Spiro ring-containing quinazoline compounds

Abstract

The present invention relates to spirocyclic quinazoline compounds, processes for their preparation, and the use of the compounds as K-Ras G12C inhibitors in the preparation of antitumor medicaments. [Formula 1] TIFF2023508482000182.tif70169

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. CN201911386239.6, filed on 27 December 2019, and Chinese Patent Application No. CN202010486384.8, filed on 1 June 2020, the contents of which are incorporated in their entirety by reference.

[0002] Technical field The present invention belongs to the field of medicinal chemistry, and more particularly to spiroring-containing quinazoline compounds, methods for preparing the same, and methods for using the said compounds as K-Ras G12C inhibitors in the preparation of antitumor drugs. [Background technology]

[0003] background Members of the Ras protein family are important signaling molecules within cells, playing crucial roles in growth and development. Extensive analyses and studies of in vitro tumor cells, animal models, and human tumor samples have shown that hyperactivation of Ras family proteins is an early event in human tumor development and a significant cause of development and progression in many types of cancer. Therefore, targeting Ras proteins and inhibiting their activity is an important means of treating related tumors.

[0004] The Ras protein exists in two forms. It is in a dormant state when bound to GDP, and becomes activated when cells receive signals such as growth factor stimulation, by binding to GTP. Activated Ras proteins recruit various signaling adapter proteins to activate the Ras signaling pathway, regulating cell proliferation, survival, migration, and differentiation by promoting the phosphorylation of downstream signaling molecules such as ERK and S6. Due to its GTPase activity, the Ras protein can hydrolyze GTP back to GDP. Furthermore, intracellular GTPase-activating proteins (GAPs) interact with Ras, significantly increasing its GTPase activity and thereby preventing overactivation of the Ras protein.

[0005] Mutations in the K-Ras, H-Ras, and N-Ras proteins of the Ras protein family are common genetic mutations in various tumors and are a major cause of Ras protein overactivation in tumors. Ras proteins with these mutations are less regulated in activity compared to wild-type Ras proteins, and are constantly activated by stably binding to GTP, thus promoting tumor cell proliferation, migration, and differentiation. Of these mutations, K-Ras protein mutations are the most common, accounting for 85% of all Ras mutations, while N-Ras (12%) and H-Ras (3%) mutations are relatively rare. K-Ras mutations are very common in many types of cancer, including pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (25%), but are relatively rare (less than 2%) in breast cancer, ovarian cancer, and brain tumors. K-Ras mutations mainly occur at position G12, with G12C mutations being the most common. For example, in non-small cell lung cancer (NSCLC), approximately 50% of K-Ras mutations are K-Ras G12C, with G12V and G12D being the second most common mutations. Genomic studies suggest that K-Ras mutations in NSCLC generally do not coexist with EGFR, ALK, ROS1, RET, or BRAF mutations, but coexist with mutations such as STK11, KEAP1, and TP53, suggesting that K-Ras mutations may synergistically contribute to cell malignancy, proliferation, and invasion in conjunction with mutations such as STK11, KEAP1, and TP53. Beyond tumors, abnormal activation of the Ras protein is also involved in non-tumor diseases such as diabetes and neurodegenerative diseases. Therefore, small molecule compounds targeting the Ras protein may benefit many cancer patients with specific gene mutations and non-cancer patients with overactivation of the Ras pathway.

[0006] Since the discovery of Ras mutations in tumors 40 years ago, progress has been made in elucidating the pathological conditions involving the Ras pathway. However, for the many patients with Ras protein mutations or hyperactivation of the Ras pathway, there are still no clinically effective treatments targeting the Ras protein on the market. Therefore, the development of highly active small molecule inhibitors targeting the Ras protein, particularly the highly mutated K-Ras G12C protein, is considered to have great clinical significance.

[0007] K-Ras G12C mutaine is currently not a well-researched therapeutic target, with only a few compounds, such as Amgen's AMG510 and Mirati's MRTX849, undergoing clinical trials. In 2018, the covalent inhibitor ARS-1620, which targets the K-Ras G12C mutation, was reported in Cell (Cell, 2018, 172: 578-589). A class of spiro compounds possessing K-Ras G12C activity and antitumor activity in mice is reported in patent WO2018 / 143315, and its general formula A, representative compound B (Example 35 of the patent), and representative compound C (Example 65 of the patent) are shown as follows (see the patent for definitions of symbols in the formula).

[0008] [ka] [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] International Publication No. 2018 / 143315 [Non-patent literature]

[0010] [Non-Patent Document 1] Cell, 2018, 172: 578-589 [Overview of the project] [Problems that the invention aims to solve]

[0011] Currently, there is an urgent need to research and discover compounds that possess good K-Ras G12C activity and excellent pharmacokinetic properties. [Means for solving the problem]

[0012] overview The present invention aims to provide a compound of a structural general formula represented by formula (1), an isomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

Chemical formula

[0013] R 3 is

Chemical formula

[0014] In another preferred embodiment, in general formula (1), R 1 These are H, F, Cl, Me, Et, vinyl, isopropyl, ethynyl, or cyclopropyl.

