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WO2021129824A1 - 新型K-Ras G12C抑制剂 - Google Patents

新型K-Ras G12C抑制剂 Download PDF

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Publication number
WO2021129824A1
WO2021129824A1 PCT/CN2020/139544 CN2020139544W WO2021129824A1 WO 2021129824 A1 WO2021129824 A1 WO 2021129824A1 CN 2020139544 W CN2020139544 W CN 2020139544W WO 2021129824 A1 WO2021129824 A1 WO 2021129824A1
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Prior art keywords
alkyl
substituted
compound
halogen
cycloalkyl
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PCT/CN2020/139544
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English (en)
French (fr)
Inventor
谢雨礼
樊后兴
曹刚
钱立晖
Original Assignee
微境生物医药科技(上海)有限公司
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Priority to CN202080090785.XA priority Critical patent/CN114901661B/zh
Publication of WO2021129824A1 publication Critical patent/WO2021129824A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more specifically, to a new type of K-Ras G12C inhibitor, its preparation method and the use method of the compound.
  • Ras protein family is an important signal transduction and transmission molecule in cells, which plays an important role in growth and development.
  • the analysis and research of a large number of in vitro tumor cells, animal models and human tumor samples show that the excessive activation of Ras family proteins is an early event in the development of human tumors, and is one of the important causes of the occurrence and development of many cancers. Therefore, targeting and inhibiting the activity of Ras protein are important means for the treatment of related tumors.
  • Ras protein There are two forms of Ras protein. It binds to GDP and is in an inactive resting state; when cells receive signals such as growth factor stimulation, Ras protein binds to GTP and is activated.
  • the activated Ras protein recruits a variety of signal transfer proteins, promotes the phosphorylation of downstream signal molecules such as ERK and S6, thereby activating the Ras signal transduction pathway, regulating cell growth, survival, migration and differentiation.
  • the GTPase activity of Ras protein itself can hydrolyze GTP back to GDP.
  • GAPs GTPase activating proteins
  • K-Ras, H-Ras and N-Ras proteins in the Ras protein family are one of the common gene mutations in many tumors, and are the main factors leading to the excessive activation of Ras protein in tumors. Compared with the wild-type Ras protein, these mutations cause the Ras protein activity to be unregulated, stably bind to GTP, and continue to activate, thereby promoting the growth, migration and differentiation of tumor cells.
  • 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 common in a variety of cancers: including pancreatic cancer (95%), colorectal cancer (45%) and lung cancer (25%), and relatively rare in breast cancer, ovarian cancer and brain cancer ( ⁇ 2%). K-Ras mutation sites are mainly concentrated in G12, and G12C mutations are 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.
  • NSCLC non-small cell lung cancer
  • Genomics studies have shown that the K-Ras mutation in non-small cell lung cancer does not coexist with EGFR, ALK, ROS1, RET, and BRAF mutations, but coexists with mutations such as STK11, KEAP1, and TP53, suggesting that K-Ras mutations may be associated with STK11, KEAP1 Synergistic effects with TP53 mutations are involved in the malignant transformation, proliferation and invasion of cells.
  • the abnormal activation of Ras protein is also involved in non-neoplastic diseases such as diabetes and neurodegenerative diseases. It can be seen that small molecule compounds targeting Ras protein can enable a large number of cancer patients and Ras with specific gene mutations. Non-cancerous patients with excessive activation of the pathway benefit.
  • Ras protein treatment is launched. Therefore, the development of highly active small molecule inhibitors against Ras protein, especially K-Ras G12C protein with high mutation frequency, has important clinical significance.
  • Mirati Company reported in patents WO2017/201161, WO2019/099524 and US2019/270743 K-Ras G12C inhibitors with tetrahydropyridopyrimidine as the core. These compounds have disadvantages such as poor activity or instability. For example, in US2019/270743 The stability of compound A (Example 7) is poor. In addition, some compounds have low activity. For example, the anti-proliferative activity of compound B (Example 494) in WO2019/099524 on NCI-H358 cells is greater than 1 ⁇ M.
  • the present invention aims to provide a compound represented by formula (1), each of its optical isomers, each of its crystal forms, its pharmaceutically acceptable salt, its hydrate or its solvate:
  • Y is a chemical bond or C1-C6 alkylene group
  • R 1 is an aryl group or a heteroaryl group, and the aryl group or heteroaryl group can be substituted by 1-3 of the following groups: halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3 -C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl or halogen-substituted C1-C3 alkoxy, when substituted by multiple substituents, the substituents may be the same or different;
  • R 2 is an aminoalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, and the heterocycloalkyl, aryl or heteroaryl group can be substituted by 1 to 3 of the following groups : H, halogen, CN, OH, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, -(C1-C3 alkyl)-cyano, -(C1-C3 alkyl)- (C1-C3 alkoxy),
  • R 3 and R 4 are independently H, D, halogen or C1-C3 alkyl
  • the saturated heterocycloalkyl, partially saturated heterocycloalkyl or heteroaryl group can be 1-3 of the following groups are substituted: H, D, halogen, CN, NMe 2 , NEt 2 , SMe, C1-C3 alkyl, C3-C6 cycloalkyl, -C(O)O-(C1-C3 alkyl), -C(O)NH-(C1-C3 alkane Group), -C(O)NMe 2 , -C(O)NEt 2 , -(C1-C3 alkyl)-NMe 2 , -(C1-C3 alkyl)-NEt 2 , halogen substituted C1-C3 alkyl Or cyano substituted C1-C3 alkyl, when it is substituted by multiple substituents,
  • R 5 is C3-C6 cycloalkyl, -(C1-C3 alkyl)-cyano, -(C1-C3 alkyl)-hydroxy, -(C1-C3 alkyl)-(C3-C6 cycloalkyl) , -(C1-C3 alkyl)-(C1-C3 alkoxy), -(C1-C3 alkyl)-(halogen substituted C1-C3 alkoxy), heterocycloalkyl, partially saturated heterocycloalkane Group, heteroaryl, -(C1-C3 alkyl)-heterocycloalkyl, -(C1-C3 alkyl)-heteroaryl or -(C1-C3 alkyl)-NR 6 R 7 , the hetero Cycloalkyl, partially saturated heterocycloalkyl, heteroaryl, -(C1-C3 alkyl)-heterocycloalkyl or -(C1-
  • substituents When substituted by multiple substituents, the substituents may be the same or Different, wherein R 6 and R 7 are independently H, C1-C3 alkyl, C3-C6 cycloalkyl, or halogen substituted C1-C3 alkyl.
  • Y is a chemical bond, -CH 2 -, -CH(Me)- or -CH 2 CH 2 -.
  • R 1 is: Wherein R a and R b are independently H, halogen, hydroxy, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl Or halogen substituted C1-C3 alkoxy.
  • R 2 is: Where n is 1, 2 or 3, R c and R d are independently H, halogen, CN, OH, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 Alkyl or halogen substituted C1-C3 alkoxy, R e is C1-C3 alkyl, C3-C6 cycloalkyl, deuterated C1-C3 alkyl, -(C1-C3 alkyl)-cyano, -( C1-C3 alkyl)-(C1-C3 alkoxy), -(C1-C3 alkyl)-(C3-C6 cycloalkyl), deuterated C1-C3 alkyl, halogen substituted C1-C3 alkyl or The halogen-substituted C1-C3 alkoxy group, when substituted
  • Q is wherein, R 3 and R 4 are independently H or D; for
  • the representative compound of the present invention has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmacologically acceptable excipient or carrier, and the compound of the general formula (1) of the present invention, its optical isomers, its crystal forms, Its pharmaceutically acceptable salt, its hydrate or its solvate is used as the active ingredient.
