WO2024088273A1 - 一种萘酰胺化合物治疗kras突变相关疾病的用途 - Google Patents

一种萘酰胺化合物治疗kras突变相关疾病的用途 Download PDF

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WO2024088273A1
WO2024088273A1 PCT/CN2023/126294 CN2023126294W WO2024088273A1 WO 2024088273 A1 WO2024088273 A1 WO 2024088273A1 CN 2023126294 W CN2023126294 W CN 2023126294W WO 2024088273 A1 WO2024088273 A1 WO 2024088273A1
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cancer
kras
mutation
compound
related disease
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PCT/CN2023/126294
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French (fr)
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丁健
段文虎
谢华
詹正生
耿美玉
杨汉煜
吕永聪
童林江
赵璐
吴彦波
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中国科学院上海药物研究所
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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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  • the present invention belongs to the field of medicine, and specifically relates to the use of a naphthamide compound in the preparation of a drug for treating KRAS mutation-related diseases, especially KRAS mutation tumors.
  • KRAS is one of the genes with the highest mutation frequency in human tumors. It is involved in driving the occurrence and development of nearly one-third of human malignant tumors and is closely related to tumor prognosis. KRAS mutations account for about 90% of pancreatic cancer, 30%-40% of colon cancer, and 15%-20% of lung cancer. KRAS mutations also occur in other tumors such as bile duct cancer, cervical cancer, bladder cancer, liver cancer, and breast cancer. KRAS mutations can produce six different mutation forms, among which KRAS G12D, G12V, and G12C mutations are the most common, while G12A, G12R, and G12S mutations are relatively rare. For many years, research on small molecule inhibitors for KRAS mutations has progressed slowly, and KRAS once became an "undruggable" target.
  • AMG 510 is a small molecule inhibitor developed by Amgen. It was approved for marketing by the FDA in May 2021 and is currently the only KRAS small molecule inhibitor approved for marketing. Its mechanism of action is mainly to lock KRAS in an inactive GDP-bound state by binding to the G12C cysteine, specifically and irreversibly inhibiting KRAS G12C.
  • MRTX849 is an oral small molecule inhibitor targeting KRAS G12C mutations developed by Mirati Therapeutics. It has a similar structural skeleton to AMG 510 and is currently in the pre-registered stage.
  • KRAS G12C inhibitors in clinical stage, including JDQ-443 (Novartis, clinical phase I/II), GFH-925 (Jinfang Pharmaceutical and Innovent Biologics, clinical phase I/II), D-1553 (Yifan Biopharma, clinical phase I/II), JAB-21822 (Jacquisition, clinical phase I/II), ARS-3248 (Jacquisition, clinical phase I), BI-1823911 (Boehringer Ingelheim, clinical phase I), GDC-6036 (Roche, clinical phase I) and LY-3537982 (Eli Lilly, clinical phase I).
  • MRTX1133 developed by Mirati Therapeutics is the currently reported small molecule inhibitor targeting KRAS G12D, which is currently in the preclinical research stage.
  • Compound (I) is a VEGFR inhibitor with excellent activity, which can inhibit the proliferation of tumor cells.
  • the prior art does not report its effect on KRAS mutation-related diseases, especially KRAS mutation tumors.
  • the object of the present invention is to provide a naphthamide compound for treating KRAS mutation-related diseases, especially KRAS mutation tumors.
  • a use of a compound (I) or a pharmaceutically acceptable salt thereof for preparing a drug for treating a KRAS mutation-related disease there is provided a use of a compound (I) or a pharmaceutically acceptable salt thereof for preparing a drug for treating a KRAS mutation-related disease;
  • the compound (I) has the following structure:
  • the KRAS mutation-related disease is a KRAS mutation tumor.
  • the KRAS mutant tumor is selected from the following group: KRAS G12D mutant tumor, KRAS G12V mutant tumor, KRAS G12C mutant tumor, KRAS G12A mutant tumor, KRAS G12R mutant tumor, and KRAS G12S mutant tumor.
