CN112300173B - Nitrogen-containing polycyclic compounds, preparation method and application - Google Patents
Nitrogen-containing polycyclic compounds, preparation method and application Download PDFInfo
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- CN112300173B CN112300173B CN202010746474.6A CN202010746474A CN112300173B CN 112300173 B CN112300173 B CN 112300173B CN 202010746474 A CN202010746474 A CN 202010746474A CN 112300173 B CN112300173 B CN 112300173B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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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
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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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
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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
- C07D471/22—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 systems contains four or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
Abstract
The invention discloses a nitrogen-containing polycyclic compound, a preparation method and application thereof, in particular to a nitrogen-containing polycyclic compound shown as a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, a preparation method and application thereof in pharmacy, wherein the definition of each group is described in the specification.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a nitrogen-containing polycyclic compound, a compound with Ras mutein inhibition activity, a preparation method and application.
Background
RAS is the first oncogene identified in human tumors and was first found in two murine sarcoma viruses. There are three members of the RAS gene family, Hras, Kras, Nras. In human tumors, Kras mutations are most common, accounting for approximately 85%. Previous studies have shown that Kras mutations are carcinogenic because codon 12 is missense mutated, altering the structure of the Kras protein and keeping it activated at all times. Ras plays a major role in signal pathway transmission, mainly activating kinases controlling gene transcription, thereby regulating cell differentiation and proliferation, and is closely related to survival, proliferation, migration, metastasis and angiogenesis of tumor cells. According to statistics, Kras G12C mutation exists in 11% -16% of lung adenocarcinoma cases, and part of pancreatic cancer, colorectal cancer, ovarian cancer and bile duct cancer is caused by Kras mutation. However, over thirty years ago since the first discovery of Kras oncogene, the targeting drugs for EGFR, BCL and other common protooncogenes have been developed for several generations, and the targeting drugs for Kras have not been successfully developed. Historically, targeted drugs against KRas pathway mutant tumors have focused primarily on farnesyl transferase inhibitors and Raf-MEK pathway inhibitors, but with little success. In recent years, inhibitors aiming at KRas specific gene mutation are developed into hot spots, and part of inhibitors gradually go from preclinical hatching to clinical research, such as KRas G12C inhibitors AMG510, MRTX1257 and the like, and show certain curative effect in early clinical experiments. The first clinical data of the first global KRASG12C inhibitor AMG510 was finally promulgated by the american clinical oncology institute held in 6 months 2019, in which clinical studies the installed drug AMG510 was shown to prevent tumor growth in most non-small cell lung and colorectal cancer patients with KRas mutations. Therefore, finding and searching for a target drug against KRas specific mutant gene with high specificity and excellent drug availability is a major hotspot in the industry.
Disclosure of Invention
One of the technical problems to be solved by the invention is to provide a novel KRas G12C inhibitor for preparing a tumor treatment medicament.
The scheme for solving the technical problems is as follows:
a nitrogen-containing polycyclic compound shown as a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,
in the formula:
r1 is independently selected from hydrogen, halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, or C1-C6A haloalkyl group; r2 and R3 are independently selected from hydrogen, halogen, cyano, nitro and C1-C6Alkyl radical, C1-C6alkyl-SO2-、C1-C6alkyl-SO-, N (R)2a)(R2b)-(CH2) x-; or, R9And R10Together forming a 5-to 10-membered quilt C1-C6An alkyl-substituted nitrogen-containing heterocycloalkyl group; wherein R is2aAnd R2bEach independently selected from hydrogen or C1-C6Alkyl, x is selected from any integer of 0-5;
w, W1, W2, M is independently selected from CR4 or N, R4 is independently selected from H, halogen, cyano, C1-C6Alkyl radical, C1-C6Alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, 3-to 8-membered cycloalkyl or heterocycloalkyl, and the like;
ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are respectively and independently selected from hydrogen, halogen, C1-C6 alkyl, alkoxy, haloalkyl and the like, or Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh form a 3-8-membered saturated or partially unsaturated ring system between every two; or any of Rg and Rh may form a 3-to 8-membered saturated or partially unsaturated or unsaturated ring system with M.
Ar is independently selected from a 5-12 membered aromatic ring or aromatic condensed ring, a 5-12 membered aromatic heterocycle or aromatic condensed heterocycle; and the Ar ring may be substituted with one or more of the following groups: hydrogen, halogen, C1-C6 alkyl, alkoxy, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted amino, amido, sulfonamido, and the like;
x, Y, Z are each independently selected from CR5 or N or ═ O and the like, wherein R5 is independently selected from hydrogen, halogen, C1-C6 alkyl, alkoxy, haloalkyl, cyano, ester, amide, 3-to 10-membered cycloalkyl or heterocycloalkyl, 5-to 12-membered aryl or heteroaryl, and the like;
one or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, C1-C8 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl; wherein said heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, the heterocycloalkyl group containing 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system including spiro, bridged, fused, etc. saturated or partially unsaturated ring systems.
In some embodiments, the compound having the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsiomer, solvate, polymorph or prodrug thereof, is preferably a compound of the general formulae (IIA), (IIB), (IIC), (IID), (IIE), (IIF), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof:
wherein R5 is independently selected from hydrogen, halogen, C1-C6 alkyl, alkoxy, haloalkyl, cyano, ester group, amide group, 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl, and the like; r6 is independently selected from hydrogen, C1-C6 alkyl, alkoxy, haloalkyl, cyano, ester, amide, 3-to 10-membered cycloalkyl or heterocycloalkyl, 5-to 12-membered aryl or heteroaryl, and the like; l is selected from O, NH, NR 6; ri and Rj are each preferably selected from hydrogen, halogen, C1-C6 alkyl, alkoxy, haloalkyl, haloalkoxy, or Ri and Rj are oxo ═ O; n is preferably from 0 to 3; r1, R2, R3, Ra, Rb, Rc, Rd, Re, Rf, Rg, W1, W2, M, Ar are as defined above.
In other embodiments, a compound having the general formula (1), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph, or prodrug thereof, characterized by:
r1 is preferably selected from hydrogen, fluoro, methyl, cyano, etc.;
ra, Rb, Rc, Rd, Re, Rf, Rg, Rh are each independently preferably selected from hydrogen, fluorine, methyl, hydroxymethyl, hydroxyethyl, cyanomethyl, etc.;
w is preferably selected from N, C-F, C-Cl, C-Me, C-OMe, C-OCH2CHF2, C-OCH2CF3, etc.; w2 and M are each independently preferably selected from N or CH, C-F, C-Cl, C-Me, C-OMe, etc.; w1 is preferably selected from CR4, R4 is independently selected from hydrogen, halogen, cyano, cyclopropyl, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and the like;
ar is independently preferably a monocyclic aromatic group such as a substituted or unsubstituted phenyl group or pyridyl group, or a substituted or unsubstituted bicyclic aromatic group such as a naphthyl group, a naphthyridinyl group, an indazolyl group or a benzimidazolyl group; said one or more substituents are preferably selected from the group consisting of: hydrogen, halogen, C1-C4 alkyl, hydroxy, amino, cyano, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and the like;
a process for preparing a compound of formula I, said process comprising steps a-c:
a) converting a compound of formula (a) to an intermediate (B) by a transition metal catalysed coupling reaction with an arylboronic acid or arylboronic ester or arylmetal reagent (Ar-M); and
b) removing the protective group PG from the compound of the general formula (B) through a conventional functional group to obtain a compound of a general formula (C);
c) the compound of the general formula (C) and acrylic acid or acryloyl chloride are subjected to condensation reaction under proper conditions to generate the general formula (I).
The definition of each group is as described above;
preferably, said steps a), b), c) are each carried out in a solvent, and said solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
Preferably, the transition metal catalyst is selected from the group consisting of: tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) Tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) Palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (tri-o-phenylphosphino) palladium dichloride, 1, 2-bis (diphenylphosphino) ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-phenylphosphine, or a combination thereof.
Preferably, the condensing agent is selected from the group consisting of: DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU, TBTU, and the like, or combinations thereof.
Preferably, the inorganic base is selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or combinations thereof; the organic base is selected from the group consisting of: pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.
Preferably, the acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid, or combinations thereof.
