WO2022206684A1 - Série de composés de pyrazine contenant du sélénium et application associées - Google Patents

Série de composés de pyrazine contenant du sélénium et application associées Download PDF

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WO2022206684A1
WO2022206684A1 PCT/CN2022/083413 CN2022083413W WO2022206684A1 WO 2022206684 A1 WO2022206684 A1 WO 2022206684A1 CN 2022083413 W CN2022083413 W CN 2022083413W WO 2022206684 A1 WO2022206684 A1 WO 2022206684A1
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compound
pharmaceutically acceptable
acceptable salt
independently selected
optionally substituted
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PCT/CN2022/083413
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English (en)
Chinese (zh)
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陈新海
姜奋
胡国平
张丽
陈兆国
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202280025158.7A priority Critical patent/CN117083285A/zh
Publication of WO2022206684A1 publication Critical patent/WO2022206684A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table

Definitions

  • the present invention relates to a series of Se-containing pyrazine compounds and their applications, in particular to the compounds represented by formula (I) and their pharmaceutically acceptable salts.
  • Src homeodomain-2 phosphatase is a subtype of the SH2 domain-containing phosphatase family, encoded by the protein tyrosine phosphatase non-receptor 11 (PTPN11) gene.
  • SHP2 is a non-receptor tyrosine phosphatase that can catalyze the dephosphorylation of phosphorylated substrates (such as receptors, kinases, and phospholipids), thereby regulating downstream signaling. Excessive activation of SHP2 is closely related to the occurrence and development of various diseases.
  • activating mutations of SHP2 exist in about 50% of patients with Noonan syndrome (a type of autosomal-related genetic disease) and about 35% of patients with juvenile myelomonocytic leukemia (a type of rare leukemia).
  • SHP2 mutations are rarely found in solid tumors, but can activate SHP2 signaling through other pathways.
  • SHP2 is a common node of multiple activated RAS signaling pathways. Activation of RAS is very important for the growth and survival of cancer cells. Almost all receptor tyrosine kinases (RTKs) activate RAS signaling pathways by activating SHP2, and then mediate Oncogenic signaling pathways, such as PI3K/AKT, RAS/Raf/MAPK, etc.
  • RTKs receptor tyrosine kinases
  • SHP2 inhibitors can "catch all" tumors mediated by different RTKs, and have the potential to become broad-spectrum anticancer drugs.
  • SHP2 can also promote the formation of natural or acquired drug resistance in tumors, so SHP2 inhibitors can be combined with kinase inhibitors to dually inhibit related signaling pathways. This combination therapy is more effective than monotherapy, is less prone to resistance and reverses acquired resistance to RTK inhibitors.
  • PD-1 relies on the participation of SHP2 protein when it works, so SHP2 inhibitor can play a synergistic effect with PD-1 monoclonal antibody in vivo, thereby enhancing the anti-tumor effect of PD-1 monoclonal antibody. Therefore, SHP2 has become a popular target for the treatment of tumors and other related diseases.
  • SHP2 adopts an autoinhibited conformation in which the N-SH2 domain binds to the PTP domain, preventing substrate access to the active site.
  • the conformation of SHP2 changes, exposing the catalytically active site of the PTP domain, which initiates downstream signaling cascades. Based on this mechanism, inhibitors targeting the allosteric site of SHP2 were developed to inhibit its activity by locking the SHP2 protein in an inactive conformation.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from phenyl and 5-6 membered heteroaryl
  • R 1 and R 2 are each independently selected from H, -NR 6 R 7 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy being any is optionally substituted with 1, 2 or 3 Ra ;
  • R 3 is each independently selected from H, F, Cl, Br, I, -NR 6 R 7 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1- 3 alkoxy is optionally substituted with 1, 2 or 3 R b ;
  • R 4 and R 5 are each independently selected from OH, NH 2 and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R c ;
  • X 1 and X 2 are each independently selected from CH 2 and O;
  • X 3 is selected from CH and N;
  • R 6 and R 7 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R d ;
  • R 8 and R 9 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 and C 1-3 alkyl optionally replaced by 1 , 2 or 3 R e substitutions;
  • n, m and p are each independently selected from 0, 1, 2 and 3;
  • R a is each independently selected from H, OH, F, Cl, Br and I;
  • Rb , Rc , Rd and Re are each independently selected from H, F, Cl, Br and I.
  • the above-mentioned Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl and thienyl, and other variables are as defined herein .
  • the above-mentioned Ring A is selected from pyridyl, and other variables are as defined herein.
  • the above R 1 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH2OH and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , -CH2 OH and -OCH3 are optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
  • the above R 1 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 , the -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 are optionally replaced by 1, 2 or 3 R a substitutions, other variables are as defined in the present invention.
