WO2019190259A1 - Nouveau dérivé de sulfonamide ayant un effet inhibiteur sur la mutation du récepteur du facteur de croissance épidermique - Google Patents

Nouveau dérivé de sulfonamide ayant un effet inhibiteur sur la mutation du récepteur du facteur de croissance épidermique Download PDF

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WO2019190259A1
WO2019190259A1 PCT/KR2019/003697 KR2019003697W WO2019190259A1 WO 2019190259 A1 WO2019190259 A1 WO 2019190259A1 KR 2019003697 W KR2019003697 W KR 2019003697W WO 2019190259 A1 WO2019190259 A1 WO 2019190259A1
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amino
phenyl
group
chloro
methylmethanesulfonamide
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PCT/KR2019/003697
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English (en)
Korean (ko)
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장선영
김미라
전지영
곽은주
이선회
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한미약품 주식회사
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Publication of WO2019190259A1 publication Critical patent/WO2019190259A1/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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and 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
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel sulfonamide derivatives having an inhibitory effect on epidermal growth factor receptor mutations, and pharmaceutical compositions containing them as active ingredients.
  • Epidermal growth factor receptor is a protein consisting of a receptor moiety and tyrosine kinase moiety, and serves to transmit signals outside the cell into the cell through the cell membrane.
  • EGFR plays an essential role in normal cellular regulation through intracellular signal transduction, but EGFR mutations that are characterized by overexpression of EGFR or ligand-independent tyrosine kinase activity also fail to modulate signaling by these receptors. It is known to induce cancer cell growth, differentiation, neovascularization, metastasis and expression of resistance by activating. In most solid cancer cells, abnormal overexpression of EGFR or frequent mutations have been reported, which is associated with poor prognosis.
  • EGFR activating mutations such as L858R point mutation of exon 21 of the EGFR tyrosine kinase domain or in-frame deletion of exon 19 are known as important causes of non-small cell lung cancer. Therefore, studies are underway to develop anticancer agents targeting epithelial growth factor receptors in anticipation that blocking cancer cell signaling through the epidermal growth factor receptors will result in superior anticancer effects.
  • the first drug developed as an EGFR tyrosine kinase inhibitor in low molecular weight is gefitinib, a reversible inhibitor that selectively inhibits EGFR (Erb-B1) in the EGFR subtype.
  • gefitinib a reversible inhibitor that selectively inhibits EGFR (Erb-B1) in the EGFR subtype.
  • Another drug with this characteristic is Erlotinib, and this EGFR targeted therapy is mainly used in patients with EGFR activating mutations, mainly non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • NSCLC patients with EGFR activating mutations administered gefitinib or erlotinib become resistant to drugs after about 8 to 16 months, of which about 60% are reported to be resistant to EGFR T790M mutations. (Helena A. Yu et al., Clin Cancer Res. 19 (8), 2240, 2013).
  • EGFR irreversible inhibitor has been proposed to overcome resistance to existing EGFR inhibitors such as gefitinib or erlotinib.
  • EGFR irreversible inhibitors also have high activity against EGFR WT (wild-type), which is also present in normal cells, causing serious side effects when doses to overcome resistance due to EGFR T790M mutations are administered. It shows the limitation of clinical application.
  • EGFR mutant selective inhibitors As an alternative, EGFR mutant selective inhibitors, osimertinib, olmutinib, naquotinib and Avitinib, and many other drugs are in development at the clinical stage.
  • Oshimtinib in patients with non-small cell lung cancer with EGFR resistance mutations, after about 10 months, the drug resistance is due to activation of other resistance mechanisms, of which a higher proportion of C797S mutations is more than 20%. It is known to appear.
  • the C797S mutation is a point mutation in which cysteine 773 (Cys773), a covalent bond that forms irreversible inhibitors of EGFR, turns into serine, resulting in a loss of reactivity to the drug as it does not form a covalent bond with irreversible inhibitors for EGFR. .
  • One aspect of the invention is selective for cancer cell growth and resistance to drugs caused by mutation of the tyrosine kinase domain in epidermal growth factor receptor (EGFR) and for drugs having such resistance, and It is to provide a novel sulfonamide derivative that effectively inhibits and has fewer side effects.
  • EGFR epidermal growth factor receptor
  • Another aspect of the present invention to provide a pharmaceutical composition for inhibiting cancer cell growth comprising the novel sulfonamide derivative.
  • One aspect of the present invention provides a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the following formula (I).
  • Another aspect of the present invention provides a method for treating cancer with an EGFR mutation comprising a sulfonamide derivative of Formula I, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a prophylactic or therapeutic pharmaceutical composition comprising a sulfonamide derivative of Formula I, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Compounds of the formula (I), solvates, stereoisomers or pharmaceutically acceptable salts thereof according to one aspect of the present invention are resistant to cancer and growth of cancer cells caused by mutation of tyrosine kinase domains in epithelial growth factor receptors. Or can effectively and effectively inhibit cancer with such resistance.
