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WO2022139386A1 - Composé dérivé d'hétéroaryle et son utilisation - Google Patents

Composé dérivé d'hétéroaryle et son utilisation Download PDF

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Publication number
WO2022139386A1
WO2022139386A1 PCT/KR2021/019439 KR2021019439W WO2022139386A1 WO 2022139386 A1 WO2022139386 A1 WO 2022139386A1 KR 2021019439 W KR2021019439 W KR 2021019439W WO 2022139386 A1 WO2022139386 A1 WO 2022139386A1
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WO
WIPO (PCT)
Prior art keywords
amino
oxazin
pyrimidin
hexahydrobenzo
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2021/019439
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English (en)
Korean (ko)
Inventor
고이경
한아름
박진희
이영덕
임혜림
김균은
황동근
남수빈
고은화
김성환
최환근
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Voronoi Inc
B2S Bio Inc
Original Assignee
Voronoi Inc
B2S Bio Inc
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Publication of WO2022139386A1 publication Critical patent/WO2022139386A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to heteroaryl derivative compounds and their medicinal uses. Specifically, the present invention relates to a heteroaryl derivative compound having EGFR inhibitory activity.
  • Protein kinases are involved in signaling pathways by acting as molecular switches, and the switching between the active and inactive states of the target protein by the kinase in the cell must be smoothly regulated. If the transition between the active and the inactive state is abnormally regulated, the intracellular signal transduction is excessively activated or inactivated to induce uncontrolled cell division and proliferation. In particular, abnormal activation by mutation, amplification and/or overexpression of protein kinase genes causes the development and progression of various tumors or plays a decisive role in the onset of various diseases such as inflammatory diseases, degenerative brain diseases, and autoimmune diseases.
  • epidermal growth factor receptor a receptor tyrosine kinase of the ErbB family
  • NSCLC non-small cell lung carcinoma
  • breast cancer glioma, squamous cell carcinoma of the head and neck, colorectal cancer
  • It is abnormally activated in many epithelial cell tumors including intestinal adenocarcinoma, head and neck cancer, gastric cancer and prostate cancer
  • activation of the EGFR-tyrosine kinase causes sustained cell proliferation, invasion into surrounding tissues, distant metastasis, angiogenesis, and cell survival has been known to increase
  • EGFR mutations EGFR_del19 or EGFR_L858R are the main causes of non-small cell lung cancer and head and neck cancer, and their therapeutic agents Iressa and Tarceva have been developed and are currently being used in clinical practice.
  • these drugs were used in patients, acquired resistance resulting from a secondary mutation of EGFR based on the structure of the drug was observed, and it was also found that this is the main cause of drug resistance.
  • the first-generation EGFR inhibitors are used for an average of 10 months, acquired resistance called the T790M mutation located in the gatekeeper of the EGFR kinase occurs, so that the first-generation EGFR inhibitors are not effective.
  • EGFR_del19_T790M or EGFR_L858R_T790M double mutation occurs, preventing the existing therapeutic agents from exhibiting drug efficacy.
  • Osimertinib a third-generation EGFR-TKI target drug that exhibits high reactivity to drug resistance according to T790M mutation, has been developed, but drug resistance has also been reported to occur from this (Clin Cancer Res, 2015, 17:21). ).
  • the EGFR C797S mutation has been suggested as one of the main mechanisms causing drug resistance to osimertinib, and it has been reported that about 40% of clinical trial patients have the C797S mutation (Nature Medicine, 2015, 21:560-562).
  • Another object of the present invention is to provide a method for preparing the heteroaryl derivative compound.
  • Another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compound, specifically, a pharmaceutical composition for the treatment or prevention of EGFR-related diseases comprising the heteroaryl derivative compound as an active ingredient, and EGFR-related use of the compound
  • a pharmaceutical use of the heteroaryl derivative compound specifically, a pharmaceutical composition for the treatment or prevention of EGFR-related diseases comprising the heteroaryl derivative compound as an active ingredient, and EGFR-related use of the compound
  • the present invention was completed by confirming that the heteroaryl derivative compounds represented by Chemical Formula 1 mentioned below inhibit the proliferation of EGFR-activated cells.