Preferably, the reducing agent is selected from the group consisting of: iron powder, zinc powder, stannous chloride, sodium thiosulfate, sodium sulfite, hydrogen and the like.
The invention provides a class of preferred compounds of formula (I) including, but not limited to, the following structures:
the invention also aims to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for realizing the purpose is as follows:
a pharmaceutical composition for treating tumor comprises nitrogen-containing polycyclic compound shown in the general formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, twisted isomer, solvate, polymorph or prodrug thereof and pharmaceutically acceptable carrier.
Another object of the present invention is to provide a use of the above compound. The technical scheme for realizing the purpose is as follows:
the nitrogen-containing polycyclic compound shown in the general formula (I) or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof is used for preparing medicaments for treating diseases related to the activity or expression quantity of Ras mutein, in particular medicaments for treating tumors. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostatic cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymph cancer, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
The invention relates to a compound with the structural characteristics of a general formula (I), which can inhibit various tumor cells, particularly can efficiently kill tumors related to abnormal KRas G12C mutant protein signal pathways, and is a treatment medicament with a brand-new action mechanism.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. The space is not described herein in a repeated fashion.
Detailed Description
The inventor has made a long-term and intensive study to prepare a compound with a novel structure shown in formula I, and finds that the compound has a better inhibitory activity for inhibiting the KRas G12C protein, the compound has a specific inhibitory effect on the KRas G12C protein at a very low concentration (which can be as low as less than 100nM), the inhibitory activity on the KRas G12C-related cell proliferation is quite excellent, and the compound has a stronger killing effect on KRas G12C-positive tumor cells at a very low concentration (which can be as low as less than 10nM), so that the compound can be used for treating related diseases such as tumors caused by KRas G12C mutation or abnormal expression. Based on the above findings, the inventors have completed the present invention.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.
Definitions for the terms of the standardization sector can be found in the literature references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols.A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH 2O-is equivalent to-OCH 2-.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.
In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.
In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine; "hydroxy" means an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxyl (-OH) group; "carbonyl" refers to a-C (═ O) -group; "nitro" means-NO2(ii) a "cyano" means-CN; "amino" means-NH2(ii) a "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino; "carboxyl" means-COOH.
In the present application, the term "alkyl", as a group or as part of another group (e.g. as used in groups such as halogen-substituted alkyl), means a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6) carbon atoms and being attached to the rest of the molecule by single bonds. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.
In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In the present application, the term "alkynyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being connected to the rest of the molecule by single bonds, such as but not limited to ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon atoms and hydrogen atoms, which may include fused, bridged or spiro ring systems, having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may be optionally oxidized. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, Bicyclo [3.2.1] octenyl, adamantyl, octahydro-4, 7-methylene-1H-indenyl, octahydro-2, 5-methylene-pentalenyl and the like.
In this application, the term "heterocyclyl" as a group or part of another group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or higher ring system, which may include fused ring systems, bridged ring systems or spiro ring systems; wherein the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In this application, the term "aryl" as a group or as part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or higher polycyclic ring system and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is attached to the remainder of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.
In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
In this application, the term "heteroaryl" as a group or part of another group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5-to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5-to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or a 5-to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, orthophenanthrolidinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthopyridyl, pyridinyl, and the like, [1,2,4] triazolo [4,3-b ] pyridazine, [1,2,4] triazolo [4,3-a ] pyrazine, [1,2,4] triazolo [4,3-c ] pyrimidine, [1,2,4] triazolo [4,3-a ] pyridine, imidazo [1,2-b ] pyridazine, imidazo [1,2-a ] pyrazine and the like.
In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.
In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.
"stereoisomers" refers to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.
When the compounds of the present invention contain olefinic double bonds, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.
The compounds of the present invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting as starting materials or intermediates racemates, diastereomers or enantiomers. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., crystallization and chiral chromatography.
Conventional techniques for the preparation/separation of individual isomers include Chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, Chiral high performance liquid chromatography, as described, for example, in Gerald Gubitz and Martin G.Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; m. Stalcup, Chiral Separations, Annu. Rev. anal. chem.3:341-63, 2010; fumiss et al (eds.), VOGEL' S ENCYCOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. TH ED., Longman Scientific and Technical Ltd., Essex,1991, 809-816; heller, acc, chem, res, 1990,23,128.
In the present application, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, 2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. These salts can be prepared by methods known in the art.
"pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
"polymorph" refers to different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form and the present invention is intended to include the various crystalline forms and mixtures thereof.
Typically, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrate, hemihydrate, sesquihydrates, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases it is also possible to retain only adventitious water or a mixture of water plus a portion of adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" denotes a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may not be active when administered to a subject in need thereof, but are converted in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific methods for preparing prodrugs can be found in Saulnier, M.G., et al, bioorg.Med.chem.Lett.1994,4, 1985-1990; greenwald, r.b., et al, j.med.chem.2000,43,475.
In the present application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
As used herein, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.
The "tumor" and "diseases related to abnormal cell proliferation" include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
The terms "preventing," "prevention," and "prevention" as used herein include reducing the likelihood of occurrence or worsening of a disease or disorder in a patient.
As used herein, the term "treatment" and other similar synonyms include the following meanings:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(ii) inhibiting the disease or disorder, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the state of the disease or condition; or
(iv) Alleviating the symptoms caused by the disease or disorder.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Administration techniques useful for The compounds and methods described herein are well known to those skilled in The art, for example, in Goodman and Gilman, The pharmaceutical Basis of therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "drug combination", "administering other treatment", "administering other therapeutic agent" and the like as used herein refer to a drug treatment obtained by mixing or combining more than one active ingredient, including fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one co-agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, concomitant administration, or sequential administration at variable intervals of at least one compound described herein and at least one synergistic formulation to a patient as separate entities. These also apply to cocktail therapy, for example the administration of three or more active ingredients.
It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include-C (O) -R "(where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting Groups is described in detail in Greene, T.W. and P.G.M.Wuts, Protective Groups in Organic Synthesis, (1999),4th Ed., Wiley. The protecting group may also be a polymeric resin.
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
The first preparation method of the intermediate comprises the following steps: synthesis of quinoline/quinazoline compound
Referring to synthetic routes and methods of patents WO2019110751A1, WO2019014402A1 and WO201367597A1, quinoline/quinazoline intermediate compounds 1A-1D are prepared
And a second intermediate preparation method comprises the following steps: synthesis of piperazine compound
Referring to the synthetic routes and methods of WO2019110751A1 and US20190062330A1, piperazine intermediate compounds 2A-2B are prepared
Examples general preparative method one
The first step is as follows: quinoline intermediate (1eq.) is dissolved in N, N-Dimethylformamide (DMF), and N, N, N-Diisopropylethylamine (DIPEA) (1.6eq.) and piperazine intermediate (1.5eq.) are added in sequence, heated to 100 ℃ under nitrogen protection, and stirred for 18 hours. TLC monitoring reaction is completed, cooling to room temperature, decompression concentrating, adding water and dichloromethane into residues for phase separation, extracting water phase with dichloromethane for three times, drying extraction liquid anhydrous sodium sulfate, decompression concentrating, separating and purifying the residues by silica gel column chromatography to obtain target products, and confirming the structure by adopting nuclear magnetism and mass spectrum.
The second step is that: the product of the first step (1eq.) was dissolved in ethanol, and a phosphate buffer solution (10mL, pH 6.7), sodium acetate (2eq.) and 40% aqueous chloroacetaldehyde (10eq.) were added, heated to 80 ℃ and stirred for 24 hours. Cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. Diluting the residue with dichloromethane, washing with saturated ammonium chloride solution and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residue with silica gel column chromatography to obtain the target product, and confirming the structure by nuclear magnetism and mass spectrometry.
The third step: dissolving the second-step product (1eq.) in a mixed solvent of anhydrous dioxane/water (4/1), and sequentially adding boric acid or boric acid pinacol ester (2eq.), anhydrous potassium carbonate powder (2.5eq.) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl2) (0.1eq.) and reflux with heating under nitrogen for 2 hours. Monitoring the reaction completion by Thin Layer Chromatography (TLC), cooling to room temperature, concentrating under reduced pressure, diluting the residue with dichloromethane, washing with saturated ammonium chloride solution and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residue with silica gel column chromatography to obtain the target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.