  • Cy 1 is C 3 -C 10 aryl or C 3 -C 10 heteroaryl, wherein the aryl or heteroaryl is halogen, hydroxy group, thiol group, cyano group, C 1 -C 6 alkyl group, and C 1 -C 6 alkoxy group May have one or more substituents selected from the group consisting of;
  • n is an integer from 0 to 5;
  • n is an integer from 1 to 4.
  • X is -NH- or -C-;
  • R 1 and R 2 are independently of each other a C 1 -C 6 alkyl group
  • R 3 is selected from hydrogen, halogen, hydroxy group, thiol group, cyano group, C 1 -C 6 haloalkyl group, and -C (O) OR 6 , wherein R 6 is C 1 -C 5 alkyl group;
  • R 4 is selected from hydrogen, halogen, thiol group, cyano group, C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, and C 1 -C 6 haloalkyl group;
  • R 5 is selected from hydrogen, halogen, a C 1 -C 6 alkyl group, and a C 1 -C 6 hydroxyalkyl group;
  • R 2 when R 2 is X is -C-, X and R 2 may be fused to form a 4- to 7-membered heteroaryl ring with the atoms to which they are bonded, or R 2 is R 1 or R 5 Fused with to form a 5-7 membered heteroaryl or heterocycloalkyl ring with the atoms to which they are attached;
  • Y is -Z- (CH 2 ) a -Q 1 -Q 2 ,
  • Z is absent or is selected from carbonyl (-CO-), amide (-CONH-), -S- and -O-,
  • A is an integer of 0 to 6
  • Q 1 is a C 3 -C 10 heterocycloalkyl group, or C 6 -C 10 heterobicycloalkyl, the heterocycloalkyl group or heterobicycloalkyl group is halogen, hydroxy group, thiol group, cyano group, C 1 -C 6 May have one or more substituents selected from the group consisting of alkyl groups,
  • Q 2 is selected from hydrogen, a C 1 -C 6 alkyl group, and a C 3 -C 10 heterocycloalkyl group, wherein the heterocycloalkyl group consists of a halogen, a hydroxy group, a thiol group, a cyano group, and a C 1 -C 6 alkyl group It may have one or more substituents selected from the group.
  • halogen herein may be F, Cl, Br, or I.
  • alkyl refers to a straight, or branched hydrocarbon moiety that may be substituted or unsubstituted unless otherwise noted.
  • the alkyl group may include without limitation all possible isomers thereof, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, or isopropyl, isobutyl, and t-butyl.
  • alkoxy refers to a straight or branched hydrocarbon moiety that is substituted or unsubstituted, connected by oxygen.
  • the alkoxy may include without limitation all possible isomers thereof, such as, for example, methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.
  • aryl refers to an aromatic group which may be substituted or unsubstituted unless otherwise indicated, including, for example, C 3 -C 30 aryl, C 3 -C 20 aryl, or C 3 -C 10 aryl. And double bonds alternate (resonance) between adjacent carbon atoms or suitable heteroatoms. For example, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof may be included without limitation.
  • heteroaryl refers to monocyclic or bicyclic or more, including one or more heteroatoms selected from B, N, O, S, P ( ⁇ O), Si and P, or An aromatic group, which may be unsubstituted.
  • Examples of monocyclic heteroaryls include pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxazozolyl, pyridine 1, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and similar groups, but is not limited to these.
  • bicyclic heteroaryl examples include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso Quinolinyl, purinyl, puropyridinyl, oxochromen, dioxoisoindolin, pyrazolopyridinyl, pyrazolo [1,5-a] pyridinyl and the like, but are not limited to these.
  • Cyclic alkyl which may be used.
  • Monoheterocycloalkyl can be C 3 -C 30 heterocycloalkyl, C 3 -C 20 heterocycloalkyl, or C 3 -C 10 heterocycloalkyl, for example piperidinyl, piperazinyl, Morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuryl, and the like, but are not limited to these.
  • heterocycloalkyl is a substitution or non-substitution of a bicyclic comprising one or more heteroatoms selected from B, N, O, S, P ( ⁇ O), Si and P Cyclic alkyl, which may be cyclic.
  • the heterobicycloalkyl may be bridged heterobicycloalkyl or (Spiro) heterobicycloalkyl, for example C 6 -C 20 heterobicycloalkyl, or C 6 -C 10 heterobicyclo Alkyl, including 3,9-diazaspiro [5.5] undecanyl, 2,6-diazaspiro [3.3] heptanyl, 2,5-diazabicyclo [2.2.1 ] Heptanyl and similar groups include, but are not limited to these.
