WO2022171135A1 - Spiro-containing quinazoline derivative - Google Patents

Abstract

Disclosed in the present invention is a spiro-containing quinazoline derivative. Specifically, the present invention relates to a compound shown in general formula (1) and a preparation method therefor, and a use of the compound of general formula (1), and each isomer thereof, each crystal form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as a G12C mutant K-Ras protein irreversible inhibitor in the preparation of a medication treating Ras-related diseases, such as tumors.

Description

含螺环的喹唑啉衍生物Spiro-containing quinazoline derivatives

本申请要求申请日为2021年2月9日的中国申请CN202110182364.6的优先权。本申请引用上述中国申请的全文。This application claims the priority of Chinese application CN202110182364.6 with a filing date of February 9, 2021. This application cites the full text of the above Chinese application.

技术领域technical field

本发明属涉及药物化学领域，更具体而言，涉及一类含螺环的喹唑啉化合物，及其制备方法和该类化合物作为K-Ras G12C抑制剂在制备抗肿瘤药物中的用途。The invention belongs to the field of medicinal chemistry, and more particularly, to a class of spiro ring-containing quinazoline compounds, a preparation method thereof, and the use of such compounds as K-Ras G12C inhibitors in the preparation of antitumor drugs.

背景技术Background technique

Ras蛋白家族是细胞内重要的信号转导传递分子，在生长发育中发挥了重要的作用。大量的体外肿瘤细胞，动物模型以及人类肿瘤样本的分析和研究表明Ras家族蛋白的过度激活是人类肿瘤发展的早期事件，是多种癌症发生和发展的重要诱因之一。因此靶向和抑制Ras蛋白的活性是治疗相关肿瘤的重要手段。The Ras protein family is an important signal transduction molecule in cells and plays an important role in growth and development. The analysis and research of a large number of in vitro tumor cells, animal models and human tumor samples have shown that the overactivation of Ras family proteins is an early event in the development of human tumors and is one of the important triggers for the occurrence and development of various cancers. Therefore, targeting and inhibiting the activity of Ras protein is an important means to treat related tumors.

Ras蛋白存在两种形式，其与GDP结合，处于未激活静息状态；而当细胞接收诸如生长因子刺激等信号时，Ras蛋白与GTP结合，被激活。活化的Ras蛋白招募多种信号转接蛋白，促进下游信号分子诸如ERK，S6的磷酸化，从而激活Ras信号转导通路，调节细胞生长、存活、迁移和分化。Ras蛋白自身的GTPase酶活性可将GTP水解回GDP。并且细胞内存在GTP酶激活蛋白(GAPs)与Ras相互作用大大促进Ras GTPase的活性，从而防止Ras蛋白的过度激活。Ras protein exists in two forms, which bind to GDP and are in an inactive resting state; and when cells receive signals such as growth factor stimulation, Ras protein binds to GTP and is activated. Activated Ras protein recruits a variety of signal transduction proteins and promotes the phosphorylation of downstream signaling molecules such as ERK and S6, thereby activating the Ras signal transduction pathway and regulating cell growth, survival, migration and differentiation. The GTPase activity of the Ras protein itself can hydrolyze GTP back to GDP. And the existence of GTPase activating proteins (GAPs) in cells interacts with Ras to greatly promote the activity of Ras GTPase, thereby preventing the over-activation of Ras protein.

Ras蛋白家族中K-Ras,H-Ras以及N-Ras蛋白上的突变是多种肿瘤的常见的基因突变之一，是导致肿瘤中Ras蛋白过度激活的主要因素。与野生型的Ras蛋白相比，这些突变导致Ras蛋白活性不为调控，稳定结合GTP，持续激活，从而促进肿瘤细胞的生长，迁移以及分化。这其中K-Ras蛋白的突变最为常见，占所有Ras突变的85％，而N-Ras(12％)和H-Ras(3％)则相对少见。K-Ras突变在多种癌症中极为普遍：包括胰腺癌(95％)、结肠直肠癌(45％)和肺癌(25％)等，而在乳腺癌、卵巢癌和脑癌中相对罕见(<2％)。K-Ras突变位点主要集中于G12位，其中G12C的突变最为常见。例如在非小细胞肺癌(NSCLC)中，K-Ras G12C占所有K-Ras突变的50％，其次是G12V和G12D。基因组学研究表明，非小细胞肺癌中的K-Ras突变不与EGFR、ALK、ROS1、RET和BRAF突变共存，而与STK11、KEAP1和TP53等突变共存，提示K-Ras突变可能与STK11、KEAP1和TP53突变等协同作用参与细胞的恶性转变，增 生和侵袭。除了肿瘤以外，Ras蛋白的异常激活也参与了包括糖尿病，神经退行性疾病等非肿瘤性疾病，由此可见，靶向Ras蛋白的小分子化合物可使大批携带特定基因变异的的癌症病人和Ras通路过度激活的非癌症性病人受益。Mutations in K-Ras, H-Ras and N-Ras proteins in the Ras protein family are one of the common gene mutations in many tumors, and are the main factors leading to the over-activation of Ras proteins in tumors. Compared with wild-type Ras protein, these mutations result in unregulated Ras protein activity, stable binding to GTP, and continuous activation, thereby promoting tumor cell growth, migration, and differentiation. Among them, K-Ras protein mutation is the most common, accounting for 85% of all Ras mutations, while N-Ras (12%) and H-Ras (3%) are relatively rare. K-Ras mutations are extremely common in a variety of cancers, including pancreatic (95%), colorectal (45%), and lung (25%), and are relatively rare in breast, ovarian, and brain cancers (< 2%). The K-Ras mutation sites are mainly concentrated in the G12 position, and the mutation of G12C is the most common. In non-small cell lung cancer (NSCLC), for example, K-Ras G12C accounts for 50% of all K-Ras mutations, followed by G12V and G12D. Genomic studies have shown that K-Ras mutations in non-small cell lung cancer do not coexist with EGFR, ALK, ROS1, RET, and BRAF mutations, but coexist with mutations such as STK11, KEAP1, and TP53, suggesting that K-Ras mutations may coexist with STK11, KEAP1 and TP53 mutations and other synergistic effects are involved in the malignant transformation, proliferation and invasion of cells. In addition to tumors, abnormal activation of Ras protein is also involved in non-tumor diseases including diabetes, neurodegenerative diseases, etc. It can be seen that small molecule compounds targeting Ras protein can make a large number of cancer patients with specific gene mutations and Ras Noncancerous patients with overactivated pathways benefit.

