WO2023046114A1 - Dérivé de ptéridinone et son utilisation - Google Patents

Dérivé de ptéridinone et son utilisation Download PDF

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WO2023046114A1
WO2023046114A1 PCT/CN2022/121058 CN2022121058W WO2023046114A1 WO 2023046114 A1 WO2023046114 A1 WO 2023046114A1 CN 2022121058 W CN2022121058 W CN 2022121058W WO 2023046114 A1 WO2023046114 A1 WO 2023046114A1
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substituted
unsubstituted
cancer
compound
egfr
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PCT/CN2022/121058
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Chinese (zh)
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李洪林
赵振江
陈卓
徐玉芳
王操林
沙文婕
钱旭红
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华东理工大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic

Definitions

  • the invention belongs to the field of medicinal chemistry; in particular, the invention relates to a compound targeting EGFR mutant protein, a preparation method thereof, and an application in treating EGFR-mediated diseases, such as tumors.
  • EGFR plays an important role in the formation and development of various cancers, so the EGFR tyrosine kinase target has become the preferred target for cancer targeted therapy, especially for non-small cell lung cancer.
  • small molecule inhibitors targeting EGFR have made good clinical progress, such as the first-generation reversible inhibitors gefitinib and erlotinib, the second-generation irreversible afatinib and Daco Tini and the third dioxitinib that has the activity of overcoming the acquired resistance mutation EGFR T790M mutation. But not all patients with EGFR mutations benefit.
  • NSCLC with EGFR exon 20 insertion mutation (EGFR 20ins) has poor or ineffective response to most EGFR inhibitor targeted therapies, and these mutations are often classified as non-classic mutations.
  • These non-canonical mutations mainly include insertion mutations and point mutations of exons 18-21, point mutations and insertion mutations of ERBB2.
  • the object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof that targets and inhibits non-classical mutant EGFR.
  • the compound should have excellent antitumor activity.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
  • R 1 is independently selected from hydrogen, substituted or unsubstituted C 1 -C 10 alkyl , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, Optionally substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic heterocyclic group;
  • R 2 , R 3 , R 4 , R 5 are independently selected from H, halogen, substituted (preferably halogen substituted, more preferably fluorine substituted) or unsubstituted C 1 -C 6 (preferably C 1 -C 3 ) alkoxy or Substituted (preferably halogen substituted, more preferably fluorine substituted) or unsubstituted C 1 -C 6 (preferably C 1 -C 3 ) deuterated alkoxy, substituted or unsubstituted C 1 -C 6 (preferably C 1 -C 3 ) Alkyl, NRcRd ; wherein Rc and Rd are each independently selected from hydrogen , C1-3 alkyl;
  • G is a benzene ring, a five-membered or six-membered heterocyclic ring or a C 3 -C 8 cycloalkyl group or does not exist;
  • R 6 is independently selected from hydrogen, unsubstituted or halogen-substituted C 1 -C 4 alkyl, nitro, amino, halogen, hydroxyl, C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 acyl Oxygen, optionally substituted C 1 -C 6 amido, optionally substituted C 1 -C 6 acyl; wherein, when G is a benzene ring, R 6 is meta-substituted;
  • n is an integer of 0-3;
  • R 7 is independently selected from substituted or unsubstituted NH 2 , substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted C 1 -C 10 alkyl;
  • A is selected from the following group or is absent:
  • L is selected from the following group or absent: C 1 -C 10 alkylene, C 1 -C 10 heteroalkylene, -A'-(CH 2 ) m' -W-(CH 2 ) n' -, - (CH 2 ) m' -W-(CH 2 ) n' -O-(CH 2 ) V -and-(CH 2 ) m' -W-[(CH 2 ) n' -O] u -(CH 2 ) v -;
  • A' is selected from the following group or does not exist: 5-membered arylene and 6-membered arylene;
  • W is selected from: phenylene, 5-membered heteroarylene, 6-membered heteroarylene, C 1 -C 10 heterocyclylene and C 1 -C 10 alkylene;
  • n' 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • n' is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • each independent u is independently 2, 3 or 4;
  • v 1, 2, 3 or 4
  • B is selected from the following group or absent:
  • R is selected from: hydrogen, methyl and fluorine
  • the compound is a compound shown in the following formula II:
  • R 7 is independently selected from: H, substituted (preferably halogen substituted, more preferably fluorine substituted) or unsubstituted C 1 -C 6 (preferably C 1 -C 3 ) alkyl, substituted (preferably halogen substituted, more preferably fluorine substituted) or unsubstituted C 1 -C 6 (preferably C 1 -C 3 ) deuterated alkyl;
  • R 8 is independently selected from: H, substituted (preferably halogen substituted, more preferably fluorine substituted) or unsubstituted C 1 -C 3 alkyl, substituted (preferably halogen substituted, more preferably fluorine substituted) or unsubstituted C 1 -C 3 deuterated alkyl.