The fourth step: the product of the third step (1eq.) was dissolved in methanol, and 4M hydrogen chloride (HCl) in methanol (20eq.) was added and stirred at room temperature for 3 hours. TLC monitors the reaction to be complete, and the reaction is concentrated under reduced pressure, the residue is dissolved in dichloromethane, DIPEA (3eq.) and acryloyl chloride (1eq.) are added in turn at 0 ℃, the mixture is stirred for 0.5 hour, the reaction solution is washed by saturated ammonium chloride solution and saturated common salt solution, anhydrous sodium sulfate is dried, the filtration and the concentration under reduced pressure are carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrometry.
EXAMPLES general preparation method II
The first step is as follows: the quinoline amino intermediate (1eq.) was suspended in isopropanol and dimethylformamide-dimethylacetal (1.2eq.) was added dropwise at room temperature. After the completion of the dropwise addition, the reaction solution was refluxed for 3 hours, cooled to room temperature, added with hydroxylamine hydrochloride (1.2eq.) and stirred at 50 ℃ overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, dried, and the residue was suspended in anhydrous tetrahydrofuran, cooled in an ice bath, and then trifluoroacetic anhydride (1.5eq.) was slowly added dropwise. After the addition was complete, the ice bath was removed and stirred at room temperature overnight. Slowly dripping saturated sodium bicarbonate solution into the reaction solution, extracting with dichloromethane, washing with water and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residue with silica gel column chromatography to obtain the target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.
The second step is that: dissolving the first step product (1eq.) in anhydrous dioxane/water (4/1), and sequentially adding boric acid or boric acid pinacol ester (2eq.), anhydrous potassium carbonate powder (2.5eq.) and Pd (dppf) Cl2(0.1eq.) and reflux with heating under nitrogen for 2 hours. TLC monitoring reaction is complete, cooling to room temperature, decompression concentrating, diluting the remainder with dichloromethane, washing with saturated ammonium chloride solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, decompression concentrating, separating and purifying the remainder with silica gel column chromatography to obtain the target product, and confirming the structure by nuclear magnetism and mass spectrum.
The third step: the second product (1eq.) was dissolved in methanol, and 4M HCl in methanol (20eq.) was added and stirred at room temperature for 3 hours. TLC monitors the reaction to be complete, and the reaction is concentrated under reduced pressure, the residue is dissolved in dichloromethane, DIPEA (3eq.) and acryloyl chloride (1eq.) are added in turn at 0 ℃, the mixture is stirred for 0.5 hour, the reaction solution is washed by saturated ammonium chloride solution and saturated common salt solution, anhydrous sodium sulfate is dried, the filtration and the concentration under reduced pressure are carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrometry.
Examples general preparative method three
The first step is as follows: quinoline intermediate (1eq.) is dissolved in tetrahydrofuran, DIPEA (1.6eq.) and piperazine intermediate (1.5eq.) are added in sequence, and the mixture is heated to 60 ℃ under the protection of nitrogen and stirred for 12 hours. TLC monitoring reaction is completed, cooling to room temperature, decompression concentrating, adding water and dichloromethane into residues for phase separation, extracting water phase with dichloromethane for three times, drying extraction liquid anhydrous sodium sulfate, decompression concentrating, separating and purifying the residues by silica gel column chromatography to obtain target products, and confirming the structure by adopting nuclear magnetism and mass spectrum.
The second step is that: the product of the first step (1eq.) is dissolved in a mixed solvent of ethanol/hydrazine hydrate (3/1), heated to 100 ℃ under the protection of nitrogen and stirred for 12 hours. And monitoring the reaction by TLC (thin layer chromatography), cooling to room temperature, pouring into saturated ammonium chloride aqueous solution, separating out solids, filtering, drying a filter cake in vacuum to obtain a target product, and confirming the structure by adopting nuclear magnetism and mass spectrum.
The third step: the second-step product (1eq.) was dissolved in dichloromethane, and trimethyl orthoformate (4eq.) was added, followed by stirring for ten minutes and then trifluoroacetic acid (1eq.) was added. And continuously stirring for one hour at room temperature, concentrating under reduced pressure, separating and purifying the residue by using a silica gel column chromatography to obtain a target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.
The fourth step: dissolving the product of the third step (1eq.) in a mixed solvent of anhydrous dioxane and water (4/1), and sequentially adding boric acid or boric acid pinacol ester (2eq.), anhydrous potassium carbonate powder (2.5eq.) and Pd (dppf) Cl2(0.1eq.) and reflux with heating under nitrogen for 2 hours. TLC monitoring reaction is complete, cooling to room temperature, decompression concentrating, diluting the remainder with dichloromethane, washing with saturated ammonium chloride solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, decompression concentrating, separating and purifying the remainder with silica gel column chromatography to obtain the target product, and confirming the structure by nuclear magnetism and mass spectrum.
The fifth step: the product of the fourth step (1eq.) was dissolved in methanol, and 4M HCl in methanol (20eq.) was added and stirred at room temperature for 3 hours. TLC monitors the reaction to be complete, and the reaction is concentrated under reduced pressure, the residue is dissolved in dichloromethane, DIPEA (3eq.) and acryloyl chloride (1eq.) are added in turn at 0 ℃, the mixture is stirred for 0.5 hour, the reaction solution is washed by saturated ammonium chloride solution and saturated common salt solution, anhydrous sodium sulfate is dried, the filtration and the concentration under reduced pressure are carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrometry.
Examples general preparative method four
The first step is as follows: quinoline intermediate (1eq.) is dissolved in tetrahydrofuran, DIPEA (1.6eq.) and piperazine intermediate (1.5eq.) are added in sequence, and the mixture is heated to 60 ℃ under the protection of nitrogen and stirred for 12 hours. TLC monitoring reaction is completed, cooling to room temperature, decompression concentrating, adding water and dichloromethane into residues for phase separation, extracting water phase with dichloromethane for three times, drying extraction liquid anhydrous sodium sulfate, decompression concentrating, separating and purifying the residues by silica gel column chromatography to obtain target products, and confirming the structure by adopting nuclear magnetism and mass spectrum.
The second step is that: the product of the first step (1eq.) was dissolved in dichloromethane, 2,4, 6-trimethylbenzenesulfonylhydroxylamine (1eq.) was added, the reaction was carried out overnight at room temperature, and the mixture was concentrated under reduced pressure, and the residue was used directly in the next reaction.
The third step: dissolving the second-step product (1eq.) in ethanol, adding methyl 3-methoxyacrylate (1eq.) and triethylamine (4eq.), and heating and refluxing for 6 hours under the protection of nitrogen. TLC monitoring reaction is complete, cooling to room temperature, decompressing and concentrating, adding water and dichloromethane into residues for phase separation, extracting water phase with dichloromethane for three times, drying extraction liquid anhydrous sodium sulfate, separating and purifying the residues by silica gel column chromatography to obtain target products, and confirming the structure by adopting nuclear magnetism and mass spectrum.
The fourth step: dissolving the product of the third step (1eq.) in a mixed solvent of anhydrous dioxane and water (4/1), and sequentially adding boric acid or boric acid pinacol ester (2eq.), anhydrous potassium carbonate powder (2.5eq.) and Pd (dppf) Cl2(0.1eq.) and reflux with heating under nitrogen for 2 hours. TLC to monitor the reaction completion, cool to room temperature, concentrate under reduced pressure, and dilute the residue with dichloromethaneWashing the product with saturated ammonium chloride solution and saturated salt solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residue with silica gel column chromatography to obtain the target product, and confirming the structure with nuclear magnetic and mass spectrometry.
The fifth step: the product of the fourth step (1eq.) was dissolved in methanol, and 4M HCl in methanol (20eq.) was added and stirred at room temperature for 3 hours. TLC monitors the reaction to be complete, and the reaction is concentrated under reduced pressure, the residue is dissolved in dichloromethane, DIPEA (3eq.) and acryloyl chloride (1eq.) are added in turn at 0 ℃, the mixture is stirred for 0.5 hour, the reaction solution is washed by saturated ammonium chloride solution and saturated common salt solution, anhydrous sodium sulfate is dried, the filtration and the concentration under reduced pressure are carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrometry.
