CN116685324A - 用于预防或治疗与ron突变相关的胰腺癌的药物组合物及其使用方法 - Google Patents
用于预防或治疗与ron突变相关的胰腺癌的药物组合物及其使用方法 Download PDFInfo
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- CN116685324A CN116685324A CN202180059877.6A CN202180059877A CN116685324A CN 116685324 A CN116685324 A CN 116685324A CN 202180059877 A CN202180059877 A CN 202180059877A CN 116685324 A CN116685324 A CN 116685324A
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- Prior art keywords
- ron
- oxo
- fluorophenyl
- oxy
- carboxamide
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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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
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Abstract
本发明涉及一种用于预防或治疗与RON突变相关的胰腺癌的药物组合物以及使用其的方法。根据本发明的用于预防或治疗癌症的药物组合物可以应用于存在RON突变的胰腺癌患者。特别是,本发明可有效地用作治疗胰腺癌患者的精准药物,该患者对常规抗癌治疗中使用的西妥昔单抗具有耐药性,并且具有RON△155、RON△160或RON△165突变。
Description
技术领域
本发明涉及一种用于预防或治疗与RON突变相关的胰腺癌的药物组合物以及使用该药物组合物预防或治疗胰腺癌的方法。
背景技术
胰腺癌是发生在胰腺中的癌细胞。发生在胰腺中的肿瘤可大体上分为源自分泌激素如胰岛素的内分泌细胞的肿瘤(5-10%)和源自与消化酶分泌相关的外分泌细胞的肿瘤(90%或更多)。源自内分泌细胞的功能性肿瘤极为罕见,源自内分泌细胞的恶性腺癌通常被称为胰腺癌。胰腺癌主要发生在男性和50岁以上的老年人中。在70岁以上的老年人中,其发病率约为每年1/1000人。
胰腺癌的危险因素包括吸烟(30%)、高热量饮食(20%)、慢性胰腺炎(4%)、遗传因素(10%)等。据悉,剩下的36%尚未能追查到原因。因为胰腺癌没有早期症状,早期发现率很低,不到10%。胰腺癌最常见的症状是腹痛,其次是黄疸、食欲下降、体重减轻等。
作为一种遗传因素,被称为KRAS(V-Ki-ras2 Kirsten大鼠肉瘤病毒癌基因同源物)的基因异常尤其引人关注。在90%以上的胰腺癌中发现该基因的修饰,并且在环境因素中,已知吸烟对致癌作用具有显著影响。特别是,有报道称肉类摄入和食物中的脂肪含量与胰腺癌的发生有相关性,但尚未得到明确证明。有报道称水果、蔬菜、膳食纤维、维生素C等对预防胰腺癌有效果,但尚未得到明确证实。由于胰腺癌的生存率不超过10%,早期诊断困难,复发率超过70-80%,为此开发治疗药物的重要性日益增加。
另一方面,西妥昔单抗(cetuximab)是一种靶向表皮生长因子受体(epidermalgrowth factor receptor,EGFR)的单克隆抗体。该抗体与细胞表面的EGFR特异性结合,从而抑制癌细胞的增殖。特别地,因为EGFR在转移性非小细胞肺癌(metastatic non-smallcell lung cancer)、转移性小细胞肺癌(metastatic small cell lung cancer)和转移性结直肠癌(metastatic colorectal cancer)的癌细胞中过表达,所以西妥昔单抗主要用于治疗此类疾病。
然而,西妥昔单抗不能用于对抗癌药物有耐药性的患者。西妥昔单抗耐药的原因有多种。代表性地,对EGFR靶向治疗剂的耐药性可以通过与RON(Recepteur d'originenantais)突变相关来表征。在肿瘤的发生、发展和转移中RON是否活跃起着重要作用。特别是,据报道其在胰腺癌、肺癌、结直肠癌和乳腺癌中的过表达或过度活跃诱导肿瘤的侵袭和转移并有助于抑制细胞凋亡。能够特异性抑制RON异常活性的物质可以有效治疗与RON相关的各种疾病,特别是胰腺癌等肿瘤。
RON(Recepteur d'origine nantais)是属于c-MET家族的蛋白质受体,是由肝脏分泌并调节巨噬细胞活动的血清蛋白(巨噬细胞刺激蛋白;MSP)的受体。为了确定西妥昔单抗等抗癌治疗的有效性,已知RON中的突变显着改善癌症患者对药物的反应和生存期,因此,这被认为是非常重要的。
因此,为了有效地治疗癌症,需要一种新的抗癌剂,该抗癌剂适用于含有对常规抗癌剂具有抗性的RON突变的癌症。
发明内容
技术问题
本发明的一个目的是提供一种用于预防或治疗胰腺癌的药物组合物,包括能够预防或治疗含有RON突变的胰腺癌的化合物或其药学上可接受的盐作为活性成分,以及使用该药物组合物预防或治疗胰腺癌的方法。
解决问题的方案
为了实现上述目的,在本发明的一个方面,提供了一种用于预防或治疗胰腺癌的药物组合物,其包含由式1或式2所示的化合物或其药学上可接受的盐作为活性成分:
[式1]
和
[式2]
在本发明的另一方面,提供了一种预防或治疗胰腺癌的方法,包括:检测源自患有胰腺癌的受试者的生物样品中的RON突变,其中RON突变为外显子5、6和11缺失的RON△155、外显子5和6缺失的RON△160、或外显子11缺失的RON△165;并将根据权利要求1所述的药物组合物施用于检测到RON突变的受试者。
在本发明的另一方面,提供了一种提供关于抗癌治疗剂的信息的方法,包括:检测源自患有胰腺癌的受试者的生物样品中的RON突变,其中RON突变为外显子5、6和11缺失的RON△155、外显子5和6缺失的RON△160、或外显子11缺失的RON△165;和向检测到RON突变的受试者提供根据权利要求1所述的药物组合物适用于预防或治疗胰腺癌的信息。
在本发明的另一方面,提供了所述药物组合物在预防或治疗胰腺癌中的用途。
发明效果
根据本发明的用于预防或治疗癌症的药物组合物可以应用于存在RON突变的胰腺癌患者。特别是,所述药物组合物可有效地用于治疗胰腺癌患者,该患者对常规抗癌治疗中使用的西妥昔单抗具有耐药性,并且具有RON△155、RON△160或RON△165突变。
附图说明
图1A至1C示出了通过比较和确认用实施例1(WM-S1-030)至5的化合物和阳性对照1(BMS-777607)分别以1μM和5μM的浓度处理RON△155突变型的胰腺癌细胞系Panc-1和Capan-1细胞系以及RON△160突变型的胰腺癌细胞系Mia-PaCa2细胞系的细胞杀伤效力所获得的结果。
图2示出了通过确认接受了30mpk剂量的实施例1(WM-S1-030)和30mpk剂量的阳性对照1(BMS-777607)的移植了RON△160突变型的胰腺癌细胞系Mia-PaCa2细胞系的小鼠模型的肿瘤生长速率所获得的结果。
图3示出了通过对接受了10mpk或30mpk剂量的实施例1(WM-S1-030)和30mpk剂量的阳性对照(BMS-777607)的移植了RON△160突变型的胰腺癌细胞系Mia-PaCa2细胞系的小鼠模型的组织切片进行免疫化学染色所获得的结果。
图4示出了通过分析8个胰腺癌细胞系中的RON突变序列所获得的结果。
实施本发明的最佳方式
在下文中,将对本发明进行更详细的描述。
在本发明的一个方面中,提供了一种用于预防或治疗胰腺癌的药物组合物,其包含由式1或式2所示的化合物或其药学上可接受的盐作为活性成分:
在这种情况下,胰腺癌可能是一种存在RON(Recepteur d'origine nantais)突变的癌症。特别地,在本说明书中,胰腺癌可对EGFR靶向治疗剂具有耐药性。此外,所述EGFR靶向治疗剂可以是选自西妥昔单抗(cetuximab)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、阿帕替尼(apatinib)、埃克替尼(icotinib)、布加替尼(brigatinib)、拉帕替尼(lapatinib)、卡拉替尼(canertinib)、AEE788、XL647、范得他尼(zactima)和帕尼单抗(panitumumab)组成的组中的至少一种。
如本文所用,术语“RON”是由人MST1R(巨噬细胞刺激1受体)基因编码的蛋白质。它是属于c-MET家族的蛋白质受体,是由肝脏分泌并调节巨噬细胞活动的血清蛋白(巨噬细胞刺激蛋白;MSP)的受体。结合在细胞表面的配体诱导细胞内结构域中RON的磷酸化,从而为下游信号分子提供对接位点。来自RON的信号通过促进伤口部位的上皮细胞迁移、增殖和存活来激活伤口愈合反应。它通过调节巨噬细胞迁移和吞噬活性在先天免疫反应中发挥作用。此外,RON还可以促进细胞迁移和增殖等信号,以响应MST1配体以外的生长因子。RON主要表达于肝、肺、肠、肾、脑、骨、肾上腺、皮肤等上皮细胞。
RON的突变形式存在于各种实体癌中,例如非小细胞肺癌(SCLC),小细胞肺癌(NSCLC),胰腺癌和结直肠癌。在这种情况下,RON可能具有SEQ ID NO:2,3或4的核苷酸序列。
如本文所用,术语“MST1R基因”是指通过与MST1配体结合将信号转导至细胞质的酪氨酸激酶受体。它调节各种生理过程,包括细胞存活、迁移和分化。
如本文所用,术语“RON突变”的特征在于,其为外显子5、6和11缺失的RON△155、外显子5和6缺失的RON△160、和外显子11缺失的RON△165中的至少一个。RON△155的cDNA可能具有SEQ ID NO:2的核苷酸序列。RON△160的cDNA可能具有SEQ ID NO:3的核苷酸序列。RON△165的cDNA可能具有SEQ ID NO:4的核苷酸序列。
如本文所用,术语“耐药性”意味着药物没有疗效,因为它对药物反应不敏感。
如本文所用,术语“EGFR靶向治疗剂”是指靶向EGFR的抗癌药物,可以应用任何靶向EGFR的治疗剂,只要该试剂表现出抗癌作用。所述EGFR靶向治疗剂可优选西妥昔单抗(cetuximab)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、阿帕替尼(apatinib)、埃克替尼(icotinib)、布加替尼(brigatinib)、拉帕替尼(lapatinib)、卡拉替尼(canertinib)、AEE788、XL647、范得他尼(zactima)或帕尼单抗(panitumumab),并且最优选西妥昔单抗。
本发明所用的式1化合物如下所示:
[式1]
在式1中,
R1和R2各自独立地为H、卤素、C1-10烷氧基或卤代C1-10烷基;
X为-C(-R3)=或-N=;
R3和R4各自独立为H、卤素、C1-10烷基或C1-10烷氧基;
R5为H、卤素或C1-10烷基;
R6和R7与其所连接的N原子一起形成4-10元杂环,或R6为-C2H4-O-CH3,以及R7为H、甲基或叔丁氧基羰基;和
除R6和R7连接的N原子外,所述杂环还具有或不具有1或2个选自N、O和S组成的组的杂原子,并且所述杂环为未被取代或被至少一个选自卤素和C1-6烷基取代。
所述C1-10烷基可包括C1-6烷基、C1-3烷基、C3-10烷基、C3-6烷基、C6-10烷基等。此外,所述C1-10烷氧基可包括C1-6烷氧基、C1-3烷氧基、C3-10烷氧基、C3-6烷氧基、C6-10烷氧基等。此外,所述4至10元杂环可包括4至7元杂环、4至6元杂环、5至7元杂环、5或6元杂环等。
根据一个实施方式,在式1中,R1和R2可以各自独立地为H、卤素、甲氧基或-CF3,其中卤素可以是F、Cl、Br或I。
根据另一个实施方式,在式1中,R3和R4可以各自独立地为H、卤素、甲基、甲氧基或乙氧基,其中卤素可以是F、Cl、Br或I。
根据另一个实施方式,在式1中,X为-C(-R3)=;R3和R4各自独立地为H、卤素、甲基、甲氧基或乙氧基,前提是R3和R4不同时为H。
根据另一个实施方式,在式1中,X可以为-N=;并且R4可以为卤素、甲基、甲氧基或乙氧基,其中卤素可以是F、Cl、Br或I。
根据另一个实施方式,在式1中,R5可以为H或卤素,其中卤素可为F、Cl、Br或I。
根据另一个实施方式,在式1中,R6和R7可以与其所连接的N原子一起形成其中Ra和Rb可以各自独立地为C1-3亚烷基;A可以为-N(-R9)-或-O-,并且R9可以为C1-6烷基。作为具体实例,R6和R7可以与其所连接的N原子一起形成氮杂环丁基、二氮杂环丁基、吡咯烷基、吡咯基、咪唑烷基、咪唑基、吡唑烷基、吡唑基、恶唑烷基、恶唑基、异恶唑烷基、异恶唑基、噻唑烷基、噻唑基、异噻唑烷基、异噻唑基、哌啶基、吡啶基、哌嗪基、二嗪基、吗啉、硫代吗啉、氮杂环庚基、二氮杂环庚基或其上被C1-6烷基取代的杂环基。此外,Ra和Rb可以各自独立地为-CH2-、-C2H4-或-C3H6-。此外,R9可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、叔戊基、仲戊基、新戊基、己基等。
根据另一个实施方式,在式1中,R1和R2可以各自独立地为H、卤素、甲氧基或-CF3;R3和R4可以各自独立地为H、卤素、甲基、甲氧基或乙氧基;R5可以为H或卤素;并且R6可以为-C2H4-O-CH3,以及R7可以为H、甲基或叔丁氧羰基,或者R6和R7可以相互连接形成吗啉或甲基哌嗪基,其中卤素可以是F、Cl、Br或I。
根据一个具体实施方式,式1化合物可由下式1a所示:
[式1a]
在式1a中,R1至R7如上式1中所定义。
具体地,在式1a中,R1和R2可以各自独立地为H、卤素或-CF3。此外,R3和R4可以各自独立地为H、卤素、甲基、甲氧基或乙氧基,条件是R3和R4不同时为H。此外,R5可以为H或卤素。
更具体地,在式1a中,R1和R2可以各自独立地为H、卤素或-CF3;R3和R4可以各自独立地为H、卤素、甲基、甲氧基或乙氧基;R5可以为H或卤素;并且R6可以为-C2H4-O-CH3,以及R7可以为H、甲基或叔丁氧基羰基。
根据另一具体实施方式,式1化合物可由下式1b所示:
[式1b]
在式1b中,R1至R7如上式1中所定义。
具体地,在式1b中,R1和R2可以各自独立地为H、卤素或-CF3。此外,R4可以为卤素、甲基、甲氧基或乙氧基。此外,R5可以为H或卤素。
更具体地,在式1b中,R1和R2可以各自独立地为H、卤素或-CF3;R4可以为卤素、甲基、甲氧基或乙氧基;R5可以为H或卤素;R6可以为-C2H4-O-CH3,并且R7可以为H、甲基或叔丁氧基羰基。
根据另一具体实施方式,式1化合物可由下式1c所示:
[式1c]
在式1c中,R1至R5如上式1中所定义;Ra和Rb可以各自独立地为C1-3亚烷基;A可以为-N(-R9)-或-O-,并且R9可以为C1-6烷基。
具体地,在式1c中,R1和R2可以各自独立地为H、卤素或-CF3。此外,R3和R4可以各自独立地为H、卤素、甲基、甲氧基或乙氧基,条件是R3和R4不同时为H。此外,R5可以为H或卤素。此外,Ra和Rb可以与它们连接的N和A一起形成吗啉或甲基哌嗪基。
根据另一具体实施方式,式1化合物可由下式1d所示:
[式1d]
在式1d中,R1至R5如上式1中所定义;Ra和Rb可以各自独立地为C1-3亚烷基;A可以为-N(-R9)-或-O-,并且R9可以为C1-6烷基。
具体地,在式1d中,R1和R2可以各自独立地为H、卤素或-CF3。此外,R4可以为卤素、甲基、甲氧基或乙氧基。此外,R5可以为H或卤素。此外,Ra和Rb可以与它们连接的N和A一起形成吗啉或甲基哌嗪基。
根据具体实施方式,所述式1所示的化合物的具体实例如下:
1)4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺;
2)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-4-甲氧基-2-氧代-1,2-二氢吡啶-3-甲酰胺;
3)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)4-甲氧基-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺;
4)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
5)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基]吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺;
6)叔丁基{[6-(7-{4-[4-乙氧基-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺基]-2-氟苯氧基}噻吩并[3,2-b]吡啶-2-基)吡啶-3-基]甲基}(2-甲氧基乙基)氨基甲酸酯;
7)4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
8)1-(4-氯苯基)-4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
9)N-(3-氯-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-4-甲氧基-2-氧代-1,2-二氢吡啶-3-甲酰胺;
10)N-(2-氯-4-{[-2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-4-甲氧基-2-氧代-1,2-二氢吡啶-3-甲酰胺;