  • R 7 is independently selected from: methyl, deuteromethyl CD 3 , trifluoromethyl, ethyl, deuteroethyl (eg, CD 2 CH 3 , CH 2 CD 3 ), CH 2 CF 3 ;
  • R 8 is independently selected from: hydrogen, methyl, deuteromethyl CD 3 , ethyl, deuteroethyl (eg, CD 2 CH 3 , CH 2 CD 3 ).
  • the compound is selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof and optionally pharmaceutically acceptable excipients.
  • the present invention provides the compound described in the first aspect, or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug in the preparation of prevention or treatment of abnormal expression of EGFR protein activity, ERBB2 overexpression Use in medicine for diseases related to point mutations thereof.
  • said EGFR is mutant EGFR.
  • the mutant EGFR includes at least one of the following mutations: EGFR sensitivity mutation L858R and 19del, EGFR T790M mutation, EGFR 18-21 exon point mutation and insertion mutation, ERBB2 overexpression and point mutation Mutations and insertional mutations.
  • the EGFR 18-21 exon point mutation and insertion mutation contain:
  • Insertion mutations and point mutations in exon 20 include: A763-Y764insFQEA, A763-Y764insFHEA, V769-D770insASV, V769-D770insDNP, D770-N771insNPG, D770-N771insNPH, D770-N771insSVD, D770-N771insP7insASVDN, D771SVG-N7 ⁇ N771-H773dupNPH ⁇ P772-H773insPNP ⁇ P772-H773insPR ⁇ H773-V774insH ⁇ A763-Y764insFQEA ⁇ H773-V774insPH ⁇ H773-V774insNPH ⁇ N771-P772insH ⁇ H771-P772insN ⁇ H773-V774insAH ⁇ D770delinsGY ⁇ V774-C775ins
  • the disease is cancer and is selected from one or more of the following: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer Carcinoma, glioma, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, colon cancer, skin cancer, leukemia, lymphoma, stomach cancer or multiple myeloma.
  • the present invention provides a method for preventing or treating diseases related to abnormal expression of EGFR protein activity, ERBB2 overexpression and point mutations thereof, the method comprising treating a therapeutically effective amount of the compound described in the first aspect, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or the pharmaceutical composition described in the second aspect to a subject in need thereof.
  • said subject is a mammal, preferably a human.
  • the EGFR is a mutant EGFR.
  • the mutant EGFR includes at least one of the following mutations: EGFR sensitivity mutation L858R and 19del, EGFR T790M mutation, EGFR 18-21 exon point mutation and insertion mutation, ERBB2 overexpression and point mutation Mutations and insertional mutations.
  • the EGFR 18-21 exon point mutation and insertion mutation contain:
  • Insertion mutations and point mutations in exon 20 include: A763-Y764insFQEA, A763-Y764insFHEA, V769-D770insASV, V769-D770insDNP, D770-N771insNPG, D770-N771insNPH, D770-N771insSVD, D770-N771insP7insASVDN, D771SVG-N7 ⁇ N771-H773dupNPH ⁇ P772-H773insPNP ⁇ P772-H773insPR ⁇ H773-V774insH ⁇ A763-Y764insFQEA ⁇ H773-V774insPH ⁇ H773-V774insNPH ⁇ N771-P772insH ⁇ H771-P772insN ⁇ H773-V774insAH ⁇ D770delinsGY ⁇ V774-C775ins
  • the disease is cancer and is selected from one or more of the following: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, pancreatic cancer, prostate cancer, ovarian Carcinoma, glioma, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, colon cancer, skin cancer, leukemia, lymphoma, stomach cancer or multiple myeloma.