Examples general preparative method five
The first step is as follows: dissolving quinoline/quinazoline intermediate (1eq.) in a mixed solvent of methanol/concentrated ammonia water (1/1), placing in a sealed tank, adding a catalytic amount of p-toluenesulfonic acid, heating to 100 ℃, and stirring for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was used directly in the next reaction.
The second step is that: the first-step product (1eq.) was suspended in isopropanol and dimethylformamide-dimethylacetal (1.2eq.) was added dropwise at room temperature. After the completion of the dropwise addition, the reaction solution was refluxed for 3 hours, cooled to room temperature, added with hydroxylamine hydrochloride (1.2eq.) and stirred at 50 ℃ overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, dried, and the residue was suspended in anhydrous tetrahydrofuran, cooled in an ice bath, and then trifluoroacetic anhydride (1.5eq.) was slowly added dropwise. After the addition was complete, the ice bath was removed and stirred at room temperature overnight. Slowly dripping saturated sodium bicarbonate solution into the reaction solution, extracting with dichloromethane, washing with water and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residue with silica gel column chromatography to obtain the target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.
The third step: dissolving the second-step product (1eq.) in a mixed solvent of anhydrous dioxane/water (4/1), and sequentially adding boric acid or boric acid pinacol ester (2eq.), anhydrous potassium carbonate powder (2.5eq.) and Pd (dppf) Cl2(0.1eq.) and reflux with heating under nitrogen for 2 hours. TLC monitoring reaction is complete, cooling to room temperature, decompression concentrating, diluting the remainder with dichloromethane, washing with saturated ammonium chloride solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, decompression concentrating, separating and purifying the remainder with silica gel column chromatography to obtain the target product, and confirming the structure by nuclear magnetism and mass spectrum.
The fourth step: the product of the third step (1eq.) was dissolved in methanol, and 4M HCl in methanol (20eq.) was added and stirred at room temperature for 3 hours. TLC monitors the reaction to be complete, and the reaction is concentrated under reduced pressure, the residue is dissolved in dichloromethane, DIPEA (3eq.) and acryloyl chloride (1eq.) are added in turn at 0 ℃, the mixture is stirred for 0.5 hour, the reaction solution is washed by saturated ammonium chloride solution and saturated common salt solution, anhydrous sodium sulfate is dried, the filtration and the concentration under reduced pressure are carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrometry.
Examples general preparative method six
The first step is as follows: quinoline intermediate (1eq.) is dissolved in tetrahydrofuran, DIPEA (1.6eq.) and piperazine intermediate (1.5eq.) are added in sequence, and the mixture is heated to 60 ℃ under the protection of nitrogen and stirred for 12 hours. TLC monitoring reaction is completed, cooling to room temperature, decompression concentrating, adding water and dichloromethane into residues for phase separation, extracting water phase with dichloromethane for three times, drying extraction liquid anhydrous sodium sulfate, decompression concentrating, separating and purifying the residues by silica gel column chromatography to obtain target products, and confirming the structure by adopting nuclear magnetism and mass spectrum.
The second step is that: the product of the first step (1eq.) is dissolved in DMF, lithium bistrimethylsilyl amide (LiHMDS) (3eq.) is added, and the mixture is heated to 100 ℃ under the protection of nitrogen and stirred for 8 hours. And monitoring the reaction by TLC (thin layer chromatography), cooling to room temperature, pouring into saturated ammonium chloride aqueous solution, separating out solids, filtering, drying a filter cake in vacuum to obtain a target product, and confirming the structure by adopting nuclear magnetism and mass spectrum.
The third step: dissolving the second-step product (1eq.) in a mixed solvent of methanol/concentrated ammonia water (1/1), placing in a sealed tank, adding a catalytic amount of p-toluenesulfonic acid, heating to 100 ℃, and stirring for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was used directly in the next reaction.
The fourth step: the product of the third step (1eq.) was suspended in isopropanol and dimethylformamide-dimethylacetal (1.2eq.) was added dropwise at room temperature. After the completion of the dropwise addition, the reaction solution was refluxed for 3 hours, cooled to room temperature, added with hydroxylamine hydrochloride (1.2eq.) and stirred at 50 ℃ overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, dried, and the residue was suspended in anhydrous tetrahydrofuran, cooled in an ice bath, and then trifluoroacetic anhydride (1.5eq.) was slowly added dropwise. After the addition was complete, the ice bath was removed and stirred at room temperature overnight. Slowly dripping saturated sodium bicarbonate solution into the reaction solution, extracting with dichloromethane, washing with water and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residue with silica gel column chromatography to obtain the target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.
The fifth step: dissolving the product of the fourth step (1eq.) in a mixed solvent of anhydrous dioxane and water (4/1), and sequentially adding boric acid or boric acid pinacol ester (2eq.), anhydrous potassium carbonate powder (2.5eq.) and Pd (dppf) Cl2(0.1eq.) and reflux with heating under nitrogen for 2 hours. TLC monitoring reaction is complete, cooling to room temperature, decompression concentrating, diluting the remainder with dichloromethane, washing with saturated ammonium chloride solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, decompression concentrating, separating and purifying the remainder with silica gel column chromatography to obtain the target product, and confirming the structure by nuclear magnetism and mass spectrum.
And a sixth step: the product of the fifth step (1eq.) was dissolved in methanol, and 4M HCl in methanol (20eq.) was added and stirred at room temperature for 3 hours. TLC monitors the reaction to be complete, and the reaction is concentrated under reduced pressure, the residue is dissolved in dichloromethane, DIPEA (3eq.) and acryloyl chloride (1eq.) are added in turn at 0 ℃, the mixture is stirred for 0.5 hour, the reaction solution is washed by saturated ammonium chloride solution and saturated common salt solution, anhydrous sodium sulfate is dried, the filtration and the concentration under reduced pressure are carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrometry.
Examples general preparative method seven
The first step is as follows: quinoline intermediate (1eq.) is dissolved in anhydrous tetrahydrofuran, DIPEA (1.6eq.) and piperazine intermediate (1.5eq.) are added in sequence, and the mixture is heated and refluxed for 18 hours under the protection of nitrogen. TLC to monitor the reaction completion, cooling to room temperature, concentrating under reduced pressure, adding water and dichloromethane to the residue, phase-separating, extracting the aqueous phase with dichloromethane three times, drying the extract with anhydrous sodium sulfate, concentrating under reduced pressure, and using the residue directly in the next reaction.
The second step is that: dissolving the crude product (1eq.) in anhydrous glacial acetic acid, slowly adding reduced iron powder (3eq.), heating to 80 ℃ under the protection of nitrogen, and stirring for 0.5 hour. After the reaction was completed, the mixture was filtered through celite, washed with ethyl acetate, and the filtrate was concentrated. Diluting the residue with dichloromethane, washing with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residue with silica gel column chromatography to obtain the target product, and confirming the structure by nuclear magnetism and mass spectrometry.
The third step: the second-step product (1eq.) was dissolved in DMF, sodium hydrogen (1.5eq.) was added at 0 ℃, stirred for 0.5 h, methyl iodide (1.1eq.) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction is finished, decompressing and concentrating the reaction liquid, diluting the remainder with dichloromethane, washing the remainder with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying the remainder with anhydrous sodium sulfate, filtering the mixture, decompressing and concentrating the mixture, separating and purifying the remainder by silica gel column chromatography to obtain a target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.
The fourth step: dissolving the product (1eq.) obtained in the third step in a mixed solvent of methanol/concentrated ammonia water (1/1), placing in a sealed tank, adding a catalytic amount of p-toluenesulfonic acid, heating to 100 ℃, and stirring for 6 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was used directly in the next reaction.
The fifth step: the product of the fourth step (1eq.) was suspended in isopropanol and dimethylformamide-dimethylacetal (1.2eq.) was added dropwise at room temperature. After the completion of the dropwise addition, the reaction solution was refluxed for 3 hours, cooled to room temperature, added with hydroxylamine hydrochloride (1.2eq.) and stirred at 50 ℃ overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, dried, and the residue was suspended in anhydrous tetrahydrofuran, cooled in an ice bath, and then trifluoroacetic anhydride (1.5eq.) was slowly added dropwise. After the addition was complete, the ice bath was removed and stirred at room temperature overnight. Slowly dripping saturated sodium bicarbonate solution into the reaction solution, extracting with dichloromethane, washing with water and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residue with silica gel column chromatography to obtain the target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.