自从肿瘤中Ras突变被发现四十年来，虽然我们对Ras通路致病机制有了更为深入的了解，但是对于大量携带Ras蛋白突变以及Ras通路过度激活的病人，临床上尚未有有效的靶向Ras蛋白的治疗手段上市。因此开发高活性的针对Ras蛋白特别是突变频率较高的K-Ras G12C蛋白的小分子抑制剂，具有重要的临床意义。Forty years since the discovery of Ras mutations in tumors, although we have gained a deeper understanding of the pathogenic mechanism of the Ras pathway, there is no effective clinical target for a large number of patients with Ras protein mutations and Ras pathway overactivation. Ras protein therapeutics are on the market. Therefore, the development of highly active small-molecule inhibitors against Ras protein, especially K-Ras G12C protein with high mutation frequency, has important clinical significance.

K-Ras G12C突变蛋白作为一个前沿的药物靶点，目前的研究还不是很多，只有少数化合物进入临床研究阶段，比如Amgen公司的AMG510和Mirati公司的MRTX849。2018年Cell上报道了靶向K-Ras G12C突变的共价抑制剂ARS-1620[Cell,2018,172:578-589]。专利WO2018/143315和WO2020/216190报道了一类螺环化合物具有K-Ras G12C活性及小鼠体内抗肿瘤活性，代表化合物A(专利WO2018/143315中实施例35)和化合物B(专利WO2020/216190中实施例1)结构如下：As a cutting-edge drug target, K-Ras G12C mutant protein has not been studied much, and only a few compounds have entered the clinical research stage, such as Amgen's AMG510 and Mirati's MRTX849. In 2018, Cell reported targeting K- A covalent inhibitor of Ras G12C mutation ARS-1620 [Cell, 2018, 172:578-589]. Patents WO2018/143315 and WO2020/216190 report a class of spiro compounds with K-Ras G12C activity and antitumor activity in mice, representing Compound A (Example 35 in Patent WO2018/143315) and Compound B (Patent WO2020/216190 Middle embodiment 1) structure is as follows:

目前，研究和发现具有K-Ras G12C活性好的化合物存在迫切的需求。At present, there is an urgent need to research and discover compounds with good K-Ras G12C activity.

发明内容SUMMARY OF THE INVENTION

本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：The present invention provides a compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

通式(1)中：In general formula (1):

m、n和v独立为1或2的整数；m, n and v are independently integers of 1 or 2;

R ¹为C2-C4烯基或C3-C6环烷基； R ¹ is C2-C4 alkenyl or C3-C6 cycloalkyl;

R ²为C1-C3烷氧基或卤代C1-C3烷氧基； R ² is C1-C3 alkoxy or halogenated C1-C3 alkoxy;

R ³为

其中R ^a、R ^b和R ^c独立为H、F、Cl或Me，R ^d为H、F、Cl、NH ₂、Me或环丙基； ^R3 is

wherein R ^a , R ^b and R ^c are independently H, F, Cl or Me, and R ^d is H, F, Cl, NH ₂ , Me or cyclopropyl;

R ⁴为H或卤素； R ⁴ is H or halogen;

R ⁵和R ⁶独立为C1-C3烷基、卤代C1-C3烷基、羟基取代C1-C3烷基、氰基取代C1-C3烷基、甲砜基取代C1-C3烷基、C3-C6环烷基、(C1-C3)烷氧基取代的(C2-C3)烷基、(卤代C1-C3)烷氧基取代的(C2-C3)烷基或(C3-C6)环烷基取代的(C1-C3)烷基，或R ⁵和R ⁶共N原子形成4-12元杂环烷基，所述4-12元杂环烷基可任选被1-3个下列基团所取代：H、OH、卤素、氰基、C1-C3烷基、C3-C6环烷基、杂环烷基、(C1-C3)烷氧基和(卤代C1-C3)烷氧基。 R ⁵ and R ⁶ are independently C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, methylsulfonyl-substituted C1-C3 alkyl, C3- C6 cycloalkyl, (C1-C3)alkoxy substituted (C2-C3)alkyl, (haloC1-C3)alkoxy substituted (C2-C3)alkyl or (C3-C6)cycloalkane (C1-C3) alkyl group substituted by a group, or a total of N atoms of R ⁵ and R ⁶ form a 4-12-membered heterocycloalkyl, which may be optionally replaced by 1-3 of the following groups group substituted: H, OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3)alkoxy and (haloC1-C3)alkoxy .

在另一优选例中，其中所述通式(1)中，R ¹为乙烯基或环丙基；R ⁴优选为乙烯基。 In another preferred example, in the general formula (1), R ¹ is vinyl or cyclopropyl; R ⁴ is preferably vinyl.

在另一优选例中，其中所述通式(1)中，R ²为CH ₃O-、CH ₃CH ₂O-、(CH ₃) ₂CHO-、CF ₃CH ₂O-或CHF ₂CH ₂O-；R ²优选为CH ₃CH ₂O-、CF ₃CH ₂O-或CHF ₂CH ₂O-。 In another preferred embodiment, in the general formula (1), R ² is CH ₃ O-, CH ₃ CH ₂ O-, (CH ₃ ) ₂ CHO-, CF ₃ CH ₂ O- or CHF ₂ CH ₂ O-; R ² is preferably CH ₃ CH ₂ O-, CF ₃ CH ₂ O- or CHF ₂ CH ₂ O-.