[0015] In another preferred embodiment, in general formula (1), R 2 CH3CH2O-, CF3CH2O-, CHF2CH2O-, [ka] That is the case.

[0016] In another preferred embodiment, in general formula (1), R 3 teeth, [ka] That is the case.

[0017] In another preferred embodiment, in general formula (1), R 4 H, F, CN, Me, CF3, [ka] That is the case.

[0018] In another preferred embodiment, in general formula (1), R 3 teeth, [ka] In that case, R 4 H is, R 5 teeth, [ka] [ka] [ka] That is the case.

[0019] In another preferred embodiment, in general formula (1), R 3 teeth, [ka] In that case, R 4 F, CN, Me, CF3, [ka] And, or, R 3 teeth, [ka] In that case, R 5 teeth, [ka] [ka] [ka] That is the case.

[0020] In another preferred embodiment, in general formula (1), R 5 teeth, [ka] [ka] That is the case.

[0021] In various embodiments, a representative compound of general formula (1) of the present invention has one of the following structures. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0022] Another aspect of the present invention aims to provide a compound having the structural general formula represented by formula (2), its isomers, its crystalline form, its pharmaceutically acceptable salt, its hydrate, or its solvate. [ka] Here, in equation (2) R 1a teeth, [ka] And, R 2a These are CH3O-, CH3CH2O-, CF3CH2O-, or CHF2CH2O-, R 3a teeth, [ka] And, Here, R c is H or F, R d is H, F, Cl, or Me, R e is H, F, Cl, or Me, and, R f It is F, NH2, Me, or cyclopropyl. R4a is H or F, and, R 5a H, [ka] And, Here, n1, n2, n3, m1, m2, and m3 are independent integers of 1 or 2. v is an integer, either 1, 2, or 3. R g These are C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6)cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl-, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl, or cyanosubstituted C1-C3 alkyl. R j These are independently halogens, CN, SO2Me, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl, or [ka] And, R k These are independently halogens, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or [ka] And, R n These are independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl, and have two R n The group forms a spiro ring with one carbon atom, or with two R atoms. n The group forms a bridging ring with different carbon atoms, R l and Rm These are independently C1-C3 alkyl, C1-C3 haloalkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy-(C2-C3) alkyl-, (halogenated C1-C3) alkoxy(C2-C3) alkyl-, or (C3-C6) siloalkyl-(C1-C3) alkyl-, or R l and R m This atom forms a 3- to 8-membered heterocycloalkyl group with the N atom, and the 3- to 8-membered heterocycloalkyl group may be substituted with 1 to 3 groups selected from OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3) alkoxy, or (halogenated C1-C3) alkoxy.

[0023] In another preferred embodiment, in general formula (2), R 3a teeth, [ka] That is the case.

[0024] In another preferred embodiment, in general formula (2), R 5a H, [ka] [ka] [ka] That is the case.

[0025] In various embodiments, a representative compound of general formula (2) of the present invention has one of the following structures. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0026] Another aspect of the present invention aims to provide a compound having the structure represented by general formula (3), its isomers, its crystalline form, its pharmaceutically acceptable salt, its hydrate, or its solvate. [ka] Here, R 5b teeth, [ka] And, Here, n1, n2, n3, m1, m2, m3 are independent integers of 1 or 2. R g These are C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6)cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl, or cyanosubstituted C1-C3 alkyl. R h teeth, [ka] And, R i is H, halogen, methyl or cyano, or R 5b H, [ka] And, Here, n1, n2, n3, m1, m2, and m3 are independent integers of 1 or 2. v is an integer, either 1, 2, or 3. R g These are C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3)alkoxy-(C2-C3)alkyl-, (halogenated C1-C3)alkoxy-(C2-C3)alkyl-, (C3-C6)cycloalkyl-(C1-C3)alkyl-, heterocycloalkyl, heterocycloalkyl-(C1-C3)alkyl-, C1-C3 haloalkyl, or cyanosubstituted C1-C3 alkyl. R j These are independently halogens, CN, SO2Me, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl, or [ka] And, R k These are independently halogens, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or [ka] And, R n These are independently halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy or C3-C6 cycloalkyl, and two R n The group forms a spiro ring with one carbon atom, or with two R atoms. n The group forms a bridging ring with different carbon atoms, Rl and R m These are independently C1-C3 alkyl, C1-C3 haloalkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy-(C2-C3) alkyl-, (halogenated C1-C3) alkoxy(C2-C3) alkyl-, (C3-C6) cycloalkyl-(C1-C3) alkyl-, or R l and R m This atom forms a 3- to 8-membered heterocycloalkyl group with the N atom, and the 3- to 8-membered heterocycloalkyl group may be substituted with 1 to 3 groups selected from OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3) alkoxy, or (halogenated C1-C3) alkoxy.

[0027] In another preferred embodiment, in general formula (3), R 5b H, [ka] [ka] [ka] [ka] [ka] [ka] That is the case.

