WO2022139386A1 - Heteroaryl derivative compound and use thereof - Google Patents

Heteroaryl derivative compound and use thereof 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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WIPO (PCT)
Prior art keywords
amino
oxazin
pyrimidin
hexahydrobenzo
phenyl
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PCT/KR2021/019439
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French (fr)
Korean (ko)
Inventor
고이경
한아름
박진희
이영덕
임혜림
김균은
황동근
남수빈
고은화
김성환
최환근
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주식회사 비투에스바이오
보로노이 주식회사
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Publication of WO2022139386A1 publication Critical patent/WO2022139386A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—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

The present invention relates to a heteroaryl derivative compound and a use thereof. A heteroaryl derivative of the present invention exhibits excellent inhibitory activity with respect to EGFR, and thus can be effectively used as a therapeutic agent for EGFR-associated diseases.

Description

헤테로아릴 유도체 화합물 및 이의 용도Heteroaryl derivative compounds and uses thereof
본 발명은 헤테로아릴 유도체 화합물 및 이의 의약적 용도에 관한 것이다. 구체적으로, 본 발명은 EGFR 억제 활성을 갖는 헤테로아릴 유도체 화합물에 관한 것이다.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.
단백질 키나아제는 분자 스위치로 작용하여 신호전달경로에 관여하는데, 세포 내에서 키나아제에 의한 표적 단백질의 활성과 비활성 상태 사이의 전환은 원활하게 조절되어야 한다. 만약, 상기 활성과 비활성 상태 사이의 전환이 비정상적으로 조절되면 세포 내 신호 전달을 과도하게 활성화하거나 비활성화시켜 통제불능의 세포 분열 및 증식을 유도하게 된다. 특히, 단백질 키나아제 유전자의 변이, 증폭 및/또는 과발현에 의한 비정상적인 활성화는 다양한 종양의 발생 및 진행을 유발하거나 염증성 질환, 퇴행성 뇌질환, 자가면역 질환 등 다양한 질병의 발병에 결정적인 역할을 하게 된다. 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.
특히, ErbB 패밀리의 수용체 티로신 키나아제(receptor tyrosine kinase)인 상피 성장 인자 수용체(epidermal growth factor receptor, EGFR)는 비소세포폐암종(NSCLC), 유방암, 신경교종, 두경부의 편평 세포 암종, 대장암, 곧창자 샘암종, 두경부암, 위암 및 전립선암을 포함한 많은 상피세포 종양에서 비정상적으로 활성화되어 있고, 상기 EGFR-티로신 키나아제의 활성화가 지속적인 세포 증식, 주변 조직에 대한 침범, 원격 전이, 혈관 형성을 일으키며 세포 생존을 증가시킴이 알려진 바 있다.In particular, epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the ErbB family, is used in non-small cell lung carcinoma (NSCLC), 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, and 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
한편, EGFR 돌연변이인 EGFR_del19 또는 EGFR_L858R이 비소세포폐암과 두경부암의 주요한 원인이라는 것이 알려져 있었고, 이들의 치료제인 이레사, 타세바가 개발되어 현재 임상에서 사용되고 있다. 하지만, 이러한 약물을 환자에 사용하였을 때 약물의 구조에 기반을 두는 EGFR 2차 돌연변이가 생기는 획득내성(acquired resistance)이 관찰되었고, 이것이 실제 약제내성의 주요 원인이라는 것도 밝혀졌다. EGFR 1세대 저해제를 평균 10개월 정도 사용하게 되면 EGFR 키나아제의 게이트키퍼(gatekeeper)에 위치한 T790M 돌연변이라는 획득내성이 발생하여 EGFR 1세대 저해제들이 약효를 내지 못하는 것이다. 즉, EGFR_del19_T790M 또는 EGFR_L858R_T790M 이중돌연변이가 발생하여 기존 치료제가 약효를 나타내지 못하게 된다. T790M 변이에 따른 약물 저항성에 대해 높은 반응성을 나타내는 3세대 EGFR-TKI 표적 약물인 오시머티닙(Osimertinib)이 개발되었으나, 이로부터 역시 약물 저항성이 생기는 것으로 보고되었다(Clin Cancer Res, 2015, 17:21). EGFR C797S 변이는 오시머티닙에 대한 약물 내성을 야기하는 주요 메커니즘 중 하나로 제시되었으며, 임상 시험 환자 중 약 40 %가 C797S 변이를 가지는 것으로 보고되었다(Nature Medicine, 2015, 21:560-562).On the other hand, it was known that 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. However, when 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. When 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. That is, 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).
이와 같이 EGFR 활성을 조절함으로써 EGFR 관련 질환의 치료에 유용하게 활용될 수 있는 신규 화합물에 대한 미충족된 수요가 증대되고 있다.As such, by regulating EGFR activity, there is an increasing unmet demand for novel compounds that can be usefully utilized for the treatment of EGFR-related diseases.
본 발명의 목적은 신규한 구조의 헤테로아릴 유도체, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.It is an object of the present invention to provide a heteroaryl derivative having a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 상기 헤테로아릴 유도체 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the heteroaryl derivative compound.
본 발명의 다른 목적은 상기 헤테로아릴 유도체 화합물의 의약용도를 제공하는 것으로서, 구체적으로 상기 헤테로아릴 유도체 화합물을 유효성분으로 포함하는 EGFR 관련 질환의 치료 또는 예방용 약학적 조성물, 상기 화합물을 이용한 EGFR 관련 질환의 치료 또는 예방 용도 또는 상기 화합물을 투여하는 단계를 포함하는 EGFR 관련 질환의 치료 또는 예방방법을 제공하는 것이다.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 To provide a method for treating or preventing an EGFR-related disease, comprising administering the compound or use for the treatment or prevention of a disease.
상기 목적을 달성하기 위하여, 본 발명자들이 연구 노력한 결과, 아래에서 언급하는 화학식 1로 표시되는 헤테로아릴 유도체 화합물들이 EGFR이 활성화된 세포의 증식을 저해하는 것을 확인함으로써 본 발명을 완성하였다.In order to achieve the above object, as a result of research efforts of the present inventors, 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.
헤테로아릴 유도체 화합물Heteroaryl Derivative Compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다:The present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2021019439-appb-img-000001
Figure PCTKR2021019439-appb-img-000001
상기 화학식 1에서,In Formula 1,
고리 A는ring A is
Figure PCTKR2021019439-appb-img-000002
,
Figure PCTKR2021019439-appb-img-000003
, 또는
Figure PCTKR2021019439-appb-img-000004
이고 {여기서,
Figure PCTKR2021019439-appb-img-000005
,
Figure PCTKR2021019439-appb-img-000006
, 또는
Figure PCTKR2021019439-appb-img-000007
의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, -할로, 또는 -C3-6사이클로알킬로 치환될 수 있음};
Figure PCTKR2021019439-appb-img-000002
,
Figure PCTKR2021019439-appb-img-000003
, or
Figure PCTKR2021019439-appb-img-000004
and {here,
Figure PCTKR2021019439-appb-img-000005
,
Figure PCTKR2021019439-appb-img-000006
, or
Figure PCTKR2021019439-appb-img-000007
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};
A1 내지 A4는 각각 독립적으로 CH 또는 N이고;A 1 to A 4 are each independently CH or N;
B1 및 B2는 각각 독립적으로 CH, CH2, N, NH, O, 또는 S이고;B 1 and B 2 are each independently CH, CH 2 , N, NH, O, or S;
B3 내지 B5는 각각 독립적으로 CH 또는 N이고;B 3 to B 5 are each independently CH or N;
Figure PCTKR2021019439-appb-img-000008
는 단일 결합 또는 이중 결합이고;
Figure PCTKR2021019439-appb-img-000008
is a single bond or a double bond;
X는
Figure PCTKR2021019439-appb-img-000009
,
Figure PCTKR2021019439-appb-img-000010
,
Figure PCTKR2021019439-appb-img-000011
,
Figure PCTKR2021019439-appb-img-000012
,
Figure PCTKR2021019439-appb-img-000013
, 또는
Figure PCTKR2021019439-appb-img-000014
이고;X is
Figure PCTKR2021019439-appb-img-000009
,
Figure PCTKR2021019439-appb-img-000010
,
Figure PCTKR2021019439-appb-img-000011
,
Figure PCTKR2021019439-appb-img-000012
,
Figure PCTKR2021019439-appb-img-000013
, or
Figure PCTKR2021019439-appb-img-000014
ego;
X1 내지 X8은 각각 독립적으로 -H, -C1-6알킬, -C1-6알콕시, -C1-6알킬아미노, -C2-8다이알킬아미노, 또는 -C3-6사이클로알킬이거나, 또는 상기 X1 및 X2는 서로 연결되어 P 원자와 함께 4 내지 7원 고리를 형성할 수 있고;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;
Y1 및 Y2는 각각 독립적으로 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, 또는 -할로이고, 또는 Y1 및 Y2는 서로 연결되어 피리미딘 고리와 함께 고리 내 N, O, 및 S 원자 중 하나 이상을 포함하는 이중 고리의 헤테로아릴을 형성할 수 있고 {여기서, 상기 이중 고리의 헤테로아릴의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, 또는 -할로로 치환될 수 있음}; 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};
Z1, Z2, 또는 Z3는 각각 독립적으로 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, 또는 -할로이고;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;
W1 및 W2는 각각 독립적으로 -CRARB-, -NRC-, -O-, -S-, -S(=O)-, 또는 -SO2-이고;W 1 and W 2 are each independently -CR A R B -, -NR C -, -O-, -S-, -S(=O)-, or -SO 2 -;
RA 내지 RC는 각각 독립적으로 -H, -C1-6알킬, 또는 -C3-6사이클로알킬, 헤테로사이클로알킬이고 {여기서, 상기 -C3-6사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬 또는 -C3-6사이클로알킬로 치환될 수 있음};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};
R1 및 R2는 각각 독립적으로 -H 또는 -C1-6알킬이고;R 1 and R 2 are each independently —H or —C 1-6 alkyl;
Ra 및 Rb는 각각 독립적으로 -H 또는 -C1-6알킬이다.R a and R b are each independently —H or —C 1-6 alkyl.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
고리 A는
Figure PCTKR2021019439-appb-img-000015
,
Figure PCTKR2021019439-appb-img-000016
, 또는
Figure PCTKR2021019439-appb-img-000017
이고 {여기서,
Figure PCTKR2021019439-appb-img-000018
,
Figure PCTKR2021019439-appb-img-000019
, 또는
Figure PCTKR2021019439-appb-img-000020
의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, -할로, 또는 -C3-6사이클로알킬로 치환될 수 있음}; ring A is
Figure PCTKR2021019439-appb-img-000015
,
Figure PCTKR2021019439-appb-img-000016
, or
Figure PCTKR2021019439-appb-img-000017
and {here,
Figure PCTKR2021019439-appb-img-000018
,
Figure PCTKR2021019439-appb-img-000019
, or
Figure PCTKR2021019439-appb-img-000020
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};
A1 내지 A4는 각각 독립적으로 CH 또는 N이고;A 1 to A 4 are each independently CH or N;
B1 및 B2는 각각 독립적으로 CH, CH2, N, NH, 또는 O이고;B 1 and B 2 are each independently CH, CH 2 , N, NH, or O;
B3 내지 B5는 각각 독립적으로 CH 또는 N이고;B 3 to B 5 are each independently CH or N;
Figure PCTKR2021019439-appb-img-000021
는 단일 결합 또는 이중 결합이고;
Figure PCTKR2021019439-appb-img-000021
is a single bond or a double bond;
X는
Figure PCTKR2021019439-appb-img-000022
,
Figure PCTKR2021019439-appb-img-000023
,
Figure PCTKR2021019439-appb-img-000024
, 또는
Figure PCTKR2021019439-appb-img-000025
이고;X is
Figure PCTKR2021019439-appb-img-000022
,
Figure PCTKR2021019439-appb-img-000023
,
Figure PCTKR2021019439-appb-img-000024
, or
Figure PCTKR2021019439-appb-img-000025
ego;
X1, X2, X4 내지 X8은 각각 독립적으로 -H 또는 -C1-6알킬이고;X 1 , X 2 , X 4 to X 8 are each independently —H or —C 1-6 alkyl;
Y1 및 Y2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, 또는 -할로이고, 또는 Y1 및 Y2는 서로 연결되어 피리미딘 고리와 함께 고리 내 N, O, 및 S 원자 중 하나 이상을 포함하는 이중 고리의 헤테로아릴을 형성할 수 있고 {여기서, 상기 이중 고리의 헤테로아릴의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -CN, 또는 -할로로 치환될 수 있음}; 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};
Z1, Z2, 또는 Z3는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, -O-C1-6알킬, 또는 -할로이고;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;
W1 및 W2는 각각 독립적으로 -CRARB-, -NRC-, 또는 -O-이고;W 1 and W 2 are each independently —CR A R B —, —NR C —, or —O—;
RA 내지 RC는 각각 독립적으로 -H, -C1-6알킬, 또는 -C3-6사이클로알킬, 헤테로사이클로알킬이고 {여기서, 상기 -C3-6사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬 또는 -C3-6사이클로알킬로 치환될 수 있음};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};
R1 및 R2는 각각 독립적으로 -H 또는 -C1-6알킬이고;R 1 and R 2 are each independently —H or —C 1-6 alkyl;
Ra 및 Rb는 각각 독립적으로 -H 또는 -C1-6알킬이다.R a and R b are each independently —H or —C 1-6 alkyl.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
고리 A는
Figure PCTKR2021019439-appb-img-000026
,
Figure PCTKR2021019439-appb-img-000027
,
Figure PCTKR2021019439-appb-img-000028
,
Figure PCTKR2021019439-appb-img-000029
, 또는
Figure PCTKR2021019439-appb-img-000030
이다 {여기서,
Figure PCTKR2021019439-appb-img-000031
,
Figure PCTKR2021019439-appb-img-000032
,
Figure PCTKR2021019439-appb-img-000033
,
Figure PCTKR2021019439-appb-img-000034
, 또는
Figure PCTKR2021019439-appb-img-000035
의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, -할로로 치환될 수 있음}.ring A is
Figure PCTKR2021019439-appb-img-000026
,
Figure PCTKR2021019439-appb-img-000027
,
Figure PCTKR2021019439-appb-img-000028
,
Figure PCTKR2021019439-appb-img-000029
, or
Figure PCTKR2021019439-appb-img-000030
is {here,
Figure PCTKR2021019439-appb-img-000031
,
Figure PCTKR2021019439-appb-img-000032
,
Figure PCTKR2021019439-appb-img-000033
,
Figure PCTKR2021019439-appb-img-000034
, or
Figure PCTKR2021019439-appb-img-000035
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}.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
X는
Figure PCTKR2021019439-appb-img-000036
,
Figure PCTKR2021019439-appb-img-000037
,
Figure PCTKR2021019439-appb-img-000038
, 또는
Figure PCTKR2021019439-appb-img-000039
이고;X is
Figure PCTKR2021019439-appb-img-000036
,
Figure PCTKR2021019439-appb-img-000037
,
Figure PCTKR2021019439-appb-img-000038
, or
Figure PCTKR2021019439-appb-img-000039
ego;
X1, X2, X4, X6, 및 X8은 각각 독립적으로 -C1-6알킬이고;X 1 , X 2 , X 4 , X 6 , and X 8 are each independently —C 1-6 alkyl;
X5는 -H이고;X 5 is -H;
X7은 각각 독립적으로 -H 또는 -C1-6알킬이다.each X 7 is independently —H or —C 1-6 alkyl.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
Y1은 -H, -C1-6알킬, -C1-6할로알킬, 또는 -할로이고, Y2는 -H이고, 또는 Y1 및 Y2는 서로 연결되어 피리미딘 고리와 함께 고리 내 N, O, 및 S 원자 중 하나 이상을 포함하는 이중 고리의 헤테로아릴을 형성할 수 있는 것이다 {여기서, 상기 이중 고리의 헤테로아릴의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -CN, 또는 -할로로 치환될 수 있음}.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}.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
Z1은 -H 또는 -O-C1-6알킬이고;Z 1 is —H or —OC 1-6 alkyl;
Z2는 -H, -C1-6알킬, 또는 -할로이고;Z 2 is —H, —C 1-6 alkyl, or —halo;
Z3는 -H이다.Z 3 is -H.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
W1 및 W2는 각각 독립적으로 -CRARB-, -NRC-, 또는 -O-이고;W 1 and W 2 are each independently —CR A R B —, —NR C —, or —O—;
RA 내지 RC는 각각 독립적으로 -H, -C1-6알킬, 또는 -C3-6사이클로알킬, 헤테로사이클로알킬이다 {여기서, 상기 -C3-6사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬 또는 -C3-6사이클로알킬로 치환될 수 있음}.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}.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
R1은 -H이고;R 1 is —H;
R2는 -H이다.R 2 is -H.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물이 하기에 기재된 표 1 내지 표 4에 나열된 화합물로 이루어진 군으로부터 선택된 것일 수 있다.According to an embodiment of the present invention, the compound represented by Formula 1 may be selected from the group consisting of compounds listed in Tables 1 to 4 described below.
본 발명에 있어서, "알킬"은, 다른 기재가 없는 한, 직쇄 또는 분지쇄의 비고리형, 고리형 또는 이들이 결합된 포화 탄화수소를 의미할 수 있다. 예를 들어, "C1-6알킬"은 탄소 원자를 1 내지 6 개 포함하는 알킬을 의미할 수 있다. 비고리형 알킬은, 일 예로서, 메틸, 에틸, n-프로필, n-부틸, 아이소프로필, 2급(sec)-부틸, 아이소부틸, 또는 3급(tert)-부틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 고리형 알킬은 본 명세서에서 "사이클로알킬"과 교환적으로 사용될 수 있으며, 일 예로서, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 또는 사이클로옥틸 등을 포함할 수 있으나, 이에 제한되지 않는다. In the present invention, unless otherwise stated, "alkyl" may mean a straight or branched acyclic, cyclic, or saturated hydrocarbon to which they are bonded. For example, "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
본 발명에 있어서, "알콕시"는 알킬 에터기로 -(O-알킬)을 의미할 수 있고, 여기서, 알킬은 상기에서 정의된 바와 같다. 예를 들어, "C1-6의 알콕시"는 C1-6의 알킬을 함유하는 알콕시, 즉, -(O-C1-6알킬)을 의미할 수 있으며, 일 예로서, 알콕시는 메톡시(methoxy), 에톡시(ethoxy), n-프로폭시(n-propoxy), 아이소프로폭시(isopropoxy), n-부톡시(n-butoxy), 아이소부톡시(isobutoxy), sec-부톡시(sec-butoxy), 또는 tert-부톡시(tert-butoxy) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "alkoxy" may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above. For example, "C 1-6 alkoxy" may mean alkoxy containing C 1-6 alkyl, that is, -(OC 1-6 alkyl). For example, alkoxy is methoxy ), ethoxy, n -propoxy, isopropoxy, n -butoxy , isobutoxy , sec -butoxy ), or tert - butoxy , etc., but is not limited thereto.
본 발명에 있어서, "할로"는 F, Cl, Br, 또는 I일 수 있다.In the present invention, "halo" may be F, Cl, Br, or I.
본 발명에 있어서, "할로알킬"은 본원에 정의된 바와 같은 하나 이상의 할로로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 상기 할로알킬의 예로는 하나 이상의 할로겐, 예를 들어 F, Cl, Br, 또는 I로 독립적으로 치환된 메틸, 에틸, 프로필, 아이소프로필, 아이소부틸 또는 n-부틸을 포함하나, 이에 한정되는 것은 아니다.In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo substituted carbon atoms as defined herein. Examples of such 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. .
본 명세서에서, "아미노알킬"은 아미노-(NR'R")로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 여기서, R' 및 R"은 각각 독립적으로 수소, 및 C1-6알킬로 이루어진 군으로부터 선택될 수 있으며, 상기 선택된 R'및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다. As used herein, "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.
본 발명에 있어서, "헤테로사이클로알킬"은 고리를 형성하는 원자로 N, O 및 S로부터 선택된 1 내지 5 개의 헤테로 원자를 함유하는 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 헤테로사이클로알켄으로 지칭될 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬은 단일 고리이거나, 스파이로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리와 같은 다중 고리일 수 있다. 또한, "3 내지 12 원자의 헤테로사이클로알킬"은 고리를 형성하는 원자를 3 내지 12 개 포함하는 헤테로사이클로알킬을 의미할 수 있으며, 일 예로서, 헤테로사이클로알킬은 피롤리딘, 피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이미드, 피페리딘, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥산, 모르폴린, 싸이오모르폴린, 싸이오모르폴린-S-옥사이드, 싸이오모르폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 싸이오오피란, 피론, 테트라하이드로퓨란, 테트라하이드로싸이오펜, 퀴누클리딘, 트로판, 2-아자스파이로[3.3]헵탄, (1R,5S)-3-아자바이사이클로[3.2.1]옥탄, (1s,4s)-2-아자바이사이클로[2.2.2]옥탄, 또는 (1R,4R)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "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. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring or a fused ring. In addition, "3 to 12 membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring, for example, 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]heptane, ( 1R , 5S )-3-azabicyclo[3.2.1 ]octane, (1 s ,4 s )-2-azabicyclo[2.2.2]octane, or ( 1R , 4R )-2-oxa-5-azabicyclo[2.2.2]octane, and the like. can, but is not limited thereto.
본 발명에 있어서, "아렌"은 방향족 탄화수소 고리를 의미할 수 있다. 아렌은 단환식 아렌 또는 다환식 아렌일 수 있다. 아렌의 고리 형성 탄소수는 5 이상 30 이하, 5 이상 20 이하, 또는 5 이상 15 이하일 수 있다. 아렌의 예로는 벤젠, 나프탈렌, 플루오렌, 안트라센, 페난트렌, 바이벤젠, 터벤젠, 쿼터벤젠, 퀸크벤젠, 섹시벤젠, 트라이페닐렌, 피렌, 벤조 플루오란텐, 크리센 등을 예시할 수 있지만, 이들에 한정되지 않는다. 본 명세서에서 상기 "아렌"에서 수소 원자 하나를 제거한 잔기를 "아릴"로 지칭한다.In the present invention, "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. In the present specification, the residue obtained by removing one hydrogen atom from "arene" is referred to as "aryl".
본 발명에 있어서, "헤테로아렌"은 이종 원소로 O, N, P, Si, 및 S 중 1 개 이상을 포함하는 고리일 수 있다. 헤테로아렌의 고리 형성 탄소수는 2 이상 30 이하 또는 2 이상 20 이하일 수 있다. 헤테로아렌은 단환식 헤테로아렌 또는 다환식 헤테로아렌일 수 있다. 다환식 헤테로아렌은 예를 들어, 2 환 또는 3 환 구조를 갖는 것일 수 있다. 헤테로아렌의 예로는 싸이오펜, 퓨린, 피롤, 피라졸, 이미다졸, 싸이아졸, 옥사졸, 아이소싸이아졸, 옥사다이아졸, 트라이아졸, 피리딘, 비피리딜, 트라이아진, 아크리딜, 피리다진, 피라진, 퀴놀린, 퀴나졸린, 퀴녹살린, 페녹사진, 프탈라진, 피리미딘, 피리도 피리미딘, 피리도 피라진, 피라지노 피라진, 아이소퀴놀린, 인돌, 카바졸, 이미다조피리다진, 이미다조피리딘, 이미다조피리미딘, 피라졸로피리미딘, 이미다조피라진 또는 피라졸로피리딘, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸, 벤조옥사졸, 벤조이미다졸, 벤조싸이아졸, 벤조카바졸, 벤조싸이오펜, 다이벤조싸이오펜, 싸이에노싸이오펜, 벤조퓨란, 페난트롤린, 아이소옥사졸, 옥사다이아졸, 싸이아다이아졸, 벤조싸이아졸, 테트라졸, 페노싸이아진, 다이벤조실롤 및 다이벤조퓨란 등이 있으나, 이들에 한정되지 않는다. 본 발명의 일 실시 태양에서 헤테로아렌은 또한 헤테로사이클로알킬 고리에 융합된 아렌 고리 또는 사이클로알킬 고리에 융합된 헤테로아렌을 포함하는 바이사이클릭 헤테로사이클로-아렌을 포함할 수 있다. 본 명세서에서 상기 "헤테로아렌"에서 수소 원자 하나를 제거한 잔기를 "헤테로아릴"로 지칭한다.In the present invention, "heteroarene" 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. Examples of 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, benzoxazole, benzoimidazole, benzothiazole , benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine , dibenzosilol and dibenzofuran, but are not limited thereto. In one embodiment of the invention heteroarenes may also include bicyclic heterocyclo-arenes, including arene rings fused to heterocycloalkyl rings or heteroarenes fused to cycloalkyl rings. In the present specification, the residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as "heteroaryl".
상기 언급된 동종 또는 이종의 치환기는 동일한 위치 또는 상이한 위치에 하나 이상 치환될 수 있고, 순차적으로도 치환될 수 있다. 상기 "순차적"으로의 의미는 화학식에서 하나의 치환기가 치환된 후 상기 치환기에 또 다른 치환기가 연속하여 치환되는 것을 의미하며, 예를 들면, 알킬기가 치환된 후 상기 알킬기에 사이클로알킬기가 치환되고 상기 사이클로알킬기에 카르보닐기가 순차적으로 치환되는 경우에, 카르보닐사이클로알킬알킬로 명명함으로써 순차적으로 치환된 것임을 나타낼 수 있다.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.
또한, 상기 나열된 연결 라디칼은 결합 방향을 명시하지 않았으며 결합방향은 임의적이다. 예를 들어
Figure PCTKR2021019439-appb-img-000040
에서 연결된 라디칼 L은 -M-W-이고, 이 때, -M-W-는 고리 A와 고리 B를 왼쪽에서 오른쪽으로 읽기 순서와 같은 방향으로 연결하여
Figure PCTKR2021019439-appb-img-000041
를 형성할 수 있고, 고리 A와 고리 B를 왼쪽에서 오른쪽으로 읽기 순서와 반대 방향으로 연결하여
Figure PCTKR2021019439-appb-img-000042
를 형성할 수 있다.In addition, the above-listed linking radicals do not specify the bonding direction, and the bonding direction is arbitrary. for example
Figure PCTKR2021019439-appb-img-000040
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.
Figure PCTKR2021019439-appb-img-000041
can be formed, and by connecting Ring A and Ring B in the reverse reading order from left to right,
Figure PCTKR2021019439-appb-img-000042
can form.
본 발명에 있어서, 용어 "광학 이성질체(enantiomer)"는 동일한 화학식 또는 분자식을 가지지만 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 각각의 광학 이성질체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다. 다른 설명이 없는 한, 비대칭 탄소 원자와 연결되는 실선 결합 (-)은 입체 중심의 절대적 배열을 나타내는 쐐기형 실선 결합
Figure PCTKR2021019439-appb-img-000043
또는 쐐기형 점선 결합
Figure PCTKR2021019439-appb-img-000044
을 포함할 수 있다.In the present invention, the term "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. Unless otherwise noted, a solid line bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid line bond indicating the absolute configuration of the stereocenter.
Figure PCTKR2021019439-appb-img-000043
or wedge-dotted join
Figure PCTKR2021019439-appb-img-000044
may include
본 발명의 화학식 1의 화합물은 "약학적으로 허용가능한 염"의 형태로 존재할 수 있다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기산 또는 무기산 부가염을 의미한다.The compound of Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt". As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. As used herein, the term "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
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토나이트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.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.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 또는 질산 등을 사용할 수 있고 유기산으로는 메테인설폰산, p-톨루엔설폰산, 아세트산, 트라이플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 또는 아이오딘화수소산(hydroiodic acid) 등을 사용할 수 있다. 다만, 이들에 제한되지 않는다.In this case, 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. As the 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. can be used However, the present invention is not limited thereto.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, 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. In this case, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto. Also, 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).
본 발명의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 하이드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 하이드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메테인설포네이트(메실레이트), 및 p-톨루엔설포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.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. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and 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.
헤테로아릴 유도체 화합물의 용도Uses of Heteroaryl Derivative Compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염의 용도를 제공한다.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.
[화학식 1][Formula 1]
Figure PCTKR2021019439-appb-img-000045
Figure PCTKR2021019439-appb-img-000045
상기 화학식 1은 위에서 정의한 바와 같다.Formula 1 is as defined above.
본 발명의 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 다양한 키나아제에 대하여 억제 활성을 나타낸다(실험예 1). 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).
본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 헤테로아릴 유도체는 여러 키나아제 중에서 EGFR(Epidermal Growth Factor Receptor)에 대해 우수한 억제 활성을 나타내므로, EGFR 관련 질환, 특히, 암에 대하여 치료 또는 예방에 유용하게 사용될 수 있다. 구체적으로, 상기 화학식 1의 화합물은 EGFR 야생형 또는 돌연변이 키나아제를 억제할 수 있으며, 이는 후술하는 실험예에 의해 뒷받침된다. 상기 EGFR 돌연변이는 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, 및 EGFR Exon20 ins ASV로 이루어지는 군으로부터 선택되는 하나 이상일 수 있으나, 이에 제한되는 것은 아니다. According to one embodiment of the present invention, 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. 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.
본 발명에 있어서, 상기 암은 EGFR 활성 억제로 인해 치료 또는 예방 효능을 나타낼 수 있는 모든　암을 포함하며, 고형암　또는 혈액암일 수 있다. 예컨대, 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성 뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인 것일 수 있으나, 이에 제한되지 않는다. 또한, 상기　암은 원발성　암뿐 아니라 전이성　암도 포함한다.In the present invention, 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. For example, 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, Parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenum Cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer , breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, Pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymus cancer It may be at least one selected from the group consisting of, but is not limited thereto. In addition, the above cancers include not only primary cancers but also metastatic cancers.
본 발명의 일 구체예에 따르면, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 EGFR 관련 질환의 치료 또는 예방용 약학적 조성물을 제공한다. 구체적으로, 상기 EGFR 관련 질환은 암일 수 있다. 상기 암의 종류는 위에서 언급한 바와 같다. According to one embodiment of the present invention, 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. to provide. Specifically, the EGFR-related disease may be cancer. The types of cancer are as described above.
본 발명의 상기 약학적 조성물은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상을 더 포함할 수 있다. 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.
또한 본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, EGFR 관련 질환을 치료 또는 예방하는 방법을 제공한다. 상기 대상(subject)은 인간을 포함하는 포유류일 수 있다.Also, according to one embodiment of the present invention, 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 It provides a method for treating or preventing EGFR-related diseases, including. The subject may be a mammal including a human.
본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 EGFR 관련 질환의 치료 또는 예방에 유효한 상기 화학식 1로 표시되는 화합물의 양을 나타낸다. 구체적으로, "치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 투여 용량은, 환자의 상태, 연령, 성별 및 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다.As used herein, 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. and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art. 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.
또한 본 발명의 일 구체예에 따르면, 본 발명은 EGFR 관련 질환의 치료 또는 예방에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 화학식 1 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공한다. 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다. Also, according to one embodiment of the present invention, 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 Provided is a use (use) of a commercially acceptable salt. The compound represented by Formula 1 for the manufacture of a drug 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.
본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the uses, compositions, and treatment methods of the present invention are equally applicable as long as they do not contradict each other.
본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.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. In addition, 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. Furthermore, in the entire specification, "including" a certain element means that other elements may be further included, rather than excluding other elements, unless otherwise stated.
본 발명의 헤테로아릴 유도체 화합물은 EGFR에 대해 우수한 억제 활성을 나타내므로, 상기 EGFR 관련 질환의 치료 또는 예방에 유용하게 사용될 수 있다.Since the 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.
이하, 본 발명을 실시예 및 실험예에 의하여 상세히 설명한다. 단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 범위가 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.
<분석 및 정제 조건><Analysis and purification conditions>
1. HPLC 분석 조건 1. HPLC analysis conditions
기기명: Waters e2695Device name: Waters e2695
컬럼: Xbridge C18, 4.6 x 150 mm, 5 μm, 40 ℃Column: Xbridge C18, 4.6 x 150 mm, 5 μm, 40 °C
이동상: 20 % -> 95 % 아세토나이트릴/H2O + 0.1 % TFA Mobile phase: 20 % -> 95 % acetonitrile/H 2 O + 0.1 % TFA
분석시간: 10 분, 유속: 1 mL/minAnalysis time: 10 min, flow rate: 1 mL/min
UV detector: 254 nmUV detector: 254 nm
2. LC-MS 분석 조건2. LC-MS analysis conditions
기기명: Waters AQUITY UPLCDevice Name: Waters AQUITY UPLC
컬럼: AQUITY UPLC® BEH C18, 50 x 2.1 mm, 5 μm, 40 ℃Column: AQUITY UPLC ® BEH C18, 50 x 2.1 mm, 5 μm, 40 °C
이동상: 아세토나이트릴/H2O + 0.1% TFAMobile phase: acetonitrile/H 2 O + 0.1% TFA
유속: 0.6 mL/minFlow rate: 0.6 mL/min
UV detector: 254 nmUV detector: 254 nm
3. MPLC 정제 조건3. MPLC Purification Conditions
기기명: CombiFlash® Rf+Device name: CombiFlash ® Rf+
UV detector: 254 nmUV detector: 254 nm
4. Prep-HPLC 정제 조건 (A)4. Prep-HPLC purification conditions (A)
기기명: Waters GX-281, waters 2555 pump, waters 2998 photodiod array detectorDevice name: Waters GX-281, waters 2555 pump, waters 2998 photodiod array detector
컬럼: XBridge® Prep Shield RP18, 250 x 30 mm, 10 μmColumn: XBridge ® Prep Shield RP18, 250 x 30 mm, 10 μm
이동상: 아세토나이트릴/0.1% TFA H2OMobile phase: acetonitrile/0.1% TFA H 2 O
유속: 30 mL/minFlow rate: 30 mL/min
UV detector: 254 nmUV detector: 254 nm
5. Prep-HPLC 정제 조건 (B)5. Prep-HPLC purification conditions (B)
기기명: ACCQPrep HP125Device Name: ACCQPrep HP125
컬럼: XBridge® Prep Shield RP18, 250 x 19 mm, 10 μmColumn: XBridge ® Prep Shield RP18, 250 x 19 mm, 10 μm
이동상: 아세토나이트릴/0.1% TFA H2OMobile phase: acetonitrile/0.1% TFA H 2 O
유속: 25 mL/minFlow rate: 25 mL/min
UV detector: 254 nmUV detector: 254 nm
6. Prep-HPLC 정제 조건 (C)6. Prep-HPLC Purification Conditions (C)
기기명: ACCQPrep HP125Device Name: ACCQPrep HP125
컬럼: XBridge® Prep Shield RP18, 250 x 19 mm, 10 μmColumn: XBridge ® Prep Shield RP18, 250 x 19 mm, 10 μm
이동상: 아세토나이트릴/0.1 % FA H2OMobile phase: acetonitrile/0.1% FA H 2 O
유속: 25 mL/minFlow rate: 25 mL/min
UV detector: 254 nmUV detector: 254 nm
7. 7. 1One H NMRH NMR
기기명: Bruker Ascend™ 400 (400 MHz)Device name: Bruker Ascend™ 400 (400 MHz)
사용된 시판 시약은 추가 정제 없이 사용하였다. 본 발명에서 실온이란 20 ~ 25 ℃ 정도의 온도를 의미하고, 상온이란 15 ~ 25 ℃의 온도를 의미한다. 감압하 농축 또는 용매 증류 제거는 회전식 증발기(rotary evaporator)를 사용하였다.Commercial reagents used were used without further purification. In the present invention, room temperature means a temperature of about 20 ~ 25 ℃, room temperature means a temperature of 15 ~ 25 ℃. Concentration or solvent distillation under reduced pressure was performed using a rotary evaporator.
제조예 1: (6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-아민의 제조Preparation Example 1: (6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[ Preparation of 1,2-d][1,4]oxazin-3-amine
하기 반응식 1로 표시된 방법을 통해 표제의 화합물을 제조하였다.The title compound was prepared by the method shown in Scheme 1 below.
[반응식 1][Scheme 1]
Figure PCTKR2021019439-appb-img-000046
Figure PCTKR2021019439-appb-img-000046
단계 1: 에틸 (R)-4-옥소-1-((S)-1-페닐에틸)피페리딘-2-카르복실레이트의 제조Step 1: Preparation of ethyl (R)-4-oxo-1-((S)-1-phenylethyl)piperidine-2-carboxylate
(S)-1-페닐에탄-1-아민(1 당량), 에틸-2-옥소아세테이트(1.1 당량), 분자체(molecular sieve)를 톨루엔(0.6 M)에 녹인 후, 0 ℃에서 1 시간 동안 교반하였다. 반응 혼합물을 농축시킨 후, DMF(0.5 M)를 넣고 (부타-1,3-다이엔-2-일옥시)트라이메틸실란을 상온에서 천천히 적가하였다. -20 ℃로 반응 혼합물의 온도를 낮추고 TFA를 첨가한 후, 상온에서 16 시간 동안 교반하였다. sat.NaHCO3 을 넣고 pH 8로 맞춘 후, 셀라이트로 여과하고, 그 여액을 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(Hx:EtOAc)를 통해 정제하였고, 흰색 고체의 목적 화합물을 수득하였다(수율: 19 %, MS (ESI): m/z 276 [M+H]+).(S)-1-phenylethan-1-amine (1 eq.), ethyl-2-oxoacetate (1.1 eq.), and molecular sieve were dissolved in toluene (0.6 M), and then at 0 °C for 1 hour. stirred. After the reaction mixture was concentrated, DMF (0.5 M) was added, and (buta-1,3-dien-2-yloxy)trimethylsilane was slowly added dropwise at room temperature. After lowering the temperature of the reaction mixture to -20 °C and adding TFA, the mixture was stirred at room temperature for 16 hours. sat.NaHCO 3 was added, adjusted to pH 8, filtered through Celite, and the filtrate was extracted with EtOAc to organic matter. The collected organic layer was concentrated after removing the remaining water using Na 2 SO 4 . The reaction mixture was purified through MPLC (Hx:EtOAc) to obtain the title compound as a white solid (yield: 19 %, MS (ESI): m/z 276 [M+H] + ).
단계 2: 에틸 (R)-8-((S)-1-페닐에틸)-1,4-다이옥사-8-아자스파이로[4.5]데칸-7-카르복실레이트의 제조Step 2: Preparation of ethyl (R)-8-((S)-1-phenylethyl)-1,4-dioxa-8-azaspiro[4.5]decane-7-carboxylate
단계 1에서 제조한 에틸 (R)-4-옥소-1-((S)-1-페닐에틸)피페리딘-2-카르복실레이트(1 당량), 에틸렌글리콜(3.6 당량), pTSA(0.1 당량)을 톨루엔(0.34 M)에 녹인 후, 120 ℃에서 3 시간 동안 교반하였다. 반응 혼합물을 농축하여 MPLC(Hx:EtOAc)를 통해 정제하였고, 흰색 고체의 목적 화합물을 수득하였다(수율: 85 %, MS (ESI): m/z 320 [M+H]+).Ethyl (R)-4-oxo-1-((S)-1-phenylethyl)piperidine-2-carboxylate (1 eq.) prepared in step 1, ethylene glycol (3.6 eq.), pTSA (0.1 equivalent) was dissolved in toluene (0.34 M), followed by stirring at 120 °C for 3 hours. The reaction mixture was concentrated and purified through MPLC (Hx:EtOAc) to obtain the title compound as a white solid (yield: 85 %, MS (ESI): m/z 320 [M+H] + ).
단계 3: ((R)-8-((S)-1-페닐에틸)-1,4-다이옥사-8-아자스파이로[4.5]데칸-7-일)메탄올의 제조Step 3: Preparation of ((R)-8-((S)-1-phenylethyl)-1,4-dioxa-8-azaspiro[4.5]decan-7-yl)methanol
단계 2에서 제조한 에틸 (R)-8-((S)-1-페닐에틸)-1,4-다이옥사-8-아자스파이로[4.5]데칸-7-카르복실레이트(1 당량)를 THF(0.2 M)에 녹인 후, 0 ℃에서 LAH를 첨가하고 상온에서 16 시간 동안 교반하였다. 0 ℃에서 물과 EtOAc를 넣고 20분간 교반한 후, 셀라이트로 여과하였다. 그 여액을 물과 brine을 이용하여 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 얻어진 흰색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 이용하였다(수율: 91 %, MS (ESI): m/z 278 [M+H]+).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] + ).
단계 4: (R)-(1,4-다이옥사-8-아자스파이로[4.5]데칸-7-일)메탄올의 제조Step 4: Preparation of (R)-(1,4-dioxa-8-azaspiro[4.5]decan-7-yl)methanol
단계 3에서 제조한 ((R)-8-((S)-1-페닐에틸)-1,4-다이옥사-8-아자스파이로[4.5]데칸-7-일)메탄올(1 당량)을 MeOH(1 M)에 녹인 후, Pd/C(10 wt%)를 넣고 수소 퍼지(purge)하여 상온에서 16 시간 동안 교반하였다. 셀라이트로 여과한 후, 여액을 농축하였다. 얻어진 노란색 액체의 목적 화합물은 추가 정제 없이 다음 반응에 이용하였다(수율: 100 %).((R)-8-((S)-1-phenylethyl)-1,4-dioxa-8-azaspiro[4.5]decan-7-yl)methanol (1 equivalent) prepared in step 3 After dissolving in MeOH (1 M), Pd/C (10 wt%) was added, hydrogen purge was performed, and the mixture was stirred at room temperature for 16 hours. After filtration through Celite, the filtrate was concentrated. The obtained target compound as a yellow liquid was used in the next reaction without further purification (yield: 100%).
단계 5: (R)-2-메톡시-3-나이트로-6a,7,9,10-테트라하이드로-6H-스파이로[벤조[b]피리도[1,2-d][1,4]옥사진-8,2'-[1,3]다이옥솔란]의 제조Step 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]
단계 4에서 제조한 (R)-(1,4-다이옥사-8-아자스파이로[4.5]데칸-7-일)메탄올(1 당량), 1,2-다이플루오로-4-메톡시-5-나이트로벤젠(1.05 당량), KOH(2.5 당량)을 DMSO(0.5 M)에 녹인 후, 상온에서 1 시간 동안 교반한 후, 60 ℃에서 추가로 12 시간 동안 교반하였다. 물과 brine을 넣고 DCM로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(Hx:EtOAc)를 통해 정제하였고, 흰색 고체의 목적 화합물을 수득하였다(수율: 46 %, MS (ESI): m/z 323 [M+H]+).(R)-(1,4-dioxa-8-azaspiro[4.5]decan-7-yl)methanol (1 equivalent) prepared in step 4, 1,2-difluoro-4-methoxy- 5-nitrobenzene (1.05 equiv.) and KOH (2.5 equiv.) were dissolved in DMSO (0.5 M), stirred at room temperature for 1 hour, and then stirred at 60° C. for additional 12 hours. Water and brine were added, and 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 MPLC (Hx:EtOAc) to obtain the title compound as a white solid (yield: 46 %, MS (ESI): m/z 323 [M+H] + ).