  • solvate may refer to a compound of the present invention or a salt thereof that includes a stoichiometric or nonstoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • Preferred solvents therein may be volatile, non-toxic, and / or solvents suitable for administration to humans.
  • stereoisomers may refer to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but which is optically or sterically different, and specifically, diastereomers, enantiomers, geometric isomers, or shapes It may be an isomer.
  • derivative refers to a compound obtained by substituting a part of the structure of the compound with another atom or group of atoms.
  • the compounds according to the invention can also be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, for example the salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, Salts derived from salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like.
  • the salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, Pyr
  • compositions according to the invention are prepared by dissolving a compound of formula (I) in a water miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an aqueous acid solution of an inorganic acid. It can then be prepared by precipitation or crystallization. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.
  • a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile
  • Cy 1 in Formula I is C 3 -C 10 aryl or C 3 -C 10 heteroaryl; m is 0 or 1; n is an integer of 1 or 2; X is -NH- or -C-; R 1 and R 2 are independently of each other a C 1 -C 6 alkyl group; R 3 is selected from hydrogen, halogen, cyano and a C 1 -C 6 haloalkyl group and —C (O) OR 6 , wherein R 6 is a C 1 -C 3 alkyl group; R 4 is selected from hydrogen, halogen, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, and a C 1 -C 6 haloalkyl group; R 5 is selected from hydrogen, a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group;
  • R 2 when X is -C-, X and R 2 are, or
  • Cy 1 in Formula I is phenyl or pyrazole; m is 0 or 1; n is an integer of 1 or 2; R 1 and R 2 are independently of each other a C 1 -C 6 alkyl group; R 3 is selected from hydrogen, halogen, cyano and a C 1 -C 6 haloalkyl group and —C (O) OR 6 , wherein R 6 is a C 1 -C 3 alkyl group;
  • the R 2 and X are the days when -C-, X and R 2 are fused to, or may form a heteroaryl ring of 5 together with the atom to which they are attached, wherein R 2 is fused with R 1 or R 5 Together with the atoms to which they are attached may form a five-membered heteroaryl or heterocycloalkyl ring;
  • Y is -Z- (CH 2 ) a -Q 1 -Q 2 , wherein Z is absent or is selected from carbonyl (-
  • R 2 may be a C 1 -C 6 alkyl group, for example, may be a methyl group.
  • the compound of formula I may be selected from the group consisting of:
  • Another aspect provides a pharmaceutical composition for preventing or treating cancer with an EGFR mutation, comprising a compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, according to one embodiment. to provide.
  • the EGFR mutation provides a pharmaceutical composition, which is an activating EGFR mutation, a mutation that causes resistance to an EGFR inhibitor, or a combination thereof.
  • the activating EGFR mutation may be del19, L858R, or a combination thereof.
  • the mutation that causes resistance to the EGFR inhibitor may be T790M, C797S, or a combination thereof.
  • the cancer having an EGFR mutation may be a cancer having a C797S mutation.
  • the cancer is lung cancer, liver cancer, esophageal cancer, gastric cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer, urethra It may be selected from the group consisting of cancer, bladder cancer, testicular cancer, hematologic cancer, lymphoma, skin cancer, psoriasis and fibroadenoma.
  • the cancer may be non-small cell lung cancer.
  • the pharmaceutical composition may comprise conventional pharmaceutically acceptable carriers, excipients or additives.
  • the pharmaceutical compositions of the present invention may be formulated according to conventional methods and may be formulated in various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions or parenteral such as intramuscular, intravenous or subcutaneous administration. It may be prepared in a dosage form.
  • examples of the additive or carrier to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid and stearic acid. Magnesium, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents and the like.
  • the additive or carrier may include water, saline, aqueous glucose solution, pseudoglucose solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, fatty acid ester , Glycerides, surfactants, suspending agents, emulsifiers and the like.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used to inhibit cancer cell growth and drug resistance caused by mutation of tyrosine kinase domain in epithelial growth factor receptor (EGFR), or such resistance. Selectively and effectively inhibit having cancer.
  • EGFR epithelial growth factor receptor
  • one aspect is directed to an individual in need of treatment of a cancer caused by an EGFR mutation, including administering to a subject a compound of the invention or a pharmaceutical composition comprising the same in a therapeutically effective amount or such a dose (e.g., , Patient).
  • the dosage of the pharmaceutical composition is an amount effective for treating or preventing an individual or a patient, and may be orally or parenterally administered as desired.
  • doses are not intended to limit the scope of the invention in any aspect.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition.
