CN116783194A - Spirocyclic quinazoline derivatives - Google Patents

Spirocyclic quinazoline derivatives Download PDF

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Publication number
CN116783194A
CN116783194A CN202280012944.3A CN202280012944A CN116783194A CN 116783194 A CN116783194 A CN 116783194A CN 202280012944 A CN202280012944 A CN 202280012944A CN 116783194 A CN116783194 A CN 116783194A
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Prior art keywords
compound
pharmaceutically acceptable
compounds
alkyl
ras
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Chinese (zh)
Inventor
谢雨礼
曹刚
钱立晖
樊后兴
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Wigen Biomedicine Technology Shanghai Co Ltd
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Wigen Biomedicine Technology Shanghai Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D471/10—Spiro-condensed systems

Abstract

Quinazoline derivatives containing spiro rings are disclosed. Specifically, the invention relates to a compound shown in a general formula (1) and a preparation method thereof, and application of the compound shown in the general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as irreversible inhibitors of G12C mutant K-Ras protein in preparation of medicaments for resisting Ras related diseases such as tumors and the like.

Description

Spirocyclic quinazoline derivatives
The present application claims priority from chinese application CN202110182364.6 with application date 2021, 2 and 9. The present application is incorporated by reference in its entirety into the above-mentioned chinese application.
Technical Field
The application belongs to the field of pharmaceutical chemistry, and in particular relates to a quinazoline compound containing spiro, a preparation method thereof and application of the quinazoline compound serving as a K-Ras G12C inhibitor in preparation of antitumor drugs.
Background
The Ras protein family is an important signaling transfer molecule within cells and plays an important role in growth and development. Analysis and study of a large number of in vitro tumor cells, animal models, and human tumor samples has shown that excessive activation of Ras family proteins is an early event in human tumor development, one of the important contributors to the development and progression of a variety of cancers. Targeting and inhibiting the activity of Ras proteins is therefore an important tool for the treatment of related tumors.
Ras proteins exist in two forms, which bind to GDP in an inactive resting state; when the cell receives a signal such as a growth factor stimulus, the Ras protein binds to GTP and is activated. The activated Ras proteins recruit a variety of signaling proteins, promoting phosphorylation of downstream signaling molecules such as ERK, S6, thereby activating the Ras signaling pathway, regulating cell growth, survival, migration, and differentiation. The GTPase enzyme activity of the Ras protein itself hydrolyzes GTP back to GDP. And the intracellular presence of GTPase Activating Proteins (GAPs) interacting with Ras greatly promotes the activity of Ras GTPase, thereby preventing the over-activation of the Ras protein.
Mutations in K-Ras, H-Ras and N-Ras proteins in the Ras protein family are one of the common genetic mutations in a variety of tumors, a major factor in the over-activation of Ras proteins in tumors. These mutations result in Ras protein activity that is not regulated, stably binds GTP, and continues to activate, thereby promoting tumor cell growth, migration, and differentiation, as compared to the wild-type Ras protein. Among these, mutations in the K-Ras protein are 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%), lung cancer (25%), etc., whereas it is relatively rare (< 2%) in breast, ovarian, and brain cancers. The K-Ras mutation site is mainly concentrated at the G12 position, with the G12C mutation being the most common. For example, in non-small cell lung cancer (NSCLC), K-Ras G12C represents 50% of all K-Ras mutations, followed by G12V and G12D. Genomic studies have shown that the K-Ras mutation in non-small cell lung cancer does not coexist with the EGFR, ALK, ROS, RET and BRAF mutations, but rather with the STK11, KEAP1 and TP53 mutations, suggesting that the K-Ras mutation may be involved in malignant transformation, proliferation and invasion of cells in synergy with the STK11, KEAP1 and TP53 mutations, etc. In addition to tumors, abnormal activation of Ras proteins is also involved in non-neoplastic diseases including diabetes, neurodegenerative diseases, and the like, and it can be seen that small molecule compounds targeting Ras proteins can benefit a large array of cancer patients carrying specific genetic variations and non-cancerous patients with excessive activation of the Ras pathway.