11)1-(4-氟苯基)-4-甲氧基-N-(4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基)氧基)苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
12)4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-2-氧代-1-(4-(三氟甲基)苯基)-1,2-二氢吡啶-3-甲酰胺;
13)1-(4-氯苯基)-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-4-甲氧基-2-氧代-1,2-二氢吡啶-3-甲酰胺;
14)4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(3-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
15)4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-甲氧基苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
16)4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(3-甲氧基苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
17)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-2-(4-氟苯基)-5-甲基-3-氧代-2,3-二氢哒嗪-4-甲酰胺;
18)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-5-甲基-3-氧代-2-苯基-2,3-二氢哒嗪-4-甲酰胺;
19)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-3-氧代-2-苯基-2,3-二氢哒嗪-4-甲酰胺;
20)N-(3-氟-4-[{2-(5-[{(2-甲氧基乙基)氨基}甲基]吡啶-2-基)噻吩并[3,2-b]吡啶-7-基}氧基]苯基)-2-(4-氟苯基)-3-氧代-2,3-二氢哒嗪-4-甲酰胺;
21)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-6-甲基-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺;
22)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-6-甲基-2-氧代-1,2-二氢吡啶-3-甲酰胺;
23)5-溴-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
24)5-氯-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
25)N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-4-甲基-2-氧代-1,2-二氢吡啶-3-甲酰胺;
26)N-(2-氯-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-4-乙氧基-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
27)N-(3-氟-4-([2-(5-{[(2-甲氧基乙基)氨基)甲基]吡啶-2-基}噻吩并[3,2-b]吡啶-7-基)氧基]苯基}-1-(4-氟苯基)-5,6-二甲基-2-氧代-1,2-二氢吡啶-3-甲酰胺;
28)N-(3-氟-4-{[-2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-4-甲基-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺;
29)N-(3-氟-4-{[-2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-5-甲基-2-氧代-1,2-二氢吡啶-3-甲酰胺;
30)4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)(甲基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
31)4-乙氧基-N-[3-氟-4-({2-[5-(吗啉甲基)吡啶-2-基]噻吩并[3,2-b]吡啶-7-基}氧基)苯基]-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
32)4-乙氧基-N-[3-氟-4-({2-[5-(吗啉甲基)吡啶-2-基]噻吩并[3,2-b]吡啶-7-基}氧基)苯基]-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺;
33)4-乙氧基-N-{3-氟-4-[(2-{5-[(4-甲基哌嗪-1-基)甲基]吡啶-2-基}噻吩并[3,2-b]吡啶-7-基)氧基]苯基}-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
34)4-乙氧基-N-{3-氟-4-[(2-{5-[(-甲基哌嗪-1-基)甲基]吡啶-2-基}噻吩并[3,2-b]吡啶-7-基)氧基]苯基}-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺;
35)1-(4-氯苯基)-4-乙氧基-N-[3-氟-4-({2-[5-(吗啉甲基)吡啶-2-基]噻吩并[3,2-b]吡啶-7-基}氧基)苯基]-2-氧代-1,2-二氢吡啶-3-甲酰胺;
36)N-[3-氯-4-({2-[5-(吗啉甲基)吡啶-2-基]噻吩并[3,2-b]吡啶-7-基}氧基)苯基]-4-乙氧基-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;和
37)N-[2-氯-4-({2-[5-(吗啉甲基)吡啶-2-基]噻吩并[3,2-b]吡啶-7-基}氧基)苯基]-4-乙氧基-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺。
优选地,所述式1所示的化合物可以是选自以下组的化合物:
4-乙氧基-N-[3-氟-4-({2-[5-(吗啉甲基)吡啶-2-基]噻吩并[3,2-b]吡啶-7-基}氧基)苯基]-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺;和
4-乙氧基-N-{3-氟-4-[(2-{5-[(-甲基哌嗪-1-基)甲基]吡啶-2-基}噻吩并[3,2-b]吡啶-7-基)氧基]苯基}-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺。
根据本发明的组合物中使用的式1化合物可以通过韩国专利No.10-2221689中公开的方法制备,并且可以通过基于有机合成领域中其它已知方法和/或技术的各种方法制备。基于上述方法,可以根据取代基的类型使用合适的合成方法合成各种衍生物。
本发明所用的式2化合物如下所示:
[式2]
在式2中,
L为-NH-或-CH2-,
R1至R4各自独立地为氢、卤素、羟基、氰基、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-7环烷基、C6-10芳基、5至9元杂芳基或3至9元杂环烷基,
X为O、S、-CH(-Rx)-或-N(-Rx)-,
Rx为氢、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C6-10芳基、C6-10芳基-C1-4烷基或3至9元杂环烷基,
Y为-N=或-CH=,并且
R5和R6各自独立地为氢、氨基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基-C1-6烷氧基、氨基羰基、C1-6烷基氨基羰基、二-C1-6烷基羰基氨基、C1-6烷基羰基氨基、C1-6烷基氨基或C1-6烷基-氨基-C1-6烷氧基,
其中R5和R6各自独立地未被取代或被3至9元环烷基或3至9元杂环烷基取代,
所述环烷基或杂环烷基具有或不具有至少一个选自卤素、氧代、氰基、羟基、羟基-C1-6烷基、氨基、二-C1-6烷基氨基、C1-6烷基、C1-6烷氧基和C1-6烷氧基-C1-6烷基组成的组中的取代基,以及
所述杂环烷基含有1至4个选自N、O和S组成的组的杂原子。
所述C1-6烷基可包括C1-3烷基、C3-6烷基等。此外,所述C1-6烷氧基可包括C1-3烷氧基、C3-6烷氧基等。
根据一个实施方式,在式2中,R1至R4可以各自独立地为氢、C1-4卤代烷基或卤素,其中卤素可以为F、Cl、Br或I。具体地,R1可以为氢、三氟甲基或氟,R2可以为氢,R3可以为氟,以及R4可以为氢。
根据另一实施方式,在式2中,X可为O或-CH(-Rx)-,且Rx可为氢或C1-6烷基。
根据另一实施方式,在式2中,R5和R6可以各自独立地为氢、氨基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基-C1-6烷氧基、氨基羰基、C1-6烷基氨基羰基、二-C1-6烷基羰基氨基、C1-6烷基羰基氨基、C1-6烷基氨基、C1-6烷基-氨基-C1-6烷氧基或5至9元杂芳基,其中R5和R6可以各自独立地未被取代或者被C1-6烷基;被C1-6烷氧基-C1-6烷基-氨基、3至9元环烷基和3至9元杂环烷基中的任一个取代的C1-6烷基或C1-6烷基-氨基-C1-6烷基;3至9元环烷基;或3至9元杂环烷基取代,其中所述环烷基或杂环烷基可具有或不具有至少一个选自卤素、氧代、氰基、羟基、羟基-C1-6烷基、氨基、二-C1-6烷基氨基、C1-6烷基、C1-6烷氧基和C1-6烷氧基-C1-6烷基组成的组中的取代基,以及所述杂芳基和所述杂环烷基可以各自独立地包含至少一个选自N、O和S组成的组的杂原子。
具体地,所述杂芳基可以为吡啶基、咪唑基或吡唑基,所述杂环烷基可以为氮杂环丁基、吡咯烷基、四氢吡喃基、吗啉、吗啉基、二氧硫代吗啉、哌嗪基、哌啶基或氧杂环丁基,所述环烷基可以为环丁基、环戊基或环己基。
此外,当所述杂芳基或所述杂环烷基含有至少一个N原子时,其可以在其中任意一个N原子的位置被取代,没有特别限制。
根据另一个实施方式,在式2中,R1和R2可以为氢、C1-4卤代烷基或卤素,R3和R4可以为氢或卤素,X可以为O或-CH(-Rx)-,Rx可以为氢或C1-4烷基,A可以是喹啉、喹唑啉、吡啶、嘧啶、噻吩并吡啶、吡咯并吡啶、吡唑并吡啶、咪唑并吡啶、吡咯并嘧啶、二氢吡咯并嘧啶、呋喃并吡啶、吡唑并嘧啶、嘌呤或吲唑,并且R5和R6可以各自独立为氢、氨基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基-C1-6烷氧基、氨基羰基、C1-6烷基氨基羰基、二-C1-6烷基羰基氨基、C1-6烷基羰基氨基、C1-6烷基氨基、C1-6烷基-氨基-C1-6烷氧基或5至9元杂芳基,其中R5和R6可以各自独立地未被取代或者被C1-6烷基;被C1-6烷氧基-C1-6烷基-氨基、3至9元环烷基和3至9元杂环烷基中的任一个取代的C1-6烷基或C1-6烷基-氨基-C1-6烷基;3至9元环烷基;或3至9元杂环烷基取代,其中所述环烷基或杂环烷基可具有或不具有至少一个选自卤素、氧代、氰基、羟基、羟基-C1-6烷基、氨基、二-C1-6烷基氨基、C1-6烷基、C1-6烷氧基和C1-6烷氧基-C1-6烷基组成的组中的取代基,以及所述杂芳基和所述杂环烷基可以各自独立地包含至少一个选自N、O和S组成的组的杂原子。
根据另一个实施方式,在式2中,R5和R6可以各自独立地为氢、硝基、氨基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基-C1-6烷氧基,氨基羰基,C1-6烷基氨基羰基,二-C1-6烷基氨基羰基、C1-6烷基羰基氨基、C1-6烷基氨基、C1-6烷基氨基-C1-6烷氧基、C6-10芳基、C6-10芳基-C1-4烷基或5至9元杂芳基,其中所述氨基、烷基、烷氧基、芳基和杂芳基可以各自独立地未被取代或被C1-6烷基;被C1-6烷氧基-C1-6烷基氨基、3至9元环烷基和3至9元杂环烷基中的任一个取代的C1-6烷基或C1-6烷基氨基-C1-6烷基;3至9元环烷基;或3至9元杂环烷基取代;并且所述环烷基或杂环烷基可以具有或可以不具有至少一个选自卤素、氧代、氰基、羟基、羟基-C1-6烷基、氨基、二-C1-6烷基氨基、C1-6烷基、C1-6烷氧基和C1-6烷氧基-C1-6烷基组成的组中的取代基,并且所述杂环、杂芳基和杂环烷基可以各自独立地包含至少一个选自N、O和S组成的组的杂原子。
根据另一个实施方式,在式2中,R5和R6可以不同时为C6-10芳基、C6-10芳基-C1-4烷基或5至9元杂芳基。根据另一个实施方式,在式1中,R5和R6可以不同时被C1-6烷基或C1-6烷基氨基-C1-6烷基中的任一个取代的3至9元环烷基和3至9元杂环烷基;3至9元环烷基;或3至9元杂环烷基取代。作为具体的实例,当R5包含芳基或杂芳基等环时,R6可以不同时包含所述环。此外,当R5被环烷基或杂环烷基等含环的基团取代时,R6可以不同时被含所述环的基团取代。
作为更具体的实例,R5可以为C6-10芳基、C6-10芳基-C1-4烷基或5至9元杂芳基,并且R6可以为氢、硝基、氨基、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基-C1-6烷氧基、氨基羰基、C1-6烷基氨基羰基、二-C1-6烷基氨基羰基、C1-6烷基羰基氨基、C1-6烷基氨基或C1-6烷基-氨基-C1-6烷氧基,其中R5可以为未被取代或被C1-6烷基;或被C1-6烷氧基-C1-6烷基氨基、3-至9-元环烷基和3-至9-元杂环烷基中的任何一个取代的C1-6烷基或C1-6烷基氨基-C1-6烷基取代。此外,R6可以是未取代的或被3-9元环烷基;或3-9元杂环烷基取代,其中所述环烷基或杂环烷基可以具有或不具有至少一个选自卤素、氧代、氰基、羟基、羟基-C1-6烷基、氨基、二-C1-6烷基氨基、C1-6烷基、C1-6烷氧基和C1-6烷氧基-C1-6烷基组成的组中的取代基,并且所述杂芳基和所述杂环烷基可以各自独立地含有至少一个选自N,O和S组成的组的杂原子。
根据另一个实施方式,在式2中,R5和R6可以各自独立地为氢、氨基、卤素、羟基、C1-6烷氧基、氨基羰基、C1-6烷基氨基羰基、二-C1-6烷基氨基羰基,C1-6烷基羰基氨基、氰基、C1-4卤代烷基、C1-6烷基、5至9元杂芳基、Ax-(CH2)a-L1-(CH2)b-L2-或Ax-(CH2)a-L1-(CH2)b-L2-吡啶基,其中Ax可以是C3-6环烷基或3至6元杂环烷基,L1和L2可以各自独立地为单键、-O-、-NH-、-C(=O)-NH-或-NH-C(=O)-,并且a和b可以各自独立地为0至3的整数,条件是当b为0时,L2是单键,并且所述环烷基、杂芳基和杂环烷基可以各自独立地具有或不具有一个或两个选自卤素、氧代、氰基、羟基、羟甲基、C1-6烷基、甲氧基、甲氧基甲基、二甲基氨基和甲氧基乙基氨基甲基组成的组中的取代基,并且所述杂芳基和所述杂环烷基可以各自独立地包含至少一个选自N、O和S组成的组的杂原子,并且所述杂芳基和所述杂环烷基可以各自独立地包含至少一个选自N、O和S组成的组的杂原子。
式2所示的化合物的具体实例如下:
40)N-{4-[(6,7-二甲氧基喹啉-4-基)氧基]-3-氟苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
41)N-{4-[(6,7-二甲氧基喹啉-4-基)氧基]-3-氟苯基}-6-氧代-5-苯基-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
42)N-{4-[(6,7-二甲氧基喹啉-4-基)氧基]-3-氟苯基}-6-氧代-5-(4-(三氟甲基)苯基]氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
43)N-{4-[(6,7-二甲氧基喹啉-4-基)氧基]-3-氟苯基}-6-氧代-5-(3-氟苯基)-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
44)N-{3-氟-4-[(6-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
45)N-{3-氟-4-[(7-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
46)N-{4-[(6,7-二甲氧基喹啉-4-基)氧基]-3-氟苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
47)N-{4-[(6-氨甲酰基-7-甲氧基喹啉-4-基)氧基]-3-氟苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
48)N-(3-氟-4-{[7-甲氧基-6-(甲基氨甲酰基)喹啉-4-基)氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
49)N-(4-{[6-(二甲基氨甲酰基)-7-甲氧基喹啉-4-基]氧基}-3-氟苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