And a sixth step: dissolving the product obtained in the fifth step (1eq.) in a mixed solvent of anhydrous dioxane and water (4/1), and sequentially adding boric acid or boric acid pinacol ester (2eq.), anhydrous potassium carbonate powder (2.5eq.) and Pd (dppf) Cl2(0.1eq.) and reflux with heating under nitrogen for 2 hours. TLC monitoring reaction is complete, cooling to room temperature, decompression concentrating, diluting the remainder with dichloromethane, washing with saturated ammonium chloride solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, decompression concentrating, separating and purifying the remainder with silica gel column chromatography to obtain the target product, and confirming the structure by nuclear magnetism and mass spectrum.
The seventh step: the product of the sixth step (1eq.) was dissolved in methanol, and 4M HCl in methanol (20eq.) was added and stirred at room temperature for 3 hours. TLC monitors the reaction to be complete, and the reaction is concentrated under reduced pressure, the residue is dissolved in dichloromethane, DIPEA (3eq.) and acryloyl chloride (1eq.) are added in turn at 0 ℃, the mixture is stirred for 0.5 hour, the reaction solution is washed by saturated ammonium chloride solution and saturated common salt solution, anhydrous sodium sulfate is dried, the filtration and the concentration under reduced pressure are carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrometry.
EXAMPLES general preparative method eight
The first step is as follows: the quinoline intermediate (1eq.) was dissolved in dichloromethane, 2,4, 6-trimethylbenzenesulfonylhydroxylamine (1eq.) was added, the reaction was carried out overnight at room temperature, and the mixture was concentrated under reduced pressure, and the residue was used directly in the next reaction.
The second step is that: dissolving the product of the first step (1eq.) in dry pyridine, dropwise adding acyl chloride (1.5eq.) under ice-bath cooling, and heating to 100 ℃ under the protection of nitrogen and stirring overnight. After the reaction is finished, cooling the reaction liquid to room temperature, concentrating under reduced pressure, diluting the residues with a saturated sodium carbonate solution, extracting with dichloromethane, washing the organic phase with water and saturated saline solution in turn, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residues with a silica gel column chromatography to obtain a target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.
The third step: dissolving the second-step product (1eq.) in a mixed solvent of anhydrous dioxane/water (4/1), and sequentially adding boric acid or boric acid pinacol ester (2eq.), anhydrous potassium carbonate powder (2.5eq.) and Pd (dppf) Cl2(0.1eq.) and reflux with heating under nitrogen for 2 hours. TLC monitoring reaction is complete, cooling to room temperature, decompression concentrating, diluting the remainder with dichloromethane, washing with saturated ammonium chloride solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, decompression concentrating, separating and purifying the remainder with silica gel column chromatography to obtain the target product, and confirming the structure by nuclear magnetism and mass spectrum.
The fourth step: the product of the third step (1eq.) was dissolved in methanol, and 4M HCl in methanol (20eq.) was added and stirred at room temperature for 3 hours. TLC monitors the reaction to be complete, and the reaction is concentrated under reduced pressure, the residue is dissolved in dichloromethane, DIPEA (3eq.) and acryloyl chloride (1eq.) are added in turn at 0 ℃, the mixture is stirred for 0.5 hour, the reaction solution is washed by saturated ammonium chloride solution and saturated common salt solution, anhydrous sodium sulfate is dried, the filtration and the concentration under reduced pressure are carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrometry.
EXAMPLES general preparative method nine
The first step is as follows: dissolving the quinoline hydrazine intermediate (1eq.) in dry pyridine, dropwise adding acyl chloride (1.5eq.) under ice-bath cooling, and heating to 100 ℃ under the protection of nitrogen and stirring overnight. After the reaction is finished, cooling the reaction liquid to room temperature, concentrating under reduced pressure, diluting the residues with a saturated sodium carbonate solution, extracting with dichloromethane, washing the organic phase with water and saturated saline solution in turn, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the residues with a silica gel column chromatography to obtain a target product, and confirming the structure by adopting nuclear magnetism and mass spectrometry.
The second step is that: dissolving the first step product (1eq.) in anhydrous dioxane/water (4/1), and sequentially adding boric acid or boric acid pinacol ester (2eq.), anhydrous potassium carbonate powder (2.5eq.) and Pd (dppf) Cl2(0.1eq.) and reflux with heating under nitrogen for 2 hours. TLC monitoring reaction is complete, cooling to room temperature, decompression concentrating, diluting the remainder with dichloromethane, washing with saturated ammonium chloride solution and saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, decompression concentrating, separating and purifying the remainder with silica gel column chromatography to obtain the target product, and confirming the structure by nuclear magnetism and mass spectrum.
The third step: the second product (1eq.) was dissolved in methanol, and 4M HCl in methanol (20eq.) was added and stirred at room temperature for 3 hours. TLC monitors the reaction to be complete, and the reaction is concentrated under reduced pressure, the residue is dissolved in dichloromethane, DIPEA (3eq.) and acryloyl chloride (1eq.) are added in turn at 0 ℃, the mixture is stirred for 0.5 hour, the reaction solution is washed by saturated ammonium chloride solution and saturated common salt solution, anhydrous sodium sulfate is dried, the filtration and the concentration under reduced pressure are carried out, the residue is separated and purified by silica gel column chromatography to obtain the target compound, and the structure is confirmed by nuclear magnetism and mass spectrometry.
Examples
Example 1: 1- (4- (3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -9- ((S) -1-methylpyrrolidin-2-yl) pyrido [3,2-e ] [1,2,4] triazolo [4,3-a ] pyrimidin-5-yl) piperazin-1-yl) prop-2-en-1-one
The first step is as follows: 2, 6-dichloro-5-fluoronicotinic acid (100g, 478.5mmol) was dissolved in methanol (1.0L) and thionyl chloride (SOCl) was added dropwise at 0 deg.C2) (69mL,949.8mmol) was refluxed for 4 hours under nitrogen. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in DCM and washed with sodium bicarbonate (NaHCO)3) The saturated solution was washed twice with water and once with saturated brine, dried and concentrated under reduced pressure to give methyl 2, 6-dichloro-5-fluoronicotinate (106g, yellow oil). LC-MS ESI [ M + H ]]+＝224.0；1H NMR(400MHz,CDCl3):δ8.01(d,J＝7.6MHz,1H),3.98(s,3H)。
The second step is that: methyl 2, 6-dichloro-5-fluoronicotinate (20g, 89.7mmol), (2-fluoro-6-methoxyphenyl) boronic acid (19.4g, 114.1mmol) and potassium phosphate (K)3PO4) (24.3g, 114.6mmol) was dissolved in 1, 4-dioxane/water (H)2O) (200mL/20mL), Pd-Xphos-G3(3.75G,4.76mmol) and 2-dicyclohexylphosphonium-2 ',6' -diisopropoxy-1, 1' -biphenyl (Ru-phos) (4.44G, 9.52mmol) were added and reacted overnight at 60 degrees under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give methyl 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (8.92g, yellow oil). LC-MS ESI [ M + H ]]+＝314.3；1H NMR(400MHz,DMSO-d6):δ8.39(d,J＝8.4MHz,1H),7.57-7.59(m,1H),6.99-7.08(m,2H),3.93(s,3H),3.79(s,3H)。