在另一优选例中，其中所述通式(1)中，R ³为

R ³优选为

R ³更优选为

In another preferred embodiment, in the general formula (1), R ³ is

R ³ is preferably

^R is more preferably

在另一优选例中，其中所述通式(1)中，R ⁴为H或F；R ⁴优选为H。 In another preferred example, in the general formula (1), R ⁴ is H or F; R ⁴ is preferably H.

在另一优选例中，其中所述通式(1)中，

为

优选为

更优选为

In another preferred embodiment, wherein in the general formula (1),

for

preferably

more preferably

在各种不同实施方式中，本发明代表性化合物具有以下结构之一：In various embodiments, representative compounds of the present invention have one of the following structures:

本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) of the present invention, or each of its isomers, Each crystal form, pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.

本发明的再一个目的提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与RAS相关疾病的药物中的应用。Another object of the present invention provides the compound represented by the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition of the present invention Use in the preparation of medicines for treating, regulating or preventing RAS-related diseases.

本发明的再一个目的还提供治疗、调节或预防与RAS相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。Another object of the present invention also provides a method for treating, regulating or preventing RAS-related diseases, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each isomer thereof , each crystal form, a pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition.

通过合成和仔细研究了多类涉及具有K-RAS G12C抑制作用的新化合物，发明人发现在通式(1)化合物中，当侧链为桥环结构时，化合物具有很强的K-RAS G12C抑制活性。Through the synthesis and careful study of various new compounds involving K-RAS G12C inhibition, the inventors found that in the compound of general formula (1), when the side chain is a bridged ring structure, the compound has a strong K-RAS G12C inhibitory activity.

应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

化合物的合成compound synthesis

下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。The preparation method of the compound of the general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.

以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 ^th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 ^th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 ^rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。 The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS ^3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by the use of appropriate reagents and conditions for the introduction of various groups into the formulae provided herein.

一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式(1)化合物可采用下列一般反应流程1制备：In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following general reaction scheme 1:

一般反应流程1General Reaction Scheme 1

通式(1)化合物的实施方式可根据一般反应流程1制备，其中m、n、v、R ¹、R ²、R ³、R ⁴、R ⁵和R ⁶如上文中所定义，PG表示保护基。如一般反应流程1所示,化合物A和化合物B反应生成化合物C，化合物C关环得到生成化合物D，化合物D和T ²H在 强碱性条件下E经缩合反应生成化合物F，合物F脱除保护基得到化合物G，化合物G和化合物H反应得到目标化合物I。 Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein m, n, v, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, and PG represents a protecting group . As shown in the general reaction scheme 1, compound A reacts with compound B to generate compound C, compound C is closed to obtain compound D, compound D and T ² H undergo condensation reaction under strong basic conditions to generate compound F, compound F Removal of the protecting group gives compound G, and compound G reacts with compound H to obtain target compound I.

化合物的进一步形式further forms of compounds

“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。"Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.

术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。The term "pharmaceutically acceptable salt" refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of general formula (1) with an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, etc. , propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.

应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。It should be understood that references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent. The organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。In other specific embodiments, compounds of general formula (1) are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms. In addition, the compound of the general formula (1) includes a crystalline form and can also be a polymorph. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.

在另一个方面，通式(1)化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。In another aspect, compounds of general formula (1) may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( ³H)、碘-125( ¹²⁵I)和C-14( ¹⁴C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), and C-14 ( ¹⁴ C). For another example, a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

术语the term

如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。Unless otherwise stated, terms used in the present application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular form "a" includes the plural unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were used unless otherwise stated. In this application, the use of "or" or "and" means "and/or" unless stated otherwise.

除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH ₃、CH ₃CH ₂、CF ₃、CHF ₂、CF ₃CH ₂、CF ₃(CH ₃)CH、 ⁱPr、 ⁿPr、 ⁱBu、 ⁿBu或 ^tBu。 Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from _CH3 , _CH3CH2 , _CF3 , _CHF2 , _CF3CH2 , _CF3 ( _{CH3 ) CH} , ^iPr , ^nPr , ^iBu , ^nBu or ^tBu .

除非另有规定，“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至14个碳原子的直链或支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.

除非另有规定，“炔基”指含有碳-碳叁键的不饱和脂肪烃基团，包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级炔基，例如乙炔基、1-丙炔基或1-丁炔基。Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, are preferred.

除非另有规定，“环烷基”是指非芳香族烃环***(单环、双环或多环)，如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫离子基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳 基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and if the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl" alkenyl", or if the carbocycle contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl". Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form oxo or thiol groups. Cycloalkyl also includes cycloalkylene. In some embodiments, the cycloalkyl group contains 0, 1 or 2 double bonds. In some embodiments, cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, cycloalkyl groups can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexane and the like.

除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH ₃、OCF ₃、CHF ₂O、CF ₃CH ₂O、 ^i-PrO、 ^n-PrO、 ^i-BuO、 ^n-BuO或 ^t-BuO。 Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens. Preferred alkoxy groups are selected from _OCH3 , OCF3, _CHF2O , _CF3CH2O , ⁱ _- PrO, ^n- _PrO , ^i- BuO, ^n- BuO or ^t- BuO.

