHC1-6烷基;所述3-10元含N杂环基任选被OH或NH2取代;
R2选自卤素、C1-6烷基、C1-6烷氧基或卤代C1-6烷基;
R3选自无取代,或任选被一个,两个或更多个Rs取代的如下基团:5-20元杂芳基,3-20元杂环基或C6-20芳基;
Rs相同或不同,彼此独立地选自=O、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟基C1-6烷基、OH、CN、NH2、-N(C1-6烷基)2或-NHC1-6烷基;
X1,X2,X3,X4相同或不同,彼此独立地选自CH或N。
在一些实施方案中,R1选自OH,NH2,3-10元含N杂环基(例如N杂环丁基、N杂环戊基、N杂环己基),-N(C1-3烷基)2或-NHC1-3烷基;
R2选自卤素或卤代C1-3烷基;
R3选自无取代,或任选被一个,两个或更多个Rs取代的如下基团:5-12元杂芳基,5-12元杂环基或C6-12芳基;
Rs选自=O,卤素,-N(C1-3烷基)2或-NHC1-3烷基;
X1,X2,X3,X4相同或不同,彼此独立地选自CH或N,条件是X1,X2,X3,X4中至多两个选自N。
在一些具体的实施方案中,R1选自OH,NH2或二甲胺基;
R2选自Cl;
R3选自如下基团:
X1,X2,X3,X4均为CH,或者X1为N,X2,X3,X4为CH。
在一些具体的实施方案中,所述化合物选自如下:
本发明还提供如上式I所示化合物的制备方法,包括如下步骤:
化合物Ia与化合物Ib反应得到式I所示化合物;
其中,X1,X2,X3,X4,R1,R2,R3具有如上所述定义;
本发明还提供如上式I所示化合物,其互变异构体、立体异构体,或其药学上可接受的盐在制备预防和/或治疗由MTAP缺失导致的疾病、病症和病况的药物中的用途。
根据本发明的实施方案,所述由MTAP缺失导致的疾病、病症和病况为MTAP缺失的肿瘤。
根据本发明的实施方案,所述MTAP缺失的肿瘤包括但不限于胶质瘤、间皮瘤、黑色素瘤、胃癌、食管癌、膀胱癌、胰腺癌、非小细胞肺癌、星形细胞瘤、骨肉瘤、头颈癌、粘液性软骨肉瘤、卵巢癌、子宫内膜癌、乳腺癌、软组织肉瘤或非霍奇金淋巴瘤。
本发明还提供一种药物组合物,其包括如上所述式I所示化合物,其互变异构体、立体异构体,或其药学上可接受的盐。
根据本发明的实施方案,所述药物组合物用于预防和/或治疗由MTAP缺失导致的疾病、病症和病况。
根据本发明的实施方案,所述由MTAP缺失导致的疾病、病症和病况为MTAP缺失的肿瘤。
有益效果
本发明提供了一系列含2-氧代喹唑啉类化合物,所述化合物被证明对MAT2A酶具有较好活性,因此可以用于预防和/或治疗由MTAP缺失导致的疾病、病症和病况。此外,该系列化合物制备方法简单,易于实施,因此具有一定的应用前景。
术语定义和说明
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
在本文中,术语“包括”、“包含”和/或“含有”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
在本文中,术语“任选(的/地)”表示所述特征存在或不存在这两种情形,这意味着随后所描述的事件可以但不必然发生,因此包括该事件发生或不发生的两类情形。例如,“任选被烷基取代的杂环基团”意味着该烷基可以但不必然存在,因此包括被烷基取代的杂环基团和没有被烷基取代的杂环基团的情形。
本申请通式中“R1,R2,R3”等的下标数字仅为标识不同的取代基,不代表R的个数。
在本文中,术语“卤素”表示氟、氯、溴和/或碘。
术语“C1-6烷基”应理解为表示具有1、2、3、4、5、或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2或3个碳原子(“C1-3烷基”),例如甲基、乙基、正丙基或异丙基。
术语“3-10元含N杂环基”应理解为表示饱和的一价单环或双环烃环,其含有1-3个选自N、O和S的杂原子且至少含有1个N原子,总成环原子数为3-10(如原子数为3、4、5、6、7、8、9、10等)。例如包括但不限于氮杂环丁烷或氮杂环戊烷等。
术语“3-20元杂环基”意指饱和的一价单环或双环烃环,其包含1-5个独立选自N、O和S的杂原子,优选“3-12元杂环基”。术语“3-12元杂环基”意指饱和的一价单环或双环烃环,其包含1-5个,优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个氮原子(如果存在的话)与分子的其余部分连接。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基,或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基。根据本发明,所述杂环基是无芳香性的。