단계 6: ((R)-2-메톡시-3-나이트로-6a,7,9,10-테트라하이드로벤조[b]피리도[1,2-d][1,4]옥사진-8(6H)-온의 제조Step 6: ((R)-2-Methoxy-3-nitro-6a,7,9,10-tetrahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-8 Preparation of (6H)-on
단계 5에서 제조한 (R)-2-메톡시-3-나이트로-6a,7,9,10-테트라하이드로-6H-스파이로[벤조[b]피리도[1,2-d][1,4]옥사진-8,2'-[1,3]다이옥솔란](1 당량)을 THF(0.3 M)에 녹인 후, 5% HCl 수용액(6.76 당량)을 첨가하고 40 ℃에서 28 시간 동안 교반하였다. 0 ℃에서 sat.Na2CO3를 넣고 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(DCM:EtOAc)를 통해 정제하였고, 주황색 고체의 목적 화합물을 수득하였다(수율: 95 %, MS (ESI): m/z 279 [M+H]+).(R)-2-methoxy-3-nitro-6a,7,9,10-tetrahydro-6H-spiro[benzo[b]pyrido[1,2-d][1] prepared in step 5 ,4]oxazine-8,2'-[1,3]dioxolane] (1 eq.) was dissolved in THF (0.3 M), 5% aqueous HCl solution (6.76 eq.) was added thereto, and at 40 °C for 28 hours stirred. At 0 °C, sat.Na 2 CO 3 was added and the organic material 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:EtOAc) to give the title compound as an orange solid (yield: 95 %, MS (ESI): m/z 279 [M+H] + ).
단계 7: (6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-3-나이트로-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진의 제조Step 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
단계 6에서 제조한 ((R)-2-메톡시-3-나이트로-6a,7,9,10-테트라하이드로벤조[b]피리도[1,2-d][1,4]옥사진-8(6H)-온(1 당량), 분자체(molecular sieve)를 무수(anhydrous) DCM(0.1 M)에 녹인 후, 1-메틸피페라진(1.2 당량), 아세트산(1 당량)을 첨가하여 상온에서 4 시간 동안 교반하였다. 반응 화합물을 0 ℃로 온도를 낮추고 NaBH(Oac)3(3 당량)을 첨가하고 상온에서 추가로 16 시간 동안 교반하였다. 물과 brine을 넣고 DCM로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 prep-HPLC를 통해 정제하였고, sat.NaHCO3를 이용하여 중화시켜 노란색 고체의 목적 화합물을 수득하였다(수율: 37 %, MS (ESI): m/z 363 [M+H]+).((R)-2-methoxy-3-nitro-6a,7,9,10-tetrahydrobenzo[b]pyrido[1,2-d][1,4]oxazine prepared in step 6 -8(6H)-one (1 equiv.) and molecular sieve were dissolved in anhydrous DCM (0.1 M), followed by addition of 1-methylpiperazine (1.2 equiv.) and acetic acid (1 equiv). The mixture was stirred at room temperature for 4 hours.The temperature of the reaction compound was lowered to 0 ° C., NaBH(Oac) 3 (3 equivalents) was added, and the mixture was stirred at room temperature for an additional 16 hours.Water and brine were added, and organics were extracted with DCM. The combined organic layers were concentrated to remove remaining water using Na 2 SO 4 , The reaction mixture was purified through prep-HPLC, and neutralized using sat.NaHCO 3 to obtain the target compound as a yellow solid (yield: 37 %, MS (ESI): m/z 363 [M+H] + ).
단계 8: (6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-아민의 제조Step 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
단계 7에서 제조한 (6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-3-나이트로-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진(1 당량)을 THF(0.1 M)에 녹인 후, Pd/C(10 wt%)를 넣고 수소 퍼지(purge)하여 상온에서 16 시간 동안 교반하였다. 셀라이트로 여과한 후, 여액을 농축하였다. 얻어진 보라색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 이용하였다(수율: 95 %, MS (ESI): m/z 333 [M+H]+).(6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-3-nitro-6,6a,7,8,9,10-hexahydrobenzo prepared in step 7 [b] After dissolving pyrido[1,2-d][1,4]oxazine (1 equivalent) in THF (0.1 M), Pd/C (10 wt%) was added, hydrogen purge was performed, and stirred for 16 hours. After filtration through Celite, the filtrate was concentrated. The obtained target compound as a purple solid was used in the following reaction without further purification (yield: 95 %, MS (ESI): m/z 333 [M+H] + ).
실시예 1: (R)-(6-((5-브로모-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드의 제조Example 1: (R)-(6-((5-bromo-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexa Hydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide Produce
하기 반응식 2로 표시된 방법을 통해 표제 화합물을 제조하였다.The title compound was prepared by the method shown in Scheme 2 below.
[반응식 2][Scheme 2]
Figure PCTKR2021019439-appb-img-000047
Figure PCTKR2021019439-appb-img-000047
단계 1: 5-요오도퀴녹살린-6-아민의 제조Step 1: Preparation of 5-iodoquinoxalin-6-amine
아세트산(2M)에 녹인 ICl(1.1 당량) 용액을 아세트산(0.66M)에 녹인 퀴녹살린-6-아민(1.0 당량) 용액에 첨가한 후, 상온에서 2 시간 동안 교반하였다. 물과 brine을 넣고 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(DCM:MeOH)를 통해 정제하였고, 갈색 고체의 목적 화합물을 수득하였다(수율: 75 %, MS (ESI): m/z 272 [M+H]+).A solution of ICl (1.1 eq) in acetic acid (2M) was added to a solution of quinoxalin-6-amine (1.0 eq) in acetic acid (0.66M), followed by stirring at room temperature for 2 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 MPLC (DCM:MeOH) to obtain the title compound as a brown solid (yield: 75 %, MS (ESI): m/z 272 [M+H] + ).
단계 2: (6-아미노퀴녹살린-5-일)다이메틸포스핀옥사이드의 제조Step 2: Preparation of (6-aminoquinoxalin-5-yl)dimethylphosphine oxide
단계 1에서 제조한 5-요오도퀴녹살린-6-아민(1.0 당량), 다이메틸포스핀옥사이드(1.5 당량), K3PO4를 DMF/H2O(5/1, 0.5M)에 녹인 후, 질소 하에서 Pd(OAc)2(0.1 당량)와 Xantphos(0.1 당량)를 첨가하고 120 ℃에서 1 시간 동안 교반하였다. 반응 혼합물을 셀라이트로 여과한 뒤, 물과 brine을 넣고 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(DCM:MeOH)를 통해 정제하였고, 노란색 고체의 목적 화합물을 수득하였다(수율: 62 %, MS (ESI): m/z 222 [M+H]+).5-iodoquinoxalin-6-amine (1.0 equiv.), dimethylphosphine oxide (1.5 equiv.), K 3 PO 4 prepared in step 1 were dissolved in DMF/H 2 O (5/1, 0.5M) Then, Pd(OAc) 2 (0.1 equiv.) and Xantphos (0.1 equiv) were added under nitrogen, and the mixture was stirred at 120° C. for 1 hour. The reaction mixture was filtered through celite, water and brine were added, and organics were 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: 62 %, MS (ESI): m/z 222 [M+H] + ).
단계 3: (6-((5-브로모-2-클로로피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드의 제조Step 3: Preparation of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide
단계 2에서 제조한 (6-아미노퀴녹살린-5-일)다이메틸포스핀옥사이드(1.0 당량), 5-브로모-2,4-다이클로로피리미딘(3 당량), DIPEA(4 당량)를 아이소프로필알코올(0.2 M)에 녹인 후, 120 ℃에서 10 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시킨 후, 5-브로모-2,4-다이클로로피리미딘(3 당량)을 추가로 넣고 120 ℃에서 13 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시킨 후, 5-브로모-2,4-다이클로로피리미딘(1.5 당량)을 추가로 넣고 120 ℃에서 5 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시킨 후, 반응 혼합물에 물과 brine을 넣고, EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(DCM:MeOH)를 통해 정제하였고, 노란색 고체의 목적 화합물을 수득하였다(수율: 54 %, MS (ESI): m/z 413 [M+H]+).(6-aminoquinoxalin-5-yl)dimethylphosphine oxide (1.0 equiv.) prepared in step 2, 5-bromo-2,4-dichloropyrimidine (3 equiv.), and DIPEA (4 equiv.) After dissolving in isopropyl alcohol (0.2 M), the mixture was stirred at 120 °C for 10 hours. After the reaction mixture was cooled to room temperature, 5-bromo-2,4-dichloropyrimidine (3 equivalents) was further added, and the mixture was stirred at 120° C. for 13 hours. After the reaction mixture was cooled to room temperature, 5-bromo-2,4-dichloropyrimidine (1.5 equivalents) was further added, and the mixture was stirred at 120° C. for 5 hours. After the reaction mixture was cooled to room temperature, water and brine were added to the reaction mixture, and organics were 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: 54 %, MS (ESI): m/z 413 [M+H] + ).
단계 4: (R)-(6-((5-브로모-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드의 제조Step 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
단계 3에서 제조한 (6-((5-브로모-2-클로로피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(1.2 당량), (R)-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-아민(1 당량)을 2-메톡시에탄올에 녹인 후 2.5 N HCl in EtOH(2.6 당량)를 첨가하고 120 ℃에서 3 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각시킨 후, 반응 혼합물에 1M NaOH 수용액을 넣어 pH를 12로 맞춘 후, DCM으로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 prep-HPLC를 통해 정제하였고, 노란색 고체의 목적 화합물을 수득하였다(수율: 26 %, MS (ESI): m/z 679 [M+H]+).(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphineoxide (1.2 equivalents) prepared in step 3, (R)-3- (1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8- After dissolving the amine (1 equivalent) in 2-methoxyethanol, 2.5 N HCl in EtOH (2.6 equivalents) was added, followed by stirring at 120° C. for 3 hours. After the 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] + ).
실시예 2 내지 실시예 64Examples 2 to 64
상기 실시예 1과 유사한 방법으로 실시예 2 내지 64 화합물을 제조하였다. 실시예 1 내지 64 화합물의 화학구조, 화합물명, NMR, 수율, 및 HPLC 분석 결과를 하기 표 1에 정리하여 나타내었다.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.
실시예Example 구조rescue 화합물명compound name 1H NMR, MS 1 H NMR, MS 수율
(%)transference number
(%) 		HPLC r.t.(min),
Purity
(%)HPLC rt (min),
Purity
(%)
1One
Figure PCTKR2021019439-appb-img-000048
Figure PCTKR2021019439-appb-img-000048
 		(R)-(6-((5-브로모-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.65 (s, 1H), 9.22 (s, 1H), 8.99-8.89 (m, 1H), 8.74 (d, J = 1.6 Hz, 2H), 8.29 (s, 1H), 8.23 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 4.22 (dd, J = 8.8, 2 Hz, 1H), 3.91 (t, J = 9.6 Hz, 1H), 3.67 (d, J = 11.6 Hz, 1H), 2.98-2.93 (m, 3H), 2.91 (d, J = 10.8 Hz, 2H), 2.52-2.50 (m, 1H), 2.34-2.22 (m, 1H), 2.21-2.15 (m, 4H), 2.05 (s, 3H), 2.01 (s, 3H), 1.91 (t, J = 10.8 Hz, 3H), 1.76 (d, J = 8.4 Hz, 2H), 1.51-1.34 (m, 2H); MS (ESI): m/z 679 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.65 (s, 1H), 9.22 (s, 1H), 8.99-8.89 (m, 1H), 8.74 (d, J = 1.6 Hz, 2H) , 8.29 (s, 1H), 8.23 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 4.22 (dd, J = 8.8, 2 Hz, 1H), 3.91 (t, J = 9.6 Hz, 1H), 3.67 (d, J = 11.6 Hz, 1H), 2.98-2.93 ( m, 3H), 2.91 (d, J = 10.8 Hz, 2H), 2.52-2.50 (m, 1H), 2.34-2.22 (m, 1H), 2.21-2.15 (m, 4H), 2.05 (s, 3H) , 2.01 (s, 3H), 1.91 (t, J = 10.8 Hz, 3H), 1.76 (d, J = 8.4 Hz, 2H), 1.51-1.34 (m, 2H); MS (ESI): m/z 679 [M+H] + 2626 3.17,
983.17;
98
22
Figure PCTKR2021019439-appb-img-000049
Figure PCTKR2021019439-appb-img-000049
 		(6-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((5-Bromo-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-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.66 (s, 1H), 8.99-8.88 (m, 1H), 8.88-8.81 (m, 2H), 8.24 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.01 (d, J = 9.5 Hz, 1H), 6.99 (s, 1H), 6.63 (s, 1H), 4.20-4.14 (m, 1H), 4.05-3.98 (m, 1H), 3.92-3.84 (m, 1H), 3.73 (s, 3H), 3.00-2.90 (m, 1H), 2.62-2.39 (m, 6H), 2.33-2.22 (m, 4H), 2.14 (s, 3H), 2.02 (d, J = 14.3 Hz, 6H), 1.95-1.79 (m, 2H), 1.50-1.36 (m, 1H), 1.16-1.04 (m, 1H); MS (ESI): m/z 708 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.66 (s, 1H), 8.99-8.88 (m, 1H), 8.88-8.81 (m, 2H), 8.24 (s, 1H), 8.23 ( s, 1H), 8.16 (s, 1H), 8.01 (d, J = 9.5 Hz, 1H), 6.99 (s, 1H), 6.63 (s, 1H), 4.20-4.14 (m, 1H), 4.05-3.98 (m, 1H), 3.92-3.84 (m, 1H), 3.73 (s, 3H), 3.00-2.90 (m, 1H), 2.62-2.39 (m, 6H), 2.33-2.22 (m, 4H), 2.14 (s, 3H), 2.02 (d, J = 14.3 Hz, 6H), 1.95-1.79 (m, 2H), 1.50-1.36 (m, 1H), 1.16-1.04 (m, 1H); MS (ESI): m/z 708 [M+H] + 4141 3.65,
993.65,
99
33
Figure PCTKR2021019439-appb-img-000050
Figure PCTKR2021019439-appb-img-000050
 		(6-((5-브로모-2-(((6aR,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((5-Bromo-2-(((6aR,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10) -hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.65 (s, 1H), 8.99-8.89 (m, 1H), 8.87 (d, J = 10.8 Hz, 2H), 8.23 (s, 1H), 8.21 (d, J = 13.6 Hz, 2H), 8.01 (d, J = 9.6 Hz, 1H), 6.97 (s, 1H), 6.55 (s, 1H), 4.61 (dd, J = 10.4, 2.4 Hz, 1H), 3.86 (t, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.52-3.40 (m, 2H), 3.30-3.21 (m, 2H), 2.83 (t, J = 10.4 Hz, 2H), 2.54-2.50 (m, 3H), 2.20-2.09 (m, 5H), 2.09-2.02 (m, 8H), 1.71 (t, J = 3.2 Hz, 1H), 1.35-1.21 (m, 2H); MS (ESI): m/z 708 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.65 (s, 1H), 8.99-8.89 (m, 1H), 8.87 (d, J = 10.8 Hz, 2H), 8.23 (s, 1H) , 8.21 (d, J = 13.6 Hz, 2H), 8.01 (d, J = 9.6 Hz, 1H), 6.97 (s, 1H), 6.55 (s, 1H), 4.61 (dd, J = 10.4, 2.4 Hz, 1H), 3.86 (t, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.52-3.40 (m, 2H), 3.30-3.21 (m, 2H), 2.83 (t, J = 10.4 Hz, 2H) ), 2.54-2.50 (m, 3H), 2.20-2.09 (m, 5H), 2.09-2.02 (m, 8H), 1.71 (t, J = 3.2 Hz, 1H), 1.35-1.21 (m, 2H); MS (ESI): m/z 708 [M+H] + 3333 3.86,
983.86,
98
44
Figure PCTKR2021019439-appb-img-000051
Figure PCTKR2021019439-appb-img-000051
 		(6-((5-브로모-2-(((6aS,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((5-Bromo-2-(((6aS,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10) -hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.65 (s, 1H), 8.99-8.89 (m, 1H), 8.87 (d, J = 10.8 Hz, 2H), 8.25 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 6.97 (s, 1H), 6.55 (s, 1H), 4.61 (dd, J = 10.4, 2.4 Hz, 1H), 3.86 (t, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.52-3.40 (m, 2H), 3.30-3.21 (m, 2H), 2.83 (t, J = 10.4 Hz, 2H), 2.54-2.50 (m, 3H), 2.20-2.09 (m, 5H), 2.09-2.02 (m, 8H), 1.71 (t, J = 3.2 Hz, 1H), 1.35-1.21 (m, 2H); MS (ESI): m/z 708 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.65 (s, 1H), 8.99-8.89 (m, 1H), 8.87 (d, J = 10.8 Hz, 2H), 8.25 (s, 1H) , 8.23 (s, 1H), 8.17 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 6.97 (s, 1H), 6.55 (s, 1H), 4.61 (dd, J = 10.4, 2.4) Hz, 1H), 3.86 (t, J = 9.2 Hz, 1H), 3.72 (s, 3H), 3.52-3.40 (m, 2H), 3.30-3.21 (m, 2H), 2.83 (t, J = 10.4 Hz) , 2H), 2.54-2.50 (m, 3H), 2.20-2.09 (m, 5H), 2.09-2.02 (m, 8H), 1.71 (t, J = 3.2 Hz, 1H), 1.35-1.21 (m, 2H) ); MS (ESI): m/z 708 [M+H] + 3737 3.80,
983.80,
98
55
Figure PCTKR2021019439-appb-img-000052
Figure PCTKR2021019439-appb-img-000052
 		(6-((5-브로모-2-(((6aS,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((5-Bromo-2-(((6aS,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10) -hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.66 (s, 1H), 8.97-8.89 (m, 1H), 8.89-8.82 (m, 2H), 8.24 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 8.01 (d, J = 9.5 Hz, 1H), 6.99 (s, 1H), 6.63 (s, 1H), 4.21-4.13 (m, 1H), 4.02 (d, J = 12.6 Hz, 1H), 3.92-3.83 (m, 1H), 3.73 (s, 3H), 2.99-2.90 (m, 1H), 2.50 (6H in dmso), 2.32-2.22 (m, 4H), 2.14 (s, 3H), 2.02 (d, J = 14.3 Hz, 6H), 1.92-1.79 (m, 2H), 1.48-1.37 (m, 1H), 1.16-1.03 (m, 1H); MS (ESI): m/z 708 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.66 (s, 1H), 8.97-8.89 (m, 1H), 8.89-8.82 (m, 2H), 8.24 (s, 1H), 8.22 ( s, 1H), 8.16 (s, 1H), 8.01 (d, J = 9.5 Hz, 1H), 6.99 (s, 1H), 6.63 (s, 1H), 4.21-4.13 (m, 1H), 4.02 (d) , J = 12.6 Hz, 1H), 3.92-3.83 (m, 1H), 3.73 (s, 3H), 2.99-2.90 (m, 1H), 2.50 (6H in dmso), 2.32-2.22 (m, 4H), 2.14 (s, 3H), 2.02 (d, J = 14.3 Hz, 6H), 1.92-1.79 (m, 2H), 1.48-1.37 (m, 1H), 1.16-1.03 (m, 1H); MS (ESI): m/z 708 [M+H] + 4747 3.50,
993.50,
99
66
Figure PCTKR2021019439-appb-img-000053
Figure PCTKR2021019439-appb-img-000053
 		(R)-(6-((5-브로모-2-((3-(1-에틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-(1-ethylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.66 (s, 1H), 9.21 (s, 1H), 8.99-8.92 (m, 1H), 8.89 (d, J = 6.4 Hz, 2H), 8.29 (s, 1H), 8.24 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.22 (dd, J = 10.8, 2 Hz, 1H), 3.91 (t, J = 9.2 Hz, 1H), 3.67 (d, J = 12 Hz, 1H), 2.98-2.91 (m, 6H), 2.34-2.26 (m, 2H), 2.19-2.16 (m, 2H), 2.05 (s, 3H), 2.01 (s, 3H), 1.92-1.72 (m, 5H), 1.45-1.39 (m, 2H), 1.00 (t, J = 7 Hz, 3H); MS (ESI): m/z 692 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.66 (s, 1H), 9.21 (s, 1H), 8.99-8.92 (m, 1H), 8.89 (d, J = 6.4 Hz, 2H) , 8.29 (s, 1H), 8.24 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.22 (dd, J = 10.8, 2 Hz, 1H), 3.91 (t, J = 9.2 Hz, 1H), 3.67 (d, J = 12 Hz, 1H), 2.98-2.91 ( m, 6H), 2.34-2.26 (m, 2H), 2.19-2.16 (m, 2H), 2.05 (s, 3H), 2.01 (s, 3H), 1.92-1.72 (m, 5H), 1.45-1.39 ( m, 2H), 1.00 (t, J = 7 Hz, 3H); MS (ESI): m/z 692 [M+H] + 1212 3.06,
993.06,
99
77
Figure PCTKR2021019439-appb-img-000054
Figure PCTKR2021019439-appb-img-000054
 		(R)-(6-((5-브로모-2-((10-플루오로-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((10-fluoro-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5- Hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.69 (s, 1H), 9.46 (s, 1H), 8.99-8.84 (m, 3H), 8.35 (s, 1H), 8.19 (s, 1H), 8.12 (d, J = 9.5 Hz, 1H), 7.17-7.07 (m, 1H), 6.94 (s, 1H), 4.16-4.08 (m, 1H), 4.08-3.99 (m, 1H), 3.10-3.01 (m, 1H), 3.00-2.89 (m, 1H), 2.84-2.74 (m, 3H), 2.70-2.63 (m, 1H), 2.46-2.36 (m, 3H), 2.22-1.94 (m, 10H), 1.89 (t, J = 11.4 Hz, 2H), 1.77-1.67 (m, 2H), 1.48-1.34 (m, 2H); MS (ESI): m/z 696 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.69 (s, 1H), 9.46 (s, 1H), 8.99-8.84 (m, 3H), 8.35 (s, 1H), 8.19 (s, 1H), 8.12 (d, J = 9.5 Hz, 1H), 7.17-7.07 (m, 1H), 6.94 (s, 1H), 4.16-4.08 (m, 1H), 4.08-3.99 (m, 1H), 3.10 -3.01 (m, 1H), 3.00-2.89 (m, 1H), 2.84-2.74 (m, 3H), 2.70-2.63 (m, 1H), 2.46-2.36 (m, 3H), 2.22-1.94 (m, 10H), 1.89 (t, J = 11.4 Hz, 2H), 1.77-1.67 (m, 2H), 1.48-1.34 (m, 2H); MS (ESI): m/z 696 [M+H] + 4242 3.92,
983.92,
98
88
Figure PCTKR2021019439-appb-img-000055
Figure PCTKR2021019439-appb-img-000055
 		(R)-(6-((5-브로모-2-((3-(1-사이클로프로필피페리딘-4-일)-10-플루오로-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-(1-cyclopropylpiperidin-4-yl)-10-fluoro-1,2,3,4,4a,5) -hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.97-8.84 (m, 3H), 8.29 (s, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.04-6.97 (m, 2H), 4.38-4.20 (m, 2H), 4.07-4.02 (m, 1H), 3.90-3.78 (m, 2H), 3.74-3.50 (m, 4H), 3.30-3.20 (m, 4H), 3.18-3.02 (m, 1H), 2.90-2.78 (m, 1H), 2.58-2.42 (m, 2H), 2.30-2.02 (m, 8H), 1.12-0.98 (m, 4H); MS (ESI): m/z 723 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.97-8.84 (m, 3H), 8.29 (s, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.04-6.97 (m, 2H), 4.38-4.20 (m, 2H), 4.07-4.02 (m, 1H), 3.90-3.78 (m, 2H), 3.74-3.50 (m, 4H), 3.30-3.20 (m, 4H), 3.18- 3.02 (m, 1H), 2.90-2.78 (m, 1H), 2.58-2.42 (m, 2H), 2.30-2.02 (m, 8H), 1.12-0.98 (m, 4H); MS (ESI): m/z 723 [M+H] + 1818 100(1) 100 (1)
99
Figure PCTKR2021019439-appb-img-000056
Figure PCTKR2021019439-appb-img-000056
 		(R)-(6-((5-브로모-2-((10-클로로-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((10-chloro-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexa Hydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.69 (s, 1H), 9.51 (s, 1H), 8.91-8.88 (m, 3H), 8.37 (s, 1H), 8.19 (s, 1H), 8.16 (d, J = 9.2 Hz, 2H), 7.28 (s, 1H), 7.17 (s, 1H), 4.43 (t, J = 10.4 Hz, 1H), 4.06 (dd, J = 10.4, 2.4 Hz, 1H), 3.38 (t, J = 11.6 Hz, 1H), 3.07 (d, J = 10.4 Hz, 1H), 2.96 (d, J = 11.6 Hz, 1H), 2.83-2.80 (m, 4H), 2.63-2.60 (m, 1H), 2.41-2.38 (m, 1H), 2.17-2.13 (m, 4H), 2.06 (s, 3H), 2.03 (s, 3H), 1.95 (t, J = 11.2 Hz, 2H), 1.72 (d, J = 10.8 Hz, 2H), 1.46-1.37 (m, 2H); MS (ESI): m/z 714 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.69 (s, 1H), 9.51 (s, 1H), 8.91-8.88 (m, 3H), 8.37 (s, 1H), 8.19 (s, 1H), 8.16 (d, J = 9.2 Hz, 2H), 7.28 (s, 1H), 7.17 (s, 1H), 4.43 (t, J = 10.4 Hz, 1H), 4.06 (dd, J = 10.4, 2.4) Hz, 1H), 3.38 (t, J = 11.6 Hz, 1H), 3.07 (d, J = 10.4 Hz, 1H), 2.96 (d, J = 11.6 Hz, 1H), 2.83-2.80 (m, 4H), 2.63-2.60 (m, 1H), 2.41-2.38 (m, 1H), 2.17-2.13 (m, 4H), 2.06 (s, 3H), 2.03 (s, 3H), 1.95 (t, J = 11.2 Hz, 2H), 1.72 (d, J = 10.8 Hz, 2H), 1.46-1.37 (m, 2H); MS (ESI): m/z 714 [M+H] + 3838 3.96,
993.96,
99
1010
Figure PCTKR2021019439-appb-img-000057
Figure PCTKR2021019439-appb-img-000057
 		(R)-(6-((5-브로모-2-((10-클로로-3-(1-에틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((10-chloro-3-(1-ethylpiperidin-4-yl)-1,2,3,4,4a,5-hexa Hydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 6) δ 9.06-9.02 (m, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 8.27 (s ,1H), 8.18 (d, J = 9.6 Hz, 1H), 7.20 (s, 1H), 7.12 (s, 1H), 4.57 (t, J = 10.4 Hz, 1H), 4.08 (dd, J = 10.8, 2.8 Hz, 1H), 3.54-3.48 (m, 3H), 3.19-3.02 (m, 4H), 2.95-2.90 (m, 4H), 2.82-2.76 (m, 1H), 2.59-2.52 (m, 2H), 2.17-2.07 (m ,8H), 1.87-1.72 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 728 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 6 ) δ 9.06-9.02 (m, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 8.27 (s) 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.20 (s, 1H), 7.12 (s, 1H), 4.57 (t, J = 10.4 Hz, 1H), 4.08 (dd, J = 10.8, 2.8) Hz, 1H), 3.54-3.48 (m, 3H), 3.19-3.02 (m, 4H), 2.95-2.90 (m, 4H), 2.82-2.76 (m, 1H), 2.59-2.52 (m, 2H), 2.17-2.07 (m,8H), 1.87-1.72 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 728 [M+H] + 3636 4.10,
984.10,
98
1111
Figure PCTKR2021019439-appb-img-000058
Figure PCTKR2021019439-appb-img-000058
 		(S)-(6-((5-브로모-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, DMSO, FA salt) δ 12.66 (s, 1H), 9.22 (s, 1H), 9.09-8.93 (m, 1H), 8.90-8.82 (m, 2H), 8.29 (s, 1H), 8.19 (s, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.23-4.17 (m, 1H), 3.95-3.84 (m, 1H), 3.66 (d, J = 11.5 Hz, 1H), 3.00 -2.84 (m, 5H), 2.57-2.52 (m, 1H), 2.28 (dd, J = 10.9, 2.3 Hz, 1H), 2.23-2.15 (m, 4H), 2.05 (s, 3H), 2.02 (s, 3H), 2.00-1.93 (m, J = 11.1 Hz, 2H), 1.89 (t, J = 10.8 Hz, 1H), 1.76 (d, J = 10.9 Hz, 2H), 1.52-1.40 (m, 2H); MS (ESI): m/z 678 [M+H]+ 1 H NMR (400 MHz, DMSO, FA salt) δ 12.66 (s, 1H), 9.22 (s, 1H), 9.09-8.93 (m, 1H), 8.90-8.82 (m, 2H), 8.29 (s, 1H) ), 8.19 (s, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H) ), 4.23-4.17 (m, 1H), 3.95-3.84 (m, 1H), 3.66 (d, J = 11.5 Hz, 1H), 3.00 -2.84 (m, 5H), 2.57-2.52 (m, 1H), 2.28 (dd, J = 10.9, 2.3 Hz, 1H), 2.23-2.15 (m, 4H), 2.05 (s, 3H), 2.02 (s, 3H), 2.00-1.93 (m, J = 11.1 Hz, 2H) , 1.89 (t, J = 10.8 Hz, 1H), 1.76 (d, J = 10.9 Hz, 2H), 1.52-1.40 (m, 2H); MS (ESI): m/z 678 [M+H] + 3232 3.19,
983.19;
98
1212
Figure PCTKR2021019439-appb-img-000059
Figure PCTKR2021019439-appb-img-000059
 		(R)-(6-((5-브로모-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드 (R)-(6-((5-bromo-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][ 1,4])oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400MHz, FA salt, methanol-d 4) δ 8.94-8.78 (m, 3H), 8.27 (s, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.04-7.01 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.40-4.30 (m, 1H), 4.22-4.12 (m, 1H), 4.12-4.02 (m, 1H), 3.70-3.60 (m, 2H), 3.54-3.46 (m, 1H), 3.30-3.20 (m, 1H), 3.14-3.02 (m, 2H), 2.99 (s, 3H), 2.19 (s, 3H), 2.15(s, 3H); MS (ESI): m/z 595 [M+1]+ 1 H NMR (400 MHz, FA salt, methanol- d 4 ) δ 8.94-8.78 (m, 3H), 8.27 (s, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.04-7.01 (m, 2H) ), 6.94 (d, J = 8.4 Hz, 1H), 4.40-4.30 (m, 1H), 4.22-4.12 (m, 1H), 4.12-4.02 (m, 1H), 3.70-3.60 (m, 2H), 3.54-3.46 (m, 1H), 3.30-3.20 (m, 1H), 3.14-3.02 (m, 2H), 2.99 (s, 3H), 2.19 (s, 3H), 2.15 (s, 3H); MS (ESI): m/z 595 [M+1] + 1616 3.52,
953.52,
95
1313
Figure PCTKR2021019439-appb-img-000060
Figure PCTKR2021019439-appb-img-000060
 		(R)-(6-((5-브로모-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1, 2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400MHz, FA salt, methanol-d 4) δ 9.00 (s, 1H), 8.98 (d, J = 9.6 Hz, 2H), 8.28 (s, 1H), 8.23 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.84 (s, 1H), 6.61 (s, 1H), 4.24-4.18 (m, 1H), 4.02-3.92 (m, 2H), 3.84 (s, 3H), 3.28-3.14 (m, 3H), 3.00-2.65 (m, 2H), 2.40-2.30 (m, 1H), 2.62 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H); MS (ESI): m/z 625 [M+1]+ 1 H NMR (400 MHz, FA salt, methanol- d 4 ) δ 9.00 (s, 1H), 8.98 (d, J = 9.6 Hz, 2H), 8.28 (s, 1H), 8.23 (s, 1H), 8.14 ( d, J = 9.2 Hz, 1H), 7.84 (s, 1H), 6.61 (s, 1H), 4.24-4.18 (m, 1H), 4.02-3.92 (m, 2H), 3.84 (s, 3H), 3.28 -3.14 (m, 3H), 3.00-2.65 (m, 2H), 2.40-2.30 (m, 1H), 2.62 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H); MS (ESI): m/z 625 [M+1] + 7373 3.83,
1003.83,
100
1414
Figure PCTKR2021019439-appb-img-000061
Figure PCTKR2021019439-appb-img-000061
 		(S)-(6-((5-브로모-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][ 1,4])oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, Neutral, Methanol-d 4) δ9.11-9.09 (m, 1H), 8.84-8.80 (m, 2H), 8.21 (s , 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.89-6.87 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.62 (s, 1H), 4.24-4.21 (m, 1H), 4.01-3.96 (m, 1H), 3.76-3.73 (m, 1H), 3.52-3.46 (m, 1H), 3.13-3.08 (m, 2H), 3.00-2.97 (m, 1H), 2.91-2.88 (m, 1H), 2.81-2.70 (m, 1H), 2.39-2.27 (m, 4H), 2.16 (s, 3H), 2.12 (s, 3H), 1.93-1.88 (m, 1H) ; MS (ESI): m/z 596 [M+H]+ 1 H NMR (400 MHz, Neutral, Methanol- d 4 ) δ9.11-9.09 (m, 1H), 8.84-8.80 (m, 2H), 8.21 (s, 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.89-6.87 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.62 (s, 1H), 4.24-4.21 (m, 1H) ), 4.01-3.96 (m, 1H), 3.76-3.73 (m, 1H), 3.52-3.46 (m, 1H), 3.13-3.08 (m, 2H), 3.00-2.97 (m, 1H), 2.91-2.88 (m, 1H), 2.81-2.70 (m, 1H), 2.39-2.27 (m, 4H), 2.16 (s, 3H), 2.12 (s, 3H), 1.93-1.88 (m, 1H); MS (ESI): m/z 596 [M+H] + 4444 4.34,
964.34,
96
1515
Figure PCTKR2021019439-appb-img-000062
Figure PCTKR2021019439-appb-img-000062
 		(S)-(6-((5-브로모-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1, 2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, CDCl3) δ12.480 (s, 1H), 9.026 (d, J = 4.0 Hz, 1 H), 9.002 (d, J = 4.0 Hz, 1H), 8.757 (s, 1H), 8.706 (d, J = 2.0 Hz, 1H), 7.759 (s, 1H), 7.376 (s, 1H), 4.217-4.184 (m, 1H), 4.035-4.009 (m, 1H), 3.825 (s, 3H), 3.685-3.655 (m, 1H), 3.334-3.327 (m, 1H), 3.077-2.957 (m, 3H), 2.445 (s, 3H), 2.415-2.386 (m, 2H), 2.139 (s, 3H), 2.103 (s, 3H); MS (ESI): m/z 625 [M+H]+ 1 H NMR (400 MHz, FA salt, CDCl 3 ) δ12.480 (s, 1H), 9.026 (d, J = 4.0 Hz, 1 H), 9.002 (d, J = 4.0 Hz, 1H), 8.757 (s) , 1H), 8.706 (d, J = 2.0 Hz, 1H), 7.759 (s, 1H), 7.376 (s, 1H), 4.217-4.184 (m, 1H), 4.035-4.009 (m, 1H), 3.825 ( s, 3H), 3.685-3.655 (m, 1H), 3.334-3.327 (m, 1H), 3.077-2.957 (m, 3H), 2.445 (s, 3H), 2.415-2.386 (m, 2H), 2.139 ( s, 3H), 2.103 (s, 3H); MS (ESI): m/z 625 [M+H] + 7070 3.70,
983.70,
98
1616
Figure PCTKR2021019439-appb-img-000063
Figure PCTKR2021019439-appb-img-000063
 		(6-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)(이미노)(메틸)- λ6-설파논(6-((5-Bromo-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-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) (imino) (methyl)- λ 6 -sulfanone MS (ESI): m/z 710 [M+H]+ MS (ESI): m/z 710 [M+H] +
1717
Figure PCTKR2021019439-appb-img-000064
Figure PCTKR2021019439-appb-img-000064
 		(6-((5-브로모-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)(이미노)(메틸)- λ6-설파논(6-((5-Bromo-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)(imino)(methyl)-λ 6 -sulfanone MS (ESI): m/z 680 [M+H]+ MS (ESI): m/z 680 [M+H] +
1818
Figure PCTKR2021019439-appb-img-000065
Figure PCTKR2021019439-appb-img-000065
 		N-(6-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드N-(6-((5-bromo-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-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) methanesulfone amide MS (ESI): m/z 726 [M+H]+ MS (ESI): m/z 726 [M+H] +
1919
Figure PCTKR2021019439-appb-img-000066
Figure PCTKR2021019439-appb-img-000066
 		N-(6-((5-브로모-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드N-(6-((5-bromo-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydro Benzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide MS (ESI): m/z 696 [M+H]+ MS (ESI): m/z 696 [M+H] +
2020
Figure PCTKR2021019439-appb-img-000067
Figure PCTKR2021019439-appb-img-000067
 		(7-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)다이메틸포스핀옥사이드(7-((5-Bromo-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-yl) amino) pyrimidin-4-yl) amino) imidazo [1,2-a] pyridine- 8-yl) dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ 10.20-10.00 (m, 1H), 9.41 (s, 1H), 9.32 (s, 1H), 9.26 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.20-7.10 (m, 1H), 5.10-5.00 (m, 1H), 4.90-4.80 (m, 1H), 4.78-4.76 (m 1H), 4.53 (s, 3H), 4.00-3.70 (m 6H), 3.50-3.40 (m, 1H), 2.80-2.70 (m, 8H), 2.38-2.22 (m, 2H), 2.05 (s, 3H), 2.01 (t, J=7.2 Hz, 4H);　MS (ESI): m/z=696　[M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ 10.20-10.00 (m, 1H), 9.41 (s, 1H), 9.32 (s, 1H), 9.26 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.20-7.10 (m, 1H), 5.10-5.00 (m, 1H), 4.90-4.80 (m, 1H), 4.78-4.76 (m 1H), 4.53 (s, 3H) ), 4.00-3.70 (m 6H), 3.50-3.40 (m, 1H), 2.80-2.70 (m, 8H), 2.38-2.22 (m, 2H), 2.05 (s, 3H), 2.01 (t, J= 7.2 Hz, 4H); MS (ESI): m/z=696 [M+H] + 1616 100(1) 100 (1)
2121
Figure PCTKR2021019439-appb-img-000068
Figure PCTKR2021019439-appb-img-000068
 		(7-((5-브로모-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)다이메틸포스핀옥사이드(7-((5-Bromo-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)imidazo[1,2-a]pyridin-8-yl)di methylphosphine oxide MS (ESI): m/z 667 [M+H]+ MS (ESI): m/z 667 [M+H] +
2222
Figure PCTKR2021019439-appb-img-000069
Figure PCTKR2021019439-appb-img-000069
 		(6-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((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-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)quinoxaline-5 -yl) dimethyl phosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 9.57-9.41 (m, 1H), 8.90 (d, J = 1.7 Hz, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.16 (m, 1H), 7.13-7.00 (m, 2H), 6.79 -6.70 (m, 2H), 4.38-4.19 (m, 2H), 4.10-4.00 (m, 1H), 3.83 (s, 3H), 3.67-3.44 (m, 10H), 2.98 (s, 3H), 2.23-2.18 (m, 8H), 1.83 (m, 1H), 1.63-1.53 (m, 1H); MS (ESI): m/z 669 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 9.57-9.41 (m, 1H), 8.90 (d, J = 1.7 Hz, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.16 (m, 1H), 7.13-7.00 (m, 2H), 6.79 -6.70 (m, 2H), 4.38-4.19 (m, 2H), 4.10-4.00 (m, 1H), 3.83 (s, 3H), 3.67 -3.44 (m, 10H), 2.98 (s, 3H), 2.23-2.18 (m, 8H), 1.83 (m, 1H), 1.63 1.53 (m, 1H); MS (ESI): m/z 669 [M+H] + 2121 3.94,
983.94,
98
2323
Figure PCTKR2021019439-appb-img-000070
Figure PCTKR2021019439-appb-img-000070
 		다이메틸(6-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드Dimethyl (6-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyri) do[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)quinoxalin-5-yl) phosphine oxide MS (ESI): m/z 639 [M+H]+ MS (ESI): m/z 639 [M+H] +
2424
Figure PCTKR2021019439-appb-img-000071
Figure PCTKR2021019439-appb-img-000071
 		(7-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)다이메틸포스핀옥사이드(7-((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-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)imidazo[1 ,2-a]pyridin-8-yl)dimethylphosphine oxide MS (ESI): m/z 657 [M+H]+ MS (ESI): m/z 657 [M+H] +
2525
Figure PCTKR2021019439-appb-img-000072
Figure PCTKR2021019439-appb-img-000072
 		다이메틸(7-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)포스핀옥사이드Dimethyl (7-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyri) do[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)imidazo[1,2- a] pyridin-8-yl) phosphine oxide MS (ESI): m/z 627 [M+H]+ MS (ESI): m/z 627 [M+H] +
2626
Figure PCTKR2021019439-appb-img-000073
Figure PCTKR2021019439-appb-img-000073
 		(6-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((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-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)quinoxalin-5-yl ) dimethyl phosphine oxide 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ 14.06 (s, 1H), 9.43 (s, 1H), 8.95-8.92 (m, 2H), 8.31 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 5.2 Hz, 1H), 7.07 (s, 1H), 6.78 (s, 1H), 4.32-4.30 (m, 2H), 3.95-3.93 (m, 2H), 3.77 (s, 3H), 3.58-3.56 (m, 4H), 3.23-3.20 (m, 4H), 2.70 (s, 3H), 2.13 (s, 3H), 2.09 (s, 3H), 2.05-2.02 (m, 2H), 1.59-1.56 (m, 1H), 1.30-1.28 (m, 1H); MS (ESI): m/z 686 [M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ 14.06 (s, 1H), 9.43 (s, 1H), 8.95-8.92 (m, 2H), 8.31 (d, J = 5.2 Hz, 1H) , 8.13 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 5.2 Hz, 1H), 7.07 (s, 1H), 6.78 (s, 1H), 4.32-4.30 (m, 2H), 3.95-3.93 (m, 2H), 3.77 (s, 3H), 3.58-3.56 (m, 4H), 3.23-3.20 (m, 4H), 2.70 (s, 3H), 2.13 (s, 3H), 2.09 (s, 3H), 2.05 -2.02 (m, 2H), 1.59-1.56 (m, 1H), 1.30-1.28 (m, 1H); MS (ESI): m/z 686 [M+H] + 36.636.6 3.90, 1003.90, 100
2727
Figure PCTKR2021019439-appb-img-000074
Figure PCTKR2021019439-appb-img-000074
 		다이메틸(6-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드Dimethyl (6-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyri) do[1,2-d][1,4]oxazin-3-yl)amino)cyeno[3,2-d]pyrimidin-4-yl)amino)quinoxalin-5-yl)phosphine oxide MS (ESI): m/z 656 [M+H]+ MS (ESI): m/z 656 [M+H] +
2828
Figure PCTKR2021019439-appb-img-000075
Figure PCTKR2021019439-appb-img-000075
 		(7-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)다이메틸포스핀옥사이드(7-((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-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) imidazo [1,2 -a] pyridin-8-yl) dimethylphosphine oxide MS (ESI): m/z 674 [M+H]+ MS (ESI): m/z 674 [M+H] +
2929
Figure PCTKR2021019439-appb-img-000076
Figure PCTKR2021019439-appb-img-000076
 		다이메틸(7-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)포스핀옥사이드Dimethyl (7-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyri) do[1,2-d][1,4]oxazin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)imidazo[1,2-a] Pyridin-8-yl)phosphine oxide MS (ESI): m/z 644 [M+H]+ MS (ESI): m/z 644 [M+H] +
3030
Figure PCTKR2021019439-appb-img-000077
Figure PCTKR2021019439-appb-img-000077
 		(6-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이디메틸포스핀옥사이드(6-((5-chloro-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-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) didimethylphosphine oxide MS (ESI): m/z 665 [M+H]+ MS (ESI): m/z 665 [M+H] +
3131
Figure PCTKR2021019439-appb-img-000078
Figure PCTKR2021019439-appb-img-000078
 		(7-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)-4-메틸-3,4-다이하이드로-2H-벤조[b][1,4]옥사진-8-일)다이메틸포스핀옥사이드(7-((5-Bromo-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-yl) amino) pyrimidin-4-yl) amino) -4-methyl-3,4-dihydro -2H-benzo [b] [1,4] oxazin-8-yl) dimethylphosphine oxide MS (ESI): m/z 684 [M+H]+ MS (ESI): m/z 684 [M+H] +
3232
Figure PCTKR2021019439-appb-img-000079
Figure PCTKR2021019439-appb-img-000079
 		(R)-(7-((5-브로모-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)-4-메틸-3,4-다이하이드로-2H-벤조[b][1,4]옥사진-8-일)다이메틸포스핀옥사이드(R)-(7-((5-bromo-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) -4-methyl-3,4-dihydro-2H-benzo [b ][1,4]oxazin-8-yl)dimethylphosphine oxide MS (ESI): m/z 654 [M+H]+ MS (ESI): m/z 654 [M+H] +
3333
Figure PCTKR2021019439-appb-img-000080
Figure PCTKR2021019439-appb-img-000080
 		(R)-(3-((5-브로모-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사히드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴놀린-4-일)다이메틸포스핀옥사이드(R)-(3-((5-bromo-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5- Hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethylphosphine oxide MS (ESI): m/z 708 [M+H]+ MS (ESI): m/z 708 [M+H] +
3434
Figure PCTKR2021019439-appb-img-000081
Figure PCTKR2021019439-appb-img-000081
 		(R)-(6-((5-브로모-2-((10-메틸-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사히드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((10-methyl-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexa Hydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide MS (ESI): m/z 693 [M+H]+ MS (ESI): m/z 693 [M+H] +
3535
Figure PCTKR2021019439-appb-img-000082
Figure PCTKR2021019439-appb-img-000082