  • Another object of the present invention is to provide the above-mentioned compound of the present invention, each of its optical isomers, each of its crystal forms, its pharmaceutically acceptable salt, its hydrate or its solvate in the preparation of drugs for the treatment of RAS-related diseases In the application.
  • Another object of the present invention is to provide a method for treating diseases mediated by K-Ras G12C mutation, which comprises administering to a subject the above-mentioned compound of the present invention, each of its optical isomers, each of its crystal forms, and its A pharmaceutically acceptable salt, its hydrate or its solvate.
  • the disease mediated by the K-Ras G12C mutation is preferably cancer, such as blood cancer and solid tumor.
  • the heteroaryl group is connected with acrylamide by a carbon-carbon single bond
  • the activity of the compound is very poor, as listed above, the anti-proliferative activity of compound B on NCI-H358 cells is greater than 1 ⁇ M; in addition, When it is a heterocycloalkyl group or lacks an electron withdrawing group such as CO beside the N atom, the compound has poor stability.
  • the inventors found that when the 2 (R 5 group) position of acrylamide is substituted with a bulky heteroaryl or substituted heteroaryl, the compound also has good K-RAS G12C inhibitory activity and compound stability
  • the 2-position of acrylamide in patent US2019/270743 is replaced with a smaller group, the stability of the compound is poor, such as compound A listed above.
  • the compound of general formula (1) described above can be synthesized using standard synthesis techniques or well-known techniques and methods combined in the text. In addition, the solvent, temperature and other reaction conditions mentioned here can be changed.
  • the starting materials for the synthesis of the compound can be synthesized or obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.).
  • the compounds described herein and other related compounds with different substituents can be synthesized using well-known techniques and raw materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for the reaction, etc. are not limited to the following explanations.
  • 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, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared by the following general reaction scheme 1, scheme 2 or scheme 3:
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 1 (method A), wherein R 1 , R 2 , Y and Q are as defined above, PG and PG 1 represent different protecting groups for amine groups, and X represents Br, I, triflate, boric acid, borate or potassium fluoroborate.
  • the raw material A1 (synthesized with reference to patent WO2017/201161) is oxidized to obtain compound A2, compound A2 and R 2 -Y-OH are reacted under alkaline conditions to obtain compound A3, and compound A3 is deprotected.
  • PG e.g.
  • Boc yields compound A4, compound A4 and R 1 -X are coupled to yield compound A5, compound A5 removes the protective group PG 1 (such as Cbz) to yield compound A6, compound A6 and Q-COOH undergo condensation reaction to form the target compound A7.
  • PG 1 such as Cbz
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 2 (method B), wherein R 1 , R 2 , Y and R 5 are as defined above, W represents Br or I, and K represents boric acid, boric acid ester Or potassium fluoroborate, in which R 5 is directly connected to K is a carbon atom.
  • the general reaction scheme, the intermediate compound A6 and B1 is a condensation reaction to give compound B2 2, R 5 -K compound B2 and a Suzuki coupling reaction to give the final product B3.
  • the embodiment of the compound of general formula (1) can be prepared according to general reaction scheme 3 (method C), wherein R 1 , R 2 , Y and R 5 are as defined above, W represents Br or I, and R 5 is directly connected to H Is the nitrogen atom. As shown in general reaction scheme 2, intermediate B2 and compound R 5 -H undergo Ullman coupling reaction to obtain the final product C1.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or a diluent, that does not make the biological activity or properties of the compound disappear, and is relatively non-toxic. For example, when a substance is administered to an individual, it will not cause unwanted biological effects or Interacts with any components it contains in a harmful way.
  • pharmaceutically acceptable salt refers to a form of a compound that does not cause important irritation to the administered organism and does not cause the biological activity and properties of the compound to disappear.
  • pharmaceutically acceptable salts are obtained by reacting compounds of formula (1) with acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, 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, p-toluenesulfonic acid, etc.
  • Organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • 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 alcoholate is formed when the solvent is ethanol.
  • the solvate of the compound of general formula (1) is conveniently prepared or formed according to the method described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent.
  • the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned here can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.
  • the compound of general formula (1) is prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-particle size forms.
  • the compound of general formula (1) includes a crystalline form and may also be a polymorphic form.
  • Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • the compound of general formula (1) has one or more stereocenters, and is therefore classified as racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers.
  • the asymmetric centers that can 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 mixtures of optical isomers and diastereomers and pure or partially pure compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. It is preferably a lower alkyl group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl.
  • alkyl includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CF 3 CH, i Pr, n Pr, i Bu, n Bu or t Bu.
  • Alkylene refers to a divalent alkyl group as defined above; for example, methylene, ethylene and the like.
  • Cycloalkyl refers to a 3- to 6-membered all-carbon monocyclic aliphatic hydrocarbon group in which one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene and the like are examples of the rings.
  • Alkoxy refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are those with 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy And tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
  • Aryl refers to a group having at least one aromatic ring structure, that is, a carbocyclic aryl group having a conjugated ⁇ -electron system, such as a benzene ring and a naphthalene ring.
  • Heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N).
  • the heteroaryl group is monocyclic or polycyclic, such as a monocyclic heteroaryl ring and one or more carbocyclic rings. Aromatic groups or other monocyclic heterocyclic groups are condensed.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, furanyl , Thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxanyl Azolyl, benzopyridinyl and pyrrolopyrimidinyl.
  • Heterocycloalkyl refers to a saturated or partially unsaturated ring system group containing one or more heteroatoms (O, S, or N), wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. Ammonization as a ring atom. Unless otherwise specified, the "heterocycloalkyl” ring system may be a monocyclic, bicyclic, spirocyclic or polycyclic ring system. "Heterocycloalkyl” can be attached to the rest of the molecule through more than one ring carbon or heteroatom.
  • heterocycloalkyl examples include, but are not limited to, pyrrolidine, piperidine, N-methylpiperidine, tetrahydroimidazole, pyrazolidine, butyrolactam, valerolactam, imidazolinone, hydantoin, Dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorph Phinoline-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, 2-Azaspiro[3.3]heptane and so on.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • halogen substitution appearing in front of a group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Replaced by F or Cl.
  • bond refers to a chemical bond between two atoms or between two fragments (when the atoms connected by a bond are considered part of a larger structure).
  • bond refers to a chemical bond between two atoms or between two fragments (when the atoms connected by a bond are considered part of a larger structure).
  • bond when the group described herein is a bond, the lack of a reference group allows a bond to be formed between the remaining defined groups.
  • membered ring includes any cyclic structure.
  • element means to indicate the number of skeletal atoms constituting the ring.
  • cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific part or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained or attached to molecules.
  • acceptable refers to a prescription component or active ingredient that does not have undue harmful effects on the health of the general treatment target.
  • treatment includes alleviating, inhibiting or improving the symptoms or conditions of diseases; inhibiting the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of diseases or symptoms, Such as controlling the development of diseases or conditions; reducing diseases or symptoms; reducing diseases or symptoms; reducing complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or condition, especially its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Regardless of fixed administration or temporary administration, continuous administration or intermittent administration, it can be attributed to or related to the situation of administration.
  • Active ingredient refers to the compound represented by the general formula (1) and the pharmaceutically acceptable inorganic or organic salt of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers, and therefore appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers.