Since the discovery of Ras mutations in tumors for forty years, although we have had a more in depth knowledge of the pathogenic mechanism of the Ras pathway, no clinically effective therapeutic means for targeting Ras proteins have been marketed for a large number of patients carrying Ras protein mutations and over-activation of the Ras pathway. Therefore, the development of a high-activity small molecule inhibitor aiming at Ras proteins, particularly K-Ras G12C proteins with higher mutation frequency, has important clinical significance.
K-Ras G12C muteins serve as a leading pharmaceutical target, and the current research is not so great, and only a few compounds enter clinical research stages, such as AMG510 from Amgen and MRTX849 from Mirati. Covalent inhibitors of the ARS-1620 targeting the K-Ras G12C mutation were reported on Cell 2018 [ Cell,2018,172:578-589]. Patent WO2018/143315 and WO2020/216190 report that a class of spiro compounds has K-Ras G12C activity and antitumor activity in mice, representing the structures of compound a (example 35 in patent WO 2018/143315) and compound B (example 1 in patent WO 2020/216190) as follows:
at present, research and discovery of compounds with good K-Ras G12C activity have urgent needs.
Disclosure of Invention
The application provides a compound shown in a general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
in the general formula (1):
m, n and v are independently integers of 1 or 2;
R 1 is C2-C4 alkenyl or C3-C6 cycloalkyl;
R 2 is C1-C3 alkoxy or halogenated C1-C3 alkoxy;
R 3 is thatWherein R is a 、R b And R is c H, F, cl or Me, R d H, F, cl, NH of a shape of H, F, cl, NH 2 Me or cyclopropyl;
R 4 is H or halogen;
R 5 and R is 6 Independently C1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy substituted C1-C3 alkyl, cyano substituted C1-C3 alkyl, methylsulfonyl substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy substituted (C2-C3)Alkyl, (halo C1-C3) alkoxy-substituted (C2-C3) alkyl or (C3-C6) cycloalkyl-substituted (C1-C3) alkyl, or R 5 And R is 6 The co-N atoms form a 4-12 membered heterocycloalkyl group, which 4-12 membered heterocycloalkyl group may be optionally substituted with 1-3 of the following groups: H. OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3) alkoxy and (halo-C1-C3) alkoxy.
In another preferred embodiment, wherein R in the general formula (1) 1 Vinyl or cyclopropyl; r is R 4 Vinyl groups are preferred.
In another preferred embodiment, wherein R in the general formula (1) 2 Is CH 3 O-、CH 3 CH 2 O-、(CH 3 ) 2 CHO-、CF 3 CH 2 O-or CHF 2 CH 2 O-；R 2 Preferably CH 3 CH 2 O-、CF 3 CH 2 O-or CHF 2 CH 2 O-。
In another preferred embodiment, wherein R in the general formula (1) 3 Is that R 3 Preferably is R 3 More preferably
In another preferred embodiment, wherein R in the general formula (1) 4 Is H or F; r is R 4 Preferably H.
In another preferred embodiment, wherein in the general formula (1),is that Preferably is More preferably
In various embodiments, representative compounds of the present application have one of the following structures:
it is another object of the present application to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) of the present application, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, as an active ingredient.
Still another object of the present application is to provide the use of the compound represented by the general formula (1) of the present application, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof or the above pharmaceutical composition for the preparation of a medicament for treating, modulating or preventing diseases associated with RAS.
Still another object of the present application is to provide a method for treating, modulating or preventing a disease associated with RAS comprising administering to a subject a therapeutically effective amount of a compound of formula (1) of the present application, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.
Through synthesis and careful study of various new compounds involved in K-RAS G12C inhibition, the inventors found that among the compounds of the general formula (1), the compounds have strong K-RAS G12C inhibition activity when the side chain is a bridged ring structure.
It is to be understood that both the foregoing general description and the following detailed description of the present application are exemplary and explanatory and are intended to provide further explanation of the application as claimed.