 		(R)-(6-((5-브로모-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노) [1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5- Hexahydrobenzo [b] pyrazino) [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 9.00-8.97 (m, 1H), 8.84 (d, J = 1.6 Hz, 1H), 8.79 (d, J = 1.6 Hz, 1), 8.21 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.32 (s, 1H), 6.56 (s, 1H), 4.20-4.17 (m, 1H), 3.97-3.92 (m, 1H), 3.81 (s, 3H), 3.79 (s, 1H), 3.50 -3.47 (m, 2H), 3.13-3.07 (m, 2H), 3.03-2.95 (m, 3H), 2.81 (s, 3H), 2.78-2.73 (m, 1H), 2.62-2.57 (m, 1H), 2.49-2.44 (m, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.09-2.03 (m, 4H), 1.83 (s, 2H); MS (ESI): m/z 709 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 9.00-8.97 (m, 1H), 8.84 (d, J = 1.6 Hz, 1H), 8.79 (d, J = 1.6 Hz, 1), 8.21 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.32 (s, 1H), 6.56 (s, 1H), 4.20-4.17 (m, 1H), 3.97-3.92 (m, 1H), 3.81 (s, 3H), 3.79 (s, 1H), 3.50 -3.47 (m, 2H), 3.13-3.07 (m, 2H), 3.03-2.95 (m, 3H), 2.81 (s, 3H), 2.78- 2.73 (m, 1H), 2.62-2.57 (m, 1H), 2.49-2.44 (m, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.09-2.03 (m, 4H), 1.83 ( s, 2H); MS (ESI): m/z 709 [M+H] + 1212 4.19,
984.19,
98
3636
Figure PCTKR2021019439-appb-img-000083
Figure PCTKR2021019439-appb-img-000083
 		(S)-(6-((5-브로모-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노)[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5- Hexahydrobenzo [b] pyrazino) [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.67 (s, 1H), 8.95-8.89 (m, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.24 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.99 (d, J = 9.5 Hz, 1H), 6.99 (s, 1H), 6.60 (s, 1H), 4.19 (dd, J = 10.7, 2.1 Hz, 1H), 3.89-3.81 (m, 2H), 3.73 (s, 3H), 3.01-2.91 (m, J = 16.5, 11.0 Hz, 3H), 2.81 (d, J = 11.0 Hz, 2H), 2.61 (dd, J = 11.5, 2.6 Hz, 1H), 2.32-2.27 (m, 1H), 2.21-2.12 (m, 4H), 2.04 (s, 3H), 2.00 (s, 3H), 1.94-1.83 (m, 3H), 1.74 (d, J = 10.9 Hz, 2H), 1.50-1.38 (m, 2H); MS (ESI): m/z 708 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.67 (s, 1H), 8.95-8.89 (m, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.24 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.99 (d, J = 9.5 Hz, 1H), 6.99 (s, 1H), 6.60 (s, 1H), 4.19 (dd, J = 10.7, 2.1 Hz, 1H), 3.89-3.81 (m, 2H), 3.73 (s, 3H), 3.01-2.91 (m, J = 16.5, 11.0 Hz, 3H), 2.81 (d, J = 11.0 Hz, 2H), 2.61 (dd, J = 11.5, 2.6 Hz, 1H), 2.32-2.27 (m, 1H), 2.21-2.12 (m, 4H), 2.04 (s, 3H), 2.00 (s, 3H), 1.94-1.83 (m, 3H), 1.74 (d, J = 10.9 Hz, 2H), 1.50-1.38 (m, 2H); MS (ESI): m/z 708 [M+H] + 2525 3.29,
983.29;
98
3737
Figure PCTKR2021019439-appb-img-000084
Figure PCTKR2021019439-appb-img-000084
 		(6-((5-브로모-2-(((6aR,8S)-8-(4-에틸피페라진-1-일)-2-메톡시-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((5-Bromo-2-(((6aR,8S)-8-(4-ethylpiperazin-1-yl)-2-methoxy-6,6a,7,8,9,10) -hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ 12.78 (s, 1H), 8.94-8.90 (m, 1H), 8.90 (d, J = 1.6 Hz, 1H), 8.87 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.02 (s, 1H), 6.71 (s, 1H), 4.45-4.32 (m, 6H), 4.22-4.05 (m, 4H),3.82 (s, 3H), 3.76-3.51 (m, 4H), 3.17-3.97 (m, 3H), 2.09-2.08 (m, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 1.57-1.55 (m, 1H), 1.32-1.29 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 722 [M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ 12.78 (s, 1H), 8.94-8.90 (m, 1H), 8.90 (d, J = 1.6 Hz, 1H), 8.87 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.02 (s, 1H), 6.71 (s, 1H), 4.45-4.32 ( m, 6H), 4.22-4.05 (m, 4H), 3.82 (s, 3H), 3.76-3.51 (m, 4H), 3.17-3.97 (m, 3H), 2.09-2.08 (m, 1H), 2.07 ( s, 3H), 2.06 (s, 3H), 1.57-1.55 (m, 1H), 1.32-1.29 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 722 [M+H] + 4040 3.75,
1003.75,
100
3838
Figure PCTKR2021019439-appb-img-000085
Figure PCTKR2021019439-appb-img-000085
 		(6-((5-브로모-2-(((6aR,8R)-8-(4-에틸피페라진-1-일)-2-메톡시-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((5-Bromo-2-(((6aR,8R)-8-(4-ethylpiperazin-1-yl)-2-methoxy-6,6a,7,8,9,10) -hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ 12.82 (s, 1H), 9.25 (s, 1H), 8.89-8.88 (m, 3H), 8.93 (s, 1H), 8.29 (s, 1H), 8.04 (d, J = 9.6 Hz, 1H), 7.02 (s, 1H), 6.59 (s, 1H), 4.32-4.18 (m, 4H), 3.72 (s, 3H), 3.56-3.53 (m, 4H), 3.35-3.30 (m, 3H), 3.18-3.11 (m, 2H), 3.10-2.98 (m, 4H), 2.33-2.25 (m, 1H), 2.06 (s, 3H), 2.02 (s, 3H), 1.91-1.80 (m, 1H), 1.41-1.40 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 722 [M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ 12.82 (s, 1H), 9.25 (s, 1H), 8.89-8.88 (m, 3H), 8.93 (s, 1H), 8.29 (s, 1H), 8.04 (d, J = 9.6 Hz, 1H), 7.02 (s, 1H), 6.59 (s, 1H), 4.32-4.18 (m, 4H), 3.72 (s, 3H), 3.56-3.53 (m) , 4H), 3.35-3.30 (m, 3H), 3.18-3.11 (m, 2H), 3.10-2.98 (m, 4H), 2.33-2.25 (m, 1H), 2.06 (s, 3H), 2.02 (s) , 3H), 1.91-1.80 (m, 1H), 1.41-1.40 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 722 [M+H] + 2626 4.65,
1004.65,
100
3939
Figure PCTKR2021019439-appb-img-000086
Figure PCTKR2021019439-appb-img-000086
 		(6-((5-브로모-2-(((6aR,8S)-8-(4-사이클로프로필피페라진-1-일)-2-메톡시-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((5-bromo-2-(((6aR,8S)-8-(4-cyclopropylpiperazin-1-yl)-2-methoxy-6,6a,7,8,9, 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphos fin oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.94-8.91 (m, 3H), 8.21-8.19 (m, 3H), 7.10 (s, 1H), 6.71 (s, 1H), 4.28-4.25 (m, 2H), 4.04-4.03 (m, 1H), 4.00 (s, 3H), 3.51-3.50 (m, 2H), 3.47-3.06 (m, 8H), 2.25-2.17 (m, 1H), 2.02 (s, 3H), 2.89-2.80 (m, 2H), 2.50-2.43 (m, 2H), 0.66-0.64 (m, 3H), 0.59-0.57 (m, 2H); MS (ESI): m/z 736 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.94-8.91 (m, 3H), 8.21-8.19 (m, 3H), 7.10 (s, 1H), 6.71 (s, 1H), 4.28- 4.25 (m, 2H), 4.04-4.03 (m, 1H), 4.00 (s, 3H), 3.51-3.50 (m, 2H), 3.47-3.06 (m, 8H), 2.25-2.17 (m, 1H), 2.02 (s, 3H), 2.89-2.80 (m, 2H), 2.50-2.43 (m, 2H), 0.66-0.64 (m, 3H), 0.59-0.57 (m, 2H); MS (ESI): m/z 736 [M+H] + 88 3.94,
993.94,
99
4040
Figure PCTKR2021019439-appb-img-000087
Figure PCTKR2021019439-appb-img-000087
 		(6-((5-브로모-2-(((6aR,8S)-8-(4-아이소프로필피페라진-1-일)-2-메톡시-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((5-bromo-2-(((6aR,8S)-8-(4-isopropylpiperazin-1-yl)-2-methoxy-6,6a,7,8,9, 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphos fin oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 9.00-8.96 (m, 1H), 8.85-8.80 (m, 2H), 8.21 (s, 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.29 (s, 1H), 6.59 (s, 1H), 4.19-4.16 (m, 1H), 4.01-3.93 (m, 2H), 3.82 (s, 3H), 3.36 (s, 1H), 3.21-3.08 (m, 1H), 3.06-2.61 (m, 10H), 2.16 (s, 3H), 2.12 (s, 3H), 2.06 (d, J = 12.4 Hz, 1H), 1.96 (d, J = 9.6 Hz, 1H), 1.63-1.60 (m, 1H), 1.29 (s, 3H), 1.26 (s, 3H); MS (ESI): m/z 737 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 9.00-8.96 (m, 1H), 8.85-8.80 (m, 2 H), 8.21 (s, 1H), 8.12 (d, J = 9.6 Hz) , 1H), 7.29 (s, 1H), 6.59 (s, 1H), 4.19-4.16 (m, 1H), 4.01-3.93 (m, 2H), 3.82 (s, 3H), 3.36 (s, 1H), 3.21-3.08 (m, 1H), 3.06-2.61 (m, 10H), 2.16 (s, 3H) , 2.12 (s, 3H), 2.06 (d, J = 12.4 Hz, 1H), 1.96 (d, J = 9.6 Hz, 1H), 1.63-1.60 (m, 1H), 1.29 (s, 3H), 1.26 ( s, 3H); MS (ESI): m/z 737 [M+H] + 12.612.6 3.80,
1003.80,
100
4141
Figure PCTKR2021019439-appb-img-000088
Figure PCTKR2021019439-appb-img-000088
 		(R)-(6-((5-브로모-2-((3-(1-아이소프로필피페리딘-4-일))-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-(1-isopropylpiperidin-4-yl))-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 9.11 (d, J = 5.8 Hz, 1H), 8.83 (d, J = 1.3 Hz, 1H), 8.78 (d, J = 1.3 Hz, 1H), 8.40 (s, 2H), 8.20 (s, 1H), 8.08 (d, J = 9.5 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.23 (dd, J = 10.5, 1.5 Hz, 1H), 3.98 (dd, J = 9.7 Hz, 1H), 3.78-3.71 (m, 1H), 3.56-3.44 (m, 3H), 3.15-2.96 (m, 5H), 2.51-2.40 (m, 3H), 2.23-2.17 (m, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.07-2.00 (m, 1H), 1.92-1.71 (m, 2H), 1.37 (s, 3H), 1.36 (s, 3H); MS (ESI): m/z 707 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 9.11 (d, J = 5.8 Hz, 1H), 8.83 (d, J = 1.3 Hz, 1H), 8.78 (d, J = 1.3 Hz, 1H) ), 8.40 (s, 2H), 8.20 (s, 1H), 8.08 (d, J = 9.5 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H) ), 6.76 (d, J = 8.8 Hz, 1H), 4.23 (dd, J = 10.5, 1.5 Hz, 1H), 3.98 (dd, J = 9.7 Hz, 1H), 3.78-3.71 (m, 1H), 3.56 -3.44 (m, 3H), 3.15-2.96 (m, 5H), 2.51-2.40 (m, 3H), 2.23-2.17 (m, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.07 -2.00 (m, 1H), 1.92-1.71 (m, 2H), 1.37 (s, 3H), 1.36 (s, 3H); MS (ESI): m/z 707 [M+H] + 22 3.31,
983.31;
98
4242
Figure PCTKR2021019439-appb-img-000089
Figure PCTKR2021019439-appb-img-000089
 		(R)-(6-((5-브로모-2-((3-(1-사이클로프로필피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-(1-cyclopropylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[ b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 9.09 (d, J = 5.4 Hz, 1H), 8.83 (d, J = 1.9 Hz, 1H), 8.78 (d, J = 1.9 Hz, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 8.07 (d, J = 9.5 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.89-6.83 (m, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.23 (dd, J = 10.6, 2.2 Hz, 1H), 3.98 (dd, J = 10.5, 8.7 Hz, 1H), 3.81-3.75 (m, 1H), 3.45-3.39 (m, 2H), 3.23-3.17 (m, 1H), 3.14-3.08 (m, 2H), 2.81-2.53 (m, 6H), 2.28-2.17 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 2.10-2.03 (m, 2H), 1.77-1.65 (m, 2H), 0.78-0.69 (m, 4H); MS (ESI): m/z 704 [M+H]+ 1H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 9.09 (d, J = 5.4 Hz, 1H), 8.83 (d, J = 1.9 Hz, 1H), 8.78 (d, J = 1.9 Hz, 1H) , 8.34 (s, 1H), 8.19 (s, 1H), 8.07 (d, J = 9.5 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.89-6.83 (m, 1H), 6.77 ( d, J = 8.8 Hz, 1H), 4.23 (dd, J = 10.6, 2.2 Hz, 1H), 3.98 (dd, J = 10.5, 8.7 Hz, 1H), 3.81-3.75 (m, 1H), 3.45-3.39 (m, 2H), 3.23-3.17 (m, 1H), 3.14-3.08 (m, 2H), 2.81-2.53 (m, 6H), 2.28-2.17 (m, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 2.10-2.03 (m, 2H), 1.77-1.65 (m, 2H), 0.78-0.69 (m, 4H); MS (ESI): m/z 704 [M+H] + 3535 3.41,
98 3.41,
98
4343
Figure PCTKR2021019439-appb-img-000090
Figure PCTKR2021019439-appb-img-000090
 		(6-((5-브로모-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(6-((5-Bromo-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, DMSO, FA salt) δ 12.66 (s, 1H), 9.21 (s, 1H), 9.03-8.94 (m, 1H), 8.89 (d, J = 1.9 Hz, 1H), 8.87 (d, J = 1.9 Hz, 1H), 8.29 (s, 1H), 8.19 (s, 2H), 8.11 (d, J = 9.5 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 4.18 (dd, J = 10.6, 2.6 Hz, 1H), 3.95-3.81 (m, 3H), 2.93-2.84 (m, 2H), 2.44-2.38 (m, 4H), 2.31-2.25 (m, 2H), 2.20-2.12 (m, 4H), 2.08-1.98 (m, 7H), 1.91-1.78 (m, 2H), 1.49-1.36 (m, 1H), 1.08 (q, J = 11.8 Hz, 1H); MS (ESI): m/z 678 [M+H]+ 1 H NMR (400 MHz, DMSO, FA salt) δ 12.66 (s, 1H), 9.21 (s, 1H), 9.03-8.94 (m, 1H), 8.89 (d, J = 1.9 Hz, 1H), 8.87 ( d, J = 1.9 Hz, 1H), 8.29 (s, 1H), 8.19 (s, 2H), 8.11 (d, J = 9.5 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.94 ( d, J = 7.8 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 4.18 (dd, J = 10.6, 2.6 Hz, 1H), 3.95-3.81 (m, 3H), 2.93-2.84 (m) , 2H), 2.44-2.38 (m, 4H), 2.31-2.25 (m, 2H), 2.20-2.12 (m, 4H), 2.08-1.98 (m, 7H), 1.91-1.78 (m, 2H), 1.49 -1.36 (m, 1H), 1.08 (q, J = 11.8 Hz, 1H); MS (ESI): m/z 678 [M+H] + 2828 3.48,
973.48,
97
4444
Figure PCTKR2021019439-appb-img-000091
Figure PCTKR2021019439-appb-img-000091
 		(R)-(6-((5-브로모-2-((10-클로로-3-(1-아이소프로필피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((10-chloro-3-(1-isopropylpiperidin-4-yl)-1,2,3,4,4a,5- Hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 9.05-9.01 (m, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.34 (s, 2H), 8.25 (s, 1H), 8.15 (d, J = 9.6 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 4.54 (t, J = 10.4 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 3.53-3.49 (m, 4H), 3.17-3.01 (m, 4H), 2.93-2.79 (m, 3H), 2.62-2.48 (m, 2H), 2.22-2.04 (m, 8H), 1.98-1.80 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H); MS (ESI): m/z 741 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 9.05-9.01 (m, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.34 (s, 2H), 8.25 (s, 1H), 8.15 (d, J = 9.6 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 4.54 (t, J = 10.4 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 3.53-3.49 (m, 4H), 3.17-3.01 (m, 4H), 2.93-2.79 (m, 3H), 2.62-2.48 (m, 2H), 2.22-2.04 (m, 8H), 1.98-1.80 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H); MS (ESI): m/z 741 [M+H] + 2323 100(1) 100 (1)
4545
Figure PCTKR2021019439-appb-img-000092
Figure PCTKR2021019439-appb-img-000092
 		(R)-(6-((5-브로모-2-((10-클로로-3-(1-사이클로프로필피페리딘-4-일))-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((10-chloro-3-(1-cyclopropylpiperidin-4-yl))-1,2,3,4,4a,5 -hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 9.00-8.90 (m, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.834 (d, J = 2.0 Hz, 1H), 8.305 (s, 1H), 8.190 (d, J = 9.2 Hz, 1H), 7.261 (d, J = 2.4 Hz, 1H), 7.164 (d, J = 2.4 Hz, 1H), 4.42-4.30 (m, 1H), 4.26-4.16 (m, 1H), 3.90-3.80 (m, 2H), 3.78-3.42 (m, 7H), 2.92-2.80 (m, 1H), 2.52-2.40 (m, 2H), 2.175 (s, 3H), 2.139 (s, 3H), 2.10-1.98 (m, 2H), 1.10-0.99 (m, 4H); MS (ESI): m/z 738 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 9.00-8.90 (m, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.834 (d, J = 2.0 Hz, 1H), 8.305 (s, 1H), 8.190 (d, J = 9.2 Hz, 1H), 7.261 (d, J = 2.4 Hz, 1H), 7.164 (d, J = 2.4 Hz, 1H), 4.42-4.30 (m, 1H) , 4.26-4.16 (m, 1H), 3.90-3.80 (m, 2H), 3.78-3.42 (m, 7H), 2.92-2.80 (m, 1H), 2.52-2.40 (m, 2H), 2.175 (s, 3H), 2.139 (s, 3H), 2.10-1.98 (m, 2H), 1.10-0.99 (m, 4H); MS (ESI): m/z 738 [M+H] + 3636 100(1) 100 (1)
4646
Figure PCTKR2021019439-appb-img-000093
Figure PCTKR2021019439-appb-img-000093
 		(R)-(6-((5-브로모-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1] ,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400MHz, HCl salt, methanol-d 4) δ 8.84-8.70 (m, 3H), 8.18 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.09 (s, 1H), 6.64 (s, 1H), 4.30-4.20 (m, 1H), 4.02-3.98 (m, 1H), 3.78 (s, 3H), 3.70-3.60 (m, 2H), 3.52-3.28 (m, 3H), 3.12-3.02 (m, 2H), 2.90-2.80 (m, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 1.12-1.05 (m, 2H), 0.98-0.94 (m, 2H); MS (ESI): m/z 651 [M+1]+ 1 H NMR (400 MHz, HCl salt, methanol- d 4 ) δ 8.84-8.70 (m, 3H), 8.18 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.09 (s, 1H), 6.64 (s, 1H), 4.30-4.20 (m, 1H), 4.02-3.98 (m, 1H), 3.78 (s, 3H), 3.70-3.60 (m, 2H), 3.52-3.28 (m, 3H), 3.12-3.02 (m, 2H), 2.90-2.80 (m, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 1.12-1.05 (m, 2H), 0.98-0.94 (m, 2H); MS (ESI): m/z 651 [M+1] + 4242 4.06,
974.06,
97
4747
Figure PCTKR2021019439-appb-img-000094
Figure PCTKR2021019439-appb-img-000094
 		(S)-(6-((5-브로모-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1] ,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, free, DMSO-d 6) δ 12.70 (s, 1H), 8.92-8.85 (m, 3H), 8.27-8.25 (m, 2H), 8.03 (d, J = 9.6 Hz, 1H), 7.13 (s, 1H), 6.74 (s, 1H), 4.28-4.25 (m, 2H), 3.97-3.93 (m, 1H), 3.76 (s, 3H), 3.64-3.62 (m, 2H), 3.38-3.16 (m, 5H), 2.04 (s, 3H), 2.01 (s, 3H), 0.96-0.83 (m, 4H); MS (ESI): m/z 652 [M+H]+ 1 H NMR (400 MHz, free, DMSO- d 6 ) δ 12.70 (s, 1H), 8.92-8.85 (m, 3 H), 8.27-8.25 (m, 2H), 8.03 (d, J = 9.6 Hz, 1H), 7.13 (s, 1H), 6.74 (s, 1H), 4.28-4.25 (m, 2H), 3.97-3.93 (m, 1H), 3.76 (s, 3H), 3.64-3.62 (m, 2H), 3.38-3.16 (m, 5H), 2.04 (s, 3H), 2.01 (s, 3H), 0.96-0.83 (m, 4H) ; MS (ESI): m/z 652 [M+H] + 4242 4.07,
1004.07,
100
4848
Figure PCTKR2021019439-appb-img-000095
Figure PCTKR2021019439-appb-img-000095
 		(R)-(6-((5-브로모-2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1] ,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, Neutral, Methanol-d 4) δ 8.99-8.96 (m, 1H), 8.84 (d, J = 2 Hz, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.21 (s, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.32 (s, 1H), 6.65 (s, 1H), 4.21-4.17 (m, 1H), 3.96-3.91 (m, 1H), 3.82 (s, 3H), 3.79 (s, 1H), 3.51-3.46 (m, 1H), 3.13-3.04 (m, 2H), 2.97 (d, J = 11.2 Hz, 1H), 2.79-2.73 (m, 2H), 2.51-2.45 (m, 1H), 2.18-2.04 (m, 7H), 1.20-1.13 (m, 7H); MS (ESI): m/z 654 [M+H]+ 1 H NMR (400 MHz, Neutral, Methanol- d 4 ) δ 8.99-8.96 (m, 1H), 8.84 (d, J = 2 Hz, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.21 ( s, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.32 (s, 1H), 6.65 (s, 1H), 4.21-4.17 (m, 1H), 3.96-3.91 (m, 1H), 3.82 (s, 3H), 3.79 (s, 1H), 3.51-3.46 (m, 1H), 3.13-3.04 (m, 2H), 2.97 (d, J = 11.2 Hz, 1H), 2.79-2.73 (m, 2H) ), 2.51-2.45 (m, 1H), 2.18-2.04 (m, 7H), 1.20-1.13 (m, 7H); MS (ESI): m/z 654 [M+H] + 3838 4.67,
964.67,
96
4949
Figure PCTKR2021019439-appb-img-000096
Figure PCTKR2021019439-appb-img-000096
 		(S)-(6-((5-브로모-2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1] ,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.87-8.84 (m, 1H), 8.73-8.68 (m, 2H), 8.09 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.21 (s, 1H), 6.44 (s, 1H), 4.10 (d, J = 10.8 Hz, 1H), 3.85-3.80 (m, 1H), 3.71 (s, 3H), 3.68 (s, 1H), 3.49 (d, J = 30 Hz, 1H), 3.20-3.07 (m, 2H), 2.98-2.89 (m, 1H), 2.71-2.66 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H); MS (ESI): m/z 654 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.87-8.84 (m, 1H), 8.73-8.68 (m, 2 H), 8.09 (s, 1H), 8.01 (d, J = 9.6 Hz) , 1H), 7.21 (s, 1H), 6.44 (s, 1H), 4.10 (d, J = 10.8 Hz, 1H), 3.85-3.80 (m, 1H), 3.71 (s, 3H), 3.68 (s, 1H), 3.49 (d, J = 30 Hz, 1H), 3.20-3.07 (m, 2H), 2.98-2.89 (m, 1H), 2.71-2.66 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H); MS (ESI): m/z 654 [M+H] + 4.94.9 4.13,
954.13;
95
5050
Figure PCTKR2021019439-appb-img-000097
Figure PCTKR2021019439-appb-img-000097
 		(R)-(6-((5-브로모-2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1, 2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, HCl salt, DMSO-d 6) δ 12.75 (s, 1H), 10.36 (s, 1H), 8.90-8.86 (m, 3H), 8.33 (s, 1H), 8.28 (s, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.14 (s, 1H), 6.74 (s, 1H), 4.29-4.22 (m, 2H), 3.97-3.93 (m, 1H), 3.91 (s, 3H), 3.64-3.56 (m, 2H), 3.21-3.06 (m,4H), 2.04 (s, 3H), 2.01 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 640 [M+H]+ 1 H NMR (400 MHz, HCl salt, DMSO- d 6 ) δ 12.75 (s, 1H), 10.36 (s, 1H), 8.90-8.86 (m, 3H), 8.33 (s, 1H), 8.28 (s, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.14 (s, 1H), 6.74 (s, 1H), 4.29-4.22 (m, 2H), 3.97-3.93 (m) , 1H), 3.91 (s, 3H), 3.64-3.56 (m, 2H), 3.21-3.06 (m,4H), 2.04 (s, 3H), 2.01 (s, 3H), 1.30 (t, J = 7.2 Hz) , 3H); MS (ESI): m/z 640 [M+H] + 6161 3.87,
1003.87,
100
5151
Figure PCTKR2021019439-appb-img-000098
Figure PCTKR2021019439-appb-img-000098
 		(S)-(6-((5-브로모-2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1, 2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.97-8.93 (m, 1H), 8.85 (d, J = 2 Hz, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.23 (s, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 4.26-4.22 (m, 1H), 4.05-3.96 (m, 2H), 3.83 (s, 3H), 3.45-3.35 (m, 2H), 3.00-2.93 (m, 3H), 2.84-2.78 (m, 1H), 2.49 (t, J = 11.2 Hz, 1H), 2.16 (s ,3H), 2.12 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 640 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.97-8.93 (m, 1H), 8.85 (d, J = 2 Hz, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.23 (s, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 4.26-4.22 (m, 1H), 4.05-3.96 (m, 2H), 3.83 (s, 3H), 3.45-3.35 (m, 2H), 3.00-2.93 (m, 3H), 2.84-2.78 (m, 1H), 2.49 (t, J = 11.2 Hz, 1H), 2.16 (s , 3H), 2.12 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 640 [M+H] + 2929 4.52,
984.52,
98
5252
Figure PCTKR2021019439-appb-img-000099
Figure PCTKR2021019439-appb-img-000099
 		(R)-(6-((5-브로모-2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4, 3-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.94-8.90 (m, 1H), 8.82-8.77 (m, 2H), 8.16 (s, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.28 (s, 1H), 6.48 (s, 1H), 5.50 (s, 1H), 4.13-4.10 (m, 1H), 4.09-3.99 (m, 1H), 3.88-3.83 (m, 2H), 3.79 (s, 3H), 3.75-3.68 (m, 1H), 3.58 (d, J = 12 Hz, 1H), 3.08-3.05 (m, 1H), 2.74-2.73 (m, 1H), 2.13 (s, 3H), 2.10 (s, 3H); MS (ESI): m/z 613 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.94-8.90 (m, 1H), 8.82-8.77 (m, 2H), 8.16 (s, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.28 (s, 1H), 6.48 (s, 1H), 5.50 (s, 1H), 4.13-4.10 (m, 1H), 4.09-3.99 (m, 1H), 3.88-3.83 (m, 2H), 3.79 (s, 3H), 3.75-3.68 (m, 1H), 3.58 (d, J = 12 Hz, 1H), 3.08 -3.05 (m, 1H), 2.74-2.73 (m, 1H), 2.13 (s, 3H), 2.10 (s, 3H); MS (ESI): m/z 613 [M+H] + 1515 5.23,
1005.23,
100
5353
Figure PCTKR2021019439-appb-img-000100
Figure PCTKR2021019439-appb-img-000100
 		(S)-(6-((5-브로모-2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4, 3-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, CDCl3) δ12.51 (s, 1H), 9.03 (d, J = 9.4 Hz, 1H), 8.76-8.75 (m, 2H), 8.71 (s, 1H), 8.24-8.19 (m, 1H), 7.77 (s, 1H), 7.33-7.26 (m, 2H), 6.38 (s, 1H), 4.17-4.16 (m, 2H), 4.14-4.13 (m, 2H), 4.04-4.03 (m, 3H), 3.99-3.76 (m, 1H), 3.48-3.45 (m, 1H), 3.32-3.22 (m, 1H), 2.89-2.88 (m, 1H), 2.89-2.88 (m, 1H), 2.13 (s, 3H), 2.10 (s, 3H); MS (ESI): m/z 612 [M+H]+ 1 H NMR (400 MHz, FA salt, CDCl 3 ) δ12.51 (s, 1H), 9.03 (d, J = 9.4 Hz, 1H), 8.76-8.75 (m, 2H), 8.71 (s, 1H), 8.24-8.19 (m, 1H), 7.77 (s, 1H), 7.33-7.26 (m, 2H), 6.38 (s, 1H), 4.17-4.16 (m, 2H), 4.14-4.13 (m, 2H), 4.04-4.03 (m, 3H), 3.99-3.76 (m, 1H), 3.48-3.45 (m, 1H), 3.32-3.22 (m, 1H), 2.89-2.88 (m, 1H), 2.89-2.88 (m) , 1H), 2.13 (s, 3H), 2.10 (s, 3H); MS (ESI): m/z 612 [M+H] + 1818 5.16,
985.16,
98
5454
Figure PCTKR2021019439-appb-img-000101
Figure PCTKR2021019439-appb-img-000101
 		(R)-(6-((5-브로모-2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][ 1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, CDCl3) δ12.550 (s, 1H), 9.04-9.00 (m, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.29 (s, 1H), 8.17-8.11 (m, 2H), 7.89 (s, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.91-6.88 (m, 1H), 6.72 (d, J = 2.2 Hz, 1H), 4.28-4.25 (m, 1H), 4.08-4.03 (m, 1H), 3.79-3.72 (m, 1H), 3.21-3.20 (m, 1H), 3.08-3.07 (m, 2H), 2.77-2.75 (m, 2H), 2.51-2.50 (m, 1H), 2.18 (s, 3H), 2.14 (s, 3H), 1.24-1.22 (m, 3H); MS (ESI): m/z 611 [M+H]+ 1 H NMR (400 MHz, FA salt, CDCl 3 ) δ12.550 (s, 1H), 9.04-9.00 (m, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 1.6) Hz, 1H), 8.29 (s, 1H), 8.17-8.11 (m, 2H), 7.89 (s, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.91-6.88 (m, 1H), 6.72 (d, J = 2.2 Hz, 1H), 4.28-4.25 (m, 1H), 4.08-4.03 (m, 1H), 3.79-3.72 (m, 1H), 3.21-3.20 (m, 1H), 3.08-3.07 (m, 2H), 2.77-2.75 (m, 2H), 2.51-2.50 (m, 1H), 2.18 (s, 3H), 2.14 (s, 3H), 1.24-1.22 (m, 3H); MS (ESI): m/z 611 [M+H] + 2929 3.76,
983.76,
98
5555
Figure PCTKR2021019439-appb-img-000102
Figure PCTKR2021019439-appb-img-000102
 		(S)-(6-((5-브로모-2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][ 1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400MHz, Neutral, methanol-d 4) δ 9.15 (s, 1H), 8.85 (d, J = 15.6 Hz, 2H), 8.22 (s, 1H), 8.15 (d, J = 9.6 Hz, 1H), 7.10 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.50 (s, 1H), 4.30-4.20 (m, 1H), 4.02-3.98 (m, 1H), 3.80-3.70 (m, 1H), 3.20-3.10 (m, 2H), 3.04-2.98 (m, 1H), 2,80-2.70 (m, 1H), 2.60-2.50 (m, 2H), 2.32-2.56 (m, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 609 [M+1]+ 1 H NMR (400 MHz, Neutral, methanol- d 4 ) δ 9.15 (s, 1H), 8.85 (d, J = 15.6 Hz, 2H), 8.22 (s, 1H), 8.15 (d, J = 9.6 Hz, 1H) ), 7.10 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 5.50 (s, 1H), 4.30-4.20 (m, 1H), 4.02 -3.98 (m, 1H), 3.80-3.70 (m, 1H), 3.20-3.10 (m, 2H), 3.04-2.98 (m, 1H), 2,80-2.70 (m, 1H), 2.60-2.50 ( m, 2H), 2.32-2.56 (m, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 609 [M+1] + 3232 3.80,
1003.80,
100
5656
Figure PCTKR2021019439-appb-img-000103
Figure PCTKR2021019439-appb-img-000103
 		(R)-(6-((5-브로모-2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] [1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 9.10-9.07 (m, 1H), 8.84 (d, J = 2 Hz, 1H), 8.79 (d, J = 2 Hz, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 9.6 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.93-6.90 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.30-4.27 (m, 1H), 4.06-3.96 (m, 2H), 3.49-3.33 (m, 2H), 3.28-3.25 (m, 1H), 3.00-2.86 (m, 2H), 2.61 (t, J = 11.2 Hz, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 1.32-1.30 (m, 6H); MS (ESI): m/z 624 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 9.10-9.07 (m, 1H), 8.84 (d, J = 2 Hz, 1H), 8.79 (d, J = 2 Hz, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 9.6 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.93-6.90 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.30-4.27 (m, 1H), 4.06-3.96 (m, 2H), 3.49-3.33 (m, 2H), 3.28-3.25 (m, 1H), 3.00-2.86 (m, 2H), 2.61 (t, J = 11.2 Hz, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 1.32-1.30 (m, 6H); MS (ESI): m/z 624 [M+H] + 2424 4.54,
984.54,
98
5757
Figure PCTKR2021019439-appb-img-000104
Figure PCTKR2021019439-appb-img-000104
 		(S)-(6-((5-브로모-2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]))옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] [1,4])) oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 9.13-9.10 (m, 1H), 8.85 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 6.89-6.86 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.26-4.29 (m, 1H), 4.02-3.97 (m, 1H), 3.82-3.80 (m, 1H), 3.07-2.95 (m, 2H), 2.90-2.89 (m, 1H), 2.77-2.71 (m, 2H), 2.47-2.46 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 2.08 (t, J = 10.8 Hz, 1H), 1.15-1.11 (m ,6H); MS (ESI): m/z 623 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 9.13-9.10 (m, 1H), 8.85 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 6.89-6.86 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H) , 4.26-4.29 (m, 1H), 4.02-3.97 (m, 1H), 3.82-3.80 (m, 1H), 3.07-2.95 (m, 2H), 2.90-2.89 (m, 1H), 2.77-2.71 ( m, 2H), 2.47-2.46 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 2.08 (t, J = 10.8 Hz, 1H), 1.15-1.11 (m, 6H); MS (ESI): m/z 623 [M+H] + 2424 4.04,
984.04,
98
5858
Figure PCTKR2021019439-appb-img-000105
Figure PCTKR2021019439-appb-img-000105
 		(R)-(6-((5-브로모-2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][ 1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 9.18-9.14 (m, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 8.15 (d, J = 10.1 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.91-6.89 (m, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.20-4.19 (m, 1H), 3.99-3.96 (m, 3H), 3.51-3.50 (m, 2H), 3.44-3.42 (m, 1H), 2.87-2.86 (m, 2H), 2.21 (s, 3H), 2.18 (s, 3H); MS (ESI): m/z 582 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 9.18-9.14 (m, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 8.15 (d, J = 10.1 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.91-6.89 (m, 1H), 6.81 (d, J = 8.8 Hz, 1H) , 4.20-4.19 (m, 1H), 3.99-3.96 (m, 3H), 3.51-3.50 (m, 2H), 3.44-3.42 (m, 1H), 2.87-2.86 (m, 2H), 2.21 (s, 3H), 2.18 (s, 3H); MS (ESI): m/z 582 [M+H] + 4242 5.20,
975.20,
97
5959
Figure PCTKR2021019439-appb-img-000106
Figure PCTKR2021019439-appb-img-000106
 		(S)-(6-((5-브로모-2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][ 1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, CDCl3) δ 12.56 (s, 1H), 9.07-9.04 (m, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.23 (s, 1H), 8.14 (d, J = 9.6 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 6.90-6.87 (m, 1H), 6.79 (s, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.20-4.19 (m, 1H), 4.03-3.98 (m, 2H), 3.89-3.87 (m, 1H), 3.77-3.76 (m, 1H), 3.49-3.47 (m, 1H), 3.34-3.28 (m, 1H), 3.19-3.12 (m, 1H), 2.85-2.84 (m, 1H), 2.18 (s, 3H), 2.14 (s, 3H); MS (ESI): m/z 582 [M+H]+ 1 H NMR (400 MHz, FA salt, CDCl 3 ) δ 12.56 (s, 1H), 9.07-9.04 (m, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 1.6 Hz) , 1H), 8.23 (s, 1H), 8.14 (d, J = 9.6 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 6.90-6.87 (m, 1H), 6.79 (s, 1H) , 6.71 (d, J = 8.8 Hz, 1H), 4.20-4.19 (m, 1H), 4.03-3.98 (m, 2H), 3.89-3.87 (m, 1H), 3.77-3.76 (m, 1H), 3.49 -3.47 (m, 1H), 3.34-3.28 (m, 1H), 3.19-3.12 (m, 1H), 2.85-2.84 (m, 1H), 2.18 (s, 3H), 2.14 (s, 3H); MS (ESI): m/z 582 [M+H] + 2525 5.11,
1005.11,
100
6060
Figure PCTKR2021019439-appb-img-000107
Figure PCTKR2021019439-appb-img-000107
 		(R)-(6-((5-브로모-2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(R)-(6-((5-bromo-2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] [1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, HCl salt, CDCl3) δ12.550 (s, 1H), 9.079 (d, J = 4.0 Hz, 1H), 8.753-8.749 (m, 2H), 8.225 (s, 1H), 8.123 (d, J = 9.6 Hz, 1H), 7.121 (s, 1H), 6.862-6.708 (m, 3H), 4.226-4.199 (m, 1H), 4.073-4.025 (m, 1H), 3.747-3.742 (m, 1H), 3.112-3.090 (m, 3H), 2.477-2.468 (m, 1H),2.489-2.480 (m, 1H), 2.131 (s, 3H), 2.121 (s, 3H), 1.567-1.564 (m, 1H), 0.888-0.880 (m, 1H), 0.509-0.474 (m, 4H); MS (ESI): m/z 623 [M+H]+ 1 H NMR (400 MHz, HCl salt, CDCl 3 ) δ12.550 (s, 1H), 9.079 (d, J = 4.0 Hz, 1H), 8.753-8.749 (m, 2H), 8.225 (s, 1H), 8.123 (d, J = 9.6 Hz, 1H), 7.121 (s, 1H), 6.862-6.708 (m, 3H), 4.226-4.199 (m, 1H), 4.073-4.025 (m, 1H), 3.747-3.742 ( m, 1H), 3.112-3.090 (m, 3H), 2.477-2.468 (m, 1H), 2.489-2.480 (m, 1H), 2.131 (s, 3H), 2.121 (s, 3H), 1.567-1.564 ( m, 1H), 0.888-0.880 (m, 1H), 0.509-0.474 (m, 4H); MS (ESI): m/z 623 [M+H] + 1717 3.90,
993.90,
99
6161
Figure PCTKR2021019439-appb-img-000108
Figure PCTKR2021019439-appb-img-000108
 		(S)-(6-((5-브로모-2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드(S)-(6-((5-bromo-2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] [1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 9.13-9.11 (m, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.56 (s, 1H), 8.82 (d, J = 1.2 Hz, 1H), 8.22 (s, 1H), 8.15 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.82 (d, J = 9.2 Hz, 1H), 4.26-4.23 (m, 1H), 4.04-4.01 (m, 1H), 3.75-3.72 (m, 1H), 3.17-3.15 (m, 2H), 3.08-3.05 (m, 2H), 2.68-2.67 (m, 1H), 2.55-2.54 (m, 1H), 2.18 (s, 3H), 2.14 (s, 3H), 1.76-1.74 (m, 1H), 0.57-0.52 (m, 4H); MS (ESI): m/z 621 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 9.13-9.11 (m, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.56 (s, 1H), 8.82 (d, J = 1.2 Hz, 1H), 8.22 (s, 1H), 8.15 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.82 (d, J = 9.2 Hz, 1H), 4.26-4.23 (m, 1H), 4.04-4.01 (m, 1H), 3.75-3.72 (m, 1H), 3.17-3.15 (m, 2H), 3.08-3.05 (m, 2H), 2.68-2.67 (m, 1H), 2.55-2.54 (m, 1H), 2.18 (s, 3H), 2.14 (s, 3H), 1.76-1.74 (m, 1H), 0.57-0.52 (m, 4H); MS (ESI): m/z 621 [M+H] + 1616 3.90,
963.90,
96
6262
Figure PCTKR2021019439-appb-img-000109
Figure PCTKR2021019439-appb-img-000109
 		(R)-다이메틸(6-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드(R)-dimethyl (6-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] ]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)quinoxalin-5-yl)phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 4) δ 13.25 (s, 1H), 11.36 (s, 1H), 9.97 (dd, J = 9.5, 4.0 Hz, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.84-8.78 (m, 2H), 8.18 (s, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.8, 2.3 Hz, 1H), 6.98-6.93 (m, 1H), 6.81 (d, J = 8.9 Hz, 1H), 6.53-6.34 (m, 1H), 4.23 (dd, J = 10.4, 2.5 Hz, 1H), 3.95-3.86 (m, 1H), 3.67 (d, J = 11.8 Hz, 1H), 3.03-2.93 (m, 1H), 2.87 (d, J = 10.5 Hz, 1H), 2.80 (d, J = 10.1 Hz, 1H), 2.64-2.55 (m, J = 13.1, 10.2 Hz, 1H), 2.23 (s, 3H), 2.14-2.05 (m, J = 13.2 Hz, 7H), 1.71 (t, J = 10.6 Hz, 1H); MS (ESI): m/z 556 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 4 ) δ 13.25 (s, 1H), 11.36 (s, 1H), 9.97 (dd, J = 9.5, 4.0 Hz, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.84-8.78 (m, 2H), 8.18 (s, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.8, 2.3 Hz, 1H), 6.98-6.93 (m, 1H), 6.81 (d, J = 8.9 Hz, 1H), 6.53-6.34 (m, 1H), 4.23 (dd, J = 10.4, 2.5 Hz) , 1H), 3.95-3.86 (m, 1H), 3.67 (d, J = 11.8 Hz, 1H), 3.03-2.93 (m, 1H), 2.87 (d, J = 10.5 Hz, 1H), 2.80 (d, J = 10.1 Hz, 1H), 2.64-2.55 (m, J = 13.1, 10.2 Hz, 1H), 2.23 (s, 3H), 2.14-2.05 (m, J = 13.2 Hz, 7H), 1.71 (t, J ) = 10.6 Hz, 1H); MS (ESI): m/z 556 [M+H] + 4242 4.05,
994.05,
99
6363
Figure PCTKR2021019439-appb-img-000110
Figure PCTKR2021019439-appb-img-000110
 		(R)-다이메틸(6-((2-((3-(1-메틸피페리딘-4-일))-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드(R)-dimethyl(6-((2-((3-(1-methylpiperidin-4-yl))-1,2,3,4,4a,5-hexahydrobenzo[b]pyra Zino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)quinoxalin-5-yl) phosphine oxide 1H NMR (400 MHz, DMSO-d 4, FA salt) δ 13.25 (s, 1H), 11.35 (s, 1H), 9.97 (dd, J = 9.5, 4.1 Hz, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.81 (d, J = 2.0 Hz, 2H), 8.20 (s, 2H), 8.12 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 8.7, 2.3 Hz, 1H), 6.99-6.94 (m, 1H), 6.79 (d, J = 8.9 Hz, 1H), 6.47 (dd, J = 3.3, 1.9 Hz, 1H), 4.29-4.19 (m, 1H), 3.97-3.86 (m, 1H), 3.69 (d, J = 11.5 Hz, 1H), 3.05-2.83 (m, 5H), 2.36-2.28 (m, 1H), 2.24-2.16 (m, 4H), 2.11 (s, 3H), 2.07 (s, 3H), 2.01-1.87 (m, 3H), 1.77 (d, J = 10.8 Hz, 2H), 1.46 (m, 2H); MS (ESI): m/z 639 [M+H]+ 1 H NMR (400 MHz, DMSO- d 4 , FA salt) δ 13.25 (s, 1H), 11.35 (s, 1H), 9.97 (dd, J = 9.5, 4.1 Hz, 1H), 8.87 (d, J = 1.8 Hz, 1H), 8.81 (d, J = 2.0 Hz, 2H), 8.20 (s, 2H), 8.12 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 8.7, 2.3 Hz, 1H), 6.99-6.94 (m, 1H), 6.79 (d, J = 8.9 Hz, 1H), 6.47 (dd, J = 3.3, 1.9 Hz, 1H), 4.29- 4.19 (m, 1H), 3.97-3.86 (m, 1H), 3.69 (d, J = 11.5 Hz, 1H), 3.05-2.83 (m, 5H), 2.36-2.28 (m, 1H), 2.24-2.16 ( m, 4H), 2.11 (s, 3H), 2.07 (s, 3H), 2.01-1.87 (m, 3H), 1.77 (d, J = 10.8 Hz, 2H), 1.46 (m, 2H); MS (ESI): m/z 639 [M+H] + 7373 3.65,
993.65,
99
6464
Figure PCTKR2021019439-appb-img-000111
Figure PCTKR2021019439-appb-img-000111
 		(R)-다이메틸(6-((2-((3-(1-메틸피페리딘-4-일))-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)티에노[3,2-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드(R)-dimethyl(6-((2-((3-(1-methylpiperidin-4-yl))-1,2,3,4,4a,5-hexahydrobenzo[b]pyra Zino [1,2-d] [1,4] oxazin-8-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) quinoxalin-5-yl) phosphine oxide 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ 13.60 (s, 1H), 9.80-9.49 (m, 3H), 8.93-8.89 (m, 2H), 8.21-8.16 (m, 1H), 7.36 (s, 1H), 7.28 (d, J = 5.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 4.37-4.34 (m, 2H), 4.23-4.04 (m, 3H), 3.68 (s, 2H), 3.63 (d, J = 11.2 Hz, 2H), 3.38-3.36 (m, 3H), 3.16-2.85 (m, 4H), 2.79 (s, 3H), 2.12(s, 3H), 2.09 (s, 3H), 1.87-1.84 (m, 2H); MS (ESI): m/z 656 [M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ 13.60 (s, 1H), 9.80-9.49 (m, 3H), 8.93-8.89 (m, 2H), 8.21-8.16 (m, 1H), 7.36 (s, 1H), 7.28 (d, J = 5.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 4.37-4.34 (m, 2H) ), 4.23-4.04 (m, 3H), 3.68 (s, 2H), 3.63 (d, J = 11.2 Hz, 2H), 3.38-3.36 (m, 3H), 3.16-2.85 (m, 4H), 2.79 (s, 3H), 2.12(s) , 3H), 2.09 (s, 3H), 1.87-1.84 (m, 2H); MS (ESI): m/z 656 [M+H] + 24.324.3 3.66
1003.66
100
(1) NMR purity (1) NMR purity
실시예 65: (R)-(2-((2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드의 제조Example 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
하기 반응식 3으로 표시된 방법을 통해 표제의 화합물을 제조하였다.The title compound was prepared by the method shown in Scheme 3 below.