  • the asymmetric centers that can 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 mixtures of optical isomers and diastereomers and pure or partially pure compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition refers to when administered to an individual (human or medicament).
  • agent a compound or composition that can induce a desired pharmaceutical and/or physiological response through local and/or systemic effects.
  • administered refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides methods 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 (such as cancer).
  • a method for cancer treatment comprises administering to an individual in need an effective amount of a pharmaceutical composition of any of the aforementioned protective structure (1) compounds.
  • the cancer is mediated by K-Ras, H-Ras, and/or G12C N-Ras mutations.
  • the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-related polyposis, or colorectal cancer.
  • the compound of the present invention and its pharmaceutically acceptable salt can be prepared into various preparations, which contain a safe and effective amount of the compound of the present invention or its pharmaceutically acceptable salt and a pharmacologically acceptable excipient or carrier. .
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipients or carriers” refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity . "Compatibility” here means that each component of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • 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.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose,
  • the compound of the present invention when administered, it can be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), or locally.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous 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.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 50 to 100 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • Compound 1 was prepared according to Method A as described below:
  • Compound 128 was prepared according to Method C as described below:
  • Example 149 Compound detection of pERK and ERK protein content in H358 cells
  • H358 cells are planted in a 24-well plate. After one day of growth, add the test compound (concentration of 1 ⁇ M). After the compound acts for 24 hours, after lysing the cells, transfer the cell lysate to a 96-well ELISA plate and use an ELISA kit (abcam 176660) Determine the levels of pERK and ERK in the lysate, calculate the ratio of pERK and ERK, and compare with the DMSO group, calculate the percentage of compounds that inhibit the activity of pERK. The results are shown in Table 6 below.
  • Compound Inhibition rate(%) Compound Inhibition rate(%) Compound Inhibition rate(%) 1 +++ 2 +++ 3 ++ 4 +++ 5 +++ 6 +++ 7 + 8 +++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 ++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ twenty one +++ twenty two +++ twenty three +++ twenty four +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 ++
  • +++ means that the inhibition rate is greater than 90%.
  • Compound IC 50 Compound IC 50 Compound IC 50 1 +++ 2 +++ 3 ++ 4 +++ 5 +++ 6 +++ 7 + 8 +++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ twenty one +++ twenty two +++ twenty three +++ twenty four +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 ++ 40 ++ 41 + 42 +
  • +++ means that the IC 50 of the compound is less than 0.3 ⁇ M.
  • the carbon-nitrogen single bond has a stronger dipole moment than the carbon-carbon single bond, and the nitrogen atom loses part of the electrons, which is beneficial to the stability of the intermediate state after the addition of acrylamide by the cysteine of the K-RAS protein.
  • the compound of the invention has strong activity.
  • the compound of the present invention has a bulky heteroaryl group or substituted heteroaryl group at the 2-position of acrylamide, such as imidazolyl or pyrimidinyl
  • the compound also has good K-RAS G12C inhibitory activity, which is presumed to be The N atom on the heteroaryl group facilitates the binding to the K-RAS protein.
  • Mia PaCa-2 cells were routinely cultured in a 1640 containing 10% fetal bovine serum in a 37°C, 5% CO 2 incubator. After passage, when the cells reached the required amount, the cells were collected. 1 ⁇ 10 7 Mia PaCa-2 cells were injected into the left back of each nude mouse. After the tumor grew to 150 mm 3 , the animals were randomly divided into groups to start the administration. Respectively 1) solvent control group, 8 animals; 2) compound 1, compound 5, compound 70, compound 92, and compound 121 groups, each with 8 animals.