术语“C6-20芳基”应理解为表示具有6~20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”),特别是具有6个碳原子的环(“C6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C13芳基”),例如芴基,或者是具有14个碳原子的环(“C14芳基”),例如蒽基。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5~20个环原子且包含1-5个独立选自N、O和S的杂原子,例如“5-12元杂芳基”。术语“5-12元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5、6、7、8、9、10、11、12个环原子,特别是5或6或9或10个碳原子,且其包含1-5个,优选1-3个独立选自N、O和S的杂原子,并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
术语“卤代C1-6烷基”,“-C1-6烷基羟基”,“C1-6烷氧基”,“-N(C1-6烷基)2”及“-NHC1-6烷基”中C1-6烷基具有如上所述定义。
在本文中,“药学上可接受的盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例 1:7-氯-4-(二甲基氨基)-1-(3-(2-(3-(4-(二甲基氨基)-2-氧嘧啶-1(2H)-基)苯氧基)乙氧基)苯基)喹唑啉-2(1H)-酮
步骤1:0摄氏度下往2,4,7-三氯喹唑啉 (2.0 g, 8.57 mmol) 的四氢呋喃 (20.0mL) 溶液中滴加二甲胺的四氢呋喃溶液 (2.0 M,4.71 mL, 9.42 mmol)。室温搅拌2个小时。浓缩后,加入100毫升水和100毫升乙醚,过滤干燥得到固体化合物1-1 (1.2 g, 产率57%)。LCMS: 242.0 [M+H]+。
步骤2:将化合物1-1 (1.2 g, 4.96 mmol) 的乙酸 (30.0 mL) 溶液加热到100摄氏度反应12个小时。浓缩后加入50毫升乙酸乙酯,室温搅拌30分钟。过滤干燥得到固体化合物1-2 (810.0 mg, 产率72%)。LCMS: 224.1 [M+H]+。
步骤3:往化合物1-2 (400.0 mg, 1.79 mmol) 的二氯甲烷 (15.0 mL) 溶液中加入(3-甲氧基苯基)硼酸 (407.7 mg, 2.68 mmol)、乙酸铜 (324.8 mg, 1.79 mmol) 和三乙胺 (5.4 g, 53.65 mmol)。在一个大气压的氧气下室温搅拌16个小时。加入甲醇,过滤。浓缩滤液后用柱层析纯化得到化合物1-3 (190.0 mg, 产率32% )。LCMS: 330.1 [M+H]+。
步骤4:-78摄氏度下往化合物1-3 (180.0 mg, 0.55 mmol) 的二氯甲烷 (10.0mL) 溶液中加入三溴化硼 (273.5 mg, 1.09 mmol)。室温下反应1个小时。-78摄氏度下加入异丙醇淬灭反应。浓缩后加入水,调节pH=7。过滤干燥得到固体化合物1-4 (90.0 mg, 产率52%)。LCMS: 316.1 [M+H]+。
步骤5:往4-(二甲基氨基)-1-(3-羟基苯基)嘧啶-2(1H)-酮 (200.0 mg, 0.86mmol) 的N,N-二甲基甲酰胺 (3.0 mL) 溶液中加入碳酸铯 (564.0 mg, 1.73 mmol) 和叔丁基(2-碘乙氧基)二甲基硅烷 (0.38 mL, 1.73 mmol)。室温下反应16个小时。加入水和乙酸乙酯。有机相水洗干燥,浓缩后纯化得到化合物1-5 (330.0 mg, 产率97%)。LCMS: 390.2[M+H]+。
步骤6:往化合物1-5 (300.0 mg, 0.77 mmol) 的四氢呋喃 (5.0 mL) 溶液中加入四丁基氟化铵的四氢呋喃溶液 (1.54 mL, 1.54 mmol, 1M)。室温反应40分钟。浓缩后纯化得到化合物1-6 (170.0 mg, 产率80%)。LCMS: 276.1 [M+H]+。