[반응식 3][Scheme 3]
Figure PCTKR2021019439-appb-img-000112
Figure PCTKR2021019439-appb-img-000112
단계 1: (2-((2-클로로-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드의 제조Step 1: (2-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl ) Preparation of dimethyl phosphine oxide
2,4-다이클로로-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘(1 당량), (2-아미노페닐)다이메틸포스핀옥사이드(1 당량)를 DMF(0.5 M)에 녹인 후, 0 ℃에서 KOtBu를 첨가하여 0 ℃에서 10분 동안 교반하였다. 물과 brine을 넣고 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(DCM:MeOH)를 통해 정제하였고, 흰색 고체의 목적 화합물을 수득하였다(수율: 37 %, MS (ESI): m/z 451 [M+H]+).2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 eq), (2-aminophenyl)dimethyl) After phosphine oxide (1 equivalent) was dissolved in DMF (0.5 M), KOtBu was added at 0 °C and stirred at 0 °C for 10 minutes. 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 white solid (yield: 37 %, MS (ESI): m/z 451 [M+H] + ).
단계 2: (R)-(2-((2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드의 제조Step 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
단계 1에서 제조한 2-((2-클로로-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(1 당량), (R)-9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-아민(1.5 당량), K2CO3(3 당량)을 sec-BuOH(0.04 M)에 녹인 후, 질소 하에서 Pd2(dba)3(0.1 당량)와 Xphos(0.1 당량)를 첨가하고 110 ℃에서 1 시간 동안 교반하였다. 셀라이트로 여과한 뒤, 농축하였다. 얻어진 갈색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 100 %, MS (ESI): m/z 678 [M+H]+).2-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) prepared in step 1 Phenyl) dimethylphosphine oxide (1 equivalent), (R)-9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2- d][1,4]oxazin-8-amine (1.5 eq.), K 2 CO 3 (3 eq.) was dissolved in sec-BuOH (0.04 M), and then Pd 2 (dba) 3 (0.1 eq.) under nitrogen and Xphos (0.1 equivalents) were added and stirred at 110 °C for 1 hour. After filtration through celite, it was concentrated. The obtained target compound as a brown solid was used in the next reaction without further purification (yield: 100 %, MS (ESI): m/z 678 [M+H] + ).
단계 3: (R)-(2-((2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드의 제조Step 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
단계 2에서 제조한 (R)-(2-((2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(1 당량)을 DCM(0.1 M)에 녹인 후, TFA를 동량 첨가하고 상온에서 1 시간 동안 교반하였다. 반응 혼합물을 농축하여 다시 THF에 녹인 후, sat.NaHCO3를 첨가하고 60 ℃에서 16 시간 동안 교반하였다. 물과 brine을 넣고 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 prep-HPLC를 통해 정제하였고, 갈색 고체의 목적 화합물을 수득하였다(수율: 49 %, MS (ESI): m/z 548 [M+H]+).(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-yl)amino)phenyl)dimethylphosphine oxide (1 equivalent) was dissolved in DCM (0.1 M), followed by the addition of the same amount of TFA, followed by stirring at room temperature for 1 hour. The 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] + ).
실시예 66 내지 실시예 136Examples 66 to 136
상기 실시예 65와 유사한 방법으로 실시예 66 내지 136 화합물을 제조하였다. 실시예 65 내지 136 화합물의 화학구조, 화합물명, NMR, 수율, 및 HPLC 분석 결과를 하기 표 2에 정리하여 나타내었다.Compounds of Examples 66 to 136 were prepared in a manner similar to that of Example 65. Chemical structures, compound names, NMR, yields, and HPLC analysis results of the compounds of Examples 65 to 136 are summarized in Table 2 below.
실시예Example 구조rescue 화합물명compound name 1H NMR, MS 1 H NMR, MS 수율
(%)transference number
(%) 		HPLC r.t.(min),
Purity
(%)HPLC rt (min),
Purity
(%)
6565
Figure PCTKR2021019439-appb-img-000113
Figure PCTKR2021019439-appb-img-000113
 		(R)-(2-((2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(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)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.58 (s, 1H), 11.28 (d, J = 2.3 Hz, 1H), 9.00-8.89 (m, 1H), 8.22 (s, 1H, FA), 7.66 (s, 1H), 7.62-7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.12-7.00 (m, 1H), 6.95-6.86 (m, 1H), 6.59 (s, 1H), 6.37-6.28 (m, 1H), 4.26-4.16 (m, 1H), 3.91-3.83 (m, 1H), 3.83-3.74 (m, 4H), 3.03-2.94 (m, 2H), 2.94-2.87 (m, 1H), 2.66-2.58 (m, 1H), 2.44-2.34 (m, 2H), 2.15-2.06 (m, 1H), 1.82 (d, J = 13.5 Hz, 6H), 1.69 (t, J = 10.5 Hz, 1H), 1.04 (t, J = 7.2 Hz, 3H); MS (ESI): 548 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.58 (s, 1H), 11.28 (d, J = 2.3 Hz, 1H), 9.00-8.89 (m, 1H), 8.22 (s, 1H, FA), 7.66 (s, 1H), 7.62-7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.12-7.00 (m, 1H), 6.95-6.86 (m, 1H), 6.59 (s, 1H), 6.37-6.28 (m, 1H), 4.26-4.16 (m, 1H), 3.91-3.83 (m, 1H), 3.83-3.74 (m, 4H), 3.03 -2.94 (m, 2H), 2.94-2.87 (m, 1H), 2.66-2.58 (m, 1H), 2.44-2.34 (m, 2H), 2.15-2.06 (m, 1H), 1.82 (d, J = 13.5 Hz, 6H), 1.69 (t, J = 10.5 Hz, 1H), 1.04 (t, J = 7.2 Hz, 3H); MS (ESI): 548 [M+H] + 4949 3.75,
983.75,
98
6666
Figure PCTKR2021019439-appb-img-000114
Figure PCTKR2021019439-appb-img-000114
 		(R)-(2-((2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][ 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.66 (dd, J = 8.2, 4.6 Hz, 1H), 8.21 (s, 1H, FA), 7.84 (s, 1H), 7.63-7.53 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 6.90 (s, 1H), 6.62 (s, 1H), 6.41 (d, J = 3.6 Hz, 1H), 4.26 (d, J = 10.6 Hz, 1H), 4.06-3.96 (m, 2H), 3.87 (s, 3H), 3.40-3.34 (m, 2H), 3.27 (s, 1H), 2.88 (d, J = 13.3 Hz, 2H), 2.74 (s, 3H), 2.57 (t, J = 11.3 Hz, 1H), 1.89 (s, 3H), 1.86 (s, 3H); MS (ESI): 534 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.66 (dd, J = 8.2, 4.6 Hz, 1H), 8.21 (s, 1H, FA), 7.84 (s, 1H), 7.63-7.53 ( m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 6.90 (s, 1H), 6.62 (s, 1H), 6.41 (d, J = 3.6 Hz, 1H), 4.26 (d, J = 10.6) Hz, 1H), 4.06-3.96 (m, 2H), 3.87 (s, 3H), 3.40-3.34 (m, 2H), 3.27 (s, 1H), 2.88 (d, J = 13.3 Hz, 2H), 2.74 (s, 3H), 2.57 (t, J = 11.3 Hz, 1H), 1.89 (s, 3H), 1.86 (s, 3H); MS (ESI): 534 [M+H] + 2121 3.46,
993.46,
99
6767
Figure PCTKR2021019439-appb-img-000115
Figure PCTKR2021019439-appb-img-000115
 		(2-((2-(((6aR,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((2-(((6aR,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2] -d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.57 (s, 1H), 11.27 (s, 1H), 8.98-8.91 (m, 1H), 8.18 (s, 1H, FA), 7.67 (s, 1H), 7.61-7.44 (m, 2H), 7.28 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.94-6.87 (m, 1H), 6.62 (s, 1H), 6.37-6.28 (m, 1H), 4.23-4.13 (m, 1H), 3.97 (d, J = 11.7 Hz, 1H), 3.93-3.85 (m, 1H), 3.79 (s, 3H), 3.58 (t, J = 4.5 Hz, 4H), 3.32 (4H in H2O), 2.92 (t, J = 9.9 Hz, 1H), 2.45-2.36 (m, 2H), 1.98-1.75 (m, 8H), 1.52-1.38 (m, 1H), 1.18-1.04 (m, 1H); MS (ESI): 604 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.57 (s, 1H), 11.27 (s, 1H), 8.98-8.91 (m, 1H), 8.18 (s, 1H, FA), 7.67 ( s, 1H), 7.61-7.44 (m, 2H), 7.28 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.94-6.87 (m, 1H), 6.62 (s, 1H), 6.37 -6.28 (m, 1H), 4.23-4.13 (m, 1H), 3.97 (d, J = 11.7 Hz, 1H), 3.93-3.85 (m, 1H), 3.79 (s, 3H), 3.58 (t, J ) = 4.5 Hz, 4H), 3.32 (4H in H 2 O), 2.92 (t, J = 9.9 Hz, 1H), 2.45-2.36 (m, 2H), 1.98-1.75 (m, 8H), 1.52-1.38 ( m, 1H), 1.18-1.04 (m, 1H); MS (ESI): 604 [M+H] + 2222 3.31,
1003.31;
100
6868
Figure PCTKR2021019439-appb-img-000116
Figure PCTKR2021019439-appb-img-000116
 		(2-((2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2] -d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.56 (s, 1H), 11.26 (s, 1H), 8.98-8.89 (m, 1H), 8.31 (s, 1H, FA), 7.65 (s, 1H), 7.61-7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.10-7.00 (m, 1H), 6.92-6.86 (m, 1H), 6.54 (s, 1H), 6.40-6.29 (m, 1H), 4.20-4.11 (m, 1H), 3.90-3.82 (m, 1H), 3.79 (s, 3H), 3.61 (t, J = 4.6 Hz, 4H), 3.48 (d, J = 11.6 Hz, 1H), 3.22 (4H in H2O), 2.87-2.77 (m, 1H), 2.50 (2H in dmso), 2.17-2.07 (m, 1H), 1.99 (d, J = 13.6 Hz, 1H), 1.82 (d, J = 13.5 Hz, 6H), 1.69 (t, J = 13.1 Hz, 1H), 1.35-1.26 (m, 1H); MS (ESI): 604 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.56 (s, 1H), 11.26 (s, 1H), 8.98-8.89 (m, 1H), 8.31 (s, 1H, FA), 7.65 ( s, 1H), 7.61-7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.10-7.00 (m, 1H), 6.92-6.86 (m, 1H) , 6.54 (s, 1H), 6.40-6.29 (m, 1H), 4.20-4.11 (m, 1H), 3.90-3.82 (m, 1H), 3.79 (s, 3H), 3.61 (t, J = 4.6 Hz) , 4H), 3.48 (d, J = 11.6 Hz, 1H), 3.22 (4H in H 2 O), 2.87-2.77 (m, 1H), 2.50 (2H in dmso), 2.17-2.07 (m, 1H), 1.99 (d, J = 13.6 Hz, 1H), 1.82 (d, J = 13.5 Hz, 6H), 1.69 (t, J = 13.1 Hz, 1H), 1.35-1.26 (m, 1H); MS (ESI): 604 [M+H] + 2828 3.40,
1003.40,
100
6969
Figure PCTKR2021019439-appb-img-000117
Figure PCTKR2021019439-appb-img-000117
 		(2-((2-(((6aS,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((2-(((6aS,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2] -d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.57 (s, 1H), 11.27 (s, 1H), 8.99-8.88 (m, 1H), 8.20 (s, 1H, FA), 7.67 (s, 1H), 7.61-7.44 (m, 2H), 7.28 (s, 1H), 7.10-7.01 (m, 1H), 6.94-6.86 (m, 1H), 6.62 (s, 1H), 6.37-6.29 (m, 1H), 4.22-4.15 (m, 1H), 3.97 (d, J = 11.9 Hz, 1H), 3.93-3.84 (m, 1H), 3.79 (s, 3H), 3.58 (t, J = 4.6 Hz, 4H), 3.32 (4H in H2O), 2.96-2.87 (m, 1H), 2.44-2.36 (m, 2H), 1.82 (d, J = 13.5 Hz, 8H), 1.52-1.39 (m, 1H), 1.16-1.05 (m, 1H); MS (ESI): 604 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.57 (s, 1H), 11.27 (s, 1H), 8.99-8.88 (m, 1H), 8.20 (s, 1H, FA), 7.67 ( s, 1H), 7.61-7.44 (m, 2H), 7.28 (s, 1H), 7.10-7.01 (m, 1H), 6.94-6.86 (m, 1H), 6.62 (s, 1H), 6.37-6.29 ( m, 1H), 4.22-4.15 (m, 1H), 3.97 (d, J = 11.9 Hz, 1H), 3.93-3.84 (m, 1H), 3.79 (s, 3H), 3.58 (t, J = 4.6 Hz) , 4H), 3.32 (4H in H 2 O), 2.96-2.87 (m, 1H), 2.44-2.36 (m, 2H), 1.82 (d, J = 13.5 Hz, 8H), 1.52-1.39 (m, 1H) ), 1.16-1.05 (m, 1H); MS (ESI): 604 [M+H] + 2828 3.51,
993.51,
99
7070
Figure PCTKR2021019439-appb-img-000118
Figure PCTKR2021019439-appb-img-000118
 		(2-((2-(((6aS,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((2-(((6aS,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2] -d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.56 (s, 1H), 11.26 (d, J = 2.3 Hz, 1H), 8.99-8.87 (m, 1H), 8.19 (s, 1H, FA), 7.65 (s, 1H), 7.61-7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.09-7.01 (m, 1H), 6.93-6.87 (m, 1H), 6.54 (s, 1H), 6.37-6.29 (m, 1H), 4.18-4.10 (m, 1H), 3.91-3.82 (m, 1H), 3.79 (s, 3H), 3.61 (t, J = 4.6 Hz, 4H), 3.52-3.45 (m, 1H), 3.31 (1H in H2O), 2.88-2.77 (m, 1H), 2.50 (2H in dmso), 2.16-2.06 (m, 1H), 2.04-1.93 (m, 1H), 1.82 (d, J = 13.5 Hz, 6H), 1.69 (t, J = 13.3 Hz, 1H), 1.36-1.26 (m, 1H); MS (ESI): 604 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.56 (s, 1H), 11.26 (d, J = 2.3 Hz, 1H), 8.99-8.87 (m, 1H), 8.19 (s, 1H, FA), 7.65 (s, 1H), 7.61-7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.09-7.01 (m, 1H), 6.93-6.87 (m, 1H), 6.54 (s, 1H), 6.37-6.29 (m, 1H), 4.18-4.10 (m, 1H), 3.91-3.82 (m, 1H), 3.79 (s, 3H), 3.61 (t) , J = 4.6 Hz, 4H), 3.52-3.45 (m, 1H), 3.31 (1H in H 2 O), 2.88-2.77 (m, 1H), 2.50 (2H in dmso), 2.16-2.06 (m, 1H) ), 2.04-1.93 (m, 1H), 1.82 (d, J = 13.5 Hz, 6H), 1.69 (t, J = 13.3 Hz, 1H), 1.36-1.26 (m, 1H); MS (ESI): 604 [M+H] + 3939 3.37,
1003.37,
100
7171
Figure PCTKR2021019439-appb-img-000119
Figure PCTKR2021019439-appb-img-000119
 		(2-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((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-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.57 (s, 1H), 11.27 (s, 1H), 9.00-8.89 (m, 1H), 8.20 (s, 1H, FA), 7.66 (s, 1H), 7.60-7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.93-6.87 (m, 1H), 6.61 (s, 1H), 6.35-6.30 (m, 1H), 4.21-4.14 (m, 1H), 3.96 (d, J = 12.0 Hz, 1H), 3.92-3.84 (m, 1H), 3.79 (s, 3H), 3.35 (2H in H2O), 2.96-2.86 (m, 1H), 2.46-2.23 (m, 8H), 2.15 (s, 3H), 1.90 (d, J = 12.6 Hz, 1H), 1.82 (d, J = 13.5 Hz, 7H), 1.52-1.41 (m, 1H), 1.16-1.04 (m, 1H); MS (ESI): 617 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.57 (s, 1H), 11.27 (s, 1H), 9.00-8.89 (m, 1H), 8.20 (s, 1H, FA), 7.66 ( s, 1H), 7.60-7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.93-6.87 (m) , 1H), 6.61 (s, 1H), 6.35-6.30 (m, 1H), 4.21-4.14 (m, 1H), 3.96 (d, J = 12.0 Hz, 1H), 3.92-3.84 (m, 1H), 3.79 (s, 3H), 3.35 (2H in H 2 O), 2.96-2.86 (m, 1H), 2.46-2.23 (m, 8H), 2.15 (s, 3H), 1.90 (d, J = 12.6 Hz, 1H), 1.82 (d, J = 13.5 Hz, 7H), 1.52-1.41 (m, 1H), 1.16-1.04 (m, 1H); MS (ESI): 617 [M+H] + 2323 3.07,
993.07,
99
7272
Figure PCTKR2021019439-appb-img-000120
Figure PCTKR2021019439-appb-img-000120
 		(2-((2-(((6aS,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((2-(((6aS,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.57 (s, 1H), 11.26 (d, J = 2.5 Hz, 1H), 8.99-8.89 (m, 1H), 8.20 (s, 1H, FA), 7.66 (s, 1H), 7.61-7.52 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.94-6.85 (m, 1H), 6.61 (s, 1H), 6.39-6.30 (m, 1H), 4.22-4.14 (m, 1H), 3.96 (d, J = 12.1 Hz, 1H), 3.93-3.85 (m, 1H), 3.79 (s, 3H), 3.34 (2H in H2O), 2.97-2.86 (m, 1H), 2.45-2.22 (m, 8H), 2.15 (s, 3H), 1.90 (d, J = 12.5 Hz, 1H), 1.82 (d, J = 13.5 Hz, 7H), 1.53-1.39 (m, 1H), 1.17-1.05 (m, 1H); MS (ESI): 617 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.57 (s, 1H), 11.26 (d, J = 2.5 Hz, 1H), 8.99-8.89 (m, 1H), 8.20 (s, 1H, FA), 7.66 (s, 1H), 7.61-7.52 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.94-6.85 (m, 1H), 6.61 (s, 1H), 6.39-6.30 (m, 1H), 4.22-4.14 (m, 1H), 3.96 (d, J = 12.1 Hz, 1H), 3.93-3.85 ( m, 1H), 3.79 (s, 3H), 3.34 (2H in H 2 O), 2.97-2.86 (m, 1H), 2.45-2.22 (m, 8H), 2.15 (s, 3H), 1.90 (d, J = 12.5 Hz, 1H), 1.82 (d, J = 13.5 Hz, 7H), 1.53-1.39 (m, 1H), 1.17-1.05 (m, 1H); MS (ESI): 617 [M+H] + 2929 3.24,
993.24,
99
7373
Figure PCTKR2021019439-appb-img-000121
Figure PCTKR2021019439-appb-img-000121
 		(2-((2-(((6aR,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((2-(((6aR,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.56 (s, 1H), 11.26 (s, 1H), 8.98-8.87 (m, 1H), 8.20 (s, 1H, FA), 7.63 (s, 1H), 7.61-7.51 (m, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.94-6.87 (m, 1H), 6.54 (s, 1H), 6.36-6.29 (m, 1H), 4.18-4.11 (m, 1H), 3.85 (t, J = 9.7 Hz, 1H), 3.78 (s, 3H), 3.26-3.12 (m, 2H), 2.86-2.75 (m, 1H), 2.45-2.25 (m, 8H), 2.21-2.07 (m, 4H), 2.05-1.95 (m, 1H), 1.82 (d, J = 13.5 Hz, 6H), 1.73-1.63 (m, 1H), 1.37-1.25 (m, 1H); MS (ESI): 617 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.56 (s, 1H), 11.26 (s, 1H), 8.98-8.87 (m, 1H), 8.20 (s, 1H, FA), 7.63 ( s, 1H), 7.61-7.51 (m, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.94-6.87 (m) , 1H), 6.54 (s, 1H), 6.36-6.29 (m, 1H), 4.18-4.11 (m, 1H), 3.85 (t, J = 9.7 Hz, 1H), 3.78 (s, 3H), 3.26- 3.12 (m, 2H), 2.86-2.75 (m, 1H), 2.45-2.25 (m, 8H), 2.21-2.07 (m, 4H), 2.05-1.95 (m, 1H), 1.82 (d, J = 13.5) Hz, 6H), 1.73-1.63 (m, 1H), 1.37-1.25 (m, 1H); MS (ESI): 617 [M+H] + 4444 3.67,
993.67,
99
7474
Figure PCTKR2021019439-appb-img-000122
Figure PCTKR2021019439-appb-img-000122
 		(2-((2-(((6aS,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((2-(((6aS,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.56 (s, 1H), 11.26 (s, 1H), 8.96-8.89 (m, 1H), 8.19 (s, 1H, FA), 7.63 (s, 1H), 7.60-7.51 (m, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.29 (s, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.94-6.86 (m, 1H), 6.54 (s, 1H), 6.36-6.30 (m, 1H), 4.18-4.11 (m, 1H), 3.85 (t, J = 9.7 Hz, 1H), 3.78 (s, 3H), 3.23-3.13 (m, 2H), 2.85-2.75 (m, 1H), 2.43-2.23 (m, 8H), 2.19-2.06 (m, 4H), 2.03-1.94 (m, 1H), 1.82 (d, J = 13.5 Hz, 6H), 1.75-1.61 (m, 1H), 1.35-1.26 (m, 1H); MS (ESI): 617 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.56 (s, 1H), 11.26 (s, 1H), 8.96-8.89 (m, 1H), 8.19 (s, 1H, FA), 7.63 ( s, 1H), 7.60-7.51 (m, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.29 (s, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.94-6.86 (m) , 1H), 6.54 (s, 1H), 6.36-6.30 (m, 1H), 4.18-4.11 (m, 1H), 3.85 (t, J = 9.7 Hz, 1H), 3.78 (s, 3H), 3.23 3.13 (m, 2H), 2.85-2.75 (m, 1H), 2.43-2.23 (m, 8H), 2.19-2.06 (m, 4H), 2.03-1.94 (m, 1H), 1.82 (d, J = 13.5) Hz, 6H), 1.75-1.61 (m, 1H), 1.35-1.26 (m, 1H); MS (ESI): 617 [M+H] + 2929 3.58,
993.58,
99
7575
Figure PCTKR2021019439-appb-img-000123
Figure PCTKR2021019439-appb-img-000123
 		(R)-(2-((2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4] oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, Free salt, Methanol-d 4) δ 8.89-8.82 (m, 1H), 7.58-7.49 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 7.18-7.11 (m, 1H), 7.03-6.95 (m, 1H), 6.86 (d, J = 3.6 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 3.6 Hz, 1H), 4.27-4.21 (m, 1H), 4.04-3.95 (m, 1H), 3.72 (d, J = 11.5 Hz, 1H), 3.18-3.11 (m, 1H), 3.08-2.96 (m, 2H), 2.65 (s, 1H), 2.58-2.48 (m, 1H), 2.16-2.09 (m, 1H), 1.88 (d, J = 13.5 Hz, 6H), 1.78-1.71 (m, 1H), 0.58-0.45 (m, 4H); MS (ESI): 530 [M+H]+ 1 H NMR (400 MHz, Free salt, Methanol- d 4 ) δ 8.89-8.82 (m, 1H), 7.58-7.49 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 7.18-7.11 ( m, 1H), 7.03-6.95 (m, 1H), 6.86 (d, J = 3.6 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 3.6 Hz, 1H), 4.27-4.21 (m, 1H), 4.04-3.95 (m, 1H), 3.72 (d, J = 11.5 Hz, 1H), 3.18-3.11 (m, 1H), 3.08-2.96 (m, 2H), 2.65 ( s, 1H), 2.58-2.48 (m, 1H), 2.16-2.09 (m, 1H), 1.88 (d, J = 13.5 Hz, 6H), 1.78-1.71 (m, 1H), 0.58-0.45 (m, 4H); MS (ESI): 530 [M+H] + 3838 3.79,
993.79,
99
7676
Figure PCTKR2021019439-appb-img-000124
Figure PCTKR2021019439-appb-img-000124
 		(R)-(2-((2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] [1,4])oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.58 (s, 1H), 11.29 (t, J = 2.1 Hz, 1H), 8.99-8.89 (m, 1H), 8.25 (s, 1H, FA), 7.66 (s, 1H), 7.62-7.51 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.30 (s, 1H), 7.09-6.98 (m, 1H), 6.95-6.84 (m, 1H), 6.59 (s, 1H), 6.38-6.29 (m, 1H), 4.25-4.17 (m, 1H), 3.92-3.83 (m, 1H), 3.83-3.74 (m, 4H), 3.01 (d, J = 10.8 Hz, 1H), 2.98-2.86 (m, 2H), 2.58-2.53 (m, 1H), 2.45-2.36 (m, 1H), 2.06-1.95 (m, 1H), 1.82 (d, J = 13.5 Hz, 6H), 1.72-1.63 (m, 1H), 0.52 - 0.29 (m, 4H); MS (ESI): 560 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.58 (s, 1H), 11.29 (t, J = 2.1 Hz, 1H), 8.99-8.89 (m, 1H), 8.25 (s, 1H, FA), 7.66 (s, 1H), 7.62-751 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.30 (s, 1H), 7.09-6.98 (m, 1H), 6.95-6.84 (m, 1H), 6.59 (s, 1H), 6.38-6.29 (m, 1H), 4.25-4.17 (m, 1H), 3.92-3.83 (m, 1H), 3.83-3.74 (m, 4H), 3.01 (d, J = 10.8 Hz, 1H), 2.98-2.86 (m, 2H), 2.58-2.53 (m, 1H), 2.45-2.36 (m, 1H), 2.06-1.95 (m, 1H), 1.82 (d , J = 13.5 Hz, 6H), 1.72-1.63 (m, 1H), 0.52 - 0.29 (m, 4H); MS (ESI): 560 [M+H] + 4545 3.93,
993.93,
99
7777
Figure PCTKR2021019439-appb-img-000125
Figure PCTKR2021019439-appb-img-000125
 		(S)-다이메틸(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(S)-dimethyl (2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] ]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.86-8.80 (m, 1H), 8.29 (s, 1H, FA), 7.60-7.50 (m, 2H), 7.27 (d, J = 2.4 Hz, 1H), 7.15 (t, J = 6.8 Hz, 1H), 7.02 (d, J = 6.7 Hz, 1H), 6.87 (d, J = 3.5 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 3.6 Hz, 1H), 4.29-4.22 (m, 1H), 4.05-3.97 (m, 1H), 3.87 (d, J = 12.5 Hz, 1H), 3.21 (d, J = 12.0 Hz, 2H), 3.12 (d, J = 10.7 Hz, 1H), 2.82 (t, J = 11.2 Hz, 1H), 2.65 (t, J = 10.4 Hz, 1H), 2.58 (s, 3H), 2.30 (t, J = 11.1 Hz, 1H), 1.89 (s, 3H), 1.86 (s, 3H); MS (ESI): 504 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.86-8.80 (m, 1H), 8.29 (s, 1H, FA), 7.60-7.50 (m, 2H), 7.27 (d, J = 2.4 Hz, 1H), 7.15 (t, J = 6.8 Hz, 1H), 7.02 (d, J = 6.7 Hz, 1H), 6.87 (d, J = 3.5 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 3.6 Hz, 1H), 4.29-4.22 (m, 1H), 4.05-3.97 (m, 1H), 3.87 (d, J = 12.5 Hz, 1H), 3.21 (d, J ) = 12.0 Hz, 2H), 3.12 (d, J = 10.7 Hz, 1H), 2.82 (t, J = 11.2 Hz, 1H), 2.65 (t, J = 10.4 Hz, 1H), 2.58 (s, 3H), 2.30 (t, J = 11.1 Hz, 1H), 1.89 (s, 3H), 1.86 (s, 3H); MS (ESI): 504 [M+H] + 4545 3.65,
983.65,
98
7878
Figure PCTKR2021019439-appb-img-000126
Figure PCTKR2021019439-appb-img-000126
 		(R)-(2-((5-클로로-2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((5-chloro-2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2] -d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.53 (d, J = 2.5 Hz, 1H), 10.43 (s, 1H), 8.29-8.20 (m, 1H), 8.16 (s, 1H, FA), 7.61-7.45 (m, 3H), 7.24 (s, 1H), 7.17-7.10 (m, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.56 (s, 1H), 4.23-4.15 (m, 1H), 3.89-3.80 (m, 1H), 3.76 (s, 4H), 3.03-2.92 (m, 2H), 2.92-2.87 (m, 1H), 2.65-2.56 (m, 1H), 2.43-2.34 (m, 2H), 2.14-2.03 (m, 1H), 1.75 (d, J = 13.4 Hz, 6H), 1.68 (t, J = 10.6 Hz, 1H), 1.04 (t, J = 7.2 Hz, 3H); MS (ESI): 583 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.53 (d, J = 2.5 Hz, 1H), 10.43 (s, 1H), 8.29-8.20 (m, 1H), 8.16 (s, 1H, FA), 7.61-7.45 (m, 3H), 7.24 (s, 1H), 7.17-7.10 (m, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.56 (s, 1H), 4.23-4.15 (m, 1H), 3.89-3.80 (m, 1H), 3.76 (s, 4H), 3.03-2.92 (m, 2H), 2.92-2.87 (m, 1H), 2.65-2.56 (m, 1H), 2.43 -2.34 (m, 2H), 2.14-2.03 (m, 1H), 1.75 (d, J = 13.4 Hz, 6H), 1.68 (t, J = 10.6 Hz, 1H), 1.04 (t, J = 7.2 Hz, 3H); MS (ESI): 583 [M+H] + 4949 3.89,
993.89,
99
7979
Figure PCTKR2021019439-appb-img-000127
Figure PCTKR2021019439-appb-img-000127
 		(R)-(2-((5-클로로-2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((5-chloro-2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][ 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.47 (d, J = 2.6 Hz, 1H), 10.35 (s, 1H), 8.60 (s, 1H), 8.33-8.28 (m, 1H), 8.27 (s, 1H, FA), 7.56-7.48 (m, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.18-7.11 (m, 1H), 7.10-7.05 (m, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 4.25-4.17 (m, 1H), 3.92-3.85 (m, 1H), 3.64 (d, J = 10.8 Hz, 1H), 2.99 (d, J = 10.3 Hz, 1H), 2.92 (d, J = 10.2 Hz, 1H), 2.89-2.80 (m, 1H), 2.45-2.35 (m, 2H), 1.98 (t, J = 10.4 Hz, 1H), 1.74 (d, J = 13.4 Hz, 6H), 1.68-1.63 (m, 1H), 0.48-0.32 (m, 4H); MS (ESI): 564 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.47 (d, J = 2.6 Hz, 1H), 10.35 (s, 1H), 8.60 (s, 1H), 8.33-8.28 (m, 1H) , 8.27 (s, 1H, FA), 7.56-7.48 (m, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.18-7.11 (m, 1H), 7.10-7.05 (m, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 4.25-4.17 (m, 1H), 3.92-3.85 (m, 1H), 3.64 (d, J = 10.8 Hz, 1H), 2.99 (d, J = 10.3 Hz, 1H), 2.92 (d, J = 10.2 Hz, 1H), 2.89-2.80 (m, 1H), 2.45-2.35 (m, 2H), 1.98 (t, J ) = 10.4 Hz, 1H), 1.74 (d, J = 13.4 Hz, 6H), 1.68-1.63 (m, 1H), 0.48-0.32 (m, 4H); MS (ESI): 564 [M] + 3232 3.99,
993.99,
99
8080
Figure PCTKR2021019439-appb-img-000128
Figure PCTKR2021019439-appb-img-000128
 		(R)-(2-((5-클로로-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((5-chloro-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1, 2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.53 (d, J = 2.6 Hz, 1H), 10.43 (s, 1H), 8.27-8.23 (m, 1H), 8.23 (s, 1H, FA), 7.65-7.42 (m, 3H), 7.23 (s, 1H), 7.19-7.09 (m, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.56 (s, 1H), 4.24-4.15 (m, 1H), 3.88-3.80 (m, 1H), 3.80-3.68 (m, 4H), 3.00 (d, J = 10.9 Hz, 1H), 2.97-2.84 (m, 2H), 2.47-2.34 (m, 2H), 1.99 (t, J = 10.4 Hz, 1H), 1.75 (d, J = 13.5 Hz, 6H), 1.69-1.63 (m, 1H), 0.52-0.32 (m, 4H); MS (ESI): 595 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.53 (d, J = 2.6 Hz, 1H), 10.43 (s, 1H), 8.27-8.23 (m, 1H), 8.23 (s, 1H, FA), 7.65-7.42 (m, 3H), 7.23 (s, 1H), 7.19-7.09 (m, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.56 (s, 1H), 4.24-4.15 (m, 1H), 3.88-3.80 (m, 1H), 3.80-3.68 (m, 4H), 3.00 (d, J = 10.9 Hz, 1H), 2.97-2.84 (m, 2H), 2.47-2.34 (m) , 2H), 1.99 (t, J = 10.4 Hz, 1H), 1.75 (d, J = 13.5 Hz, 6H), 1.69-1.63 (m, 1H), 0.52-0.32 (m, 4H); MS (ESI): 595 [M+H] + 4242 4.08,
994.08,
99
8181
Figure PCTKR2021019439-appb-img-000129
Figure PCTKR2021019439-appb-img-000129
 		(S)-다이메틸(2-((2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(S)-dimethyl (2-((2-((3- (1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.58 (s, 1H), 11.22 (d, J = 2.3 Hz, 1H), 9.17-9.08 (m, 1H), 8.63 (s, 1H), 8.24 (s, 2H, FA), 7.61-7.41 (m, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.15-7.08 (m, 1H), 7.08-7.00 (m, 1H), 6.92-6.85 (m, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.39-6.30 (m, 1H), 4.27-4.19 (m, 1H), 3.94-3.86 (m, 1H), 3.67 (d, J = 11.5 Hz, 1H), 2.98 (d, J = 10.8 Hz, 1H), 2.94-2.86 (m, 2H), 2.82 (d, J = 11.4 Hz, 2H), 2.57-2.52 (m, 1H), 2.37-2.27 (m, 1H), 2.23-2.12 (m, 4H), 1.90 (t, J = 11.1 Hz, 3H), 1.82 (d, J = 13.5 Hz, 6H), 1.75 (d, J = 12.3 Hz, 2H), 1.51-1.36 (m, 2H); MS (ESI): 587 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.58 (s, 1H), 11.22 (d, J = 2.3 Hz, 1H), 9.17-9.08 (m, 1H), 8.63 (s, 1H) , 8.24 (s, 2H, FA), 7.61-7.41 (m, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.15-7.08 (m, 1H), 7.08-7.00 (m, 1H), 6.92 -6.85 (m, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.39-6.30 (m, 1H), 4.27-4.19 (m, 1H), 3.94-3.86 (m, 1H), 3.67 (d) , J = 11.5 Hz, 1H), 2.98 (d, J = 10.8 Hz, 1H), 2.94-2.86 (m, 2H), 2.82 (d, J = 11.4 Hz, 2H), 2.57-2.52 (m, 1H) , 2.37-2.27 (m, 1H), 2.23-2.12 (m, 4H), 1.90 (t, J = 11.1 Hz, 3H), 1.82 (d, J = 13.5 Hz, 6H), 1.75 (d, J = 12.3) Hz, 2H), 1.51-1.36 (m, 2H); MS (ESI): 587 [M+H] + 6161 2.84,
1002.84,
100
8282
Figure PCTKR2021019439-appb-img-000130
Figure PCTKR2021019439-appb-img-000130
 		(S)-4-((2-(다이메틸포스포릴)페닐)아미노)-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴(S)-4-((2-(dimethylphosphoryl)phenyl)amino)-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[ 1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.28 (s, 1H, FA), 8.09-8.03 (m, 1H), 7.67-7.58 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.24 (d, J = 8.8 Hz, 1H), 3.99 (t, d, J = 8.8 Hz, 1H), 3.83 (d, J = 12.4 Hz, 1H), 3.22-3.11 (m, 3H), 2.79 (br, 1H), 2.67 (t, J = 9.6 Hz, 1H), 2.59 (s, 3H), 2.32 (t, J = 11.6 Hz, 1H), 1.84 (s, 3H), 1.81 (s, 3H); MS (ESI): m/z 529 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.28 (s, 1H, FA), 8.09-8.03 (m, 1H), 7.67-7.58 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.27 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.24 (d, J = 8.8 Hz, 1H), 3.99 ( t, d, J = 8.8 Hz, 1H), 3.83 (d, J = 12.4 Hz, 1H), 3.22-3.11 (m, 3H), 2.79 (br, 1H), 2.67 (t, J = 9.6 Hz, 1H) ), 2.59 (s, 3H), 2.32 (t, J = 11.6 Hz, 1H), 1.84 (s, 3H), 1.81 (s, 3H); MS (ESI): m/z 529 [M+H] + 2424 3.66,
993.66,
99
8383
Figure PCTKR2021019439-appb-img-000131
Figure PCTKR2021019439-appb-img-000131
 		(S)-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(S)-(2-((5-chloro-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1] ,4])oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.22 (s, 1H, FA), 8.16-8.13 (m, 1H), 7.66-7.59 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.20 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.25 (d, J = 10.8 Hz, 1H), 3.99 (t, J = 8.4 Hz, 1H), 3.87 (d, J = 12.4 Hz, 1H), 3.25 (d, J = 10.8 Hz, 1H), 3.16 (d, J = 12 Hz, 2H), 2.83 (t, J = 9.4 HZ, 1H), 2.71 (t, J = 9.2 Hz, 1H), 2.61 (s, 3H), 2.37 (t, J = 11.6 Hz, 1H), 1.84 (s, 3H), 1.81 (s, 3H); MS (ESI): m/z 538 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.22 (s, 1H, FA), 8.16-8.13 (m, 1H), 7.66-7.59 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.20 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.25 (d, J = 10.8) Hz, 1H), 3.99 (t, J = 8.4 Hz, 1H), 3.87 (d, J = 12.4 Hz, 1H), 3.25 (d, J = 10.8 Hz, 1H), 3.16 (d, J = 12 Hz, 2H), 2.83 (t, J = 9.4 HZ, 1H), 2.71 (t, J = 9.2 Hz, 1H), 2.61 (s, 3H), 2.37 (t, J = 11.6 Hz, 1H), 1.84 (s, 3H), 1.81 (s, 3H); MS (ESI): m/z 538 [M+H] + 4444 3.48,
993.48,
99
8484
Figure PCTKR2021019439-appb-img-000132
Figure PCTKR2021019439-appb-img-000132
 		(R)-4-((2-(다이메틸포스포릴)페닐)아미노)-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴(R)-4-((2-(dimethylphosphoryl)phenyl)amino)-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[ b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.34 (s, 1H, FA), 7.98-7.95 (m, 1H), 7.78-7.62 (m ,4H), 7.33 (t, J = 7.6 Hz, 1H), 6.54 (s, 1H), 4.20 (d, J = 10.4 Hz, 1H), 3.92-3.70 (br, 5H), 3.17-3.05 (m, 3H), 2.61-2.53 (m ,5H), 2.23 (t, J = 10.8 Hz, 1H), 1.84 (s, 3H), 1.81 (s, 3H); MS (ESI): m/z 559 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.34 (s, 1H, FA), 7.98-7.95 (m, 1H), 7.78-7.62 (m, 4H), 7.33 (t, J = 7.6 Hz, 1H), 6.54 (s, 1H), 4.20 (d, J = 10.4 Hz, 1H), 3.92-3.70 (br, 5H), 3.17-3.05 (m, 3H), 2.61-2.53 (m, 5H) , 2.23 (t, J = 10.8 Hz, 1H), 1.84 (s, 3H), 1.81 (s, 3H); MS (ESI): m/z 559 [M+H] + 4242 3.90,
1003.90,
100
8585
Figure PCTKR2021019439-appb-img-000133
Figure PCTKR2021019439-appb-img-000133
 		(R)-(2-((5-클로로-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((5-chloro-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2] -d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.27 (s, 1H, FA), 8.07-8.03 (m, 1H), 7.74 (br, 1H), 7.67-7.60 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 6.89 (br, 1H), 6.55 (s, 1H), 4.20 (d, J = 10 Hz, 1H), 3.96-3.82 (m, 4H), 3.30-3.28 (m, 1H), 3.19 (d, J = 11.6 Hz, 1H), 2.75 (t, J = 10.4 Hz, 1H), 2.64 (s, 3H), 2.43 (t, J = 11.2 Hz, 1H), 1.85 (s, 3H), 1.81 (s, 3H), 3H in solvent peak; MS (ESI): m/z 568 [M]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.27 (s, 1H, FA), 8.07-8.03 (m, 1H), 7.74 (br, 1H), 7.67-7.60 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 6.89 (br, 1H), 6.55 (s, 1H), 4.20 (d, J = 10 Hz, 1H), 3.96-3.82 (m, 4H), 3.30-3.28 (m, 1H), 3.19 (d, J = 11.6 Hz, 1H), 2.75 (t, J = 10.4 Hz, 1H), 2.64 (s, 3H), 2.43 (t, J = 11.2 Hz, 1H), 1.85 (s, 3H), 1.81 (s, 3H), 3H in solvent peak; MS (ESI): m/z 568 [M] + 2424 3.85,