The third step: methyl 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinate (8.92g, 28.5mmol) was dissolved in tetrahydrofuran/water (THF/H)2O) (90mL/45mL), monohydrate was addedLithium hydroxide (lioh. h)2O) (3.58g,85.2mmol), and reacted at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to remove most of the organic solvent, the pH was adjusted to 3-4 with 3N hydrogen chloride (HCl), and then DCM was used for extraction, and the organic phases were combined, washed with saturated brine, dried, and concentrated under reduced pressure to obtain 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.33g, yellow solid). LC-MS ESI [ M + H ]]+＝300.0。
The fourth step: 2-chloro-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (8.33g, 27.9mmol) was dissolved in N-methylpyrrolidone (NMP) (25mL), and p-methoxybenzylamine (PMB-NH) was added2) (11.44g, 83.5mmol) and DIPEA (10.77g,83.5mmol) were reacted at 180 ℃ under nitrogen for 16 hours. The reaction solution was cooled to room temperature, and saturated ammonium chloride (NH) was slowly poured in4Cl) aqueous solution, filtering, dissolving a filter cake by methanol, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain 5-fluoro-6- (2-fluoro-6-methoxyphenyl-2- ((4-methoxybenzyl) amino) nicotinic acid (13.6g, tan oily substance, crude product). LC-MS ESI [ M + H ]]+＝401.1。
The fifth step: 5-fluoro-6- (2-fluoro-6-methoxyphenyl-2- ((4-methoxybenzyl) amino) nicotinic acid (5.8g, crude) was dissolved in DCM/TFA (32mL/16mL), reacted at 40 ℃ for 6 hours, the reaction was concentrated under reduced pressure, diluted with DCM, and saturated Na was used2CO3The solution was washed twice with saturated brine, once again, dried, concentrated under reduced pressure, and purified by column chromatography to give 2-amino-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (3.3g, yellow solid). LC-MS ESI [ M + H ]]+＝281.4。
And a sixth step: 2-amino-5-fluoro-6- (2-fluoro-6-methoxyphenyl) nicotinic acid (1.65g, 5.89mmol) and urea (12g, 200mmol) were reacted at 200 ℃ for 3 hours. Cooling the reaction solution slightly, adding 5% sodium hydroxide (NaOH) solution, adjusting pH to neutral with 2N HCl solution, filtering, dissolving the filter cake with methanol, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain 6-fluoro-7- (2-fluoro-6-methoxyphenyl) pyrido [2, 3-d%]Pyrimidine-2, 4-diol (0.77g, yellow solid). LC-MS ESI [ M + H ]]+＝306.0；1H NMR(400MHz,DMSO-d6):δ11.81(s,1H),11.58(s,1H),8.22(d,J＝8.0MHz,1H),7.55-7.57(m,1H),6.96-7.07(m,2H),3.77(s,3H)。
The seventh step: reacting 6-fluoro-7- (2-fluoro-6-methoxyphenyl) pyrido [2,3-d]Pyrimidine-2, 4-diol (570mg, 1.87mmol) dissolved in phosphorus oxychloride (POCl)3) To the solution (6mL) was added N, N-dimethylaniline (0.5mL) and the mixture was reacted at 90 ℃ for 3 hours. Cooling the reaction solution to room temperature, concentrating under reduced pressure, adding water, extracting with DCM, mixing the organic phases, washing with saturated saline, drying, concentrating under reduced pressure, and purifying by column chromatography to obtain 2, 4-dichloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) pyrido [2,3-d]Pyrimidine (410mg, yellow solid). LC-MS ESI [ M + H ]]+＝342.0/344/0；1H NMR(400MHz,DMSO-d6):δ8.40(d,J＝8.0MHz,1H),7.56-7.59(m,1H),6.99-7.09(m,2H),3.77(s,3H)。
Eighth step: 2, 4-dichloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) pyrido [2,3-d]Pyrimidine (500mg, 1.47mmol) was dissolved in 1, 4-dioxane (10mL), and 1-benzyloxycarbonylpiperazine (355mg, 1.61mmol) and DIPEA (568mg, 4.40mmol) were added and reacted at room temperature overnight. The reaction liquid is decompressed and concentrated, and is purified by column chromatography to obtain 4- (2-chloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) pyrido [2,3-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (740mg, yellow solid). LC-MS ESI [ M + H ]]+＝526.2。
The ninth step: reacting 4- (2-chloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) pyrido [2,3-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (440mg, 0.84mmol) was dissolved in 1, 4-dioxane (8mL) and hydrazine hydrate (N)2H4.H2O) (400mg,8.0mmol), and reacted at room temperature overnight. The reaction liquid is decompressed and concentrated, and is purified by column chromatography to obtain 4- (6-fluorine-7- (2-fluorine-6-methoxyphenyl) -2-hydrazinopyrido [2, 3-d)]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (410mg, tan solid). LC-MS ESI [ M + H ]]+＝522.2。
The tenth step: reacting 4- (6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2-hydrazinopyrido [2, 3-d)]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (310mg, 0.60mmol) and L-proline methyl ester (77mg, 0.60mmol) were dissolved in DCM (6mL), DIPEA (768mg, 5.95mmol) and 1-propylphosphoric anhydride (757mg, 50% in ethyl acetate, 1.19mmol) were added and reacted at room temperature overnight. Diluting the reaction solution with DCM (10mL), washing with saturated saline (10 mL. multidot.2), drying, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain 4- (6-Fluoro-7- (2-fluoro-6-methoxyphenyl) -2- (2- (methyl-L-prolineyl) hydrazino) pyrido [2,3-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (yellow solid). LC-MS ESI [ M + H ]]+＝633.3。
The eleventh step: reacting 4- (6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2- (2- (methyl-L-prolino) hydrazino) pyrido [2,3-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester (50mg, 0.079mmol) dissolved in POCl3(3mL) at 100 ℃ for 10 hours. The reaction was cooled to room temperature, diluted with DCM (10mL) and saturated NaHCO3Washing the solution (10 mL. times.2), drying, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain 4- (3-fluoro-2- (2-fluoro-6-methoxyphenyl) -9- ((S) -1-methylpyrrolidin-2-yl) pyrido [3,2-e][1,2,4]Triazole [4,3-a ]]Pyrimidin-5-yl) piperazine-1-carboxylic acid benzyl ester (35mg, yellow solid). LC-MS ESI [ M + H ]]+＝615.3。
The twelfth step: mixing 4- (3-fluoro-2- (2-fluoro-6-methoxyphenyl) -9- ((S) -1-methylpyrrolin-2-yl) pyrido [3,2-e][1,2,4]Triazole [4,3-a ]]Pyrimidin-5-yl) piperazine-1-carboxylic acid benzyl ester (35mg, 0.057mmol) was dissolved in DCM (4mL) and boron tribromide (BBr) was added dropwise at-78 deg.C3) (1.0M in DCM, 0.28mL) and the reaction was allowed to warm to room temperature naturally overnight. After the LC-MS detection reaction is not completed, BBr is supplemented3(1.0M in DCM, 0.28mL) and the reaction was continued for 6 h. Concentrating the reaction solution under reduced pressure to obtain 3-fluoro-2- (3-fluoro-9- ((S) -1-methylpyrrolin-2-yl) -5- (piperazine-1-yl) pyrido [3,2-e][1,2,4]Triazole [4,3-a ]]Pyrimidin-2-yl) phenol (yellow solid) was used directly in the next reaction. LC-MS ESI [ M + H ]]+＝467.2。
The thirteenth step: mixing 3-fluoro-2- (3-fluoro-9- ((S) -1-methylpyrrolidin-2-yl) -5- (piperazine-1-yl) pyrido [3,2-e][1,2,4]Triazole [4,3-a ]]Pyrimidin-2-yl) phenol (crude) was dissolved in dichloromethane (6mL), Triethylamine (TEA) (23mg, 0.23mmol) and acryloyl chloride (5mg, 0.057mmol) were added sequentially at 0 ℃ and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, dissolved in methanol (MeOH), and potassium carbonate (K) was added2CO3) (30mg), stirring for 1.5 hours, adjusting the pH value to 6-7 with 3N HCl, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by preparative chromatography to obtain the target compound (yellow solid). LC-MS ESI [ M + H ]]+＝521.2；1H NMR(400MHz,CD3OD):δ8.55-8.57(m,1H),7.39-7.43(m,1H),6.78-6.87(m,3H),6.26-6.30(m,1H),5.80-5.83(m,1H),5.35-5.37(m,1H),3.93(brs,8H),3.59-3.63(m,1H),3.17-3.25(m,1H),2.75-2.84(m,4H),2.36-2.38(m,1H),2.14(brs,2H)。
Example 2: 1- (4- (3-fluoro-2- (2-fluoro-6-hydroxyphenyl) pyrido [3,2-e ] [1,2,4] triazolo [4,3-a ] pyrimidin-5-yl) piperazin-1-yl) prop-2-en-1-one