50)N-[3-氟-4-({7-甲氧基-6-[(2-吗啉乙基)氨甲酰基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
51)N-(4-{[6-(乙基氨甲酰基)-7-甲氧基喹啉-4-基]氧基}-3-氟苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
52)N-{4-[(6-乙酰氨基-7-甲氧基喹啉-4-基)氧基]-3-氟苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
53)N-(3-氟-4-{[7-甲氧基-6-(2-吗啉乙酰氨基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
76)N-(3-氟-4-{[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
77)N-(3-氟-4-{[6-甲氧基-7-(3-吗啉丙氧基)喹啉-4-基]氧基}苯基)-2-(4-氟苯基)-3-氧代-3,5,6,7-四氢-2H-环戊[c]吡啶-4-甲酰胺;
78)N-(3-氟-4-{[6-甲氧基-7-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
79)N-(3-氟-4-{[6-甲氧基-7-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-6-氧代-5-苯基-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
80)N-[3-氟-4-({6-甲氧基-7-[3-(4-甲基哌嗪-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
81)N-[3-氟-4-({7-[3-(3-羟基氮杂环丁烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
82)N-[3-氟-4-({7-[3-(3-羟基-3-甲基氮杂环丁烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
83)N-{3-氟-4-[(7-{3-[3-(羟甲基)氮杂环丁烷-1-基]丙氧基}-6-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
84)N-[3-氟-4-({6-甲氧基-7-[3-(3-甲氧基氮杂环丁烷-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
85)N-[3-氟-4-({6-甲氧基-7-[3-(3-甲氧基-3-甲基氮杂环丁烷-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
86)N-[3-氟-4-({7-[3-(3-氟氮杂环丁烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
87)N-[4-({7-[3-(3,3-二氟氮杂环丁烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
88)N-[4-({7-[3-(3-氰基氮杂环丁烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
89)N-[3-氟-4-({6-甲氧基-7-[3-(3-甲基氮杂环丁烷-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
90)N-[3-氟-4-({7-[3-(3-羟基吡咯烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
91)N-[3-氟-4-({7-[3-(3-羟基-3-甲基吡咯烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
92)N-[3-氟-4-({6-甲氧基-7-[3-(3-甲氧基吡咯烷-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
93)N-[3-氟-4-({6-甲氧基-7-[3-(吡咯烷-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
94)N-[3-氟-4-({7-[3-(3-氟吡咯烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
95)N-[4-({7-[3-(3,3-二氟吡咯烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
96)N-[3-氟-4-({7-[3-(4-羟基哌啶-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
97)N-[3-氟-4-({7-[3-(3-羟基哌啶-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
98)N-[3-氟-4-({7-[3-(4-羟基-4-甲基哌啶-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
99)N-[3-氟-4-({6-甲氧基-7-[3-(4-甲氧基哌啶-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
100)N-[3-氟-4-({6-甲氧基-7-[3-(3-甲氧基哌啶-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
101)N-[3-氟-4-({6-甲氧基-7-[3-(4-氧代哌啶-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
102)N-[4-({7-[3-(1,1-二氧硫代吗啉)丙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
103)N-[3-氟-4-({6-甲氧基-7-[3-(哌啶-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
104)N-[3-氟-4-({7-[3-(4-氟哌啶-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
105)N-[4-({7-[3-(4,4-二氟哌啶-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
106)N-[3-氟-4-({6-甲氧基-7-[3-(4-甲基哌啶-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
107)N-[4-({7-[3-(4,4-二甲基哌啶-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
108)N-{3-氟-4-[(7-{3-[(3-羟基环丁基)氨基]丙氧基}-6-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
109)N-{3-氟-4-[(6-甲氧基-7-{3-[(3-甲氧基环丁基)氨基]丙氧基}喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃{3,2-c]吡啶-7-甲酰胺;
110)N-[3-氟-4-({6-甲氧基-7-[3-(氧杂环丁烷-3-基氨基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
111)N-{3-氟-4-({6-甲氧基-7-[3-(氧杂环丁烷-3-基甲基)氨基]丙氧基}喹啉-4-基)氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
112)N-{3-氟-4-[(7-{3-[(3-羟基环戊基)氨基]丙氧基}-6-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
113)N-{3-氟-4-[(7-{3-[(3-羟基环己基)氨基]丙氧基}-6-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
114)N-(3-氟-4-{[7-(3-{[(3-羟基环己基)甲基]氨基}丙氧基)-6-甲氧基喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
115)N-{3-氟-4-[(6-甲氧基-7-{3-[(四氢-2H-吡喃-4-基)氨基]丙氧基}喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
116)N-(3-氟-4-{[6-甲氧基-7-(3-{[(四氢-2H-吡喃-4-基)甲基]氨基}丙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c}吡啶-7-甲酰胺;
117)N-[3-氟-4-({7-[2-(3-羟基氮杂环丁烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
118)N-[3-氟-4-({7-[2-(3-羟基-3-甲基氮杂环丁烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
119)N-{3-氟-4-[(7-{2-[3-(羟甲基)氮杂环丁烷-1-基]乙氧基}-6-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
120)N-[3-氟-4-({6-甲氧基-7-[2-(3-甲氧基氮杂环丁烷-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
121)N-[3-氟-4-({6-甲氧基-7-[2-(3-甲氧基-3-甲基氮杂环丁烷-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
122)N-{3-氟-4-[(6-甲氧基-7-{2-[3-(甲氧基甲基)氮杂环丁烷-1-基]乙氧基}喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
123)N-[3-氟-4-({7-[2-(3-氟氮杂环丁烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
124)N-[4-({7-[2-(3,3-二氟氮杂环丁烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
125)N-[4-({7-[2-(3-乙基氮杂环丁烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
126)N-[3-氟-4-({6-甲氧基-7-[2-(3-甲基氮杂环丁烷-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
127)N-[4-({7-[2-(3,3-二甲基氮杂环丁烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
128)N-{4-[(7-{2-[3-(二甲氨基)氮杂环丁烷-1-基]乙氧基}-6-甲氧基喹啉-4-基)氧基]-3-氟苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
129)N-[3-氟-4-({7-[2-(3-羟基吡咯烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
130)N-[3-氟-4-({7-[2-(3-羟基-3-甲基吡咯烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
131)N-[3-氟-4-({6-甲氧基-7-[2-(3-甲氧基吡咯烷-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
132)N-[3-氟-4-({6-甲氧基-7-[2-(吡咯烷-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
133)N-[3-氟-4-({7-[2-(3-氟吡咯烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
134)N-[4-({7-[2-(3,3-二氟吡咯烷-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
135)N-[3-氟-4-({7-[2-(4-羟基哌啶-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
136)N-[3-氟-4-({7-[2-(3-羟基哌啶-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
137)N-[3-氟-4-({7-[2-(4-羟基-4-甲基哌啶-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
138)N-[3-氟-4-({6-甲氧基-7-[2-(4-甲氧基哌啶-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
139)N-[3-氟-4-({6-甲氧基-7-[2-(3-甲氧基哌啶-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
140)N-[3-氟-4-({6-甲氧基-7-[2-(4-氧代哌啶-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
141)N-[3-氟-4-({6-甲氧基-7-[2-(3-氧代哌啶-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
142)N-[4-({7-[2-(1,1-二氧硫代吗啉)乙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
143)N-[3-氟-4-({6-甲氧基-7-[2-(哌啶-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
144)N-[3-氟-4-({7-[2-(4-氟哌啶-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
145)N-[4-({7-[2-(4,4-二氟哌啶-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
146)N-[3-氟-4-({6-甲氧基-7-[2-(4-甲基哌啶-1-基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
147)N-[4-({7-[2-(4,4-二甲基哌啶-1-基)乙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
148)N-{3-氟-4-[(7-{2-[(3-羟基环丁基)氨基]乙氧基}-6-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
149)N-{3-氟-4-[(6-甲氧基-7-{2-[(3-甲氧基环丁基)氨基]乙氧基}喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
150)N-[3-氟-4-({6-甲氧基-7-[2-(氧杂环丁烷-3-基氨基)乙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
151)N-{3-氟-4[(6-甲氧基-7-{2-[(氧杂环丁烷-3-基甲基)氨基]乙氧基}喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
152)N-{3-氟-4-[(7-{2-[(4-羟基环己基)氨基]乙氧基}-6-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-[3,2-c]吡啶-7-甲酰胺;
153)N-{3-氟-4-[(7-{2-[(3-羟基环己基)氨基]乙氧基}-6-甲氧基喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
154)N-(3-氟-4-{[7-(2-{[(3-羟基环己基)甲基]氨基}乙氧基)-6-甲氧基喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
155)N-{3-氟-4-((6-甲氧基-7-{2-[(四氢-2H-吡喃-4-基)氨基]乙氧基}喹啉-4-基)氧基)苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
156)N-{3-氟-4-[(6-甲氧基-7-{2-[(4-甲氧基环己基)氨基]乙氧基}喹啉-4-基)氧基]苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃{3,2-c]吡啶-7-甲酰胺;
157)N-(3-氟-4-{[7-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