  • the present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
  • a 1 to A 4 are each independently CH or N;
  • B 1 and B 2 are each independently CH, CH 2 , N, NH, O, or S;
  • B 3 to B 5 are each independently CH or N;
  • X is , , , , , or ego
  • X 1 to X 8 are each independently -H, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 alkylamino, -C 2-8 dialkylamino, or -C 3-6 cyclo or alkyl, or X 1 and X 2 may be linked to each other to form a 4 to 7 membered ring together with the P atom;
  • Y 1 and Y 2 are each independently -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NR a R b , -OH, -OC 1-6 alkyl, or -halo, or Y 1 and Y 2 are a double ring linked to each other and including one or more of the N, O, and S atoms in the ring together with the pyrimidine ring can form a heteroaryl of ⁇ wherein at least one H of the heteroaryl of the double ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1 6 may be substituted with haloalkyl, -CN, -NR a R b , -OH, -OC 1-6 alkyl, or -halo ⁇ ;
  • Z 1 , Z 2 , or Z 3 are each independently —H, —C 1-6 alkyl, —C 1-6 aminoalkyl, —C 1-6 hydroxyalkyl, —C 1-6 haloalkyl, —CN , —NR a R b , —OH, —OC 1-6 alkyl, or —halo;
  • R A to R C are each independently —H, —C 1-6 alkyl, or —C 3-6 cycloalkyl, heterocycloalkyl ⁇ wherein one or more of the —C 3-6 cycloalkyl or heterocycloalkyl H may be substituted with -C 1-6 alkyl or -C 3-6 cycloalkyl ⁇ ;
  • R 1 and R 2 are each independently —H or —C 1-6 alkyl
  • R a and R b are each independently —H or —C 1-6 alkyl.
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • ring A is , , or and ⁇ here, , , or at least one H of is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NR a R b , -OH, - may be substituted with OC 1-6 alkyl, -halo, or -C 3-6 cycloalkyl ⁇ ;
  • a 1 to A 4 are each independently CH or N;
  • B 1 and B 2 are each independently CH, CH 2 , N, NH, or O;
  • B 3 to B 5 are each independently CH or N;
  • X is , , , or ego
  • X 1 , X 2 , X 4 to X 8 are each independently —H or —C 1-6 alkyl;
  • Y 1 and Y 2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo, or Y 1 and Y 2 are linked to each other and together with the pyrimidine ring N in the ring , O, and S atoms to form a double ring heteroaryl, wherein at least one H of the double ring heteroaryl is -C 1-6 alkyl, -C 1-6 haloalkyl , -CN, or -halo which may be substituted ⁇ ;
  • Z 1 , Z 2 , or Z 3 are each independently —H, —C 1-6 alkyl, —C 1-6 haloalkyl, —OC 1-6 alkyl, or —halo;
  • W 1 and W 2 are each independently —CR A R B —, —NR C —, or —O—;
  • R A to R C are each independently —H, —C 1-6 alkyl, or —C 3-6 cycloalkyl, heterocycloalkyl ⁇ wherein one or more of the —C 3-6 cycloalkyl or heterocycloalkyl H may be substituted with -C 1-6 alkyl or -C 3-6 cycloalkyl ⁇ ;
  • R 1 and R 2 are each independently —H or —C 1-6 alkyl
  • R a and R b are each independently —H or —C 1-6 alkyl.
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • ring A is , , , , or is ⁇ here, , , , , or at least one H of is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -NR a R b , -OH, - OC 1-6 alkyl, which may be substituted with -halo ⁇ .
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • X is , , , or ego
  • X 1 , X 2 , X 4 , X 6 , and X 8 are each independently —C 1-6 alkyl;
  • X 5 is -H
  • each X 7 is independently —H or —C 1-6 alkyl.
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • Y 1 is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo
  • Y 2 is -H, or Y 1 and Y 2 are linked to each other and together with the pyrimidine ring in the ring capable of forming a double ring heteroaryl comprising at least one of N, O, and S atoms ⁇ wherein at least one H of the double ring heteroaryl is —C 1-6 alkyl, —C 1-6 may be substituted with haloalkyl, -CN, or -halo ⁇ .