步骤7:0摄氏度下往化合物1-6 (106.0 mg, 0.39 mmol) 的二氯甲烷 (4.0 mL)溶液中加入三乙胺 (70.0 mg, 0.69 mmol) 和甲基磺酰氯 (52.0 mg, 0.46 mmol),反应1个小时。加入水和二氯甲烷。有机相干燥浓缩后得到的产物再与化合物1-4 (123.0 mg,0.39 mmol)、碳酸钾 (106.5 mg, 0.77 mmol)、碘化钾 (31.5 mg, 0.19 mmol) 在N,N-二甲基甲酰胺 (2.0 ml) 中反应,加热到60摄氏度反应16个小时,升温到80摄氏度再反应6个小时。冷却后过滤,将滤液浓缩,用制备HPLC纯化得到化合物1 (2.4 mg, 产率 0.5% )。LCMS: 573.1 [M+H]+。1H NMR (400 MHz, CD3OD) δ 8.06 (d, J = 8.8 Hz, 1H), 7.63(d, J = 7.6 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.24-7.17 (m, 2H), 7.06 - 6.98 (m, 2H), 6.98 - 6.92 (m, 2H), 6.90 - 6.88 (m, 1H),6.58 (d, J = 2.0 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 4.40 (s, 4H), 3.42 (s,6H), 3.21 (s, 3H), 3.16 (s, 3H)。
实施例2:2-(3-(7-氯-4-(二甲氨基)-2-氧代喹唑啉-1(2H)-基)苯氧基)-N-(3-(7-氯-4-(二甲氨基)-2-氧代喹唑啉-1(2H)-基)苯基)乙酰胺
步骤1:往化合物1-2 (350.0 mg, 1.56 mmol) 的二氯甲烷 (15.0 mL) 溶液中加入 (3-硝基苯基)硼酸 (392.0 mg, 2.35 mmol)、乙酸铜 (284.5 mg, 1.56 mmol) 和三乙胺 (4.8 g, 46.95 mmol)。在一个大气压的氧气下室温搅拌16个小时。加入甲醇,过滤。浓缩滤液后用柱层析纯化得到化合物2-1 (200 mg, 产率37% )。LCMS: 345.1 [M+H]+。
步骤2:往化合物2-1 (190.0 mg, 0.55 mmol) 的乙醇 (10.0 mL) 和水 (2.0mL) 溶液中加入铁粉 (153.9 mg, 2.76 mmol) 和氯化铵 (294.8 mg, 5.51 mmol)。加热到80摄氏度反应5个小时。冷却后加入甲醇稀释,过滤。滤液浓缩后纯化得到化合物2-2(120.0 mg, 产率69%)。LCMS: 315.1 [M+H]+。
步骤3:往化合物2-2 (110.0 mg, 0.35 mmol) 的乙腈 (6.0 mL) 溶液中加入2-氯乙酰氯 (79.0 mg, 0.70 mmol) 和碳酸钠 (74.0 mg, 0.70 mmol)。室温下反应2个小时。加入水,用乙酸乙酯萃取。有机相水洗干燥,浓缩后纯化得到化合物2-3 (110.0 mg, 产率80%)。LCMS: 391.1 [M+H]+。
步骤4:往化合物1-4 (70.0 mg, 0.22 mmol) 的乙腈 (8.0 mL) 溶液中加入化合物 2-3 (90.0 mg, 0.23 mmol)和碳酸钾(61.3 mg, 0.44 mmol)。加热到90摄氏度反应4个小时。浓缩后纯化得到化合物2 (68.0 mg, 产率45%)。LCMS: 670.2 [M+H]+。1H NMR (400MHz, DMSO-d 6) δ 10.31 (s, 1H), 8.03 (dd,J=11.6, 8.8 Hz, 2H), 7.71 (d,J = 8.4Hz, 1H), 7.63 (t,J= 2.0 Hz, 1H), 7.52 (dd,J=15.2, 7.6 Hz, 2H), 7.21 (dd,J=8.8, 1.0 Hz, 1H), 7.17 - 7.12 (m, 2H), 7.02 (dd,J=8.0, 0.8 Hz, 1H), 6.99 (t,J= 2.0 Hz, 1H), 6.90 (dd,J=7.6, 0.8 Hz, 1H), 6.38 (dd,J=6.4, 2.4 Hz, 2H), 4.78(s, 2H), 3.31 (s, 6H), 3.30 (s, 6H)。
实施例3:2-(3-(7-氯-4-(二甲基氨基)- 2-氧代喹唑啉-1(2H)-基)苯氧基)-N-(3-(4-(二甲基氨基)-2-氧代嘧啶-1(2H) -基)苯基)乙酰胺
步骤1:往2,4-二氯嘧啶 (5.0 g, 33.56 mmol) 的甲醇 (50.0 mL) 溶液中加入二甲基胺的四氢呋喃溶液 (17.62 mL, 35.24 mmol, 2M)。室温下反应3个小时。浓缩后用柱层析纯化得到化合物3-1 (3.2 g, 产率 60%)。LCMS: 158 [M+H]+。