158)N-(3-氟-4-{[7-(3-吗啉丙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
159)N-(3-氟-4-{[7-(3-吗啉丙氧基)喹啉-4-基]氧基}苯基)-2-(4-氟苯基)-3-氧代-3,5,6,7-四氢-2H-环戊[c]吡啶-4-甲酰胺;
160)N-[3-氟-4-({7-[3-(4-甲基哌嗪-1-基)丙氧基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
161)7-{2-[3-氟-4-({7-[3-(哌啶-1-基)丙氧基]喹啉-4-基}氧基)苯基]乙酰基}-5-(4-氟苯基)-3,5-二氢呋喃[3,2-c]吡啶-6(2H)-酮;
162)7-{2-[3-氟-4-({7-[3-(4-甲基哌啶-1-基)丙氧基]喹啉-4-基}氧基)苯基]乙酰基}-5-(4-氟苯基)-3,5-二氢呋喃[3,2-c]吡啶-6(2H)-酮;
163)N-(3-氟-4-{[6-(甲基氨甲酰基)-7-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
164)N-(3-氟-4-{[-(甲基氨甲酰基)-7-(3-吗啉丙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
165)N-(3-氟-4-{[6-甲氧基-7-(甲基氨甲酰基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
166)N-(3-氟-4-{[7-(甲基氨甲酰基)-6-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
167)N-(3-氟-4-{[6-氟-7-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
168)N-(3-氟-4-{[6-氟-7-(3-吗啉丙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
169)N-(3-氟-4-{[7-(2-吗啉乙氧基)-6-(三氟甲基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
170)N-(3-氟-4-{[7-(3-吗啉丙氧基)-6-(三氟甲基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
171)N-(4-{[6-氯-7-(2-吗啉乙氧基)喹啉-4-基]氧基}-3-氟苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
172)N-(4-{[6-氯-7-(3-吗啉丙氧基)喹啉-4-基]氧基}-3-氟苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
173)N-(4-{[6-氰基-7-(2-吗啉乙氧基)喹啉-4-基]氧基}-3-氟苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
174)N-(4-{[6-氰基-7-(3-吗啉丙氧基)喹啉-4-基]氧基}-3-氟苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
175)N-(3-氟-4-{[7-甲氧基-6-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
176)N-(3-氟-4-{[7-甲氧基-6-(3-吗啉丙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
177)N-(3-氟-4-{[6-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
178)N-(3-氟-4-{[6-(3-吗啉丙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
179)N-{4-[(6-氨基-7-甲氧基喹啉-4-基)氧基]-3-氟苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
180)N-(3-氟-4-{[7-甲氧基-6-(3-吗啉丙酰胺基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
181)N-{4-[(7-氨基-6-甲氧基喹啉-4-基)氧基]-3-氟苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
182)N-(3-氟-4-{[6-甲氧基-7-(2-吗啉乙酰氨基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
183)N-(3-氟-4-{[6-甲氧基-7-(3-吗啉丙酰胺基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
184)N-{4-[(7-乙酰胺基-6-甲氧基喹啉-4-基)氧基]-3-氟苯基}-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
185)N-[3-氟-4-({7-甲氧基-6-[(2-吗啉乙基)氨基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
186)N-[3-氟-4-({7-甲氧基-6-[(3-吗啉丙基)氨基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
187)N-[3-氟-4-({6-甲氧基-7-[(2-吗啉乙基)氨基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;
188)N-[3-氟-4-({6-甲氧基-7-[(3-吗啉丙基)氨基]喹啉-4-基}氧基)苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺。
优选地,式2所示的化合物可以是
N-(3-氟-4-{[6-甲氧基-7-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;或
N-[4-({7-[3-(3-氰基氮杂环丁烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺。
在下文中,将描述制备式2化合物的方法。式2化合物可以通过以下反应方案中所示的方法制备,但不限于通过这些方法制备。特别地,本领域普通技术人员将充分理解,本发明的式2化合物可通过使用本领域公知技术的各种方法制备。
以下反应方案示出了逐步制备式2化合物的方法,并且可以通过改变以下制备步骤中使用的试剂和溶剂或通过改变反应顺序来制备几种式2化合物。
根据一个实施方式,式2化合物可以根据以下反应方案1和2的流程制备。
[反应方案1]
在反应方案1中,R1、R2和X如上式2中所定义。
在反应方案1中,羧酸化合物(6a)是使用基于内酯的化合物(2)作为起始原料制备的,所述内酯类化合物(2)可市售易得或通过已知方法制备。
下面将详细描述上述反应方案1的每个步骤。
在步骤1中,使用二甲基二甲氧基乙缩醛对市售易得的化合物(2)进行甲酰化反应,制备式(3)化合物。通常,反应可以在高温下进行,但反应需要很长时间,因此反应使用微波反应器进行。
在步骤2中,使用步骤1中的甲酰化的内酯化合物(3)和市售易得的三乙基氧鎓四氟硼酸盐,制备化合物(4)。该反应在无水条件下进行,优选使用N,N-二氯甲烷或氯仿等对反应无不良影响的溶剂进行反应。所述反应一般在室温下进行。
在步骤3中,将步骤2中制备的化合物(4)与通过常规已知方法制备的乙基-3-氨基-3-氧代丙酸酯化合物在乙醇钠存在下反应,制备环化的化合物(5)。该反应优选使用不会对反应产生不利影响的乙醇溶剂进行。反应温度没有特别限制,但该反应通常可以在低温至加热温度下进行反应,优选在室温下进行反应。
可选择地,为了制备环化的化合物(5),在步骤4中,可以通过将市售易得的基于内酯的化合物(2)用作起始材料,与经常规已知方法制备的乙基-3-氨基-3-氧代丙酸酯化合物在四氯化钛和吡啶的存在下发生反应,制备化合物(6)。该反应优选使用不会对反应产生不利影响的二氯甲烷进行。所述反应的温度没有特别限制,但所述反应一般可以在低温至室温中进行,所述反应优选最初在低温下进行,然后在室温下进行。
此后,在步骤5中,使用二甲基二甲氧基乙缩醛将步骤4中制备的化合物(6)进行甲酰化和环化,以制备化合物(5)。通常,反应可以在加热温度和高温下进行,但反应优选在加热温度下进行。
在步骤6中,将步骤3和5中制备的环化的化合物(5)进行水解以制备羧酸化合物(6a)。一般而言,使用氢氧化钠水溶液或氢氧化锂水溶液等碱性水溶液进行水解反应。该反应在可用于水解反应的氢氧化锂水溶液的存在下,使用对反应没有不利影响的溶剂进行,例如乙醇、甲醇或四氢呋喃。所述反应的温度没有特别限制。所述反应一般可以在室温至加热温度下进行,所述反应优选在加热温度下进行以制备羧酸化合物(6a)。
[反应方案2]
在反应方案2中,R1至R6、X和Y如上式2中所定义,W为离去基团。
将详细描述用于制备本发明所需化合物(10)的以上反应方案2的每一步。
步骤1中,在碳酸钾等碱的存在下,使市售易得或通过已知方法制备的单环或双环化合物(7)与市售易得的硝基苯酚化合物反应,制备苯氧基化合物(8)。该反应通常是苯酚化合物的醚化反应,并且在可用于醚化反应的碱的存在下进行。可用于此目的的碱的实例包括氢化钠(NaH)、碳酸钾、碳酸钠、碳酸铯、醇钠或醇钾等。此外,上述反应优选在对反应没有不利影响的溶剂的存在下进行,所述反应在使用二氯甲烷、氯仿、四氢呋喃、乙醚、甲苯、N,N-二甲基甲酰胺、乙腈或二苯醚等溶剂下进行。所述反应的温度没有特别限制,但所述反应通常可以在室温至加热温度下进行,优选在加热温度下进行。
步骤2中,将以上步骤1中制备的硝基苯酚化合物(8)在铁和氯化铵的存在下还原,以制备胺化合物(9)。该反应通常是硝基化合物至胺的还原反应,并且所述反应可以使用各种还原剂如氢气、铁、锡(±氯化物)、锌等来进行。此外,所述反应优选使用不会对反应产生不利影响的溶剂,例如二氯甲烷、乙酸乙酯、甲醇、乙醇、四氢呋喃或N,N-二甲基甲酰胺,所述反应视情况使用水作为共溶剂来进行。所述反应的温度没有特别限制,但所述反应通常可以在室温至加热温度下进行,优选在加热温度下进行。
步骤3中,通过常见的酰胺化反应制备所需化合物(10),其中以上步骤2中制备的胺化合物(9)与反应方案1中制备的羧酸化合物(6a)使用偶联剂进行反应。通常,所述反应是使用1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC)、1,3-二环己基碳二亚胺(DCC)、1,1-羰基二咪唑(CDI)、1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑[4,5-b]吡啶鎓)3-氧化物六氟磷酸盐(HATU)等市售易得的偶联剂进行。该反应可以在不使用碱的情况下进行,但所述反应在可用于酰胺化反应的常用碱的存在下,例如4-二甲基氨基吡啶、吡啶、三乙胺、二乙基异丙胺、N-甲基吗啉或二甲基苯胺,使用不会对反应产生不利影响的溶剂进行,例如乙腈、二甲基甲酰胺或二氯甲烷。所述反应的温度没有特别限制,但所述反应通常可以在室温至加热温度下进行,所述反应优选在室温下进行以制备所需化合物(10)。
在上述反应方案中制备的所需化合物可以使用常规方法进行分离和纯化,例如柱层析、重结晶等。
如本文所用,除非另有说明,术语“卤素”是指F、Cl、Br或I。
除非另有说明,术语“烷基”是指直链或支链的饱和烃部分。例如,“C1-10烷基”是指具有1至10个碳原子骨架的烷基。具体地,C1-10烷基可以包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、叔戊基、仲戊基、新戊基、己基、庚基、辛基、壬基、癸基等。
术语“卤代烷基”是指被至少一个卤素取代的烷基。具体地,卤代烷基可以为被两个或多个相同或两种及以上卤素取代的烷基。
除非另有说明,术语“烷氧基”是指具有式-O-烷基的基团,其中如上文所定义的烷基通过一个氧原子连接到母体化合物。所述烷氧基的烷基部分可以有1至20个碳原子(即C1-C20烷氧基)、1至12个碳原子(即C1-C12烷氧基),或1至6个碳原子(即C1-C6烷氧基)。合适的烷氧基的实例包括甲氧基(-O-CH3或-OMe)、乙氧基(-OCH2CH3或-OEt)、叔丁氧基(-O-C(CH3)3或-O-tBu)等。
术语“芳基”是指通过从构成母体芳香环体系的碳原子上去除一个氢原子而得到的芳香烃基。例如,芳基可以有6至20个碳原子、6至14个碳原子,或6至10个碳原子。
术语“环烷基”是指环中只含有碳原子的饱和单环或多环。环烷基作为单环可以有3至7个碳原子,作为双环可以有7至12个碳原子,作为多环可以有多达约20个碳原子。
术语“杂芳基”是指在环中具有至少一个杂原子的芳香杂环基。杂芳基的非限制性实例包括吡啶基、吡咯基、噁唑基、吲哚基、异吲哚基、嘌呤基、呋喃基、噻吩基、苯并呋喃基、苯并噻吩基、咔唑基、咪唑基、噻唑基、异恶唑基、吡唑基、异噻唑基、喹啉基、异喹啉基、哒嗪基、嘧啶基、吡嗪基(其环中可以至少有一个取代基)等。
术语“杂环”是指具有至少一个杂原子的芳香或非芳香环,它可以是饱和的或不饱和的,可以是单环的或多环的。例如,“4至10元杂环”是指具有总计4至10个原子(包括杂原子和碳原子)骨架的杂环。具体地,4至10元杂环可以包括氮杂环丁烷、二氮杂环丁烷、吡咯烷、吡咯、咪唑烷、咪唑、吡唑烷、吡唑、恶唑烷、恶唑、异恶唑烷、异恶唑、噻唑烷、噻唑、异噻唑烷、异噻唑、哌啶、吡啶、哌嗪、二嗪、吗啉、硫代吗啉、氮杂环庚烷、二氮杂环庚烷等。
术语“杂环烷基”是指在环中具有至少一个杂原子的非芳香杂环基。杂环烷基可以在环中具有至少一个碳-碳双键或碳-杂原子双键,以至于该环由于双键的存在而不具有芳香性。杂环烷基的非限制性示例包括氮杂环丁烷基、氮丙啶基、吡咯烷基、哌啶基、哌嗪基、高哌嗪基、吗啉、硫代吗啉、四氢呋喃基、四氢硫代呋喃基、四氢吡喃基、吡喃基(其环中可以至少有一个取代基)等。
术语“杂原子”是指碳(C)以外的原子,具体地,可以是氮(N)、氧(O)或硫(S)原子。上述杂芳基和杂环烷基含有至少一个杂原子,并且可以含有例如1、1至2、1至3、或1至4个杂原子。
术语“取代”是指用取代基替换分子结构中的氢原子,使得通过取代得到化学上稳定的化合物而不超过指定原子的化合价。例如,“基团A被取代基B取代”或“基团A具有取代基B”可以指与构成基团A的骨架的原子(如碳)键合的氢原子被取代基B取代,并且基团A和取代基B形成共价键。因此,对于没有可去除的氢原子的基团来说,基本上是难以或不可能具有取代基。所以,在本说明书中,当举例说明各种基团(包括难以具有取代基的基团)与取代基的组合范围时,取代基与明显不可能具有取代基的基团的组合应被解释为排除在该范围之外。
本发明的药物组合物包含由式1或式2所示的化合物的药学上可接受的盐作为活性成分。
所述药学上可接受的盐对人体应具有低毒性,并且不应对其母体化合物的生物活性和理化性质产生不利影响。
例如,所述药学上可接受的盐可以是由药学上可接受的游离酸形成的酸加成盐。
所述游离酸可以是无机酸或有机酸,其中所述无机酸可以为盐酸、硫酸、硝酸、磷酸、高氯酸、溴酸等,以及有机酸可以为乙酸、甲磺酸、乙磺酸、对甲苯磺酸、富马酸、马来酸、丙二酸、邻苯二甲酸、琥珀酸、乳酸、柠檬酸、葡萄糖酸、酒石酸、水杨酸、苹果酸、草酸、苯甲酸、扑酸、天冬氨酸、谷氨酸等。
所述酸加成盐可以通过常规方法制备,例如,通过将式1或式2化合物溶解在过量的酸的水溶液中,并使用水溶性有机溶剂如甲醇、乙醇、丙酮或乙腈来沉淀该盐。
此外,药学上可接受的盐可以是碱金属盐(钠盐等)或碱土金属盐(钾盐等)。
所述碱金属盐或碱土金属盐可以通过例如将式1或式2化合物溶解在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的盐,然后蒸发和干燥滤液而得到。
此外,本发明的化合物可以具有一个手性碳中心,因此可以以R或S异构体、外消旋化合物、单个对映异构体或其混合物、或单个非对映异构体或其混合物的形式存在。所有这些立体异构体及其混合物都可以包括在本发明的范围内。
此外,本发明的化合物可以包括式1或式2化合物的水合物和溶剂化物。所述水合物和溶剂化物可以使用已知的方法制备,并且它们优选是无毒的和水溶性的。特别地,优选的是,所述水合物和溶剂化物可以是分别结合了1至5个分子的水和醇溶剂(特别是乙醇等)。
本发明的药物组合物可以包含作为活性成分的式1或式2所示的化合物或其药学上可接受的盐,基于组合物的总重量,其量为约0.1%重量至约90%重量,特别是约0.5%重量至约75%重量,更特别是约1%重量至约50%重量。
本发明的药物组合物可以包含根据常规方法配置成制剂的常规且无毒的药学上可接受的添加剂。例如,所述药物组合物可以进一步包含药学上可接受的载体、稀释剂或赋形剂。
本发明的组合物中使用的添加剂的实例可以包括甜味剂、粘合剂、溶剂、助溶剂、润湿剂、乳化剂、等渗剂、吸附剂、崩解剂、抗氧化剂、防腐剂、润滑剂、助流剂、填充剂、调味剂等。例如,所述添加剂可以包括乳糖、葡萄糖、蔗糖、甘露醇、山梨糖醇、纤维素、甘氨酸、二氧化硅、滑石粉、硬脂酸、硬脂酸甘油酯、硬脂酸镁、铝硅酸镁、淀粉、明胶、黄蓍胶、海藻酸、海藻酸钠、甲基纤维素、羧甲基纤维素钠、琼脂、水、乙醇、聚乙二醇、聚乙烯吡咯烷酮、氯化钠、氯化钙、橙子精油、草莓精油、香草调料等。
本发明的组合物可配制成各种制剂形式,用于口服给药(例如,片剂、丸剂、粉末、胶囊、糖浆或乳剂)或肠胃外给药(例如,肌肉内、静脉内或皮下注射。