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • Z 1 is —H or —OC 1-6 alkyl
  • Z 2 is —H, —C 1-6 alkyl, or —halo
  • Z 3 is -H.
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • W 1 and W 2 are each independently —CR A R B —, —NR C —, or —O—;
  • R A to R C are each independently —H, —C 1-6 alkyl, or —C 3-6 cycloalkyl, heterocycloalkyl ⁇ wherein one or more of the —C 3-6 cycloalkyl or heterocycloalkyl H may be substituted with -C 1-6 alkyl or -C 3-6 cycloalkyl ⁇ .
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • R 1 is —H
  • R 2 is -H.
  • the compound represented by Formula 1 may be selected from the group consisting of compounds listed in Tables 1 to 4 described below.
  • alkyl may mean a straight or branched acyclic, cyclic, or saturated hydrocarbon to which they are bonded.
  • C 1-6 alkyl can mean an alkyl containing 1 to 6 carbon atoms.
  • Acyclic alkyl may include, as an example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc., It is not limited thereto.
  • Cyclic alkyl may be used interchangeably with “cycloalkyl” herein, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. doesn't happen
  • alkoxy may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above.
  • C 1-6 alkoxy may mean alkoxy containing C 1-6 alkyl, that is, -(OC 1-6 alkyl).
  • alkoxy is methoxy ), ethoxy, n -propoxy, isopropoxy, n -butoxy , isobutoxy , sec -butoxy ), or tert - butoxy , etc., but is not limited thereto.
  • halo may be F, Cl, Br, or I.
  • haloalkyl may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo substituted carbon atoms as defined herein.
  • haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .
  • aminoalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino-(NR'R"), wherein R' and R" are each independently hydrogen. , and may be selected from the group consisting of C 1-6 alkyl, wherein the selected R′ and R′′ may each independently be substituted or unsubstituted.
  • heterocycloalkyl may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated.
  • unsaturated it may be referred to as a heterocycloalkene.
  • heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring or a fused ring.
  • heterocycloalkyl may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring
  • heterocycloalkyl is pyrrolidine, piperidine, Imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H ) -Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline , thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3
  • arene may mean an aromatic hydrocarbon ring.
  • the arene may be a monocyclic arene or a polycyclic arene.
  • the ring carbon number of arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less.
  • examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. , but not limited to these.
  • the residue obtained by removing one hydrogen atom from "arene” is referred to as "aryl".
  • heteroene may be a ring including at least one of O, N, P, Si, and S as a heterogeneous element.
  • the number of ring carbon atoms in the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less.
  • the heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene.
  • the polycyclic heteroarene may have, for example, a two- or three-ring structure.
  • heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine , pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine , imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, be
  • heteroarenes may also include bicyclic heterocyclo-arenes, including arene rings fused to heterocycloalkyl rings or heteroarenes fused to cycloalkyl rings.
  • heteroaryl the residue obtained by removing one hydrogen atom from the "heteroarene” is referred to as "heteroaryl”.
  • the above-mentioned homologous or heterogeneous substituents may be substituted one or more at the same position or different positions, and may also be substituted sequentially.
  • the term "sequentially” means that in the formula, one substituent is substituted and then another substituent is successively substituted in the substituent, for example, after the alkyl group is substituted, a cycloalkyl group is substituted in the alkyl group and the When a carbonyl group is sequentially substituted for a cycloalkyl group, it can be indicated that the cycloalkyl group is sequentially substituted by naming it carbonylcycloalkylalkyl.
  • linking radicals do not specify the bonding direction, and the bonding direction is arbitrary.
  • the connected radical L is -MW-, where -MW- connects Ring A and Ring B in the same direction as the reading order from left to right. can be formed, and by connecting Ring A and Ring B in the reverse reading order from left to right, can form.
  • enantiomer means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention.
  • a solid line bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid line bond indicating the absolute configuration of the stereocenter. or wedge-dotted join may include
  • the compound of Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt".
  • a pharmaceutically acceptable salt As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt refers to any of the compounds at a concentration having an effective action that is relatively non-toxic and harmless to a patient, and the side effects due to the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). Any organic or inorganic acid addition salt of
  • Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of compound and acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • an organic acid and an inorganic acid may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid.