993.85,
99
8686
Figure PCTKR2021019439-appb-img-000134
Figure PCTKR2021019439-appb-img-000134
 		(2-((5-클로로-2-(((6aS,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((5-chloro-2-(((6aS,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido [1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.51 (s, 1H), 10.42 (s, 1H), 8.26-8.22 (m, 1H), 8.18 (s, 1H, FA), 7.56-7.48 (m, 3H), 7.23 (s, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H), 6.51 (s, 1H), 4.13 (d, J = 8.4 Hz, 1H), 3.85 (t, J = 10 Hz, 1H), 3.74 (s, 3H), 3.60 (s, 3H), 3.46-3.39 (m, 2H), 3.21-3.16 (m, 2H), 2.82 (t, J = 10.8 Hz, 1H), 2.48-2.42 (m, 2H), 2.19-1.96 (m ,5H), 1.76-1.63 (m, 8H), 1.31 (t, J = 12 Hz, 1H); MS (ESI): m/z 638 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.51 (s, 1H), 10.42 (s, 1H), 8.26-8.22 (m, 1H), 8.18 (s, 1H, FA), 7.56 7.48 (m, 3H), 7.23 (s, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H), 6.51 (s, 1H), 4.13 (d, J = 8.4 Hz, 1H) ), 3.85 (t, J = 10 Hz, 1H), 3.74 (s, 3H), 3.60 (s, 3H), 3.46-3.39 (m, 2H), 3.21-3.16 (m, 2H), 2.82 (t, J = 10.8 Hz, 1H), 2.48-2.42 (m, 2H), 2.19-1.96 (m,5H), 1.76-1.63 (m, 8H), 1.31 (t, J = 12 Hz, 1H); MS (ESI): m/z 638 [M] + 5353 3.88,
963.88,
96
8787
Figure PCTKR2021019439-appb-img-000135
Figure PCTKR2021019439-appb-img-000135
 		(2-((5-클로로-2-(((6aS,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((5-chloro-2-(((6aS,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido [1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.29 (s, 1H, FA), 8.08-8.05 (m ,1H), 7.64-7.60 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 6.85 (br, 1H), 6.55 (s, 1H), 4.18 (d, J = 10 Hz, 1H), 3.95 (t, J = 8.4 Hz, 2H), 3.90 (br, 1H), 3.79 (t, J = 4.8 Hz, 6H), 2.86-2.79 (m, 6H), 2.15-2.01 (m, 2H), 1.85 (s, 3H), 1.81 (s, 3H), 1.65-1.52 (m, 1H); MS (ESI): m/z 638 [M]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.29 (s, 1H, FA), 8.08-8.05 (m, 1H), 7.64-7.60 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 6.85 (br, 1H), 6.55 (s, 1H), 4.18 (d, J = 10 Hz, 1H), 3.95 (t, J = 8.4 Hz, 2H), 3.90 (br, 1H), 3.79 (t, J = 4.8 Hz, 6H), 2.86-2.79 (m, 6H), 2.15-2.01 (m, 2H), 1.85 (s, 3H), 1.81 (s, 3H), 1.65-1.52 (m, 1H); MS (ESI): m/z 638 [M] + 5959 3.91,
993.91,
99
8888
Figure PCTKR2021019439-appb-img-000136
Figure PCTKR2021019439-appb-img-000136
 		(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((5-chloro-2-(((6aR,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido [1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.52 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.20 (s, 1H, FA), 7.57-7.47 (m, 3H), 7.22 (s, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 4.18 (d, J = 10.4 Hz, 1H), 3.96 (d, J = 12 Hz, 1H), 3.88 (t, J = 8.4 Hz, 1H), 3.76 (s, 3H), 3.64-3.57 (m, 4H), 2.91 (t, J = 8.8 Hz, 1H), 2.40-2.37 (m, 2H), 1.93-1.83 (m, 2H), 1.76 (s, 3H), 1.73 (s, 3H), 1.45-1.42 (m, 1H), 1.13 (q, J = 12 Hz, 1H) 4H in solvent peak; MS (ESI): m/z 638 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.52 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.20 (s, 1H, FA), 7.57- 7.47 (m, 3H), 7.22 (s, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 4.18 (d, J = 10.4 Hz, 1H) ), 3.96 (d, J = 12 Hz, 1H), 3.88 (t, J = 8.4 Hz, 1H), 3.76 (s, 3H), 3.64-3.57 (m, 4H), 2.91 (t, J = 8.8 Hz) , 1H), 2.40-2.37 (m, 2H), 1.93-1.83 (m, 2H), 1.76 (s, 3H), 1.73 (s, 3H), 1.45-1.42 (m, 1H), 1.13 (q, J ) = 12 Hz, 1H) 4H in solvent peak; MS (ESI): m/z 638 [M] + 4545 3.86,
993.86,
99
8989
Figure PCTKR2021019439-appb-img-000137
Figure PCTKR2021019439-appb-img-000137
 		(2-((5-클로로-2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((5-chloro-2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido [1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.51 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.19 (s, 1H, FA), 7.56-7.47 (m, 3H), 7.23 (s, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H), 6.51 (s, 1H), 4.12 (d, J = 10 Hz, 1H), 3.85 (t, J = 9.6 Hz, 1H), 3.80 (s, 3H), 3.67-3.56 (m, 4H), 3.47 (d, J = 10.8 Hz, 1H), 3.23-3.17 (m, 1H), 2.82 (t, J = 10.4 Hz, 1H), 2.46-2.38 (m, 2H), 2.11 (d, J = 12 Hz, 1H), 1.99 (d, J = 12 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H), 1.70-1.67 (t, J = 13.6 Hz, 1H), 1.31 (t, J = 11.6 Hz, 1H), 4H in solvent peak; MS (ESI): m/z 638 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.51 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.19 (s, 1H, FA), 7.56 7.47 (m, 3H), 7.23 (s, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H), 6.51 (s, 1H), 4.12 (d, J = 10 Hz, 1H) ), 3.85 (t, J = 9.6 Hz, 1H), 3.80 (s, 3H), 3.67-3.56 (m, 4H), 3.47 (d, J = 10.8 Hz, 1H), 3.23-3.17 (m, 1H) , 2.82 (t, J = 10.4 Hz, 1H), 2.46-2.38 (m, 2H), 2.11 (d, J = 12 Hz, 1H), 1.99 (d, J = 12 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H), 1.70-1.67 (t, J = 13.6 Hz, 1H), 1.31 (t, J = 11.6 Hz, 1H), 4H in solvent peak; MS (ESI): m/z 638 [M] + 4646 3.96,
983.96,
98
9090
Figure PCTKR2021019439-appb-img-000138
Figure PCTKR2021019439-appb-img-000138
 		(2-((5-클로로-2-(((6aR,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((5-chloro-2-(((6aR,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10- Hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) Phenyl) dimethyl phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.50 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.17 (s, 1H, FA), 7.56-7.46 (m, 3H), 7.24 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.04 (s, 1H), 4.14 (d, J = 8.4 Hz, 1H), 3.84 (t, J = 10 Hz, 1H), 3.74 (s, 3H), 3.45-3.40 (m, 3H), 3.21-3.15 (m, 3H), 2.80 (t, J = 10.4 Hz, 1H), 2.45-2.32 (m, 3H), 2.14-2.08 (m, 5H), 2.00 (d, J = 13.2 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H), 1.69 (t, J = 12 Hz, 2H), 1.31 (t, J = 11.6 Hz, 1H); MS (ESI): m/z 651 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.50 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.17 (s, 1H, FA), 7.56 7.46 (m, 3H), 7.24 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.04 (s, 1H), 4.14 (d, J = 8.4 Hz, 1H), 3.84 (t, J = 10 Hz, 1H), 3.74 (s, 3H), 3.45-3.40 (m, 3H), 3.21-3.15 (m, 3H), 2.80 (t, J = 10.4 Hz, 1H), 2.45-2.32 (m, 3H), 2.14-2.08 (m, 5H), 2.00 (d, J = 13.2 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H), 1.69 (t, J = 12 Hz, 2H), 1.31 (t, J = 11.6 Hz, 1H); MS (ESI): m/z 651 [M] + 3434 3.78,
983.78,
98
9191
Figure PCTKR2021019439-appb-img-000139
Figure PCTKR2021019439-appb-img-000139
 		(2-((5-클로로-2-(((6aS,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((5-chloro-2-(((6aS,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10- Hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) Phenyl) dimethyl phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.51 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.16 (s, 1H, FA), 7.55-7.48 (m, 3H), 7.24 (s, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.50 (s, 1H), 4.14 (d, J = 10 Hz, 1H), 3.82 (t, J = 9.6 Hz, 1H), 3.74 (s, 3H), 3.45-3.40 (m, 3H), 3.21-3.15 (m, 3H), 2.80 (t, J = 10.4 Hz, 1H), 2.45-2.32 (m, 3H), 2.14-2.08 (m, 5H), 2.00 (d, J = 13.2 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H), 1.69 (t, J = 12 Hz, 2H), 1.31 (t, J = 11.6 Hz, 1H); MS (ESI): m/z 651 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.51 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.16 (s, 1H, FA), 7.55 7.48 (m, 3H), 7.24 (s, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.50 (s, 1H), 4.14 (d, J = 10 Hz, 1H) ), 3.82 (t, J = 9.6 Hz, 1H), 3.74 (s, 3H), 3.45-3.40 (m, 3H), 3.21-3.15 (m, 3H), 2.80 (t, J = 10.4 Hz, 1H) , 2.45-2.32 (m, 3H), 2.14-2.08 (m, 5H), 2.00 (d, J = 13.2 Hz, 1H), 1.76 (s, 3H), 1.73 (s, 3H), 1.69 (t, J = 12 Hz, 2H), 1.31 (t, J = 11.6 Hz, 1H); MS (ESI): m/z 651 [M] + 3434 3.84,
943.84,
94
9292
Figure PCTKR2021019439-appb-img-000140
Figure PCTKR2021019439-appb-img-000140
 		(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((5-chloro-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-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) Phenyl) dimethyl phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.51 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.15 (s, 1H, FA), 7.57-7.47 (m, 3H), 7.22 (s, 1H), 7.14 (t, J = 6.8 Hz, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 4.17 (d, J =10.4 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H), 3.88 (t, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.91 (t, J = 10.4 Hz, 1H), 2.46-2.32 (m, 6H), 2.16 (s, 3H), 1.90-1.80 (m, 3H), 1.76 (s, 3H), 1.73 (s, 3H), 1.48-1.39 (m, 1H), 1.13 (q, J = 12 Hz, 1H), 4H in solvent peak; MS (ESI): m/z 651 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.51 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.15 (s, 1H, FA), 7.57- 7.47 (m, 3H), 7.22 (s, 1H), 7.14 (t, J = 6.8 Hz, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 4.17 (d, J =10.4 Hz, 1H) ), 3.95 (d, J = 11.2 Hz, 1H), 3.88 (t, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.91 (t, J = 10.4 Hz, 1H), 2.46-2.32 (m) , 6H), 2.16 (s, 3H), 1.90-1.80 (m, 3H), 1.76 (s, 3H), 1.73 (s, 3H), 1.48-1.39 (m, 1H), 1.13 (q, J = 12 Hz, 1H), 4H in solvent peak; MS (ESI): m/z 651 [M] + 3939 3.53,
983.53,
98
9393
Figure PCTKR2021019439-appb-img-000141
Figure PCTKR2021019439-appb-img-000141
 		(2-((5-클로로-2-(((6aS,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((5-chloro-2-(((6aS,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10- Hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) Phenyl) dimethyl phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.51 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.15 (s, 1H, FA), 7.57-7.47 (m, 3H), 7.22 (s, 1H), 7.14 (t, J = 6.8 Hz, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 4.17 (d, J =10.4 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H), 3.88 (t, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.91 (t, J = 10.4 Hz, 1H), 2.46-2.32 (m, 6H), 2.16 (s, 3H), 1.90-1.80 (m, 3H), 1.76 (s, 3H), 1.73 (s, 3H), 1.48-1.39 (m, 1H), 1.13 (q, J = 12 Hz, 1H), 4H in solvent peak; MS (ESI): m/z 651 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.51 (s, 1H), 10.43 (s, 1H), 8.26-8.23 (m, 1H), 8.15 (s, 1H, FA), 7.57- 7.47 (m, 3H), 7.22 (s, 1H), 7.14 (t, J = 6.8 Hz, 1H), 7.04 (s, 1H), 6.58 (s, 1H), 4.17 (d, J =10.4 Hz, 1H) ), 3.95 (d, J = 11.2 Hz, 1H), 3.88 (t, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.91 (t, J = 10.4 Hz, 1H), 2.46-2.32 (m) , 6H), 2.16 (s, 3H), 1.90-1.80 (m, 3H), 1.76 (s, 3H), 1.73 (s, 3H), 1.48-1.39 (m, 1H), 1.13 (q, J = 12 Hz, 1H), 4H in solvent peak; MS (ESI): m/z 651 [M] + 4646 3.53,
983.53,
98
9494
Figure PCTKR2021019439-appb-img-000142
Figure PCTKR2021019439-appb-img-000142
 		(R)-(2-((2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4] oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.87-8.83 (m, 1H), 8.34 (s, 1H, FA), 7.58-7.52 (m, 2H), 7.31 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.88-6.83 (m, 2H), 6.41 (d, J = 3.6 Hz, 1H), 4.32 (d, J = 10.8 Hz, 1H), 4.07-4.02 (m, 2H), 3.48-3.35 (m, 3H), 3.29-3.25 (m, 1H), 3.04 (t, 9.2 Hz, 1H), 2.91 (t, J = 12.4 Hz, 1H), 2.69 (t, J = 11.4 Hz, 1H), 1.89 (s, 3H), 1.86 (s, 3H), 1.33 (d, J = 2 Hz, 3H), 1.32 (d, J = 2 Hz, 3H); MS (ESI): m/z 532 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.87-8.83 (m, 1H), 8.34 (s, 1H, FA), 7.58-7.52 (m, 2H), 7.31 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.88-6.83 (m, 2H), 6.41 (d, J = 3.6 Hz, 1H), 4.32 (d, J = 10.8 Hz, 1H), 4.07-4.02 (m, 2H), 3.48-3.35 (m, 3H), 3.29-3.25 (m, 1H), 3.04 (t, 9.2 Hz, 1H), 2.91 (t, J = 12.4 Hz, 1H), 2.69 (t, J = 11.4 Hz, 1H), 1.89 (s, 3H), 1.86 (s, 3H), 1.33 (d, J = 2 Hz, 3H), 1.32 (d, J = 2 Hz, 3H); MS (ESI): m/z 532 [M+H] + 3535 3.88,
993.88,
99
9595
Figure PCTKR2021019439-appb-img-000143
Figure PCTKR2021019439-appb-img-000143
 		(R)-(2-((5-클로로-2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((5-chloro-2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][ 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.35 (s, 1H, FA), 8.16-8.13 (m, 1H), 7.66-7.59 (m, 2H), 7.28-7.26 (m, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.28 (dd, J = 10.8, 2.4 Hz, 1H), 4.02-3.93 (m, 2H), 3.42 (d, J = 11.2 Hz, 1H), 3.39-3.34 (m ,1H), 3.30-3.19 (m, 2H), 3.00 (td, J = 12, 3 Hz, 1H), 2.87 (td, 12, 3 Hz, 2.65 (t, J = 11.2 Hz, 1H), 1.85 (s, 3H), 1.81 (s, 3H), 1.32 (d, J = 2 Hz, 3H), 1.30 (d, J = 2 Hz, 3H); MS (ESI): m/z 566 [M]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.35 (s, 1H, FA), 8.16-8.13 (m, 1H), 7.66-7.59 (m, 2H), 7.28-7.26 (m, 1H) ), 7.22 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.28 (dd , J = 10.8, 2.4 Hz, 1H), 4.02-3.93 (m, 2H), 3.42 (d, J = 11.2 Hz, 1H), 3.39-3.34 (m, 1H), 3.30-3.19 (m, 2H), 3.00 (td, J = 12, 3 Hz, 1H), 2.87 (td, 12, 3 Hz, 2.65 (t, J = 11.2 Hz, 1H), 1.85 (s, 3H), 1.81 (s, 3H), 1.32 (d, J = 2 Hz, 3H), 1.30 (d, J = 2 Hz, 3H); MS (ESI): m/z 566 [M] + 3636 3.97,
1003.97,
100
9696
Figure PCTKR2021019439-appb-img-000144
Figure PCTKR2021019439-appb-img-000144
 		(R)-(2-((2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] [1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.68-8.65 (m, 1H), 8.37 (s, 1H, FA), 7.84 (s, 1H), 7.61-7.55 (m, 2H), 7.20-7.16 (m, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.61 (s, 1H), 6.41 (d, J = 3.6 Hz, 1H), 4.29 (dd, J = 10.4, 2.4 Hz, 1H), 4.08-3.98 (m, 2H), 3.87 (s, 3H), 3.42-3.36 (m, 3H), 3.31-3.30 (m ,1H), 3.00-2.90 (m, 2H), 2.67 (t, J = 12 Hz, 1 H), 1.89 (s, 3H), 1.85 (s, 3H), 1.33 (d, J = 2 Hz, 3H), 1.31 (d, J = 2 Hz, 3H); MS (ESI): m/z 562 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.68-8.65 (m, 1H), 8.37 (s, 1H, FA), 7.84 (s, 1H), 7.61-7.55 (m, 2H), 7.20-7.16 (m, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.61 (s, 1H), 6.41 (d, J = 3.6 Hz, 1H), 4.29 (dd, J = 10.4, 2.4 Hz) , 1H), 4.08-3.98 (m, 2H), 3.87 (s, 3H), 3.42-3.36 (m, 3H), 3.31-3.30 (m, 1H), 3.00-2.90 (m, 2H), 2.67 (t) , J = 12 Hz, 1 H), 1.89 (s, 3H), 1.85 (s, 3H), 1.33 (d, J = 2 Hz, 3H), 1.31 (d, J = 2 Hz, 3H); MS (ESI): m/z 562 [M+H] + 2929 4.00,
994.00,
99
9797
Figure PCTKR2021019439-appb-img-000145
Figure PCTKR2021019439-appb-img-000145
 		(R)-(2-((5-클로로-2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((5-chloro-2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1, 2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.33 (s, 1H, FA), 8.07-8.03 (m ,1H), 7.77 (s, 1H), 7.68-7.61 (m, 2H), 6.32 (t, J = 6.8 Hz, 1H), 6.90 (s, 1H), 6.57 (s, 1H), 4.25 (dd, J = 10.8, 2.4 Hz, 1H), 4.00-3.93 (m, 2H), 3.83 (s, 3H), 3.43-3.34 (m, 2H), 3.26-3.18 (m, 2H), 3.03-2.86 (m, 2H), 2.68 (t, J = 12 Hz, 1H), 1.85 (s, 3H), 1.82 (s, 3H), 1.33 (dd, J = 6.8, 2 Hz, 6H); MS (ESI): m/z 596 [M]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.33 (s, 1H, FA), 8.07-8.03 (m, 1H), 7.77 (s, 1H), 7.68-7.61 (m, 2H), 6.32 (t, J = 6.8 Hz, 1H), 6.90 (s, 1H), 6.57 (s, 1H), 4.25 (dd, J = 10.8, 2.4 Hz, 1H), 4.00-3.93 (m, 2H), 3.83 (s, 3H), 3.43-3.34 (m, 2H), 3.26-3.18 (m, 2H), 3.03-2.86 (m, 2H), 2.68 (t, J = 12 Hz, 1H), 1.85 (s, 3H) ), 1.82 (s, 3H), 1.33 (dd, J = 6.8, 2 Hz, 6H); MS (ESI): m/z 596 [M] + 5252 4.09,
994.09,
99
9898
Figure PCTKR2021019439-appb-img-000146
Figure PCTKR2021019439-appb-img-000146
 		(R)-(2-((2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]ox photo-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.86-8.83 (m, 1H), 8.32 (s, 1H, FA), 7.57-7.52 (m, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.15 (td, J = 7.2, 1.2 Hz, 1H), 7.05 (dd, J = 8.8, 2 Hz, 1H), 6.88-6.82 (m, 2H), 6.41 (d, J =3.6 Hz, 1H), 4.30 (dd, J = 10.8, 2.4 Hz, 1H), 4.05-4.00 (m, 1H), 3.96 (d, J = 12 Hz, 1H), 3.43 (d, J = 10 Hz, 1H), 3.38-3.34 (m, 1H), 3.28-3.24 (m, 1H), 2.94 (q, J = 6.8 Hz, 2H), 2.88-2.73 (m, 2H), 2.47 (t, J = 12 Hz, 1H), 1.89 (s, 3H), 1.86 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 518 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.86-8.83 (m, 1H), 8.32 (s, 1H, FA), 7.57-7.52 (m, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.15 (td, J = 7.2, 1.2 Hz, 1H), 7.05 (dd, J = 8.8, 2 Hz, 1H), 6.88-6.82 (m, 2H), 6.41 (d, J =3.6 Hz) , 1H), 4.30 (dd, J = 10.8, 2.4 Hz, 1H), 4.05-4.00 (m, 1H), 3.96 (d, J = 12 Hz, 1H), 3.43 (d, J = 10 Hz, 1H) , 3.38-3.34 (m, 1H), 3.28-3.24 (m, 1H), 2.94 (q, J = 6.8 Hz, 2H), 2.88-2.73 (m, 2H), 2.47 (t, J = 12 Hz, 1H) ), 1.89 (s, 3H), 1.86 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 518 [M+H] + 3434 3.55,
993.55,
99
9999
Figure PCTKR2021019439-appb-img-000147
Figure PCTKR2021019439-appb-img-000147
 		(R)-(2-((5-클로로-2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((5-chloro-2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1] ,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.27 (s, 2H, FA), 8.16-8.13 (m, 1H), 7.66-7.59 (m ,2H), 7.30-7.25 (m, 1H), 7.23 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.28 (td, J = 10.8, 2.8 Hz, 1H), 4.01-3.97 (m, 2H), 3.46-3.36 (m, 2H), 3.28-3.20 (m, 1H), 3.00-2.96 (m, 2H), 2.86-2.83 (m, 2H), 2.53 (t, J = 12 Hz, 1H), 1.85 (s, 3H), 1.81 (s, 3H), 1.32 (t, J =, 7.2 Hz, 3H); MS (ESI): m/z 552 [M]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.27 (s, 2H, FA), 8.16-8.13 (m, 1H), 7.66-7.59 (m, 2H), 7.30-7.25 (m, 1H) ), 7.23 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.28 (td) , J = 10.8, 2.8 Hz, 1H), 4.01-3.97 (m, 2H), 3.46-3.36 (m, 2H), 3.28-3.20 (m, 1H), 3.00-2.96 (m, 2H), 2.86-2.83 (m, 2H), 2.53 (t, J = 12 Hz, 1H), 1.85 (s, 3H), 1.81 (s, 3H), 1.32 (t, J =, 7.2 Hz, 3H); MS (ESI): m/z 552 [M] + 4949 3.77,
993.77,
99
100100
Figure PCTKR2021019439-appb-img-000148
Figure PCTKR2021019439-appb-img-000148
 		다이메틸(2-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드Dimethyl (2-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b]pyri) do[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.58 (s, 1H), 11.22 (s, 1H), 9.14-9.11 (m, 1H), 8.62 (s, 1H), 8.19 (s, 2H, FA), 7.55-7.46 (m, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.12 (dd, J = 8.8, 2.4 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.80 (d, J =8.8 Hz, 1H), 6.34 (d, J =3.2 Hz, 1H), 4.21 (dd, J = 10.4, 2.4 Hz, 1H), 3.94-3.85 (m, 3H), 2.88-2.83 (m, 1H), 2.42-2.39 (m, 7H), 2.15 (s, 3H), 1.88-1.80 (m, 8H), 1.48-1.48 (m, 1H), 1.11 (q, J = 11.6 Hz, 1H); MS (ESI): m/z 587 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.58 (s, 1H), 11.22 (s, 1H), 9.14-9.11 (m, 1H), 8.62 (s, 1H), 8.19 (s, 2H, FA), 7.55-7.46 (m, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.12 (dd, J = 8.8, 2.4 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H) ), 6.89 (d, J = 2.4 Hz, 1H), 6.80 (d, J =8.8 Hz, 1H), 6.34 (d, J =3.2 Hz, 1H), 4.21 (dd, J = 10.4, 2.4 Hz, 1H) ), 3.94-3.85 (m, 3H), 2.88-2.83 (m, 1H), 2.42-2.39 (m, 7H), 2.15 (s, 3H), 1.88-1.80 (m, 8H), 1.48-1.48 (m) , 1H), 1.11 (q, J = 11.6 Hz, 1H); MS (ESI): m/z 587 [M+H] + 4545 2.58,
992.58,
99
101101
Figure PCTKR2021019439-appb-img-000149
Figure PCTKR2021019439-appb-img-000149
 		(R)-(2-((2-((10-플루오로-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((10-fluoro-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphos fin oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.62 (s, 1H), 11.33 (s, 1H), 9.08-9.06 (m, 1H), 8.91 (s, 1H), 8.19 (s, 2H, FA), 7.58-7.46 (m, 2H), 7.37 (dd, J = 16, 2.4 Hz, 1H), 7.15 (s, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.37-6.35 (m, 1H), 4.15-4.08 (m, 2H), 3.06-3.04 (m, 1H), 2.98 (t, J = 8 Hz, 2H), 2.85 (d, J =11.6 Hz, 2H), 2.77 (d, J = 8 Hz, 1H), 2.65-2.54 (m, 2H), 2.19-2.12 (m, 4H), 1.98 (t, J = 11.6 Hz, 2H)1.84 (d, J = 13.6 Hz, 6H), 1.75 (d, J = 11.2 Hz, 1.47 (q, J = 10 Hz, 2H); MS (ESI): m/z 605 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.62 (s, 1H), 11.33 (s, 1H), 9.08-9.06 (m, 1H), 8.91 (s, 1H), 8.19 (s, 2H, FA), 7.58-7.46 (m, 2H), 7.37 (dd, J = 16, 2.4 Hz, 1H), 7.15 (s, 1H), 7.06 (t, J = 7.2 Hz, 1H), 6.93 (d , J = 2.4 Hz, 1H), 6.37-6.35 (m, 1H), 4.15-4.08 (m, 2H), 3.06-3.04 (m, 1H), 2.98 (t, J = 8 Hz, 2H), 2.85 ( d, J = 11.6 Hz, 2H), 2.77 (d, J = 8 Hz, 1H), 2.65-2.54 (m, 2H), 2.19-2.12 (m, 4H), 1.98 (t, J = 11.6 Hz, 2H) )1.84 (d, J = 13.6 Hz, 6H), 1.75 (d, J = 11.2 Hz, 1.47 (q, J = 10 Hz, 2H); MS (ESI): m/z 605 [M+H] + 5757 3.31,
973.31;
97
102102
Figure PCTKR2021019439-appb-img-000150
Figure PCTKR2021019439-appb-img-000150
 		(R)-(2-((2-((3-(1-사이클로프로필피페리딘-4-일)-10-플루오로-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((3-(1-cyclopropylpiperidin-4-yl)-10-fluoro-1,2,3,4,4a,5-hexahydrobenzo[ b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.61 (s, 1H), 11.33 (s, 1H), 9.09-9.05 (m, 1H), 8.90 (s, 1H), 8.18 (s, 1H, FA), 7.59-7.48 (m, 2H), 7.36 (d, J = 13.6 Hz, 7.14 (s, 1H), 7.06 (t, J = 6.4 Hz, 1H), 6.94 (d, J = 3.2 Hz, 1H), 6.36 (d, 3.2 Hz, 1H), 4.12-4.07 (m, 2H), 3.10-3.03 (m, 1H), 2.96 (d, J = 10 Hz, 2H), 2.77 (d, J = 8 Hz, 1H), 2.64-2.56 (m, 4H), 2.18-2.09 (m, 4H), 1.84 (s, 3H), 11.81 (s, 3H), 1.71 (d, J = 11.6 Hz, 2H), 1.57-1.52 (m ,1H), 1.35 (q, J = 8.8 Hz, 2H), 0.39-0.37 (m, 2H), 0.27-0.25 (m, 2H); MS (ESI): m/z 631 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.61 (s, 1H), 11.33 (s, 1H), 9.09-9.05 (m, 1H), 8.90 (s, 1H), 8.18 (s, 1H, FA), 7.59-7.48 (m, 2H), 7.36 (d, J = 13.6 Hz, 7.14 (s, 1H), 7.06 (t, J = 6.4 Hz, 1H), 6.94 (d, J = 3.2 Hz) , 1H), 6.36 (d, 3.2 Hz, 1H), 4.12-4.07 (m, 2H), 3.10-3.03 (m, 1H), 2.96 (d, J = 10 Hz, 2H), 2.77 (d, J = 8 Hz, 1H), 2.64-2.56 (m, 4H), 2.18-2.09 (m, 4H), 1.84 (s, 3H), 11.81 (s, 3H), 1.71 (d, J = 11.6 Hz, 2H), 1.57-1.52 (m,1H), 1.35 (q, J = 8.8 Hz, 2H), 0.39-0.37 (m, 2H), 0.27-0.25 (m, 2H); MS (ESI): m/z 631 [M +H] + 3838 3.40,
993.40,
99
103103
Figure PCTKR2021019439-appb-img-000151
Figure PCTKR2021019439-appb-img-000151
 		(R)-(2-((2-((10-클로로-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((10-chloro-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.66 (s, 1H), 11.35 (s, 1H), 9.11-9.04 (m, 1H), 8.96 (s, 1H), 8.21 (s, 1H, FA), 7.59-7.48 (m, 2H), 7.46 (dd, J = 13.2, 2.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.95-6.94 (m, 1H), 6.38-6.36 (m, 1H), 4.43 (t, J = 10.4 Hz, 1H), 4.10 (dd, J = 10.4, 2.4 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.10 (d, J = 10.4 Hz, 1H), 2.98 (d, J = 12 Hz, 1H), 2.83-2.77 (m, 4H), 2.64 (dd, J = 12, 4.4 Hz, 1H), 2.42-2.37 (m, 1H), 2.17-2.13 (m, 4H), 1.95 (t, J = 11.6 Hz, 2H), 1.84 (s, 3H), 1.81 (s, 3H), 1.72 (d, J = 10.8 Hz, 2H), 1.48-1.38 (m, 2H); MS (ESI): m/z 621 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.66 (s, 1H), 11.35 (s, 1H), 9.11-9.04 (m, 1H), 8.96 (s, 1H), 8.21 (s, 1H, FA), 7.59-7.48 (m, 2H), 7.46 (dd, J = 13.2, 2.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.95-6.94 (m, 1H), 6.38 -6.36 (m, 1H), 4.43 (t, J = 10.4 Hz, 1H), 4.10 (dd, J = 10.4, 2.4 Hz, 1H), 3.38 (d, J = 10.4 Hz, 1H), 3.10 (d, J = 10.4 Hz, 1H), 2.98 (d, J = 12 Hz, 1H), 2.83-2.77 (m, 4H), 2.64 (dd, J = 12, 4.4 Hz, 1H), 2.42-2.37 (m, 1H) ), 2.17-2.13 (m, 4H), 1.95 (t, J = 11.6 Hz, 2H), 1.84 (s, 3H), 1.81 (s, 3H), 1.72 (d, J = 10.8 Hz, 2H), 1.48 -1.38 (m, 2H); MS (ESI): m/z 621 [M] + 7373 3.43,
993.43,
99
104104
Figure PCTKR2021019439-appb-img-000152
Figure PCTKR2021019439-appb-img-000152
 		(R)-(2-((2-((3-(1-에틸피페리딘-4-일)-10-플루오로-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((3-(1-ethylpiperidin-4-yl)-10-fluoro-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphos fin oxide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.62 (s, 1H), 11.33 (s, 1H), 9.11-9.06 (m, 1H), 8.91 (s, 1H), 8.19 (s, 1H, FA), 7.61-7.49 (m, 2H), 7.37 (dd, J = 16, 2 Hz, 1H), 7.15 (s, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.36 (t, J = 4 Hz, 1H), 4.16-4.08 (m, 2H), 3.48-3.40 (m, 1H), 3.11-3.06 (m, 1H), 2.98 (d, J = 11.2 Hz, 3H), 2.78-2.75 (m, 1H), 2.67-2.55 (m, 2H), 2.43-2.37 (m ,3H), 2.21-2.16 (m, 1H), 2.02 (t, J = 11.2 Hz, 2H), 1.84 (s, 3H), 1.81 (s, 3H), 1.77 (d, J = 11.2 Hz, 2H), 1.47 (q, J = 10 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 619 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.62 (s, 1H), 11.33 (s, 1H), 9.11-9.06 (m, 1H), 8.91 (s, 1H), 8.19 (s, 1H, FA), 7.61-7.49 (m, 2H), 7.37 (dd, J = 16, 2 Hz, 1H), 7.15 (s, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.94 (d , J = 2.4 Hz, 1H), 6.36 (t, J = 4 Hz, 1H), 4.16-4.08 (m, 2H), 3.48-3.40 (m, 1H), 3.11-3.06 (m, 1H), 2.98 ( d, J = 11.2 Hz, 3H), 2.78-2.75 (m, 1H), 2.67-2.55 (m, 2H), 2.43-2.37 (m, 3H), 2.21-2.16 (m, 1H), 2.02 (t, J = 11.2 Hz, 2H), 1.84 (s, 3H), 1.81 (s, 3H), 1.77 (d, J = 11.2 Hz, 2H), 1.47 (q, J = 10 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 619 [M+H] + 6161 3.15,
983.15,
98
105105
Figure PCTKR2021019439-appb-img-000153
Figure PCTKR2021019439-appb-img-000153
 		(S)-다이메틸(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-5-(트라이플루오로메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(S)-dimethyl (2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] ]oxazin-8-yl)amino)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 7.79-7.66 (m, 2H), 7.64-7.62 (m, 1H) 7.45-7.37 (m, 2H), 7.16 (d, J = 2.4 Hz, 1H), 6.95-6.92 (m, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.29-4.26 (m, 1H), 4.11-3.99 (m, 2H), 3.78-3.48 (m, 2H), 3.25-3.19 (m, 2H), 2.98-2.91 (m, 5H), 1.79 (s, 3H), 1.76 (s, 3H); MS (ESI): m/z 572 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 7.79-7.66 (m, 2H), 7.64-7.62 (m, 1H) 7.45-7.37 (m, 2H), 7.16 (d, J = 2.4 Hz) , 1H), 6.95-6.92 (m, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.29-4.26 (m, 1H), 4.11-3.99 (m, 2H), 3.78-3.48 (m, 2H) ), 3.25-3.19 (m, 2H), 2.98-2.91 (m, 5H), 1.79 (s, 3H), 1.76 (s, 3H); MS (ESI): m/z 572 [M+H] + 33 4.30,
1004.30,
100
106106
Figure PCTKR2021019439-appb-img-000154
Figure PCTKR2021019439-appb-img-000154
 		(R)-(2-((2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-5-(트라이플루오로메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][ 1,4]oxazin-8-yl)amino)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 7.80-7.70 (m, 2H), 7.69-7.32 (m, 4H), 6.60 (s, 1H), 4.28-4.10 (m, 2H), 4.02-3.96 (m, 1H), 3.89 (s, 3H), 3.70-3.52 (m, 2H), 3.48-3.12 (m, 2H), 3.12-2.90 (m, 5H), 1.81 (s, 3H), 1.77 (s, 3H); MS (ESI): m/z 602 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 7.80-7.70 (m, 2H), 7.69-7.32 (m, 4H), 6.60 (s, 1H), 4.28-4.10 (m, 2H), 4.02-3.96 (m, 1H), 3.89 (s, 3H), 3.70-3.52 (m, 2H), 3.48-3.12 (m, 2H), 3.12-2.90 (m, 5H), 1.81 (s, 3H), 1.77 (s, 3H); MS (ESI): m/z 602 [M+H] + 1111 4.45,
984.45,
98
107107
Figure PCTKR2021019439-appb-img-000155
Figure PCTKR2021019439-appb-img-000155
 		4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10- Hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ 12.34 (s, 1H), 10.67 (s, 1H), 9.23 (s, 1H), 8.20-8.08 (m, 1H), 7.89-7.40 (m, 4H), 7.30-7.20 (m, 1H), 6.61 (s, 1H), 4.28-4.20 (m, 1H) 4.18-4.10 (m, 3H), 3.98-3.80 (m, 3H), 3.40-3.22 (m, 4H), 3.20-3.00 (m, 3H), 2.40-2.22 (m, 3H), 2.20-2.02 (m, 2H), 1.98-1.70 (m, 8H); MS (ESI): m/z 629 [M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ 12.34 (s, 1H), 10.67 (s, 1H), 9.23 (s, 1H), 8.20-8.08 (m, 1H), 7.89-7.40 ( m, 4H), 7.30-7.20 (m, 1H), 6.61 (s, 1H), 4.28-4.20 (m, 1H) 4.18-4.10 (m, 3H), 3.98-3.80 (m, 3H), 3.40-3.22 (m, 4H), 3.20-3.00 (m, 3H), 2.40-2.22 (m, 3H), 2.20-2.02 (m, 2H), 1.98-1.70 (m, 8H); MS (ESI): m/z 629 [M+H] + 1111 3.88,
1003.88,
100
108108
Figure PCTKR2021019439-appb-img-000156
Figure PCTKR2021019439-appb-img-000156
 		4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aS,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aS,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10- Hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ12.33 (s, 1H), 10.67 (s, 1H), 9.18 (s, 1H), 8.10-8.00 (m, 1H), 7.74-7.30 (m, 4H), 7.20-7.08 (m, 1H), 6.61 (s, 1H), 4.20-4.06 (m, 1H), 4.02-3.88 (m, 7H), 3.40-3.22 (m, 3H), 3.20-2.88 (m, 4H), 2.30-2.12 (m, 4H), 2.10-1.92 (m, 2H), 1.77 (s, 3H), 1.74 (s, 3H); MS (ESI): m/z 629 [M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ12.33 (s, 1H), 10.67 (s, 1H), 9.18 (s, 1H), 8.10-8.00 (m, 1H), 7.74-7.30 (m, 4H), 7.20-7.08 (m, 1H), 6.61 (s, 1H), 4.20-4.06 (m, 1H), 4.02-3.88 (m, 7H), 3.40-3.22 (m, 3H), 3.20 -2.88 (m, 4H), 2.30-2.12 (m, 4H), 2.10-1.92 (m, 2H), 1.77 (s, 3H), 1.74 (s, 3H); MS (ESI): m/z 629 [M+H] + 1616 3.96,
1003.96,
100
109109
Figure PCTKR2021019439-appb-img-000157
Figure PCTKR2021019439-appb-img-000157