Synthesis of Compounds
The process for preparing the compound of the general formula (1) of the present application is specifically described below, but these specific processes do not constitute any limitation on the present application.
The compounds of formula (1) described above may be synthesized using standard synthetic techniques or well known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials for the synthesis of the compounds may be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., vols.A and B (Plenum 2000, 2001), green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). Chemical treatmentThe general method of preparation of the compounds may be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae provided herein.
In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as the reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the explanation below. The compounds of the present application may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present application pertains. In one aspect, the present application also provides a method for preparing the compound represented by the general formula (1), wherein the compound represented by the general formula (1) can be prepared by the following general reaction scheme 1:
general reaction scheme 1
Embodiments of the compounds of formula (1) may be prepared according to general scheme 1, wherein m, n, v, R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 As defined hereinabove, PG represents a protecting group. As shown in general reaction scheme 1, compound A and compound B react to form compound C, and compound C is cyclized to form compound D, compounds D and T 2 And (3) carrying out condensation reaction on the H under a strong alkaline condition to generate a compound F, removing a protecting group from the compound F to obtain a compound G, and carrying out reaction on the compound G and the compound H to obtain a target compound I.
Further forms of the compounds
By "pharmaceutically acceptable" is meant herein a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and which is relatively non-toxic, e.g., administration of a material to an individual does not cause an undesired biological effect or interact in a deleterious manner with any of the components thereof in which it is contained.
The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered, and does not abrogate the biological activity and properties of the compound. In certain specific aspects, the pharmaceutically acceptable salts are obtained by reacting a compound of formula (1) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, 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, and other organic acids, and an acidic amino acid, e.g., aspartic acid, glutamic acid.
References to pharmaceutically acceptable salts are understood to include solvent-added forms or crystalline forms, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of formula (1) are conveniently prepared or formed in accordance with the methods described herein. For example, the hydrate of the compound of formula (1) is conveniently prepared by recrystallisation from a mixed solvent of water/organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, solvated forms are considered to correspond to unsolvated forms.
In other specific embodiments, the compounds of formula (1) are prepared in different forms including, but not limited to, amorphous, crushed and nano-sized forms. In addition, the compound of formula (1) includes crystalline forms and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.
In another aspect, the compounds of formula (1) may have chiral centers and/or axial chiralities and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric forms, and cis-trans isomeric forms. Each chiral center or axial chiral will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the application. The present application is meant to include all such isomeric forms of these compounds.
The compounds of the present application may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) And C-14% 14 C) A. The application relates to a method for producing a fibre-reinforced plastic composite For another example, deuterium can be substituted for a hydrogen atom to form a deuterated compound, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, and generally deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, prolonging in vivo half-life of drugs, and the like, compared to non-deuterated drugs. All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.
Terminology
The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. It must be noted that, in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In the present application, the use of "or" and "means" and/or "unless otherwise indicated.
Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups preferably having 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butylButyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, particularly 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 2 、CF 3 (CH 3 )CH、 i Pr、 n Pr、 i Bu、 n Bu or t Bu。
Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, and includes straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl are preferred.
Unless otherwise specified, "alkynyl" refers to unsaturated aliphatic hydrocarbon groups containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, for example ethynyl, 1-propynyl or 1-butynyl.
Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), a partially unsaturated cycloalkyl may be referred to as "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) groups and spiro rings. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of cycloalkyl groups may optionally be oxidized to form oxo or thioionic groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused to aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, pinyl, carenyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexane, and the like.
Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly alkoxy groups 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。
Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If the heterocycloalkyl group contains at least one double bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkenyl", or if the heterocycloalkyl group contains at least one triple bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1,2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can optionally be oxidized to form oxo or thioxo groups or other oxidized bonds (e.g., C (O), S (O), C (S) or S (O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains from 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are benzo derivatives having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, thienyl, or the like. The heterocycloalkyl group containing the fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro [5.5 ]]Undecyl, 1-oxa-8-azaspiro [4.5 ]]Decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3, 4-tetrahydroquinolinyl, tropanyl, 4,5,6, 7-tetrahydrothiazolo [5,4-c ]]Pyridyl, 4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyllactam, valerolactam, imidazolone, hydantoin, dioxolanyl, phthalimido, pyrimidine-2, 4 (1H, 3H) -dione, 1, 4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S, S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro [3.3 ]]Heptyl, indolinyl, and,
Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted with F, cl, br or I, preferably F or Cl, in any combination.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Substituent "-O-CH 2 -O- "means that two oxygen atoms in the substituent are attached to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, such as:
when the number of one linking group is 0, such as- (CH) 2 ) 0 -it is meant that the linking group is a single bond.
When one of the variables is selected from a bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in X-L-Y represents a bond, it is indicated that the structure is in fact X-Y.
The term "membered ring" includes any cyclic structure. The term "meta" is meant to indicate the number of backbone atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings and cyclopentyl, pyrrolyl, furanyl and thiophenyl are five-membered rings.
The term "fragment" refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.
Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysOr straight dotted line key
Unless otherwise indicated, use ofRepresents a single bond or a double bond.
Specific pharmaceutical and medical terminology
The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.
The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
"active ingredient" refers to a compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the application may contain one or more asymmetric centers (chiral centers or axial chiralities) and thus appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the application. The present application is meant to include all such isomeric forms of these compounds.
The terms "compound", "composition", "agent" or "pharmaceutical (medicine or medicament)" are used interchangeably herein and refer to a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic effects when administered to an individual (human or animal).
The term "administration (administered, administering or administeration)" as used herein refers to the administration of the compound or composition directly, or the administration of a prodrug (pro), derivative (derivative), or analog (analog) of the active compound, and the like.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the average value, as determined by one of ordinary skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, ratios of amounts, and the like) are to be understood to be modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties. At least these numerical parameters should be construed as indicating the number of significant digits and by applying ordinary rounding techniques.
Unless defined otherwise herein, the meanings of scientific and technical terms used herein are the same as commonly understood by one of ordinary skill in the art. Furthermore, as used in this specification, the singular noun encompasses the plural version of the noun without conflict with the context; plural nouns as used also encompasses singular versions of the noun.
Therapeutic use
The present application provides methods of treating diseases, including but not limited to conditions (e.g., cancer) involving G12C K-Ras, G12C H-Ras, and/or G12C N-Ras mutations, using compounds of formula (1) or pharmaceutical compositions of the present application.
In some embodiments, there is provided a method for treating cancer, the method comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of formula (1). In some embodiments, the cancer is mediated by K-Ras, H-Ras and/or G12C N-Ras mutations. In other embodiments, the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-related polyposis, or colorectal cancer. In other embodiments, the cancer is hematologic and solid tumors, including, but not limited to, leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastasis.
Route of administration
The compounds of the present application and pharmaceutically acceptable salts thereof can be formulated into a variety of formulations comprising a safe and effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: 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 specific conditions such as age, illness and treatment course of the subject.
"pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present application without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soya oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agents (e.g. tween) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The compounds of the present application may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present application for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the application may be administered alone or in combination with other pharmaceutically acceptable compounds. When a pharmaceutical composition is used, a safe and effective amount of the compound of the present application is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The above-mentioned features of the application, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
Detailed Description
The details of the various specific aspects, features and advantages of the above-described compounds, methods, pharmaceutical compositions will be set forth in the following description in order to provide a thorough understanding of the present application. It is to be understood that the detailed description and examples, which follow, describe specific embodiments for reference only. Various changes and modifications to the present application will become apparent to those skilled in the art upon reading the description of the application, and such equivalents are intended to fall within the scope of the application.
In all of the embodiments described herein, the present application, 1 H-NMR was recorded on a Vian Mercury 400 Nuclear magnetic resonance apparatus, and chemical shifts were expressed as delta (ppm); the silica gel for separation is not illustrated as 200-300 meshes, and the ratio of the eluents is volume ratio.