步骤2:将化合物3-1 (3.1 g, 19.67 mmol) 的浓盐酸 (30.0 mL) 溶液加热到100摄氏度,反应4个小时。浓缩后得到粗产品化合物3-2 (3.5 g)。LCMS: 140 [M+H]+。
步骤3:往化合物3-2 (20 mg, 0.143 mmol) 的二甲基亚砜 (1.0 mL) 溶液中加入(3-溴苯基)氨基甲酸叔丁酯(77.8 mg, 0.286 mmol)、8-羟基喹啉 (2 mg, 0.0143mmol)、碳酸铯 (93.71 mg, 0.288 mmol)、碘化亚铜 (54.74 mg, 0.288 mmol)和三乙胺(29 mg, 0.288 mmol)。加热到135摄氏度反应16个小时。冷却后加入水和乙酸乙酯。有机相水洗干燥,浓缩后纯化得到化合物3-3 (10 mg, 产率30%)。LCMS: 231 [M+H]+。1HNMR (400MHz, DMSO-d6) δ 7.57 (d, J = 7.6 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.51 (dd,J = 8.1, 1.4 Hz, 1H), 6.44 (t, J = 2.0 Hz, 1H), 6.35 (dd, J = 7.7, 1.2 Hz,1H), 6.02 (d, J = 7.6 Hz, 1H), 5.24(brs, 2H) , 3.02 (s, 6H)。
步骤4:0摄氏度下往化合物3-3 (485 mg, 2.11 mmol) 的二氯甲烷 (5 mL) 溶液中加入三乙胺(639 mg, 6.32 mmol)和2-氯乙酰氯 (285 mg, 2.53 mmol)。室温搅拌4个小时。浓缩后用硅胶柱层析纯化得到化合物3-4 (380 mg, 收率 58%)。LCMS: 307 [M+H]+。
步骤5:往化合物3-4 (100 mg, 0.326 mmol)的N,N-二甲基甲酰胺 (2.0 mL) 溶液加入化合物1-4 (123.5 mg, 0.391 mmol) 和碳酸铯 (319 mg, 0.978 mmol)。加热到50摄氏度反应6个小时。冷却后加入水,用二氯甲烷萃取。有机相水洗干燥,浓缩后用制备HPLC纯化得到化合物3 (70 mg, 产率36.64% )。LCMS: 586.0 [M+H]+。1HNMR (400 MHz, DMSO-d6) δ 10.23(s, 1H) , 7.98 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.63- 7.58 (m, 2H), 7.52 - 7.46 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.16 - 7.13(m, 1H), 7.13 – 7.10 (m, 1H), 7.00-7.02 (m, 1H), 6.97 - 6.94 (m, 1H), 6.87-6.89 (m, 1H), 6.36 (d, J = 2.1 Hz, 1H), 6.08 (d, J = 7.6 Hz, 1H), 4.73(s, 2H), 3.26(s, 6H) , 3.05(s, 6H)。
实施例4:2-(3-(7-氯-4-(二甲基氨基)-2-氧代喹唑啉-1(2H)-基)苯氧基)-N-(3-(2-氧代吡啶-1(2H)-基)苯基)乙酰胺
步骤1:在间溴苯胺 (1.5 g, 8.72 mmol) 的二甲基亚砜 (5 mL) 溶液中加入2-羟基吡啶 (1.0 g, 10.46mmol)、碘化亚铜 (83 mg, 0.44 mmol)、碳酸钾 (2.4 g, 17.4mmol)和 4,7-二甲氧基-1,10-菲罗啉 (156 mg, 0.65 mmol)。加热到110摄氏度反应16个小时。冷却后倒入水中,用乙酸乙酯萃取。有机相干燥浓缩后用柱层析纯化得到化合物4-1(1 g, 产率 61%)。LCMS: 187 [M+H]+。
步骤2:参考实施例3的步骤4制备得到化合物4-2。
步骤3:采用化合物4-2和化合物1-4作原料,参考实施例3的步骤5得到化合物4。LCMS: 542.0 [M+H]+。1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.98 (d, J = 8.8Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 6.5 Hz, 1H),7.43-7.46 (m, 3H), 7.13 (t, J = 9.8 Hz, 2H), 7.06 (d, J = 7.8 Hz, 1H), 6.95(s, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.46 - 6.41 (m, 1H), 6.36 (s, 1H), 6.27(t, J = 6.5 Hz, 1H), 4.74 (s, 2H), 3.25 (s, 6H)。