  • the KRAS mutation-related disease is selected from the following group: KRAS G12C mutation tumor, KRAS G12D mutation tumor.
  • the KRAS mutation-related disease is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, Cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, breast cancer, endometrial cancer, skin cancer, ovarian cancer, gastric cancer, urinary tract cancer, soft tissue sarcoma, esophageal cancer, multiple myeloma, prostate cancer, kidney cancer, gastrointestinal neuroendocrine tumors, gastrointestinal stromal tumors, head and neck cancer, glioma, salivary gland cancer, bone cancer, anal cancer, thyroid cancer, melanoma, mature B-cell tumors, small intestine cancer, ampullary cancer.
  • the lung cancer is selected from the group consisting of small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma.
  • the KRAS mutation-related disease is selected from the following group: pancreatic cancer and lung cancer.
  • the KRAS mutation-related disease is pancreatic cancer with KRAS G12D mutation.
  • the KRAS mutation-related disease is lung cancer with KRAS G12C mutation.
  • the KRAS mutation-related disease is non-small cell lung cancer with KRAS G12C mutation.
  • the patient suffering from the KRAS mutation-related disease is a human.
  • the second aspect of the present invention provides a pharmaceutical composition for treating KRAS mutation-related diseases, comprising a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;
  • the compound (I) has the following structure:
  • the pharmaceutical composition is an oral preparation.
  • the KRAS mutation-related disease is as described above.
  • the third aspect of the present invention provides a method for treating a KRAS mutation-related disease, comprising the steps of:
  • the compound (I) has the following structure:
  • step 1) the following steps are also included before step 1):
  • the KRAS mutation-related disease is as described above.
  • a fourth aspect of the present invention provides a method for treating a KRAS mutation-related disease, comprising the steps of:
  • step 1) the following steps are also included before step 1):
  • the KRAS mutation-related disease is as described above.
  • the inventor unexpectedly found that the compound (I) of the present invention has significant inhibitory activity against KRAS mutation-related diseases, especially KRAS mutation tumors, and can significantly inhibit the growth of KRAS mutation tumors, and is expected to develop effective anti-tumor drugs. On this basis, the inventor completed the present invention.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • administration methods include but are not limited to: Not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
  • the drug of the present invention can be prepared into various clinically acceptable dosage forms, including oral dosage forms, injection dosage forms, local administration dosage forms or external dosage forms, etc.
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.
  • the compounds of the present invention can be prepared into drugs alone, or can be combined with other pharmaceutically acceptable compounds (such as anti-tumor drugs) to prepare drugs.
  • other pharmaceutically acceptable compounds such as anti-tumor drugs
  • different active ingredients can be prepared into pharmaceutically acceptable preparations respectively, and further combined and packaged to obtain the final product; or, under pharmaceutically acceptable conditions, different active ingredients are contained in the same preparation product.
  • the therapeutically effective amount refers to the effective dosage considered in medicine, that is, the amount of active compound is sufficient to significantly improve the condition without causing serious side effects.
  • the daily dosage is usually 0.01 to 2000 mg, preferably 1 to 500 mg. It can be administered as a single dose once a day, can be administered multiple times a day, or can be used at intervals.
  • the specific dosage and frequency of administration should take into account factors such as the route of administration and the patient's health status, which can be determined by skilled physicians based on routine skills.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof or a medicament containing the compound (I) or a pharmaceutically acceptable salt thereof is administered to a mammal (such as a human) in need of treatment.
  • a mammal such as a human
  • a mammal such as a human
  • KRAS mutations There are many methods for gene detection of KRAS mutation in the prior art, including direct sequencing, pyrophosphate sequencing, high-resolution melting (HRM), amplification refractory mutation system (ARMS), real-time PCR, polymerase chain reaction-single strand conformation polymorphism (PCR-single strand conformation polymorphism, PCR-SSCP), co-amplification at lower denaturation temperature PCR (COLD-PCR) and high performance liquid chromatography, etc.