  • a physician or veterinarian may use a dose of a compound of the invention for use in a pharmaceutical composition, starting at a lower level than required to achieve the desired therapeutic effect, and gradually increasing the dosage until the desired effect is achieved. Can be increased.
  • treating refers to inhibiting a disease, eg, inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the pathology or indication of the disease, condition or disorder, ie Preventing further development of the pathology and / or signs, or ameliorating the disease, eg, improving a disease, condition or disorder in an individual experiencing or exhibiting the pathology or sign of the disease, condition or disorder, ie Reversing pathology and / or signs, such as reducing disease severity.
  • preventing refers to preventing a disease, eg, a disease in an individual who may be inclined to a disease, condition or disorder but has not yet experienced or exhibits the pathology or signs of the disease, To prevent a condition or disorder.
  • the term “individual” or “patient” refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and humans. .
  • compositions according to one embodiment include within their scope pharmaceutical compositions comprising, as active ingredient, a therapeutically effective amount of at least one of the compounds according to one embodiment, alone or in combination with a pharmaceutical carrier.
  • the compound according to one embodiment may be used alone, in combination with a compound according to another embodiment, or in combination with one or more other therapeutic agents, for example anticancer agents or other pharmaceutically active substances.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may enhance the therapeutic effect of the anticancer agent by co-administration with other anticancer agents.
  • Another aspect provides a compound library comprising at least one of the compounds according to the invention, salts, isomers, hydrates and solvates thereof.
  • Another aspect includes a method of preventing or treating cancer comprising administering to a subject a pharmaceutical composition comprising a compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof; And the pharmaceutical use of a compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof according to one embodiment for the prevention or treatment of cancer; There is provided a medicinal use of a compound, solvate, stereoisomer or pharmaceutically acceptable salt thereof according to one embodiment for the preparation of a cancer treatment.
  • the compounds of formula (I) according to the present invention may be prepared using chemical transformations well known to those skilled in the organic / medical chemistry art according to the methods representatively shown in Scheme 1 below.
  • a compound (ii ') commercially available from commercially available pyrimidine compound (i) is prepared by using a Lewis acid such as AlCl 3 with 1,2-di
  • the compound (iii ') in which the chloride at position 4 of the pyrimidine is substituted may be obtained by reacting in a solvent such as methoxyethane at a temperature ranging from room temperature to 100 ° C.
  • the prepared compound (iii) and amine compound (iv) are reacted in an alcohol solvent such as 2-butanol in the presence of an inorganic acid such as hydrochloric acid or an organic acid such as p -toluenesulfonic acid or trifluoroacetic acid at a temperature ranging from 70 ° C. to reflux.
  • an alcohol solvent such as 2-butanol
  • an inorganic acid such as hydrochloric acid or an organic acid such as p -toluenesulfonic acid or trifluoroacetic acid
  • a palladium catalyst such as tris (dibenzylideneacetone) dipalladium (0)
  • the halogen at the pyrimidine 2-position is replaced with an amine in a temperature range of about 100 ° C. in an organic solvent such as 2-butanol or 1,4-dioxane.
  • the compounds of formula I of the present invention can be obtained.
  • the amine compound (iv) used for the reaction can be obtained by the same method as in Scheme 3 below.
  • Scheme 2 is a scheme for preparing compound (ii) intermediate
  • Cy 1 , R 1 , R 2 , R 5 , m and X are as defined in formula (I) above and X 'is trityl, tert-butyldimethylsilane, tert-butyldiphenylsilane or tert-butylcarbamate X or NO 2 substituted with the same protecting group and X 'is halogen.
  • a sulfonyl chloride R 2 S (O) 2 Cl commercially available from a commercially available amine compound (v) can be used in a range of room temperature to 100 ° C. under a solvent such as pyridine. It is reacted at temperature, and the compound (vi) which the sulfone group is substituted by amine can be obtained.
  • compound (vii) in which sulfonamide is substituted.
  • the sulfonamide compound (viii) used in the reaction is commercially available or commercially available
  • R 1 is Substituted amine compound and R 2 substituted sulfonyl chloride compound with 1,8- diazabicyclo [5.4.0] undec-7-ene and 4-dimethylaminopyridine, potassium carbonate, triethylamine or N
  • Compound (viii) may be prepared by reacting in a solvent such as pyridine or dichloromethane in a basic condition of suitable strength such as N -diisopropylethylamine at a temperature ranging from room temperature to 50 ° C.
  • Scheme 3 is a scheme for preparing compound (iv) intermediate
  • R 4 , n, and Y are as defined in Formula I above, X '' is halogen, R is H or substituted or unsubstituted alkyl, and when R is alkyl, two R can form a fused ring have.