[0028] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of general formula (1) to (3) of the present invention, its isomer, its crystalline form, its pharmaceutically acceptable salt, its hydrate, or its solvate as an active ingredient.

[0029] A further object of the present invention is to provide the use of the compounds of the present invention described above, their isomers, their crystalline forms, their pharmaceutically acceptable salts, their hydrates, or their solvates in the preparation of agents for treating RAS-related diseases.

[0030] Through the synthesis and diligent study of various novel compounds having K-RAS G12C inhibitory activity, the inventors have found that in compounds of general formulas (1) to (3), R 5 (or R 5a or R 5b When the substituent R at position 2 of acrylamide is a spiro ring or other substituted heterocycle, the compound exhibits very high K-RAS G12C inhibitory activity, while the pharmacokinetic properties of the compound are greatly improved, and the in vivo activity of the compound is enhanced, thus completing the present invention. In another embodiment, the inventors found that when the substituent R at position 2 of acrylamide is a spiro ring or other substituted heterocycle, the compound exhibits very high K-RAS G12C inhibitory activity, while the pharmacokinetic properties of the compound are greatly improved and the in vivo activity of the compound is enhanced. 4 We found that when the ) is substituted with a smaller F atom, the compound also possesses good K-RAS G12C inhibitory activity and pharmacokinetic properties.

[0031] It should be understood that both the above general description of the present invention and the following detailed description are illustrative and explanatory, and are intended to provide a further explanation of the claimed invention.

[0032] Compound synthesis The following describes in detail the preparation methods for the compounds of the general formulas (1) to (3) of the present invention, but these specific methods do not limit the present invention in any way.

[0033] The compounds of general formulas (1) to (3) described above can be synthesized using standard or well-known techniques, in combination with the methods described herein. The solvents, temperatures, and other reaction conditions described herein may also vary. Starting materials for the synthesis of the compounds can be obtained synthetically or commercially. The compounds described herein and other related compounds with different substituents can be synthesized using well-known techniques and starting materials, including 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), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3 rd This includes the methods described in Ed., (Wiley 1999). General methods for preparing the compounds can be modified by using appropriate reagents and conditions for introducing different groups into the formulas provided herein.

[0034] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions relating to the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, and reaction time, are not limited to those described below. Furthermore, the compounds of the present invention can be easily prepared by arbitrarily combining various synthesis methods described herein or known in the art, and such combinations can be easily determined by those skilled in the art to which the present invention belongs. In one embodiment, the present invention also provides a method for preparing compounds of general formulas (1) to (3) using the general reaction scheme 1 below.

[0035] General reaction scheme 1 [ka]

[0036] In an embodiment of the compound of general formula (1), the preparation can be carried out according to the general reaction scheme 1, where T represents H, F, Cl, or I, T 1 represents R 5 、R 5a 、or R 5b as defined above, T 2 represents R 3 、or R 3a as defined above, T 3 represents R 1 、or R 1a as defined above, T 4 represents R 2 、or R 2a as defined above, T 5 represents R 4 、or R 4a as defined above, R 1 、R 1a 、R 2 、R 2a 、R k 3 、R 3a 、R 4 、R 4a 、R 5 、R 5a 、and R 5b are defined as above, PG represents a protecting group, X represents boric acid, borate, or trifluoroborate.

[0037] In general, as shown in Reaction Scheme 1, compound A1 (synthesized according to WO2018 / 143315) is reacted with compound A2 under basic conditions to obtain compound A3, and compound A3 is reacted with T 1 H under basic conditions to obtain compound A4, and compound A4 is reacted with T 2 H under basic conditions to obtain compound A5. When T = I, compound A5 is subjected to a coupling reaction with T 3 X to obtain compound A6, and compound A6 is reacted with T 4Further coupling reaction of X yields compound A7. 4 Compound A7 can be directly obtained by further coupling reaction with X. Compound A8 can be obtained by removing the protecting group from compound A7, and then compound A8 can be reacted with compound A9 to obtain the target compound A10.

[0038] Further aspects of the compound In this specification, "pharmaceutically acceptable" refers to a substance such as a carrier or diluent that does not cause the compound to lose its biological activity or properties. It also refers to a substance that is relatively non-toxic and, for example, does not cause undesirable biological effects or adverse interactions with its components when administered to an individual.

[0039] A "pharmaceutically acceptable salt" means a form of a compound that does not cause significant irritation to the body for drug administration and does not eliminate the biological activity and properties of the compound. In certain contexts, a pharmaceutically acceptable salt can be obtained by reacting compounds of general formulas (1) to (3) with acids, such as inorganic acids like hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, and nitric 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.

[0040] References to pharmaceutically acceptable salts should be understood to include solvated or crystalline forms, particularly solvates or polymorphs. Solvates are selectively formed during crystallization with pharmaceutically acceptable solvents such as water and ethanol, in stoichiometric or nonstoichiometric amounts of solvent. Hydrates are formed when the solvent is water, and alkoxides are formed when the solvent is ethanol. Solvates of the compounds of general formulas (1) to (3) can be easily prepared or formed according to the methods described herein. For example, hydrates of the compounds of general formulas (1) to (3) can be easily prepared by recrystallization from a water / organic solvent mixture, the organic solvents used here including, but not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds described herein can exist in both non-solvated and solvated forms. In general, the solvated form is considered equivalent to the non-solvated form for the purposes of the compounds and methods provided herein.