  • the solvent control group was given 0.5% CMC-Na by intragastric administration once a day; compound 1, compound 5, compound 70, compound 92, and compound 121 groups were given 0.5% CMC-Na suspension once a day.
  • the tumor volume was measured every Tuesday and Thursday, and the body weight of the mice was measured. Nude mice were sacrificed on the 21st day of administration. The test results are shown in Table 9 below.
  • the compound of the present invention Compared with the control drug A, the compound of the present invention has stronger in vitro activity and compound stability. At the same time, the in vivo anti-tumor test also shows that the compound of the present invention has better in vivo activity, indicating that the compound of the present invention has better clinical application. Efficacy and medicinal properties.

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Abstract

本发明涉及一种式(1)所示的化合物及其制备方法，及式(1)化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物作为G12C突变体K-Ras蛋白不可逆抑制剂在制备抗肿瘤等Ras相关疾病的药物中的用途。

Description

新型K-Ras G12C抑制剂
本申请要求申请日为2019年12月27日的中国专利申请CN201911386644.8的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属涉及药物化学领域，更具体而言，涉及一类新型K-Ras G12C抑制剂，及其制备方法和该类化合物的使用方法。
背景技术
Ras蛋白家族是细胞内重要的信号转导传递分子，在生长发育中发挥了重要的作用。大量的体外肿瘤细胞，动物模型以及人类肿瘤样本的分析和研究表明Ras家族蛋白的过度激活是人类肿瘤发展的早期事件，是多种癌症发生和发展的重要诱因之一。因此靶向和抑制Ras蛋白的活性是治疗相关肿瘤的重要手段。
Ras蛋白存在两种形式，其与GDP结合，处于未激活静息状态；当细胞接收诸如生长因子刺激等信号时，Ras蛋白与GTP结合，被激活。活化的Ras蛋白招募多种信号转接蛋白，促进下游信号分子诸如ERK，S6的磷酸化，从而激活Ras信号转导通路，调节细胞生长、存活、迁移和分化。Ras蛋白自身的GTPase酶活性可将GTP水解回GDP。细胞内存在GTP酶激活蛋白(GAPs)与Ras相互作用大大促进Ras GTPase的活性，从而防止Ras蛋白的过度激活。
Ras蛋白家族中K-Ras,H-Ras以及N-Ras蛋白上的突变是多种肿瘤的常见的基因突变之一，是导致肿瘤中Ras蛋白过度激活的主要因素。与野生型的Ras蛋白相比，这些突变导致Ras蛋白活性不为调控，稳定结合GTP，持续激活，从而促进肿瘤细胞的生长，迁移以及分化。这其中K-Ras蛋白的突变最为常见，占所有Ras突变的85％，而N-Ras(12％)和H-Ras(3％)则相对少见。K-Ras突变在多种癌症中极为普遍：包括胰腺癌(95％)、结肠直肠癌(45％)和肺癌(25％)等，而在乳腺癌、卵巢癌和脑癌中相对罕见(<2％)。K-Ras突变位点主要集中于G12位，其中G12C的突变最为常见。例如在非小细胞肺癌(NSCLC)中，K-Ras G12C占所有K-Ras突变的50％，其次是G12V和G12D。基因组学研究表明，非小细胞肺癌中的K-Ras突变不与EGFR、ALK、ROS1、RET和BRAF突变共存，而与STK11、KEAP1和TP53等突变共存，提示K-Ras突变可能与STK11、KEAP1和TP53突变等协同作用参与细胞的恶性转变，增生和侵袭。除了肿瘤 以外，Ras蛋白的异常激活也参与了包括糖尿病，神经退行性疾病等非肿瘤性疾病，由此可见，靶向Ras蛋白的小分子化合物可使大批携带特定基因变异的的癌症病人和Ras通路过度激活的非癌症性病人受益。
自从肿瘤中Ras突变被发现四十年来，虽然我们对Ras通路致病机制有了更为深入的了解，但是对于大量携带Ras蛋白突变以及Ras通路过度激活的病人，临床上尚未有有效的靶向Ras蛋白的治疗手段上市。因此开发高活性的针对Ras蛋白特别是突变频率较高的K-Ras G12C蛋白的小分子抑制剂，具有重要的临床意义。
Mirati公司在专利WO2017/201161、WO2019/099524和US2019/270743中报道了母核为四氢吡啶并嘧啶的K-Ras G12C抑制剂,这些化合物存在活性差或者不稳定等缺点，例如US2019/270743中的化合物A(Example 7)稳定性差。此外，部分化合物活性较低，例如WO2019/099524中化合物B(Example 494)对NCI-H358细胞的抗增殖活性大于1μM。
Figure PCTCN2020139544-appb-000001
因此，目前有研究和发现活性高和稳定性好的K-Ras G12C抑制剂的需要。
发明内容
本发明旨在提供一种通式如式(1)所示的化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物：
Figure PCTCN2020139544-appb-000002
式(1)中：
Y为化学键或C1-C6亚烷基；
R 1为芳基或杂芳基，所述芳基或杂芳基可被1-3个下述基团所取代：卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基，当被多个取代基取代时，所述取代基可以相同或不同；
R 2为胺基烷基、环烷基、杂环烷基、芳基或杂芳基，所述杂环烷基、芳基或杂芳基均可被1-3个下述基团所取代：H、卤素、CN、OH、C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、-(C1-C3烷基)-氰基、-(C1-C3烷基)-(C1-C3烷氧基)、
-(C1-C3烷基)-(C3-C6环烷基)、氘代C1-C3烷基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基，当被多个取代基取代时，所述取代基可以相同或不同。
Q为
Figure PCTCN2020139544-appb-000003
其中，R 3和R 4独立为H、D、卤素或C1-C3烷基；
Figure PCTCN2020139544-appb-000004
为至少有一个N原子的4-7元饱和杂环烷基、部分饱和的杂环烷基或杂芳基，所述饱和杂环烷基、部分饱和的杂环烷基或杂芳基可被1-3个下述基团所取代：H、D、卤素、
Figure PCTCN2020139544-appb-000005
CN、NMe 2、NEt 2、SMe、C1-C3烷基、C3-C6环烷基、-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3烷基)、-C(O)NMe 2、-C(O)NEt 2、-(C1-C3烷基)-NMe 2、-(C1-C3烷基)-NEt 2、卤素取代C1-C3烷基或氰基取代C1-C3烷基，当被多个取代基取代时，所述取代基可以相同或不同；
R 5为C3-C6环烷基、-(C1-C3烷基)-氰基、-(C1-C3烷基)-羟基、-(C1-C3烷基)-(C3-C6环烷基)、-(C1-C3烷基)-(C1-C3烷氧基)、-(C1-C3烷基)-(卤素取代C1-C3烷氧基)、杂环烷基、部分饱和的杂环烷基、杂芳基、-(C1-C3烷基)-杂环烷基、-(C1-C3烷基)-杂芳基或-(C1-C3烷基)-NR 6R 7，所述杂环烷基、部分饱和的杂环烷基、杂芳基、-(C1-C3烷基)-杂环烷基或-(C1-C3烷基)-杂芳基可被1-3个下述基团所取代：卤素、OH、
Figure PCTCN2020139544-appb-000006
CN、NMe 2、NEt 2、-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3烷基)、-C(O)NMe 2、-C(O)NEt 2、C1-C3烷基、C3-C6环烷基、卤素取代C1-C3烷基或氰基取代C1-C3烷基，当被多个取代基取代时，所述取代基可以相同或不同，其中R 6和R 7独立为H、C1-C3烷基、C3-C6环烷基、或卤素取代C1-C3烷基。
在另一优选例中，其中所述通式(1)中，Y为化学键、-CH 2-、-CH(Me)-或-CH 2CH 2-。
在另一优选例中，其中所述通式(1)中，R 1为：
Figure PCTCN2020139544-appb-000007
Figure PCTCN2020139544-appb-000008
其中R a和R b独立地为H、卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基。
在另一优选例中，其中所述通式(1)中，R 2为：
Figure PCTCN2020139544-appb-000009
Figure PCTCN2020139544-appb-000010
其中n为1、2或3，R c和R d独立地为H、卤素、CN、OH、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基，R e为C1-C3烷基、C3-C6环烷基、氘代C1-C3烷基、-(C1-C3烷基)-氰基、-(C1-C3烷基)-(C1-C3烷氧基)、-(C1-C3烷基)-(C3-C6环烷基)、氘代C1-C3烷基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基，当被多个取代基取代时，所述取代基可以相同或不同。
在另一优选例中，其中所述通式(1)中，Q为
Figure PCTCN2020139544-appb-000011
其中，R 3和R 4独立为H或D；
Figure PCTCN2020139544-appb-000012
为
Figure PCTCN2020139544-appb-000013
Figure PCTCN2020139544-appb-000014
Figure PCTCN2020139544-appb-000015
Figure PCTCN2020139544-appb-000016
在另一优选例中，其中所述通式(1)中，Q为