 		4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aS,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aS,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10- Hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ 12.32 (s, 1H), 10.67 (s, 1H) 9.73 (s, 1H), 8.10-8.00 (m, 1H), 7.64-7.32 (m, 4H), 7.20-7.08 (m, 1H), 6.66 (s, 1H), 4.22-4.00 (m, 4H), 3.77 (s, 3H), 3.76-3.60 (m, 3H), 3.70-3.42 (m, 2H), 3.20-2.98 (m, 4H), 2.70-2.50 (m, 1H), 2.20-2.10 (m, 2H), 1,82-1,52 (m, 8H); MS (ESI): m/z 629 [M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ 12.32 (s, 1H), 10.67 (s, 1H) 9.73 (s, 1H), 8.10-8.00 (m, 1H), 7.64-7.32 (m , 4H), 7.20-7.08 (m, 1H), 6.66 (s, 1H), 4.22-4.00 (m, 4H), 3.77 (s, 3H), 3.76-3.60 (m, 3H), 3.70-3.42 (m) , 2H), 3.20-2.98 (m, 4H), 2.70-2.50 (m, 1H), 2.20-2.10 (m, 2H), 1,82-1,52 (m, 8H); MS (ESI): m/z 629 [M+H] + 2323 4.00,
984.00,
98
110110
Figure PCTKR2021019439-appb-img-000158
Figure PCTKR2021019439-appb-img-000158
 		4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aR,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aR,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10- Hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ 12.32 (s, 1H), 10.67 (s, 1H), 9.65 (s, 1H), 8.10-8.00 (m, 1H), 7.98-7.91 (m, 1H), 7.70-7.40 (m, 3H), 7.20-7.10 (m, 1H), 6.66 (s, 1H), 4.28-4.10 (m, 2H), 4.09-3.90 (m, 5H), 3.22-3.00 (m, 5H), 2.74-2.64 (m, 2H), 2.30-2.12 (m, 3H), 1.90-1.60 (m, 8H), 1.56-1.40 (m, 2H); MS (ESI): m/z 629 [M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ 12.32 (s, 1H), 10.67 (s, 1H), 9.65 (s, 1H), 8.10-8.00 (m, 1H), 7.98-7.91 ( m, 1H), 7.70-7.40 (m, 3H), 7.20-7.10 (m, 1H), 6.66 (s, 1H), 4.28-4.10 (m, 2H), 4.09-3.90 (m, 5H), 3.22 3.00 (m, 5H), 2.74-2.64 (m, 2H), 2.30-2.12 (m, 3H), 1.90-1.60 (m, 8H), 1.56-1.40 (m, 2H); MS (ESI): m/z 629 [M+H] + 4848 4.04,
1004.04,
100
111111
Figure PCTKR2021019439-appb-img-000159
Figure PCTKR2021019439-appb-img-000159
 		4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴4-((2-(dimethylphosphoryl)phenyl)amino)-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-yl)amino)-7H-pyrrolo[2,3-d]pyri Midin-5-carbonitrile 1H NMR (400 MHz, TFA salt, CDCl3) δ 11.25 (s, 1H), 8.12-8.08 (m, 1H), 7.58-7.51 (m, 1H), 7.46 (s, 1H), 7.39-7.28 (m, 2H), 7.19-7.12 (m, 1H), 6.39 (s, 1H), 4.21-4.12 (m, 1H), 4.10-3.98 (m, 3H), 3.88-3.72 (m, 4H), 3.82-3.62 (m, 6H), 3.40-3.28 (m, 1H), 3.20-3.10 (m, 1H), 2.88 (s, 3H), 2.87-2.72 (m, 1H), 2.30-2.02 (m, 4H), 1.88 (s, 3H), 1.85 (s, 3H); MS (ESI): m/z 642 [M+H]+ 1 H NMR (400 MHz, TFA salt, CDCl 3 ) δ 11.25 (s, 1H), 8.12-8.08 (m, 1H), 7.58-7.51 (m, 1H), 7.46 (s, 1H), 7.39-7.28 ( m, 2H), 7.19-7.12 (m, 1H), 6.39 (s, 1H), 4.21-4.12 (m, 1H), 4.10-3.98 (m, 3H), 3.88-3.72 (m, 4H), 3.82- 3.62 (m, 6H), 3.40-3.28 (m, 1H), 3.20-3.10 (m, 1H), 2.88 (s, 3H), 2.87-2.72 (m, 1H), 2.30-2.02 (m, 4H), 1.88 (s, 3H), 1.85 (s, 3H); MS (ESI): m/z 642 [M+H] + 5555 3.74,
1003.74,
100
112112
Figure PCTKR2021019439-appb-img-000160
Figure PCTKR2021019439-appb-img-000160
 		4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aR,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aR,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a, 7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyri Midin-5-carbonitrile 1H NMR (400 MHz, TFA salt, DMSO-d 6) δ 12.31 (s, 1H), 10.65 (s, 1H), 9.36 (s, 1H), 8.13-7.74 (m, 2H), 7.68-7.30 (m, 3H), 7.16 (s, 1H), 6.52 (s, 1H), 4.22-3.50 (m, 9H), 3.10-2.84 (m, 7H), 2.82-2.70 (m, 4H), 2.32-1.88 (m, 4H), 1.77 (s, 3H), 1.73 (s, 3H); MS (ESI): m/z 642 [M+H]+ 1 H NMR (400 MHz, TFA salt, DMSO- d 6 ) δ 12.31 (s, 1H), 10.65 (s, 1H), 9.36 (s, 1H), 8.13-7.74 (m, 2H), 7.68-7.30 ( m, 3H), 7.16 (s, 1H), 6.52 (s, 1H), 4.22-3.50 (m, 9H), 3.10-2.84 (m, 7H), 2.82-2.70 (m, 4H), 2.32-1.88 ( m, 4H), 1.77 (s, 3H), 1.73 (s, 3H); MS (ESI): m/z 642 [M+H] + 2626 3.89,
953.89,
95
113113
Figure PCTKR2021019439-appb-img-000161
Figure PCTKR2021019439-appb-img-000161
 		4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aS,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aS,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a, 7,8,9,10-hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyri Midin-5-carbonitrile 1H NMR (400 MHz, TFA salt, CDCl3) δ 11.26 (s, 1H), 8.13-8.10 (m, 1H), 7.60-7.54 (m, 1H), 7.42-7.36 (m, 1H), 7.35-7.00 (m, 3H), 6.36 (s, 1H), 4.09-3.90 (m, 3H), 3.82-3.74 (m, 4H), 3.62-3.52 (m, 3H), 3.50-3.32 (m, 2H), 3.30-3.28 (m, 2H), 3.16-3.00 (m, 3H), 2.90-2.72 (m, 7H), 1.86 (s, 3H), 1.83 (s, 3H); MS (ESI): m/z 642 [M+H]+ 1 H NMR (400 MHz, TFA salt, CDCl 3 ) δ 11.26 (s, 1H), 8.13-8.10 (m, 1H), 7.60-7.54 (m, 1H), 7.42-7.36 (m, 1H), 7.35 7.00 (m, 3H), 6.36 (s, 1H), 4.09-3.90 (m, 3H), 3.82-3.74 (m, 4H), 3.62-3.52 (m, 3H), 3.50-3.32 (m, 2H), 3.30-3.28 (m, 2H), 3.16-3.00 (m, 3H), 2.90-2.72 (m, 7H), 1.86 (s, 3H), 1.83 (s, 3H); MS (ESI): m/z 642 [M+H] + 3434 3.88,
973.88,
97
114114
Figure PCTKR2021019439-appb-img-000162
Figure PCTKR2021019439-appb-img-000162
 		(R)-(2-((5-클로로-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((5-chloro-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.01-7.99 (m, 1H), 7.72-7.63 (m, 2H), 7.42-7.28 (m, 1H), 7.05-7.02 (m, 2H), 6.92-6.84 (m, 2H), 4.34 (d, J = 9.2 Hz, 1H), 4.12-4.02 (m, 2H), 3.80-3.68 (m, 4H), 3.66-3.52 (m, 1H), 3.50-3.40 (m, 1H), 3.30-3.02 (m, 4H), 3.01-2.88 (m, 4H), 2.58-2.40 (m, 2H), 2.24-2.20 (m, 2H), 1.85 (s, 3H), 1.82 (s, 3H); MS (ESI): m/z 621 [M]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.01-7.99 (m, 1H), 7.72-7.63 (m, 2H), 7.42-7.28 (m, 1H), 7.05-7.02 (m, 2H) ), 6.92-6.84 (m, 2H), 4.34 (d, J = 9.2 Hz, 1H), 4.12-4.02 (m, 2H), 3.80-3.68 (m, 4H), 3.66-3.52 (m, 1H), 3.50-3.40 (m, 1H), 3.30-3.02 (m, 4H), 3.01-2.88 (m, 4H), 2.58-2.40 (m, 2H), 2.24-2.20 (m, 2H), 1.85 (s, 3H) ), 1.82 (s, 3H); MS (ESI): m/z 621 [M] + 3737 3.31,
983.31;
98
115115
Figure PCTKR2021019439-appb-img-000163
Figure PCTKR2021019439-appb-img-000163
 		(R)-(2-((5-클로로-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((5-chloro-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexa Hydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl ) dimethyl phosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.00-7.90 (m, 1H), 7.74-7.65 (m, 2H), 7.44-7.40 (m, 2H), 7.03 (s, 1H), 6.64 (s, 1H), 4.29-4.20 (m, 1H), 4.20-4.04 (m, 1H), 4.02-3.92 (m, 1H), 3.92-3.80 (m, 3H), 3.80-3.62 (m, 4H), 3.60-3.39 (m, 2H), 3.30-3.02 (m, 4H), 3.00-2.80 (m, 4H), 2.54-2.38 (m, 2H), 2.20-2.00 (m, 2H), 1.87 (d, J = 1.6 Hz, 3H), 1.83 (d, J = 1.6 Hz, 3H) ; MS (ESI): m/z 651 [M]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.00-7.90 (m, 1H), 7.74-7.65 (m, 2H), 7.44-7.40 (m, 2H), 7.03 (s, 1H), 6.64 (s, 1H), 4.29-4.20 (m, 1H), 4.20-4.04 (m, 1H), 4.02-3.92 (m, 1H), 3.92-3.80 (m, 3H), 3.80-3.62 (m, 4H) ), 3.60-3.39 (m, 2H), 3.30-3.02 (m, 4H), 3.00-2.80 (m, 4H), 2.54-2.38 (m, 2H), 2.20-2.00 (m, 2H), 1.87 (d , J = 1.6 Hz, 3H), 1.83 (d, J = 1.6 Hz, 3H) ; MS (ESI): m/z 651 [M] + 2929 3.29,
993.29;
99
116116
Figure PCTKR2021019439-appb-img-000164
Figure PCTKR2021019439-appb-img-000164
 		(R)-다이메틸(2-((2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(R)-dimethyl (2-((2-((3- (1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.60-8.48 (m, 1H), 7.70-7.60 (m, 1H), 7.58-7.48 (m, 1H), 7.38-7.22 (m, 1H), 7.10-6.90 (m, 4H), 6.57 (s, 1H), 4.39-4.36 (m, 1H), 4.18-4.02 (m, 2H), 3.80-3.60 (m, 4H), 3.50-3.38 (m, 2H), 3.20-3.00 (m, 4H), 2.99-2.79 (m, 4H), 2.52-2.40 (m, 2H), 2.15-2.00 (m, 2H), 1.91 (s, 3H), 1.87 (s, 3H); MS (ESI): m/z 587 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.60-8.48 (m, 1H), 7.70-7.60 (m, 1H), 7.58-7.48 (m, 1H), 7.38-7.22 (m, 1H) ), 7.10-6.90 (m, 4H), 6.57 (s, 1H), 4.39-4.36 (m, 1H), 4.18-4.02 (m, 2H), 3.80-3.60 (m, 4H), 3.50-3.38 (m) , 2H), 3.20-3.00 (m, 4H), 2.99-2.79 (m, 4H), 2.52-2.40 (m, 2H), 2.15-2.00 (m, 2H), 1.91 (s, 3H), 1.87 (s) , 3H); MS (ESI): m/z 587 [M+H] + 6666 2.76,
1002.76,
100
117117
Figure PCTKR2021019439-appb-img-000165
Figure PCTKR2021019439-appb-img-000165
 		(R)-(2-((2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphos fin oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.58-8.34 (m, 1H), 7.72-7.62 (m, 1H), 7.60-7.52 (m, 1H), 7.38-7.29 (m, 1H), 7.28-7.14 (m, 1H), 7.01(d, J = 3.6 Hz, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 4.38-4.28 (m, 1H), 4.20-4.10 (m, 1H), 4.09-3.98 (m, 1H), 3.83 (s, 3H), 3.78-3.64 (m, 2H), 3.60-3.48 (m, 2H), 3.48-3.40 (m, 2H), 3.20-3.02 (m, 4H), 2.92 (s, 3H), 2.85-2.72 (m, 1H), 2.50-2.36 (m, 2H), 2.11-1.96 (m, 2H), 1.91 (s, 3H), 1.87 (s, 3H); MS (ESI): m/z 617 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.58-8.34 (m, 1H), 7.72-7.62 (m, 1H), 7.60-7.52 (m, 1H), 7.38-7.29 (m, 1H) ), 7.28-7.14 (m, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 4.38-4.28 (m, 1H), 4.20-4.10 ( m, 1H), 4.09-3.98 (m, 1H), 3.83 (s, 3H), 3.78-3.64 (m, 2H), 3.60-3.48 (m, 2H), 3.48-3.40 (m, 2H), 3.20- 3.02 (m, 4H), 2.92 (s, 3H), 2.85-2.72 (m, 1H), 2.50-2.36 (m, 2H), 2.11-1.96 (m, 2H), 1.91 (s, 3H), 1.87 ( s, 3H); MS (ESI): m/z 617 [M+H] + 4848 3.02,
993.02,
99
118118
Figure PCTKR2021019439-appb-img-000166
Figure PCTKR2021019439-appb-img-000166
 		(S)-(2-((2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(S)-(2-((2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphos fin oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.46 (s, 1H), 7.74-7.60 (m, 1H), 7.59-7.52( m, 1H), 7.38-7.30 (m, 1H), 7.29-7.20 (m, 1H), 7.11-6.98 (m, 1H), 6.72 (s, 1H), 6.60-6.52(m, 1H), 4.38-4.28 (m, 1H), 4.24-4.14 (m, 1H), 4.10-4.00 (m, 2H), 3.84 (s, 3H), 3.82-3.60 (m, 5H), 3.59-3.40 (m, 2H), 3.22-3.20 (m, 2H), 2.98-2.80 (m, 4H), 2.60-2.40 (m, 2H), 2.20-2.02 (m, 2H), 1.90 (s, 3H), 1.87 (s, 3H); MS (ESI): m/z 617 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.46 (s, 1H), 7.74-7.60 (m, 1H), 7.59-7.52 (m, 1H), 7.38-7.30 (m, 1H), 7.29-7.20 (m, 1H), 7.11-6.98 (m, 1H), 6.72 (s, 1H), 6.60-6.52 (m, 1H), 4.38-4.28 (m, 1H), 4.24-4.14 (m, 1H) ), 4.10-4.00 (m, 2H), 3.84 (s, 3H), 3.82-3.60 (m, 5H), 3.59-3.40 (m, 2H), 3.22-3.20 (m, 2H), 2.98-2.80 (m) , 4H), 2.60-2.40 (m, 2H), 2.20-2.02 (m, 2H), 1.90 (s, 3H), 1.87 (s, 3H); MS (ESI): m/z 617 [M+H] + 1111 3.04,
953.04,
95
119119
Figure PCTKR2021019439-appb-img-000167
Figure PCTKR2021019439-appb-img-000167
 		(R)-(2-((2-((3-(1-아이소프로필피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((3-(1-isopropylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[ 1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.54-8.44 (m, 1H), 7.70-7.61 (m, 1H), 7.60-7.50 (m, 1H), 7.40-7.28 (m, 1H), 7.06 (d, J = 2 Hz, 1H), 7.00-6.88 (m, 3H), 6.56 (s, 1H), 4.40-4.32 (m, 1H), 4.22-4.02 (m, 2H), 3.80-3.48 (m, 7H), 3.38-3.23 (m, 1H), 3.22-3.08 (m, 3H), 3.06-2.96 (m, 1H), 2.60-2.48 (m, 2H), 2.60-2.48 (m, 2H), 2.28-2.10 (m, 2H), 1.90 (s, 3H), 1.87 (s, 3H), 1.39 (d, J = 6.8 Hz, 6H); MS (ESI): m/z 615 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.54-8.44 (m, 1H), 7.70-7.61 (m, 1H), 7.60-7.50 (m, 1H), 7.40-7.28 (m, 1H) ), 7.06 (d, J = 2 Hz, 1H), 7.00-6.88 (m, 3H), 6.56 (s, 1H), 4.40-4.32 (m, 1H), 4.22-4.02 (m, 2H), 3.80- 3.48 (m, 7H), 3.38-3.23 (m, 1H), 3.22-3.08 (m, 3H), 3.06-2.96 (m, 1H), 2.60-2.48 (m, 2H), 2.60-2.48 (m, 2H) ), 2.28-2.10 (m, 2H), 1.90 (s, 3H), 1.87 (s, 3H), 1.39 (d, J = 6.8 Hz, 6H); MS (ESI): m/z 615 [M+H] + 6565 3.14,
993.14,
99
120120
Figure PCTKR2021019439-appb-img-000168
Figure PCTKR2021019439-appb-img-000168
 		(R)-(2-((2-((10-플루오로-3-(1-아이소프로필피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((10-fluoro-3-(1-isopropylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[ b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.52-8.45 (m, 1H), 7.72-7.68 (m, 1H), 7.62-7.50 (m, 1H), 7.38-7.22 (m, 1H), 7.10-6.99 (m, 2H), 6.93 (s, 1H), 6.54 (d, J = 3.6 Hz, 1H), 4.36-4.22 (m, 2H), 4.12-4.01 (m, 1H), 3.70-3.50 (m, 6H), 3.41-3.32 (m, 1H), 3.28-3.18 (m, 2H), 3.17-2.97 (m, 3H), 2.52-2.42 (m, 2H), 2.12-1.98 (m, 2H), 1.90 (s, 3H), 1.86 (s, 3H), 1.39 (d, J = 6.4 Hz, 6H); MS (ESI): m/z 633 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.52-8.45 (m, 1H), 7.72-7.68 (m, 1H), 7.62-7.50 (m, 1H), 7.38-7.22 (m, 1H) ), 7.10-6.99 (m, 2H), 6.93 (s, 1H), 6.54 (d, J = 3.6 Hz, 1H), 4.36-4.22 (m, 2H), 4.12-4.01 (m, 1H), 3.70- 3.50 (m, 6H), 3.41-3.32 (m, 1H), 3.28-3.18 (m, 2H), 3.17-2.97 (m, 3H), 2.52-2.42 (m, 2H), 2.12-1.98 (m, 2H) ), 1.90 (s, 3H), 1.86 (s, 3H), 1.39 (d, J = 6.4 Hz, 6H); MS (ESI): m/z 633 [M+H] + 5050 3.35,
1003.35,
100
121121
Figure PCTKR2021019439-appb-img-000169
Figure PCTKR2021019439-appb-img-000169
 		(R)-(2-((2-((3-(1-에틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((3-(1-ethylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1] ,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.54-8.42 (m, 1H), 7.70-7.60 (m, 1H), 7.58-7.52 (m, 1H), 7.36-7.24 (m, 1H), 7.08-6.90 (m, 4H), 6.55 (s, 1H), 4.42-4.32 (m, 1H), 4.22-4.02 (m, 2H), 3.82-3.68 (m, 4H), 3.63-3.45 (m, 2H), 3.30-2.90 (m, 7H), 2.60-2.42 (m, 2H), 2.22-2.08 (m, 2H), 1.90 (s, 3H), 1.87 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H): m/z 601 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.54-8.42 (m, 1H), 7.70-7.60 (m, 1H), 7.58-7.52 (m, 1H), 7.36-7.24 (m, 1H) ), 7.08-6.90 (m, 4H), 6.55 (s, 1H), 4.42-4.32 (m, 1H), 4.22-4.02 (m, 2H), 3.82-3.68 (m, 4H), 3.63-3.45 (m) , 2H), 3.30-2.90 (m, 7H), 2.60-2.42 (m, 2H), 2.22-2.08 (m, 2H), 1.90 (s, 3H), 1.87 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H): m/z 601 [M+H] + 6060 2.58,
1002.58,
100
122122
Figure PCTKR2021019439-appb-img-000170
Figure PCTKR2021019439-appb-img-000170
 		(R)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(R)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4] ]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide 1H NMR (400MHz, free base, Methanol-d 4) δ 8.84-8.81 (m, 1H), 8.13 (s, 1H), 7.57-7.51 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H), 7.17-7.15 (m, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 3.6 Hz, 1H), 6.78(d, J = 8.8 Hz, 1H), 6.41 (d, J = 3.6 Hz, 1H), 4.20-4.17 (m, 1H), 4.00-3.87 (m, 3H), 3.77-3.74 (m, 1H), 3.58-3.51 (m, 1H), 3.15-3.05 (m, 1H), 2.77-2.71 (m, 1H), 1.89 (d, J = 13.6 Hz, 6H); MS (ESI): m/z 491 [M+H]+ 1 H NMR (400 MHz, free base, Methanol- d 4 ) δ 8.84-8.81 (m, 1H), 8.13 (s, 1H), 7.57-7.51 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H) ), 7.17-7.15 (m, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 3.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.41 (d) , J = 3.6 Hz, 1H), 4.20-4.17 (m, 1H), 4.00-3.87 (m, 3H), 3.77-3.74 (m, 1H), 3.58-3.51 (m, 1H), 3.15-3.05 (m) , 1H), 2.77-2.71 (m, 1H), 1.89 (d, J = 13.6 Hz, 6H); MS (ESI): m/z 491 [M+H] + 5050 5.21,
1005.21,
100
123123
Figure PCTKR2021019439-appb-img-000171
Figure PCTKR2021019439-appb-img-000171
 		(S)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(S)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4] ]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide 1H NMR (400 MHz, HCl salt, Methanol-d 4) δ 8.62 (s, 1H), 7.68-7.63 (m, 1H), 7.58-7.54 (m, 1H), 7.34-7.31 (m, 1H), 6.98 (s, 1H), 6.91 (br, 3H), 6.58 (s, 1H), 4.25 (d, J = 12 Hz, 1H), 4.05 (d, J = 8 Hz, 1H), 3.99-3.91 (m, 2H), 3.77-3.71 (m, 1H), 3.66-3.62 (m, 1H), 3.16 (br, 1H), 2.81 (br, 1H), 2.15 (s, 1H), 1.91 (s, 3H), 1.88 (s, 3H), 1.30 (s, 1H); MS (ESI): m/z=491 [M+H]+ 1 H NMR (400 MHz, HCl salt, Methanol- d 4 ) δ 8.62 (s, 1H), 7.68-7.63 (m, 1H), 7.58-7.54 (m, 1H), 7.34-7.31 (m, 1H), 6.98 (s, 1H), 6.91 (br, 3H), 6.58 (s, 1H), 4.25 (d, J = 12 Hz, 1H), 4.05 (d, J = 8 Hz, 1H), 3.99-3.91 (m , 2H), 3.77-3.71 (m, 1H), 3.66-3.62 (m, 1H), 3.16 (br, 1H), 2.81 (br, 1H), 2.15 (s, 1H), 1.91 (s, 3H), 1.88 (s, 3H), 1.30 (s, 1H); MS (ESI): m/z=491 [M+H] + 7979 3.57,
993.57,
99
124124
Figure PCTKR2021019439-appb-img-000172
Figure PCTKR2021019439-appb-img-000172
 		(R)-(2-((2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][ 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.78 (s, 1H), 7.98-7.80 (m, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.30-7.14 (m, 2H), 6.88-6.81 (m, 2H), 4.44-3.82 (m, 9H), 3.29 (s, 3H), 1.91 (s, 3H), 1.89 (s, 3H); MS (ESI): m/z=521 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.78 (s, 1H), 7.98-7.80 (m, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.30-7.14 (m, 2H), 6.88-6.81 (m, 2H), 4.44-3.82 (m, 9H), 3.29 (s, 3H), 1.91 (s, 3H), 1.89 (s, 3H); MS (ESI): m/z=521 [M+H] + 4949 5.18,
1005.18,
100
125125
Figure PCTKR2021019439-appb-img-000173
Figure PCTKR2021019439-appb-img-000173
 		(S)-(2-((2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(S)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][ 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.55 (s, 1H), 7.72-7.59 (m, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.09-6.92 (m, 2H), 6.66-6.59 (m, 2H), 4.22-3.60 (m, 9H), 3.29 (s, 3H), 1.91 (s, 3H), 1.89 (s, 3H); MS (ESI): m/z=521 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.55 (s, 1H), 7.72-7.59 (m, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.09-6.92 (m, 2H), 6.66-6.59 (m, 2H), 4.22-3.60 (m, 9H), 3.29 (s, 3H), 1.91 (s, 3H), 1.89 (s, 3H); MS (ESI): m/z=521 [M+H] + 4646 4.89
1004.89
100
126126
Figure PCTKR2021019439-appb-img-000174
Figure PCTKR2021019439-appb-img-000174
 		(R)-(2-((2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-5-(트라이플루오로메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][ 1,4]oxazin-8-yl)amino)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400MHz, free base, Methanol-d 4) δ 7.79-7.73 (m, 1H), 7.73-7.70 (m, 1H), 7.67-7.63 (m, 2H), 7.45 (d, J=1.6 Hz, 1H), 7.40-7.36 (m, 1H), 6.50 (s, 1H), 4.12-4.11 (m, 1H), 4.03-3.99 (m, 1H), 3.90-3.85 (m, 2H), 3.82 (s, 3H), 3.76-3.69 (m, 1H), 3.60-3.57 (m, 1H), 3.31-3.26 (m, 1H), 3.08-3.06 (m, 1H), 2.76-2.72 (m, 1H), 1.84 (s, 3H), 1.79 (s, 3H); MS (ESI): m/z 589 [M+H]+ 1 H NMR (400 MHz, free base, Methanol- d 4 ) δ 7.79-7.73 (m, 1H), 7.73-7.70 (m, 1H), 7.67-7.63 (m, 2H), 7.45 (d, J =1.6 Hz) , 1H), 7.40-7.36 (m, 1H), 6.50 (s, 1H), 4.12-4.11 (m, 1H), 4.03-3.99 (m, 1H), 3.90-3.85 (m, 2H), 3.82 (s) , 3H), 3.76-3.69 (m, 1H), 3.60-3.57 (m, 1H), 3.31-3.26 (m, 1H), 3.08-3.06 (m, 1H), 2.76-2.72 (m, 1H), 1.84 (s, 3H), 1.79 (s, 3H); MS (ESI): m/z 589 [M+H] + 4444 5.65,
1005.65,
100
127127
Figure PCTKR2021019439-appb-img-000175
Figure PCTKR2021019439-appb-img-000175
 		(R)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(R)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4] ] oxazin-8-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) phenyl) phosphine oxide 1H NMR (400MHz, TFA salt, Methanol-d 4) δ 8.58 (s, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.42-7.69 (m, 1H), 7.62-7.61 (m, 1H), 7.44-7.40 (m, 1H), 7.32 (d, J=5.6 Hz, 1H), 6.96-6.90 (m, 3H), 4.29-4.26 (m, 1H), 4.09-4.05 (m, 1H), 4.01-3.94 (m, 2H), 3.80-3.74 (m, 1H), 3.68 (d, J=12.4 Hz, 1H), 3.29-3.21 (m, 2H), 2.88-2.81 (m, 1H), 1.95 (s, 3H), 1.91 (s, 3H); MS (ESI): m/z 508 [M+H]+ 1 H NMR (400MHz, TFA salt, Methanol- d 4 ) δ 8.58 (s, 1H), 8.22 (d, J =5.2 Hz, 1H), 7.42-7.69 (m, 1H), 7.62-7.61 (m, 1H) ), 7.44-7.40 (m, 1H), 7.32 (d, J =5.6 Hz, 1H), 6.96-6.90 (m, 3H), 4.29-4.26 (m, 1H), 4.09-4.05 (m, 1H), 4.01-3.94 (m, 2H), 3.80-3.74 (m, 1H), 3.68 (d, J =12.4 Hz, 1H), 3.29-3.21 (m, 2H), 2.88-2.81 (m, 1H), 1.95 ( s, 3H), 1.91 (s, 3H); MS (ESI): m/z 508 [M+H] + 9393 5.25,
1005.25,
100
128128
Figure PCTKR2021019439-appb-img-000176
Figure PCTKR2021019439-appb-img-000176
 		(S)-(2-((2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진 -8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(S)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][ 1,4]oxazin-8-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400MHz, TFA salt, Methanol-d 4) δ 8.58 (s, 1H), 8.21 (d, 1H, J=5.2 Hz), 7.74-7.62 (m, 2H), 7.43-7.40 (m, 1H), 7.32-7.28 (m, 1H), 6.90 (s, 1H), 6.65 (s, 1H), 4.88-3.73 (m, 8H), 3.29 (s, 3H), 3.24-2.90 (m, 2H), 1.95 (s, 3H), 1.91 (s, 3H); MS (ESI): m/z 538 [M+H]+ 1 H NMR (400MHz, TFA salt, Methanol- d 4 ) δ 8.58 (s, 1H), 8.21 (d, 1H, J =5.2 Hz), 7.74-7.62 (m, 2H), 7.43-7.40 (m, 1H) ), 7.32-7.28 (m, 1H), 6.90 (s, 1H), 6.65 (s, 1H), 4.88-3.73 (m, 8H), 3.29 (s, 3H), 3.24-2.90 (m, 2H), 1.95 (s, 3H), 1.91 (s, 3H); MS (ESI): m/z 538 [M+H] + 3030 5.28,
975.28,
97
129129
Figure PCTKR2021019439-appb-img-000177
Figure PCTKR2021019439-appb-img-000177
 		(2-((2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[1,2] -d][1,4]oxazin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400 MHz, TFA salt Methanol-d 4) δ 8.56 (s, 1H), 8.20 (d, J = 4 Hz, 1H), 7.75-7.68 (m, 1H), 7.61 (s, 1H), 7.42-7.38 (m, 1H), 7.28 (d, J = 8 Hz, 1H), 6.95 (s, 1H), 6.67 (s, 1H), 4.25-4.24 (m, 1H), 3.98-3.93 (m, 2H), 3.70-3.64 (m, 2H), 3.63-3.56 (m, 2H), 2.35-2.21 (m, 3H), 2.01-1.89 (m, 8H); MS (ESI): m/z=621 [M+H]+ 1 H NMR (400 MHz, TFA salt Methanol- d 4 ) δ 8.56 (s, 1H), 8.20 (d, J = 4 Hz, 1H), 7.75-7.68 (m, 1H), 7.61 (s, 1H), 7.42-7.38 (m, 1H), 7.28 (d, J = 8 Hz, 1H), 6.95 (s, 1H), 6.67 (s, 1H), 4.25-4.24 (m, 1H), 3.98-3.93 (m, 2H), 3.70-3.64 (m, 2H), 3.63-3.56 (m, 2H), 2.35-2.21 (m, 3H), 2.01-1.89 (m, 8H); MS (ESI): m/z=621 [M+H] + 8282 3.75,
1003.75,
100
130130
Figure PCTKR2021019439-appb-img-000178
Figure PCTKR2021019439-appb-img-000178
 		(2-((2-(((6aS,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(2-((2-(((6aS,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400MHz, free base, Methanol-d 4) δ 8.55 (s, 1H), 8.21 (d, J = 5.2Hz, 1H), 7.73-7.61 (m, 2H), 7.42-7.40 (m, 1H), 7.30 (d, J = 4.8 Hz, 1H), 6.91 (s, 1H), 6.72 (s, 1H), 4.27-4.19 (m, 2H), 4.04-3.99 (m, 1H), 3.81 (s, 3H), 3.58-3.33 (m, 9H), 3.21-3.18 (m, 1H), 2.97 (s, 3H), 2.86-2.80 (m, 1H), 2.27-2.16 (m, 2H), 1.94-1.77 (m,7H), 1.58-1.49 (m, 1H); MS (ESI): m/z 634 [M+H]+ 1 H NMR (400 MHz, free base, Methanol- d 4 ) δ 8.55 (s, 1H), 8.21 (d, J = 5.2Hz, 1H), 7.73-7.61 (m, 2H), 7.42-7.40 (m, 1H) ), 7.30 (d, J = 4.8 Hz, 1H), 6.91 (s, 1H), 6.72 (s, 1H), 4.27-4.19 (m, 2H), 4.04-3.99 (m, 1H), 3.81 (s, 3H), 3.58-3.33 (m, 9H), 3.21-3.18 (m, 1H), 2.97 (s, 3H), 2.86-2.80 (m, 1H), 2.27-2.16 (m, 2H), 1.94-1.77 (m,7H), 1.58-1.49 (m, 1H); MS (ESI): m/z 634 [M+H] + 5252 LC/MS 1.18,
100LC/MS 1.18,
100
131131
Figure PCTKR2021019439-appb-img-000179
Figure PCTKR2021019439-appb-img-000179
 		(R)-다이메틸(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(R)-dimethyl (2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] ] oxazin-8-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) phenyl) phosphine oxide 1H NMR (400MHz, TFA salt, Methanol-d 4) δ 8.51 (s, 1H), 8.30 (d, 1H, J=5.2 Hz), 7.77-7.74 (m, 1H), 7.65-7.64 (m, 1H), 7.46-7.45 (m, 1H), 7.36-7.45 (m, 1H), 7.36 (d, 1H, J=5.6 Hz), 7.10-7.01 (m, 3H), 4.45-4.41 (m, 1H), 4.23-4.22 (m, 1H), 4.17-4.12 (m, 1H), 3.72-3.65 (m, 2H), 3.54-3.53 (m, 1H), 3.37-3.09 (m, 3H), 3.06 (s, 3H), 1.96 (s, 3H), 1.93 (s, 3H); MS (ESI): m/z 521 [M+H]+ 1 H NMR (400MHz, TFA salt, Methanol- d 4 ) δ 8.51 (s, 1H), 8.30 (d, 1H, J =5.2 Hz), 7.77-7.74 (m, 1H), 7.65-7.64 (m, 1H) ), 7.46-7.45 (m, 1H), 7.36-7.45 (m, 1H), 7.36 (d, 1H, J =5.6 Hz), 7.10-7.01 (m, 3H), 4.45-4.41 (m, 1H), 4.23-4.22 (m, 1H), 4.17-4.12 (m, 1H), 3.72-3.65 (m, 2H), 3.54-3.53 (m, 1H), 3.37-3.09 (m, 3H), 3.06 (s, 3H) ), 1.96 (s, 3H), 1.93 (s, 3H); MS (ESI): m/z 521 [M+H] + 8585 3.09,
1003.09,
100
132132
Figure PCTKR2021019439-appb-img-000180
Figure PCTKR2021019439-appb-img-000180
 		(S)-다이메틸(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(S)-dimethyl (2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] ] oxazin-8-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) phenyl) phosphine oxide 1H NMR (400MHz, TFA salt, Methanol-d 4) δ 8.44 (s, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.71-7.66 (m, 1H), 7.54-7.51 (m, 1H), 7.40-7.30 (m, 2H), 7.02-6.94 (m, 3H), 4.34-4.30 (m, 1H), 4.17-4.05 (m, 2H), 3.71-3.51 (m, 3H), 3.32-3.20 (m, 1H), 3.17-2.99 (m, 5H), 1.91 (d, J = 13.6 Hz, 6H); MS (ESI): m/z 521 [M+H]+ 1 H NMR (400MHz, TFA salt, Methanol- d 4 ) δ 8.44 (s, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.71-7.66 (m, 1H), 7.54-7.51 (m, 1H) ), 7.40-7.30 (m, 2H), 7.02-6.94 (m, 3H), 4.34-4.30 (m, 1H), 4.17-4.05 (m, 2H), 3.71-3.51 (m, 3H), 3.32-3.20 (m, 1H), 3.17-2.99 (m, 5H), 1.91 (d, J = 13.6 Hz, 6H) ; MS (ESI): m/z 521 [M+H] + 8888 3.43,
1003.43,
100
133133
Figure PCTKR2021019439-appb-img-000181
Figure PCTKR2021019439-appb-img-000181
 		(S)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(S)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4] ] oxazin-8-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) phenyl) phosphine oxide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.74 (m, 1H), 7.90 (d, J = 8 Hz, 1H), 7.62-7.54 (m, 2H), 7.24-7.21 (m, 1H), 7.16 (d. J = 4 Hz, 1H), 7.12 (d, J = 4 Hz, 1H), 7.00-6.97 (m, 1H), 6.79 (d, J = 12 Hz, 1H), 4.21-4.18 (m, 1H), 4.08-3.84 (m, 3H), 3.77-3.74 (m, 1H), 3.58 (d, J = 8 Hz, 1H), 3.13-3.07 (m, 1H), 2.78-2.71 (m, 1H), 1.88 (d, J = 12 Hz, 6H); MS (ESI): m/z = 508 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.74 (m, 1H), 7.90 (d, J = 8 Hz, 1H), 7.62-7.54 (m, 2H), 7.24-7.21 (m, 1H), 7.16 (d. J = 4 Hz, 1H), 7.12 (d, J = 4 Hz, 1H), 7.00-6.97 (m, 1H), 6.79 (d, J = 12 Hz, 1H), 4.21- 4.18 (m, 1H), 4.08-3.84 (m, 3H), 3.77-3.74 (m, 1H), 3.58 (d, J = 8 Hz, 1H), 3.13-3.07 (m, 1H), 2.78-2.71 ( m, 1H), 1.88 (d, J = 12 Hz, 6H); MS (ESI): m/z = 508 [M+H] + 4040 5.24,
1005.24,
100
134134
Figure PCTKR2021019439-appb-img-000182
Figure PCTKR2021019439-appb-img-000182
 		(R)-(2-((2-((9-메 톡시-1,2,4a,5-테트라하이드로-4H-벤조 [b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)싸이에노[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드(R)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][ 1,4]oxazin-8-yl)amino)thieno[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide 1H NMR (400MHz, TFA salt, DMSO-d 6) δ 12.02 (s, 1H), 8.91-8.88 (m, 1H), 7.95 (s, 1H), 7.62-7.59 (m, 1H), 7.58-7.56 (m, 1H), 7.56-7.12 (m, 4H), 7.12 (s, 1H), 4.21-4.18 (m, 1H), 4.11-4.07 (m, 1H), 3.99-3.60 (m, 8H), 3.23-3.09 (m, 3H), 2.74-2.51 (m, 1H), 1.84 (d, J = 13.6 Hz, 1H); MS (ESI): m/z 538 [M+H]+ OneH NMR (400MHz, TFA salt, DMSO-d 6) δ 12.02 (s, 1H), 8.91-8.88 (m, 1H), 7.95 (s, 1H), 7.62-7.59 (m, 1H), 7.58-7.56 (m, 1H), 7.56-7.12 (m, 4H) ), 7.12 (s, 1H), 4.21-4.18 (m, 1H), 4.11-4.07 (m, 1H), 3.99-3.60 (m, 8H), 3.23-3.09 (m, 3H), 2.74-2.51 (m, 1H), 1.84 ( d,J = 13.6 Hz, 1H); MS (ESI): m/z 538 [M+H]+ 2020 5.80,
1005.80,
100
135135
Figure PCTKR2021019439-appb-img-000183
Figure PCTKR2021019439-appb-img-000183
 		(R)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)싸이에노[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(R)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4] ] oxazin-8-yl) amino) thieno [2,3-d] pyrimidin-4-yl) amino) phenyl) phosphine oxide 1H NMR (400MHz, TFA salt, DMSO-d 6) δ 12.03 (s, 1H), 9.15-9.06 (m, 2H), 7.64-7.50 (m, sH), 7.40-7.38 (d, J = 6 Hz, 1H), 7.25-7.11 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 5.75 (s, 1H), 4.23-4.20 (m, 1H), 3.98-3.84 (m, 3H), 3.65-3.56 (m, 2H), 3.21-3.16 (m, 1H), 3.06-3.01 (m, 1H), 2.67-2.63 (m, 1H), 1.87-1.83 (d, J = 13.6 Hz, 6H); MS (ESI): m/z 508 [M+H]+ 1 H NMR (400MHz, TFA salt, DMSO- d 6 ) δ 12.03 (s, 1H), 9.15-9.06 (m, 2H), 7.64-7.50 (m, sH), 7.40-7.38 (d, J = 6 Hz) , 1H), 7.25-7.11 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 5.75 (s, 1H), 4.23-4.20 (m, 1H), 3.98-3.84 (m, 3H), 3.65-3.56 (m, 2H), 3.21-3.16 (m, 1H), 3.06-3.01 (m, 1H), 2.67- 2.63 (m, 1H), 1.87-1.83 (d, J = 13.6 Hz, 6H); MS (ESI): m/z 508 [M+H] + 2828 5.72,
1005.72,
100
136136
Figure PCTKR2021019439-appb-img-000184
Figure PCTKR2021019439-appb-img-000184
 		(R)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-5-(트라이플루오로메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드(R)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4] ]oxazin-8-yl)amino)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide 1H NMR (400MHz, HCl salt, Methanol-d 4) δ 7.81-7.69 (m, 3H), 7.61 (s, 1H), 7.55-7.52 (m, 1H), 6.85 (d, J=16.4 Hz, 3H), 4.26 (d, J=10.4 Hz, 1H), 4.06 (d, J=10 Hz, 1H), 3.99-3.92 (m, 2H), 3.77-3.72 (m, 1H), 3.67 (d, J=17.2 Hz, 1H), 3.32-3.30 (m, 1H), 3.26-3.24 (m, 1H), 3.02-2.79 (m, 1H), 1.85 (s, 3H), 1.82 (s, 3H); MS (ESI): m/z 559 [M+H]+ 1 H NMR (400MHz, HCl salt, Methanol- d 4 ) δ 7.81-7.69 (m, 3H), 7.61 (s, 1H), 7.55-7.52 (m, 1H), 6.85 (d, J =16.4 Hz, 3H ), 4.26 (d, J =10.4 Hz, 1H), 4.06 (d, J =10 Hz, 1H), 3.99-3.92 (m, 2H), 3.77-3.72 (m, 1H), 3.67 (d, J = 17.2 Hz, 1H), 3.32-3.30 (m, 1H), 3.26-3.24 (m, 1H), 3.02-2.79 (m, 1H), 1.85 (s, 3H), 1.82 (s, 3H); MS (ESI): m/z 559 [M+H] + 9292 5.97,
1005.97,
100
실시예 137: N-(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조Example 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
하기 반응식 4로 표시된 방법을 통해 표제의 화합물을 제조하였다.The title compound was prepared by the method shown in Scheme 4 below.