  • Figure 1 shows the in vivo drug efficacy (EGFR L858R/T790M xenograft tumor) activity of compound 2 and compound 3;
  • Figure 2 shows the in vivo drug effect (EGFR L858R/T790M xenograft tumor) activity of compound 5;
  • Figure 3 shows the drug-time curves of compounds 0, 1, 2, 3, 4, 5 in SD rat plasma.
  • alkyl refers to a saturated branched or linear alkyl group with a carbon chain length of 1-10 carbon atoms
  • preferred alkyl groups include 2-8 carbon atoms, 1-6, 1-4 carbon atoms, alkyl groups ranging from 1 to 3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isoisoyl, heptyl, and the like.
  • Alkyl groups may be substituted by one or more substituents, such as halogen or haloalkyl.
  • the alkyl group may be an alkyl group substituted with 1-4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.
  • alkoxy refers to an oxy group substituted with an alkyl group.
  • Preferred alkoxy groups are those with a length of 1 to 6 carbon atoms, more preferably those with a length of 1 to 3 carbon atoms. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
  • Alkoxy may be substituted by one or more substituents, such as halogen or haloalkyl.
  • an alkoxy group can be an alkyl group substituted with 1-4 fluorine atoms, or an alkyl group can be an alkyl group substituted with a fluoroalkyl group.
  • alkenyl generally means a monovalent hydrocarbon group having at least one double bond, usually containing 2 to 8 carbon atoms, preferably containing 2 to 6 carbon atoms, and may be straight or branched.
  • alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • acylamino refers to a group with the structural formula "-R'-NH-C(O)-R", wherein R' can be selected from hydrogen or alkyl, and R can be selected from alkyl, alkenyl , alkynyl, alkyl substituted by NRcRd, alkenyl substituted by NRcRd and alkynyl substituted by NRcRd, alkyl substituted by halogen, alkenyl substituted by cyano, wherein Rc and Rd can be selected from alkyl group and alkenyl group.
  • aryl refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, fenyl, tetralin base, indanyl, etc.
  • Aryl may be optionally substituted with 1-5 (eg, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C1-4 aldehyde, C1-6 alkyl, cyano, Nitro, amino, amido, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1-4 alkoxy , ethoxy formyl, N(CH3) and C1-4 acyl, etc., heterocyclyl or heteroaryl, etc.
  • 1-5 eg, 1, 2, 3, 4 or 5
  • substituents selected from the group consisting of halogen, C1-4 aldehyde, C1-6 alkyl, cyano, Nitro, amino, amido, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1-4 alkoxy
  • heterocyclic group includes, but is not limited to, 5-membered or 6-membered heterocyclic groups containing 1-3 heteroatoms selected from O, S or N, including but not limited to furyl, thienyl, pyrrolyl , pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl, etc.
  • aromatic heterocyclic group refers to a group containing 5-14 ring atoms, and 6, 10 or 14 electrons are shared on the ring system. And the contained ring atoms are carbon atoms and optional 1-3 heteroatoms selected from oxygen, nitrogen and sulfur.
  • Useful aromatic heterocyclic groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to Yu pyrimidinyl and so on.
  • the aromatic heterocyclic group can be optionally substituted by 1-5 (for example, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C1-4 aldehyde, C1-6 straight chain or branched Alkanyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1- 4 alkoxy, ethoxy formyl, N(CH3) and C1-4 acyl.
  • 1-5 for example, 1, 2, 3, 4 or 5
  • substituents selected from the group consisting of halogen, C1-4 aldehyde, C1-6 straight chain or branched Alkanyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1- 4 alk
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • substituents selected from the group consisting of halogen, C1 -4 aldehyde, C1-6 straight chain or branched alkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, halogen substituted alkyl (such as trifluoromethyl), halogen substituted alkoxy ( Examples include trifluoromethoxy), carboxy, C1-4 alkoxy, ethoxyformyl, N(CH3) and C1-4 acyl.