  • HRM high-resolution melting
  • ARMS amplification refractory mutation system
  • real-time PCR polymerase chain reaction-single strand conformation polymorphism
  • PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
  • COLD-PCR co-amplification at lower denaturation temperature PCR
  • COLD-PCR high performance liquid chromatography
  • the present invention has the following main advantages:
  • the compound (I) of the present invention is simpler to synthesize than the marketed drug AMG510 targeting KRAS G12C and the MRTX1133 targeting KRAS G12D which is in the preclinical research stage;
  • AMG510 can only treat KRAS G12C-related tumors, MRTX1133 is only effective against KRAS G12D-related tumors, and compound (I) of the present invention is effective against both KRAS G12C and KRAS G12D-related tumors;
  • the compound (I) of the present invention has significant inhibitory activity on the growth of human pancreatic cancer PANC-1 cell nude mouse transplant tumors with KRAS G12D mutation, and there is currently no effective therapeutic drug in this field.
  • the 10 mg/kg and 5 mg/kg groups of compound (I) were orally administered twice a day, which significantly inhibited the growth of subcutaneous transplant tumors of human pancreatic cancer PANC-1 nude mice, and the T/C percentages obtained on the 30th day were 18.2% and 27.3%, respectively; during the experiment, the mice in each group were in good condition.
  • Compound (I) of the present invention has significant tumor inhibition activity against nude mouse transplanted tumors of human non-small cell lung cancer NCI-H358 cells with KRAS G12C mutation.
  • Compound (I) was orally administered twice a day at a dose of 10 mg/kg, significantly inhibiting the growth of subcutaneous transplanted tumors of non-small cell lung cancer NCI-H358 nude mice, with a T/C percentage of 17.6% on the 21st day; and was orally administered twice a day at a dose of 10 mg/kg, with a T/C percentage of 9.2% on the 54th day. In the experiment, all groups of mice were in good condition.
  • the reagents and raw materials used in the experiments were purchased commercially or prepared by us.
  • Blank preparation The formulation is the same as that in Table A, except that it does not contain compound (I).
  • the latent solvent was evaporated and removed during the preparation process, and the obtained test substance and blank preparation did not contain the latent solvent.
  • the preparation containing compound (I) or the blank preparation was diluted with water to the desired concentration or volume.
  • Human pancreatic cancer PANC-1 and human non-small cell lung cancer NCI-H358 were purchased from ATCC (American Type Culture Collection).
  • Example 1 Inhibitory effect of compound (I) on the growth of KRAS G12D mutant human pancreatic cancer PANC-1 cells transplanted in nude mice
  • mice BALB/c nude mice, female, age: 3-4 weeks.
  • KRAS G12D mutant human pancreatic cancer PANC-1 cells were inoculated subcutaneously in the right axilla of nude mice, with a cell inoculation amount of 5 ⁇ 10 6 /mouse.
  • the mice were randomly divided into the following groups: (1) Compound (I) group: Compound (I) was orally administered at a dose of 5 mg/kg and 10 mg/kg twice a day for 30 consecutive days; (2) Solvent control group was given an equal volume of blank preparation to the 10 mg/kg Compound (I) group.
  • Example 2 Inhibitory effect of compound (I) on the growth of nude mouse transplanted tumors bearing KRAS G12C mutant human non-small cell lung cancer NCI-H358 cells (administered for 21 days)
  • mice BALB/c nude mice, female, age: 3-4 weeks.
  • Human non-small cell lung cancer NCI-H358 cells with KRAS G12C mutation were inoculated subcutaneously in the right axilla of nude mice, with a cell inoculation amount of 5 ⁇ 10 6 /mouse.
  • the mice were randomly divided into the following groups: (1) Compound (I) group: Compound (I) was orally administered at a dose of 10 mg/kg and 5 mg/kg twice a day for 21 consecutive days; (2) Solvent control group was given an equal volume of blank preparation to the 10 mg/kg Compound (I) group.