Figure PCTCN2020139544-appb-000017
其中，R 5为
Figure PCTCN2020139544-appb-000018
Figure PCTCN2020139544-appb-000019
在各种不同实施方式中，本发明代表性化合物具有以下结构之一：
Figure PCTCN2020139544-appb-000020
Figure PCTCN2020139544-appb-000021
Figure PCTCN2020139544-appb-000022
Figure PCTCN2020139544-appb-000023
Figure PCTCN2020139544-appb-000024
Figure PCTCN2020139544-appb-000025
Figure PCTCN2020139544-appb-000026
本发明的另一个目的是提供了一种药物组合物，它含有药理上可接受的赋形剂或载体，以及本发明通式(1)化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物作为活性成分。
本发明的再一个目的提供了本发明的上述化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物在制备治疗RAS相关疾病的药物中的应用。
本发明的再一个目的提供了一种治疗由K-Ras G12C突变介导的疾病的方法，其包括给与受试者本发明的上述化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物。所述由K-Ras G12C突变介导的疾病优选癌症，例如血液癌和实体瘤。
通过合成和仔细研究了多类涉及具有K-RAS G12C抑制作用的新化合物，发明人发现在通式(1)化合物中，当Q为烯胺结构
Figure PCTCN2020139544-appb-000027
时，其中
Figure PCTCN2020139544-appb-000028
为杂芳基或取代杂芳基时，化合物的K-RAS G12C抑制活性得到大幅提高，同时化合物具有很好的稳定性，而专利WO2019/099524中芳杂基以碳碳单键和丙烯酰胺连接的化合物活性很差，如前文所列化合物B对NCI-H358细胞的抗增殖活性大于1μM；此外，
Figure PCTCN2020139544-appb-000029
为杂环烷基或者N原子旁边缺少CO等吸电子基团的时候，化合物稳定性差。另一方面，本发明人发现丙烯酰胺的2(R 5基团)位用体积较大杂芳基或取代杂芳基取代时，化合物也具有很好的K-RAS G12C抑制活性和化合物稳定性，而专利US2019/270743中丙烯酰胺的2位用较小的基团取代时，化合物稳定性差，如前文所列的化物A。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得，如，但不限于Aldrich Chemical Co.(Milwaukee，Wis.)或Sigma Chemical Co.(St.Louis，Mo.)。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其采用下列一般反应流程1、流程2或流程3制备：
一般反应流程1
Figure PCTCN2020139544-appb-000030
通式(1)化合物的实施方式可根据一般反应流程1(方法A)制备，其中R 1、R 2、Y及Q如上文中所定义，PG和PG 1表示胺基的不同保护基，X表示Br、I、三氟甲磺酸酯、硼酸、硼酸酯或氟硼酸钾盐。如一般反应流程1所示,原料A1(参考专利WO2017/201161合成)经氧化反应得到化合物A2,化合物A2和R 2-Y-OH在碱性条件下反应得到化合物A3，化合物A3脱除保护基PG(例如Boc)得到化合物A4,化合物A4和R 1-X偶联得到化合物A5,化合物A5脱除保护基PG 1(例如Cbz)得到化合物A6，化合物A6和Q-COOH进行缩合反应生成目标化合物A7。
一般反应流程2
Figure PCTCN2020139544-appb-000031
通式(1)化合物的实施方式可根据一般反应流程2(方法B)制备，其中R 1、R 2、Y及R 5如上文中所定义，W表示Br或I，K表示硼酸、硼酸酯或氟硼酸钾盐，R 5中直接和K连接的是碳原子。如一般反应流程2所示,中间体A6和化合物B1进行缩合反应得到化合物B2，化合物B2和R 5-K进行Suzuki偶联反应得到终产物B3。
一般反应流程3
Figure PCTCN2020139544-appb-000032
通式(1)化合物的实施方式可根据一般反应流程3(方法C)制备，其中R 1、R 2、Y及R 5如上文中所定义，W表示Br或I，R 5中直接和H连接的是氮原子。如一般反应流程2所示,中间体B2和化合物R 5-H进行乌尔曼偶联反应得到终产物C1。
化合物的进一步形式
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质 消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射图、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，通式(1)化合物有一个或多个立体中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组 DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH、 iPr、 nPr、 iBu、 nBu或 tBu。
“亚烷基”指二价的如上所定义的烷基；例如亚甲基、亚乙基等。
“环烷基”指3至6元全碳单环脂肪烃基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。例如，环丙基、环丁基、环戊基、环己烷、环己二烯等。
“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。
“芳基”指具有至少一个芳环结构的基团，即具有共轭的π电子系统的碳环芳基，如苯环和萘环。
“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的，例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、喹啉基、异喹啉基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基和吡咯并嘧啶基。
“杂环烷基”指含有一个或多个杂原子(O、S或N)的饱和或部分不饱和环体系基团，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化，作为环原子。除非另有说明，“杂环烷基”的环体系可以是单环、双环、螺环或多环的环体系。“杂环烷基”可以通过一个以上环碳或杂原子连接于分子的其余部分。“杂环烷基”的例子包括但不限于吡咯烷、哌啶、N-甲基哌啶、四氢咪唑、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、嘧啶-2,4(1H,3H)-二酮、1,4-二氧六环、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环、2-氮杂螺[3.3]庚烷等。
“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤素取代”(或“卤 代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。
术语“键”或“单键”指两个原子间或两个片断间(当通过键来连接的原子被认为是大结构的一部分时)的化学键。一方面，当本文所述的基团是一个键时，缺少参考基团，允许在剩余的确定基团间形成一个键。
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。这样，如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。
术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。
如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的 化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明化合物或药物组合物治疗疾病的方法，包括但不限于涉及G12C K-Ras、G12C H-Ras和/或G12C N-Ras突变的病况(例如癌症)。
在一些事实方案中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的保护结构(1)化合物的药物组合物。在一些实施方案中，癌症由K-Ras、H-Ras和/或G12C N-Ras突变介导。在其它实施方案中，该癌症是肺癌、胰腺癌、结肠癌、MYH相关息肉病或结肠直肠癌。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的 药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020139544-appb-000033
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和 非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～100mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中， 1H-NMR用Vian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
本发明采用下述缩略词：Ar代表氩气；BFMO代表N1,N2-二(呋喃-2-基甲基)氧醛酰胺；CDCl 3代表氘代氯仿；CH 3CN代表乙腈；Cs 2CO 3代表碳酸铯；CuI代表碘化亚铜；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；Dioxane代表1,4-二氧六环；DMF代表二甲基甲酰胺；DMSO代表二甲基亚风；EA代表乙酸乙酯；EtOH代表乙醇；h代表小时；NaOH代表氢氧化钠；KOAc代表醋酸钾；LC-MS代表液相-质谱；m-CPBA代表间氯过氧苯甲酸；MeOH代表甲醇；min代表分钟；MS代表质谱；Na 2SO 4代表硫酸钠；NMR代表核磁共振；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；Pd(dppf)Cl 2代表1,1'-双(二苯基膦基)二茂铁]二氯化钯；PE代表石油醚；Ruphos代表2-双环已基膦-2',6'-二异丙氧基联苯； t-BuOK代表叔丁醇钾；T3P代表1-丙基磷酸酐；TFA(CF 3COOH)代表三氟乙酸；THF代表四氢呋喃；Toluene代表甲苯。
具体实施方式:
制备例1 2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(A-6a)的合成
Figure PCTCN2020139544-appb-000034
(S)-4-(4-((苄氧基)羰基)-3-(氰甲基)哌嗪-1-基)-2-(甲基磺酰基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(A-2)
1L单口瓶中加入A-1(72.5g,134.6mmol)和DCM(725mL)，Ar保护下，冰盐浴冷却至0-5℃，加入m-CPBA(81.3g,471.1mmol)，继续反应2小时。LC-MS监测反应完全后，混合液过滤，滤饼用DCM(50mL*3)洗涤，滤液中加入饱和碳酸氢钠溶液(200mL)和饱和硫代硫酸钠溶液(300mL)，室温搅拌30min，分液，有机相依次用饱和硫代硫酸钠溶液(200mL*2)和饱和氯化钠溶液(200mL)洗涤，无水Na 2SO 4干燥，过滤，滤液浓缩，得到粗产物A-2(80g，收率100％)，ESI-MS m/z:571.3[M+H] +。
4-((S)-4-((苄氧基)羰基)-3-(氰基甲基)哌嗪-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,8-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(A-3a)
1L单口瓶中加入A-2(80g,134.6mmol)、THF(600mL)和(S)-(1-甲基吡咯烷-2-基)甲醇(31g,269.2mmol)，Ar保护下，冰盐浴冷却至0-5℃，后加入叔丁醇钠(32.3g,336.5mmol)，继续反应2h。TLC和LC-MS监测反应完全后，体系加入EA(300mL)，饱和氯化铵溶液(200mL)淬灭，搅拌，分液，水相再用EA(200mL)萃取，合并有机相并用饱和氯化钠溶液(200mL*2)洗涤，浓缩，残留物经柱层析纯化(DCM/MeOH＝50/1to 30/1)得黄棕色油状产物A-3a(60.5g,收率74％)，ESI-MS m/z:606.3[M+H] +。
(S)-2-(氰基甲基)-4-(2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧 啶-4-基)哌嗪-1-甲酸苄酯(A-4a)
1L单口瓶中加入A-3a(60.5g,99.88mmol)和DCM(150mL)，混合液在Ar保护下用冰盐浴降温至0-5℃，后加入TFA(228g,2mol)，r.t.搅拌反应2h,LC-MS监测反应完成后，体系浓缩，残留物加入DCM(300mL)，后用饱和碳酸钠溶液调pH至8～9，搅拌，分液，水相再用DCM(200mL*5)萃取，合并有机相用无水Na 2SO 4干燥，过滤，滤液浓缩后得黄色泡沫状固体产物A-4a(54.2g,收率107％)，ESI-MS m/z:506.3[M+H] +。
(S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-2-(氰基甲基)哌嗪-1-甲酸苄酯(A-5a)
1L单口瓶中加入A-4a(45.5g,90.1mmol)，1-溴-8-氯萘(32.6g,135mmol),碳酸铯(73.3g,225mmol)，Ruphos(8.4g,18mmol)和甲苯(800mL)，混合液Ar置换保护后，加入Pd 2(dba) 3(16.5g,18mmol)，Ar保护下升至90℃搅拌反应6h。LC-MS监测反应完全后，体系趁热过滤，滤饼用DCM(100mL)洗涤，滤液浓缩后经柱层析纯化(DCM/MeOH＝50/1 to 20/1)得黄棕色泡沫状固体产物A-5a(36.6g,收率:61％)，ESI-MS m/z:666.4[M+H] +。
2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(A-6a)
1L单口瓶中加入A-5a(40.9g,61.39mmol)，THF(100mL)，MeOH(600mL)，和10％Pd/C(5g,wet％＝50％)，H 2置换三次后室温常压剧烈搅拌反应20h。LC-MS监测反应完全后，体系加入氨甲醇溶液(20mL,7M)，搅拌15min后硅藻土助滤，滤液浓缩至干得黄棕色泡沫状固体产物A-6a(31.3g,收率:95％)，ESI-MS m/z:532.3[M+H] +。
制备例2-10中间体A-6b至A-6j的合成
利用不同原料，采用中间体A-6a的合成方法得到目标中间体A-6b至A-6j。
表1
Figure PCTCN2020139544-appb-000035
Figure PCTCN2020139544-appb-000036
制备例11 2-((S)-1-(2-溴丙烯酰基)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(B-2a)的合成
Figure PCTCN2020139544-appb-000037
2-((S)-1-(2-溴丙烯酰基)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(B-2a)
100mL单口瓶中加入A-6a(10.64g,20.0mmol)和2-溴丙烯酸(B-1，9.06g,60mmol),DIPEA(25.8g,200mmol)和DMF(200mL),混合液Ar保护下室温缓慢滴加T 3P(50.9g,50％in DMF,80mmol)，滴加完毕，混合液室温搅拌反应1h后加入水(200mL)淬灭，EA(200mL*2)萃取，合并有机相，浓缩，残留物经柱层析纯化(DCM/MeOH＝50/1 to 20/1得淡棕色固体产物(5.45g,收率41％),ESI-MS m/z:664.2/666.2[M+H] +。
制备例12-20中间体B-2b至B-2j的合成
利用不同原料，采用中间体B-2a的合成方法得到目标中间体B-2b至B-2j。
表2
Figure PCTCN2020139544-appb-000038
Figure PCTCN2020139544-appb-000039
实施例1 2-((S)-1-((E)-3-(1H-1,2,4-三唑-1-基)丙烯酰基)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(化合物1)的合成
Figure PCTCN2020139544-appb-000040
化合物1根据如下文所述的方法A制备:
2-((S)-1-((E)-3-(1H-1,2,4-三唑-1-基)丙烯酰基)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
100mL单口瓶中加入A-6a(369mg,0.693mmol)，(E)-3-(1H-1,2,4-三唑-1-基)丙烯酸(145mg,1.04mmol)，DIPEA(269mg,2.08mmol)和DMF(10mL),混合液在Ar保护下室温滴加T 3P(662mg,50％in DMF,1.04mmol)，室温搅拌反应1h后加入水淬灭，EA(10 mL*2)萃取，合并有机相相，浓缩，残留物经pre-TLC(DCM/MeOH/NH 3.H 2O＝500/20/1)纯化得淡黄色固体化合物1(205mg,收率45％)。
1H NMR(400MHz,CDCl 3)δ:8.32(s,1H),8.08(d,J＝14.0Hz,2H),7.73(d,J＝8.1Hz,1H),7.60(t,J＝7.2Hz,1H),7.50(d,J＝7.5Hz,1H),7.41(dd,J＝11.5,7.9Hz,1H),7.31(t,J＝7.8Hz,1H),7.24-7.16(m,1H),7.12(d,J＝9.6Hz,1H),5.14(s,1H),4.52-4.34(m,2H),4.15(dt,J＝35.4,22.5Hz,4H),3.90-3.76(m,1H),3.57(s,1H),3.45(d,J＝13.9Hz,1H),3.13(td,J＝42.7,39.9,21.0Hz,5H),2.86-2.69(m,2H),2.55(dd,J＝28.8,9.7Hz,4H),2.33(s,1H),2.06(s,1H),1.77(s,4H)；ESI-MS m/z:653.4[M+H] +.
实施例2-实施例85化合物2-化合物85的合成
以中间体A-6a至A-6j为起始原料，采用合成方法A，类似于化合物1的合成方法，可以得到化合物2-化合物85。
表3
Figure PCTCN2020139544-appb-000041
Figure PCTCN2020139544-appb-000042
Figure PCTCN2020139544-appb-000043
Figure PCTCN2020139544-appb-000044
Figure PCTCN2020139544-appb-000045
Figure PCTCN2020139544-appb-000046
Figure PCTCN2020139544-appb-000047
Figure PCTCN2020139544-appb-000048
实施例86 2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-1-(2-苯基丙烯酰基)哌嗪-2-基)乙腈(化合物86)的合成
Figure PCTCN2020139544-appb-000049
化合物86根据如下文所述的方法B制备:
2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-1-(2-苯基丙烯酰基)哌嗪-2-基)乙腈
50mL单口瓶中加入B-2a(50mg,0.075mmol)，苯硼酸(18mg,0.15mmol),KOAc(19mg,0.192mmol)，Dioxane(5mL)和H 2O(1mL)，Ar置换保护后，加入Pd(dppf)Cl 2(10mg)，混合液在Ar保护下快速升温至回流，搅拌反应20min后，体系加入水(5mL)和EA(10mL)搅拌，分液，有机相浓缩，残留物pre-TLC(DCM/MeOH/NH 3.H 2O＝500/20/1)纯化得产物(8mg,收率16％)。
1H NMR(400MHz,CDCl 3)δ:7.75(dt,J＝8.1,1.6Hz,1H),7.61-7.52(m,1H),7.45-7.31(m,7H),7.22(dt,J＝7.5,1.5Hz,1H),7.17-7.02(m,1H),6.03(s,1H),5.82(s,1H),5.04(m,1H),4.44-4.24(m,2H),4.15-4.05(m,2H),4.00-3.71(m,3H),3.52(d,J＝11.3Hz,2H),3.43-3.33(m,1H),3.26-2.76(m,7H),2.63(q,J＝6.5,5.9Hz,1H),2.54(d,J＝14.1Hz,1H),2.42(s,3H),2.22(dt,J＝9.8,7.3Hz,1H),2.03(d,J＝11.9Hz,1H),1.89-1.75(m,2H)；ESI-MS m/z: 663.2[M+H] +.