  • organic acid methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc.
  • the present invention is not limited thereto.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group
  • other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a known salt.
  • the present invention provides the use of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against various kinases (Experimental Example 1).
  • the heteroaryl derivative represented by Formula 1 since the heteroaryl derivative represented by Formula 1 exhibits excellent inhibitory activity on EGFR (Epidermal Growth Factor Receptor) among various kinases, it treats or prevents EGFR-related diseases, particularly cancer. can be usefully used for Specifically, the compound of Formula 1 can inhibit EGFR wild-type or mutant kinase, which is supported by the experimental examples described below.
  • EGFR Epidermal Growth Factor Receptor
  • the EGFR mutation is EGFR Del19/T790M, EGFR Del19/T790M/C797S, EGFR L858R/T790M, EGFR L858R, EGFR Exon20 ins NPH, EGFR Exon20 ins SVD, EGFR Exon20 ins FQEA, EGFR Exon20 ins H, and EGFR Exon20 ins A It may be one or more selected from the group consisting of, but is not limited thereto.
  • the cancer includes all cancers capable of exhibiting therapeutic or preventive efficacy due to inhibition of EGFR activity, and may be solid cancer or blood cancer.
  • pseudomyxoma intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell cancer, ovarian cancer Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, Parat
  • the present invention provides a pharmaceutical composition for the treatment or prevention of EGFR-related diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the EGFR-related disease may be cancer.
  • the types of cancer are as described above.
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the step of administering to a subject in need thereof a therapeutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof provides a method for treating or preventing EGFR-related diseases, including.
  • the subject may be a mammal including a human.
  • the term "therapeutically effective amount” refers to an amount of the compound represented by Formula 1 effective for the treatment or prevention of EGFR-related diseases. Specifically, “therapeutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and effective dose level includes the subject type and severity, age, sex, type of disease, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field may be determined according to factors.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents.
  • the dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used even more than the determined dosage.
  • the present invention is a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutical thereof for use in the preparation of a medicament for use in the treatment or prevention of EGFR-related diseases
  • a use (use) of a commercially acceptable salt may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients by being prepared as a complex formulation together with other active agents.
  • Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.
  • the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art.
  • "including" a certain element means that other elements may be further included, rather than excluding other elements, unless otherwise stated.
  • heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against EGFR, it can be usefully used for the treatment or prevention of EGFR-related diseases.
  • room temperature means a temperature of about 20 ⁇ 25 °C
  • room temperature means a temperature of 15 ⁇ 25 °C.
  • Concentration or solvent distillation under reduced pressure was performed using a rotary evaporator.
  • Step 1 Preparation of ethyl (R)-4-oxo-1-((S)-1-phenylethyl)piperidine-2-carboxylate
  • Step 2 Preparation of ethyl (R)-8-((S)-1-phenylethyl)-1,4-dioxa-8-azaspiro[4.5]decane-7-carboxylate
  • Step 3 Preparation of ((R)-8-((S)-1-phenylethyl)-1,4-dioxa-8-azaspiro[4.5]decan-7-yl)methanol
  • Ethyl (R)-8-((S)-1-phenylethyl)-1,4-dioxa-8-azaspiro[4.5]decane-7-carboxylate (1 equivalent) prepared in step 2 was After dissolving in THF (0.2 M), LAH was added at 0 °C and stirred at room temperature for 16 hours. Water and EtOAc were added at 0 °C, stirred for 20 minutes, and filtered through Celite. The organic matter was extracted from the filtrate using water and brine. The collected organic layer was concentrated after removing the remaining water using Na 2 SO 4 . The obtained white solid target compound was used in the following reaction without further purification (yield: 91 %, MS (ESI): m/z 278 [M+H] + ).