  • Example 3 Effect of Compound (I) on the proliferation of KRAS G12C mutant human non-small cell lung cancer NCI-H358 cells Inhibitory effect on growth of transplanted tumors in nude mice (administered for 54 days)
  • mice BALB/c nude mice, female, age: 3-4 weeks.
  • Human non-small cell lung cancer NCI-H358 cells with KRAS G12C mutation were inoculated subcutaneously in the right axilla of nude mice, with a cell inoculation amount of 5 ⁇ 10 6 /mouse.
  • the mice were randomly divided into the following groups: (1) Compound (I) group: Compound (I) was orally administered at a dose of 10 mg/kg and 5 mg/kg twice a day for 54 consecutive days; (2) Solvent control group was given an equal volume of blank preparation to the 10 mg/kg Compound (I) group.

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Abstract

本发明涉及一种萘酰胺化合物治疗KRAS突变相关疾病的用途。具体地，本发明公开了化合物(I)或其药学上可接受的盐用于制备用于治疗KRAS突变相关疾病尤其是KRAS突变肿瘤的药物的用途，所述化合物可有效抑制KRAS突变肿瘤的生长，尤其是KRAS G12C突变肿瘤和KRAS G12D突变肿瘤。

Description

一种萘酰胺化合物治疗KRAS突变相关疾病的用途 技术领域
本发明属于医药领域，具体涉及一种萘酰胺化合物在制备治疗KRAS突变相关疾病尤其是KRAS突变肿瘤的药物中的应用。
背景技术
KRAS是人类肿瘤中突变频率最高的基因之一，参与驱动了人类近三分之一的恶性肿瘤的发生和发展，并与肿瘤预后密切相关。KRAS突变在胰腺癌中占90％左右，结肠癌中占30％-40％，肺癌中占15％-20％，在其他肿瘤如胆管癌、宫颈癌、膀胱癌、肝癌和乳腺癌中也会发生KRAS突变。KRAS突变可产生六种不同的突变形式，其中KRAS G12D、G12V和G12C突变最为常见，而G12A、G12R和G12S突变较为少见。多年来针对KRAS突变的小分子抑制剂研究进展缓慢，KRAS一度成为“不可成药”的靶点。
目前，靶向KRAS G12C突变的小分子抑制剂取得突破。AMG 510是Amgen公司开发的一种小分子抑制剂，已于2021年5月由FDA获批上市，是目前唯一一个获批上市的KRAS小分子抑制剂，其作用机制主要是通过与G12C半胱氨酸结合将KRAS锁定在非活性的GDP结合状态，特异性且不可逆地抑制KRAS G12C。MRTX849是由Mirati Therapeutics公司开发的针对KRAS G12C突变的口服小分子抑制剂，与AMG 510具有类似的结构骨架，目前处于预注册(pre-registered)阶段。此外还有多个KRAS G12C抑制剂处于临床阶段，包括JDQ-443(Novartis公司，临床Ⅰ/Ⅱ期)，GFH-925(中国劲方医药与信达生物，临床Ⅰ/Ⅱ期)，D-1553(中国益方生物，临床Ⅰ/Ⅱ期)，JAB-21822(中国加科思公司，临床Ⅰ/Ⅱ期)，ARS-3248(中国加科思公司，临床Ⅰ期)，BI-1823911(Boehringer Ingelheim公司，临床Ⅰ期)，GDC-6036(Roche公司，临床Ⅰ期)和LY-3537982(Eli Lilly公司，临床Ⅰ期)。然而，靶向KRAS G12D突变的抑制剂研究非常有限，尚无化合物进入临床研究，Mirati Therapeutics公司开发的MRTX1133是目前报导的针对KRAS G12D的小分子抑制剂，现处于临床前研究阶段。