优选地,本发明的所述组合物可以配制成用于口服给药的制剂。在这种情况下,使用的所述添加剂可以包括纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、葡萄糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石粉、表面活性剂、悬浮剂、乳化剂、稀释剂等。具体地,所述助流剂的实例可以包括胶体二氧化硅、硅酸镁等;所述稀释剂的实例可以包括微晶纤维素、乳糖Fast Flo无水乳糖、乳糖一水合物、硅化MCC HD 90等;所述崩解剂的实例可以包括交联羧甲基纤维素钠、交联聚维酮等;所述润滑剂的实例可以包括硬脂酸镁、月桂硫酸酯钠、硬脂酸等。
此外,用于口服给药的液体制剂,可以以混悬剂、乳剂和糖浆等作为实例,其中除了常用的简单稀释剂水和液体石蜡之外,还可以包括各种赋形剂,如润湿剂、甜味剂、芳香剂和防腐剂等。
此外,用于肠胃外给药的制剂包括无菌水溶液、非水溶液、混悬剂、乳剂、冻干制剂和栓剂。可以使用丙二醇、聚乙二醇、植物油如橄榄油、可注射酯如油酸乙酯等作为非水溶液或混悬剂。可以使用Witepsol、聚乙二醇(Macrogol)、Tween 61、可可脂、月桂脂、甘油明胶等作为栓剂的基质。另一个方面,注射剂可包含常规添加剂,例如增溶剂、等渗剂、混悬剂、乳化剂、稳定剂和防腐剂。
术语“预防”是指通过施用药物组合物来抑制胰腺癌的发生或延缓胰腺癌发病的任何行为。术语“治疗”是指通过施用药物组合物来改善或有益地改变胰腺癌症状的任何行为。
本发明的化合物或组合物可以以治疗有效量或药学有效量施用于患者。
在本文中,术语“治疗有效量”或“药学有效量”是指用于预防或治疗目标疾病有效的化合物或组合物的量,并且是指足以以适用于医疗的合理效益/风险比治疗所述疾病且不引起副作用的量。有效量的水平可以根据包括患者的健康状况、疾病的类型和严重程度、药物活性、对药物的敏感性、给药方法、给药时间、给药途径和排泄率、治疗时间、联合或同时使用药物、以及医学领域公知的其他因素来确定。
如本文所用,术语“给药”是指通过任何合适的方法将预定的物质引入患者,并且只要药物可以到达目标组织,缀合物可以通过任何一般途径给药。所述给药途径可包括腹膜内给药、静脉内给药、肌肉内给药、皮下给药、皮内给药、口服给药、局部给药、鼻内给药、肺内给药、直肠内给药等,但不限于此。
本发明的化合物或组合物可以作为单独的治疗剂或与其他治疗剂联合给药,并且可以与常规治疗剂顺序或同时给药,并且可以单次或多次给药。考虑到上述所有因素,重要的是施用可以通过具有最小副作用或无副作用的最小量提供最大效果的量,这可以由本领域的普通技术人员容易地确定。
具体而言,本发明的药物组合物中的化合物的有效量可以根据患者的年龄、性别和体重而变化,通常,可以每天或每隔一天、或者可以分为每天1至3次以每千克体重约0.1mg至约1,000mg,或约5mg至约200mg的量给药。然而,有效量可以根据给药途径、疾病的严重程度、性别、体重、年龄等进行增加或减少,本发明的范围不限于此。
优选地,本发明的化合物或药物组合物可以与化学疗法、放射疗法、免疫疗法、激素疗法、骨髓移植、干细胞替代疗法、其他生物疗法、手术干预或其组合一起施用于肿瘤治疗。例如,本发明的化合物或组合物可以作为辅助疗法与其他长期治疗策略联合使用,或可以用于在危重患者的肿瘤消退或化学预防治疗后维持患者的状态。
本发明的药物组合物可以进一步包含一种或多种活性成分,额外的活性成分可以是,但不限制于抗增殖化合物,如芳香酶抑制剂,抗雌激素,拓扑异构酶I抑制剂,拓扑异构酶II抑制剂,微管活性化合物,烷基化化合物,组蛋白脱乙酰酶抑制剂,诱导细胞分化过程的化合物,环氧合酶抑制剂,MMP抑制剂,mTOR抑制剂,抗肿瘤物,抗代谢物,铂化合物,靶向/降低蛋白质或脂质激酶活性的化合物,抗血管生成化合物,靶向、降低或抑制蛋白质或脂质磷酸酶活性的化合物,促性腺激素激动剂,抗雄激素,甲硫氨酸胺基肽酶抑制剂,双膦酸盐,生物反应调节剂,抗增殖抗体,乙酰肝素酶抑制剂,Ras致瘤同种型的抑制剂,端粒酶抑制剂,蛋白酶体抑制剂,用于治疗血液系统恶性肿瘤的化合物,靶向、降低或抑制Flt-3活性的化合物,Hsp90抑制剂,纺锤体驱动蛋白抑制剂,MEK抑制剂,亚叶酸,EDG结合剂,抗白血病化合物,核糖核苷酸还原酶抑制剂,S-腺苷甲硫氨酸脱羧酶抑制剂,止血类固醇,皮质类固醇,其他化疗化合物或光敏化合物。
所述额外的活性成分可以是已知的抗癌剂。所述抗癌剂的非限制性实例包括DNA烷化剂,如氮芥(mechloethamine)、苯丁酸氮芥(chlorambucil)、苯丙氨酸(phenylalanine)、芥(mustard)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、卡莫司汀(carmustine,BCNU)、洛莫司汀(lomustine,CCNU)、链脲霉素(streptozotocin)、白消安(busulfan)、噻替派(thiotepa)、顺铂(cisplatin)和卡铂(carboplatin);抗癌抗生素,如放线菌素(dactinomycin,actinomycin D)、多柔比星(doxorubicin,adriamycin)、柔红霉素(daunorubicin)、伊达比星(idarubicin)、米托蒽醌(mitoxantrone)、普卡霉素(plicamycin)、丝裂霉素C(mitomycin C)和博来霉素(bleomycin);以及植物生物碱,例如长春新碱(vincristine)、长春花碱(vinblastine)、紫杉醇(paclitaxel)、多西他赛(docetaxel)、依托泊苷(etoposide)、替尼泊苷(teniposide)、拓扑替康(topotecan)和伊立替康(irinotecan)等。
在这种情况下,所述药物可以是由式1或式2所示的化合物或其药学上可接受的盐。
在这种情况下,对EGFR靶向治疗剂的耐药性如上所述。此外,所述EGFR靶向治疗剂可优选西妥昔单抗(cetuximab)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、阿帕替尼(apatinib)、埃克替尼(icotinib)、布加替尼(brigatinib)、拉帕替尼(lapatinib)、卡拉替尼(canertinib)、AEE788、XL647、范得他尼(zactima)或帕尼单抗(panitumumab)。
在本发明的另一方面,提供了所述药物组合物在预防或治疗胰腺癌中的用途。在这种情况下,所述药物组合物如上所述。
在本发明的另一方面,提供了一种预防或治疗胰腺癌的方法,包括:检测源自患有胰腺癌的受试者的生物样品中的RON突变,其中RON突变为外显子5、6和11缺失的RON△155、外显子5和6缺失的RON△160、或外显子11缺失的RON△165;并将根据本发明一方面所述的药物组合物施用于检测到RON突变的受试者。
所述RON、RON突变、药物组合物、给药、预防和治疗如上所述。
所述生物样本是指从受试者获得的样本。所述生物样本可以是组织、血液、血浆、血清、骨髓液、淋巴液、唾液、泪液、粘膜液、羊水或其组合。
所述受试者可以是哺乳动物,例如人、牛、马、猪、狗、绵羊、山羊或猫。所述受试者可以是患有与RON突变相关的疾病的患者,例如胰腺癌,或者具有很高可能性患有胰腺癌的受试者
所述方法还可以进一步包括向受试者施用抗癌剂。所述抗癌剂可以与所述药物组合物同时、分开或顺序给药。
所述给药方法可以是口服或肠胃外给药。所述给药方法可以是,例如,口服、经皮、皮下、直肠、静脉内、动脉内、腹膜内、肌肉内、胸骨内、局部、鼻内、气管内或皮内途径。所述组合物可以全身或局部、单独或与其他药物活性化合物联合施用。
所述药物组合物的优选剂量根据患者的状况和体重、疾病的严重程度、药物形式、给药途径和持续时间而变化,但可以由本领域普通技术人员适当地选择。
所述剂量可以是,例如,以成年人为基础,在约0.001mg/kg至约100mg/kg、约0.01mg/kg至约10mg/kg或约0.1mg/kg至约1mg/kg的范围内。所述给药可以每天一次、一天多次、或每周一次、每两周一次、每三周一次、或每四个星期一次至每年一次。
在本发明的另一方面,提供了一种提供关于抗癌治疗剂的信息的方法,包括:检测源自患有胰腺癌的受试者的生物样品中的RON突变,其中RON突变为外显子5、6和11缺失的RON△155、外显子5和6缺失的RON△160、或外显子11缺失的RON△165;和向检测到RON突变的受试者提供根据本发明一方面所述的药物组合物适用于预防或治疗胰腺癌的信息。
所述生物样本、RON、RON突变、药物组合物、受试者、预防、和治疗如上所述。
实施发明的方式
[实施例]
在下文中,将通过以下实施例对本发明进行更详细的描述。然而,以下实施例仅用于说明本发明,本发明的范围不限于以下实施例。
制备实施例1:5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酸
步骤1:3-[(二甲氨基)亚甲基]-二氢呋喃-2-(3H)-酮的合成
搅拌γ-丁内酯(2.69mL,35.0mmol)和二甲基二甲氧基乙缩醛(11.62mL,87.5mmol),然后在微波反应器中以230℃的温度反应至少70分钟。将反应混合物浓缩以除去过量的二甲基二甲氧基乙缩醛。用乙醚固化,过滤沉淀的固体,同时用乙醚洗涤。过滤出的固体经减压浓缩得到目标化合物(2.9g,收率:59%,褐色固体)。
1H NMR(500MHz,CDCl3)δ7.13(s,1H),4.24(t,J=7.5Hz,2H),3.11(t,J=7.5Hz,2H),3.03(s,6H);1H NMR(500MHz,DMSO-d6)δ7.00(t,J=1.5Hz,1H),4.11(t,J=7.5Hz,2H),3.06(t,J=7.5Hz,2H),3.00(s,3H)
步骤2:3-[(二甲氨基)亚甲基]-2-(3H)-二氢呋喃亚基乙基氧鎓四氟硼酸盐的合成
将步骤1得到的化合物(1.085g,7.68mmol)溶解于8mL氯仿中,加入三乙基氧鎓四氟硼酸盐(1.729g,7.68mmol),并在氮气下将混合物室温搅拌至少1天。减压浓缩反应混合物,用核磁共振仪确认原料和生成的产物比例约为15:85,无需纯化即可进行下一步反应。
1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),4.86-4.82(m,2H),4.51(q,J=7.0Hz,2H),3.33(s,3H),3.30(t,J=8.5Hz,2H),3.26(s,3H),1.36(t,J=7.0Hz,3H)
步骤3:5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酸乙酯的合成
将步骤2得到的粗品混合物(1.96g)溶于10mL乙醇中,然后在0℃的水浴中加入乙醇钠(20wt%乙醇溶液,2.56mL,6.53mmol),然后将混合物缓慢搅拌30分钟至室温。将3-{(4-氟苯基)氨基}-3-氧代丙酸乙酯(1.47g,6.53mmol)加入到反应混合物中,并将混合物在室温下搅拌至少20小时。将反应混合物减压浓缩,并用水和二氯甲烷萃取。分离出的有机层用无水硫酸镁干燥,过滤并减压浓缩。所得残余物通过柱色谱纯化,得到目标化合物(900mg,收率:39%(以步骤2和3的总收率计)/46%(以步骤3的收率计),黄色固体)。
1H NMR(500MHz,DMSO-d6)δ7.70(t,J=1.5Hz,1H),7.42-7.40(m,2H),7.34-7.31(m,2H),4.74(t,J=8.0Hz,2H),4.17(q,J=7.0Hz,2H),3.05(td,J=8.0Hz,2H),1.21(t,J=7.0Hz,3H)
步骤4:5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酸的合成
将步骤3得到的化合物(0.9g,2.97mmol)溶于10mL乙醇和5mL蒸馏水中,将一水氢氧化锂(249mg,5.94mmol)加入其中,并将混合物加热至50℃并搅拌至少4小时。将反应混合物减压浓缩,并用水和二氯甲烷萃取。向分离的水层中加入1N盐酸溶液,然后用水和二氯甲烷萃取。分离出的有机层用无水硫酸镁干燥,过滤并减压浓缩。浓缩残余物用少量二氯甲烷和乙醚沉淀出固体,过滤,滤出的固体干燥,得目标化合物(680mg,收率:84%,灰白色固体)。
1H NMR(500MHz,DMSO-d6)δ14.5(bs,OH),7.97(s,1H),7.54-7.51(m,2H),7.41-7.37(m,2H),4.90(t,J=8.5Hz,2H),3.11(td,J=8.5,1.0Hz,2H)
实施例1:4-乙氧基-N-[3-氟-4-({2-[5-(吗啉甲基)吡啶-2-基]噻吩并[3,2-b]吡啶-7-基}氧基)苯基]-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺盐酸盐
目标化合物,即化合物WM-S1-030,通过韩国专利No.10-2221689实施例31中描述的方法合成。
1H NMR(500MHz,DMSO-d6)δ10.66(s,1H),8.81(s,1H),8.60(d,J=5.0Hz,1H),8.48(s,1H),8.43(d,J=5.0Hz,1H),8.23(d,J=5.0Hz,1H),7.96(d,J=15.0Hz,1H),7.87(d,J=5.0Hz,1H),7.52-7.45(m,4H),7.39-7.36(m,2H),6.83(d,J=5.0Hz,1H),6.53(d,J=10.0Hz,1H),4.44(s,2H),4.26(qt,J=5.0H,2H),3.96-3.94(m,2H),3.77(t,J=10.0Hz,2H),3.32-3.30(m,2H),3.14(qt,J=10.0 2H),1.31(t,J=5.0Hz,3H)
实施例2:4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺盐酸盐
目标化合物通过韩国专利No.10-2221689实施例1中描述的方法合成。
1H NMR(500MHz,DMSO-d6)δ10.70(brs,1H),9.50(brs,2H),8.80(s,1H),8.69(d,J=5.0Hz,1H),8.47(s,1H),8.44(d,J=5.0Hz,1H),8.22(dd,J=10.0and 5.0Hz,1H),7.99(d,J=10.0Hz,1H),7.88(d,J=5.0Hz,1H),7.57-7.40(m,7H),6.97(d,J=5.0Hz,1H),6.53(d,J=5.0Hz,1H),4.29-4.25(m,4H),3.65(t,J=5.0Hz,2H),3.31(s,3H),3.16-3.12(m,2H),1.31(t,J=5.0Hz,3H)
实施例3:4-乙氧基-N-{3-氟-4-[(2-{5-[(-甲基哌嗪-1-基)甲基]吡啶-2-基}噻吩并[3,2-b]吡啶-7-基)氧基]苯基}-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺盐酸盐
目标化合物通过韩国专利No.10-2221689实施例34中描述的方法合成。
1H NMR(500MHz,DMSO-d6)δ10.68(s,1H),8.82(brs,1H),8.61(d,J=5.0Hz,1H),8.47(s,1H),8.41(d,J=5.0Hz,1H),8.23(s,1H),7.97(d,J=15.0Hz,1H),7.87(d,J=5.0Hz,1H),7.56-7.46(m,5H),7.42-7.40(m,2H),6.86(d,J=5.0Hz,1H),6.52(d,J=5.0Hz,1H),4.26(qt,J=5.0H,2H),3.93(brs,8H),3.58(brs,2H),2.81(s,3H),1.31(t,J=5.0Hz,3H)
实施例4:N-(3-氟-4-{[6-甲氧基-7-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺
步骤1:4-{2-[(4-氯-6-甲氧基喹啉-7-基)氧基]乙基}吗啉的合成
将4-氯-6-甲氧基喹啉-7-醇(500mg,2.39mmol)溶于二甲基甲酰胺中,然后依次加入碳酸铯(2.33g,7.16mmol)、碘化钠(536mg,3.58mmol)和4-((2-氯乙基)吗啉)盐酸盐(666mg,3.58mmol),并在60℃的温度下搅拌过夜。然后,用乙酸乙酯和水萃取混合物,用无水硫酸钠干燥,过滤并减压浓缩。所得残余物通过柱色谱纯化,得到目标化合物(310mg,收率:40%,乳白色固体)。
1H NMR(500MHz,CDCl3)δ8.57(d,J=5.2Hz,1H),7.40(d,J=6.0Hz,2H),7.35(d,J=5.2Hz,1H),4.33(t,J=6.4Hz,2H),4.02(s,3H),3.74(t,J=4.8Hz,4H),2.95(t,J=6.0Hz,2H),3.74(t,J=5.2Hz,4H)δ8.58(d,J=5.0Hz,1H),7.42(s,1H),7.40(s,1H),7.36(d,J=5.0Hz,1H),4.28(t,J=5.0Hz,2H),4.03(s,3H),3.85(m,4H),2.65(m,4H),2.32(m,2H),2.15(m,2H)
步骤2:4-(2-{[4-(2-氟-4-硝基苯氧基)-6-甲氧基喹啉-7-基]氧基}乙基)吗啉的合成
将步骤1中制备的化合物(310mg,0.96mmol)溶解在二苯醚中,然后,依次加入无水碳酸钾(199mg,1.44mmol)和2-氟-4-硝基酚(302mg,1.92mmol),并在220℃的温度下搅拌过夜。之后,将混合物冷却至室温,用乙酸乙酯和水萃取,然后用无水硫酸钠干燥,过滤并减压浓缩。所得残余物通过柱色谱纯化,得到目标化合物(362mg,收率:85%,黄色固体)。