The first step is as follows: 2, 4-dichloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) pyrido [2,3-d]Pyrimidine (410mg, 1.20mmol) was dissolved in 1, 4-dioxane (12mL), and 1-tert-butoxycarbonylpiperazine (246mg, 1.32mmol) was added and reacted at room temperature for 3 hours. Concentrating the reaction solution under reduced pressure, pulping and purifying ethyl acetate to obtain 4- (2-chloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) pyrido [2,3-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (0.42g, white solid). LC-MS ESI [ M + H ]]+＝492.4。
The second step is that: reacting 4- (2-chloro-6-fluoro-7- (2-fluoro-6-methoxyphenyl) pyrido [2,3-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (420mg, 0.86mmol) was dissolved in 1, 4-dioxane (8mL) and N was added dropwise2H4.H2O (428mg,8.56mmol), and reacted at room temperature overnight. Concentrating the reaction solution, and purifying by preparative chromatography to obtain 4- (6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2-hydrazinopyrido [2,3-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (170mg, yellow solid). LC-MS ESI [ M + H ]]+＝488.2。
The third step: reacting 4- (6-fluoro-7- (2-fluoro-6-methoxyphenyl) -2-hydrazinopyrido [2, 3-d)]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (70mg, 0.14mmol) was dissolved in acetonitrile (5mL), triethyl orthoformate (CH (OEt)3) (43mg, 0.29mmol), stirred at room temperature for 0.5 h, and 2 drops of acetic acid (AcOH) were added dropwise and refluxed for 2.5 h. Cooling the reaction solution to room temperature, concentrating under reduced pressure, and purifying by column chromatography to obtain 4- (3-fluoro-2- (2-fluoro-6-methoxyphenyl) pyrido [3,2-e][1,2,4]Triazole [4,3-a ]]Pyrimidin-5-yl) piperazine-1-carboxylic acid tert-butylEster (64mg, yellow oil). LC-MS ESI [ M + H ]]+＝498.2。
The fourth step: reacting 4- (3-fluoro-2- (2-fluoro-6-methoxyphenyl) pyrido [3, 2-e)][1,2,4]Triazole [4,3-a ]]Pyrimidin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (64mg, 0.13mmol) was dissolved in Dichloromethane (DCM) (4mL), trifluoroacetic acid (TFA) (1mL) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was treated with sodium bicarbonate (NaHCO)3) Washing the solution twice, washing the solution once with saturated saline, drying, and concentrating under reduced pressure to obtain 3-fluoro-2- (2-fluoro-6-methoxyphenyl) -5- (piperazin-1-yl) pyrido [3,2-e][1,2,4]Triazole [4,3-a ]]Pyrimidine (51.2mg, yellow solid). LC-MS ESI [ M + H ]]+＝398.2。
The fifth step: reacting 3-fluoro-2- (2-fluoro-6-methoxyphenyl) -5- (piperazin-1-yl) pyrido [3,2-e][1,2,4]Triazole [4,3-a ]]Pyrimidine (25.6mg, 0.064mmol) in DCM (2mL) was added BBr at-78 deg.C3(1.0M, 0.65mL) and reacted at room temperature overnight. The reaction solution is decompressed and concentrated, and is purified by preparative chromatography to obtain 3-fluoro-2- (3-fluoro-5- (piperazine-1-yl) pyridine [3,2-e][1,2,4]Triazole [4,3-a ]]Pyrimidin-2-yl) phenol (9.2mg, yellow solid). LC-MS ESI [ M + H ]]+＝384.1。
And a sixth step: reacting 3-fluoro-2- (3-fluoro-5- (piperazin-1-yl) pyridine [3, 2-e)][1,2,4]Triazole [4,3-a ]]Pyrimidin-2-yl) phenol (9.2mg, 0.024mmol) was dissolved in THF/H2O (2mL/1mL), K was added2CO3(10mg, 0.072mmol) was stirred for 5 minutes, and 3-chloropropionyl chloride (3mg, 0.024mmol) was added thereto to react at room temperature for 0.5 hours. Then NaOH (3.8mg, 0.095mmol) is added and stirred for 0.5 hour, and 3N HCl is added dropwise to adjust the pH value to 5-6. The reaction mixture was concentrated under reduced pressure and purified by preparative chromatography to give the objective compound (3.4mg, yellow solid). LC-MS ESI [ M + H ]]+＝438.2；1H NMR(400MHz,DMSO-d6):δ10.46(s,1H),9.38(s,1H),8.59(d,J＝9.2Hz,1H),7.39-7.45(m,1H),6.83-6.90(m,3H),6.16-6.20(m,1H),5.74-5.77(m,1H),3.74-3.86(m,8H)。
The following compounds of examples were prepared using intermediates 1-2 and other commercial reagents as starting materials, using the synthetic methods of examples general preparative procedures one to nine, respectively.
Test example 1 Kras G12C functional analysis
All enzyme and substrate solutions were prepared with reaction buffer (20mM HEPES (pH7.5), 5mM MgCl2,150mM NaCl and 0.01% tween 20). The experimental procedure was as follows: using reaction buffer configuration of 10nM GDP loaded biotinylated KRASG12C and 37.5ng/ml streptavidin europium cryptate, 384 well HiBase micro polystyrene microwell plates were loaded with 5 μ L of the above protein reaction per well, along with test sample or control compound configured with DMSO and incubated for 4 hours. Separately, 20nM GST-Raf Ras binding domain (GST-Raf RBD) and 4. mu.g/ml anti-GST XL665 antibody (Cisbio) in reaction buffer (50mM potassium fluoride and 0.05mg/ml BSA) were mixed, and after 4 hours of equilibration, 0.6. mu.M GTP. gamma.S (Sigma) and 0.08. mu.M SOS were added. Mu.l of GST-RAF RBD mixture was added to each well of the plate. Addition of this mixture at this stage initiates a nucleotide exchange reaction which facilitates conversion of the non-activated GDP-loaded KRasG12C to activated GTP γ S KRasG 12C. The specific binding between activated GTP γ S KRasG12C and GST-RAF RBD draws the distance between europium and XL665 to enhance the FRET signal, which is detected using a Pherastar (BMG) plate reader equipped with an HTRF filter module. Any compound if inhibiting nucleotidesExchanging or inhibiting the combination of the activated KRAS and the RAF RBD can cause the attenuation of FRET signals, and the Genetida Screneer is used for carrying out curve fitting on FRET dose-effect data and calculating IC50。
Test example 2KRAS G12C Mass Spectrometry addition analysis
All enzyme and substrate solutions were prepared with reaction buffer (20mM HEPES (pH7.5), 5mM MgCl2,150mM NaCl and 0.01% tween 20). mu.L of GDP-loaded biotinylated KRAS G12C (4. mu.M) and 1mM test compound (final concentration: 10. mu.M) in a reaction buffer (4. mu.M) were added to each well of a 96-well polypropylene microplate, and the reaction was terminated by adding 50. mu.L of 1% formic acid after 4 hours of reaction. The plates were sealed and then read by Xevo G2 QTOF (Waters) and Acquity LC system (Waters). 10 μ L of the sample was injected into Xbridge BEH 300; c4; 3.5 μm; gradient analysis was performed for 3 min on 2.1X 50mm columns (Waters). A blank sample needs to be run between each test sample. Data analysis was performed using Mass Lynx Software (Waters) using total ion number (TIC) and combining the eluted protein peak data. Apo-protein KRASG12C (Apo) and KRAS + relative compound masses (sums) were tested and the percentage of sums calculated using the following formula: sum percentage is 100x (sum of sum peak area/APO and sum peak).
Test example 3: test of Effect of Compounds of the present invention on the cell proliferation of NCI-H358, MiaPaca-2 and phosphorylation of downstream Signal ERK
Test method one (2D) NCI-H358 (lung cancer) and MiaPaca-2 cells (pancreatic cancer) cells (100. mu.L/well, 20000 cells/mL) were seeded into 96-well culture plates and supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin sulfate, respectively. Cells were treated with a 0.5% dimethyl sulfoxide blank, diluted with an initial 10 μ M solution of test compound diluted three times with an eight gradient, and incubated in a 5% CO2 incubator for a defined period of time (5-7 days). At the end of the incubation, 10. mu.L of MTT stock solution (5mg/mL) was added to each well. The plates were incubated at 37 ℃ for 4 hours and then the medium was removed. Dimethylsulfoxide (100 μ L) was added to each well, followed by sufficient shaking. The absorbance of the formazan product was measured at 570nm on a Thermo Scientific Varioskan Flash multimodal reader. Formulations were prepared by using GraphPad Prism 6.0 softwareFitting the quantitative response data to a three-parameter nonlinear regression model to obtain IC50The value is obtained.