  • 1-5 eg, 1, 2, 3, 4 or 5
  • substituents selected from the group consisting of halogen, C1 -4 aldehyde, C1-6 straight chain or branched alkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, halogen substituted alkyl (such as trifluoromethyl), halogen substituted alkoxy ( Examples include trifluoromethoxy), carboxy, C1-4 alkoxy, ethoxyformyl, N(CH3) and C1-4 acyl.
  • the compound of the present invention refers to a compound represented by the following general formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
  • the present invention provides a compound represented by formula II, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
  • the present invention provides the following compounds capable of inhibiting EGFR activity, and these compounds have significant inhibitory activity on mutant EGFR (L858R/T790M, 20ins):
  • each group in the compound of the present invention can be further substituted, so as to obtain derivatives that can have the same or similar activity as the compound disclosed in the present invention. things.
  • Each group in the compound of the present invention can be substituted by various conventional substituents in the art, as long as the substitution does not violate the rules of chemical synthesis or valence.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • the specific substituents may be correspondingly described substituents above, specific substituents appearing in each embodiment or conventional substituents in the art. Therefore, in the present invention, the substituents in the general formula can also be independently the corresponding groups in the specific compounds in the examples; Combinations of some of the substituents shown in and other specific substituents appearing in the examples. It is not difficult for those skilled in the art to prepare a compound having such a combination of substituents and to detect whether the obtained compound is active based on conventional technical means in this field.
  • pharmaceutically acceptable salt refers to a salt formed of a compound of the present invention with an acid or a base which is suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid,
  • the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereoisomers and geometric isomers (or conformational isomers)): for example, containing asymmetric The R, S configuration of the center, the (Z), (E) isomer of the double bond, etc. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers or geometric isomers (or conformers) are within the scope of the present invention.
  • tautomer means that structural isomers with different energies can cross a low energy barrier and thereby interconvert.
  • proton tautomers ie, prototropism
  • Valence tautomers include interconversion by recombination of some of the bonding electrons.
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • hydrate refers to a complex formed by coordination between the compound of the present invention and water.
  • the compound of the present invention can obviously be used as a medicine. Therefore, in addition to the various properties that have been examined in the Examples, the compounds of the present invention can also possess various activities inherent as drugs. For example, in vivo activity, bioavailability, druggability, toxicity, differential inhibitory activity, etc.
  • drugs for example, in vivo activity, bioavailability, druggability, toxicity, differential inhibitory activity, etc.
  • those skilled in the art know how to obtain various compounds within the scope of the present invention and detect various activities of various compounds within the scope of the present invention; in other words, based on the teachings of the present invention With conventional technical means in the field, those skilled in the art know how to repeat, verify and implement the present invention.
  • compositions and methods of administration are provided.
  • the compounds of the present invention have targeted inhibition of non-classical mutant EGFR, especially for mutant EGFR
  • the pharmaceutical composition of active ingredients can be used to prevent and/or treat diseases related to abnormal expression of EGFR protein activity, ERBB2 overexpression and point mutations thereof.
  • said EGFR is mutant EGFR.
  • the mutant EGFR includes at least one of the following mutations: EGFR sensitivity mutations L858R and 19del, EGFR T790M mutation, EGFR exon 18-21 point mutation and insertion mutation, ERBB2 point mutation and insertion mutation.
  • the EGFR exon 18-21 point mutation and insertion mutation include: exon 18 G719X, E709X, K716A, K728A point mutation and codon 709 deletion mutation; exon 19 insertion mutation I744 -K745insKIPVAI, K745-E746insIPVAIK, K745-E746insVPVAIK, K745-E746insTPVAIK and point mutation D761Y; exon 20 insertion mutation and point mutation include: A763-Y764insFQEA, A763-Y764insFHEA, V769-D770insASV, V710insNPD-ND777 D770-N771insNPH ⁇ D770-N771insSVD ⁇ D770-N771insASVDN ⁇ D770-N771insG ⁇ N771-P772insSVDNP ⁇ N771-H773dupNPH ⁇ P772-
  • the disease is cancer, for example, one or more selected from the following: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, pancreatic cancer, prostate cancer, Ovarian cancer, glioma, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, colon cancer, skin cancer, leukemia, lymphoma, stomach cancer, or multiple myeloma.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention and pharmaceutically acceptable excipients or carriers in a safe and effective amount range.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds.