除非另有规定，“杂环烷基”指非芳香族环或环***，其可以任选地含有一个或多个亚烯基作为环结构的一部分，其具有至少一个独立地选自硼、磷、氮、硫、氧和磷的杂原子环成员。如果杂环烷基含有至少一个双键，那么部分不饱和杂环烷基可被称为“杂环烯基”，或如果杂环烷基含有至少一个三键，那么部分不饱和杂环烷基可被称为“杂环炔基”。杂环烷基可以包括单环、双环、螺环或多环(例如具有两个稠合或桥接环)环***。在一些实施例中，杂环烷基为具有1、2或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可以任选地氧化以形成氧代或硫离子基或其他氧化键(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等)，或氮原子可以季铵化。杂环烷基可以经由成环碳原子或成环杂原子而连接。在一些实施例中，杂环烷基含有0至3个双键。在一些实施例中，杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即，与其共用键)的芳香族环的部分，例如哌啶、吗啉、氮杂环庚三烯或噻吩基等的苯并衍生物。含有稠合芳香族环的杂环烷基可以经由任何成环原子，包括稠合芳香族环的成环原子而连接。杂环烷基的实例包括但不限于氮杂环丁基、氮杂环庚基、二氢苯并呋喃基、二氢呋喃基、二氢吡喃基、N-吗啉基、3-氧杂-9-氮杂螺[5.5]十一烷基、1-氧杂-8-氮杂螺[4.5]癸烷基、哌啶基、哌嗪基、氧代哌嗪基、吡喃基、吡咯烷基、奎宁基、四氢呋喃基、四氢吡喃基、1,2,3,4-四氢喹啉基、莨菪烷基、4,5,6,7-四氢噻唑并[5,4-c]吡啶基、4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶、N-甲基哌啶基、四氢咪唑基、吡唑烷基、丁内酰胺基、戊内酰胺基、咪唑啉酮基、乙内酰脲基、二氧戊环基、邻苯二甲酰亚胺基、嘧啶-2,4(1H,3H)-二酮基、1,4-二氧六环基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物基、硫代吗啉-S,S-氧化物基、哌嗪基、吡喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氢噻吩基、2-氮杂螺[3.3]庚烷基、吲哚啉基、

Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one , nitrogen, sulfur, oxygen and phosphorus heteroatom ring members. A partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl" if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond May be referred to as "heterocycloalkynyl". Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (eg, having two fused or bridged rings) ring systems. In some embodiments, a heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (eg C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. A heterocycloalkyl group can be attached via a ring carbon atom or a ring heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (ie, sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azacyclotriene or Benzo derivatives of thienyl and the like. A heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom, including a ring-forming atom of a fused aromatic ring. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidine, butyrolactone Amido, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1 ,4-dioxane, morpholinyl, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl , pyridone, 3-pyrroline, thiopyranyl, pyranone, tetrahydrothienyl, 2-azaspiro[3.3]heptyl, indolinyl,

除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen-substituted") appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.

“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

取代基“-O-CH ₂-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如：

Substituent "-O-CH ₂ -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:

当一个连接基团的数量为0时，比如-(CH ₂) ₀-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a single bond.

当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.

术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。The term "membered ring" includes any cyclic structure. The term "membered" is meant to denote the number of backbone atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings, and cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.

术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。The term "fragment" refers to a specific portion or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity contained in or attached to a molecule.

除非另有说明，用楔形实线键

和楔形虚线键

表示一个立体中心的绝对构型，用直形实线键

和直形虚线键

表示立体中心的相对构型，用波浪线

表示楔形实线键

或楔形虚线键

或用波浪线

表示直形实线键

或直形虚线键

Use solid wedge keys unless otherwise specified

and wedge-dotted keys

Indicate the absolute configuration of a stereocenter, using a straight solid key

and straight dashed keys

Indicate the relative configuration of the stereocenter, with a wavy line

Represents a solid wedge key

or wedge-dotted key

or with wavy lines

Represents a straight solid key

or straight dashed key

除非另有说明，用

表示单键或双键。 Unless otherwise specified, use

Indicates a single or double bond.

特定药学及医学术语Certain Pharmacy and Medical Terms

术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。The term "acceptable", as used herein, refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.

术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可 以归因于或与给药有关的情况。The terms "treatment", "course of treatment" or "therapy" as used herein include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, conditions may be attributable to or related to the administration.

“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。"Active ingredient" refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers. The number of asymmetric centers that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein, and all refer to when administered to an individual (human or animal), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。The term "administered, administering or, administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.

虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。Notwithstanding that the numerical ranges and parameters setting forth the broader scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains the standard deviation resulting from individual testing methods. As used herein, "about" generally means within plus or minus 10%, 5%, 1%, or 0.5% of the actual value of a particular value or range. Alternatively, the word "about" means that the actual value lies within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless expressly stated otherwise, all ranges, quantities, values and percentages used herein (for example, to describe material amounts, time durations, temperatures, operating conditions, quantity ratios and the like) should be understood ) are modified by "about". Accordingly, unless stated to the contrary, the numerical parameters disclosed in this specification and the appended claims are approximations that can be modified as required. At a minimum, these numerical parameters should be construed to mean the number of significant digits indicated and the numerical values obtained using ordinary rounding.

除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。Unless otherwise defined in this specification, scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless contradicting the context, the singular noun used in this specification covers the plural form of the noun; and the plural noun used also covers the singular form of the noun.

治疗用途therapeutic use

本发明提供了使用本发明通式(1)化合物或药物组合物治疗疾病的方法，包括但不限于涉及G12C K-Ras、G12C H-Ras和/或G12C N-Ras突变的病况(例如癌症)。The present invention provides methods of treating diseases, including but not limited to, conditions involving mutations in G12C K-Ras, G12CH H-Ras and/or G12C N-Ras (eg, cancer) using the compounds or pharmaceutical compositions of the present invention of general formula (1) .