[반응식 4][Scheme 4]
Figure PCTKR2021019439-appb-img-000185
Figure PCTKR2021019439-appb-img-000185
단계 1: NStep 1: N 1One -(2,5-다이클로로피리미딘-4-일)벤젠-1,2-다이아민의 제조Preparation of -(2,5-dichloropyrimidin-4-yl)benzene-1,2-diamine
2,4,5-트라이클로로피리미딘(1 당량), 벤젠-1,2-다이아민(1 당량), DIPEA(2 당량)을 n-BuOH(0.2 M)에 녹인 후, 상온에서 1 시간 동안 교반하였다. 물과 brine을 넣고 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 얻어진 흰색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 99%, MS (ESI): m/z 255 [M]+).2,4,5-trichloropyrimidine (1 eq.), benzene-1,2-diamine (1 eq.), and DIPEA (2 eq.) were dissolved in n-BuOH (0.2 M), and then at room temperature for 1 hour stirred. 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 target compound as a white solid obtained was used in the next reaction without further purification (yield: 99%, MS (ESI): m/z 255 [M] + ).
단계 2: N-(2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조Step 2: Preparation of N-(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide
단계 1에서 제조한 N1-(2,5-다이클로로피리미딘-4-일)벤젠-1,2-다이아민(1 당량), 메탄설포닐클로라이드(1.2 당량)을 피리딘(0.2 M)에 녹인 후, 상온에서 1 시간 동안 교반하였다. 물과 brine을 넣고 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(DCM:MeOH)를 통해 정제하였고, 노란색 고체의 목적 화합물을 수득하였다(수율: 57 %, MS (ESI): m/z 333 [M]+).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] + ).
단계 3: N-(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조Step 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
단계 2에서 제조한 N-(2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)메탄설폰아마이드(1 당량), (6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-아민(1.2 당량)을 2-메톡시에탄올(0.232 M)에 녹인 후, 2.5 M HCl in EtOH(2.6 당량)을 첨가하고 120 ℃에서 4 시간 동안 교반하였다. 반응 혼합물을 상온으로 냉각시킨 후, 2 M NaOH 수용액을 이용해 pH 12로 맞추었다. 물과 brine을 넣고 DCM로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 prep-HPLC를 통해 정제하였고, 노란색 고체의 목적 화합물을 수득하였다(수율: 36 %, MS (ESI): m/z 630 [M+H]+).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. Water and brine were added, and 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: 36 %, MS (ESI): m/z 630 [M+H] + ).
실시예 138 내지 실시예 166Examples 138 to 166
상기 실시예 137과 유사한 방법으로 실시예 138 내지 166 화합물을 제조하였다. 실시예 137 내지 166 화합물의 화학구조, 화합물명, NMR, 수율, 및 HPLC 분석 결과를 하기 표 3에 정리하여 나타내었다.Compounds of Examples 138 to 166 were prepared in a manner similar to that of Example 137. Chemical structures, compound names, NMR, yield, and HPLC analysis results of the compounds of Examples 137 to 166 are summarized in Table 3 below.
실시예Example 구조rescue 화합물명compound name 1H NMR, MS 1 H NMR, MS 수율
(%)transference number
(%) 		HPLC r.t.(min),
Purity
(%)HPLC rt (min),
Purity
(%)
137137
Figure PCTKR2021019439-appb-img-000186
Figure PCTKR2021019439-appb-img-000186
 		N-(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드N-(2-((5-chloro-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-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 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), 4.20-4.11 (m, 1H), 4.00-3.92 (m, 1H), 3.90-3.81 (m, 1H), 3.71 (s, 3H), 2.97-2.85 (m, 4H), 2.50-2.25 (m, 10H), 2.17 (s, 3H), 1.93-1.79 (m, 2H), 1.51-1.37 (m, 1H), 1.16-1.05 (m, 1H); MS (ESI): m/z 630 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 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), 4.20-4.11 (m, 1H), 4.00- 3.92 (m, 1H), 3.90-3.81 (m, 1H), 3.71 (s, 3H), 2.97-2.85 (m, 4H), 2.50-2.25 (m, 10H), 2.17 (s, 3H), 1.93- 1.79 (m, 2H), 1.51-1.37 (m, 1H), 1.16-1.05 (m, 1H); MS (ESI): m/z 630 [M+H] + 3636 3.56,
993.56,
99
138138
Figure PCTKR2021019439-appb-img-000187
Figure PCTKR2021019439-appb-img-000187
 		(R)-N-(2-((5-클로로-2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((5-chloro-2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4] ,3-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 9.29 (s, 1H), 8.49 (s, 1H), 8.10 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.84 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.19-7.09 (m, 2H), 6.55 (s, 1H), 4.19-4.13 (m, 1H), 3.96 (d, J = 10.7 Hz, 1H), 3.88-3.76 (m, 2H), 3.72 (s, 3H), 3.71-3.56 (m, 2H), 3.18 (t, J = 10.7 Hz, 1H), 3.09-3.01 (m, 1H), 2.96 (s, 3H), 2.73-2.64 (m, 1H); MS (ESI): m/z 533 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 9.29 (s, 1H), 8.49 (s, 1H), 8.10 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.84 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.19-7.09 (m, 2H), 6.55 (s, 1H), 4.19-4.13 (m, 1H), 3.96 (d, J = 10.7 Hz, 1H), 3.88-3.76 (m, 2H), 3.72 (s, 3H), 3.71-3.56 (m, 2H), 3.18 (t, J = 10.7 Hz, 1H), 3.09 -3.01 (m, 1H), 2.96 (s, 3H), 2.73-2.64 (m, 1H); MS (ESI): m/z 533 [M] + 3030 5.35,
995.35,
99
139139
Figure PCTKR2021019439-appb-img-000188
Figure PCTKR2021019439-appb-img-000188
 		N-(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)-N-메틸프로판-2-설폰아마이드N-(2-((5-chloro-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-yl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylpropane-2- sulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 8.27 (s, 1H), 8.21 (s, 1H, FA) 8.18 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.60-7.51 (m, 1H), 7.34-7.28 (m, 1H), 7.22-7.16 (m, 1H), 7.06 (s, 1H), 6.58 (s, 1H), 4.19-4.12 (m, 1H), 4.00-3.93 (m, 1H), 3.89-3.83 (m, 1H), 3.71 (s, 3H), 3.60-3.50 (m, 1H), 3.20 (s, 3H), 2.96-2.88 (m, 1H), 2.50-2.25 (m, 10H), 2.16 (s, 3H), 1.94-1.79 (m, 2H), 1.50-1.37 (m, 1H), 1.31 (d, J = 6.7 Hz, 6H), 1.17-1.05 (m, 1H); MS (ESI): m/z 672 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 8.27 (s, 1H), 8.21 (s, 1H, FA) 8.18 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H) ), 7.60-7.51 (m, 1H), 7.34-7.28 (m, 1H), 7.22-7.16 (m, 1H), 7.06 (s, 1H), 6.58 (s, 1H), 4.19-4.12 (m, 1H) ), 4.00-3.93 (m, 1H), 3.89-3.83 (m, 1H), 3.71 (s, 3H), 3.60-3.50 (m, 1H), 3.20 (s, 3H), 2.96-2.88 (m, 1H) ), 2.50-2.25 (m, 10H), 2.16 (s, 3H), 1.94-1.79 (m, 2H), 1.50-1.37 (m, 1H), 1.31 (d, J = 6.7 Hz, 6H), 1.17- 1.05 (m, 1H); MS (ESI): m/z 672 [M+H] + 5757 4.70,
994.70,
99
140140
Figure PCTKR2021019439-appb-img-000189
Figure PCTKR2021019439-appb-img-000189
 		(R)-N-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(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)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 9.05 (s, 1H), 8.52 (s, 1H), 8.14(s, 2H, FA), 8.11 (s, 1H), 8.07 (d, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 7.22 (t, J = 8 Hz, 1H), 7.01 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 4.20 (d, J = 10.4 Hz, 1H), 3.88 (t, J = 9.2 Hz, 1H), 2.96-2.93 (m ,4H), 2.86 (d, J = 10.8 Hz, 1H), 2.83 (d, J = 10.8 Hz, 1H), 2.60-2.54 (m, 1H), 2.21 (s, 3H), 2.10 (t, J = 11.2 Hz, 1H), 1.70 (t, J = 10.4 Hz, 1H); MS (ESI): m/z 516 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 9.05 (s, 1H), 8.52 (s, 1H), 8.14 (s, 2H, FA), 8.11 (s, 1H), 8.07 (d, J = 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 7.22 (t, J = 8 Hz, 1H), 7.01 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H) , 6.67 (d, J = 8.8 Hz, 1H), 4.20 (d, J = 10.4 Hz, 1H), 3.88 (t, J = 9.2 Hz, 1H), 2.96-2.93 (m ,4H), 2.86 (d, J = 10.8 Hz, 1H), 2.83 (d, J = 10.8 Hz, 1H), 2.60-2.54 (m, 1H), 2.21 (s, 3H), 2.10 (t, J = 11.2 Hz, 1H), 1.70 ( t, J = 10.4 Hz, 1H); MS (ESI): m/z 516 [M] + 7272 3.41,
993.41,
99
141141
Figure PCTKR2021019439-appb-img-000190
Figure PCTKR2021019439-appb-img-000190
 		(R)-N-(2-((5-클로로-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((5-chloro-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1] ,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 9.34 (br, 1H), 8.45 (s, 1H), 8.13 (s, 1H, FA), 8.09 (s, 1H) 8.05 (d, J = 8 Hz, 1H), 7.83 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 8 Hz, 1H), 7.18 (t, J = 8 Hz, 1H), 7.10 (s, 1H), 6.56 (s, 1H), 4.19 (d, J = 10.4 Hz, 1H), 3.86-3.78 (m, 2H), 3.71 (s, 3H), 3.04-2.85 (m, 6H), 2.69 (t, J = 9.6 Hz, 1H), 2.32-2.19 (m ,4H), 1.85-1.79 (m, 1H); MS (ESI): m/z 546 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 9.34 (br, 1H), 8.45 (s, 1H), 8.13 (s, 1H, FA), 8.09 (s, 1H) 8.05 (d, J ) = 8 Hz, 1H), 7.83 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 8 Hz, 1H), 7.18 (t, J = 8 Hz, 1H), 7.10 (s, 1H), 6.56 (s, 1H), 4.19 (d, J = 10.4 Hz, 1H), 3.86-3.78 (m, 2H), 3.71 (s, 3H), 3.04-2.85 (m, 6H) , 2.69 (t, J = 9.6 Hz, 1H), 2.32-2.19 (m, 4H), 1.85-1.79 (m, 1H); MS (ESI): m/z 546 [M] + 5656 3.55,
993.55,
99
142142
Figure PCTKR2021019439-appb-img-000191
Figure PCTKR2021019439-appb-img-000191
 		(R)-N-(2-((5-클로로-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((5-chloro-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5) -hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.45 (s, 1H, FA), 8.00-7.98 (m, 2H), 7.41 (dd, J = 7.6, 1.6 Hz, 1H), 7.37-7.31 (m, 2H), 7.24 (td, J = 7.6, 1.2 Hz, 1H), 6.51 (s, 1H), 4.85 (dd, J = 10.8, 2.4 Hz, 1H), 3.93-3.88 (m, 1H), 3.79-3.76 (m, 4H), 3.46-3.43 (d, 12.4 Hz, 2H), 3.10-2.91 (m, 6H), 2.78-2.69 (m, 4H), 2.61-2.53 (m, 1H), 2.46-2.41 (m, 1H), 2.13-2.04 (m, 3H), 1.87-1.74 (m, 2H); MS (ESI): m/z 629 [M]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.45 (s, 1H, FA), 8.00-7.98 (m, 2H), 7.41 (dd, J = 7.6, 1.6 Hz, 1H), 7.37- 7.31 (m, 2H), 7.24 (td, J = 7.6, 1.2 Hz, 1H), 6.51 (s, 1H), 4.85 (dd, J = 10.8, 2.4 Hz, 1H), 3.93-3.88 (m, 1H) , 3.79-3.76 (m, 4H), 3.46-3.43 (d, 12.4 Hz, 2H), 3.10-2.91 (m, 6H), 2.78-2.69 (m, 4H), 2.61-2.53 (m, 1H), 2.46 -2.41 (m, 1H), 2.13-2.04 (m, 3H), 1.87-1.74 (m, 2H); MS (ESI): m/z 629 [M] + 2121 3.27,
993.27,
99
143143
Figure PCTKR2021019439-appb-img-000192
Figure PCTKR2021019439-appb-img-000192
 		(R)-N-(2-((5-클로로-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)-N-메틸프로판-2-설폰아마이드(R)-N-(2-((5-chloro-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5) -hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylpropane-2-sulfone amide 1H NMR (400 MHz, FA salt, DMSO-d 4) δ 8.26 (s, 1H), 8.21-8.18 (m, 2H, FA-1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.56 (dd, J = 8, 1.2 Hz, 1H), 7.30 (t, J = 8 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.06 (s, 1H), 6.55 (s, 1H), 4.20 (dd, J = 8, 2 Hz, 1H), 3.86-3.77 (m, 2H), 3.71 (s, 3H), 3.57-3.50 (m, 1H), 3.20 (s, 3H), 2.98-2.91 (m, 4H), 2.84 (d, J = 11.6 Hz, 3H), 2.67-2.59 (m, 1H), 2.20-2.16 (m, 4H), 1.92-1.88 (m, 3H), 1.76 (d, J = 11.6 Hz, 2H), 1.50-1.39 (m, 2H), 1.31 (d, J = 6.8 Hz, 6H); MS (ESI): m/z 671 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 4 ) δ 8.26 (s, 1H), 8.21-8.18 (m, 2H, FA-1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.56 (dd, J = 8, 1.2 Hz, 1H), 7.30 (t, J = 8 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.06 (s, 1H), 6.55 (s, 1H) ), 4.20 (dd, J = 8, 2 Hz, 1H), 3.86-3.77 (m, 2H), 3.71 (s, 3H), 3.57-3.50 (m, 1H), 3.20 (s, 3H), 2.98- 2.91 (m, 4H), 2.84 (d, J = 11.6 Hz, 3H), 2.67-2.59 (m, 1H), 2.20-2.16 (m, 4H), 1.92-1.88 (m, 3H), 1.76 (d, J = 11.6 Hz, 2H), 1.50-1.39 (m, 2H), 1.31 (d, J = 6.8 Hz, 6H); MS (ESI): m/z 671 [M] + 2525 4.60,
994.60,
99
144144
Figure PCTKR2021019439-appb-img-000193
Figure PCTKR2021019439-appb-img-000193
 		(S)-N-(2-((5-클로로 -2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(S)-N-(2-((5-chloro-2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d] [1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 9.07 (s, 1H), 8.57 (s, 1H), 8.16 (s, 1H, FA), 8.12-8.07 (m, 1H), 7.36-7.28 (m, 1H), 7.26-7.20 (m, 1H), 7.20-7.02 (m, 1H), 7.10-6.90 (m, 2H), 6.67 (d, J = 8.8 Hz, 1H), 4.20-4.10 (m, 1H), 3.98-3.88 (m, 1H), 3.82-3.76 (m, 2H), 3.60-3.48 (m, 2H), 3.22-3.16 (m, 2H), 3.08-2.98 (m, 1H), 2.96 (s, 3H); MS (ESI): m/z 503 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 9.07 (s, 1H), 8.57 (s, 1H), 8.16 (s, 1H, FA), 8.12-8.07 (m, 1H), 7.36 7.28 (m, 1H), 7.26-7.20 (m, 1H), 7.20-7.02 (m, 1H), 7.10-6.90 (m, 2H), 6.67 (d, J = 8.8 Hz, 1H), 4.20-4.10 ( m, 1H), 3.98-3.88 (m, 1H), 3.82-3.76 (m, 2H), 3.60-3.48 (m, 2H), 3.22-3.16 (m, 2H), 3.08-2.98 (m, 1H), 2.96 (s, 3H); MS (ESI): m/z 503 [M+H] + 3535 5.26,
935.26,
93
145145
Figure PCTKR2021019439-appb-img-000194
Figure PCTKR2021019439-appb-img-000194
 		(R)-N-(2-((5-클로로-2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((5-chloro-2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d] [1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 9.08 (s, 1H), 8.52 (s, 1H), 8.15 (s, 1H, FA), 8.12 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.36-7.24 (m, 1H), 7.23-7.18 (m, 1H), 7.10-6.96 (m, 2H), 6.67 (d, J = 8.8 Hz, 1H), 4.20-4.12 (m, 1H), 4.00-3.90 (m, 1H), 3.90-3.78 (m, 2H), 3.68-3.42 (m, 2H), 3.20-3.12 (m, 1H), 3.08-3.00 (m, 4H), 2.64-2.60 (m, 1H); MS (ESI): m/z 503 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 9.08 (s, 1H), 8.52 (s, 1H), 8.15 (s, 1H, FA), 8.12 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.36-7.24 (m, 1H), 7.23-7.18 (m, 1H), 7.10-6.96 (m, 2H), 6.67 (d , J = 8.8 Hz, 1H), 4.20-4.12 (m, 1H), 4.00-3.90 (m, 1H), 3.90-3.78 (m, 2H), 3.68-3.42 (m, 2H), 3.20-3.12 (m) , 1H), 3.08-3.00 (m, 4H), 2.64-2.60 (m, 1H); MS (ESI): m/z 503 [M+H] + 2828 5.20,
985.20,
98
146146
Figure PCTKR2021019439-appb-img-000195
Figure PCTKR2021019439-appb-img-000195
 		(R)-N-(2-((5-클로로-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((5-chloro-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[ b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.27 (s, 3H, FA), 8.10-8.08 (m, 1H), 8.00 (s, 1H), 7.42-7.36 (m, 1H), 7.34-7.26 (m, 1H), 7.24-7.12 (m, 1H), 6.97(d, J = 2.8 Hz, 1H), 6.88-6.81 (m, 1H), 6.70-6.62 (m, 1H), 4.22-4.18 (m, 1H), 4.00-3.86 (m, 1H), 3.72-3.68 (m, 1H), 3.54-3.46 (m, 2H), 3.20-2.94 (m, 8H), 2.83 (s, 3H), 2.72-2.54 (m, 2H), 2.50-2.40 (m, 1H), 2.20-2.01 (m, 3H), 1.90-1.74 (m, 2H); MS (ESI): m/z 599 [M]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.27 (s, 3H, FA), 8.10-8.08 (m, 1H), 8.00 (s, 1H), 7.42-7.36 (m, 1H), 7.34-7.26 (m, 1H), 7.24-7.12 (m, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.88-6.81 (m, 1H), 6.70-6.62 (m, 1H), 4.22 4.18 (m, 1H), 4.00-3.86 (m, 1H), 3.72-3.68 (m, 1H), 3.54-3.46 (m, 2H), 3.20-2.94 (m, 8H), 2.83 (s, 3H), 2.72-2.54 (m, 2H), 2.50-2.40 (m, 1H), 2.20-2.01 (m, 3H), 1.90-1.74 (m, 2H); MS (ESI): m/z 599 [M] + 3939 2.98,
1002.98,
100
147147
Figure PCTKR2021019439-appb-img-000196
Figure PCTKR2021019439-appb-img-000196
 		(R)-N-(2-((5-클로로 -2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리 미딘-4-일)아미노)페닐)-N-메틸프로판-2-설폰아마이드(R)-N-(2-((5-chloro-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[ b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylpropane-2-sulfonamide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.28 (s, 3H, FA), 8.25 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.58-7.49 (m, 1H), 7.46-7.36 (m, 1H), 7.30-7.22 (m, 1H), 7.02 (d, J=2.4 Hz, 1H), 6.98-6.88 (m, 1H), 6.80-6.70 (m, 1H), 4.30-4.20 (m, 1H), 4.00-3.92 (m, 1H), 3.80-3.70 (m, 1H), 3.60-3.48 (m, 3H), 3.27 (s,3H), 3.20-3.00 (m, 5H), 2.85(s, 3H), 2.78-2.60 (m, 2H), 2.50-2.40 (m, 1H), 2.20-2.02 (m, 3H), 1.96-1.80 (m, 2H), 1.42 (d, J=6.8 Hz, 6H); MS (ESI): m/z 642 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.28 (s, 3H, FA), 8.25 (d, J =7.2 Hz, 1H), 8.01 (s, 1H), 7.58-7.49 (m, 1H), 7.46-7.36 (m, 1H), 7.30-7.22 (m, 1H), 7.02 (d, J =2.4 Hz, 1H), 6.98-6.88 (m, 1H), 6.80-6.70 (m, 1H) , 4.30-4.20 (m, 1H), 4.00-3.92 (m, 1H), 3.80-3.70 (m, 1H), 3.60-3.48 (m, 3H), 3.27 (s,3H), 3.20-3.00 (m, 5H), 2.85(s, 3H), 2.78-2.60 (m, 2H), 2.50-2.40 (m, 1H), 2.20-2.02 (m, 3H), 1.96-1.80 (m, 2H), 1.42 (d, J =6.8 Hz, 6H); MS (ESI): m/z 642 [M+H] + 1515 4.54,
1004.54,
100
148148
Figure PCTKR2021019439-appb-img-000197
Figure PCTKR2021019439-appb-img-000197
 		(S)-N-(2-((5-클로로-2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(S)-N-(2-((5-chloro-2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1] ,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400MHz, free base, Methanol-d 4) δ 8.04 (d, J=8 Hz, 1H), 8.02 (s, 1H), 7.43-7.35 (m, 2H), 7.34 (s, 1H), 7.26-7.22 (m, 1H), 6.54 (s, 1H), 4.22-4.19 (m, 1H), 3.94-3.89 (m, 1H), 3.77 (s, 3H), 3.76 (s, 1H), 3.12-3.08 (m, 2H), 3.01-2.98 (m, 1H), 2.97 (s, 3H), 2.81-2.74 (m, 1H), 2.56-2.50 (m, 2H), 2.30-2.26 (m, 1H), 1.89-1.84 (m, 1H), 1.31-1.20 (m, 3H); MS (ESI): m/z 560 [M+H]+ 1 H NMR (400 MHz, free base, Methanol- d 4 ) δ 8.04 (d, J =8 Hz, 1H), 8.02 (s, 1H), 7.43-7.35 (m, 2H), 7.34 (s, 1H), 7.26-7.22 (m, 1H), 6.54 (s, 1H), 4.22-4.19 (m, 1H), 3.94-3.89 (m, 1H), 3.77 (s, 3H), 3.76 (s, 1H), 3.12- 3.08 (m, 2H), 3.01-2.98 (m, 1H), 2.97 (s, 3H), 2.81-2.74 (m, 1H), 2.56-2.50 (m, 2H), 2.30-2.26 (m, 1H), 1.89-1.84 (m, 1H), 1.31-1.20 (m, 3H); MS (ESI): m/z 560 [M+H] + 4545 3.79,
1003.79,
100
149149
Figure PCTKR2021019439-appb-img-000198
Figure PCTKR2021019439-appb-img-000198
 		(S)-N-(2-((5-클로로-2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(S)-N-(2-((5-chloro-2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] [1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400MHz, free base, Methanol-d 4) δ 8.12 (d, J=8 Hz, 1H), 8.02 (s, 1H), 7.43-7.41 (m, 1H), 7.37-7.35 (m, 1H), 7.26-7.22 (m, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.90-6.87 (m, 1H), 6.74 (d, J=8.8 Hz, 1H), 4.26-4.22 (m, 1H), 4.15-4.09 (m, 1H), 3.99-3.94 (m, 1H), 3.75-3.72 (m, 1H), 3.13-3.08 (m, 2H), 2.97 (s, 3H), 2.73-2.70 (m, 1H), 2.56-2.50 (m, 2H), 2.27-2.26 (m, 1H), 1.20-1.16 (m, 3H); MS (ESI): m/z 530 [M+H]+ 1 H NMR (400 MHz, free base, Methanol- d 4 ) δ 8.12 (d, J =8 Hz, 1H), 8.02 (s, 1H), 7.43-7.41 (m, 1H), 7.37-7.35 (m, 1H) ), 7.26-7.22 (m, 1H), 6.98 (d, J =2.4 Hz, 1H), 6.90-6.87 (m, 1H), 6.74 (d, J =8.8 Hz, 1H), 4.26-4.22 (m, 1H), 4.15-4.09 (m, 1H), 3.99-3.94 (m, 1H), 3.75-3.72 (m, 1H), 3.13-3.08 (m, 2H), 2.97 (s, 3H), 2.73-2.70 ( m, 1H), 2.56-2.50 (m, 2H), 2.27-2.26 (m, 1H), 1.20-1.16 (m, 3H); MS (ESI): m/z 530 [M+H] + 4444 3.61,
1003.61,
100
150150
Figure PCTKR2021019439-appb-img-000199
Figure PCTKR2021019439-appb-img-000199
 		(S)-N-(2-((5-클로로 -2-((9-메톡시-3-(테트라하이드로-2H-피란-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(S)-N-(2-((5-chloro-2-((9-methoxy-3-(tetrahydro-2H-pyran-4-yl)-1,2,3,4,4a,5) -hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide 1H NMR (400MHz, free base, Methanol-d 4) δ 7.90 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.26-7.19 (m, 2H), 7.10-7.08 (m, 1H), 6.33 (s, 1H), 5.35 (s, 1H), 4.01-3.98 (m, 1H), 3.87-3.83 (m, 2H), 3.76-3.70 (m, 1H), 3.64 (s, 3H), 3.60-3.50 (m, 1H), 3.30-3.25 (m, 2H), 3.23 (s, 3H), 3.00-2.82 (m, 2H), 2.60-2.50 (m, 1H), 2.38-2.16 (m, 2H), 1.85-1.65 (m, 3H), 1.48-1.34 (m, 2H); MS (ESI): m/z 617 [M+H]+ 1 H NMR (400 MHz, free base, Methanol- d 4 ) δ 7.90 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.26-7.19 (m, 2H), 7.10-7.08 (m, 1H) ), 6.33 (s, 1H), 5.35 (s, 1H), 4.01-3.98 (m, 1H), 3.87-3.83 (m, 2H), 3.76-3.70 (m, 1H), 3.64 (s, 3H), 3.60-3.50 (m, 1H), 3.30-3.25 (m, 2H), 3.23 (s, 3H), 3.00-2.82 (m, 2H), 2.60-2.50 (m, 1H), 2.38-2.16 (m, 2H) ), 1.85-1.65 (m, 3H), 1.48-1.34 (m, 2H); MS (ESI): m/z 617 [M+H] + 3636 3.81,
1003.81,
100
151151
Figure PCTKR2021019439-appb-img-000200
Figure PCTKR2021019439-appb-img-000200
 		(S)-N-(2-((5-클로로-2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(S)-N-(2-((5-chloro-2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[ 1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400MHz, TFA salt, Methanol-d 4) δ 8.10 (s, 1H), 7.79 (d, J = 6.0 Hz, 1H), 7.53-7.51 (m, 1H), 7.42-7.35 (m, 2H), 6.98 (s, 1H), 6.68 (s, 1H), 4.33-4.22 (m, 2H), 4.03-4.00 (m, 1H), 3.82 (s, 3H), 3.66-3.59 (m, 4H), 3.51-3.45 (m, 1H), 3.15-3.10 (m, 1H), 3.01-2.92 (m, 4H), 1.46-1.42 (m, 6H); MS (ESI): m/z 575 [M+H]+ 1 H NMR (400MHz, TFA salt, Methanol- d 4 ) δ 8.10 (s, 1H), 7.79 (d, J = 6.0 Hz, 1H), 7.53-7.51 (m, 1H), 7.42-7.35 (m, 2H) ), 6.98 (s, 1H), 6.68 (s, 1H), 4.33-4.22 (m, 2H), 4.03-4.00 (m, 1H), 3.82 (s, 3H), 3.66-3.59 (m, 4H), 3.51-3.45 (m, 1H), 3.15-3.10 (m, 1H), 3.01-2.92 ( m, 4H), 1.46-1.42 (m, 6H); MS (ESI): m/z 575 [M+H] + 99 3.98,
1003.98,
100
152152
Figure PCTKR2021019439-appb-img-000201
Figure PCTKR2021019439-appb-img-000201
 		(S)-N-(2-((5-클로로-2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(S)-N-(2-((5-chloro-2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] ][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400MHz, TFA salt, Methanol-d 4) δ 8.08 (s, 1H), 7.82-7.80 (m, 1H), 7.52-7.50 (m, 1H), 7.40-7.36 (m, 2H), 6.91-6.85 (m, 3H), 4.37-4.33 (m, 1H), 4.13-4.02 (m, 2H), 3.66-3.58 (m, 3H), 3.46-3.44 (m, 1H), 3.28-3.20 (m, 1H), 3.10-2.95 (m, 5H), 1.44-1.42 (m, 6H); MS (ESI): m/z 545 [M+H]+ 1 H NMR (400MHz, TFA salt, Methanol- d 4 ) δ 8.08 (s, 1H), 7.82-7.80 (m, 1H), 7.52-7.50 (m, 1H), 7.40-7.36 (m, 2H), 6.91 -6.85 (m, 3H), 4.37-4.33 (m, 1H), 4.13-4.02 (m, 2H), 3.66-3.58 (m, 3H), 3.46-3.44 (m, 1H), 3.28-3.20 (m, 1H), 3.10-2.95 (m, 5H), 1.44- 1.42 (m, 6H); MS (ESI): m/z 545 [M+H] + 3535 3.85,
1003.85,
100
153153
Figure PCTKR2021019439-appb-img-000202
Figure PCTKR2021019439-appb-img-000202
 		(S)-N-(2-((5-클로로-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(S)-N-(2-((5-chloro-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[ 1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.15 (s, 1H), 8.00-7.98 (m, 2h), 7.41-7.38 (m, 1H), 7.37-7.32 (m, 1H), 7.25-7.20 (m, 1H), 6.52 (s, 1H), 4.19-4.16 (m, 1H), 3.93-3.89 (m, 1H), 3.19-3.07 (m, 2H), 2.91 (s, 3h), 2.61-2.56 (m, 1H), 2.23-2.15 (m, 1H), 1.87-1.82 (m, 1H), 0.61-0.51 (m, 4H); MS (ESI): m/z 572 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.15 (s, 1H), 8.00-7.98 (m, 2h), 7.41-7.38 (m, 1H), 7.37-7.32 (m, 1H), 7.25-7.20 (m, 1H), 6.52 (s, 1H), 4.19-4.16 (m, 1H), 3.93-3.89 (m, 1H), 3.19-3.07 (m, 2H), 2.91 (s, 3h), 2.61-2.56 (m, 1H), 2.23-2.15 (m, 1H), 1.87-1.82 (m, 1H), 0.61-0.51 (m, 4H); MS (ESI): m/z 572 [M+H] + 5656 3.95,
963.95,
96
154154
Figure PCTKR2021019439-appb-img-000203
Figure PCTKR2021019439-appb-img-000203
 		(S)-N-(2-((5-클로로-2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(S)-N-(2-((5-chloro-2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] ][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.08 (d, J = 8 Hz, 1H), 7.98 (s, 1H), 7.41-7.38 (m, 1H), 7.35-7.31 (m,1H), 7.24-7.19 (m, 1H), 6.94 (d, J = 4 Hz, 1H), 6.86-6.84 (m, 1H), 6.70 (d, J = 8 Hz, 1H), 4.22-4.19 (m, 1H), 3.97-3.93 (m, 1H), 3.69 (d, J = 12 Hz, 1H), 3.14-3.12 (m, 1H), 3.04-2.93 (m, 5H), 2.65-2.59 (m, 1H), 2.54-2.50 (m, 1H), 2.12-2.07 (m, 1H), 1.76-1.70 (m, 1H), 0.56-0.46 (m, 1H); MS (ESI): m/z 542 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.08 (d, J = 8 Hz, 1H), 7.98 (s, 1H), 7.41-7.38 (m, 1H), 7.35-7.31 (m, 1H), 7.24-7.19 (m, 1H), 6.94 (d, J = 4 Hz, 1H), 6.86-6.84 (m, 1H), 6.70 (d, J = 8 Hz, 1H), 4.22-4.19 (m) , 1H), 3.97-3.93 (m, 1H), 3.69 (d, J = 12 Hz, 1H), 3.14-3.12 (m, 1H), 3.04-2.93 (m, 5H), 2.65-2.59 (m, 1H) ), 2.54-2.50 (m, 1H), 2.12-2.07 (m, 1H), 1.76-1.70 (m, 1H), 0.56-0.46 (m, 1H); MS (ESI): m/z 542 [M+H] + 1212 3.81,
923.81,
92
155155
Figure PCTKR2021019439-appb-img-000204
Figure PCTKR2021019439-appb-img-000204
 		N-(2-((5-클로로-2-(((6aS,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드N-(2-((5-chloro-2-(((6aS,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b] pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400MHz, TFA salt, DMSO-d 6) δ 9.28 (s, 1H), 8.47 (s, 1H), 8.10-8.05 (m, 2H), 7.82 (s, 1H), 7.35-7.33 (m, 1H), 7.25-7.08 (m, 3H), 6.57 (s, 1H), 4.17-4.09 (m, 1H), 3.98-3.85 (m, 2H), 3.71 (s, 3H), 3.57-3.56 (m, 4H), 3.17-3.16 (d, J = 5.2 Hz, 1H), 2.96-2.91 (m, 4H), 1.93-1.84 (m, 2H), 1.44-1.42 (m, 1H), 1.23 (s, 1H), 1.10-1.07 (m, 1H); MS (ESI): m/z 617 [M+H]+ 1 H NMR (400MHz, TFA salt, DMSO- d 6 ) δ 9.28 (s, 1H), 8.47 (s, 1H), 8.10-8.05 (m, 2H), 7.82 (s, 1H), 7.35-7.33 (m , 1H), 7.25-7.08 (m, 3H), 6.57 (s, 1H), 4.17-4.09 (m, 1H), 3.98-3.85 (m, 2H), 3.71 (s, 3H), 3.57-3.56 (m, 4H), 3.17-3.16 (d, J = 5.2 Hz, 1H), 2.96-2.91 (m, 4H), 1.93-1.84 (m, 2H), 1.44-1.42 (m, 1H), 1.23 (s, 1H), 1.10-1.07 (m, 1H) ; MS (ESI): m/z 617 [M+H] + 2222 3.95,
1003.95,
100
156156
Figure PCTKR2021019439-appb-img-000205
Figure PCTKR2021019439-appb-img-000205
 		N-(2-((5-클로로-2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드N-(2-((5-chloro-2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b] pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400MHz, free base, Methanol-d 4) δ 8.05 (d, J=9.2 Hz, 1H), 8.01 (s, 1H), 7.43-7.37 (m, 2H), 7.31 (s, 1H), 7.24-7.23 (m, 1H), 6.52 (s, 1H), 4.12-4.09 (m, 1H), 3.93-3.88 (m, 1H), 3.80 (s, 3H), 3.75-3.71 (m, 4H), 3.47-3.44 (m, 1H), 3.33-3.32 (m, 1H), 3.02-2.97 (m, 1H), 2.97 (s, 3H), 2.59-2.52 (m, 4H), 2.41-2.40 (m, 1H), 2.17-2.16 (m, 1H), 2.02-1.99 (m, 1H), 1.87-1.79 (m, 1H), 1.50-1.44 (m, 1H); MS (ESI): m/z 616 [M+H]+ 1 H NMR (400 MHz, free base, Methanol- d 4 ) δ 8.05 (d, J =9.2 Hz, 1H), 8.01 (s, 1H), 7.43-7.37 (m, 2H), 7.31 (s, 1H), 7.24-7.23 (m, 1H), 6.52 (s, 1H), 4.12-4.09 (m, 1H), 3.93-3.88 (m, 1H), 3.80 (s, 3H), 3.75-3.71 (m, 4H), 3.47-3.44 (m, 1H), 3.33-3.32 (m, 1H), 3.02-2.97 (m, 1H), 2.97 (s, 3H), 2.59-2.52 (m, 4H), 2.41-2.40 (m, 1H) ), 2.17-2.16 (m, 1H), 2.02-1.99 (m, 1H), 1.87-1.79 (m, 1H), 1.50-1.44 (m, 1H); MS (ESI): m/z 616 [M+H] + 5151 3.74,
993.74,
99
157157
Figure PCTKR2021019439-appb-img-000206
Figure PCTKR2021019439-appb-img-000206
 		N-(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-모르폴리노-6,6a, 7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드N-(2-((5-chloro-2-(((6aR,8S)-2-methoxy-8-morpholino-6,6a, 7,8,9,10-hexahydrobenzo[b] pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400MHz, TFA salt, Methanol-d 4) δ 8.06 (s, 1H), 7.83-7.82 (m, 1H), 7.53-7.51 (m, 1H), 7.38-7.37 (m, 1H), 6.93 (s, 1H), 6.66 (s, 1H), 4.29-3.81 (m, 8 H), 3.58-3.50 (m, 3H), 3.33-3.32 (m, 6H), 3.00-2.82 (m, 2H), 1.56-1.52 (m, 1H), 1.11-1.23 (m, 1H); MS (ESI): m/z 616 [M+H]+ 1 H NMR (400MHz, TFA salt, Methanol- d 4 ) δ 8.06 (s, 1H), 7.83-7.82 (m, 1H), 7.53-7.51 (m, 1H), 7.38-7.37 (m, 1H), 6.93 (s, 1H), 6.66 (s, 1H), 4.29-3.81 (m, 8 H), 3.58-3.50 (m, 3H), 3.33-3.32 (m, 6H), 3.00-2.82 (m, 2H), 1.56-1.52 (m, 1H), 1.11-1.23 (m, 1H); MS (ESI): m/z 616 [M+H] + 55 3.96,
1003.96,
100
158158
Figure PCTKR2021019439-appb-img-000207
Figure PCTKR2021019439-appb-img-000207
 		N-(2-((5-클로로-2-(((6aS,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드N-(2-((5-chloro-2-(((6aS,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b] pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.05 (s, 1H), 7.82-7.80 (m, 1H), 7.51-7.48 (m, 1H), 7.39-7.34 (m, 2H), 6.94 (s, 1H), 6.59 (s, 1H), 4.18 (d, J = 12 Hz, 1H), 3.98 (s, 1H), 3.94-3.89 (m, 2H), 3.80 (s, 3H), 3.57 (br, 2H), 3.50-3.48 (m, 2H), 3.21 (br, 2H), 2.97 (s, 3H), 2.28-2.23 (m, 4H), 1.96-1.93 (m, 1H); MS (ESI): m/z 616 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.05 (s, 1H), 7.82-7.80 (m, 1H), 7.51-7.48 (m, 1H), 7.39-7.34 (m, 2H), 6.94 (s, 1H), 6.59 (s, 1H), 4.18 (d, J = 12 Hz, 1H), 3.98 (s, 1H), 3.94-3.89 (m, 2H), 3.80 (s, 3H), 3.57 (br, 2H), 3.50-3.48 (m, 2H), 3.21 (br, 2H), 2.97 (s, 3H), 2.28-2.23 (m, 4H), 1.96-1.93 (m, 1H); MS (ESI): m/z 616 [M+H] + 1212 3.81,
973.81,
97
159159
Figure PCTKR2021019439-appb-img-000208
Figure PCTKR2021019439-appb-img-000208
 		(S)-5-클로로-N4-(2-(메틸설포닐)페닐)-N2-(1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)피리미딘-2,4-다이아민(S)-5-chloro-N4-(2-(methylsulfonyl)phenyl)-N2-(1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4] ,3-d][1,4]oxazin-8-yl)pyrimidine-2,4-diamine 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.40 (d, J = 8 Hz, 1H), 8.11 (s, 1H), 8.03-8.01 (m, 1H), 7.74-7.70 (m, 1H), 7.47-7.43 (m, 1H), 6.91 (d, J = 4 Hz, 1H), 6.85-6.79 (m, 2H), 4.86 (s, 26H), 4.23-4.20 (m, 1H), 4.04-4.01 (m, 1h), 3.95-3.88 (m, 2H), 3.76-3.69 (m, 1H), 3.59 (d, J = 12 Hz, 1H), 3.15-3.10 (m, 4H), 2.79-2.73 (m, 1H); MS (ESI): m/z 487 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.40 (d, J = 8 Hz, 1H), 8.11 (s, 1H), 8.03-8.01 (m, 1H), 7.74-7.70 (m, 1H), 7.47-7.43 (m, 1H), 6.91 (d, J = 4 Hz, 1H), 6.85-6.79 (m, 2H), 4.86 (s, 26H), 4.23-4.20 (m, 1H), 4.04 -4.01 (m, 1h), 3.95-3.88 (m, 2H), 3.76-3.69 (m, 1H), 3.59 (d, J = 12 Hz, 1H), 3.15-3.10 (m, 4H), 2.79-2.73 (m, 1H); MS (ESI): m/z 487 [M+H] + 1212 5.99,
995.99,
99
160160
Figure PCTKR2021019439-appb-img-000209
Figure PCTKR2021019439-appb-img-000209
 		(R)-5-클로로-N4-(2-(메틸설포닐)페닐)-N2-(1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)피리미딘-2,4-다이아민(R)-5-chloro-N4-(2-(methylsulfonyl)phenyl)-N2-(1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4 ,3-d][1,4]oxazin-8-yl)pyrimidine-2,4-diamine 1H NMR (400 MHz, TFA salt, Methanol-d 4) δ 8.62 (d, J = 8 Hz, 1H), 8.10 (s, 1H), 7.96-7.87 (m, 1H), 7.69-7.65 (m, 1H), 7.34-7.30 (m, 1H), 7.05 (d, J = 4 Hz, 1H), 6.91-6.88 (m, 1H), 6.75 (d, J = 8 Hz, 1H), 4.20-4.17 (m, 1H), 4.03-3.99 (m, 1H), 3.95-3.87 (m, 2H), 3.76-3.69 (m, 1H), 3.56 (d, J = 12 Hz, 1H), 3.14-3.05 (m, 4H), 2.76-2.70 (m, 1H); MS (ESI): m/z 487 [M+H]+ 1 H NMR (400 MHz, TFA salt, Methanol- d 4 ) δ 8.62 (d, J = 8 Hz, 1H), 8.10 (s, 1H), 7.96-7.87 (m, 1H), 7.69-7.65 (m, 1H), 7.34-7.30 (m, 1H), 7.05 (d, J = 4 Hz, 1H), 6.91-6.88 (m, 1H), 6.75 (d, J = 8 Hz, 1H), 4.20-4.17 (m) , 1H), 4.03-3.99 (m, 1H), 3.95-3.87 (m, 2H), 3.76-3.69 (m, 1H), 3.56 (d, J = 12 Hz, 1H), 3.14-3.05 (m, 4H) ), 2.76-2.70 (m, 1H); MS (ESI): m/z 487 [M+H] + 2424 4.18,
944.18,
94
161161
Figure PCTKR2021019439-appb-img-000210
Figure PCTKR2021019439-appb-img-000210
 		(R)-5-클로로-N2-(9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)-N4-(2-(메틸설포닐)페닐)피리미딘-2,4-다이아민(R)-5-chloro-N2-(9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1, 4]oxazin-8-yl)-N4-(2-(methylsulfonyl)phenyl)pyrimidine-2,4-diamine 1H NMR (400 MHz, TFA salt, CDCl3-d) δ 9.29 (s, 1H), 8.59 (d, J = 8 Hz, 1H), 8.13 (s, 1H), 7.99-7.90 (m 1H), 7.76 (s, 1H), 7.70-7.66 (m, 1H), 7.32 (s, 1H), 6.37 (s, 1H), 4.15-4.12 (m, 1H), 4.07-4.03 (m, 1H), 3.97-3.92 (m, 1H), 3.90-3.86 (m, 1H), 3.83 (s, 3H), 3.79-3.73 (m, 1H), 3.47 (d, J = 12 Hz, 1H), 3.34-3.28 (m, 1H), 3.25-3.18 (m, 1H), 3.07 (s, 3H), 2.91-2.84 (m, 1H), 1.54 (s, 6H); MS (ESI): m/z 518 [M+H]+ 1 H NMR (400 MHz, TFA salt, CDCl 3 -d ) δ 9.29 (s, 1H), 8.59 (d, J = 8 Hz, 1H), 8.13 (s, 1H), 7.99-7.90 (m 1H), 7.76 (s, 1H), 7.70-7.66 (m, 1H), 7.32 (s, 1H), 6.37 (s, 1H), 4.15-4.12 (m, 1H), 4.07-4.03 (m, 1H), 3.97- 3.92 (m, 1H), 3.90-3.86 (m, 1H), 3.83 (s, 3H), 3.79-3.73 (m, 1H), 3.47 (d, J = 12 Hz, 1H), 3.34-3.28 (m, 1H), 3.25-3.18 (m, 1H), 3.07 (s, 3H), 2.91-2.84 (m, 1H), 1.54 (s, 6H); MS (ESI): m/z 518 [M+H] + 2828 6.10,
996.10;
99
162162
Figure PCTKR2021019439-appb-img-000211
Figure PCTKR2021019439-appb-img-000211
 		(R)-N-(2-((5-클로로-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((5-chloro-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[ 1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, HCl salt, Methanol-d 4) δ 7.99 (s, 1H), 7.65 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.33-7.25 (m, 2H), 6.81 (s, 1H), 6.60 (s, 1H), 4.30-4.08 (m, 2H), 3.98-3.90 (m, 1H), 3.82-3.53 (m, 2H), 3.51-3.26 (m, 2H), 3.29 (s, 3H), 3.16-3.02 (m, 2H), 2.88 (s, 3H), 2.88-2.80 (m, 1H), 1.10-1.08 (m, 2H), 1.07-1.05 (m, 2H); MS (ESI): m/z 609 [M+H]+ 1 H NMR (400 MHz, HCl salt, Methanol- d 4 ) δ 7.99 (s, 1H), 7.65 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.33-7.25 (m, 2H) , 6.81 (s, 1H), 6.60 (s, 1H), 4.30-4.08 (m, 2H), 3.98-3.90 (m, 1H), 3.82-3.53 (m, 2H), 3.51-3.26 (m, 2H) , 3.29 (s, 3H), 3.16-3.02 (m, 2H), 2.88 (s, 3H), 2.88-2.80 (m, 1H), 1.10-1.08 (m, 2H), 1.07-1.05 (m, 2H) ; MS (ESI): m/z 609 [M+H] + 3131 3.92,
1003.92,
100
163163
Figure PCTKR2021019439-appb-img-000212
Figure PCTKR2021019439-appb-img-000212
 		(2-((5-클로로-2-(((R)-9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)(이미노)(메틸)-λ6-설파논(2-((5-chloro-2-(((R)-9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexa Hydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) phenyl) (imino) (methyl) -λ 6 - sulfanone MS (ESI): m/z 614 [M+H]+ MS (ESI): m/z 614 [M+H] +
164164
Figure PCTKR2021019439-appb-img-000213
Figure PCTKR2021019439-appb-img-000213
 		(2-((5-클로로-2-(((R)-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)(이미노)(메틸)-λ6-설파논(2-((5-chloro-2-(((R)-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)(imino)(methyl)-λ 6 -sulfanone MS (ESI): m/z 584 [M+H]+ MS (ESI): m/z 584 [M+H] +
165165
Figure PCTKR2021019439-appb-img-000214
Figure PCTKR2021019439-appb-img-000214
 		(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)(이미노)(메틸)-λ6-설파논(2-((5-chloro-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-yl) amino) pyrimidin-4-yl) amino) phenyl) (imino) (methyl) -λ 6 -sulfanone MS (ESI): m/z 614 [M+H]+ MS (ESI): m/z 614 [M+H] +
166166
Figure PCTKR2021019439-appb-img-000215
Figure PCTKR2021019439-appb-img-000215
 		(2-((5-클로로-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)(이미노)(메틸)-λ6-설파논(2-((5-chloro-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[b] ]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)(imino)(methyl)-λ 6 -sulfanone MS (ESI): m/z 584 [M+H]+ MS (ESI): m/z 584 [M+H] +
실시예 167: (R)-N-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조Example 167: (R) -N- (2-((5-chloro-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1, Preparation of 2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide
하기 반응식 5로 표시된 방법을 통해 표제의 화합물을 제조하였다.The title compound was prepared by the method shown in Scheme 5 below.