[0041] In other specific examples, compounds of general formulas (1) to (3) may be prepared in different forms, such as amorphous materials, pulverized materials, and nanoparticles, but are not limited to these. Furthermore, compounds of general formula (1) may include crystalline forms as well as polymorphs. Polymorphs include different lattice arrangements of the same element in the compound. Polymorphs typically differ in X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystalline forms, optical properties, electrical properties, stability, and solubility. Depending on various factors such as the recrystallization solvent, crystallization rate, and storage temperature, single crystals may be dominant.

[0042] In another embodiment, the compounds of general formulas (1) to (3) exist in the form of racemates, racemic mixtures, single enantiomers, diastereomer compounds, and single diastereomers, because they have axial chirality and / or chiral centers (chiral centers). Each of these axial chiralities independently gives rise to two optical isomers, and all possible optical isomers, diastereomer mixtures, and pure or partially pure compounds are included within the scope of the present invention. The present invention means that it includes all such isomeric forms of these compounds.

[0043] Glossary Unless otherwise specified, terms used in this Application, including those used in this Specification and Claims, are defined as follows: It should be noted that in this Specification and the Appendix Claims, the singular forms "a" and "an" have plural meanings unless otherwise clearly indicated in the context. Unless otherwise specified, conventional methods of mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. In this Application, "or" or "and" is used to mean "and / or" unless otherwise specified.

[0044] Unless otherwise specified, “alkyl” refers to a saturated aliphatic hydrocarbon group, including linear and branched groups containing 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl, are preferred. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, particularly alkyl groups substituted with one or more halogens. Preferred alkyl groups include CH3, CH3CH2, CF3, CHF2, CF3CH, i Pr, n Pr, i Bu, n Bu and t Selected from Bu.

[0045] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, and includes linear and branched groups containing 1 to 6 carbon atoms. Lower alkenyls containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl, are preferred.

[0046] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group having a carbon-carbon triple bond, and includes linear and branched groups containing 1 to 6 carbon atoms. Lower alkenyls containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl, are preferred.

[0047] Unless otherwise specified, "cycloalkyl" refers to a 3- to 6-membered all-carbon monocyclic aliphatic hydrocarbon group, where one or more rings may contain one or more double bonds, but none of them have a fully conjugated π-electron system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, and cyclohexadiene.

[0048] Unless otherwise specified, “alkoxy” refers to an alkyl group that is bonded to the rest of the molecule via an ether oxygen atom. Typical alkoxy groups include those containing 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 alkoxys, in particular alkoxys substituted with one or more halogens. Preferred alkoxys include OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO and t- Selected from BuO.

[0049] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), which may be monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocyclyl groups. Examples of heteroaryls include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, and pyrrolopyrimidinyl.

[0050] Unless otherwise specified, “heterocycloalkyl” refers to a saturated or partially unsaturated cyclic group containing one or more heteroatoms (O, S, or N), where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized as a ring atom. Unless otherwise specified, the “heterocycloalkyl” cyclic system may be monocyclic, bicyclic, spirocyclic, or polycyclic. The “heterocycloalkyl” may be linked to the rest of the molecule via one or more ring carbons or heteroatoms. Examples of "heterocycloalkyl" compounds include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and 2-azaspiro[3,3]heptane.

[0051] Unless otherwise specified, "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "halogenated" (or "halogenated") preceding a group name indicates that the group is partially or completely halogenated, i.e., substituted with F, Cl, Br, or I, preferably any combination of F or Cl.

[0052] Specific pharmaceutical and medical terms As used herein, the term “acceptable” means that the formulation ingredient or active ingredient does not unduely adversely affect the health of the general therapeutic target.

[0053] As used herein, the terms “treatment,” “course of treatment,” or “treatment” include, for example, the alleviation, suppression, or improvement of the symptoms or condition of a disease, the suppression of the onset of complications, the improvement or prevention of an underlying metabolic syndrome, the suppression of the onset of a disease or symptom, and including control of the progression of a disease or symptom, alleviation of a disease or symptom, calming of a disease or symptom, alleviation of complications caused by a disease or symptom, or prevention or treatment of signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, meaning in particular to improve the severity of a disease, delay its onset, delay its progression, or shorten its duration. Fixed or temporary administration, or continuous or intermittent administration, may be caused by or related to the administration.

[0054] "Active ingredient" refers to the compounds of general formulas (1) to (3), and pharmaceutically acceptable inorganic or organic salts of the compounds of general formulas (1) to (3). The compounds of the present invention may contain one or more asymmetric centers (axial chirality) and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomer compounds, and single diastereomers. The possible asymmetric centers depend on the properties of various substituents on the molecule. Each of these asymmetric centers independently produces two optical isomers, and all possible optical isomers, diastereomer mixtures, and pure or partially pure compounds are within the scope of the present invention. The present invention means that it includes all such isomers of these compounds.