  • One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with the compound of the present invention.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 20-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the compound of the present invention has the activity of inhibiting EGFR protein, especially mutant EGFR (L858R/T790M, 20ins). Therefore, the compound of the present invention can be used for the treatment of diseases related to abnormal expression of EGFR protein, such as various cancers.
  • the compounds of the present invention have excellent pharmacokinetic properties
  • the compound of the present invention has excellent antitumor activity and antitumor activity, so it has great application prospects in the field of medicine.
  • reaction mixture was spin-dried, extracted with ethyl acetate, washed three times with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and recrystallized from petroleum ether to obtain a yellow solid (16.30 g, 87.00%).
  • reaction mixture was spin-dried, extracted with dichloromethane, washed three times with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. Methanol was recrystallized to obtain a reddish-brown solid.
  • N-(3-((2-((2-(methoxy-d 3 )-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-nitropyrimidine-4 -yl)amino)phenyl)acrylamide (1.18g, 2.33mmol), iron powder (0.50g, 9.32mmol), ammonium chloride (0.62g, 11.65mmol) and ethanol:water (8mL, 4:1) mixed In a 100mL single-necked bottle, stir at 80°C for 24h.
  • reaction mixture was suction-filtered, the filtrate was adjusted to alkali, extracted with ethyl acetate, washed three times with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a purple-black solid (0.45 g, 36.00%).
  • Embodiment 2 N-(3-(2-((2-methoxy-4-(piperazin-1-yl) phenyl) amino)-7-oxo-6-phenylpteridine-8( Synthesis of 7H)-yl)phenyl)acrylamide (intermediate)
  • N-(3-nitrophenyl)acrylamide (5g, 26.1mmol) in a 250mL round bottom flask, add solvent 150mL ethanol to dissolve, 20ml water, then add iron powder (5.8g, 104.4mmol), chlorination Ammonium (6.7g, 130.5mmol) was reacted with stirring at 80°C, followed by TLC, and the reaction was completed after 3h.
  • the reaction solution was filtered with diatomaceous earth, the filtrate was rotary evaporated, and the residue was extracted with EA and 20ml 20% NaOH water, repeated three times. Several layers were combined and evaporated under reduced pressure to obtain 3.5 g of a light green solid with a yield of about 83%. The product was directly used in the next step without purification.
  • reaction solution was filtered with diatomaceous earth, the filtrate was rotary evaporated, and the residue was extracted with EA and 10ml 20% NaOH water, repeated three times. There were several layers combined, and the vacuum rotary After steaming, 0.92 g of a light green solid was obtained, with a yield of about 61%.
  • the product was directly used in the next step without purification.
  • Salts of other compounds were also obtained in a similar manner.
  • reaction mixture was spin-dried, extracted with ethyl acetate, washed three times with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and recrystallized from petroleum ether to obtain a yellow solid (19.60 g, 87.00%).
  • reaction mixture was suction-filtered, the filtrate was adjusted to alkali, extracted with ethyl acetate, washed three times with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a purple-black solid (0.47 g, 36.00%).
  • reaction mixture was spin-dried, extracted with dichloromethane, washed with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow pure product (2.2 g, 90.2%).
  • tert-butyl 4-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)piperazine-1-carboxylate (1.52g, 3.76mmol), 10% palladium on carbon ( 0.39g, 0.38mmol) and ethanol (8.00mL) were mixed in a 100mL three-neck flask, protected by hydrogen, and stirred at 80°C for 24h.
  • reaction mixture was spin-dried, extracted with dichloromethane, washed three times with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. An aqueous methanol solution was recrystallized to obtain a reddish-brown solid (0.70 g, 50.72%).
  • reaction mixture was suction-filtered, the filtrate was adjusted to alkali, extracted with ethyl acetate, washed 3 times with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a dark brown solid (0.56 g, 75.75%).
  • reaction mixture was spin-dried, extracted with dichloromethane, washed three times with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. Recrystallized from methanol: water to obtain a reddish-brown solid (0.70 g, 50.72%).
  • reaction mixture was filtered with suction, the filtrate was adjusted to alkali, extracted with ethyl acetate, washed with saturated aqueous sodium chloride three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a dark brown solid (0.50 g, 75.75%).