  • YH commercially available from commercially available halogen-substituted nitro compound (ix) is subjected to normal temperature to 100 ° C. in a solvent such as acetonitrile under basic conditions such as potassium carbonate. Substitution reaction is carried out at a temperature in the range of to obtain compound (x) in which the halogen of compound (ix) is substituted with Y.
  • compound (x) can be obtained by coupling compound (ix) with boronic acid or boronate ester YB (OR) 2 under Suzuki conditions by a synthesis method under other conditions.
  • this reaction involves the reaction of a halogen compound with boronic acid or ester with a base such as potassium carbonate and a catalyst, such as 1,1 ′ ′-bis (diphenylphosphino) ferrocene, in a solvent such as dioxane or N, N -dimethylformamide.
  • a catalyst such as 1,1 ′ ′-bis (diphenylphosphino) ferrocene
  • Compound (iv) can be obtained by converting the nitro group of the prepared compound (x) into an amine through a hydrogenation reaction using palladium / carbon as a catalyst or a reduction reaction via iron.
  • a pharmaceutical composition comprising as an active ingredient a compound of formula (I), a solvate, a stereoisomer and a pharmaceutically acceptable salt thereof synthesized by this preparation method is caused by a mutation of the tyrosine kinase domain in the epidermal growth factor receptor Growth of cancer cells and resistance to drugs, or to treat cancer with such resistance.
  • Example 1 Except for using 1-methyl-4-piperazin-4-yl-piperidine hydrochloride instead of 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 above , 45 mg (final step yield: 42%) of the title compound were obtained in the same manner as the Example 1 above.
  • Example 3 isopropyl 2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -4-((2- ( N Preparation of -methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
  • Example 2 The same process as in Example 1 was carried out except that 3,4-difluoronitrobenzene was used instead of 5-fluoro-2-nitroanisole in step 5) of Example 1. 52 mg (final step yield: 62%) were obtained.
  • 2,4-dichloropyrimidine is used instead of 2,4,5-trichloropyrimidine in step 4) of Example 1, and 5-fluoro-2-nitro in step 5) of Example 1 Except for using 3,4-trifluoronitrobenzene instead of anisole, the same process as in Example 1 was carried out to obtain 40 mg of the title compound (final step yield: 44%).
  • Example 2 The same process as in Example 1 was performed except that 2,3,4-trifluoronitrobenzene was used instead of 5-fluoro-2-nitroanisole in step 5) of Example 1. 31 mg (final step yield: 29%) of the title compound were obtained.
  • 2,4-dichloropyrimidine is used instead of 2,4,5-trichloropyrimidine in step 4) of Example 1, and 5-fluoro-2-nitro in step 5) of Example 1 Except for using 2,3,4-trifluoronitrobenzene instead of anisole, the same process as in Example 1 was carried out to obtain 31 mg (final step yield: 33%) of the title compound.
  • Example 5 in step 5) instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride and 3,4-difluoronitrobenzene Except for using the compound prepared in Step 2), the same process as in Example 1 was carried out to obtain 6 mg (final step yield: 7%) of the title compound.
  • Step 2) N -(2-((5-chloro-2-((5-fluoro-2-methoxy-4- (9-methyl-3,9-diazaspiro [5.5] undecane-3-yl) phenyl ) Amino) pyrimidin-4-yl) amino) phenyl)- N
  • Example 2 120 mg (0.39 mmol) of the compound prepared in Step 2) and 150 mg (0.4328 mmol) of the compound prepared in Step 4) of Example 1 were diluted in 5 ml of 1,4-dioxane and 2-dicyclohexylphosphino 25 mg (0.04 mmol) of -2 ', 4', 6'-triisopropylbiphenyl and 119 mg (0.86 mmol) of cesium carbonate were stirred at room temperature for 5 minutes, followed by tris (dibenzylideneacetone) dipalladium. (O) 40 mg (0.04 mmol) was added thereto and stirred at 100 ° C. for 3 hours.
  • step 2 The compound prepared in step 2) was used instead of 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline in step 7) of Example 1 Except that, to give the title compound 14 mg (final step yield: 10%) in the same manner as in Step 7).
  • Example 5 in step 5) instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride and 1-fluoro-4-nitrobenzene Except for using 1-methylpiperazine, the same process as in Example 1 was carried out to obtain 24 mg of the title compound (final step yield: 16%).
  • Example 5 in step 5) instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride and 3,4-difluoronitrobenzene Except for using 1-methylpiperazine, the same process as in Example 1 was carried out to obtain 120 mg (final step yield: 47%) of the title compound.
  • Example 1 The compound prepared in step 1) and 1- in place of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 Except for using methyl piperazine, the same process as in Example 1 was carried out to obtain 89 mg (final step yield: 49%) of the title compound.