  • Step 5 (R)-2-Methoxy-3-nitro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1,4 ]Preparation of oxazine-8,2'-[1,3]dioxolane]
  • Step 7 (6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-3-nitro-6,6a,7,8,9,10-hexahydrobenzo[b ] Preparation of pyrido [1,2-d] [1,4] oxazine
  • Step 8 (6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1 Preparation of ,2-d][1,4]oxazin-3-amine
  • Step 4 (R)-(6-((5-bromo-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydro Preparation of benzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
  • reaction mixture was cooled to room temperature, 1M aqueous NaOH solution was added to the reaction mixture to adjust the pH to 12, and then the organic matter was extracted with DCM. The collected organic layer was concentrated after removing the remaining water using Na 2 SO 4 .
  • the reaction mixture was purified through prep-HPLC to obtain the title compound as a yellow solid (yield: 26 %, MS (ESI): m/z 679 [M+H] + ).
  • Examples 2 to 64 were prepared in a manner similar to Example 1 above. Chemical structures, compound names, NMR, yield, and HPLC analysis results of the compounds of Examples 1 to 64 are summarized in Table 1 below.
  • Example 65 (R)-(2-((2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2] Preparation of -d][1,4])oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
  • Step 1 (2-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl ) Preparation of dimethyl phosphine oxide
  • Step 2 (R)-(2-((2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2- d][1,4]oxazin-8-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Preparation of work) amino) phenyl) dimethyl phosphine oxide
  • Step 3 (R)-(2-((2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-] Preparation of d][1,4])oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
  • reaction mixture was concentrated and dissolved in THF again, sat.NaHCO 3 was added, and the mixture was stirred at 60° C. for 16 hours. Water and brine were added, and organic matter was extracted with EtOAc. The collected organic layer was concentrated after removing the remaining water using Na 2 SO 4 .
  • the reaction mixture was purified through prep-HPLC to obtain the title compound as a brown solid (yield: 49 %, MS (ESI): m/z 548 [M+H] + ).
  • Example 137 N-(2-((5-chloro-2-(((6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7, of 8,9,10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide Produce
  • Step 1 N One Preparation of -(2,5-dichloropyrimidin-4-yl)benzene-1,2-diamine
  • N 1 -(2,5-dichloropyrimidin-4-yl)benzene-1,2-diamine (1 eq.) and methanesulfonylchloride (1.2 eq.) prepared in step 1 were dissolved in pyridine (0.2 M) After dissolving, the mixture was stirred at room temperature for 1 hour. Water and brine were added, and organic matter was extracted with EtOAc. The collected organic layer was concentrated after removing the remaining water using Na 2 SO 4 . The reaction mixture was purified through MPLC (DCM:MeOH) to obtain the title compound as a yellow solid (yield: 57 %, MS (ESI): m/z 333 [M] + ).
  • Step 3 N-(2-((5-chloro-2-(((6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8) Preparation of ,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide
  • N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide (1 eq) prepared in step 2, (6aR,8S)-2-methoxy-8- (4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-amine (1.2 eq.) was dissolved in 2-methoxyethanol (0.232 M), 2.5 M HCl in EtOH (2.6 eq) was added and stirred at 120 °C for 4 hours. After the reaction mixture was cooled to room temperature, the pH was adjusted to 12 using 2 M aqueous NaOH solution.
  • 1 H NMR 400 MHz, FA salt, DMSO- d 6 ) ⁇ 8.54 (s, 1H), 8.16 (s, 1H, FA), 8.12-8.05 (m, 2H), 7.82 (s, 1H), 7.36 7.29 (m, 1H), 7.22-7.14 (m, 1H), 7.14-7.06 (m, 2H), 6.57 (s, 1H), 5.75 (s, 1H), 4.20-4.
  • Step 2 N-(2-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Preparation of yl) amino) phenyl) methanesulfonamide
  • Step 3 (R)-N-(2-((5-chloro-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2] -d][1,4]oxazin-8-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 Preparation of -yl)amino)phenyl)methanesulfonamide
  • Step 4 (R)-N-(2-((5-chloro-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2] Preparation of -d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide
  • reaction mixture was concentrated and dissolved in THF again, sat.NaHCO 3 was added, and the mixture was stirred at 60° C. for 16 hours. Water and brine were added, and organic matter was extracted with EtOAc. The collected organic layer was concentrated after removing the remaining water using Na 2 SO 4 .
  • the reaction mixture was purified through prep-HPLC to obtain the title compound as a brown solid (yield: 32 %, MS (ESI): m/z 555 [M] + ).