在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的包括结构通式(1)化合物的药物组合物。在一些实施例中，癌症由K-Ras、 H-Ras和/或G12C N-Ras突变介导。在其它实施方案中，该癌症是肺癌、胰腺癌、结肠癌、MYH相关息肉病或结肠直肠癌。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于白血病、乳腺癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、***癌、肝癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。In some embodiments, methods for cancer treatment are provided, the methods comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of general structural formula (1). In some embodiments, the cancer is mediated by K-Ras, H-Ras and/or G12C N-Ras mutations. In other embodiments, the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-associated polyposis, or colorectal cancer. In other embodiments, the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.

给药途径Route of administration

本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：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。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount. . The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective dose of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.

“药学上可以接受的赋形剂或载体”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份能与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。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温

)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity . "Compatibility" as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants ( Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween)

), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.

用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

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。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.

除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

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。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

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。Dosage forms for topical administration of the compounds of this 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 if necessary.

本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above features mentioned in the present invention or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in this specification can be used in combination with any composition, and each feature disclosed in the specification can be replaced by any alternative features that serve the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.

具体实施方式Detailed ways

在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了 具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。In the following description, various specific aspects, properties and advantages of the above-described compounds, methods, and pharmaceutical compositions will be set forth in detail so that the content of the present invention will become apparent. It should be understood herein that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by the present application.

所有实施例中， ¹H-NMR用Vian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。 In all examples, ¹ H-NMR was recorded with a Vian Mercury 400 nuclear magnetic resonance apparatus, and chemical shifts were expressed in δ (ppm); silica gel for separation was 200-300 mesh not specified, and the proportions of eluents were all volume ratios.

本发明采用下述缩略词：BOP代表苯并***-1-三(三甲氨基)-三氟磷酸酯；DBU代表1,8-二氮杂环十一烯；DCM代表二氯甲烷；DMF代表二甲基甲酰胺；EA代表乙酸乙酯；HPLC代表液相色谱仪；K ₂CO ₃代表碳酸钾；MeOH代表甲醇；min代表分钟；MS代表质谱；NMR代表核磁共振；TFA(CF ₃COOH)代表三氟乙酸；TLC代表薄层色谱；THF代表四氢呋喃。 The following abbreviations are used in the present invention: BOP stands for benzotriazole-1-tris(trimethylamino)-trifluorophosphate; DBU stands for 1,8-diazacycloundecene; DCM stands for dichloromethane; DMF stands for dimethylformamide; EA stands for ethyl acetate; HPLC stands for liquid chromatography; K ₂ CO ₃ stands for potassium carbonate; MeOH stands for methanol; min stands for minutes; MS stands for mass spectrometry; NMR stands for nuclear magnetic resonance; TFA (CF ₃ COOH ) represents trifluoroacetic acid; TLC represents thin layer chromatography; THF represents tetrahydrofuran.

实施例1 1-(7-(7-(5-甲基-1H-吲唑-4-基)-2-(3-(吡咯烷-1-基)双环[1.1.1]戊烷-1-基)-8-(2,2,2-三氟乙氧基-6-乙烯基喹唑啉-4-基)-2,7-二氮杂螺[3.5]壬-2-基)丙-2-烯-1-酮(化合物1)的合成Example 1 1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(3-(pyrrolidin-1-yl)bicyclo[1.1.1]pentane-1 -yl)-8-(2,2,2-trifluoroethoxy-6-vinylquinazolin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)propane Synthesis of -2-en-1-one (Compound 1)

步骤1：化合物1-3的合成Step 1: Synthesis of Compounds 1-3

于50mL单口瓶中依次加入1-1(1.6g,2.94mmol,1eq)的THF(25mL)溶液，1-2(586 mg,2.94mmol,1eq)，体系升温至40℃，搅拌30min,TLC检测反应完全。体系浓缩得粗品，粗品经柱层析分离得淡黄色固体1-3(1.33g,收率64％)，LC-MS:708.3[M+H] ⁺。 In a 50mL single-necked flask, the THF (25mL) solution of 1-1 (1.6g, 2.94mmol, 1eq) and 1-2 (586mg, 2.94mmol, 1eq) were added successively, the system was heated to 40°C, stirred for 30min, and detected by TLC The reaction is complete. The system was concentrated to obtain a crude product, and the crude product was separated by column chromatography to obtain a pale yellow solid 1-3 (1.33 g, yield 64%), LC-MS: 708.3 [M+H] ⁺ .

步骤2：化合物1-4的合成Step 2: Synthesis of Compounds 1-4

于100mL单口瓶中加入1-3(1.33g,1.88mmol,1eq)的THF(10mL)溶液，然后在体系中加入浓氨水，调至pH＝11,体系升温至40℃，搅拌12h，TLC检测原料反应完全。体系经DCM(30mL*2)萃取，合并有机相，饱和食盐水洗涤，干燥浓缩得粗品，粗品经柱层析分离得白色固体1-4(600mg,收率46％)，LC-MS:690.3[M+H] ⁺。 Add 1-3 (1.33g, 1.88mmol, 1eq) of THF (10mL) solution to a 100mL single-neck bottle, then add concentrated ammonia water to the system, adjust to pH=11, heat the system to 40°C, stir for 12h, and detect by TLC The raw materials reacted completely. The system was extracted with DCM (30 mL*2), the organic phases were combined, washed with saturated brine, dried and concentrated to obtain the crude product, which was separated by column chromatography to obtain a white solid 1-4 (600 mg, yield 46%), LC-MS: 690.3 [M+H] ⁺ .

