Spirocyclic quinazoline derivatives

Abstract

The application discloses a quinazoline derivative containing a spiro ring. Specifically, the application relates to a compound shown in a general formula (1) and a preparation method of the compound, and application of the compound shown in the general formula (1) and each isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate of the compound as an irreversible inhibitor of G12C mutant K-Ras protein in preparation of a drug for resisting a tumor and other Ras-related diseases.

Description

[0001] This application claims priority to Chinese application CN202110182364.6, filed on February 9, 2021. The full text of the aforementioned Chinese application is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of medicinal chemistry, and more specifically, to a class of spirocyclic quinazoline compounds, their preparation methods, and the use of such compounds as K-Ras G12C inhibitors in the preparation of antitumor drugs. Background Technology

[0003] The Ras protein family consists of important intracellular signal transduction molecules that play a crucial role in growth and development. Extensive analysis and research of in vitro tumor cells, animal models, and human tumor samples have shown that overactivation of Ras family proteins is an early event in human tumor development and a significant contributing factor to the occurrence and progression of various cancers. Therefore, targeting and inhibiting Ras protein activity is an important approach for treating related tumors.

[0004] Ras protein exists in two forms: it binds to GDP and remains in an inactive, quiescent state; however, when cells receive signals such as growth factor stimulation, Ras protein binds to GTP and becomes activated. Activated Ras protein recruits various signal transduction proteins, promoting the phosphorylation of downstream signaling molecules such as ERK and S6, thereby activating the Ras signaling pathway and regulating cell growth, survival, migration, and differentiation. Ras protein's own GTPase activity can hydrolyze GTP back to GDP. Furthermore, the interaction between Ras and intracellular GTPase-activating proteins (GAPs) significantly promotes Ras GTPase activity, thus preventing overactivation of Ras protein.

[0005] Mutations in the K-Ras, H-Ras, and N-Ras proteins of the Ras protein family are among the most common gene mutations in various tumors and are major factors leading to the overactivation of Ras proteins in tumors. Compared to wild-type Ras proteins, these mutations result in unregulated Ras protein activity, stable binding to GTP, and continuous activation, thereby promoting tumor cell growth, migration, and differentiation. K-Ras protein mutations are 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 prevalent in various cancers, including pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (25%), but relatively rare in breast cancer, ovarian cancer, and brain cancer (<2%). K-Ras mutation sites are mainly concentrated at the G12 position, with G12C mutations being the most common. For example, in non-small cell lung cancer (NSCLC), 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 NSCLC do not coexist with EGFR, ALK, ROS1, RET, and BRAF mutations, but do coexist with STK11, KEAP1, and TP53 mutations, suggesting that K-Ras mutations may synergistically participate in malignant transformation, proliferation, and invasion of cells with STK11, KEAP1, and TP53 mutations. Besides tumors, abnormal activation of Ras proteins is also involved in non-tumor diseases including diabetes and neurodegenerative diseases. Therefore, small molecule compounds targeting Ras proteins could benefit a large number of cancer patients carrying specific gene variants and non-cancer patients with overactivated Ras pathways.

[0006] Forty years since Ras mutations were discovered in tumors, although our understanding of the pathogenic mechanism of the Ras pathway has deepened, there are still no effective Ras protein-targeting therapies available clinically for patients with a large number of Ras protein mutations and overactivation of the Ras pathway. Therefore, developing highly active small molecule inhibitors targeting Ras proteins, especially the K-Ras G12C protein with a high mutation frequency, is of great clinical significance.