目前，临床上采用基因检测的方式确定病人KRAS突变类型，随后进行药 物靶向治疗，但KRAS G12D突变的病人目前处于无药可治的阶段，因此针对这类病人，甚至KRAS其他突变，如G12V、G12A、G12R或G12S突变的病人，急需安全、有效的药物治疗方案。
化合物(I)首次公开于CN104860885A中，结构式如下式(Ⅰ)所示，
化合物(Ⅰ)是一种具有优异活性的VEGFR抑制剂，能够抑制肿瘤细胞血管增生。现有技术未报道其对KRAS突变相关疾病尤其是KRAS突变肿瘤的作用。
发明内容
本发明的目的在于提供一种萘酰胺化合物治疗KRAS突变相关疾病尤其是KRAS突变肿瘤的用途。
本发明的第一方面，提供了一种化合物(I)或其药学上可接受的盐的用途，用于制备药物，所述药物用于治疗KRAS突变相关疾病；
所述化合物(I)具有如下结构：
在另一优选例中，所述KRAS突变相关疾病为KRAS突变肿瘤。
在另一优选例中，所述KRAS突变肿瘤选自下组：KRAS G12D突变肿瘤、KRAS G12V突变肿瘤、KRAS G12C突变肿瘤、KRAS G12A突变肿瘤、KRAS G12R突变肿瘤、KRAS G12S突变肿瘤。
在另一优选例中，所述KRAS突变相关疾病选自下组：KRAS G12C突变肿瘤、KRAS G12D突变肿瘤。
在另一优选例中，所述KRAS突变相关疾病选自下组：胰腺癌、结直肠癌、肺 癌、胆管癌、宫颈癌、膀胱癌、肝癌、乳腺癌、子宫内膜癌、皮肤癌、卵巢癌、胃癌、泌尿道癌、软组织肉瘤、食管癌、多发性骨髓瘤、前列腺癌、肾癌、胃肠道神经内分泌肿瘤、胃肠道间质肿瘤、头颈癌、神经胶质瘤、唾腺癌、骨癌、肛门癌、甲状腺癌、黑色素瘤、成熟B细胞肿瘤、小肠癌、壶腹癌。
在另一优选例中，所述肺癌选自下组：小细胞肺癌、非小细胞肺癌、肺腺癌。
在另一优选例中，所述KRAS突变相关疾病选自下组：胰腺癌、肺癌。
在另一优选例中，所述KRAS突变相关疾病为KRAS G12D突变的胰腺癌。
在另一优选例中，所述KRAS突变相关疾病为KRAS G12C突变的肺癌。
在另一优选例中，所述KRAS突变相关疾病为KRAS G12C突变的非小细胞肺癌。
在另一优选例中，所述KRAS突变相关疾病的患者为人。
本发明的第二方面，提供了一种用于治疗KRAS突变相关疾病的药物组合物，包含治疗有效量的化合物(I)或其药学上可接受的盐和药学上可接受的载体；
所述化合物(I)具有如下结构：
在另一优选例中，所述药物组合物为口服制剂。
在另一优选例中，所述KRAS突变相关疾病如上文所述。
本发明的第三方面，提供了一种治疗KRAS突变相关疾病的方法，包括步骤：
1)将治疗有效量的化合物(I)或其药学上可接受的盐施用于需要治疗的KRAS突变相关疾病的患者；
所述化合物(I)具有如下结构：
在另一优选例中，步骤1)之前还包括如下步骤：
采用基因检测的方式确定患者的KRAS突变类型。
在另一优选例中，所述KRAS突变相关疾病如上文所述。
本发明的第四方面，提供了一种治疗KRAS突变相关疾病的方法，包括步骤：
1)将本发明第二方面所述药物组合物施用于需要治疗的KRAS突变相关疾病的患者。
在另一优选例中，步骤1)之前还包括如下步骤：
采用基因检测的方式确定患者的KRAS突变类型。
在另一优选例中，所述KRAS突变相关疾病如上文所述。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