As a result, the compounds of the examples provided in the present invention have proliferation inhibitory activity, IC, on NCI-H358 and MiaPaca-2 cells50All values are less than 5000nM, the IC50 values for the cell proliferation inhibitory activity of some of the compounds of the examples are less than 1000nM, and the inhibitory activity of some of the examples is even less than 200nM, as in examples 9,10, 12, 14, 17, etc.
Test method two (3D) tumor cells in logarithmic growth phase were diluted to a certain concentration with culture medium and seeded in 96-well plates with ultra-low attachment surface at 80. mu.L/well. Cells were incubated overnight at 37 ℃ in a humidity chamber. The next day the plate was added serial dilutions of test compound (10 concentrations, 3-fold dilution), 20 μ L/well and incubated in incubator for 96 h. Taking out the plate, standing at room temperature, and adding the same volume
Incubation with 3D reagent for 1h, En VisionTMThe plate reader detects the signal. The signal was converted to percent inhibition using the following equation: % inhibition 100- [ (test compound signal-median minimum signal)/(median maximum signal-median minimum signal) x 100]. The maximum signal is the signal value for wells without inhibitor and the minimum signal is the signal value for wells containing a reference inhibitor sufficient to completely inhibit cell proliferation, a four-parameter non-linear regression fit curve was performed on the percent inhibition for each concentration of compound and the IC50 was calculated.
As a result: the compounds of the examples provided herein have proliferation inhibitory activity against NCI-H358 and MiaPaca-2 cells, both with an IC50 of less than 1000nM, and some examples, e.g., examples 3,4, 5,6, 9,10, 12, 14, 15, 17, etc., have cell proliferation inhibitory activity against NCI-H358 and MiaPaca-2, IC50 of less than 200 nM.
Test method three (ERK phosphorylation): miapaca-2 or H358 cells were seeded at a certain concentration in 96-well plates and placed at 37 ℃ in 5% CO2The next day the plate was incubated overnight with serial dilutions of test compounds (5 concentrations, 3-fold dilutions) for 24H (Miapaca-2) or 3H (H358), followed by protease and phosphataseThe lysate of the inhibitor is used for cracking cells to extract protein, and the western blot method is used for detecting the level of p-ERK.
As a result: the example compound provided by the invention has obvious inhibition effect on the level of phosphorylation ERK of NCI-H358 and MiaPaca-2, and IC50Less than 500 nM.
Test example 4: examples in vivo pharmacokinetic parameter testing of Compounds in rats and mice
6 male SPF-grade SD rats (Shanghai Spill-Bikea laboratory animals) were divided into two groups, and the test compounds were formulated into appropriate solutions or suspensions; one group was administered intravenously and one group was administered orally. Blood is collected by jugular venipuncture, about 0.2 mL/time point of each sample is collected, heparin sodium is anticoagulated, and the blood collection time points are as follows: pre-and post-dose 5, 15 and 30min, 1,2,4, 6, 8 and 24 h; blood samples were collected and placed on ice, plasma was centrifuged (centrifugation conditions: 8000 rpm, 6 min, 2-8 ℃) and collected plasma was stored at-80 ℃ before analysis. Plasma samples were analyzed by LC-MS/MS.
According to the data of the blood concentration of the drug, pharmacokinetic calculation software WinNonlin5.2 non-atrioventricular model is used for respectively calculating the pharmacokinetic parameters AUC of the test sample0-t、AUC0-∞、MRT0-∞、Cmax、Tmax、T1/2And VdIsoparametric and their mean and standard deviation.
In addition, the bioavailability (F) will be calculated by the following formula.
For samples with concentrations below the lower limit of quantitation, when pharmacokinetic parameter calculations are performed, C is reachedmaxThe previously sampled samples should be calculated to zero when C is reachedmaxSamples from later sampling points should be calculated as not quantifiable (BLQ).
Test example 5: EXAMPLES test of the Compounds for growth inhibition of MiaPaca-2, NCI-H358 tumor cells in nude mice transplanted tumors
To obtain vigorous growthStage tumor tissue was cut to 1.5mm3And left and right, under aseptic conditions, inoculated subcutaneously in the right axilla of nude mice. Measuring the diameter of the transplanted tumor by using a vernier caliper in the nude mouse subcutaneous transplanted tumor until the average tumor volume reaches 130mm3Animals were randomized into groups. The compound of the example (prepared to the required concentration with water for injection containing 1% Tween 80) was administered orally at the given dose daily for three weeks with the solvent control group given an equal amount of solvent. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week, while the body weight of the mice was weighed. The formula for Tumor Volume (TV) is: TV 1/2 × a × b2Wherein a and b represent length and width, respectively. Calculating Relative Tumor Volume (RTV) according to the measurement result, wherein the calculation formula is as follows: RTV is Vt/V0. Where V0 is the tumor volume measured at the time of caged administration (i.e., d0) and Vt is the tumor volume at each measurement. The evaluation index of the antitumor activity is 1) the relative tumor proliferation rate T/C (%), and the calculation formula is as follows:
T/C (%) (TRTV/CRTV) × 100%, TRTV: treatment group RTV; CRTV: negative control group RTV; 2) the tumor volume increase inhibition rate GI% is calculated according to the following formula: GI% ([ 1- (TVt-TV0)/(CVt-CT0) ] × 100%, TVt is the tumor volume per measurement in the treatment group; TV0 is the tumor volume obtained when therapeutic components were administered in cages; CVt is the tumor volume measured in each time in the control group; CV0 is the tumor volume obtained when the control component was administered in cages; 3) the tumor weight inhibition rate is calculated according to the following formula: tumor weight inhibition ratio (% Wc-WT)/Wc × 100%, Wc: tumor weight of control group, WT: the treated group had heavy tumor.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (7)
1. A nitrogen-containing polycyclic compound shown as a general formula I or pharmaceutically acceptable salt thereof,
in the formula:
r1 is independently selected from hydrogen;
r2, R3 are independently selected from hydrogen;
w, W1, W2 are independently selected from CR4 or N, R4 is independently selected from H or halogen;
m is independently selected from C (CN) or N;
ra, Rb, Rc, Rd, Re, Rf, Rg, Rh are each independently selected from hydrogen or C1-C6 alkyl.
Ar is independently selected from a 5-12 membered aromatic ring or a fused aromatic heterocycle, wherein the 5-12 membered fused aromatic heterocycle contains 1-3 heteroatoms independently selected from S or N; the 5-12 membered aromatic ring or aromatic fused heterocycle is further substituted with one or more of the following groups: halogen, hydroxy, methyl, amino;
x, Y, Z are each independently selected from CR5 or N, wherein R5 is independently selected from hydrogen, 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl group contains 1N atom, and the 4-8 membered heterocycloalkyl group may be further substituted with a C1-C6 alkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
r1 is selected from hydrogen;
ra, Rb, Rg, Rh are independently selected from hydrogen or methyl;
rc, Rd, Re, Rf are each independently selected from hydrogen;
w2 is CH; w1 is CR4, R4 is independently selected from F or Cl;
w is selected from N or C-F; (ii) a
R5 is selected from H;
ar is independently selected from phenyl, benzimidazolyl or benzothiazolyl substituted with one or more substituents; the one or more substituents are independently selected from halogen, hydroxy, methyl, amino.
3. A nitrogenous polycyclic compound or pharmaceutically acceptable salt thereof is characterized in that the compound is any one of the following compounds:
4. the use of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with a Ras protein mutation.
5. The use according to claim 4, wherein the disease is a tumor.
6. The use according to claim 5, wherein the tumor is selected from lung cancer, pancreatic cancer, liver cancer, colorectal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, melanoma, thyroid cancer or nasopharyngeal cancer.
7. A pharmaceutical composition, comprising:
(i) an effective amount of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof; and
(ii) a pharmaceutically acceptable carrier.
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