  • R 1 is selected from H, NH 2 and CH 3 , and other variables are as defined herein.
  • the above R 2 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH2OH and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , -CH2 OH and -OCH3 are optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
  • the above R 2 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 , the -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 are optionally replaced by 1, 2 or 3 R a substitutions, other variables are as defined in the present invention.
  • R 2 is selected from H and -CH 2 OH, and other variables are as defined herein.
  • the above R3 is selected from H, F, Cl , Br, I, NH2 , -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2 CH3 , CH( CH3 ) 2 and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 and -OCH 3 is optionally substituted with 1, 2 or 3 R b , other variables are as defined in the present invention.
  • R3 is selected from H, Cl and NH2 , and other variables are as defined herein.
  • R 4 is selected from NH 2 and CH 3 , and other variables are as defined herein.
  • R 5 is selected from NH 2 and CH 3 , and other variables are as defined herein.
  • each of the above R 6 and R 7 is independently selected from H, and other variables are as defined herein.
  • each of the above R 8 is independently selected from H, NH 2 and CH 3 , and other variables are as defined herein.
  • each of the above R 9s is independently selected from H and F, and other variables are as defined herein.
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 2 , R 3 and R 8 are as defined in the present invention.
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 8 is selected from F, Cl, Br, I, -OH, -NH 2 and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F; R 1 , R 2 and R3 are as defined in the present invention.
  • the present invention also provides the following compounds or their pharmaceutically acceptable salts,
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • the compounds of the present invention can significantly inhibit the SHP2 enzyme activity, and can also significantly inhibit the proliferation of NCI-H358 cells; meanwhile, the compounds of the present invention have good in vivo pharmacokinetic properties and exhibit excellent tumor-inhibiting effects.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
  • the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or exists in two forms of formula (B-1) and formula (B-2) exists as a mixture of isomers.
  • the following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2) exists in the form of a mixture.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • variable e.g. R
  • the variable e.g. R
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • Compounds are named according to conventional nomenclature in the art or are used Software naming, commercially available compounds use supplier catalog names.
  • Raw material 1-3 (5g, 18.26mmol, 1eq) was dissolved in dimethyl sulfoxide (50mL), selenium powder (5.91g, 73.02mmol, 4eq), potassium hydroxide (2.05g, 36.51mmol, 2eq) and selenium powder were added. Copper oxide (145.22 mg, 1.83 mmol, 0.1 eq) was stirred under nitrogen protection at 90°C for 2 hours. The reaction solution was cooled to room temperature.
  • reaction solution was cooled to room temperature, and the crude product was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; B (acetonitrile)% : 15%-38%, 5 min) to obtain compound 1.
  • the raw material 2-1 (2g, 7.77mmol, 1eq) was dissolved in N-methylpyrrolidone (20mL), ammonia water (18.20g, 145.39mmol, 20mL, 28% purity, 18.71eq) was added, and stirred at 100°C 16 hours.
  • the reaction solution was cooled to room temperature.
  • Methyl tert-butyl ether 50 mL*3 was added to the reaction solution for extraction, the organic phases were combined, washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the reaction solution was cooled to room temperature, ethyl acetate (10 mL) and water (10 mL) were added to dilute the reaction solution, filtered, the filter cake was washed with ethyl acetate (10 mL*3), the filtrate was collected, separated, the organic phase was collected and saturated with Washed with brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Compound 2-2 (10g, 39.30mmol, 1.20mL, 1eq) was dissolved in dimethyl sulfoxide (100mL), selenium powder (12.73g, 157.20mmol, 12.48mL, 4eq), potassium hydroxide (6.62g, 117.90 mmol, 3 eq) and copper oxide (1.56 g, 19.65 mmol, 247.33 ⁇ L, 0.5 eq), replaced with nitrogen three times, and stirred at 90° C. for 12 hours.
  • reaction solution was cooled to room temperature, quenched by adding water (10 mL), extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, washed with saturated aqueous sodium sulfite solution (10 mL ⁇ 2), saturated brine ( 10 mL ⁇ 2) washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product.
  • reaction solution was heated to 0°C, quenched by adding saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), and the organic phases were combined and washed with saturated brine (10 mL ⁇ 2). , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product.
  • reaction solution was cooled to room temperature, filtered, ethyl acetate (10 mL) and water (10 mL) were added to the filtrate, the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2), and the organic phases were combined, Washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product.