  • the following experiments were performed. Specifically, with respect to the compound of Example 2 selected from among the compounds of the examples of the present invention, the enzyme (kinase) selectivity was measured by requesting DiscoverX, and the experiment was conducted using the scanMAX TM Kinase analysis panel. At this time, the concentration of the drug treated with the enzyme was 1 ⁇ M in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below.
  • the positive control refers to a compound showing a percentage control of 0%
  • the negative control indicates a percentage control of 100% with DMSO.
  • the enzyme selectivity of the present invention was determined to have activity for each enzyme if the control percentage was ⁇ 30% (ie, less than 30%) for each enzyme.
  • the compound of Example 2 had an activity against the following enzymes with a control percentage of ⁇ 30% (ie, less than 30%) for the following enzymes: EGFR, EGFR (E746-A750del), EGFR (G719C), EGFR (G719S), EGFR (L747-E749del, A750P), EGFR (L747-S752del, P753S), EGFR (L747-T751del, Sins), EGFR (L858R), EGFR (L858R, T790M), EGFR ( L861Q), EGFR (S752-I759del), EGFR (T790M).
  • BaF3-EGFR (WT), BaF3-EGFR (Del19/T790M/C797S) cells were seeded in clear bottom white 96-well plates at a volume of 3 ⁇ 10 3 /100 ⁇ l/well, and 12 concentrations were serially diluted in triplicate ( 0.00001 - 2 mM) of the compound and the DMSO control were added at 0.5 ⁇ l/well to a final concentration of 0.00005 - 10 ⁇ M, followed by incubation at 37 ° C. CO 2 in an incubator for 72 hours. After 72 hours, the plate treated with the compound was taken out, and 100 ⁇ l/well of CellTiter-Glo® 2.0 Assay (Promega) solution was treated and mixed well.
  • Table 5 shows the results of evaluation of the proliferation inhibitory activity of Ba/F3 cells expressing EGFR mutations.
  • Example Ba/F3 (GI 50 , ⁇ M) Example Ba/F3 (GI 50 , ⁇ M) Example Ba/F3 (GI 50 , ⁇ M) EGFR WT EGFR Del19/T790M/C797S EGFR WT EGFR Del19/T790M/C797S EGFR WT EGFR Del19/T790M/C797S One B A 46 B A 94 B A 2 B A 47 B B 95 C B 3 C C 48 B A 96 C B 5 B B 49 B B 98 C A 6 A A 50 C C 99 C B 8 A A 51 B B 100 C A 9 A A 52 C C 101 C A 10 A A 53 C B 103 C A 11 B A 54 A A 104 C B 12 B A 55 C C C 116 C A 13 C B 56 A A A 120 C A 14 C B 57 B A 121 C A 15 B C 58 B B B 131 C B 22 C C C 59 B A 132 C B 26 C C 60 B B 137 B B

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Abstract

La présente invention concerne un composé dérivé d'hétéroaryle et son utilisation. Un dérivé d'hétéroaryle de la présente invention présente une excellente activité inhibitrice vis-à-vis de l'EGFR, et peut donc être utilisé efficacement en tant qu'agent thérapeutique pour des maladies associées à EGFR.
PCT/KR2021/019439 2020-12-21 2021-12-20 Composé dérivé d'hétéroaryle et son utilisation Ceased WO2022139386A1 (fr)

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WO2024153248A1 (fr) * 2023-01-19 2024-07-25 杭州英创医药科技有限公司 Composé tricyclique fusionné utilisé en tant qu'inhibiteur de kinase

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WO2025055976A1 (fr) * 2023-09-13 2025-03-20 深圳众格生物科技有限公司 Inhibiteur d'ulk1, son procédé de préparation et son utilisation

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Publication number Priority date Publication date Assignee Title
US12037346B2 (en) 2021-04-13 2024-07-16 Nuvalent, Inc. Amino-substituted heteroaryls for treating cancers with EGFR mutations
WO2024153248A1 (fr) * 2023-01-19 2024-07-25 杭州英创医药科技有限公司 Composé tricyclique fusionné utilisé en tant qu'inhibiteur de kinase

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