本发明人经过长期而深入的研究，意外地发现本发明化合物(I)对KRAS突变相关疾病尤其是KRAS突变肿瘤具有显著的抑制活性，可显著抑制KRAS突变肿瘤的生长，有望开发出有效的抗肿瘤药物。在此基础上，发明人完成了本发明。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组分能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。
本发明药物组合物的施用方式没有特别限制，代表性的施用方式包括但并 不限于：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
相应地，本发明药物可制成临床上可接受的各种剂型，包括口服剂型、注射剂型、局部给药剂型或外用剂型等。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
本发明化合物可以单独制成药物，或者与药学上可接受的其他化合物(如抗肿瘤药物)联合制备药物。当本发明化合物与药学上可接受的其他化合物(如抗肿瘤药物)联合制备药物时，不同活性成分可分别制成药学上可接受的制剂，进一步组合包装得到终产品；或者，在药学可接受的情况下，不同活性成分包含在同一制剂产品中。
在本发明中，所述治疗有效量是指药学上认为的有效给药剂量，即活性化合物的量足以明显改善病情，而不至于产生严重的副作用。对于60kg体重的人而言，日给药剂量通常为0.01～2000mg，优选1～500mg。可以每日一次单剂量施用，可以每天分多次施用，也可以间隔使用。具体剂量和给药频率应考虑给药途径、病人健康状况等因素，这些都是熟练医师根据常规技能可以确定的。
在一些实施方式中，将本发明化合物(I)或其药学上可接受的盐或者含有化合物(I)或其药学上可接受的盐的药物施用于需要治疗的哺乳动物(如人) 之前，对需要治疗的哺乳动物(如人)进行KRAS突变的基因检测，以确定病人KRAS突变类型。现有技术有关KRAS突变的基因检测方法很多，包括直接测序法、焦磷酸测序法、高分辨率熔解曲线分析法(high-resolution melting，HRM)、扩增阻滞突变系统法(amplification refractory mutation system，ARMS)、荧光定量PCR法(real-timePCR)、聚合酶链反应-单链构象多态性分析法(PCR-single strand conformation polymorphism，PCR-SSCP)、低变性温度下复合扩增聚合酶链反应法(co-amplification at lower denaturation temperature PCR，COLD-PCR)以及高效液相色谱分析法等。本领域技术人员可以根据需要选用。
与现有技术相比，本发明具有以下主要优点：
(1)本发明的化合物(Ⅰ)较已上市的靶向KRAS G12C的药物AMG510及处于临床前研究阶段的靶向KRAS G12D的MRTX1133合成更为简单；
(2)AMG510仅可治疗KRAS G12C相关肿瘤，MRTX1133仅对KRAS G12D相关肿瘤有效，本发明的化合物(Ⅰ)对KRAS G12C和KRAS G12D相关的肿瘤均有效；
(3)体内研究显示：
1)本发明化合物(Ⅰ)对KRAS G12D突变的人胰腺癌PANC-1细胞裸小鼠移植瘤生长具有显著的抑制活性，而本领域目前没有有效的治疗药物。化合物(Ⅰ)10mg/kg和5mg/kg组，每天口服给药两次，显著抑制人胰腺癌PANC-1裸小鼠皮下移植瘤的生长，第30天所得T/C百分数分别为18.2％和27.3％；实验中，各组小鼠均状态良好。
2)本发明化合物(Ⅰ)对KRAS G12C突变的人非小细胞肺癌NCI-H358细胞裸小鼠移植瘤具有明显的抑瘤活性。化合物(Ⅰ)以10mg/kg剂量每天口服给药2次，显著抑制非小细胞肺癌NCI-H358裸小鼠皮下移植瘤的生长，第21天所得T/C百分数为17.6％；以10mg/kg剂量每天口服给药2次，第54天所得T/C百分数为9.2％。实验中，各组小鼠均状态良好。
以上实验表明，本发明化合物(I)或其药学上可接受的盐能显著抑制KRAS突变(尤其是KRAS G12C突变和/或KRAS G12D突变)的肿瘤生长，有望开发出有效的抗肿瘤药物。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实验材料来源或配制：