  • Example 13 Prepared in step 1) of Example 13 instead of 5-fluoro-2-nitroanisole and 1-methyl-4-piperidin-4-yl-piperazine hydrochloride in step 5) of Example 1 Except for using the compound and the compound prepared in step 2) of Example 8, the same process as in Example 1 was carried out to obtain 110 mg (final step yield: 70%) of the title compound.
  • Example 24 N - (2 - ( (5- chloro-2 - ((2-methoxy -4 - ((1 S, 4 S) -5- methyl-2,5-diazabicyclo [2.2. ] Heptan-2-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide
  • Step 2 tert-butyl (1 S ,4 S ), 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate
  • Example 6 the compound prepared in Step 3) instead of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazin Except for using, Step 6) and Step 7) of Example 1 were carried out sequentially to obtain 22 mg (yield: 32%) of the title compound.
  • Step 1) (3 S , 5 R ) -1- (3-methoxy-4-nitrophenyl) -3,5-dimethylpeperazine
  • Step 2) (2 S , 6 R ) -4- (3-methoxy-4-nitrophenyl) -1,2,6-trimethylpiperazine
  • Example 6 above using the compound of step 2) in place of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazin Except that, the steps 6) and 7) of Example 1 were carried out sequentially to obtain 22 mg of the title compound (final step yield: 25%).
  • Step 1) 4-((5-chloro-4-((2- N Preparation of -methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxybenzoic acid
  • Example 27 4-((5-chloro-4-((2- ( N -Methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N Preparation of-(1-methylpiperidin-4-yl) benzamide
  • Example 28 4-((5-chloro-4-((2- ( N -Methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N Preparation of-(2- (pyrrolidin-1-yl) ethyl) benzamide
  • Step 3 4-((5-chloro-4-((2- ( N -Methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N
  • Step 3 4-((5-chloro-4-((2- ( N -Methylmethylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxy- N
  • Example 6 Step 6 instead of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine, the compound prepared in Step 4) was used. Except for, step 6) and 7) of Example 1 were carried out sequentially to obtain 3.5 mg (final step yield: 3%) of the title compound.
  • Example 6 Step 6 instead of 1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine, the compound prepared in Step 3) was used. Except for, step 6) and 7) of Example 1 were carried out sequentially to give 65 mg (final step yield: 46%) of the title compound.
  • Step 2) methyl 4-amino-3- ( N Preparation of -methylmethylsulfonamido) benzoate
  • Example 1 50 mg (0.13 mmol) of the resulting residue and 40 mg (0.13 mmol) of the compound prepared in Step 6) of Example 1 were diluted with 1 mL of 2-butanol and 0.03 mL (0.39 mmol) of trifluoroacetic acid was added. After that, the mixture was stirred at 100 ° C for 16 hours. Upon completion of the reaction, the resulting reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution.
  • the resulting organic layer was dried over anhydrous sodium sulfate, and then filtered under reduced pressure and distilled under reduced pressure.
  • the obtained residue was diluted with 12 ml of dichloromethane and 6 ml of trifluoroacetic acid was added, followed by stirring at room temperature for 2 hours. After the reaction was completed, the resulting reaction mixture was distilled under reduced pressure, diluted with a chloroform: 2-propanol (3: 1 (volume ratio)) mixed solvent, and washed with a saturated aqueous sodium bicarbonate solution.
  • the resulting residue was diluted with 10 ml of a tetrahydrofuran: 1N aqueous sodium hydroxide aqueous solution (2: 3 (volume ratio)) mixed solvent and stirred for 1 hour.
  • the resulting mixture was neutralized with 2N aqueous hydrochloric acid solution and extracted with chloroform: 2-propanol (3: 1 (volume ratio)) mixed solvent.
  • step 5 Except for using the compound prepared in step 5) instead of N -methyl- N- (2-nitrophenyl) methane sulfonamide in step 3) of Example 1, in step 3 of Example 1 Sequentially following the same procedure as in step 7, 36 mg (final step yield: 34%) of the title compound were obtained.
  • Step 2) 2- (2-((5-chloro-2-((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino Preparation of Pyrimidin-4-yl) amino) phenyl) isothiazol 1,1-dioxide
  • Step 3) of Example 1 except that the compound prepared in Step 1) is used instead of N -methyl- N- (2-nitrophenyl) methanesulfonamide in Step 3) of Example 1
  • Step 3) of Example 1 To give 112 mg (final step yield: 64%) of the title compound in the same manner as in step 7).
  • step 1) The compound prepared in step 1) instead of N- (2-((2,5-dichloropyrimidin-4-yl) amino) phenyl) -N -methylmethanesulfonamide in step 7) of Example 1 Except for the use, the procedure was carried out in the same manner as in Step 7) of Example 1 to obtain 50 mg of the title compound (final step yield: 28%).