[0007] K-Ras G12C mutant protein is a cutting-edge drug target, but current research is limited, with only a few compounds entering clinical trials, such as Amgen's AMG510 and Mirati's MRTX849. In 2018, Cell reported a covalent inhibitor targeting the K-Ras G12C mutation, ARS-1620 [Cell, 2018, 172:578-589]. Patents WO2018 / 143315 and WO2020 / 216190 reported a class of spirocyclic compounds possessing K-Ras G12C activity and in vivo antitumor activity in mice. The structures of compound A (Example 35 in patent WO2018 / 143315) and compound B (Example 1 in patent WO2020 / 216190) are as follows:

[0008]

[0009] Currently, there is an urgent need to research and discover compounds with good K-Ras G12C activity. Summary of the Invention

[0010] This invention provides a compound of general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0011]

[0012] In general formula (1):

[0013] m, n, and v are independent integers of 1 or 2;

[0014] R 1 It is C2-C4 alkenyl or C3-C6 cycloalkyl;

[0015] R 2 It is a C1-C3 alkoxy or a halo-C1-C3 alkoxy;

[0016] R 3 for Where R a R b and R c Independently, H, F, Cl or Me, R d It can be H, F, Cl, NH2, Me, or cyclopropyl;

[0017] R 4 It is H or halogen;

[0018] R 5 and R 6Independently defined as C1-C3 alkyl, halo-C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, sulfone-substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-substituted (C2-C3)alkyl, (halo-C1-C3)alkoxy-substituted (C2-C3)alkyl, or (C3-C6)cycloalkyl-substituted (C1-C3)alkyl, or R 5 and R 6 The N atoms together form a 4-12 membered heterocyclic alkyl group, which may optionally be substituted by 1-3 of the following groups: H, OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocyclic alkyl, (C1-C3)alkoxy and (halogenated C1-C3)alkoxy.

[0019] In another preferred embodiment, in the general formula (1), R 1 It is vinyl or cyclopropyl; R 4 Vinyl is preferred.

[0020] In another preferred embodiment, in the general formula (1), R 2 It is CH3O-, CH3CH2O-, (CH3)2CHO-, CF3CH2O-, or CHF2CH2O-; R 2 Preferably, it is CH3CH2O-, CF3CH2O-, or CHF2CH2O-.

[0021] In another preferred embodiment, in the general formula (1), R 3 for R 3 Preferred R 3 More preferably

[0022] In another preferred embodiment, in the general formula (1), R 4 For H or F; R 4 H is preferred.

[0023] In another preferred embodiment, wherein the general formula (1) is, for Preferred More preferably

[0024] In various embodiments, the representative compounds of the present invention have one of the following structures:

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a diluent and / or an excipient, and a compound of general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0033] Another object of the present invention is to provide the use of the compound of general formula (1) of the present invention, or any isomer thereof, crystal form thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for the treatment, regulation or prevention of RAS-related diseases.

[0034] Another object of the present invention is to provide a method for treating, modulating or preventing RAS-related diseases, including administering to a subject a therapeutically effective amount of a compound of general formula (1) of the present invention, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate of the present invention, or a pharmaceutical composition thereof.

[0035] Through the synthesis and careful study of various new compounds involving K-RAS G12C inhibition, the inventors discovered that in the compound of general formula (1), when the side chain is a bridged ring structure, the compound has strong K-RAS G12C inhibitory activity.

[0036] It should be understood that the foregoing general description of the invention and the following detailed description are exemplary and illustrative, and are intended to provide further explanation of the claimed invention.

[0037] Compound Synthesis

[0038] The preparation method of the compound of general formula (1) of the present invention is described in detail below, but these specific methods do not constitute any limitation on the present invention.

[0039] The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with the methods described herein. Furthermore, the solvents, temperatures, and other reaction conditions mentioned herein can be varied. Starting materials used for the synthesis of the compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using known techniques and starting materials, including those discovered 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 3 rd The method described in Ed. (Wiley 1999) can be used to prepare compounds by employing appropriate reagents and by introducing different groups into the molecular formulas provided herein.

[0040] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the explanations below. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art. On the other hand, the present invention also provides a method for preparing the compound of general formula (1), wherein the compound of general formula (1) can be prepared by the following general reaction procedure 1:

[0041] General reaction process 1

[0042]

[0043] Compounds of general formula (1) can be prepared according to general reaction procedure 1, wherein m, n, v, R 1 R 2 R 3 R 4 R 5 and R 6 As defined above, PG represents a protecting group. As shown in general reaction flow 1, compound A and compound B react to form compound C, compound C undergoes cyclization to give compound D, and compound D and T... 2 Under strongly alkaline conditions, H undergoes a condensation reaction with E to generate compound F. Compound F is deprotected to give compound G. Compound G reacts with compound H to give the target compound I.