步骤3：化合物1-6的合成Step 3: Synthesis of Compounds 1-6

于50mL单口瓶中依次加入1-4(600mg,0.87mmol,1eq),1-5(295mg,1.30mmol,1.5eq),DMF(20mL,dry)，在冰水浴下依次加入DBU(793mg,5.22mmol,6eq),BOP(960mg,2.17mmol,2.5eq)，体系升温至45℃，搅拌1h，原料反应完全。体系经EA(50mL*2)萃取，合并有机相，饱和食盐水洗涤3次，干燥浓缩，粗品经柱层析分离得固体1-6(550mg,收率70％)，LC-MS:898.4[M+H] ⁺。 1-4 (600mg, 0.87mmol, 1eq), 1-5 (295mg, 1.30mmol, 1.5eq), DMF (20mL, dry) were added to the 50mL single-necked bottle in turn, and DBU (793mg, 5.22mg) was added successively in an ice-water bath. mmol, 6eq), BOP (960mg, 2.17mmol, 2.5eq), the system was heated to 45°C, stirred for 1h, the reaction of the raw materials was complete. The system was extracted with EA (50 mL*2), the organic phases were combined, washed with saturated brine 3 times, dried and concentrated, and the crude product was separated by column chromatography to obtain solid 1-6 (550 mg, yield 70%), LC-MS: 898.4 [ M+H] ⁺ .

步骤4：化合物1-7的合成Step 4: Synthesis of Compounds 1-7

于50mL单口瓶中依次加入1-6(550mg,0.61mmol,1eq)的甲醇(20mL)溶液，K ₂CO ₃(761mg,5.51mmol,9eq)，巯基乙酸(226mg,2.44mmol,4eq)，体系升温至70℃，搅拌30min，原料反应完全。体系经EA(50mL*2)萃取，合并有机相，干燥浓缩，粗品经柱层析分离得固体1-7(318mg,70％)，LC-MS:744.4[M+H] ⁺。 In a 50mL single-necked flask, add methanol (20mL) solution of 1-6 (550mg, 0.61mmol, 1eq), K ₂ CO ₃ (761mg, 5.51mmol, 9eq), thioglycolic acid (226mg, 2.44mmol, 4eq), and the system The temperature was raised to 70° C. and stirred for 30 min, and the reaction of the raw materials was completed. The system was extracted with EA (50 mL*2), the organic phases were combined, dried and concentrated, and the crude product was separated by column chromatography to obtain solid 1-7 (318 mg, 70%), LC-MS: 744.4 [M+H] ⁺ .

步骤5：化合物1-8的合成Step 5: Synthesis of Compounds 1-8

于50mL单口瓶中加入1-7(318mg,0.43mmol,1eq)的DCM/TFA＝5/1(10mL/2mL)溶液，室温搅拌1h，原料反应完全。体系浓缩，用饱和碳酸氢钠水溶液调节pH至碱性，经抽滤，冻干得粗品1-8(280mg)，LC-MS:644.3[M+H] ⁺。 A solution of 1-7 (318 mg, 0.43 mmol, 1 eq) in DCM/TFA=5/1 (10 mL/2 mL) was added to a 50 mL single-necked bottle, stirred at room temperature for 1 h, and the reaction of the raw materials was complete. The system was concentrated, the pH was adjusted to alkaline with saturated aqueous sodium bicarbonate solution, filtered with suction, and lyophilized to obtain crude product 1-8 (280 mg), LC-MS: 644.3 [M+H] ⁺ .

步骤6：化合物1的合成Step 6: Synthesis of Compound 1

于50mL单口瓶中依次加入1-8(280mg,粗品)的MeOH(25mL)溶液，加入咪唑(120mg,1.74mmol,4eq)搅拌，冰水浴下加入丙烯酸酐(55mg,0.43mmol,1eq)，搅拌30min，原料反应完全。反应液用饱和食盐水洗，有机相干燥浓缩，经HPLC分离得白色固体化合物1(230mg,收率％)。Add 1-8 (280mg, crude product) MeOH (25mL) solution to a 50mL single-necked bottle in turn, add imidazole (120mg, 1.74mmol, 4eq) and stir, add acrylic anhydride (55mg, 0.43mmol, 1eq) under ice-water bath, stir 30min, the raw material reacts completely. The reaction solution was washed with saturated brine, the organic phase was dried and concentrated, and a white solid compound 1 (230 mg, yield %) was obtained by HPLC separation.

¹H NMR(400MHz,DMSO-d ₆)δ:13.01(s,1H),7.98(s,1H),7.49(d,J＝8.5Hz,1H),7.40(s,1H),7.32(d,J＝8.6Hz,1H),6.35(dd,J＝17.0,10.3Hz,1H),6.18-6.03(m,2H),5.81-5.64(m,2H),5.11(d,J＝11.3Hz,1H),5.03-4.90(m,1H),4.73-4.60(m,1H),4.04(s,2H),3.76(s,6H),2.58(s,4H),2.13-1.92(m,13H),1.72(s,4H),LC-MS:698.3[M+H] ⁺。 ¹ H NMR (400MHz, DMSO-d ₆ )δ: 13.01(s, 1H), 7.98(s, 1H), 7.49(d, J=8.5Hz, 1H), 7.40(s, 1H), 7.32(d, J=8.6Hz,1H),6.35(dd,J=17.0,10.3Hz,1H),6.18-6.03(m,2H),5.81-5.64(m,2H),5.11(d,J=11.3Hz,1H) ), 5.03-4.90(m, 1H), 4.73-4.60(m, 1H), 4.04(s, 2H), 3.76(s, 6H), 2.58(s, 4H), 2.13-1.92(m, 13H), 1.72 (s, 4H), LC-MS: 698.3 [M+H] ⁺ .

实施例2-79化合物2-79的合成Example 2-79 Synthesis of Compound 2-79

采用不同原料，根据实施例1中类似的合成方法得到目标化合物2-79。Using different starting materials, the target compound 2-79 was obtained according to the synthetic method similar to that in Example 1.