  • step 3 The compound prepared in step 3), instead of N- (2-((2,5-dichloropyrimidin-4-yl) amino) phenyl) -N -methylmethane sulfonamide in step 7) of Example 1 Aside from using, the same procedure as in Step 7) of Example 1 gave 12 mg (17% of final step yield) of the title compound.
  • the cell line stored in the liquid nitrogen tank was taken out and rapidly dissolved at 37 ° C., and then centrifuged to remove the cryopreservation medium.
  • the recovered cell pellets were mixed well in the culture medium and placed in a culture flask and passaged under 37 ° C. and 5% carbon dioxide conditions to stabilize the cells by logarithmic growth.
  • Cells were then taken from the flask, centrifuged to remove culture medium, washed with DPBS (Dulbecco's Phosphate Buffered Saline), centrifuged to remove DPBS and diluted to 1 ⁇ 10 5 cells / ml with culture medium. .
  • the diluted cells were dispensed at 100 ⁇ l per well in 96-well plates.
  • DMSO dimethyl sulfoxide
  • the initial cell density value was subtracted from the final cell density value of the wells that were not treated with the test substance, and the value of GI 50 was determined at the concentration at which each compound inhibited cell growth by 50%.
  • the GI 50 value of each compound was determined by nonlinear regression of GraphPadprism; log [inhibitor] vs. It was calculated using normalized response analysis, and the results are shown in Table 1 below.
  • Example 1 it was intended to confirm whether the compound obtained in Example 1 exhibits EGFR normal (WT) or mutant (T790M / L858R, del19 / T790M / C797S) inhibitory activity.
  • WT EGFR normal
  • T790M / L858R mutant
  • del19 / T790M / C797S enzyme inhibitory activity
  • Each enzyme human EGFR WT, EGFR T790M / L858R or EGFR del19 / T790M / C797S was mixed with 0.2 mg / ml of poly [Glu: Tyr] (4: 1) substrate and 10 ⁇ M of ATP together with the compound for phosphorylation of the substrate. Measured.
  • the compounds prepared in the Examples were made with 10 mM DMSO solution, from which they were diluted 1/10 multiples up to 0.1 nM.
  • substrate to kinase solution (20 mM Hepes (pH7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35.
  • the enzymes were mixed lightly after each addition.
  • To the mixed solution was added a compound prepared using Acoustic Technology (Echo550; nanoiter range) and reacted for 20 minutes at room temperature. Thereafter, 33 P-ATP was further added, followed by reaction at room temperature for 2 hours.
  • Echo550 Acoustic Technology
  • 33 P-ATP was further added, followed by reaction at room temperature for 2 hours.

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Abstract

La présente invention concerne le composé représenté par la formule chimique 1 suivante, ou une composition pharmaceutique, pour la prévention ou le traitement d'un cancer ayant une mutation EGFR, la composition comprenant le composé et un véhicule pharmaceutiquement acceptable : [Formule chimique I].
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WO2020119739A1 (fr) * 2018-12-12 2020-06-18 暨南大学 Composé de 2-aminopyrimidine et son utilisation
CN113717156A (zh) * 2020-05-25 2021-11-30 南京红云生物科技有限公司 Egfr抑制剂、其制备方法及用途
CN113840823A (zh) * 2019-10-31 2021-12-24 昂科比克斯有限公司 显示癌细胞生长抑制效果的新型杂环取代的嘧啶衍生物，以及包含其的药物组合物
CN113896744A (zh) * 2020-07-06 2022-01-07 成都先导药物开发股份有限公司 一种选择性egfr抑制剂
WO2022055181A1 (fr) * 2020-09-11 2022-03-17 제이투에이치바이오텍 주식회사 Composés destinés à éliminer le cancer mutant de l'egfr et leur utilisation pharmaceutique
WO2022068849A1 (fr) * 2020-09-30 2022-04-07 Beigene, Ltd. Composés bifonctionnels pour la dégradation de l'egfr et procédés d'utilisation associés