[0044] Further forms of the compound

[0045] "Pharmaceutical acceptable" here means that a substance, such as a carrier or diluent, will not destroy the biological activity or properties of a compound and is relatively non-toxic. For example, when given to an individual, a substance will not cause unwanted biological effects or interact with any of its components in a harmful manner.

[0046] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the administered organism and does not diminish the compound's biological activity and properties. In some specific respects, pharmaceutically acceptable salts are obtained by reacting compounds of general formula (1) with acids, such as inorganic acids like hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, and phosphoric acid; organic acids like formic acid, acetic acid, 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, and p-toluenesulfonic acid; and acidic amino acids like aspartic acid and glutamic acid.

[0047] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is ethanol. Solvates of compounds of general formula (1) are readily prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are readily prepared by recrystallization from a mixture of water and organic solvents, including but not limited to tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds mentioned herein can exist in both solvated and non-solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0048] In other specific embodiments, compounds of general formula (1) are prepared in various forms, including but not limited to amorphous, pulverized, and nano-particle forms. Furthermore, compounds of general formula (1) include crystalline forms and can also be polymorphic. Polymorphs comprise different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvents, crystallization rates, and storage temperatures may cause a single crystal form to dominate.

[0049] In another aspect, compounds of general formula (1) may possess a chiral center and / or axial chirality, and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of this invention. This invention means including all such isomeric forms of these compounds.

[0050] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 ( 125 I) and C-14 14 C). For example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs generally have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0051] the term

[0052] Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0053] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and 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, etc. i Pr、 n Pr、 i Bu、 n Bu or t Bu.

[0054] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight-chain or branched groups with 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms are preferred, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl.

[0055] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched groups with 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, such as ethynyl, 1-propynyl or 1-butynyl.

[0056] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic). A partially unsaturated cycloalkyl group may be referred to as "cycloalkenyl" if the carbon ring contains at least one double bond, or as "cycloynyl" if the carbon ring contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The cycloforming carbon atom of the cycloalkyl group may optionally be oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, the cycloalkyl group may be fused with aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl and heterocyclic alkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norcamphenyl, norpinel, norcarel, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and so on.

[0057] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, etc. i- PrO, n- PrO, i- BuO、 n- BuO or t- BuO.

[0058] Unless otherwise specified, "heterocyclic alkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenyl groups as part of a ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If a heterocyclic alkyl contains at least one double bond, then a partially unsaturated heterocyclic alkyl may be referred to as a "heterocyclic alkenyl," or if a heterocyclic alkyl contains at least one triple bond, then a partially unsaturated heterocyclic alkyl may be referred to as a "heterocyclic ynyl." Heterocyclic alkyl can include monocyclic, bicyclic, spirocyclic, or polycyclic (e.g., having two fused or bridging rings) ring systems. In some embodiments, a heterocyclic alkyl is a monocyclic group having one, two, or three heteroatoms independently selected from nitrogen, sulfur, and oxygen. The cyclic carbon atom and heteroatom of a heterocyclic alkyl may optionally be oxidized to form an oxo or thio ion group or other oxidized bond (e.g., C(O), S(O), C(S), or S(O)₂, N-oxide, etc.), or the nitrogen atom may be quaternized. Heterocyclic alkyl may be linked via cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. The definition of heterocyclic alkyl group also includes a portion having one or more aromatic rings fused with (i.e., sharing bonds with) the heterocyclic alkyl ring, such as benzo[a] derivatives of piperidine, morpholine, aziridine-heptadiene, or thiophene. Heterocyclic alkyl groups containing fused aromatic rings can be linked via any cyclizing atom, including the cyclizing atom of the fused aromatic ring. Examples of heterocyclic alkyl groups include, but are not limited to, azirrobutyl, azirroheptyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxoperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazo[5,4-c]pyridinyl, and 4,5,6,7-tetrahydro-1H-imidazolium. Azo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolyl, butyrolactam, valproic acid, imidazolinone, hydantoin, dioxolane, phthalimide, pyrimidin-2,4(1H,3H)-diketoyl, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S,S-oxide, piperazine, pyranyl, pyridinone, 3-pyrrololinyl, thiaranyl, pyranone, tetrahydrothiophene, 2-azaspiro[3,3]heptyl, indololinyl,