  • EGFR-TK can catalyze the transfer of a phosphate group of adenosine triphosphate (ATP) to the polypeptide substrate poly(Glu,Tyr) 4:1 , and the polypeptide substrate is labeled with two fluorescent groups coumarin ( coumarin) and fluorescein.
  • FRET fluorescence resonance energy transfer
  • EGFR-TK catalyzes the reaction of ATP to cause two fluorescent groups to approach, the donor (coumarin) is excited at 400nM, part of the energy is released, the emission wavelength is 445nM, and the other part of the energy is transferred To fluorescein, the emission wavelength is 520nM.
  • Different compounds have different degrees of inhibition of EGFR-TK, resulting in different degrees of substrate phosphorylation, so the inhibition rate of different compounds is calculated by measuring the ratio of the enzyme-catalyzed substrate phosphorylation percentage.
  • Concentrations of different kinases were determined by optimization experiments and compounds were diluted three-fold from 5.1x10 -9 M to 1x l0 -4 M in DMSO. 4 ⁇ L of compound was dissolved in 96 ⁇ L of water to obtain a 4x compound solution. 40 ⁇ M ATP is dissolved in 1.33x Kinase Buffer, the Kinase/Peptide Mix contains 2x Kinase, 4 ⁇ M Acetine 4-Peptide is ready for use.
  • a 10 ⁇ L kinase reaction consists of 2.5 ⁇ L compound solution, 5 ⁇ L kinase/peptide mix, 2.5 ⁇ L ATP solution.
  • H1975 (EGFR L858R/T790M ) cells were obtained from ATCC. Cell proliferation activity was assessed by MTS assay. The cells were exposed to the treatment conditions for 72 hours, and the number of cells used in each experiment of each cell line was adjusted according to the absorbance value (absorbance value at 490 nm was 1.3-2.2). Six concentration gradients (0.1 nM-10 ⁇ M) were set up for the compounds to be tested, and at least six groups of parallel controls were used for each concentration value.
  • H1975 cells were cultured in the corresponding medium, and the cells were passaged at least twice after recovery, and then used in experiments. Cells in log phase are trypsinized and resuspended in medium. H1975 (1000 cells per well) were seeded in a 96-well plate with a volume of 100 ⁇ L; 6 parallel groups and 7 columns were set up. The orifice plate was placed in an incubator with 5% carbon dioxide at 37°C overnight.
  • the compounds were dissolved in DMSO to prepare a concentration of 10 ⁇ M per liter, and then the compound concentrations were gradually diluted to obtain compound concentrations of 10 ⁇ M, 1 ⁇ M, 0.1 ⁇ M, 0.01 ⁇ M, 0.001 ⁇ M, and 0.0001 ⁇ M per liter, respectively.
  • 2 ⁇ L of compound solution was added to 998 ⁇ L of culture medium, and the mixture was mixed well. 100 ⁇ L of the mixture was added to a 96-well plate. 2 ⁇ L of DMSO was used instead of the compound solution as a 0% inhibition control. After culturing for 68 hours, 20 ⁇ L of MTT (5 mg/mL) was added.
  • the IC 50 (nM) of the deuterated compounds of the present invention for inhibiting EGFR L858R/T790M at the kinase level is between 1.0-1.5, which is similar to that of non-deuterated compounds. It shows that the deuterated derivatives do not affect the interaction between the inhibitor and the kinase. However, compound 4 and compound 5 substituted by trifluoroethoxy group will reduce the kinase inhibitory activity by about 1 times, and it is understandable that the introduction of a larger group will lead to a decrease in the interaction between the two.
  • the inhibitory activity of the compounds of the present invention on H1975 cells is not regular, which is related to the changes in the physical and chemical properties and metabolic properties of the derivatives, and there are many factors.
  • the cellular activity of deuterated compounds was similar to that of non-deuterated compounds.
  • the compounds of the present invention have excellent inhibitory activity on kinases with rare EGFR mutations and 20ins insertion mutations, which is better than the 20ins insertion mutation-positive drug TAK788 that will be launched in 2021.
  • compound 2 performed best and had good application prospects.