  • Compound 5 was separated by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; gradient: B%: 60%-60%) to obtain compound 5a and compound 5b.
  • SFC separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; gradient: B%: 60%-60%) to obtain compound 5a and compound 5b.
  • reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (5 mL ⁇ 2), the organic phases were combined, washed with water (5 mL ⁇ 2), saturated brine (5 mL), and anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product.
  • Compound 7 was resolved by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; gradient: B %: 60%-60%) to obtain compound 7a (impure) and compound 7b.
  • Compound 7a (impure, SFC analysis conditions: Column: Cellulose 2 100 x 4.6 mm ID, 3 ⁇ m, Mobile phase: Phase A: CO 2 , Phase B: Ethanol (0.05% diethylamine); Gradient: B%: 60 %; flow rate: 2.8mL/min, retention time is 2.540min) and then prepared, separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 80*40mm*3 ⁇ m; mobile phase: [water (0.05% ammonia water)-acetonitrile]; Acetonitrile %: 27%-57%) to give compound 7a.
  • chromatographic column: Phenomenex C18 80*40mm*3 ⁇ m; mobile phase: [water (0.05% ammonia water)-acetonitrile]; Acetonitrile %: 27%-57%) to give compound 7a.
  • 1-fold buffer preparation (for current use): Dilute 5-fold buffer with deionized water to 1-fold buffer, and place on ice for later use.
  • the compounds to be tested were diluted with 100% DMSO to 100 ⁇ M as the first concentration, and then 4-fold diluted to the eighth concentration with a drain gun, ie, from 100 ⁇ M to 6.1 nM.
  • Each compound to be tested was diluted with 1-fold buffer into a working solution with 10% DMSO, and 5 ⁇ L/well was added to the corresponding well to set up a double-well experiment. Centrifuge at 1000 rpm for 1 minute.
  • Compound background reading detection Take 5 ⁇ L of each compound to be tested diluted in 100% DMSO into a new compound plate, add 45 ⁇ L of 1-fold buffer for 10-fold dilution, prepare a working solution of 10% DMSO, and then take the compound 5 ⁇ L/well of working solution was added to the detection plate, and then 45 ⁇ L of 1-fold buffer was added for 10-fold dilution. At this time, the final concentration of DMSO was 1%, 1000 rpm/min. Wavelength: 360nm, test wavelength: 460nm.
  • Table 1 shows the inhibitory results of the compounds of the present invention on SHP2 enzymatic activity.
  • NCI-H358 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 4000 NCI-H358 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 5-fold to the ninth concentration, that is, from 2000 ⁇ M to 5.12 nM, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.026 nM. The cell plates were placed in a carbon dioxide incubator for 5 days.
  • Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • Table 2 shows the results of the inhibitory activity of the compounds of the present invention on the proliferation of NCI-H358 cells.
  • test compound was dissolved in 5% DMSO+95% (10% hydroxypropyl- ⁇ -cyclodextrin aqueous solution), vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use.
  • Balb/c male mice of 17 to 20 grams were selected, and the candidate compound solution was administered intravenously or orally at a dose of 1 or 2 mg/kg, respectively.
  • Whole blood was collected at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, and plasma was prepared.
  • the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.3.
  • Table 3 The test results are shown in Table 3:
  • C max maximum drug concentration
  • T 1/2 half-life
  • V dss apparent volume of distribution
  • Cl drug clearance rate
  • AUC 0-last plasma concentration-time curve from 0 to the last time point Area under
  • AUCo -inf area under the plasma concentration-time curve from 0 to infinity
  • F bioavailability
  • "--" means not tested or data not obtained.
  • the compound of the present invention has good pharmacokinetic properties in mice.
  • mice To study the in vivo efficacy of the compounds of the present invention in the subcutaneous xenograft tumor model of human non-small cell lung cancer NCI-H358 cells BALB/c nude mice
  • mice Female BALB/c nude mice, 6-8 weeks old, weighing 18-22 grams, supplier: Laboratory Animal Management Department, Shanghai Institute of Family Planning Science
  • NCI-H358 cells Human non-small cell lung cancer NCI-H358 cells were cultured in monolayer in vitro, and the culture conditions were Gibco RMPI1640 medium plus 10% fetal bovine serum, 37°C, 5% CO 2 incubator. Conventional digestion with trypsin-EDTA was performed twice a week for passage. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and seeded.
  • 0.2mL (1 ⁇ 10 7 cells) of NCI-H358 cells were subcutaneously inoculated into the right back of each mouse, and the group administration started when the average tumor volume reached about 138 mm 3 (Vehicle control group and compound group).
  • the vehicle was 5% DMSO + 95% (10% hydroxypropyl-beta-cyclodextrin in water).
  • Tumor diameters were measured twice a week with a caliper, and tumor volume (V) and tumor growth inhibition (TGI) were calculated.
  • V tumor volume
  • TGI tumor growth inhibition
  • Table 4 Tumor inhibition results of compounds of the present invention on NCI-H358 cell BALB/c nude mice subcutaneous xenograft tumor model
  • the compounds of the present invention exhibit excellent tumor-inhibiting effect in the subcutaneous xenograft tumor model of human non-small cell lung cancer NCI-H358 cells BALB/c nude mice.