[0055] In this specification, terms such as “compound,” “composition,” “drug,” or “medicine or medicament” are used interchangeably and all refer to compounds or compositions that, when administered to an organism (human or animal), can induce a desired pharmacological and / or physiological response through local and / or systemic effects.

[0056] In this specification, "administered, given, or administered" means the direct administration of a compound or composition, or the administration of a prodrug, derivative, analog, etc., of an active compound.

[0057] While the numerical ranges and parameters defining the broad scope of this invention are approximations, the relevant numerical values ​​shown in specific examples are presented herein as accurately as possible. However, any numerical value inherently includes a standard deviation that inevitably arises from certain test methods. Here, “approximately” generally means that the actual value is within a specific value or range of ±10%, 5%, 1%, or 0.5%. Alternatively, the term “approximately” indicates that the actual value is within the acceptable standard error of the mean, as those skilled in the art would consider. All ranges, quantities, values, and percentages used herein (e.g., describing quantities of material, durations of time, temperatures, operating conditions, quantitative ratios, etc.) shall be understood to be modified by the word “approximately” unless explicitly indicated in experimental examples or elsewhere. Thus, unless otherwise stated, all numerical parameters described herein and in the appended claims are approximations that may be modified as needed. At a minimum, these numerical parameters should be interpreted as numerical values ​​obtained using the indicated significant figures or conventional rounding rules.

[0058] The scientific and technical terms used herein have the same meanings as those generally understood by those skilled in the art, unless otherwise defined herein. Furthermore, singular nouns used herein encompass their plural forms unless otherwise inconsistent with the context, and plural nouns used also encompass their singular forms.

[0059] therapeutic use The present invention provides a method of using the compounds or pharmaceutical compositions of the present invention to treat diseases including, but not limited to, conditions involving G12C K-Ras, G12C H-Ras, and / or G12C N-Ras mutations (e.g., cancer).

[0060] In some embodiments, a method is provided for treating cancer, the method comprising administering an effective amount of a pharmaceutical composition of any of the protected structural general formulas (1) to (3) described above to an individual in need thereof. 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.

[0061] Route of administration The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations comprising the compounds disclosed herein or their pharmaceutically acceptable salts in a safe and effective amount, and a pharmaceutically acceptable excipient or carrier, where “safe and effective amount” means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject being treated.

[0062] A "pharmaceutically acceptable excipient or carrier" means one or more compatible solid or liquid fillers or gels that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "Compatibility" means that the components of the composition can be mixed with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, or sorbitol), emulsifiers (e.g., Tween®), humectants (e.g., sodium lauryl sulfate), colorants, fragrances, stabilizers, antioxidants, preservatives, and pyrogen-free water.

[0063] The compounds of the present invention can be administered orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), or topically.

[0064] Solid dosage forms for oral administration include capsules, tablets, pills, powders (pulvises), and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inactive excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with any of the following components: (a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders such as paraffin; (f) absorption enhancers such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffering agent.

[0065] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using materials well known in the art, such as coatings and shells, including enteric coatings. They may also contain opacifiers, and the active compound or compound in such compositions can be released with a delay in specific parts of the digestive tract. Examples of usable embedding components include polymers and waxes. If necessary, the active compound may also be in the form of microcapsules together with one or more of the above excipients.

[0066] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. In addition to the active compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as 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 thereof.

[0067] In addition to such inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances.

[0068] In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar, or mixtures thereof.

[0069] Parenteral injection compositions may include physiologically acceptable sterile aqueous or aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for redissolution in sterile injection solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0070] Dosage forms for topical administration of the compounds of the present invention include ointments, powders (pulvises), patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and, if necessary, required preservatives, buffers, or sprays.

[0071] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0072] When using the pharmaceutical composition of the present invention, a safe and effective amount of the compound of the present invention is administered to the target mammal (such as a human), and the dosage is a pharmaceutically effective dosage. For a human weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. In determining the specific dosage, factors such as the route of administration and the patient's health condition are also taken into consideration, but these are well known to experienced physicians.

[0073] The features described above in this invention and in the examples can be combined in any way. All features disclosed herein can be used in any configuration, and various features disclosed herein can be replaced with any alternative features that serve the same, equivalent, or similar purpose. Accordingly, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0074] Various specific embodiments, features, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions are described in detail in the following description, thereby clarifying the present invention. It should be understood that the following detailed description and examples illustrate specific embodiments for reference. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present invention as defined herein.

[0075] In all examples, 1H-NMR spectra were recorded using a Vian Mercury 400 nuclear magnetic resonance spectrometer, chemical shifts were expressed in δ (ppm), 200-300 mesh silica gel was used for separation unless otherwise specified, and the eluent ratio was expressed as a volume ratio.