1H NMR(500MHz,DMSO-d6)δ8.57(d,J=5.5Hz,1H),8.47-8.45(dd,J=3.0Hz,J=10.5Hz,1H),8.21(m,1H),7.63(t,J=8.5Hz,1H),7.48(s,1H),7.45(s,1H),6.78(d,J=5.0Hz,1H),4.30(t,J=5.5Hz,2H),3.92(s,3H),3.60(t,J=4.5Hz,4H),2.80(t,J=5.5Hz,2H),2.52-2.49(m,4H,与DMSO部分重叠)
步骤3:3-氟-4-{[6-甲氧基-7-(2-吗啉乙氧基)喹啉-4-基]氧基}苯胺的合成
将步骤2中制备的化合物(360mg,0.81mmol)溶于乙醇和水中。然后,在室温下依次加入铁(136mg,2.43mmol)和氯化铵(433mg,8.10mmol),将混合物加热至80℃的温度,搅拌4小时。反应完成后,使用硅藻土垫过滤并在减压下浓缩。所得残余物用二氯甲烷和水萃取。分离的有机层用无水硫酸钠干燥,减压浓缩,然后用己烷过滤以得到目标化合物(280mg,产率:83%,黄色固体)。
1H NMR(500MHz,DMSO-d6)δ8.45(d,J=5.0Hz,1H),7.50(s,1H),7.41(s,1H),7.07(t,J=10.0Hz,1H),6.54(d,J=10.0Hz,1H),6.47(d,J=10.0Hz,1H),6.38(d,J=5.0Hz,1H),5.50(brs,2H),4.27(t,J=10.0Hz,2H),3.94(s,3H),3.60(t,J=5.0Hz,4H),2.79(brs,2H)2.52(brs,4H,与DMSO部分重叠)
步骤4:N-(3-氟-4-{[6-甲氧基-7-(2-吗啉乙氧基)喹啉-4-基]氧基}苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺的合成
将制备例1中制备的化合物(149mg,0.54mmol)溶解在二甲基甲酰胺中,然后,依次加入1-[双(二甲基氨基)亚甲基)-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU,205mg,0.54mmol)、二异丙基乙胺(293μL,1.80mmol)和步骤3中制备的化合物(150mg,0.36mmol),并在室温下搅拌过夜。然后,用乙酸乙酯和饱和碳酸氢钠水溶液萃取混合物,用无水硫酸钠干燥,过滤并减压浓缩。所得残余物通过柱色谱纯化,得到目标化合物(170mg,收率:70%,白色固体)。
1H NMR(500MHz,DMSO-d6)δ11.89(s,1H),8.48(d,J=5.0Hz,1H),8.00(d,J=10.0Hz,1H),7.88(s,1H),7.54-7.49(m,3H),7.45-7.37(m,5H),6.48(d,J=5.0Hz,1H),4.85(t,J=10.0Hz,2H),4.32(brs,2H),3.95(s,3H),3.63(brs,4H),3.11(t,J=10.0Hz,2H),2.52(m,2H,与DMSO部分重叠),2.50(m,4H,与DMSO重叠)
实施例5:N-[4-({7-[3-(3-氰基氮杂环丁烷-1-基)丙氧基]-6-甲氧基喹啉-4-基}氧基)-3-氟苯基]-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺
除了使用氮杂环丁烷-3-甲腈为起始原料外,以与上述实施例4的合成路线相同的方式得到目标化合物(收率:57%,灰白色固体)。
1H NMR(400MHz,CDCl3)δ12.04(S,1H),8.48(d,J=5.2Hz,1H),8.03(dd,J=12.4,2.4Hz,1H),7.57(s,1H),7.40-7.37(m,5H),7.26-7.22(m,2H),7.17(t,J=8.8Hz,1H),6.44(d,J=5.6Hz,1H),5.01(t,J=8.4Hz,2H),4.26(t,J=6.4Hz,2H),4.03(s,3H),3.64(t,J=11.6Hz,4H),3.20(t,J=8.0Hz,2H),2.81(t,J=6.8Hz,2H),2.05(q,J=6.8Hz,3H)
阳性对照1
作为阳性对照1的化合物,使用N-{4-[(2-氨基-3-氯-4-吡啶基)氧基]-3-氟苯基}-4-乙氧基-1-(4-氟苯基)-2-氧代-1,2-二氢-3-吡啶甲酰胺,其为公开于美国专利8,536,200B2中的化合物1。其为BMS-777607,是一种众所周知的RON抑制剂。
实验实施例1.胰腺癌细胞系中细胞生长抑制能力的确认
为了比较和确认实施例1(WM-S1-030)至5和阳性对照1(BMS-777607)在RON△155突变型的两个胰腺癌细胞系(Panc-1和Capan-1)和RON△160突变型的一个胰腺癌细胞系(Mia-PaCa2)中的细胞生长抑制能力,进行MTS试验。
对于MTS试验,每孔每个胰腺癌细胞系的1,000个细胞接种于96孔板中,24小时后,在每孔100μL的10%FBS-RPMI培养基(Welgene)中,以不同浓度(0.000001μM到10μM)的实施例1至5的化合物和阳性对照1处理。此后,培养细胞72h。加入20μL的MTS溶液(Promega)培养2h,然后在490nm处测定吸光度。通过使用GraphPad PrismTM5得到实施例1至5化合物和阳性对照1的IC50来分析细胞毒性。经证实,RON△155突变型的两个胰腺癌细胞系和RON△160突变型的一个胰腺癌细胞系对实施例1至5表现出高反应并且细胞生长受到抑制。另一方面,在阳性对照1中,经证实对该药物的反应低(表1)。
[表1]
实验实施例2.胰腺癌细胞系中细胞杀伤效力的确认
分配RON△155突变型的两个胰腺癌细胞系(Panc-1和Capan-1)和RON△160突变型的一个胰腺癌细胞系(Mia-PaCa2),并且在24小时后,分别用实施例1(WM-S1-030)至5和阳性对照1(BMS-777607)的化合物处理,同时更换培养基。48小时后,收获细胞和细胞液(1,500rpm,4分钟),并通过台盼蓝(trypan blue,15250-061,Gibco)排除试验定量活细胞和死细胞。使用Excel中的T检验进行统计分析。
结果证实,在用实施例1至5的化合物处理的RON突变型的胰腺癌细胞系中,细胞死亡被诱导。另一方面,证实用阳性对照1处理时,对该药物的反应低(图1A至1C)。
实验实施例3.实施例1在胰腺癌细胞系(Mia-PaCa2:mRON△160)移植动物模型中对肿瘤生长抑制效力的确认
通过将上述实施例1(WM-S1-030)以30mpk的剂量施用于移植了RON△160突变型的胰腺癌细胞系Mia-PaCa2的小鼠模型来确认是否抑制肿瘤生长。
具体地,购买5周龄雌性BALB/c裸鼠并使其适应1周。此后,将RON△160突变型的胰腺癌细胞系Mia-PaCa2(2Х106个细胞/小鼠)稀释在PBS(磷酸盐缓冲盐水)和Matrigel基质胶中,并将100μL皮下注射到小鼠的右侧背部。当肿瘤的大小达到约100mm3时,将阴性对照(赋形剂)和实施例1口服给药。在这种情况下,阳性对照1(BMS-777607)以30mpk的剂量给药。该药物每天给药一次,持续4周,每周测量两次肿瘤大小和体重。给药完成后,对小鼠实施安乐死,摘除肿瘤,并称重。
结果证实,将上述实施例1以30mpk的剂量施用于小鼠中,肿瘤生长受到明显抑制。另一方面,在阳性对照1的情况下,证实肿瘤生长受到相对较小的抑制(表2和图2)。
[表2]
实验实施例4.实施例1在移植胰腺癌细胞系Mia-PaCa2细胞系(胰腺癌细胞系)动物模型中蛋白表达变化的分析
将实施例1(WM-S1-030)以各浓度(10mpk、30mpk)给药,阳性对照1(BMS-777607)以30mpk的剂量给药至移植了RON△160突变型胰腺癌细胞系的Mia-PaCa2细胞系的小鼠模型。摘取肿瘤,通过免疫化学染色分析蛋白表达变化。
具体地,使用从处死的小鼠中分离的组织制备石蜡载玻片。将组织切片脱蜡并再水化,浸入目标回收缓冲液1×(ScyTek实验室,Cat#CBB999)中并加热15分钟以进行抗原回收过程。反应后,组织切片用Tris缓冲盐水-0.05%吐温20(TBS-T)(T&I,BTT-9310)洗涤5分钟,然后用非特异性抗体反应阻断试剂(载体,SP-5035)进行反应1小时。
组织切片在4℃下用mRON(Abcam,ab52927,1:50)、pTyr-mRON(Mybioscience,MBS462024,1:100)、裂解的半胱天冬酶3(Asp175)(R&DSystems,MAB835,1:50)或细胞周期蛋白D1(cyclin D1(SP4),#Z2027RS,1:100)培养过夜,然后用TBS-T洗涤5分钟,然后使用过氧化物酶阻断试剂(Cellmarque,925B-05)阻断内源性过氧化物酶活性。此后,用TBS-T洗涤组织切片5分钟,然后在室温下用兔二抗(载体,PK-6101)孵育1小时。组织切片用TBS-T洗涤5分钟,然后用二氨基联苯胺(cat#SK-4100)着色。为了对组织的细胞核进行染色,将它们用苏木精(ScyTek实验室,HMM999)染色1分钟,脱水,然后封装。
结果证实,在施用实施例1(WM-S1-030)的组中,pTyr-mRON的表达降低,并且裂解的半胱天冬酶3的表达被诱导。此外,证实了细胞周期蛋白D1(PD标志物)的表达降低(图3)。
实验实施例5.胰腺癌细胞系中RON突变序列的分析
收集8个胰腺癌细胞系,使用Trizol(Invitrogen)进行RNA抽提(制备)。从获得的RNA中,使用RT PreMix试剂盒(Bioneer)合成cDNA。使用合成的cDNA,通过PCR确认了外显子5和6的缺失以及外显子11的缺失。所用引物分别示于SEQ ID NOs:5、6、7和8:(外显子5和6缺失F:5'-GAGCTGGTCAGGTCACTAAAC-3';外显子5和6缺失R:5'-CAGACACTCAGTCCCATTGAC-3';外显子11缺失F:5'-ATCTGTGGCCAGCATCTAAC-3';外显子11缺失R:5'-AAAGGCAGCAGGATACCAAG-3')。/>
经凝胶电泳确认PCR完成产物,使用QIAquick凝胶提取试剂盒(QIAGEN)提取条带,然后委托Macrogen进行Sanger测序,并分析序列以确认RON是否突变。
作为总共8个胰腺癌细胞系的分析结果,1个具有mRON△160的细胞系,其5和6外显子缺失(Mia-PaCa2)和1个具有mRON△155细胞系,其5、6和11外显子均缺失(Panc-1)。此外,鉴定出mRON△155和仅外显子6缺失型作为异型存在(Capan-1,Capan-2,和Panc03.27)的三个样本,以及,mRON△165和仅外显子6缺失型作为异型存在的三个样本(ASPC-1,Panc08.13,和BXPC3)(图4)。
SEQUENCE LISTING
<110> 伟迈可生物有限公司
<120> 用于预防或治疗与RON突变相关的胰腺癌的药物组合物及其使用方法
<130> P22118301WP
<140> CN 2021800598776
<141> 2021-05-18
<150> KR 10-2020-0059150
<151> 2020-05-18
<160> 8
<170> PatentIn version 3.5
<210> 1
<211> 188
<212> PRT
<213> 人类(Homo sapiens)
<400> 1
Met Thr Glu Tyr Lys Leu Val Val Val Gly Ala Gly Gly Val Gly Lys
1 5 10 15
Ser Ala Leu Thr Ile Gln Leu Ile Gln Asn His Phe Val Asp Glu Tyr
20 25 30
Asp Pro Thr Ile Glu Asp Ser Tyr Arg Lys Gln Val Val Ile Asp Gly
35 40 45
Glu Thr Cys Leu Trp Asp Ile Leu Asp Thr Ala Gly Gln Glu Glu Tyr
50 55 60
Ser Ala Met Arg Asp Gln Tyr Met Arg Thr Gly Glu Gly Phe Leu Cys
65 70 75 80
Val Phe Ala Ile Asn Asn Thr Lys Ser Phe Glu Asp Ile His His Tyr
85 90 95
Arg Glu Gln Ile Lys Arg Val Lys Asp Ser Glu Asp Val Pro Met Val
100 105 110
Leu Val Gly Asn Lys Cys Asp Leu Pro Ser Arg Thr Val Asp Thr Lys
115 120 125
Gln Ala Gln Asp Leu Ala Arg Ser Tyr Gly Ile Pro Phe Ile Glu Thr
130 135 140
Ser Ala Lys Thr Arg Gln Gly Val Asp Asp Ala Phe Tyr Thr Leu Val
145 150 155 160
Arg Glu Ile Arg Lys His Lys Glu Lys Met Ser Lys Asp Gly Lys Lys
165 170 175
Lys Lys Lys Lys Ser Lys Thr Lys Cys Val Ile Met
180 185
<210> 2
<211> 3732
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> RON 155 cDNA
<400> 2
atggagctcc tcccgccgct gcctcagtcc ttcctgttgc tgctgctgtt gcctgccaag 60
cccgcggcgg gcgaggactg gcagtgcccg cgcaccccct acgcggcctc tcgcgacttt 120
gacgtgaagt acgtggtgcc cagcttctcc gccggaggcc tggtacaggc catggtgacc 180
tacgagggcg acagaaatga gagtgctgtg tttgtagcca tacgcaatcg cctgcatgtg 240
cttgggcctg acctgaagtc tgtccagagc ctggccacgg gccctgctgg agaccctggc 300
tgccagacgt gtgcagcctg tggcccagga ccccacggcc ctcccggtga cacagacaca 360
aaggtgctgg tgctggatcc cgcgctgcct gcgctggtca gttgtggctc cagcctgcag 420
ggccgctgct tcctgcatga cctagagccc caagggacag ccgtgcatct ggcagcgcca 480
gcctgcctct tctcagccca ccataaccgg cccgatgact gccccgactg tgtggccagc 540
ccattgggca cccgtgtaac tgtggttgag caaggccagg cctcctattt ctacgtggca 600
tcctcactgg acgcagccgt ggctgccagc ttcagcccac gctcagtgtc tatcaggcgt 660
ctcaaggctg acgcctcggg attcgcaccg ggctttgtgg cgttgtcagt gctgcccaag 720
catcttgtct cctacagtat tgaatacgtg cacagcttcc acacgggagc cttcgtgtac 780
ttcctgactg tacagccggc cagcgtgaca gatgatccta gtgccctgca cacacgcctg 840
gcacggctta gcgccactga gccagagttg ggtgactatc gggagctggt cctcgactgc 900
agatttgctc caaaacgcag gcgccggggg gccccagaag gcggacagcc ctaccctgtg 960
ctgcgggtgg cccactccgc tccagtgggt gcccaacttg ccactgagct gagcatcgcc 1020
gagggccagg aagtactatt tggggtcttt gtgactggca aggatggtgg tcctggcgtg 1080
ggccccaact ctgtcgtctg tgccttcccc attgacctgc tggacacact aattgatgag 1140
ggtgtggagc gctgttgtga atccccagtc catccaggcc tccggcgagg cctcgacttc 1200
ttccagtcgc ccagtttttg ccccaacccg cctggcctgg aagccctcag ccccaacacc 1260
agctgccgcc acttccctct gctggtcagt agcagcttct cacgtgtgga cctattcaat 1320
gggctgttgg gaccagtaca ggtcactgca ttgtatgtga cacgccttga caacgtcaca 1380
gtggcacaca tgggcacaat ggatgggcgt atcctgcagg tggagctggt caggtcacta 1440
aactacttgc tgtatgtgtc caacttctca ctgggtgaca gtgggcagcc cgtgcagcgg 1500
gatgtcagtc gtcttgggga ccacctactc tttgcctctg gggaccaggt tttccaggta 1560