[0059] Unless otherwise specified, "halogen" (or halogenated group) means fluorine, chlorine, bromine or iodine. The term "halogenated" (or "halogen substituted") appearing before the group name indicates that the group is partially or completely halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0060] "Optional" or "optionally" means that the event or condition described below may, but is not required, occur, and the description includes both the scenario in which the event or condition occurs and the scenario in which the event or condition does not occur.

[0061] The substituent "-O-CH2-O-" indicates that the two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocyclic alkyl, aryl, or heteroaryl group. For example:

[0062] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a single bond.

[0063] When one of the variables is selected as a chemical bond, it means that the two groups connected are directly linked. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0064] The term "membered ring" includes any ring structure. The term "membered" refers to the number of skeleton atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thioranyl are six-membered rings, while cyclopentyl, pyrroleyl, furanyl, and thiophenyl are five-membered rings.

[0065] The term "fragment" refers to a specific part or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.

[0066] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0067] Unless otherwise stated, use Indicates a single bond or a double bond.

[0068] Specific pharmaceutical and medical terminology

[0069] The term “acceptable,” as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for general therapeutic purposes.

[0070] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndromes; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; alleviating a disease or symptom; reducing complications arising from a disease or symptom; or preventing or treating signs arising from a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, may improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether administered regularly or intermittently, continuously or intermittently, it may be attributable to or related to the administration.

[0071] "Active ingredient" refers to the compound represented by general formula (1), and pharmaceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers. The asymmetric centers that may exist depend 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 diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention means including all such isomeric forms of these compounds.

[0072] The terms “compound,” “composition,” “agent,” or “medicine or medicament” may be used interchangeably here, and all refer to a compound or composition that, when applied to an individual (human or animal), can induce a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0073] The term “administered, administering, or administration” here refers to the direct application of the compound or composition described herein, or the application of a prodrug, derivative, or analog of the active compound.

[0074] While the numerical ranges and parameters used to define the broader scope of this invention are approximate values, the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any value inevitably contains standard deviations due to individual test methods. Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "approximately" may mean that the actual value falls within the acceptable standard error of the mean, as determined by those skilled in the art. Except for experimental examples, or unless explicitly stated otherwise, it is understood that all ranges, quantities, values, and percentages used herein (e.g., to describe material usage, duration, temperature, operating conditions, quantity ratios, and others similar) are modified with "approximately". Therefore, unless otherwise stated, the numerical parameters disclosed in this specification and the accompanying claims are approximate values ​​and are subject to change as needed. At a minimum, these numerical parameters should be understood as the indicated significant digits and values ​​obtained using general rounding.

[0075] Unless otherwise defined in this specification, scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. Furthermore, unless conflicting with the context, singular nouns used herein include their plural forms, and vice versa.

[0076] Therapeutic uses

[0077] The present invention provides a method for treating diseases using compounds or pharmaceutical compositions of general formula (1) of the present invention, including but not limited to conditions involving G12C K-Ras, G12C H-Ras and / or G12C N-Ras mutations (e.g., cancer).

[0078] In some embodiments, a method for treating cancer is provided, the method comprising administering to an individual in need an effective amount of any of the aforementioned 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 a hematologic malignancy and a solid tumor, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial carcinoma, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all metastatic cancers.

[0079] route of administration

[0080] The compounds of this invention and their pharmaceutically acceptable salts can be formulated into various preparations, comprising, within a safe and effective range, the compounds of this invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective range of the compound is determined based on the age, condition, and duration of treatment of the patient.