实施例5:2-(3-(7-氯-4-(二甲基氨基)-2-氧代喹唑啉-1(2H)-基)苯氧基)-N-(2-吗啉吡啶-4-基) 乙酰胺
步骤1:将2-氯-4-氨基吡啶(1.0 g, 7.8 mmol) 的吗啉 (5.0 mL) 溶液用微波加热到180摄氏度反应2个小时。冷却后加入水和乙酸乙酯。有机相干燥浓缩后用柱层析纯化得到化合物5-1 (470 mg, 产率33%)。LCMS: 180 [M+H]+。
步骤2:参考实施例3的步骤4,利用化合物5-1制备得到化合物5-2。
和步骤3:采用化合物5-2和化合物1-4作原料,参考实施例3的步骤5得到化合物5。LCMS: 535.0 [M+H]+。1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.00 - 7.96 (m,2H), 7.48 (t, J = 8.1 Hz, 1H), 7.15 (dd, J = 8.8, 2.1 Hz, 1H), 7.11 - 7.08(m, 2H), 6.94 (t, J = 2.2 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.34 (d, J = 2.1 Hz,1H), 4.73 (s, 2H), 3.65 - 3.62 (m, 4H), 3.47-3.49 (m, 4H), 3.26 (s, 6H)。
实施例6:N-([1,1'-联苯]-3-基)-2-(3-(7-氯-4-(二甲基氨基)-2-氧代喹唑啉-1(2H)-基)苯氧基)乙酰胺
采用化合物[1,1'-联苯]-3-胺作原料,参考实施例3的步骤4和步骤5相同的方法得到化合物6。LCMS: 525.5 [M+H]+。1H-NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.98(d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.60 - 7.34 (m, 9H), 7.13-7.15 (m, 2H),6.98 (s, 1H), 6.88 (d, J = 7.4 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 4.75 (s,2H), 3.26 (s, 6H)。
实施例7:生物学实施例
酶反应过程:
(1) 配制 1× Assay buffer 。
(2) 化合物浓度梯度的配制:受试化合物测试起始浓度为1μM,3倍稀释,10个浓度,复孔测试。在384孔板中梯度稀释成100倍终浓度的10个不同浓度的溶液。然后用Echo550转移250 nL到384反应板中备用。阴性对照孔和阳性对照孔中分别加250 nL的100%DMSO。
(3) 用1×Assay buffer 配制1.67 倍终浓度的MAT2A酶溶液。
(4) 在化合物孔和阳性对照孔中分别加15μL的1.67倍终浓度的MAT2A酶溶液;在阴性对照孔中加15 μL的1× Assay buffer。
(5) 1000rpm离心60秒,振荡混匀后孵育15分钟。
(6) 用1×Assay buffer 配制25倍终浓度的底物混合溶液。
(7) 加入10 μL的2.5倍终浓度的底物混合溶液,起始反应。
(8) 将384 孔板1000rpm离心60秒,振荡混匀后孵育150分钟。
(9) 加入50μLBiomol 终止反应,1000 rpm离心60秒后孵育15分钟。读取OD620,处理数据。
数据分析:
计算公式
% Inhibition =(OD620_max−OD620_sample)/(OD620_max−OD620_min)×100%
其中:OD620 _sample 是化合物样品孔吸光值;OD620 _min:阴性对照孔吸光值,代表没有酶活孔的读数;OD620 _max:阳性对照孔吸光值,代表没有化合物抑制孔的读数。
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MAT2A酶活性的IC50值。
上述化合物1-6的活性数据如下表1所示:
表1
化合物 | IC50(nM) |
1 | >1000 |
2 | 6.5 |
3 | 8.2 |
4 | 7.99 |
5 | 47 |
6 | 10 |