[0076] In this invention, the following abbreviations are used: CD3OD is deuterated methanol, MeCN is acetonitrile, DCM is dichloromethane, DIPEA is diisopropylethylamine, Dioxane is 1,4-dioxane, DMF is dimethylformamide, K3PO4 is potassium phosphate, min is minute, MS is mass spectrum, NaH is sodium hydride, NMR is nuclear magnetic resonance, Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium, Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, TFA(CF3COOH) is trifluoroacetic acid, TLC is thin-layer chromatography, THF is tetrahydrofuran, and Xantphos is 4,5-bis(diphenylphosphan)-9,9-dimethylxanthene. [Brief explanation of the drawing]

[0077] [Figure 1] Figure 1 shows the inhibition of intracellular phosphorylated ERK (pERK) levels by the compound. [Modes for carrying out the invention]

[0078] Detailed description

[0079] Example 1: Synthesis of 1-(7-(6-cyclopropyl-8-ethoxy-2-((1-(2-methoxyethyl)piperidine-4-yl)oxy)-7-(5-methyl-1H-indazole-4-yl)quinazolin-4-yl)-2,7-diazaspiro[3·5]nonanane-2-yl)-2-fluoroprop-2-en-1-one (Compound 1) [ka]

[0080] Step 1: Synthesis of Compounds 1-3 Compound 1-1 (5.5 g, 13.1 mmol) was suspended in dioxane (80 mL). Under ice bath conditions, DIPEA (10.1 g, 78.6 mmol) was added, followed by the addition of 1-2 (3.0 g, 13.1 mmol). The mixture was stirred for 30 minutes and then stirred at room temperature for 1 hour. The reaction was completed by detection by TLC. Water was added, followed by extraction with EA. The organic phase was dried and concentrated, and the residue was slurryed with EA to obtain yellow solid 1-3 (4.5 g, yield 56%).

[0081] 1 H NMR(400MHz,DMSO-d6)δ:8.26(d,J=1.5Hz,1H),3.79(s,4H),3.65(s,4H),1.86(t,J=5.3Hz,4H),1.39(s,9H);MS(ESI):ms(ESI):611.2[M+1] + .

[0082] Step 2: Synthesis of Compounds 1-4 Compound 1-3 (4.5 g, 7.4 mmol) was dissolved in a mixed solution of DMF (40 mL) and THF (40 mL). 1-(2-methoxyethyl)-4-hydroxypiperidine (2.4 g, 14.8 mmol) and DABCO (0.2 g, 1.5 mmol) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, water was added, and then the mixture was extracted with EA. The organic phase was dried and concentrated, and the residue was subjected to column chromatography to obtain compound 1-4 (4.1 g, 76% yield).

[0083] 1 H NMR(400MHz,DMSO-d6)δ:8.14(s,1H),4.99(ddd,J=11.7,8.5,3.6Hz,1H),3.66(s,9H),3.44(t,J=5.8Hz,2H),3.24(s,3H),3.17(d,J=5.2Hz,1H),2. 77(dt,J=9.5,8.8Hz,2H),2.26(t,J=9.8Hz,2H),2.00(d,J=12.0Hz,2H),1 .84(d,J=4.3Hz,4H),1.74-1.61(m,2H),1.39(s,9H);MS(ESI):734.2[M+1] + .

[0084] Step 3: Synthesis of Compounds 1-5 Trifluoroethanol (0.9 g, 8.4 mmol) was dissolved in anhydrous DMF (10 mL). NaH was added under ice bath conditions. The mixture was stirred at room temperature for 5 minutes to obtain sodium trifluoroethoxide. Compound 1-4 (4.1 g, 5.6 mmol) was dissolved in anhydrous THF (40 mL). The solution of sodium trifluoroethoxide in DMF prepared above was added. The mixture was stirred at room temperature overnight. After the reaction was complete, water was added, and then the mixture was extracted with EA. The organic phase was dried and concentrated, and the residue was subjected to column chromatography to obtain compound 1-5 (4.5 g, 99% yield). MS(ESI):814.2[M+1] + .

[0085] Step 4: Synthesis of Compounds 1-6 Compounds 1-5 (4.1 g, 5.5 mmol), cyclopropylboronic acid (0.5 g, 6.1 mmol), Pd(dppf)Cl2 (0.9 g, 1.1 mmol), and K3PO4 (0.4 g, 1.7 mmol) were added to a single-necked flask. Then, MeCN (40 mL), dioxane (40 mL), and H2O (16.5 mL) were added. The mixture was stirred under nitrogen at 100 °C for 5 hours. After the reaction was complete, the mixture was subjected to column chromatography to obtain compound 1-6 (2.5 g, 62% yield). MS(ESI): 728.3[M+1] + .

[0086] Step 5: Synthesis of Compounds 1-7 Compounds 1-6 (2.5 g, 3.4 mmol), 5-methyl-1H-indazole-4-boronic acid (0.9 g, 5.1 mmol), Pd2(dba)3 (0.3 g, 0.4 mmol), Xatphos (0.3 g, 0.7 mmol), and K3PO4 (2.2 g, 10.2 mmol) were added to a single-neck flask, followed by the addition of dioxane (40 mL) and H2O (4 mL). The mixture was stirred overnight at 120°C under nitrogen. After the reaction was complete, the mixture was subjected to column chromatography to obtain compound 1-7 (1 g, 38% yield). MS(ESI): 780.4[M+1]+ .