[0081] "Pharmaceutically acceptable excipients or carriers" refers to one or more compatible solid or liquid fillers or gelling substances that 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 and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipients or carriers include 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, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0082] When applying the compounds of this invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0083] 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 the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0084] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0085] 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 used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0086] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0087] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0088] 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.

[0089] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0090] The compounds of this invention can 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 this invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0091] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features. Detailed Implementation

[0092] The following description will elaborate on the specific aspects, characteristics, and advantages of the aforementioned compounds, methods, and pharmaceutical compositions, making the content of this invention readily apparent. It should be understood that the detailed descriptions and examples described below are specific embodiments and are for reference only. After reading this description, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by this application.

[0093] In all embodiments, 1 H-NMR was recorded using a Vian Mercury 400 NMR spectrometer, and chemical shifts are expressed as δ (ppm). Unless otherwise specified, the silica gel used for separation was 200-300 mesh, and all eluent ratios were by volume.

[0094] The following abbreviations are used in this invention: BOP represents benzotriazole-1-tris(trimethylamino)-trifluorophosphate; DBU represents 1,8-diazacycloundecene; DCM represents dichloromethane; DMF represents dimethylformamide; EA represents ethyl acetate; HPLC represents liquid chromatography; K2CO3 represents potassium carbonate; MeOH represents methanol; min represents minutes; MS represents mass spectrometry; NMR represents nuclear magnetic resonance; TFA(CF3COOH) represents trifluoroacetic acid; TLC represents thin-layer chromatography; THF represents tetrahydrofuran.

[0095] Example 1 Synthesis of 1-(7-(7-(5-methyl-1H-indazol-4-yl)-2-(3-(pyrrolidine-1-yl)bicyclo[1.1.1]pentan-1-yl)-8-(2,2,2-trifluoroethoxy-6-vinylquinazoline-4-yl)-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (compound 1)

[0096]

[0097] Step 1: Synthesis of compounds 1-3

[0098] Add 1-1 (1.6 g, 2.94 mmol, 1 eq) of THF (25 mL) solution and 1-2 (586 mg, 2.94 mmol, 1 eq) sequentially to a 50 mL single-necked flask. Heat the system to 40 °C and stir for 30 min. The reaction was monitored by TLC until complete. The system was concentrated to obtain a crude product, which was then separated by column chromatography to obtain a pale yellow solid 1-3 (1.33 g, yield 64%). LC-MS: 708.3 [M+H] + .

[0099] Step 2: Synthesis of compounds 1-4

[0100] A 10 mL THF solution (1.33 g, 1.88 mmol, 1 eq) of 1-3 was added to a 100 mL single-necked flask. Concentrated ammonia was then added to adjust the pH to 11. The system was heated to 40 °C and stirred for 12 h. TLC analysis confirmed complete reaction of the starting material. The system was extracted with DCM (30 mL x 2), the organic phases were combined, washed with saturated brine, dried, and concentrated to obtain the crude product. The crude product was separated by column chromatography to obtain a white solid 1-4 (600 mg, yield 46%). LC-MS: 690.3 [M + H₂]. + .

[0101] Step 3: Synthesis of compounds 1-6

[0102] In a 50 mL single-necked flask, 1-4 (600 mg, 0.87 mmol, 1 eq), 1-5 (295 mg, 1.30 mmol, 1.5 eq), and DMF (20 mL, dry) were added sequentially. Then, under ice-water bath conditions, DBU (793 mg, 5.22 mmol, 6 eq) and BOP (960 mg, 2.17 mmol, 2.5 eq) were added sequentially. The system was heated to 45 °C and stirred for 1 h until the reactants were fully reacted. The system was extracted with EA (50 mL * 2), the organic phases were combined, washed three times with saturated brine, dried, and concentrated. The crude product was separated by column chromatography to obtain solid 1-6 (550 mg, 70% yield). LC-MS: 898.4 [M + H]. + .