实施例87-实施例127化合物87-化合物127的合成
以中间体B-2a至B-2j为起始原料，采用合成方法B，类似于化合物86的合成方法，可以得到化合物87-化合物127。
表4
Figure PCTCN2020139544-appb-000050
Figure PCTCN2020139544-appb-000051
Figure PCTCN2020139544-appb-000052
Figure PCTCN2020139544-appb-000053
实施例128 2-((S)-1-(2-(1H-咪唑-1-基)丙烯酰基)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷酮-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈(化合物128)的合成
Figure PCTCN2020139544-appb-000054
化合物128根据如下文所述的方法C制备:
2-((S)-1-(2-(1H-咪唑-1-基)丙烯酰基)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基) 甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)哌嗪-2-基)乙腈
10mL单口瓶中加入B-2a(25mg,0.038mmol)，咪唑(4mg,0.056mmol)，CuI(2mg,0.008mmol)，Cs 2CO 3(33mg,0.098mmol)，DMSO(2mL)和BFMO(2mg,0.008mmol)，混合液于Ar保护下升温至80℃搅拌反应1h。MS监测原料基本反应完全后，混合液加入EA(10mL)和H 2O(10mL)，搅拌后分液，有机相浓缩，残留物经pre-TLC(DCM/MeOH/NH 3.H 2O＝500/20/1)纯化得化合物128(5mg，收率20％)。
1H NMR(400MHz,DMSO-d 6)δ:8.22(s,1H),8.10-8.03(m,1H),7.93(d,J＝7.6Hz,1H),7.87(s,1H),7.78-7.72(m,1H),7.57(dd,J＝18.4,7.7Hz,2H),7.49-7.42(m,1H),7.38(s,2H),7.10(s,1H),5.33(t,J＝4.7Hz,1H),5.03(s,2H),4.66(s,1H),4.42(s,1H),4.34-4.12(m,4H),4.06(s,3H),3.22-3.00(m,5H),2.94(s,3H),2.69-2.66(m,1H),2.37-2.32(m,3H),2.05-1.90(m,3H)；ESI-MS m/z:652.3[M+H] +.
实施例129-实施例148化合物129-化合物148的合成
以中间体B-2a至B-2j为起始原料，采用合成方法C，类似于化合物128的合成方法，可以得到化合物129-化合物148。
表5
Figure PCTCN2020139544-appb-000055
Figure PCTCN2020139544-appb-000056
Figure PCTCN2020139544-appb-000057
实施例149化合物对H358细胞内pERK和ERK蛋白含量的检测
H358细胞种植于24孔板中，生长一天后，加入待测化合物(浓度为1μM)，化合物作用24小时后，裂解细胞后，将细胞裂解液，转移至96孔ELISA板子中，运用ELISA试剂盒(abcam 176660)测定裂解液中pERK和ERK水平,计算pERK和ERK的比值，并与DMSO组对比，计算化合物抑制pERK活性的百分比，结果见下列表6。
表6.本发明化合物对H358细胞内pERK水平的抑制活性
化合物 抑制率(％) 化合物 抑制率(％) 化合物 抑制率(％)
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 +++ 80 +++ 81 ++
82 +++ 83 +++ 84 +++
85 +++ 86 +++ 87 +++
88 ++ 89 ++ 90 +++
91 +++ 92 +++ 93 +
94 ++ 95 +++ 96 +++
97 +++ 98 +++ 99 +++
100 +++ 101 +++ 102 +++
103 +++ 104 +++ 105 +++
106 +++ 107 +++ 108 +++
109 +++ 110 +++ 111 +++
112 ++ 113 +++ 114 +++
115 + 116 +++ 117 +++
118 ++ 119 +++ 120 +++
121 +++ 122 +++ 123 +++
124 +++ 125 +++ 126 +++
127 +++ 128 +++ 129 ++
130 +++ 131 +++ 132 +++
133 ++ 134 +++ 135 +++
136 +++ 137 +++ 138 +++
139 +++ 140 +++ 141 +++
142 +++ 143 +++ 144 ++
145 +++ 146 +++ 147 +++
148 +++ A +++ B +
+表示抑制率小于或等于50％
++表示抑制率为50％至90％
+++表示抑制率大于90％。
实施例150化合物对H358细胞的抗增殖活性
2500个H358细胞种植于超低吸附的96孔板(corning,7007)中，生长一天后，加入梯度稀释化合物(最高5μM,5倍稀释，一共五个剂量)，加入化合物三天后，加入Cell Titer Glow(Promega,G9681)评价小球的生长情况，计算IC 50值，结果见下列表7。
表7.本发明化合物对H358细胞的抗增殖活性
化合物 IC 50 化合物 IC 50 化合物 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 +++ 80 +++ 81 +++
82 +++ 83 +++ 84 +++
85 +++ 86 +++ 87 +++
88 ++ 89 ++ 90 +++
91 +++ 92 +++ 93 +
94 ++ 95 +++ 96 +++
97 +++ 98 +++ 99 +++
100 +++ 101 +++ 102 +++
103 +++ 104 +++ 105 +++
106 +++ 107 +++ 108 +++
109 +++ 110 +++ 111 +++
112 ++ 113 +++ 114 +++
115 + 116 +++ 117 +++
118 +++ 119 +++ 120 +++
121 +++ 122 +++ 123 +++
124 +++ 125 +++ 126 +++
127 +++ 128 +++ 129 +++
130 +++ 131 +++ 132 +++
133 ++ 134 +++ 135 +++
136 +++ 137 +++ 138 +++
139 +++ 140 +++ 141 +++
142 +++ 143 +++ 144 ++
145 +++ 146 +++ 147 +++
148 +++ A +++ B +
+表示化合物的·IC 50大于1μM
++表示化合物的IC 50为0.3至1μM
+++表示化合物的IC 50小于0.3μM。
从上表7和表8的活性数据可知，在通式(1)化合物中，当Q为烯胺结构
Figure PCTCN2020139544-appb-000058
时，其中
Figure PCTCN2020139544-appb-000059
为杂芳基或取代杂芳基时，化合物的K-RAS G12C抑制活性得到大幅提高，而专利WO2019/099524中芳杂基以碳碳单键和丙烯酰胺连接的化合物活性很差，如化合物B对NCI-H358细胞的抗增殖活性大于1μM。推测是碳氮单键比碳碳单键具有更强的偶极矩，氮原子失去部分电子，有利于K-RAS蛋白的半胱氨酸对丙烯酰胺加成后的中间态的稳定，因此本发明化合物具有很强的活性。另一方面，本发明化合物在丙烯酰胺的2位具有体积较大杂芳基或取代杂芳基取代时，比如咪唑基或嘧啶基，化合物也具有很好的K-RAS G12C抑制活性，推测是杂芳基上的N原子有利于和K-RAS蛋白的结合。
实施例151化合物的稳定性测试
准确称取供试化合物两份(每份2-3mg)，一份于冰箱-20℃保存，一份放置于室温中，72小时后，分别将样品于50mL容量瓶中，加甲醇适量溶解，加水定容到刻度，摇匀得待测溶液。高效液相色谱测定两份溶液的液相峰面积，并求出室温放置样品的单位浓度的液相峰面积除以冰箱中-20℃保存样品的单位浓度峰面积，所得百分比表示化合物室温放置72小时后的剩余量。
表8.化合物室温放置72小时后的稳定性
化合物 剩余量 化合物 剩余量
1 98.5％ 70 98.2％
5 98.9％ 73 98.5％
8 98.5％ 92 98.3％
9 98.2％ 128 97.6％
12 98.4％ 140 96.8％
26 99.0％ 142 97.3％
69 97.9％ A 76.2％