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Abstract

L'invention concerne une série de composés de pyrazine contenant du Se et une application associée. L'invention concerne plus précisément un composé représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2022/083413 2021-03-31 2022-03-28 Série de composés de pyrazine contenant du sélénium et application associées WO2022206684A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105916845A (zh) * 2014-01-17 2016-08-31 诺华股份有限公司 用于抑制shp2活性的n-氮杂螺环烷取代的n-杂芳基化合物和组合物
CN109983001A (zh) * 2016-07-12 2019-07-05 锐新医药公司 作为变构shp2抑制剂的2,5-双取代型3-甲基吡嗪及2,5,6-三取代型3-甲基吡嗪
WO2020061101A1 (fr) * 2018-09-18 2020-03-26 Nikang Therapeutics, Inc. Dérivés hétéroaryles tri-substitués utilisés en tant qu'inhibiteurs de la phosphatase src à homologie-2
WO2020063760A1 (fr) * 2018-09-26 2020-04-02 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2
WO2020073949A1 (fr) * 2018-10-10 2020-04-16 江苏豪森药业集团有限公司 Régulateur de dérivés hétéroaromatiques contenant de l'azote, procédé de préparation associé et utilisation correspondante
WO2020201991A1 (fr) * 2019-04-02 2020-10-08 Array Biopharma Inc. Inhibiteurs de protéine tyrosine phosphatase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105916845A (zh) * 2014-01-17 2016-08-31 诺华股份有限公司 用于抑制shp2活性的n-氮杂螺环烷取代的n-杂芳基化合物和组合物
CN109983001A (zh) * 2016-07-12 2019-07-05 锐新医药公司 作为变构shp2抑制剂的2,5-双取代型3-甲基吡嗪及2,5,6-三取代型3-甲基吡嗪
WO2020061101A1 (fr) * 2018-09-18 2020-03-26 Nikang Therapeutics, Inc. Dérivés hétéroaryles tri-substitués utilisés en tant qu'inhibiteurs de la phosphatase src à homologie-2
WO2020063760A1 (fr) * 2018-09-26 2020-04-02 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2
WO2020073949A1 (fr) * 2018-10-10 2020-04-16 江苏豪森药业集团有限公司 Régulateur de dérivés hétéroaromatiques contenant de l'azote, procédé de préparation associé et utilisation correspondante
WO2020201991A1 (fr) * 2019-04-02 2020-10-08 Array Biopharma Inc. Inhibiteurs de protéine tyrosine phosphatase

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