cctatccaag gccctggctg ccgccacttc ctgacctgtg ggcgttgcct aagggcatgg 1620
catttcatgg gctgtggctg gtgtgggaac atgtgcggcc agcagaagga gtgtcctggc 1680
tcctggcaac aggaccactg cccacctaag cttactgagg agccagtgct gatagcagtg 1740
caacccctct ttggcccacg ggcaggaggc acctgtctca ctcttgaagg ccagagtctg 1800
tctgtaggca ccagccgggc tgtgctggtc aatgggactg agtgtctgct agcacgggtc 1860
agtgaggggc agcttttatg tgccacaccc cctggggcca cggtggccag tgtccccctt 1920
agcctgcagg tggggggtgc ccaggtacct ggttcctgga ccttccagta cagagaagac 1980
cctgtcgtgc taagcatcag ccccaactgt ggctacatca actcccacat caccatctgt 2040
ggccagcatc taacttcagc atggcactta gtgctgtcat tccatgacgg gcttagggca 2100
gtggaaagca ggcagtgtga gaggcagctt ccagagcagc agctgtgccg ccttcctgaa 2160
tatgtggtcc gagaccccca gggatgggtg gcagggaatc tgagtgcccg aggggatgga 2220
gctgctggct ttacactgcc tggctttcgc ttcctacccc caccccatcc acccagtgcc 2280
aacctagttc cactgaagcc tgaggagcat gccattaagt ttgaggtctg cgtagatggt 2340
gaatgtcata tcctgggtag agtggtgcgg ccagggccag atggggtccc acagagcacg 2400
ctccttggta tcctgctgcc tttgctgctg cttgtggctg cactggcgac tgcactggtc 2460
ttcagctact ggtggcggag gaagcagcta gttcttcctc ccaacctgaa tgacctggca 2520
tccctggacc agactgctgg agccacaccc ctgcctattc tgtactcggg ctctgactac 2580
agaagtggcc ttgcactccc tgccattgat ggtctggatt ccaccacttg tgtccatgga 2640
gcatccttct ccgatagtga agatgaatcc tgtgtgccac tgctgcggaa agagtccatc 2700
cagctaaggg acctggactc tgcgctcttg gctgaggtca aggatgtgct gattccccat 2760
gagcgggtgg tcacccacag tgaccgagtc attggcaaag gccactttgg agttgtctac 2820
cacggagaat acatagacca ggcccagaat cgaatccaat gtgccatcaa gtcactaagt 2880
cgcatcacag agatgcagca ggtggaggcc ttcctgcgag aggggctgct catgcgtggc 2940
ctgaaccacc cgaatgtgct ggctctcatt ggtatcatgt tgccacctga gggcctgccc 3000
catgtgctgc tgccctatat gtgccacggt gacctgctcc agttcatccg ctcacctcag 3060
cggaacccca ccgtgaagga cctcatcagc tttggcctgc aggtagcccg cggcatggag 3120
tacctggcag agcagaagtt tgtgcacagg gacctggctg cgcggaactg catgctggac 3180
gagtcattca cagtcaaggt ggctgacttt ggtttggccc gcgacatcct ggacagggag 3240
tactatagtg ttcaacagca tcgccacgct cgcctacctg tgaagtggat ggcgctggag 3300
agcctgcaga cctatagatt taccaccaag tctgatgtgt ggtcatttgg tgtgctgctg 3360
tgggaactgc tgacacgggg tgccccacca taccgccaca ttgacccttt tgaccttacc 3420
cacttcctgg cccagggtcg gcgcctgccc cagcctgagt attgccctga ttctctgtac 3480
caagtgatgc agcaatgctg ggaggcagac ccagcagtgc gacccacctt cagagtacta 3540
gtgggggagg tggagcagat agtgtctgca ctgcttgggg accattatgt gcagctgcca 3600
gcaacctaca tgaacttggg ccccagcacc tcgcatgaga tgaatgtgcg tccagaacag 3660
ccgcagttct cacccatgcc agggaatgta cgccggcccc ggccactctc agagcctcct 3720
cggcccactt ga 3732
<210> 3
<211> 3879
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> RON 160 cDNA
<400> 3
atggagctcc tcccgccgct gcctcagtcc ttcctgttgc tgctgctgtt gcctgccaag 60
cccgcggcgg gcgaggactg gcagtgcccg cgcaccccct acgcggcctc tcgcgacttt 120
gacgtgaagt acgtggtgcc cagcttctcc gccggaggcc tggtacaggc catggtgacc 180
tacgagggcg acagaaatga gagtgctgtg tttgtagcca tacgcaatcg cctgcatgtg 240
cttgggcctg acctgaagtc tgtccagagc ctggccacgg gccctgctgg agaccctggc 300
tgccagacgt gtgcagcctg tggcccagga ccccacggcc ctcccggtga cacagacaca 360
aaggtgctgg tgctggatcc cgcgctgcct gcgctggtca gttgtggctc cagcctgcag 420
ggccgctgct tcctgcatga cctagagccc caagggacag ccgtgcatct ggcagcgcca 480
gcctgcctct tctcagccca ccataaccgg cccgatgact gccccgactg tgtggccagc 540
ccattgggca cccgtgtaac tgtggttgag caaggccagg cctcctattt ctacgtggca 600
tcctcactgg acgcagccgt ggctgccagc ttcagcccac gctcagtgtc tatcaggcgt 660
ctcaaggctg acgcctcggg attcgcaccg ggctttgtgg cgttgtcagt gctgcccaag 720
catcttgtct cctacagtat tgaatacgtg cacagcttcc acacgggagc cttcgtgtac 780
ttcctgactg tacagccggc cagcgtgaca gatgatccta gtgccctgca cacacgcctg 840
gcacggctta gcgccactga gccagagttg ggtgactatc gggagctggt cctcgactgc 900
agatttgctc caaaacgcag gcgccggggg gccccagaag gcggacagcc ctaccctgtg 960
ctgcgggtgg cccactccgc tccagtgggt gcccaacttg ccactgagct gagcatcgcc 1020
gagggccagg aagtactatt tggggtcttt gtgactggca aggatggtgg tcctggcgtg 1080
ggccccaact ctgtcgtctg tgccttcccc attgacctgc tggacacact aattgatgag 1140
ggtgtggagc gctgttgtga atccccagtc catccaggcc tccggcgagg cctcgacttc 1200
ttccagtcgc ccagtttttg ccccaacccg cctggcctgg aagccctcag ccccaacacc 1260
agctgccgcc acttccctct gctggtcagt agcagcttct cacgtgtgga cctattcaat 1320
gggctgttgg gaccagtaca ggtcactgca ttgtatgtga cacgccttga caacgtcaca 1380
gtggcacaca tgggcacaat ggatgggcgt atcctgcagg tggagctggt caggtcacta 1440
aactacttgc tgtatgtgtc caacttctca ctgggtgaca gtgggcagcc cgtgcagcgg 1500
gatgtcagtc gtcttgggga ccacctactc tttgcctctg gggaccaggt tttccaggta 1560
cctatccaag gccctggctg ccgccacttc ctgacctgtg ggcgttgcct aagggcatgg 1620
catttcatgg gctgtggctg gtgtgggaac atgtgcggcc agcagaagga gtgtcctggc 1680
tcctggcaac aggaccactg cccacctaag cttactgagg agccagtgct gatagcagtg 1740
caacccctct ttggcccacg ggcaggaggc acctgtctca ctcttgaagg ccagagtctg 1800
tctgtaggca ccagccgggc tgtgctggtc aatgggactg agtgtctgct agcacgggtc 1860
agtgaggggc agcttttatg tgccacaccc cctggggcca cggtggccag tgtccccctt 1920
agcctgcagg tggggggtgc ccaggtacct ggttcctgga ccttccagta cagagaagac 1980
cctgtcgtgc taagcatcag ccccaactgt ggctacatca actcccacat caccatctgt 2040
ggccagcatc taacttcagc atggcactta gtgctgtcat tccatgacgg gcttagggca 2100
gtggaaagca ggcagtgtga gaggcagctt ccagagcagc agctgtgccg ccttcctgaa 2160
tatgtggtcc gagaccccca gggatgggtg gcagggaatc tgagtgcccg aggggatgga 2220
gctgctggct ttacactgcc tggctttcgc ttcctacccc caccccatcc acccagtgcc 2280
aacctagttc cactgaagcc tgaggagcat gccattaagt ttgagtatat tgggctgggc 2340
gctgtggctg actgtgtggg tatcaacgtg accgtgggtg gtgagagctg ccagcacgag 2400
ttccgggggg acatggttgt ctgccccctg cccccatccc tgcagcttgg ccaggatggt 2460
gccccattgc aggtctgcgt agatggtgaa tgtcatatcc tgggtagagt ggtgcggcca 2520
gggccagatg gggtcccaca gagcacgctc cttggtatcc tgctgccttt gctgctgctt 2580
gtggctgcac tggcgactgc actggtcttc agctactggt ggcggaggaa gcagctagtt 2640
cttcctccca acctgaatga cctggcatcc ctggaccaga ctgctggagc cacacccctg 2700
cctattctgt actcgggctc tgactacaga agtggccttg cactccctgc cattgatggt 2760
ctggattcca ccacttgtgt ccatggagca tccttctccg atagtgaaga tgaatcctgt 2820
gtgccactgc tgcggaaaga gtccatccag ctaagggacc tggactctgc gctcttggct 2880
gaggtcaagg atgtgctgat tccccatgag cgggtggtca cccacagtga ccgagtcatt 2940
ggcaaaggcc actttggagt tgtctaccac ggagaataca tagaccaggc ccagaatcga 3000
atccaatgtg ccatcaagtc actaagtcgc atcacagaga tgcagcaggt ggaggccttc 3060
ctgcgagagg ggctgctcat gcgtggcctg aaccacccga atgtgctggc tctcattggt 3120
atcatgttgc cacctgaggg cctgccccat gtgctgctgc cctatatgtg ccacggtgac 3180
ctgctccagt tcatccgctc acctcagcgg aaccccaccg tgaaggacct catcagcttt 3240
ggcctgcagg tagcccgcgg catggagtac ctggcagagc agaagtttgt gcacagggac 3300
ctggctgcgc ggaactgcat gctggacgag tcattcacag tcaaggtggc tgactttggt 3360
ttggcccgcg acatcctgga cagggagtac tatagtgttc aacagcatcg ccacgctcgc 3420
ctacctgtga agtggatggc gctggagagc ctgcagacct atagatttac caccaagtct 3480
gatgtgtggt catttggtgt gctgctgtgg gaactgctga cacggggtgc cccaccatac 3540
cgccacattg acccttttga ccttacccac ttcctggccc agggtcggcg cctgccccag 3600
cctgagtatt gccctgattc tctgtaccaa gtgatgcagc aatgctggga ggcagaccca 3660
gcagtgcgac ccaccttcag agtactagtg ggggaggtgg agcagatagt gtctgcactg 3720
cttggggacc attatgtgca gctgccagca acctacatga acttgggccc cagcacctcg 3780
catgagatga atgtgcgtcc agaacagccg cagttctcac ccatgccagg gaatgtacgc 3840
cggccccggc cactctcaga gcctcctcgg cccacttga 3879
<210> 4
<211> 4056
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> RON 165 cDNA
<400> 4
atggagctcc tcccgccgct gcctcagtcc ttcctgttgc tgctgctgtt gcctgccaag 60
cccgcggcgg gcgaggactg gcagtgcccg cgcaccccct acgcggcctc tcgcgacttt 120
gacgtgaagt acgtggtgcc cagcttctcc gccggaggcc tggtacaggc catggtgacc 180
tacgagggcg acagaaatga gagtgctgtg tttgtagcca tacgcaatcg cctgcatgtg 240
cttgggcctg acctgaagtc tgtccagagc ctggccacgg gccctgctgg agaccctggc 300
tgccagacgt gtgcagcctg tggcccagga ccccacggcc ctcccggtga cacagacaca 360