化合物(I)：参照CN104860885A实施例21制备得到。
实验中所用试剂、原材料均为商业购买或自行配制。
体内实验受试物配制方法见表A：
表A
空白制剂：配方同表A，区别为不含化合物(I)。
所述潜溶剂在制备过程中蒸发去除，所得受试物和空白制剂中不含所述潜溶剂。
临用前将含化合物(I)的制剂或空白制剂以水稀释至所需浓度或所需体积。
细胞株来源及获得：人胰腺癌PANC-1和人非小细胞肺癌NCI-H358购于ATCC(美国模式培养物集存库)。
实施例1：化合物(Ⅰ)对KRAS G12D突变的人胰腺癌PANC-1细胞裸小鼠移植瘤生长抑制作用
1.实验方法
实验动物：BALB/c裸小鼠，雌性，鼠龄：3-4周龄。KRAS G12D突变的人胰腺癌PANC-1细胞接种于裸小鼠右侧腋窝皮下，细胞接种量为5×106/只，待肿瘤平均体积达到100mm3左右，将小鼠进行随机分组：(1)化合物(I)组：化合物(I)分别按5mg/kg和10mg/kg的剂量，每天口服给药两次，连续给药30天；(2)溶剂对照组给10mg/kg化合物(Ⅰ)给药组等体积空白制剂。
实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝0.5×a×b2，其中a、b分别表示长、宽；相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0；其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积；抗肿瘤活性的评价指标为：相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：溶剂对照组RTV。
2.实验结果
结果如表1所示，与溶剂对照组相比，化合物(I)10mg/kg和5mg/kg组，每天口服给药两次，显著抑制人胰腺癌PANC-1裸小鼠皮下移植瘤的生长，第30天所得T/C百分数分别为18.2％和27.3％。实验中，各组小鼠均状态良好。鉴于本领域目前对于KRAS G12D突变人胰腺癌尚无有效的治疗药物，本发明提供的化合物(I)对人胰腺癌PANC-1裸小鼠移植瘤表现出突出的治疗活性，因而有望开发KRAS G12D突变人胰腺癌的有效治疗药物。
表1.化合物(I)对人胰腺癌PANC-1裸小鼠移植瘤的治疗作用

实验数据采用t检验分析统计，与溶剂对照组比较，*p<0.05，**p<0.01，
***p<0.001。
实施例2：化合物(Ⅰ)对KRAS G12C突变人非小细胞肺癌NCI-H358细胞裸小鼠移植瘤生长抑制作用(给药21天)
1.实验方法
实验动物：BALB/c裸小鼠，雌性，鼠龄：3-4周龄。KRAS G12C突变的人非小细胞肺癌NCI-H358细胞接种于裸小鼠右侧腋窝皮下，细胞接种量为5×106/只，待肿瘤平均体积达到100mm3左右，将小鼠进行随机分组：(1)化合物(I)组：化合物(Ⅰ)分别按10mg/kg和5mg/kg剂量，每天口服给药两次，连续给药21天；(2)溶剂对照组给10mg/kg化合物(Ⅰ)给药组等体积空白制剂。
实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝0.5×a×b2，其中a、b分别表示长、宽；相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0；其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积；抗肿瘤活性的评价指标为：相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：溶剂对照组RTV。
2.实验结果
结果如表2所示，与溶剂对照组相比，化合物(I)10mg/kg和5mg/kg组，每天口服给药两次，显著抑制了非小细胞肺癌NCI-H358裸小鼠皮下移植瘤的生长，第21天所得T/C百分数分别为17.6％和29.4％。实验中，各组小鼠均状态良好，未表现出明显的毒性反应。表明化合物(I)对KRAS G12C突变肿瘤具有突出的抑瘤活性。