The application adopts the following abbreviations: BOP represents benzotriazole-1-tris (trimethylamino) -trifluorophosphate; DBU represents 1, 8-diazacycloundecene; DCM represents dichloromethane; DMF represents dimethylformamide; EA represents ethyl acetate; HPLC represents liquid chromatograph; k (K) 2 CO 3 Represents potassium carbonate; meOH represents methanol; min represents minutes; MS stands for mass spectrum; NMR represents nuclear magnetic resonance; TFA (CF) 3 COOH) represents trifluoroacetic acid; TLC stands for thin layer chromatography; THF represents tetrahydrofuran.
Example 11 Synthesis of- (7- (7- (5-methyl-1H-indazol-4-yl) -2- (3- (pyrrolidin-1-yl) bicyclo [1.1.1] pentan-1-yl) -8- (2, 2-trifluoroethoxy-6-vinylquinazolin-4-yl) -2, 7-diazaspiro [3.5] non-2-yl) prop-2-en-1-one (Compound 1)
Step 1: synthesis of Compounds 1-3
A50 mL single flask was charged with 1-1 (1.6 g,2.94mmol,1 eq) of THF (25 mL) and 1-2 (586 mg,2.94mmol,1eq) in sequence, the system was warmed to 40℃and stirred for 30min, and TLC detection was complete. The crude product was concentrated by column chromatography to give 1-3 (1.g, 64% yield) as pale yellow solid, LC-MS:708.3[M+H] + 。
Step 2: synthesis of Compounds 1-4
A solution of 1-3 (1.33 g,1.88mmol,1 eq) in THF (10 mL) was added to a 100mL single-necked flask, then concentrated aqueous ammonia was added to the system to adjust pH=11, the system was warmed to 40 ℃, stirred for 12h, and TLC checked for complete reaction of the starting materials. The system was extracted with DCM (30 mL. Times.2), the organic phases were combined, washed with saturated brine, dried and concentrated to give crude product, which was separated by column chromatography to give white solid 1-4 (600 mg, 46% yield), LC-MS:690.3[ M+H ]] + 。
Step 3: synthesis of Compounds 1-6
1-4 (600 mg,0.87mmol,1 eq), 1-5 (295 mg,1.30mmol,1.5 eq), DMF (20 mL, dry) and DBU (793 mg,5.22mmol,6 eq) and BOP (960 mg,2.17mmol,2.5 eq) were added sequentially in a 50mL single-port flask, the system was warmed to 45℃and stirred for 1h, and the reaction was complete. The system was extracted with EA (50 mL. Times.2), the organic phases were combined, washed 3 times with saturated brine, dried and concentrated, and the crude product was isolated as a solid 1-6 (550 mg,70% yield) by column chromatography, LC-MS:898.4[ M+H ]] + 。
Step 4: synthesis of Compounds 1-7
1-6 (550 mg,0.61mmol,1 eq) of methanol (20 mL) solution, K, are added sequentially in a 50mL single-necked flask 2 CO 3 (761 mg,5.51mmol,9 eq), thioglycollic acid (226 mg,2.44mmol,4 eq), the system was warmed to 70 ℃, stirred for 30min, and the starting material reacted completely. The system was extracted with EA (50 mL. Times.2), the organic phases were combined, dried and concentrated, and the crude product was separated by column chromatography to give solid 1-7 (318 mg, 70%), LC-MS:744.4[ M+H ]] + 。
Step 5: synthesis of Compounds 1-8
A50 mL single flask was charged with 1-7 (318 mg,0.43mmol,1 eq) of DCM/TFA=5/1 (10 mL/2 mL) and stirred at room temperature for 1h, the starting material was complete. Concentrating the system, adjusting pH to alkaline with saturated sodium bicarbonate aqueous solution, vacuum filtering, and lyophilizing to obtain crude product 1-8 (280 mg), LC-MS:644.3[ M+H ]] + 。
Step 6: synthesis of Compound 1
To a 50mL single-necked flask was added a solution of 1-8 (280 mg, crude) in MeOH (25 mL), imidazole (120 mg,1.74mmol,4 eq) was added and stirred, acrylic anhydride (55 mg,0.43mmol,1 eq) was added under ice-water bath, and stirring was continued for 30min to complete the reaction. The reaction mixture was washed with saturated brine, and the organic phase was concentrated by drying, and compound 1 (230 mg, yield%) was isolated as a white solid by HPLC.