由上述结果可知,本发明含2-氧代喹唑啉-1(2H)-基)苯氧基)乙酰胺结构的化合物2-化合物6对MAT2A酶的抑制活性显著优于不含该基团的化合物1。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.式I所示的化合物或其药学上可接受的盐:
其中,R1选自H、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟基C1-6烷基、OH、CN、NH2、3-10元含N杂环基、-N(C1-6烷基)2或-NHC1-6烷基;所述3-10元含N杂环基任选被OH或NH2取代;
R2选自卤素、C1-6烷基、C1-6烷氧基或卤代C1-6烷基;
R3选自无取代,或任选被一个,两个或更多个RS取代的如下基团:5-20元杂芳基,3-20元杂环基或C6-20芳基;
RS相同或不同,彼此独立地选自=O、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、羟基C1-6烷基、OH、CN、NH2、-N(C1-6烷基)2或-NHC1-6烷基;
X1,X2,X3,X4相同或不同,彼此独立地选自CH或N。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,R1选自OH,NH2,3-10元含N杂环基,-N(C1-3烷基)2或-NHC1-3烷基;
R2选自卤素或卤代C1-3烷基。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,R3选自无取代,或任选被一个,两个或更多个Rs取代的如下基团:5-12元杂芳基,5-12元杂环基或C6-12芳基;
Rs选自=O,卤素,-N(C1-3烷基)2或-NHC1-3烷基;
X1,X2,X3,X4相同或不同,彼此独立地选自CH或N,条件是X1,X2,X3,X4中至多两个选自N。
6.权利要求1-5任一项所述式I所示化合物或其药学上可接受的盐在制备预防和/或治疗由MTAP缺失导致的疾病、病症或病况的药物中的用途。
7.根据权利要求6所述的用途,其特征在于,所述由MTAP缺失导致的疾病、病症或病况为MTAP缺失的肿瘤。
8.根据权利要求7所述的用途,其特征在于,所述MTAP缺失的肿瘤选自:胶质瘤、间皮瘤、黑色素瘤、胃癌、食管癌、膀胱癌、胰腺癌、非小细胞肺癌、星形细胞瘤、骨肉瘤、头颈癌、粘液性软骨肉瘤、卵巢癌、子宫内膜癌、乳腺癌、软组织肉瘤或非霍奇金淋巴瘤。
9.一种药物组合物,其包括权利要求1-5任一项所述式I所示化合物或其药学上可接受的盐。
10.权利要求9所述的药物组合物在制备用于预防和/或治疗由MTAP缺失导致的疾病、病症或病况的药物中的用途。
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Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113166078A (zh) * | 2018-12-10 | 2021-07-23 | 伊迪亚生物科学有限公司 | 2-氧代喹唑啉衍生物作为甲硫氨酸腺苷转移酶2a抑制剂 |
WO2021252680A1 (en) * | 2020-06-10 | 2021-12-16 | Ideaya Biosciences, Inc. | 4-arylquinazoline derivatives as methionine adenosyltransferase 2a inhibitors |
WO2021252678A1 (en) * | 2020-06-10 | 2021-12-16 | Ideaya Biosciences, Inc. | Heteroaryl alkylene substituted 2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors |
CN113999232A (zh) * | 2020-07-28 | 2022-02-01 | 南京正大天晴制药有限公司 | Mat2a抑制剂 |
CN114874207A (zh) * | 2021-02-05 | 2022-08-09 | 江苏先声药业有限公司 | 作为mat2a抑制剂的双环类化合物 |
CN115260187A (zh) * | 2021-04-30 | 2022-11-01 | 武汉人福创新药物研发中心有限公司 | 吡啶酮化合物及其用途 |
WO2022256808A1 (en) * | 2021-06-02 | 2022-12-08 | Ideaya Biosciences Inc. | Combination therapy comprising a mat2a inhibitor and type i prmt inhibitor |