从表8中化合物A的稳定性数据所示，化合物稳定性较差推测是分子中碱性的氮原子和丙烯酰胺的双键发生了分子间的聚合反应导致的。而和对照药物A相比，由于本发明化合物在丙稀酰胺上进行了较大体积基团的取代，因此本发明化合物稳定性得到大幅提高，这对于化合物工艺合成、质量控制和成药性具有非常重要的意义。
实施例152小鼠体内抗肿瘤活性评价
人胰腺癌Mia PaCa-2细胞用含10％胎牛血清的1640于37℃、5％CO 2培养箱中常规培养，传代后，待细胞达到所需量时，收集细胞。将1×10 7个Mia PaCa-2细胞注射入每只裸小鼠左侧背部，待肿瘤生长至150mm 3后，将动物随机分组开始给药。分别为1)溶剂对照组，8只；2)化合物1组、化合物5组、化合物70组、化合物92组和化合物121组，每组8只。溶剂对照组每天一次灌胃0.5％CMC-Na；化合物1组、化合物5组、化合物70组、化合物92组和化合物121组每天一次灌胃化合物0.5％CMC-Na悬浮液。每周二、四测定肿瘤体积，测量小鼠体重，于给药第21天处死裸小鼠，试验结果见下表9。
表9.化合物对人胰腺癌Mia PaCa-2裸小鼠移植瘤的实验治疗作用
化合物 剂量(mg/kg) 给药方案 抗肿瘤作用
1 10 qd*21 67％抑制
5 10 qd*21 63％抑制
70 10 qd*21 77％抑制
92 10 qd*21 72％抑制
121 10 qd*21 76％抑制
A 10 qd*21 58％抑制
和对照药物A相比，本发明化合物具有更强的体外活性和化合物稳定性，同时体内 抗肿瘤试验也显示本发明化合物具有更好的体内活性，预示本发明化合物在临床应用中具有更好的药效和成药性。

Claims (11)

  1. 一种通式(1)所示的化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物：
    Figure PCTCN2020139544-appb-100001
    通式(1)中：
    Y为化学键或C1-C6亚烷基；
    R 1为芳基或杂芳基，所述芳基或杂芳基可被1-3个下述基团所取代：卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基，当被多个取代基取代时，所述取代基可以相同或不同；
    R 2为胺基烷基、环烷基、杂环烷基、芳基或杂芳基，所述杂环烷基、芳基或杂芳基均可被1-3个下述基团所取代：H、卤素、CN、OH、C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、-(C1-C3烷基)-氰基、-(C1-C3烷基)-(C1-C3烷氧基)、
    -(C1-C3烷基)-(C3-C6环烷基)、氘代C1-C3烷基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基，当被多个取代基取代时，所述取代基可以相同或不同。
    Q为
    Figure PCTCN2020139544-appb-100002
    其中，R 3和R 4独立为H、D、卤素或C1-C3烷基；
    Figure PCTCN2020139544-appb-100003
    为至少有一个N原子的4-7元饱和杂环烷基、部分饱和的杂环烷基或杂芳基，所述饱和杂环烷基、部分饱和的杂环烷基或杂芳基可被1-3个下述基团所取代：H、D、卤素、
    Figure PCTCN2020139544-appb-100004
    CN、NMe 2、NEt 2、SMe、C1-C3烷基、C3-C6环烷基、-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3烷基)、-C(O)NMe 2、-C(O)NEt 2、-(C1-C3烷基)-NMe 2、-(C1-C3烷基)-NEt 2、卤素取代C1-C3烷基或氰基取代C1-C3烷基，当被多个取代基取代时，所述取代基可以相同或不同；
    R 5为C3-C6环烷基、-(C1-C3烷基)-氰基、-(C1-C3烷基)-羟基、-(C1-C3烷基)-(C3- C6环烷基)、-(C1-C3烷基)-(C1-C3烷氧基)、-(C1-C3烷基)-(卤素取代C1-C3烷氧基)、杂环烷基、部分饱和的杂环烷基、杂芳基、-(C1-C3烷基)-杂环烷基、-(C1-C3烷基)-杂芳基或-(C1-C3烷基)-NR 6R 7，所述杂环烷基、部分饱和的杂环烷基、杂芳基、-(C1-C3烷基)-杂环烷基或-(C1-C3烷基)-杂芳基可被1-3个下述基团所取代：卤素、OH、
    Figure PCTCN2020139544-appb-100005
    CN、NMe 2、NEt 2、-C(O)O-(C1-C3烷基)、-C(O)NH-(C1-C3烷基)、-C(O)NMe 2、-C(O)NEt 2、C1-C3烷基、C3-C6环烷基、卤素取代C1-C3烷基或氰基取代C1-C3烷基，当被多个取代基取代时，所述取代基可以相同或不同，其中R 6和R 7独立为H、C1-C3烷基、C3-C6环烷基、或卤素取代C1-C3烷基。
  2. 如权利要求1所述的化合物，其中所述通式(1)中，Y为化学键、-CH 2-、-CH(Me)-或-CH 2CH 2-。
  3. 如权利要求1或2所述的化合物，其中所述通式(1)中，R 1为：
    Figure PCTCN2020139544-appb-100006
    Figure PCTCN2020139544-appb-100007
    其中R a和R b独立地为H、卤素、羟基、氨基、C1-C3烷基、C2-C4烯基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基。
  4. 如权利要求1-3中任一项所述的化合物，其中所述通式(1)中，R 2为：
    Figure PCTCN2020139544-appb-100008
    Figure PCTCN2020139544-appb-100009
    其中n为1、2或3，R c和R d独立地为H、卤素、CN、OH、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基，R e为C1-C3烷基、C3-C6环烷基、氘代C1-C3烷基、-(C1-C3烷基)-氰基、-(C1-C3烷基)-(C1-C3烷氧基)、-(C1-C3烷基)-(C3-C6环烷基)、氘代C1-C3烷基、卤素取代C1-C3烷基或卤素取代C1-C3烷氧基，当被多个取代基取代时，所述取代基可以相同或不同。
  5. 如权利要求1-4中任一项所述的化合物，其中所述通式(1)中，Q为
    Figure PCTCN2020139544-appb-100010
    其中，R 3和R 4独立为H或D；
    Figure PCTCN2020139544-appb-100011
    为
    Figure PCTCN2020139544-appb-100012
    Figure PCTCN2020139544-appb-100013
    Figure PCTCN2020139544-appb-100014
  6. 如权利要求1-4中任一项所述的化合物，其中所述通式(1)中，Q为
    Figure PCTCN2020139544-appb-100015
    其中，R 5为
    Figure PCTCN2020139544-appb-100016
    Figure PCTCN2020139544-appb-100017
  7. 如权利要求1-6中任一项所述的化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2020139544-appb-100018
    Figure PCTCN2020139544-appb-100019
    Figure PCTCN2020139544-appb-100020
    Figure PCTCN2020139544-appb-100021
    Figure PCTCN2020139544-appb-100022
    Figure PCTCN2020139544-appb-100023
    Figure PCTCN2020139544-appb-100024
  8. 一种的药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及作为活性成分的如权利要求1-7任一项所述的化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物。
  9. 一种如权利要求1-7任一项所述的化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物在制备治疗RAS相关疾病的药物中的应用。
  10. 一种治疗由K-Ras G12C突变介导的疾病的方法，其包括给与受试者如权利要求1-6中任一项所述的化合物、其各光学异构体、其各晶型、其药学上可接受的盐、其水合物或其溶剂合物。
  11. 如权利要求10所述的方法，其中所述的疾患是癌症，所述癌症是血液癌和实体瘤。
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