表2.化合物(I)对人非小细胞肺癌NCI-H358裸小鼠移植瘤的治疗作用

实验数据采用t检验分析统计，与溶剂对照组相比，*p<0.05，**p<0.01，
***p<0.001。
实施例3：化合物(Ⅰ)对KRAS G12C突变人非小细胞肺癌NCI-H358细 胞裸小鼠移植瘤生长抑制作用(给药54天)
1.实验方法
实验动物：BALB/c裸小鼠，雌性，鼠龄：3-4周龄。KRAS G12C突变的人非小细胞肺癌NCI-H358细胞接种于裸小鼠右侧腋窝皮下，细胞接种量为5×106/只，待肿瘤平均体积达到100mm3左右，将小鼠进行随机分组：(1)化合物(I)组：化合物(Ⅰ)分别按10mg/kg和5mg/kg剂量，每天口服给药两次，连续给药54天；(2)溶剂对照组给10mg/kg化合物(Ⅰ)给药组等体积空白制剂。
实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝0.5×a×b2，其中a、b分别表示长、宽；相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0；其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积；抗肿瘤活性的评价指标为：相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：溶剂对照组RTV。
2.实验结果
结果如表3所示，与溶剂对照组相比，化合物(I)10mg/kg和5mg/kg组，每天口服给药两次，显著抑制了非小细胞肺癌NCI-H358裸小鼠皮下移植瘤的生长，第54天所得T/C百分数分别为9.2％和10.5％。实验中，各组小鼠均状态良好，未表现出明显的毒性反应。表明化合物(I)对KRAS G12C突变肿瘤具有突出的抑瘤活性。
表3.化合物(I)对人非小细胞肺癌NCI-H358裸小鼠移植瘤的治疗作用

实验数据采用t检验分析统计，与溶剂对照组相比，*p<0.05，**p<0.01，
***p<0.001。
以上实验表明，本发明化合物(I)或其药学上可接受的盐能显著抑制KRAS突变(尤其是KRAS G12C突变和/或KRAS G12D突变)的肿瘤生长，有望开发出有效的抗肿瘤药物。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (8)

  1. 一种化合物(I)或其药学上可接受的盐的用途，其特征在于，用于制备药物，所述药物用于治疗KRAS突变相关疾病；
    所述化合物(I)具有如下结构：
  2. 如权利要求1所述用途，其特征在于，所述KRAS突变相关疾病为KRAS突变肿瘤。
  3. 如权利要求2所述用途，其特征在于，所述KRAS突变相关疾病选自下组：KRAS G12C突变肿瘤、KRAS G12D突变肿瘤。
  4. 如权利要求1-3任一项所述用途，其特征在于，所述KRAS突变相关疾病选自下组：胰腺癌、结直肠癌、肺癌、胆管癌、宫颈癌、膀胱癌、肝癌、乳腺癌、子宫内膜癌、皮肤癌、卵巢癌、胃癌、泌尿道癌、软组织肉瘤、食管癌、多发性骨髓瘤、前列腺癌、肾癌、胃肠道神经内分泌肿瘤、胃肠道间质肿瘤、头颈癌、神经胶质瘤、唾腺癌、骨癌、肛门癌、甲状腺癌、黑色素瘤、成熟B细胞肿瘤、小肠癌、壶腹癌。
  5. 如权利要求4所述用途，其特征在于，所述KRAS突变相关疾病选自下组：胰腺癌、肺癌。
  6. 如权利要求1所述用途，其特征在于，所述KRAS突变相关疾病为KRAS G12D突变的胰腺癌。
  7. 如权利要求1所述用途，其特征在于，所述KRAS突变相关疾病为KRAS G12C突变的肺癌。
  8. 如权利要求1所述用途，其特征在于，所述KRAS突变相关疾病为KRAS G12C突变的非小细胞肺癌。
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