[0087] Step 6: Synthesis of Compounds 1-8 Compound 1-7 (1 g, 1.3 mmol) was dissolved in DCM (15 mL). TFA (5 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated, basicized with saturated sodium carbonate, and extracted with EA. The organic phase was dried and concentrated to obtain compound 1-8 (0.9 g, 99% yield). MS(ESI): 680.4[M+1] + .

[0088] Step 7: Synthesis of Compound 1 Compounds 1-8 (150 mg, 0.2 mmol) and 2-fluoroacrylic acid (20 mg, 0.22 mmol) were dissolved in DCM (15 mL). Dipea (52 mg, 0.4 mmol) and HATU (114 mg, 0.3 mmol) were added under ice bath conditions. The mixture was stirred overnight. After the reaction was complete, the reaction mixture was washed with saturated brine. The organic phase was dried and concentrated, and the residue was subjected to column chromatography to obtain compound 1 (30 mg, 20% yield).

[0089] 1 H NMR(400MHz,CD3OD)δ:7.47-7.37(m,2H),7.30(d,J=8.6Hz,1H),7.24(s,1H),5.52(d,J=3.4Hz,0.5H),5.40 (d,J=3.4Hz,0.5H),4.54(dq,J=17.7,8.8Hz,1H),4.23-4.12(m,3H),3.83(s,2H),3.73-3.59(m,4H),3.54( t,J=5.2Hz,2H),3.28(s,3H),3.10(dd,J=10.1,6.2Hz,2H),2.88(s,2H),2.85-2.72(m,2H),2.13(d,J=26.2 Hz,5H),1.97(dd,J=11.9,6.8Hz,6H),1.36(dt,J=14.0,6.6Hz,1H),1.27-1.17(m,5H);MS(ESI):752.4[M+1] + .

[0090] Example 2-341: Synthesis of Compound 2-341 By changing the starting materials and following the same synthesis method as in Example 1, the target compound 2-341 was obtained.

[0091] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15]

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

[0092] Example 342: Chiral Resolution of Compound 142 The compounds of the present invention may have axial asymmetry. Compounds having axial asymmetry can be resolved to obtain two chiral isomers.

[0093] Compound 142 (50 mg) was dissolved in ethanol (2 mL) at a concentration of 25 mg / mL. Each injection volume was 500 μL. Preparative chromatography conditions: CHIRALPAK AD-H (20 × 250 mm, 5 μm) chromatography column, mobile phase: ethanol-n-hexane (40 / 60), flow rate: 12 mL / min, detection wavelength: 254 nm. The stepwise eluates were concentrated by rotary evaporation and dried to obtain two chiral isomers of compound 142, 142-a and 142-b.

[0094] The first chiral isomer, 142-a: retention time on a chromatography column was 6.662 minutes, and The second chiral isomer, 142-b, had a retention time of 10.831 minutes on a chromatography column.

[0095] Compounds 171, 174, and 270 were chiral-cleared using a similar decomposition procedure to obtain two of their chiral isomers, 171-a / 171-b, 174-a / 174-b, and 270-a / 270-b, respectively. Their retention times on a chromatography column are as follows:

[0096] [Table 2]

[0097] Other compounds of the present invention can also be chiralized in a similar manner.

[0098] Example 343: Method for determining pERK and ERK protein content in H358 cells using a compound. H358 cells were seeded in a 24-well plate. After 1 day of incubation, the test compound (concentration 1 μM) was added. After allowing the compound to act for 24 hours, the cells were lysed, and the cell lysate was transferred to a 96-well ELISA plate. The levels of pERK and ERK in the lysate were measured using an ELISA kit (abcam 176660). The ratio of pERK to ERK was calculated and compared with the DMSO group to determine the inhibition rate of pERK activity by the compound. The results are shown in Table 3 below.

[0099] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0100] Example 344: Antiproliferative activity of the compound against H358 cells 2500 H358 cells were seeded in a 96-well ultra-low adhesion plate (corning, 7007). After 1 day of growth, serially diluted compounds (maximum concentration 5 μM, 5-fold dilution, total of 5 doses) were added. Three days after compound addition, Cell Titer Glow (Promega, G9681) was added to evaluate pellet growth, and IC50 was measured. 50 The values ​​were calculated. The results are shown in Table 4 below.