CN114829352A (zh) * 2019-12-16 2022-07-29 昂科比克斯有限公司 新型氘代嘧啶衍生物及包含其的药物组合物
CN115667226A (zh) * 2020-04-14 2023-01-31 齐鲁制药有限公司 作为egfr抑制剂的三环化合物
KR20230054567A (ko) 2021-10-15 2023-04-25 제이투에이치바이오텍 (주) Alk 및/또는 egfr 돌연변이 키나제 억제 효과를 나타내는 화합물 및 이의 의약 용도
RU2811770C1 (ru) * 2019-12-16 2024-01-17 Онкобикс Ко., Лтд. Новое замещенное дейтерием производное пиримидина и содержащая его фармацевтическая композиция

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KR20220136931A (ko) 2021-04-01 2022-10-11 주식회사 테라펙스 단백질 키나아제 저해 활성을 갖는 피리미딘 유도체 및 이를 포함하는 치료용 약학 조성물
AU2022250976A1 (en) 2021-04-01 2023-08-17 Industry-Academic Cooperation Foundation, Yonsei University Pyrimidine derivative having protein kinase inhibitory activity, and therapeutic pharmaceutical composition comprising same
CN117203199A (zh) * 2021-04-02 2023-12-08 毕利吉生物科技股份有限公司 N2-苯基嘧啶-2,4-二胺化合物及其制备方法和使用方法
KR102568168B1 (ko) * 2021-07-13 2023-08-18 한국화학연구원 신규한 피리미딘-2,4-디아민 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물
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CA3238857A1 (fr) * 2021-12-09 2023-06-15 Oncobix Co., Ltd. Nouveau derive de pyrimidine a substitution heterocyclique presentant un effet inhibiteur de la croissance des cellules cancereuses, et composition pharmaceutique le contenant
WO2023163527A1 (fr) * 2022-02-23 2023-08-31 주식회사 카나프테라퓨틱스 Nouveau composé ayant une activité inhibitrice contre la tyrosine kinase du récepteur du facteur de croissance épidermique, et ses utilisations
KR102524856B1 (ko) * 2022-06-23 2023-04-24 주식회사 카나프테라퓨틱스 표피 성장인자 수용체 티로신 키나제에 대한 억제 활성을 갖는 신규 화합물 및 이의 용도

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CN113166110B (zh) * 2018-12-12 2023-08-11 暨南大学 2-氨基嘧啶类化合物及其应用
WO2020119739A1 (fr) * 2018-12-12 2020-06-18 暨南大学 Composé de 2-aminopyrimidine et son utilisation
CN113840823A (zh) * 2019-10-31 2021-12-24 昂科比克斯有限公司 显示癌细胞生长抑制效果的新型杂环取代的嘧啶衍生物，以及包含其的药物组合物
EP4053121A4 (fr) * 2019-10-31 2023-10-25 Oncobix Co., Ltd. Nouveau dérivé de pyrimidine à substitution hétérocyclique présentant un effet inhibiteur de la croissance des cellules cancéreuses, et composition pharmaceutique le contenant
CN114829352A (zh) * 2019-12-16 2022-07-29 昂科比克斯有限公司 新型氘代嘧啶衍生物及包含其的药物组合物
CN114829352B (zh) * 2019-12-16 2024-05-31 昂科比克斯有限公司 新型氘代嘧啶衍生物及包含其的药物组合物
RU2811770C1 (ru) * 2019-12-16 2024-01-17 Онкобикс Ко., Лтд. Новое замещенное дейтерием производное пиримидина и содержащая его фармацевтическая композиция
CN115667226A (zh) * 2020-04-14 2023-01-31 齐鲁制药有限公司 作为egfr抑制剂的三环化合物
CN113717156B (zh) * 2020-05-25 2023-05-09 南京红云生物科技有限公司 Egfr抑制剂、其制备方法及用途
WO2021238827A1 (fr) * 2020-05-25 2021-12-02 南京红云生物科技有限公司 Inhibiteur d'egfr, son procédé de préparation et son utilisation
CN113717156A (zh) * 2020-05-25 2021-11-30 南京红云生物科技有限公司 Egfr抑制剂、其制备方法及用途
CN113896744A (zh) * 2020-07-06 2022-01-07 成都先导药物开发股份有限公司 一种选择性egfr抑制剂
CN113896744B (zh) * 2020-07-06 2024-04-16 成都先导药物开发股份有限公司 一种选择性egfr抑制剂
KR20220035014A (ko) 2020-09-11 2022-03-21 제이투에이치바이오텍 (주) Egfr 돌연변이 암의 억제용 화합물 및 이들의 의약 용도
KR20230082011A (ko) 2020-09-11 2023-06-08 제이투에이치바이오텍 (주) Egfr 돌연변이 암의 억제용 화합물 및 이들의 의약 용도
WO2022055181A1 (fr) * 2020-09-11 2022-03-17 제이투에이치바이오텍 주식회사 Composés destinés à éliminer le cancer mutant de l'egfr et leur utilisation pharmaceutique
WO2022068849A1 (fr) * 2020-09-30 2022-04-07 Beigene, Ltd. Composés bifonctionnels pour la dégradation de l'egfr et procédés d'utilisation associés
KR20230054567A (ko) 2021-10-15 2023-04-25 제이투에이치바이오텍 (주) Alk 및/또는 egfr 돌연변이 키나제 억제 효과를 나타내는 화합물 및 이의 의약 용도

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