[0103] Step 4: Synthesis of compounds 1-7

[0104] In a 50 mL single-necked flask, 1-6 (550 mg, 0.61 mmol, 1 eq) of methanol (20 mL), K₂CO₃ (761 mg, 5.51 mmol, 9 eq), and mercaptoacetic acid (226 mg, 2.44 mmol, 4 eq) were added sequentially. The system was heated to 70 °C and stirred for 30 min until the reactants were completely reacted. The system was extracted with EA (50 mL * 2), the organic phases were combined, dried, and concentrated. The crude product was separated by column chromatography to obtain solid 1-7 (318 mg, 70%), LC-MS: 744.4 [M + H₂].+ .

[0105] Step 5: Synthesis of compounds 1-8

[0106] A solution of 1-7 (318 mg, 0.43 mmol, 1 eq) of DCM / TFA = 5 / 1 (10 mL / 2 mL) was added to a 50 mL single-necked flask and stirred at room temperature for 1 h until the reactants reacted completely. The system was concentrated, and the pH was adjusted to alkaline with a saturated sodium bicarbonate aqueous solution. After filtration, the crude product 1-8 (280 mg) was lyophilized. LC-MS: 644.3 [M+H] + .

[0107] Step 6: Synthesis of Compound 1

[0108] In a 50 mL single-necked flask, 1–8 (280 mg, crude product) of MeOH solution (25 mL) was added sequentially, followed by the addition of imidazole (120 mg, 1.74 mmol, 4 eq) and stirring. Acrylic anhydride (55 mg, 0.43 mmol, 1 eq) was then added under ice-water bath conditions, and the mixture was stirred for 30 min until the reaction was complete. The reaction solution was washed with saturated brine, and the organic phase was dried and concentrated. The resulting white solid compound 1 (230 mg, yield %) was obtained by HPLC separation.

[0109] 1 H NMR (400MHz, DMSO-d6) 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] + .

[0110] Example 2-79 Synthesis of Compound 2-79

[0111] Using different raw materials, target compounds 2-79 were obtained by a similar synthesis method as described in Example 1.

[0112] Table 1

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122] Example 80 Chiral resolution of compound 1

[0123] The compounds of this application may be axially chiral. Axially chiral compounds can be resolved to yield two chiral isomers.

[0124] A suitable amount of compound 1 was dissolved in ethanol to prepare a test solution with a concentration of 10 mg / mL. The test solution was injected into a preparative liquid chromatograph, and the data were detected and recorded according to the chromatographic conditions of this invention. Preparative chromatographic conditions: Shimadzu LC-20AP preparative liquid chromatograph (Japan); column: UniChiral CMD-5H (30×250 mm, 5 μm); mobile phase: ethanol / n-hexane = 20 / 80; flow rate: 30.0 mL / min; detection wavelength: 254 nm; injection volume: 1000 μL. Chiral separation yielded 1-a and 1-b, with retention times of 6.238 min and 7.952 min, respectively, and ee% values ​​of 100 and 98.95, respectively.

[0125]

[0126] Other compounds in this application can also be chirally resolved using a similar method, such as compound 67, which was chirally resolved to yield 67-a and 67-b:

[0127]

[0128] Example 81: Antiproliferative activity of the compound of the present invention against H358 cells

[0129] 2500 H358 cells were seeded per well in a 96-well plate (corning, 7007) with ultra-low adsorption. After one day of growth, serially diluted compounds (maximum 5 μM, 5-fold dilution, for a total of five doses) were added. Three days after adding the compounds, CellTiter Glow (Promega, G9681) was added to evaluate the growth of the cells, and the IC50 was calculated. 50The values ​​are shown in Table 2 below.

[0130] Table 2. Antiproliferative activity of the compounds of the present invention against H358 cells

[0131] compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 ++ 8 +++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 +++ 22 ++ 23 +++ 24 +++ 25 +++ 26 +++ 27 ++ 28 ++ 29 ++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 ++ 36 ++ 37 +++ 38 +++ 39 +++ 40 ++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 ++ 49 +++ 50 +++ 51 ++ 52 +++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 +++ 59 +++ 60 +++ 61 +++ 62 +++ 63 +++ 64 ++ 65 +++ 66 ++ 67 +++ 68 +++ 69 +++ 70 +++ 71 +++ 72 +++ 73 +++ 74 +++ 75 +++ 76 +++ 77 +++ 78 +++ 79 +++ 1-a +++ 1-b +++ 67-a +++ 67-b +++ A +++

[0132] + indicates the compound's IC. 50 Greater than 1 μM

[0133] ++ indicates the IC of the compound. 50 0.3 to 1 μM

[0134] +++ indicates the IC of the compound. 50 Less than 0.3 μM.