1 H NMR(400MHz,DMSO-d 6 )δ:13.01(s,1H),7.98(s,1H),7.49(d,J＝8.5Hz,1H),7.40(s,1H),7.32(d,J＝8.6Hz,1H),6.35(dd,J＝17.0,10.3Hz,1H),6.18-6.03(m,2H),5.81-5.64(m,2H),5.11(d,J＝11.3Hz,1H),5.03-4.90(m,1H),4.73-4.60(m,1H),4.04(s,2H),3.76(s,6H),2.58(s,4H),2.13-1.92(m,13H),1.72(s,4H),LC-MS:698.3[M+H] + 。
Examples 2-79 Synthesis of Compounds 2-79
Using different starting materials, the title compounds 2-79 were obtained according to similar synthetic methods as in example 1.
TABLE 1
Example 80 chiral resolution of Compound 1
The compounds of the application may have axial chirality. Compounds with axial chirality can be resolved to give two chiral isomers.
Dissolving a proper amount of compound 1 in ethanol to prepare a test solution with the concentration of 10mg/mL, taking the test solution, injecting the test solution into a preparation liquid chromatograph, detecting according to the chromatographic conditions of the application and recording data. The preparation type chromatographic condition is that a liquid chromatograph is prepared by adopting the Shimadzu LC-20 AP; chromatographic column UniChiral CMD-5H (30X 250mm,5 um); mobile phase ethanol/n-hexane=20/80; flow rate: 30.0mL/min; the detection wavelength is 254nm; the sample injection amount is 1000 mu L. Chiral separation gave 1-a and 1-b with retention times of 6.238min and 7.952min, respectively, and ee% values of 100 and 98.95, respectively.
Other compounds of the application may also be chiral resolved by similar methods, such as compound 67 via chiral resolution to afford 67-a and 67-b:
EXAMPLE 81 antiproliferative Activity of the Compounds of the application against H358 cells
2500H 358 cells were plated in ultra-low adsorption 96-well plates (burning, 7007) and after one day of growth, gradient dilution compounds (up to 5. Mu.M, 5-fold dilution, total five doses) were added, three days after compound addition, cell Titer Glow (Promega, G9681) was added to evaluate pellet growth and IC was calculated 50 Values, results are shown in Table 2 below.
TABLE 2 antiproliferative activity of the compounds of the application on H358 cells
Compounds of formula (I) IC 50 Compounds of formula (I) IC 50 Compounds of formula (I) IC 50
1 +++ 2 +++ 3 +++
4 +++ 5 +++ 6 +++
7 ++ 8 +++ 9 +++
10 +++ 11 +++ 12 +++
13 +++ 14 +++ 15 +++
16 +++ 17 +++ 18 +++
19 +++ 20 +++ 21 +++
22 ++ 23 +++ 24 +++
25 +++ 26 +++ 27 ++
28 ++ 29 ++ 30 +++
31 +++ 32 +++ 33 +++
34 +++ 35 ++ 36 ++
37 +++ 38 +++ 39 +++
40 ++ 41 +++ 42 +++
43 +++ 44 +++ 45 +++
46 +++ 47 +++ 48 ++
49 +++ 50 +++ 51 ++
52 +++ 53 +++ 54 +++
55 +++ 56 +++ 57 +++
58 +++ 59 +++ 60 +++
61 +++ 62 +++ 63 +++
64 ++ 65 +++ 66 ++
67 +++ 68 +++ 69 +++
70 +++ 71 +++ 72 +++
73 +++ 74 +++ 75 +++
76 +++ 77 +++ 78 +++
79 +++ 1-a +++ 1-b +++
67-a +++ 67-b +++ A +++
IC of compound represented by + 50 Greater than 1 mu M
++ represents the IC of the compound 50 0.3 to 1. Mu.M
++ represents IC of compound 50 Less than 0.3 μm.