  • H1975 cells were transferred from Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
  • the condition of the cell culture medium is 1640+10% FBS (Gibco)
  • the condition of the incubator is a constant temperature carbon dioxide incubator at 37°C
  • the concentration of carbon dioxide is 5%
  • the cells are changed and passaged once every 2-3 days, and the culture is continuously expanded.
  • the cells were digested with trypsin for 4 min, and then the digestion was terminated with medium.
  • Collect the obtained cells centrifuge at 1000r/min for 3min, remove the supernatant, wash twice with serum-free 1640, the cell viability should be maintained above 95% before transplantation, and use serum-free 1640 as a solvent to suspend the cells, the concentration of the suspended cells is 20 million/mL, put the prepared cell suspension on ice for use, in order to maintain cell viability, the cell suspension should be inoculated within 0.5-1h.
  • mice Seventy-two male BALB/c nude mice, 4-5 weeks old, weighing 17-23g, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. Cell inoculation was carried out after 2-3 days of adaptation to the animal room environment. Select the rich capillaries on the upper side of the forelimb of nude mice to inject the cell suspension subcutaneously, and the volume of the cell suspension injected per mouse is 0.1 mL.
  • the transplanted tumors can be seen in about 1-2 weeks.
  • the average size of the tumors reaches 100-200mm 3 , they are randomly divided into groups, with 8 mice in each group, so that the tumor volume in each group is basically the same.
  • it can be administered, and the administration is carried out according to the administration compound, administration dose and administration method of each group. After that, it was administered every day, and the tumor volume and mouse body weight were recorded once every 2 days.
  • the same amount of solvent (0.1 mL) was given to the solvent control.
  • the tumor volume and weight of mice need to be recorded before administration. Data were plotted using GraphPad Prism version 4.0. During the whole experiment, the diameter of the transplanted tumor was measured every other day, and the body weight of the mice was weighed at the same time.
  • V0 is the tumor volume measured at the time of cage administration (ie, d0)
  • Vt is the tumor volume at each measurement.
  • Example 11 Inhibitory activity of compounds on cells with high expression of Her2: breast cancer cell SKBR3, lung cancer cell H2170, gastric cancer cell N87
  • Breast cancer cells SKBR3, lung cancer cells H2170, and gastric cancer cells N87 were obtained from the Cell Bank of the Chinese Academy of Sciences. Cell proliferation activity was assessed using a CCK8 assay. Cells were exposed to the treatment conditions for 72 hours, and the number of cells used in each experiment for each cell line was adjusted according to the absorbance value (absorbance value at 450 nm was 1-1.2). Eight concentration gradients (0.1 nM-10 ⁇ M) were set up for the compounds to be tested, and at least six groups of parallel controls were used for each concentration value.
  • the cells were cultured in the corresponding medium, and the cells were subcultured at least twice after thawing, and the cell growth was in the logarithmic growth phase, and then used for the experiment.
  • 3,000 SKBR3 cells/well, 6,000/well H2170 cells, and 9,000/well N87 cells were spread in a 96-well plate with a volume of 90 ⁇ L; 6 parallel groups and 7 columns were set up.
  • the orifice plate was placed in an incubator with 5% carbon dioxide at 37°C overnight.
  • Dissolve the compound in DMSO For the SKBR3 cell line, prepare the stock solution at a concentration of 10 mM per liter, then dilute the compound 100 times with the medium to obtain a maximum concentration of 100 ⁇ M, and then serially dilute the compound concentration by 2 times to gradually dilute 8 concentration gradients; for H2170 For cell lines, the concentration of the mother solution is prepared to be 100 ⁇ M per liter, and then the compound is diluted 100 times with the medium to obtain a maximum concentration of 1 ⁇ M, and then the compound concentration is serially diluted by 3 times to gradually dilute 8 concentration gradients; for the N87 cell line, the concentration of the prepared mother solution is 1 ⁇ M per liter.
  • the compound was diluted 100 times with medium to obtain a maximum concentration of 1 ⁇ M, and then the compound concentration was serially diluted 5 times and gradually diluted to 8 concentration gradients; 10 ⁇ L of the compound solution was added to the laid 96-well plate. Control supplemented with 10ul medium containing 1% DMSO instead of the compound solution was used as 0% inhibition control. After culturing for 72 hours, 10 ⁇ l of CCK8 was added. After 1.5 hours, the plate was read with a microplate reader. Data were calculated using GraphPad Prism version 4.0, and IC50 values were adjusted by non-linear regression models using dose-response curves.