表1Table 1

实施例80化合物1的手性拆分Example 80 Chiral Resolution of Compound 1

本申请的化合物可以有轴手性。有轴手性的化合物可以拆分得到二个手性异构体。The compounds of the present application may have axial chirality. Compounds with axial chirality can be resolved into two chiral isomers.

将适量化合物1溶于乙醇中，配制浓度为10mg/mL的供试品溶液，取上述供试品溶 液，注入制备液相色谱仪，按照本发明色谱条件进行检测并记录数据。制备型色谱条件:采用日本岛津LC-20AP制备液相色谱仪；色谱柱:UniChiral CMD-5H(30×250mm，5um)；流动相:乙醇/正己烷＝20/80；流速：30.0mL/min；检测波长:254nm；进样量:1000μL。经手性分离得到1-a和1-b，保留时间分别是6.238min和7.952min，ee％值分别是100和98.95。Dissolve an appropriate amount of compound 1 in ethanol, prepare a test solution with a concentration of 10 mg/mL, get the above test solution, inject it into a preparative liquid chromatograph, and detect and record data according to the chromatographic conditions of the present invention. Preparative chromatographic conditions: Japan Shimadzu LC-20AP preparative liquid chromatograph; chromatographic column: UniChiral CMD-5H (30×250mm, 5um); Mobile phase: ethanol/n-hexane=20/80; Flow rate: 30.0mL/ min; detection wavelength: 254 nm; injection volume: 1000 μL. 1-a and 1-b were obtained by chiral separation with retention times of 6.238 min and 7.952 min, and ee% values of 100 and 98.95, respectively.

本申请中的其它化合物也可以用相似的方法进行手性拆分，如化合物67通过手性拆分得到67-a和67-b：Other compounds in this application can also be chiral resolved by a similar method, such as compound 67 by chiral resolution to obtain 67-a and 67-b:

实施例81本发明化合物对H358细胞的抗增殖活性Example 81 Antiproliferative activity of the compounds of the present invention on H358 cells

2500个H358细胞每孔种植于超低吸附的96孔板(corning,7007)中，生长一天后，加入梯度稀释化合物(最高5μM,5倍稀释，一共五个剂量)，加入化合物三天后，加入Cell Titer Glow(Promega,G9681)评价小球的生长情况，计算IC ₅₀值，结果见下列表2。 2500 H358 cells per well were seeded in an ultra-low adsorption 96-well plate (corning, 7007). After one day of growth, the compound was added in a series of dilutions (up to 5 μM, 5-fold dilution, a total of five doses). Three days after the compound was added, the compound was added Cell Titer Glow (Promega, G9681) evaluated the growth of the pellets and calculated the _IC50 value. The results are shown in Table 2 below.

表2.本发明化合物对H358细胞的抗增殖活性Table 2. Antiproliferative activity of compounds of the invention on H358 cells

化合物compound	IC 50 IC50	化合物compound	IC 50 IC50	化合物compound	IC 50 IC50
11	++++++	22	++++++	33	++++++
44	++++++	55	++++++	66	++++++
77	++++	88	++++++	99	++++++
1010	++++++	1111	++++++	1212	++++++
1313	++++++	1414	++++++	1515	++++++
1616	++++++	1717	++++++	1818	++++++
1919	++++++	2020	++++++	21twenty one	++++++
22twenty two	++++	23twenty three	++++++	24twenty four	++++++
2525	++++++	2626	++++++	2727	++++
2828	++++	2929	++++	3030	++++++
3131	++++++	3232	++++++	3333	++++++
3434	++++++	3535	++++	3636	++++
3737	++++++	3838	++++++	3939	++++++
4040	++++	4141	++++++	4242	++++++
4343	++++++	4444	++++++	4545	++++++
4646	++++++	4747	++++++	4848	++++
4949	++++++	5050	++++++	5151	++++
5252	++++++	5353	++++++	5454	++++++
5555	++++++	5656	++++++	5757	++++++
5858	++++++	5959	++++++	6060	++++++
6161	++++++	6262	++++++	6363	++++++
6464	++++	6565	++++++	6666	++++
6767	++++++	6868	++++++	6969	++++++
7070	++++++	7171	++++++	7272	++++++
7373	++++++	7474	++++++	7575	++++++
7676	++++++	7777	++++++	7878	++++++
7979	++++++	1-a1-a	++++++	1-b1-b	++++++
67-a67-a	++++++	67-b67-b	++++++	AA	++++++

+表示化合物的·IC ₅₀大于1μM + indicates a compound with _IC50 greater than 1 μM

++表示化合物的IC ₅₀为0.3至1μM ++ indicates that the compound has an _IC50 of 0.3 to 1 μM

+++表示化合物的IC ₅₀小于0.3μM。 +++ indicates that the compound has an _IC50 of less than 0.3 μM.

从表2数据可知，本发明化合物对H358细胞的抗增殖活性绝大多数化合物都小于0.3μM，充分说明本发明侧链中含有螺环结构的化合物具有很强的K-RAS G12C抑制活性。It can be seen from the data in Table 2 that the antiproliferative activity of the compounds of the present invention on H358 cells is less than 0.3 μM, which fully demonstrates that the compounds containing the spiro ring structure in the side chain of the present invention have strong K-RAS G12C inhibitory activity.