aaggtgctgg tgctggatcc cgcgctgcct gcgctggtca gttgtggctc cagcctgcag 420
ggccgctgct tcctgcatga cctagagccc caagggacag ccgtgcatct ggcagcgcca 480
gcctgcctct tctcagccca ccataaccgg cccgatgact gccccgactg tgtggccagc 540
ccattgggca cccgtgtaac tgtggttgag caaggccagg cctcctattt ctacgtggca 600
tcctcactgg acgcagccgt ggctgccagc ttcagcccac gctcagtgtc tatcaggcgt 660
ctcaaggctg acgcctcggg attcgcaccg ggctttgtgg cgttgtcagt gctgcccaag 720
catcttgtct cctacagtat tgaatacgtg cacagcttcc acacgggagc cttcgtatac 780
ttcctgactg tacagccggc cagcgtgaca gatgatccta gtgccctgca cacacgcctg 840
gcacggctta gcgccactga gccagagttg ggtgactatc gggagctggt cctcgactgc 900
agatttgctc caaaacgcag gcgccggggg gccccagaag gcggacagcc ctaccctgtg 960
ctgcgggtgg cccactccgc tccagtgggt gcccaacttg ccactgagct gagcatcgcc 1020
gagggccagg aagtactatt tggggtcttt gtgactggca aggatggtgg tcctggcgtg 1080
ggccccaact ctgtcgtctg tgccttcccc attgacctgc tggacacact aattgatgag 1140
ggtgtggagc gctgttgtga atccccagtc catccaggcc tccggcgagg cctcgacttc 1200
ttccagtcgc ccagtttttg ccccaacccg cctggcctgg aagccctcag ccccaacacc 1260
agctgccgcc acttccctct gctggtcagt agcagcttct cacgtgtgga cctattcaat 1320
gggctgttgg gaccagtaca ggtcactgca ttgtatgtga cacgccttga caacgtcaca 1380
gtggcacaca tgggcacaat ggatgggcgt atcctgcagg tggagctggt caggtcacta 1440
aactacttgc tgtatgtgtc caacttctca ctgggtgaca gtgggcagcc cgtgcagcgg 1500
gatgtcagtc gtcttgggga ccacctactc tttgcctctg gggaccaggt tttccaggta 1560
cctatccaag gccctggctg ccgccacttc ctgacctgtg ggcgttgcct aagggcatgg 1620
catttcatgg gctgtggctg gtgtgggaac atgtgcggcc agcagaagga gtgtcctggc 1680
tcctggcaac aggaccactg cccacctaag cttactgagt tccaccccca cagtggacct 1740
ctaaggggca gtacaaggct gaccctgtgt ggctccaact tctaccttca cccttctggt 1800
ctggtgcctg agggaaccca tcaggtcact gtgggccaaa gtccctgccg gccactgccc 1860
aaggacagct caaaactcag accagtgccc cggaaagact ttgtagagga gtttgagtgt 1920
gaactggagc ccttgggcac ccaggcagtg gggcctacca acgtcagcct caccgtgact 1980
aacatgccac cgggcaagca cttccgggta gacggcacct ccgtgctgag aggcttctct 2040
ttcatggagc cagtgctgat agcagtgcaa cccctctttg gcccacgggc aggaggcacc 2100
tgtctcactc ttgaaggcca gagtctgtct gtaggcacca gccgggctgt gctggtcaat 2160
gggactgagt gtctgctagc acgggtcagt gaggggcagc ttttatgtgc cacaccccct 2220
ggggccacgg tggccagtgt cccccttagc ctgcaggtgg ggggtgccca ggtacctggt 2280
tcctggacct tccagtacag agaagaccct gtcgtgctaa gcatcagccc caactgtggc 2340
tacatcaact cccacatcac catctgtggc cagcatctaa cttcagcatg gcacttagtg 2400
ctgtcattcc atgacgggct tagggcagtg gaaagcaggt gtgagaggca gcttccagag 2460
cagcagctgt gccgccttcc tgaatatgtg gtccgagacc cccagggatg ggtggcaggg 2520
aatctgagtg cccgagggga tggagctgct ggctttacac tgcctggctt tcgcttccta 2580
cccccacccc atccacccag tgccaaccta gttccactga agcctgagga gcatgccatt 2640
aagtttgagg tctgcgtaga tggtgaatgt catatcctgg gtagagtggt gcggccaggg 2700
ccagatgggg tcccacagag cacgctcctt ggtatcctgc tgcctttgct gctgcttgtg 2760
gctgcactgg cgactgcact ggtcttcagc tactggtggc ggaggaagca gctagttctt 2820
cctcccaacc tgaatgacct ggcatccctg gaccagactg ctggagccac acccctgcct 2880
attctgtact cgggctctga ctacagaagt ggccttgcac tccctgccat tgatggtctg 2940
gattccacca cttgtgtcca tggagcatcc ttctccgata gtgaagatga atcctgtgtg 3000
ccactgctgc ggaaagagtc catccagcta agggacctgg actctgcgct cttggctgag 3060
gtcaaggatg tgctgattcc ccatgagcgg gtggtcaccc acagtgaccg agtcattggc 3120
aaaggccact ttggagttgt ctaccacgga gaatacatag accaggccca gaatcgaatc 3180
caatgtgcca tcaagtcact aagtcgcatc acagagatgc agcaggtgga ggccttcctg 3240
cgagaggggc tgctcatgcg tggcctgaac cacccgaatg tgctggctct cattggtatc 3300
atgttgccac ctgagggcct gccccatgtg ctgctgccct atatgtgcca cggtgacctg 3360
ctccagttca tccgctcacc tcagcggaac cccaccgtga aggacctcat cagctttggc 3420
ctgcaggtag cccgcggcat ggagtacctg gcagagcaga agtttgtgca cagggacctg 3480
gctgcgcgga actgcatgct ggacgagtca ttcacagtca aggtggctga ctttggtttg 3540
gcccgcgaca tcctggacag ggagtactat agtgttcaac agcatcgcca cgctcgccta 3600
cctgtgaagt ggatggcgct ggagagcctg cagacctata gatttaccac caagtctgat 3660
gtgtggtcat ttggtgtgct gctgtgggaa ctgctgacac ggggtgcccc accataccgc 3720
cacattgacc cttttgacct tacccacttc ctggcccagg gtcggcgcct gccccagcct 3780
gagtattgcc ctgattctct gtaccaagtg atgcagcaat gctgggaggc agacccagca 3840
gtgcgaccca ccttcagagt actagtgggg gaggtggagc agatagtgtc tgcactgctt 3900
ggggaccatt atgtgcagct gccagcaacc tacatgaact tgggccccag cacctcgcat 3960
gagatgaatg tgcgtccaga acagccgcag ttctcaccca tgccagggaa tgtacgccgg 4020
ccccggccac tctcagagcc tcctcggccc acttga 4056
<210> 5
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> RON d5_6正义引物
<400> 5
gagctggtca ggtcactaaa c 21
<210> 6
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> RON d5_6 antisense primer
<400> 6
cagacactca gtcccattga c 21
<210> 7
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> RON d11正义引物
<400> 7
atctgtggcc agcatctaac 20
<210> 8
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> RON d11反义引物
<400> 8
aaaggcagca ggataccaag 20
Claims (10)
1.一种用于预防或治疗胰腺癌的药物组合物,其包含由以下式1或式2所示的化合物或其药学上可接受的盐作为活性成分:
[式1]
在式1中,
R1和R2各自独立地为H、卤素、C1-10烷氧基或卤代C1-10烷基;
X为-C(-R3)=或-N=;
R3和R4各自独立为H、卤素、C1-10烷基或C1-10烷氧基;
R5为H、卤素或C1-10烷基;
R6和R7与其所连接的N原子一起形成4-10元杂环,或R6为-C2H4-O-CH3,以及R7为H、甲基或叔丁氧基羰基;和
除R6和R7连接的N原子外,所述杂环还具有或不具有1或2个选自N、O和S组成的组的杂原子,并且所述杂环为未被取代或被至少一个选自卤素和C1-6烷基取代;
[式2]
在式2中,
L为-NH-或-CH2-,
R1至R4各自独立地为氢、卤素、羟基、氰基、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-7环烷基、C6-10芳基、5至9元杂芳基或3至9元杂环烷基,
X为O、S、-CH(-Rx)-或-N(-Rx)-,
Rx为氢、C1-4烷基、C1-4烷氧基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C6-10芳基、C6-10芳基-C1-4烷基或3至9元杂环烷基,
Y为-N=或-CH=,并且
R5和R6各自独立地为氢、氨基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基-C1-6烷氧基、氨基羰基、C1-6烷基氨基羰基、二-C1-6烷基羰基氨基、C1-6烷基羰基氨基、C1-6烷基氨基或C1-6烷基-氨基-C1-6烷氧基,
其中R5和R6各自独立地未被取代或被3至9元环烷基或3至9元杂环烷基取代,
所述环烷基或杂环烷基具有或不具有至少一个选自卤素、氧代、氰基、羟基、羟基-C1-6烷基、氨基、二-C1-6烷基氨基、C1-6烷基、C1-6烷氧基和C1-6烷氧基-C1-6烷基组成的组中的取代基,以及
所述杂环烷基含有1至4个选自N、O和S组成的组的杂原子。
2.根据权利要求1所述的药物组合物,其特征在于,所述式1所示的化合物是选自以下组的化合物:
4-乙氧基-N-[3-氟-4-({2-[5-(吗啉甲基)吡啶-2-基]噻吩并[3,2-b]吡啶-7-基}氧基)苯基]-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-甲酰胺;
4-乙氧基-N-(3-氟-4-{[2-(5-{[(2-甲氧基乙基)氨基]甲基}吡啶-2-基)噻吩并[3,2-b]吡啶-7-基]氧基}苯基)-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺;和
4-乙氧基-N-{3-氟-4-[(2-{5-[(-甲基哌嗪-1-基)甲基]吡啶-2-基}噻吩并[3,2-b]吡啶-7-基)氧基]苯基}-2-氧代-1-苯基-1,2-二氢吡啶-3-甲酰胺。
3.根据权利要求1所述的药物组合物,其特征在于,所述式2所示的化合物为N-(3-氟-4-((6-甲氧基-7-(2-吗啉乙氧基)喹啉-4-基)氧基)苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺;或
N-(4-((7-(3-(3-氰基氮杂环丁烷-1-基)丙氧基)-6-甲氧基喹啉-4-基)氧基)-3-氟苯基)-5-(4-氟苯基)-6-氧代-2,3,5,6-四氢呋喃[3,2-c]吡啶-7-甲酰胺。
4.根据权利要求1所述的用于预防或治疗胰腺癌的药物组合物,其特征在于,所述胰腺癌为存在RON(Recepteur d'origine nantais)突变的胰腺癌。
5.根据权利要求1所述的用于预防或治疗胰腺癌的药物组合物,其特征在于,所述胰腺癌对EGFR靶向治疗剂具有耐药性。
6.根据权利要求4所述的用于预防或治疗胰腺癌的药物组合物,其特征在于,所述RON突变为外显子5、6和11缺失的RON△155、外显子5和6缺失的RON△160、或外显子11缺失的RON△165。
7.根据权利要求5所述的用于预防或治疗胰腺癌的药物组合物,其特征在于,所述EGFR靶向治疗剂为西妥昔单抗、吉非替尼、厄洛替尼、阿帕替尼、埃克替尼、布加替尼、拉帕替尼、卡拉替尼、AEE788、XL647、范得他尼或帕尼单抗。
8.一种预防或治疗胰腺癌的方法,包括:
检测源自患有胰腺癌的受试者的生物样本中的RON突变,
其中RON突变为外显子5、6和11缺失的RON△155、外显子5和6缺失的RON△160、或外显子11缺失的RON△165;和
将根据权利要求1所述的药物组合物施用于检测到RON突变的受试者。
9.一种提供关于抗癌治疗剂的信息的方法,包括:
检测源自患有胰腺癌的受试者的生物样本中的RON突变,
其中RON突变为外显子5、6和11缺失的RON△155、外显子5和6缺失的RON△160、或外显子11缺失的RON△165;和
向检测到RON突变的受试者提供根据权利要求1的药物组合物适用于预防或治疗胰腺癌的信息。
10.根据权利要求1至7任一项所述的药物组合物在预防或治疗胰腺癌中的用途。
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KR10-2020-0059150 | 2020-05-18 | ||
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PCT/KR2021/006183 WO2021235813A1 (ko) | 2020-05-18 | 2021-05-18 | Ron 돌연변이와 관련된 췌장암 예방 또는 치료용 약학 조성물 및 이를 이용한 방법 |
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JO3300B1 (ar) * | 2012-06-06 | 2018-09-16 | Novartis Ag | مركبات وتركيبات لتعديل نشاط egfr |
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US11946934B2 (en) * | 2014-09-03 | 2024-04-02 | Wellmarker Bio Co., Ltd. | Biomarker for predicting the sensitivity to a protein kinase inhibitor and a use thereof |
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