  • compound 1, compound 2 and compound 3 have the best cell activity on lung cancer H2170 and gastric cancer N87 cells.
  • the cellular activity of the deuterated compound was slightly lower compared to Poziotinib.
  • the inhibitory activity IC 50 of the deuterated compound is between 2-3 ⁇ M, which is better than the IC 50 (11 ⁇ M) activity of Poziotinib.
  • the pharmacokinetic properties test of the compound of the present invention is entrusted to Hangzhou Leading Pharmaceutical Technology Co., Ltd. and Medicipia Pharmaceutical Technology (Shanghai) Co., Ltd. to conduct.

Abstract

La présente invention concerne un composé représenté par la formule I ou un sel pharmaceutiquement acceptable de celui-ci. De tels composés présentent un excellent effet d'inhibition ciblée de mutations non canoniques d'EGFR et ont une bonne activité antitumorale. La présente invention concerne en outre l'utilisation du composé dans la préparation d'un médicament pour la prévention et/ou le traitement de maladies médiées par une mutation d'EGFR, comme le cancer, et une composition pharmaceutique contenant le composé.
PCT/CN2022/121058 2021-09-24 2022-09-23 Dérivé de ptéridinone et son utilisation WO2023046114A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1373763A (zh) * 1999-09-15 2002-10-09 沃尼尔·朗伯公司 作为激酶抑制剂的蝶啶酮
WO2006002367A1 (fr) * 2004-06-23 2006-01-05 Irm Llc Composes et compositions utilises en tant qu'inhibiteurs des proteines kinases
WO2013170671A1 (fr) * 2012-05-14 2013-11-21 华东理工大学 Dérivé de ptéridine cétone et ses applications en tant qu'inhibiteur d'egfr, de blk et de flt3
WO2016192609A1 (fr) * 2015-05-29 2016-12-08 华东理工大学 Utilisation de dérivés de ptéridinone en tant qu'inhibiteur de l'egfr
CN108721298A (zh) * 2017-04-19 2018-11-02 华东理工大学 作为布鲁顿酪氨酸激酶抑制剂的嘧啶并杂环化合物及其应用
WO2020142612A1 (fr) * 2019-01-03 2020-07-09 Genentech, Inc. Composés de pyrido-pyrimidinone et de ptéridinone utilisés en tant qu'inhibiteurs de l'enzyme nécessitant l'inositol i (ire i alpha) à activité endoribonucléase pour le traitement de maladies cancéreuses
WO2022042755A1 (fr) * 2020-08-28 2022-03-03 华东理工大学 Composé destiné à inhiber un mutant d'egfr et son utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1373763A (zh) * 1999-09-15 2002-10-09 沃尼尔·朗伯公司 作为激酶抑制剂的蝶啶酮
WO2006002367A1 (fr) * 2004-06-23 2006-01-05 Irm Llc Composes et compositions utilises en tant qu'inhibiteurs des proteines kinases
WO2013170671A1 (fr) * 2012-05-14 2013-11-21 华东理工大学 Dérivé de ptéridine cétone et ses applications en tant qu'inhibiteur d'egfr, de blk et de flt3
WO2016192609A1 (fr) * 2015-05-29 2016-12-08 华东理工大学 Utilisation de dérivés de ptéridinone en tant qu'inhibiteur de l'egfr
CN108721298A (zh) * 2017-04-19 2018-11-02 华东理工大学 作为布鲁顿酪氨酸激酶抑制剂的嘧啶并杂环化合物及其应用
WO2020142612A1 (fr) * 2019-01-03 2020-07-09 Genentech, Inc. Composés de pyrido-pyrimidinone et de ptéridinone utilisés en tant qu'inhibiteurs de l'enzyme nécessitant l'inositol i (ire i alpha) à activité endoribonucléase pour le traitement de maladies cancéreuses
WO2022042755A1 (fr) * 2020-08-28 2022-03-03 华东理工大学 Composé destiné à inhiber un mutant d'egfr et son utilisation

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