实施例82小鼠体内抗肿瘤活性评价Example 82 Evaluation of antitumor activity in mice

人胰腺癌Mia PaCa-2细胞用含10％胎牛血清的1640于37℃、5％CO ₂培养箱中常规培养，传代后，待细胞达到所需量时，收集细胞。将1×10 ⁷个Mia PaCa-2细胞注射入每只裸小鼠左侧背部，待肿瘤生长至400mm ³后，将动物随机分组开始给药。分别为1)溶剂对照组，8只；2)化合物1组、化合物67组和化合物A组，每组8只。溶剂对照组每天两次灌胃0.5％CMC-Na；化合物1组、化合物67组和化合物A组每天一次灌胃化合物0.5％CMC-Na悬浮液。每周二、四测定肿瘤体积，测量小鼠体重，于给药第21天处死裸小鼠，试验结果见下表3。 Human pancreatic cancer Mia PaCa-2 cells were routinely cultured with 1640 containing 10% fetal bovine serum in a 37°C, 5% _CO2 incubator, and after passage, when the cells reached the required amount, the cells were collected. 1×10 ⁷ Mia PaCa-2 cells were injected into the left back of each nude mouse. After the tumor grew to 400 mm ³ , the animals were randomly divided into groups and started to be administered. They were 1) solvent control group, with 8 animals; 2) compound 1 group, compound 67 group and compound A group, with 8 animals in each group. The solvent control group was intragastrically administered 0.5% CMC-Na twice a day; the compound 1 group, the compound 67 group and the compound A group were intragastrically administered compound 0.5% CMC-Na suspension once a day. The tumor volume was measured every Tuesday and Thursday, and the body weight of the mice was measured. Nude mice were sacrificed on the 21st day of administration. The test results are shown in Table 3 below.

表3.化合物对人胰腺癌Mia PaCa-2裸小鼠移植瘤的实验治疗作用Table 3. Experimental therapeutic effects of compounds on human pancreatic cancer Mia PaCa-2 xenografts in nude mice

化合物compound	剂量(mg/kg)Dosage (mg/kg)	给药方案dosing regimen	抗肿瘤作用Anti-tumor effect
11	1010	qd*21qd*21	36％退缩36% back off
6767	1010	qd*21qd*21	32％退缩32% back off
AA	1010	qd*21qd*21	25％退缩25% back off

由上表数据可知，本发明化合物具有很强的体内抗肿瘤活性，10mg/kg/day连续给药21天后可以使肿瘤退缩，化合物1和67体内活性均强于对照药物A。It can be seen from the data in the above table that the compounds of the present invention have strong anti-tumor activity in vivo. After continuous administration of 10 mg/kg/day for 21 days, the tumor can regress. Compounds 1 and 67 have stronger in vivo activities than control drug A.

虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims (9)

1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

   

   

   通式(1)中：In general formula (1):

   m、n和v独立为1或2的整数；m, n and v are independently integers of 1 or 2;

   R ¹为C2-C4烯基或C3-C6环烷基； R ¹ is C2-C4 alkenyl or C3-C6 cycloalkyl;

   R ²为C1-C3烷氧基或卤代C1-C3烷氧基； R ² is C1-C3 alkoxy or halogenated C1-C3 alkoxy;

   R ³为

   

   其中R ^a、R ^b和R ^c独立为H、F、Cl或Me，R ^d为H、F、Cl、NH ₂、Me或环丙基； ^R3 is

   

   wherein R ^a , R ^b and R ^c are independently H, F, Cl or Me, and R ^d is H, F, Cl, NH ₂ , Me or cyclopropyl;

   R ⁴为H或卤素； R ⁴ is H or halogen;

   R ⁵和R ⁶独立为C1-C3烷基、卤代C1-C3烷基、羟基取代C1-C3烷基、氰基取代C1-C3烷基、甲砜基取代C1-C3烷基、C3-C6环烷基、(C1-C3)烷氧基取代的(C2-C3)烷基、(卤代C1-C3)烷氧基取代的(C2-C3)烷基或(C3-C6)环烷基取代的(C1-C3)烷基，或R ⁵和R ⁶共N原子形成4-12元杂环烷基，所述4-12元杂环烷基可任选被1-3个下列基团所取代：H、OH、卤素、氰基、C1-C3烷基、C3-C6环烷基、杂环烷基、(C1-C3)烷氧基和(卤代C1-C3)烷氧基。 R ⁵ and R ⁶ are independently C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, methylsulfonyl-substituted C1-C3 alkyl, C3- C6 cycloalkyl, (C1-C3)alkoxy substituted (C2-C3)alkyl, (haloC1-C3)alkoxy substituted (C2-C3)alkyl or (C3-C6)cycloalkane (C1-C3) alkyl group substituted by a group, or a total of N atoms of R ⁵ and R ⁶ form a 4-12-membered heterocycloalkyl, which may be optionally replaced by 1-3 of the following groups group substituted: H, OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3)alkoxy and (haloC1-C3)alkoxy .
2. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R ¹为乙烯基或环丙基。 The compound according to claim 1 or each of its isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R ¹ is vinyl or cyclic propyl.
3. 如权利要求1或2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R ²为CH ₃O-、CH ₃CH ₂O-、(CH ₃) ₂CHO-、CF ₃CH ₂O-或CHF ₂CH ₂O-。 The compound according to claim 1 or 2, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R ² is CH _{3 O-} , _CH3CH2O- , _{( CH3 ) 2CHO-} , _CF3CH2O- or _CHF2CH2O- .
4. 如权利要求1-3中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R ³为

   

   

   The compound according to any one of claims 1-3, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R ³ for

   

   
5. 如权利要求1-4中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R ⁴为H或F。 The compound according to any one of claims 1-4, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R ⁴ is H or F.
6. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，

   

   为

   

   

   The compound according to any one of claims 1-5, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1),

   

   for

   

   

   

   
7. 如权利要求1-6中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：The compound of any one of claims 1-6, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:

   

   

   

   

   

   

   

   

   

   

   

   
8. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-7中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-7, or each isomer, each crystal form, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
9. 一种如权利要求1-7中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求8所述的药物组合物在制备治疗K-Ras G12C突变体蛋白相关疾病药物中的应用。A compound as claimed in any one of claims 1-7, or each of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the drug of claim 8 Application of the composition in the preparation of a medicine for treating K-Ras G12C mutant protein-related diseases.