As can be seen from the data in Table 2, most of the compounds of the present application have antiproliferative activity against H358 cells of less than 0.3. Mu.M, which fully demonstrates that the compounds of the present application having spiro structures in the side chains have strong K-RAS G12C inhibitory activity.
EXAMPLE 82 evaluation of in vivo antitumor Activity in mice
Human pancreatic cancer Mia PaCa-2 cells were treated with 1640 containing 10% fetal bovine serum at 37℃with 5% CO 2 After conventional culture in an incubator and passage, the cells are collected when the cells reach the required amount. Will be 1X 10 7 Mia PaCa-2 cells were injected into the left dorsal aspect of each nude mouse until the tumor grew to 400mm 3 Animals were then randomized and dosed. Respectively 1) solvent control group, 8; 2) Group 1, group 67 and group a, 8 each. The solvent control group was lavaged twice daily with 0.5% cmc-Na; compound 1, compound 67 and compound a groups were infused with a 0.5% cmc-Na suspension of gastric compound once daily. Tumor volumes were measured every two and four weeks, body weights of mice were measured, nude mice were sacrificed on day 21 of administration, and test results are shown in table 3 below.
TABLE 3 Experimental therapeutic Effect of Compounds on human pancreatic cancer Mia PaCa-2 nude mice transplantable tumors
Compounds of formula (I) Dosage (mg/kg) Dosing regimen Antitumor effect
1 10 qd*21 36% recession
67 10 qd*21 32% withdrawal
A 10 qd*21 25% recession
As can be seen from the data in the table, the compound of the application has strong in vivo anti-tumor activity, and the tumor can be retracted after the continuous administration of 10mg/kg/day for 21 days, and the in vivo activity of the compound 1 and 67 is stronger than that of the control medicine A.
While particular embodiments of the present application have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the application. Accordingly, the scope of the application is defined by the appended claims.

Claims (9)

  1. A compound represented by general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
    in the general formula (1):
    m, n and v are independently integers of 1 or 2;
    R 1 is C2-C4 alkenyl or C3-C6 cycloalkyl;
    R 2 is C1-C3 alkoxy or halogenated C1-C3 alkoxy;
    R 3 is thatWherein R is a 、R b And R is c H, F, cl or Me, R d H, F, cl, NH of a shape of H, F, cl, NH 2 Me or cyclopropyl;
    R 4 is H or halogen;
    R 5 and R is 6 Independently isC1-C3 alkyl, halogenated C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, cyano-substituted C1-C3 alkyl, methylsulfonyl-substituted C1-C3 alkyl, C3-C6 cycloalkyl, (C1-C3) alkoxy-substituted (C2-C3) alkyl, (halogenated C1-C3) alkoxy-substituted (C2-C3) alkyl or (C3-C6) cycloalkyl-substituted (C1-C3) alkyl, or R 5 And R is 6 The co-N atoms form a 4-12 membered heterocycloalkyl group, which 4-12 membered heterocycloalkyl group may be optionally substituted with 1-3 of the following groups: H. OH, halogen, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, (C1-C3) alkoxy and (halo-C1-C3) alkoxy.
  2. The compound according to claim 1, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 1 Is vinyl or cyclopropyl.
  3. The compound according to claim 1 or 2, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 2 Is CH 3 O-、CH 3 CH 2 O-、(CH 3 ) 2 CHO-、CF 3 CH 2 O-or CHF 2 CH 2 O-。
  4. A compound according to any one of claims 1 to 3, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 3 Is that
  5. As claimed inThe compound according to any one of claims 1 to 4, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R in the general formula (1) 4 H or F.
  6. The compound according to any one of claim 1 to 5, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1),is that
  7. The compound of any one of claims 1-6, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound has one of the following structures:
  8. a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as active ingredient, a compound according to any one of claims 1 to 7, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.
  9. Use of a compound according to any one of claims 1 to 7, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment of a K-Ras G12C mutant protein-related disorder.
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