[0101] [Table 4-1] [Table 4-2] [Table 4-3]

[0102] As can be seen from the data in Tables 3 and 4, the antiproliferative activity of the compounds of the present invention against most H358 cells is 0.3 μM or less, and R 5 (or R 5a or R 5b When the compound is a spiro ring or other substituted heterocycle, it was confirmed that the compound has very high K-RAS G12C inhibitory activity. Compounds 131, 142, and 171 all showed good antiproliferative activity against H358 cells, and their IC 50 The values ​​are 1.5 nM, 2.5 nM, and 1.4 nM, respectively, but the ICs of reference compounds B and C are different. 50 The values ​​were 4.6 nM and 5.1 nM, respectively, indicating that the amino group on the side chain of the compound was cyclized, significantly improving cell activity. Furthermore, the 2-position (substituent R) of the acrylamide... 4 It was confirmed that the compound exhibits very high K-RAS G12C inhibitory activity even when the atom is replaced with a smaller F atom.

[0103] Example 345: Evaluation of pharmacokinetics in mice The compound was administered intravenously at a dose of 2 mg / kg and orally via enteral nutrition at a dose of 10 mg / kg (0.5% CMC-Na suspension). Fifteen male ICR mice were selected from each group, and blood samples were collected from each mouse at three discrete time points, with three mice used at each time point. Sampling times were before administration and at 5, 15, 30 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, and 24 hours after administration. At each time point after administration, 80 μL of blood was collected from the mouse's orbit or heart. All whole blood samples were collected in tubes containing EDTA K2, centrifuged at 4°C for 10 minutes (1500-1600 rpm) to separate the plasma, and stored in a refrigerator at -90 to -60°C for sample analysis. The compound concentration in plasma was measured by liquid chromatography-tandem mass spectrometry, and the corresponding pharmacokinetic parameters were determined according to the plasma concentration-time curve.

[0104] [Table 5]

[0105] As can be seen from the table above, compound 131 has better oral absorption and half-life (t) compared to compound B. 1 / 2 ), maximum plasma concentration (C max ), Area under the drug-time curve (AUC) 0-t ), metabolic parameters such as oral bioavailability are improved. Of particular note is that, compared to reference compound C in the patent (Example 65 of WO2018 / 143315), compound 171 has superior metabolic parameters, and compound 142 also has superior metabolic parameters. max and AUC 0-t Metabolic parameters such as those mentioned above have been significantly improved, demonstrating that the metabolic properties after cyclization of the amino group of the side chain are greatly improved. The metabolic properties of compounds similar to compounds 131 and 171 of this application have also been significantly improved. Good oral absorption is of great significance in improving pharmacological efficacy, reducing dosage, and reducing costs.

[0106] Example 346. Evaluation of antitumor activity in mice Human pancreatic cancer Mia PaCa-2 cells were cultured in 1640 medium containing 10% fetal bovine serum in a 37°C / 5% CO2 incubator as usual. After subculturing, cells were harvested when the desired volume was reached. 1 × 10⁶ 7 Mia PaCa-2 cells were injected into the left dorsal region of each nude mouse, and the tumor was 150 mm. 3 After growing to maturity, the animals were randomly divided into groups for administration. The groups were as follows: 1) a solvent control group of 8 mice, and 2) compound groups 1, 2, 5, 31, 131, 142, 171, B, and C, each consisting of 8 mice. The solvent control group mice were administered 0.5% CMC-Na intragastricly once daily, while the mice in compound groups 1, 2, 5, 31, 131, 142, 171, B, and C were administered the compounds suspended in 0.5% CMC-Na intragastricly once daily. Tumor volume and body weight of the mice were measured every Tuesday and Thursday, and nude mice were sacrificed on day 21 of administration. The test results are shown in Table 6 below.

[0107] [Table 6]

[0108] As can be seen from the data in the table above, the compounds of the present invention have high in vivo antitumor activity, and tumor regression can be achieved when administered continuously at 10 mg / kg / day for 21 days. Compounds 1, 5, 31, 131, 142, and 171 have higher in vivo activity than reference compounds B and C, and compounds 142 and 171 show significantly higher in vivo activity than compound C. It has also been shown that the in vivo activity of the compounds is greatly improved even after the cyclization of the amino group in the side chain.

[0109] Example 346: pERK level assay by Western blotting H358 cells in 2 × 10⁶ 5 Cells were plated in 24-well plates at a rate of one cell / well. Serially diluted compounds, including AMG510, MRTX849, compound 142, and compound 171, were added. After incubation overnight, cells were lysed, proteins were quantified, and the cells were subjected to gel electrophoresis. The results of the phosphorylated ERK (pERK) level assay by Western blotting are shown in Figure 1.

[0110] As can be seen from the results in Figure 1, compounds 142 and 171 of the present invention inhibit intracellular phosphorylated ERK (pERK) levels more strongly than the reference drugs AMG510 and MRTX849 at the same concentrations.

Claims

1. Compounds having the structure represented by general formula (1), pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof. 【Chemistry 1】 Here, in equation (1) R １ It is cyclopropyl, R ２ It is CF3CH2O-, R ３ The basis of the following equation 【Chemistry 2】 And, R ４ H is, R ５ The basis of the following equation 【Transformation 3】 That is the case.

2. The compound according to claim 1, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, wherein the compound is a compound selected from the following compounds 131, 142, and 171. 【Chemistry 4】

3. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

4. A method of using the compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof in the preparation of a drug for the treatment of cancer.

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