WO2022256806A1 (en) * | 2021-06-02 | 2022-12-08 | Ideaya Biosciences, Inc. | Combination therapy comprising a mat2a inhibitor and a type ii prmt inhibitor |
CN115867541A (zh) * | 2020-06-22 | 2023-03-28 | 豪夫迈·罗氏有限公司 | 氨基嘧啶酮衍生物 |
WO2023066283A1 (en) * | 2021-10-20 | 2023-04-27 | Insilico Medicine Ip Limited | Methionine adenosyltransferase 2a (mat2a) inhibitors and uses thereof |
-
2023
- 2023-05-16 CN CN202310545934.2A patent/CN116283800B/zh active Active
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113166078A (zh) * | 2018-12-10 | 2021-07-23 | 伊迪亚生物科学有限公司 | 2-氧代喹唑啉衍生物作为甲硫氨酸腺苷转移酶2a抑制剂 |
WO2021252680A1 (en) * | 2020-06-10 | 2021-12-16 | Ideaya Biosciences, Inc. | 4-arylquinazoline derivatives as methionine adenosyltransferase 2a inhibitors |
WO2021252678A1 (en) * | 2020-06-10 | 2021-12-16 | Ideaya Biosciences, Inc. | Heteroaryl alkylene substituted 2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors |
CN115867541A (zh) * | 2020-06-22 | 2023-03-28 | 豪夫迈·罗氏有限公司 | 氨基嘧啶酮衍生物 |
CN113999232A (zh) * | 2020-07-28 | 2022-02-01 | 南京正大天晴制药有限公司 | Mat2a抑制剂 |
CN114874207A (zh) * | 2021-02-05 | 2022-08-09 | 江苏先声药业有限公司 | 作为mat2a抑制剂的双环类化合物 |
CN115260187A (zh) * | 2021-04-30 | 2022-11-01 | 武汉人福创新药物研发中心有限公司 | 吡啶酮化合物及其用途 |
WO2022256808A1 (en) * | 2021-06-02 | 2022-12-08 | Ideaya Biosciences Inc. | Combination therapy comprising a mat2a inhibitor and type i prmt inhibitor |
WO2022256806A1 (en) * | 2021-06-02 | 2022-12-08 | Ideaya Biosciences, Inc. | Combination therapy comprising a mat2a inhibitor and a type ii prmt inhibitor |
WO2023066283A1 (en) * | 2021-10-20 | 2023-04-27 | Insilico Medicine Ip Limited | Methionine adenosyltransferase 2a (mat2a) inhibitors and uses thereof |
Non-Patent Citations (2)
Title |
---|
CLAUDIA DE FUSCO ET AL.: "Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model", 《JOURNAL OF MEDICINAL CHEMISTRY》, pages 6814 - 6826 * |
王鹏飞等: "甲硫氨酸腺苷转移酶2A 在肿瘤发生中的作用及其抑制剂研发现状", 《药学进展》, pages 884 - 897 * |
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