[0135] As shown in Table 2, the antiproliferative activity of the compounds of the present invention against H358 cells is less than 0.3 μM for the vast majority of the compounds, which fully demonstrates that the compounds containing spirocyclic structures in the side chains of the present invention have strong K-RAS G12C inhibitory activity.

[0136] Example 82 Evaluation of antitumor activity in mice

[0137] Human pancreatic cancer Mia PaCa-2 cells were routinely cultured in a 37°C, 5% CO2 incubator using 1640 culture medium containing 10% fetal bovine serum. After passage, cells were collected when the desired cell count was reached. 1×10⁻⁶ cells were then cultured. 7 Mia PaCa-2 cells were injected into the left back of each nude mouse, and the tumor was allowed to grow to 400 mm. 3 Afterwards, the animals were randomly divided into three groups to begin drug administration: 1) a solvent control group (n=8); and 2) compound 1 group, compound 67 group, and compound A group (n=8 in each group). The solvent control group was administered 0.5% CMC-Na by gavage twice daily; the compound 1, compound 67, and compound A groups were administered 0.5% CMC-Na suspension by gavage once daily. Tumor volume and mouse weight were measured every Tuesday and Thursday. Nude mice were sacrificed on day 21 of drug administration. The experimental results are shown in Table 3 below.

[0138] Table 3. Experimental therapeutic effects of compounds on human pancreatic cancer xenografts in Mia PaCa-2 nude mice.

[0139] compound Dosage (mg / kg) Dosing regimen Anti-tumor effect 1 10 qd*21 36% retreat 67 10 qd*21 32% Retreat A 10 qd*21 25% Retreat

[0140] As can be seen from the data in the table above, the compounds of the present invention have strong in vivo antitumor activity. After continuous administration of 10 mg / kg / day for 21 days, tumors can shrink. The in vivo activities of compounds 1 and 67 are stronger than those of control drug A.

[0141] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of general formula (1) or an optical isomer thereof or a pharmaceutically acceptable salt thereof: In general formula (1): m, n, and v are independent integers of 1 or 2; R 1 It is C2-C4 alkenyl or C3-C6 cycloalkyl; R 2 It is a C1-C3 alkoxy or a halo-C1-C3 alkoxy; R 3 for Where R a R b and R c Independently, H, F, Cl or Me, R d It can be H, F, Cl, NH2, Me, or cyclopropyl; R 4 It is H or halogen; R 5 and R 6 Independently defined as C1-C3 alkyl, halo-C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, sulfone-substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-substituted (C2-C3)alkyl, (halo-C1-C3)alkoxy-substituted (C2-C3)alkyl, or (C3-C6)cycloalkyl-substituted (C1-C3)alkyl, or R 5 and R 6 The N atoms together form a 4-12 membered heterocyclic alkyl group, which may optionally be substituted by 1-3 of the following groups: H, OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocyclic alkyl, (C1-C3)alkoxy and (halogenated C1-C3)alkoxy.

2. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 1 It is vinyl or cyclopropyl.

3. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 2 It can be CH3O-, CH3CH2O-, (CH3)2CHO-, CF3CH2O- or CHF2CH2O-.

4. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 3 for 5. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 4 It can be H or F.

6. The compound of any one of claims 1-5, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), for 7. The compound of claim 1, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:

8. A pharmaceutical composition, characterized in that, It contains a pharmaceutically acceptable excipient or carrier, and a compound or its optical isomer or pharmaceutically acceptable salt as any one of claims 1-7 as the active ingredient.

9. The use of a compound as described in any one of claims 1-7, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 8, in the preparation of a medicament for treating diseases related to the K-Ras G12C mutant protein.

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