[반응식 5][Scheme 5]
Figure PCTKR2021019439-appb-img-000216
Figure PCTKR2021019439-appb-img-000216
단계 1: NStep 1: N 1One -(2,5-다이클로로-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)벤젠-1,2-다이아민의 제조-(2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzene-1,2- Preparation of diamine
2,4,5-트라이클로로-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘(1 당량), 벤젠-1,2-다이아민(1.1 당량), DIPEA(2 당량)을 n-BuOH(0.2 M)에 녹인 후, 상온에서 1 시간 동안 교반하였다. 물과 brine을 넣고 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 얻어진 갈색 액체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 100%, MS (ESI): m/z 424 [M]+).2,4,5-Trichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 eq), benzene-1,2- Diamine (1.1 equivalents) and DIPEA (2 equivalents) were dissolved in n-BuOH (0.2 M), followed by stirring 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 obtained target compound as a brown liquid was used in the next reaction without further purification (yield: 100%, MS (ESI): m/z 424 [M] + ).
단계 2: N-(2-((2,5-다이클로로-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아미드의 제조Step 2: N-(2-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Preparation of yl) amino) phenyl) methanesulfonamide
단계 1에서 제조한 N1-(2,5-다이클로로-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)벤젠-1,2-다이아민(1 당량), 메탄설포닐클로라이드(2 당량)를 피리딘(0.4 M)에 녹인 후, 상온에서 2 시간 동안 교반하였다. 물과 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(DCM:MeOH)를 통해 정제하였고, 하얀색 고체의 목적 화합물을 수득하였다(수율: 79 %, MS (ESI): m/z 502 [M]+).N 1 -(2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl prepared in step 1 ) Benzene-1,2-diamine (1 eq.) and methanesulfonyl chloride (2 eq.) were dissolved in pyridine (0.4 M), followed by stirring at room temperature for 2 hours. The organics were extracted with water and 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 white solid (yield: 79 %, MS (ESI): m/z 502 [M] + ).
단계 3: (R)-N-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아미드의 제조Step 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
단계 2에서 제조한 N-(2-((2,5-다이클로로-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아미드(1 당량), (R)-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-아민(1.2 당량), K2CO3(3 당량)를 sec-BuOH(0.04 M)에 녹인 후, 질소 하에서 Pd2(dba)3(0.1 당량)와 Xphos(0.1 당량)를 첨가하고 100 ℃에서 16 시간 동안 교반하였다. 셀라이트로 여과한 뒤, 농축하였다. 반응 혼합물은 MPLC(DCM:MeOH)를 통해 정제하였고, 갈색 액체의 목적 화합물을 수득하였다(수율: 64 %, MS (ESI): 686 m/z [M+H]+).N-(2-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino)phenyl)methanesulfonamide (1 equivalent), (R)-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d ][1,4]oxazin-8-amine (1.2 eq.), K 2 CO 3 (3 eq.) was dissolved in sec-BuOH (0.04 M), and then Pd 2 (dba) 3 (0.1 eq.) and Xphos (0.1 eq) was added and stirred at 100 °C for 16 h. After filtration through celite, it was concentrated. The reaction mixture was purified through MPLC (DCM:MeOH) to obtain the title compound as a brown liquid (yield: 64 %, MS (ESI): 686 m/z [M+H] + ).
단계 4: (R)-N-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아미드의 제조Step 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
단계 3에서 제조한 (R)-N-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7-((2-(트라이메틸실릴)에톡시)메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아미드(1 당량)을 DCM(0.1 M)에 녹인 후, TFA를 동량 첨가하고 상온에서 1 시간 동안 교반하였다. 반응 혼합물을 농축하여 다시 THF에 녹인 후, sat.NaHCO3를 첨가하고 60 ℃에서 16 시간 동안 교반하였다. 물과 brine을 넣고 EtOAc로 유기물을 추출하였다. 모아진 유기층은 Na2SO4를 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 prep-HPLC를 통해 정제하였고, 갈색 고체의 목적 화합물을 수득하였다(수율: 32 %, MS (ESI): m/z 555 [M]+).(R)-N-(2-((5-chloro-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1] prepared in step 3) ,2-d][1,4]oxazin-8-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)amino)phenyl)methanesulfonamide (1 equivalent) was dissolved in DCM (0.1 M), followed by the addition of the same amount of TFA, followed by stirring at room temperature for 1 hour. The 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] + ).
실시예 168 내지 실시예 174Examples 168 to 174
상기 실시예 167과 유사한 방법으로 실시예 168 내지 174 화합물을 제조하였다. 실시예 167 내지 174 화합물의 화학구조, 화합물명, NMR, 수율, 및 HPLC 분석 결과를 하기 표 4에 정리하여 나타내었다.Compounds of Examples 168 to 174 were prepared in a manner similar to that of Example 167. Chemical structures, compound names, NMR, yield, and HPLC analysis results of the compounds of Examples 167 to 174 are summarized in Table 4 below.
실시예Example 구조rescue 화합물명compound name 1H NMR, MS 1 H NMR, MS 수율
(%)transference number
(%) 		HPLC r.t.(min),
Purity
(%)HPLC rt (min),
Purity
(%)
167167
Figure PCTKR2021019439-appb-img-000217
Figure PCTKR2021019439-appb-img-000217
 		(R)-N-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드(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)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, CDCl3-d) δ 8.61 (d, J = 8.4 Hz, 1H), 8.29 (s, 2H, FA), 7.41-7.30 (m, 2H), 7.25 (d, J = 1 Hz, 1H), 7.20-7.10 (m, 1H), 7.09-7.00 (m, 1H), 6.86 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.30-4.20 (m, 1H), 4.10-4.00 (m, 1H), 3.98-3.90 (m, 1H), 3.40-3.20 (m, 3H), 3.00 (s, 3H), 2.98-2.78 (m, 2H), 2.70 (s, 3H), 2.58-2.48 (m, 1H); MS (ESI): m/z 555 [M]+ 1 H NMR (400 MHz, FA salt, CDCl 3 -d ) δ 8.61 (d, J = 8.4 Hz, 1H), 8.29 (s, 2H, FA), 7.41-7.30 (m, 2H), 7.25 (d, J = 1 Hz, 1H), 7.20-7.10 (m, 1H), 7.09-7.00 (m, 1H), 6.86 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.30-4.20 (m) , 1H), 4.10-4.00 (m, 1H), 3.98-3.90 (m, 1H), 3.40-3.20 (m, 3H), 3.00 (s, 3H), 2.98-2.78 (m, 2H), 2.70 (s) , 3H), 2.58-2.48 (m, 1H); MS (ESI): m/z 555 [M] + 3232 4.46,
994.46,
99
168168
Figure PCTKR2021019439-appb-img-000218
Figure PCTKR2021019439-appb-img-000218
 		N-(2-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드N-(2-((2-(((6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydro benzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl) Methanesulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.31 (d, J = 2.6 Hz, 1H), 8.72 (s, 1H), 8.22 (s, 1H), 8.22 (s, 1H, FA), 7.91-7.83 (m, 1H), 7.74 (s, 1H), 7.42-7.34 (m, 1H), 7.30-7.21 (m, 1H), 7.21-7.12 (m, 1H), 7.08 (s, 1H), 6.94-6.89 (m, 1H), 6.58 (s, 1H), 6.33-6.25 (m, 1H), 4.18-4.11 (m, 1H), 3.96-3.90 (m, 1H), 3.89-3.81 (m, 1H), 3.76 (s, 3H), 2.92-2.82 (m, 4H), 2.45-2.24 (m, 10H), 2.14 (s, 3H), 1.93-1.78 (m, 2H), 1.52-1.37 (m, 1H), 1.15-1.04 (m, 1H); MS (ESI): m/z 634 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.31 (d, J = 2.6 Hz, 1H), 8.72 (s, 1H), 8.22 (s, 1H), 8.22 (s, 1H, FA) , 7.91-7.83 (m, 1H), 7.74 (s, 1H), 7.42-7.34 (m, 1H), 7.30-7.21 (m, 1H), 7.21-7.12 (m, 1H), 7.08 (s, 1H) , 6.94-6.89 (m, 1H), 6.58 (s, 1H), 6.33-6.25 (m, 1H), 4.18-4.11 (m, 1H), 3.96-3.90 (m, 1H), 3.89-3.81 (m, 1H), 3.76 (s, 3H), 2.92-2.82 (m, 4H), 2.45-2.24 (m, 10H), 2.14 (s, 3H), 1.93-1.78 (m, 2H), 1.52-1.37 (m, 1H), 1.15-1.04 (m, 1H); MS (ESI): m/z 634 [M+H] + 2525 3.79,
993.79,
99
169169
Figure PCTKR2021019439-appb-img-000219
Figure PCTKR2021019439-appb-img-000219
 		(R)-N-(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4] ]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.29 (s, 1H, FA), 7.83 (d, J = 8 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.25 (t, J = 8 Hz, 1H), 7.17 (s, 1H), 6.96 (d, J = 6.8 Hz, 1H), 6.87 (d, J = 3.2 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 3.6 Hz, 1H), 4.25 (d, J = 10.4 Hz, 1H), 4.01 (t, J = 8.4 Hz, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.24 (d, J = 10.8 Hz, 1H), 3.16 (d, J = 12 Hz, 2.89-2.85 (m, 4H), 2.70-2.61 (m, 5H), 2.37 (t, J = 10.8 Hz, 1H); MS (ESI): m/z 521 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.29 (s, 1H, FA), 7.83 (d, J = 8 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.25 (t, J = 8 Hz, 1H), 7.17 (s, 1H), 6.96 (d, J = 6.8 Hz, 1H), 6.87 (d, J = 3.2 Hz) , 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 3.6 Hz, 1H), 4.25 (d, J = 10.4 Hz, 1H), 4.01 (t, J = 8.4 Hz, 1H) ), 3.87 (d, J = 13.2 Hz, 1H), 3.24 (d, J = 10.8 Hz, 1H), 3.16 (d, J = 12 Hz, 2.89-2.85 (m, 4H), 2.70-2.61 (m, 5H), 2.37 (t, J = 10.8 Hz, 1H); MS (ESI): m/z 521 [M+H] + 1111 3.76,
973.76,
97
170170
Figure PCTKR2021019439-appb-img-000220
Figure PCTKR2021019439-appb-img-000220
 		(R)-N-(2-((2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] ][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.28 (s, 2H, FA), 7.78 (d, J = 7.2 Hz, 1H), 7.70 (s, 1H), 7.48 (d, J = 6.8 Hz, 1H), 7.36 (t, J = 8 Hz, 1H), 7.27 (t, J = 8 Hz, 1H), 6.88 (s, 1H), 6.57 (s, 1H), 6.39 (d, J = 3.6 Hz, 1H), 4.21 (d, J = 8.8 Hz, 1H), 3.98-3.82 (m, 5H), 3.31-3.18 (m, 3H), 2.90-2.86 (m. 4H), 2.77 (t, J = 11.2 Hz, 1H), 2.65 (s, 3H), 2.47 (t, J = 11.2 Hz, 1H); MS (ESI): m/z 551 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.28 (s, 2H, FA), 7.78 (d, J = 7.2 Hz, 1H), 7.70 (s, 1H), 7.48 (d, J = 6.8 Hz, 1H), 7.36 (t, J = 8 Hz, 1H), 7.27 (t, J = 8 Hz, 1H), 6.88 (s, 1H), 6.57 (s, 1H), 6.39 (d, J = 3.6 Hz, 1H), 4.21 (d, J = 8.8 Hz, 1H), 3.98-3.82 (m, 5H), 3.31-3.18 (m, 3H), 2.90-2.86 (m. 4H), 2.77 (t, J ) = 11.2 Hz, 1H), 2.65 (s, 3H), 2.47 (t, J = 11.2 Hz, 1H); MS (ESI): m/z 551 [M+H] + 3030 3.87,
993.87,
99
171171
Figure PCTKR2021019439-appb-img-000221
Figure PCTKR2021019439-appb-img-000221
 		(R)-N-(2-((2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl) methane sulfonamide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.43 (s, 3H, FA), 7.82 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.47 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 (td, J = 7.6, 1.2 Hz, 1H), 7.26 (td, J = 7.6, 1.6 Hz, 1H), 6.87 (s, 1H), 6.51 (s, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.17 (dd, J = 10, 2 Hz, 1H), 3.91-3.82 (m, 4H), 3.48 (d, J = 12 Hz, 2H), 3.08-2.92 (m, 4H), 2.88 (s, 3H) 2.79 (s, 3H), 2.55 (t, J = 10.8 Hz, 1H), 2.15-2.03 (m, 7H), 1.87-1.75 (m, 2H); MS (ESI): m/z 634 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.43 (s, 3H, FA), 7.82 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.47 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 (td, J = 7.6, 1.2 Hz, 1H), 7.26 (td, J = 7.6, 1.6 Hz, 1H), 6.87 (s, 1H), 6.51 (s, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.17 (dd, J = 10, 2 Hz, 1H), 3.91-3.82 (m, 4H), 3.48 (d, J = 12 Hz, 2H), 3.08-2.92 (m, 4H), 2.88 (s, 3H) 2.79 (s, 3H), 2.55 (t, J = 10.8 Hz, 1H), 2.15-2.03 (m, 7H), 1.87-1.75 (m, 2H); MS (ESI): m/z 634 [M+H] + 1717 3.44,
993.44,
99
172172
Figure PCTKR2021019439-appb-img-000222
Figure PCTKR2021019439-appb-img-000222
 		(R)-N-(2-((5-시아노-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((5-cyano-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d] ][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 12.30 (s, 1H), 8.81 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.24 (s, 1H, FA), 8.22 (s, 2H), 7.92 (s, 1H), 7.38-7.32 (m, 1H), 7.25-7.20 (m, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.10-7.02 (m, 2H), 6.71 (d, J = 8.9 Hz, 1H), 4.24-4.16 (m, 1H), 3.92-3.84 (m, 1H), 3.63 (d, J = 11.6 Hz, 1H), 3.00-2.90 (m, 4H), 2.90-2.74 (m, 2H), 2.61-2.53 (m, 1H), 2.22 (s, 3H), 2.14-2.04 (m, 1H), 1.69 (t, J = 10.6 Hz, 1H); MS (ESI): m/z 546 [M+H]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 12.30 (s, 1H), 8.81 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.24 (s, 1H, FA) , 8.22 (s, 2H), 7.92 (s, 1H), 7.38-7.32 (m, 1H), 7.25-7.20 (m, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.10-7.02 (m) , 2H), 6.71 (d, J = 8.9 Hz, 1H), 4.24-4.16 (m, 1H), 3.92-3.84 (m, 1H), 3.63 (d, J = 11.6 Hz, 1H), 3.00-2.90 ( m, 4H), 2.90-2.74 (m, 2H), 2.61-2.53 (m, 1H), 2.22 (s, 3H), 2.14-2.04 (m, 1H), 1.69 (t, J = 10.6 Hz, 1H) ; MS (ESI): m/z 546 [M+H] + 1414 4.08,
974.08,
97
173173
Figure PCTKR2021019439-appb-img-000223
Figure PCTKR2021019439-appb-img-000223
 		(R)-N-(2-((2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰 아마이드(R)-N-(2-((2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino) [1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, Methanol-d 4) δ 8.52 (s, 3H, FA), 7.84-7.80 (m, 1H), 7.49-7.38 (m, 1H), 7.36-7.26 (m, 1H), 7,24-7,16 (m, 1H), 7,13 (d, J=2.4 Hz, 1H), 7.00-6.84 (m, 2H), 6.74 (d, J=8.8 Hz, 1H), 6.40 (d, J=3.2 Hz, 1H), 4.30-4.18 (m, 1H), 4.01-3.94 (m, 1H), 3.80-3.62 (m, 1H), 3.40-3.30 (m, 3H), 3.20-2.98 (m, 3H), 2.86 (s, 3H), 2.80-2.60 (m, 5H), 2.59-2.42 (m, 2H), 2.16-2.00 (m, 3H), 1.90-1.70 (m, 2H); MS (ESI): m/z 604 [M+H]+ 1 H NMR (400 MHz, FA salt, Methanol- d 4 ) δ 8.52 (s, 3H, FA), 7.84-7.80 (m, 1H), 7.49-7.38 (m, 1H), 7.36-7.26 (m, 1H) ), 7,24-7,16 (m, 1H), 7,13 (d, J =2.4 Hz, 1H), 7.00-6.84 (m, 2H), 6.74 (d, J =8.8 Hz, 1H), 6.40 (d, J =3.2 Hz, 1H), 4.30-4.18 (m, 1H), 4.01-3.94 (m, 1H), 3.80-3.62 (m, 1H), 3.40-3.30 (m, 3H), 3.20- 2.98 (m, 3H), 2.86 (s, 3H), 2.80-2.60 (m, 5H), 2.59-2.42 (m, 2H), 2.16-2.00 (m, 3H), 1.90-1.70 (m, 2H); MS (ESI): m/z 604 [M+H] + 77 3.45,
983.45,
98
174174
Figure PCTKR2021019439-appb-img-000224
Figure PCTKR2021019439-appb-img-000224
 		(R)-N-(2-((5-클로로-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드(R)-N-(2-((5-chloro-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1] ,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide 1H NMR (400 MHz, FA salt, DMSO-d 6) δ 11.53 (d, J = 2.6 Hz, 1H), 8.72 (s, 1H), 8.62 (d, J = 8.3 Hz, 1H), 8.16 (s, 1H, FA), 7.46 (d, J = 13.4 Hz, 2H), 7.36-7.31 (m, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.11-7.03 (m, 2H), 6.58 (s, 1H), 4.22-4.15 (m, 1H), 3.90-3.82 (m, 1H), 3.81-3.71 (m, 4H), 3.07-2.97 (m, 4H), 2.92-2.83 (m, 1H), 2.83-2.75 (m, 1H), 2.66-2.59 (m, 1H), 2.23 (s, 3H), 2.15-2.06 (m, 1H), 1.71 (t, J = 10.6 Hz, 1H); MS (ESI): m/z 585 [M]+ 1 H NMR (400 MHz, FA salt, DMSO- d 6 ) δ 11.53 (d, J = 2.6 Hz, 1H), 8.72 (s, 1H), 8.62 (d, J = 8.3 Hz, 1H), 8.16 (s) , 1H, FA), 7.46 (d, J = 13.4 Hz, 2H), 7.36-7.31 (m, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.11-7.03 (m, 2H), 6.58 ( s, 1H), 4.22-4.15 (m, 1H), 3.90-3.82 (m, 1H), 3.81-3.71 (m, 4H), 3.07-2.97 (m, 4H), 2.92-2.83 (m, 1H), 2.83-2.75 (m, 1H), 2.66-2.59 (m, 1H), 2.23 (s, 3H), 2.15-2.06 (m, 1H), 1.71 (t, J = 10.6 Hz, 1H); MS (ESI): m/z 585 [M] + 5151 4.52,
994.52,
99
실험예 1. 본 발명에 따른 화합물의 다양한 키나아제 저해 활성 평가Experimental Example 1. Evaluation of various kinase inhibitory activities of the compounds according to the present invention
본 발명에 따른 화합물의 다양한 효소에 대한 저해 활성을 평가하기 위해 하기와 같은 실험을 수행하였다. 구체적으로, 본 발명의 실시예 화합물 중 선별된 실시예 2의 화합물에 대하여, DiscoverX 사에 의뢰하여 효소(kinase) 선택성을 측정하기로 하고, scanMAXTM Kinase 분석용 패널을 사용하여 실험을 진행하였다. 이때, 효소에 처리되는 약물의 농도는 DMSO에 1 μM로 하였고, 하기 수학식 1과 같은 방법으로 조절 백분율(% control)을 정하였다.In order to evaluate the inhibitory activity of the compounds according to the present invention to various enzymes, 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 μM in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below.
[수학식 1][Equation 1]
(실시예 화합물 - 양성 대조군) / (음성 대조군 - 양성대조군) Х 100(Example compound - positive control) / (negative control - positive control) Х 100
여기서, 상기 양성 대조군은 0 %의 조절 백분율을 나타내는 화합물을 말하며, 음성 대조군은 DMSO로 100 %의 조절 백분율을 나타낸다. 또한, 본 발명의 효소 선택성은 각각의 효소에 대하여 조절 백분율이 < 30 % (즉, 30 % 미만)이면 해당 효소에 대하여 활성을 갖는 것으로 판단하였다.Here, the positive control refers to a compound showing a percentage control of 0%, and the negative control indicates a percentage control of 100% with DMSO. In addition, 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.
그 결과, 실시예 2의 화합물은 하기 효소에 대해 조절 백분율이 < 30 % (즉, 30 % 미만)으로, 하기 효소에 대하여 활성을 갖는 것을 확인할 수 있었다: 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).As a result, it was confirmed that 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).
실험예 2. Ba/F3 세포 증식 억제 활성 평가Experimental Example 2. Ba/F3 cell proliferation inhibitory activity evaluation
본 발명에 따른 화학식 1로 표시되는 화합물의 EGFR의 돌연변이를 발현하는 Ba/F3 세포 증식에 대한 억제 활성을 평가하기 위해 하기와 같은 실험을 수행하였다.The following experiment was performed to evaluate the inhibitory activity of the compound represented by Formula 1 according to the present invention on the proliferation of Ba/F3 cells expressing EGFR mutations.
BaF3-EGFR(WT), BaF3-EGFR(Del19/T790M/C797S) 세포를 clear bottom white 96-웰 플레이트에 3 Х 103/100 μl/웰이 되도록 심은 뒤, 3 배수로 연속 희석된 12 가지 농도(0.00001 - 2 mM)의 화합물 및 DMSO 대조군이 포함된 배양액을 0.5 μl/웰씩 첨가하여 최종농도가 0.00005 - 10 μM이 되도록 처리한 뒤 37 ℃ CO2 배양기에서 72 시간 동안 배양하였다. 72 시간 후, 화합물을 처리한 플레이트를 꺼내어, CellTiter-Glo® 2.0 Assay (Promega) 용액을 100 μl/웰 처리 후, 잘 섞어 주었다. 상온에서 10분 정도 잘 섞어주고, 마이크로 플레이트 판독기로 형광도를 측정하였다. 데이터는 비히클 기준 처리된 세포에 비례하여 백분율로 GraphPad Prism 8.3.0(GraphPad software Inc., San Diego)을 이용하여 GI50(μM) 값을 산출하였다. 결과값은 대조군과 비교한 세포성장비율 (%)로 산출하였다. GraphPad Prism version 5.0 프로그램을 사용하여 그래프를 그리고 GI50(μM)값을 계산하였다. BaF3-EGFR (WT), BaF3-EGFR (Del19/T790M/C797S) cells were seeded in clear bottom white 96-well plates at a volume of 3 Х 10 3 /100 μl/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 µl/well to a final concentration of 0.00005 - 10 µM, 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 μl/well of CellTiter-Glo® 2.0 Assay (Promega) solution was treated and mixed well. After mixing well for about 10 minutes at room temperature, the fluorescence was measured with a microplate reader. Data were calculated as GI 50 (μM) values using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) as a percentage relative to vehicle reference treated cells. The result value was calculated as the cell growth rate (%) compared to the control group. The graph was drawn using the GraphPad Prism version 5.0 program and the GI 50 (μM) value was calculated.
하기 표 5에 EGFR 돌연변이를 발현하는 Ba/F3 세포의 증식 억제 활성 평가 결과를 나타내었다.Table 5 below shows the results of evaluation of the proliferation inhibitory activity of Ba/F3 cells expressing EGFR mutations.
실시예Example Ba/F3
(GI50, μM)Ba/F3
(GI 50 , μM) 		실시예Example Ba/F3
(GI50, μM)Ba/F3
(GI 50 , μM) 		실시예Example Ba/F3
(GI50, μM)Ba/F3
(GI 50 , μM)
EGFR WTEGFR WT EGFR Del19/T790M/C797SEGFR Del19/T790M/C797S EGFR WTEGFR WT EGFR Del19/T790M/C797SEGFR Del19/T790M/C797S EGFR WTEGFR WT EGFR Del19/T790M/C797SEGFR Del19/T790M/C797S
1One BB AA 4646 BB AA 9494 BB AA
22 BB AA 4747 BB BB 9595 CC BB
33 CC CC 4848 BB AA 9696 CC BB
55 BB BB 4949 BB BB 9898 CC AA
66 AA AA 5050 CC CC 9999 CC BB
88 AA AA 5151 BB BB 100100 CC AA
99 AA AA 5252 CC CC 101101 CC AA
1010 AA AA 5353 CC BB 103103 CC AA
1111 BB AA 5454 AA AA 104104 CC BB
1212 BB AA 5555 CC CC 116116 CC AA
1313 CC BB 5656 AA AA 120120 CC AA
1414 CC BB 5757 BB AA 121121 CC AA
1515 BB CC 5858 BB BB 131131 CC BB
2222 CC CC 5959 BB AA 132132 CC BB
2626 CC CC 6060 BB BB 137137 BB BB
3535 BB CC 6161 BB AA 139139 BB BB
3636 CC BB 6262 AA AA 140140 AA AA
3737 CC BB 6363 BB BB 142142 BB BB
3838 CC CC 6464 CC CC 145145 AA AA
3939 CC CC 6565 CC BB 146146 AA AA
4040 BB BB 6666 CC AA 147147 AA AA
4141 BB AA 7171 CC BB 152152 AA AA
4242 CC BB 7474 CC BB 159159 AA AA
4343 AA AA 7777 CC AA 167167 AA AA
4444 AA AA 7979 BB BB 168168 CC CC
4545 AA BB 8181 CC BB
(A: GI50 ≤ 0.1 μM; B: 0.1 μM < GI50 ≤ 0.3 μM; C: 0.3 μM < GI50)(A: GI 50 ≤ 0.1 μM; B: 0.1 μM < GI 50 ≤ 0.3 μM; C: 0.3 μM < GI 50 )

Claims (15)

  1. 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염:A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2021019439-appb-img-000225
    Figure PCTKR2021019439-appb-img-000225
    상기 화학식 1에서,In Formula 1,
    고리 A는
    Figure PCTKR2021019439-appb-img-000226
    ,
    Figure PCTKR2021019439-appb-img-000227
    , 또는
    Figure PCTKR2021019439-appb-img-000228
    이고 {여기서,
    Figure PCTKR2021019439-appb-img-000229
    ,
    Figure PCTKR2021019439-appb-img-000230
    , 또는
    Figure PCTKR2021019439-appb-img-000231
    의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, -할로, 또는 -C3-6사이클로알킬로 치환될 수 있음};     ring A is
    Figure PCTKR2021019439-appb-img-000226
    ,
    Figure PCTKR2021019439-appb-img-000227
    , or
    Figure PCTKR2021019439-appb-img-000228
    and {here,
    Figure PCTKR2021019439-appb-img-000229
    ,
    Figure PCTKR2021019439-appb-img-000230
    , or
    Figure PCTKR2021019439-appb-img-000231
    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};
    A1 내지 A4는 각각 독립적으로 CH 또는 N이고;A 1 to A 4 are each independently CH or N;
    B1 및 B2는 각각 독립적으로 CH, CH2, N, NH, O, 또는 S이고;B 1 and B 2 are each independently CH, CH 2 , N, NH, O, or S;
    B3 내지 B5는 각각 독립적으로 CH 또는 N이고;B 3 to B 5 are each independently CH or N;
    Figure PCTKR2021019439-appb-img-000232
    는 단일 결합 또는 이중 결합이고;
    Figure PCTKR2021019439-appb-img-000232
    is a single bond or a double bond;
    X는
    Figure PCTKR2021019439-appb-img-000233
    ,
    Figure PCTKR2021019439-appb-img-000234
    ,
    Figure PCTKR2021019439-appb-img-000235
    ,
    Figure PCTKR2021019439-appb-img-000236
    ,
    Figure PCTKR2021019439-appb-img-000237
    , 또는
    Figure PCTKR2021019439-appb-img-000238
    이고;    X is
    Figure PCTKR2021019439-appb-img-000233
    ,
    Figure PCTKR2021019439-appb-img-000234
    ,
    Figure PCTKR2021019439-appb-img-000235
    ,
    Figure PCTKR2021019439-appb-img-000236
    ,
    Figure PCTKR2021019439-appb-img-000237
    , or
    Figure PCTKR2021019439-appb-img-000238
    ego;
    X1 내지 X8은 각각 독립적으로 -H, -C1-6알킬, -C1-6알콕시, -C1-6알킬아미노, -C2-8다이알킬아미노, 또는 -C3-6사이클로알킬이거나, 또는 상기 X1 및 X2는 서로 연결되어 P 원자와 함께 4 내지 7원 고리를 형성할 수 있고;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;
    Y1 및 Y2는 각각 독립적으로 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, 또는 -할로이고, 또는 Y1 및 Y2는 서로 연결되어 피리미딘 고리와 함께 고리 내 N, O, 및 S 원자 중 하나 이상을 포함하는 이중 고리의 헤테로아릴을 형성할 수 있고 {여기서, 상기 이중 고리의 헤테로아릴의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, 또는 -할로로 치환될 수 있음}; 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};
    Z1, Z2, 또는 Z3는 각각 독립적으로 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, 또는 -할로이고;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;
    W1 및 W2는 각각 독립적으로 -CRARB-, -NRC-, -O-, -S-, -S(=O)-, 또는 -SO2-이고;W 1 and W 2 are each independently -CR A R B -, -NR C -, -O-, -S-, -S(=O)-, or -SO 2 -;
    RA 내지 RC는 각각 독립적으로 -H, -C1-6알킬, 또는 -C3-6사이클로알킬, 헤테로사이클로알킬이고 {여기서, 상기 -C3-6사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬 또는 -C3-6사이클로알킬로 치환될 수 있음};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};
    R1 및 R2는 각각 독립적으로 -H 또는 -C1-6알킬이고;R 1 and R 2 are each independently —H or —C 1-6 alkyl;
    Ra 및 Rb는 각각 독립적으로 -H 또는 -C1-6알킬이다.R a and R b are each independently —H or —C 1-6 alkyl.
  2. 제 1 항에 있어서,The method of claim 1,
    고리 A는
    Figure PCTKR2021019439-appb-img-000239
    ,
    Figure PCTKR2021019439-appb-img-000240
    , 또는
    Figure PCTKR2021019439-appb-img-000241
    이고 {여기서,
    Figure PCTKR2021019439-appb-img-000242
    ,
    Figure PCTKR2021019439-appb-img-000243
    , 또는
    Figure PCTKR2021019439-appb-img-000244
    의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, -할로, 또는 -C3-6사이클로알킬로 치환될 수 있음};     ring A is
    Figure PCTKR2021019439-appb-img-000239
    ,
    Figure PCTKR2021019439-appb-img-000240
    , or
    Figure PCTKR2021019439-appb-img-000241
    and {here,
    Figure PCTKR2021019439-appb-img-000242
    ,
    Figure PCTKR2021019439-appb-img-000243
    , or
    Figure PCTKR2021019439-appb-img-000244
    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};
    A1 내지 A4는 각각 독립적으로 CH 또는 N이고;A 1 to A 4 are each independently CH or N;
    B1 및 B2는 각각 독립적으로 CH, CH2, N, NH, 또는 O이고;B 1 and B 2 are each independently CH, CH 2 , N, NH, or O;
    B3 내지 B5는 각각 독립적으로 CH 또는 N이고;B 3 to B 5 are each independently CH or N;
    Figure PCTKR2021019439-appb-img-000245
    는 단일 결합 또는 이중 결합이고;
    Figure PCTKR2021019439-appb-img-000245
    is a single bond or a double bond;
    X는
    Figure PCTKR2021019439-appb-img-000246
    ,
    Figure PCTKR2021019439-appb-img-000247
    ,
    Figure PCTKR2021019439-appb-img-000248
    , 또는
    Figure PCTKR2021019439-appb-img-000249
    이고;    X is
    Figure PCTKR2021019439-appb-img-000246
    ,
    Figure PCTKR2021019439-appb-img-000247
    ,
    Figure PCTKR2021019439-appb-img-000248
    , or
    Figure PCTKR2021019439-appb-img-000249
    ego;
    X1, X2, X4 내지 X8은 각각 독립적으로 -H 또는 -C1-6알킬이고;X 1 , X 2 , X 4 to X 8 are each independently —H or —C 1-6 alkyl;
    Y1 및 Y2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, 또는 -할로이고, 또는 Y1 및 Y2는 서로 연결되어 피리미딘 고리와 함께 고리 내 N, O, 및 S 원자 중 하나 이상을 포함하는 이중 고리의 헤테로아릴을 형성할 수 있고 {여기서, 상기 이중 고리의 헤테로아릴의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -CN, 또는 -할로로 치환될 수 있음}; 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};
    Z1, Z2, 또는 Z3는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, -O-C1-6알킬, 또는 -할로이고;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;
    W1 및 W2는 각각 독립적으로 -CRARB-, -NRC-, 또는 -O-이고;W 1 and W 2 are each independently —CR A R B —, —NR C —, or —O—;
    RA 내지 RC는 각각 독립적으로 -H, -C1-6알킬, 또는 -C3-6사이클로알킬, 헤테로사이클로알킬이고 {여기서, 상기 -C3-6사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬 또는 -C3-6사이클로알킬로 치환될 수 있음};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};
    R1 및 R2는 각각 독립적으로 -H 또는 -C1-6알킬이고;R 1 and R 2 are each independently —H or —C 1-6 alkyl;
    Ra 및 Rb는 각각 독립적으로 -H 또는 -C1-6알킬인;R a and R b are each independently —H or —C 1-6 alkyl;
    화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  3. 제 1 항에 있어서,The method of claim 1,
    고리 A는
    Figure PCTKR2021019439-appb-img-000250
    ,
    Figure PCTKR2021019439-appb-img-000251
    ,
    Figure PCTKR2021019439-appb-img-000252
    ,
    Figure PCTKR2021019439-appb-img-000253
    , 또는
    Figure PCTKR2021019439-appb-img-000254
    인 {여기서,
    Figure PCTKR2021019439-appb-img-000255
    ,
    Figure PCTKR2021019439-appb-img-000256
    ,
    Figure PCTKR2021019439-appb-img-000257
    ,
    Figure PCTKR2021019439-appb-img-000258
    , 또는
    Figure PCTKR2021019439-appb-img-000259
    의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -NRaRb, -OH, -O-C1-6알킬, -할로로 치환될 수 있음};    ring A is
    Figure PCTKR2021019439-appb-img-000250
    ,
    Figure PCTKR2021019439-appb-img-000251
    ,
    Figure PCTKR2021019439-appb-img-000252
    ,
    Figure PCTKR2021019439-appb-img-000253
    , or
    Figure PCTKR2021019439-appb-img-000254
    in {here,
    Figure PCTKR2021019439-appb-img-000255
    ,
    Figure PCTKR2021019439-appb-img-000256
    ,
    Figure PCTKR2021019439-appb-img-000257
    ,
    Figure PCTKR2021019439-appb-img-000258
    , or
    Figure PCTKR2021019439-appb-img-000259
    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};
    화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  4. 제 1 항에 있어서,The method of claim 1,
    X는
    Figure PCTKR2021019439-appb-img-000260
    ,
    Figure PCTKR2021019439-appb-img-000261
    ,
    Figure PCTKR2021019439-appb-img-000262
    , 또는
    Figure PCTKR2021019439-appb-img-000263
    이고;    X is
    Figure PCTKR2021019439-appb-img-000260
    ,
    Figure PCTKR2021019439-appb-img-000261
    ,
    Figure PCTKR2021019439-appb-img-000262
    , or
    Figure PCTKR2021019439-appb-img-000263
    ego;
    X1, X2, X4, X6, 및 X8은 각각 독립적으로 -C1-6알킬이고;X 1 , X 2 , X 4 , X 6 , and X 8 are each independently —C 1-6 alkyl;
    X5는 -H이고;X 5 is -H;
    X7은 각각 독립적으로 -H 또는 -C1-6알킬인;each X 7 is independently —H or —C 1-6 alkyl;
    화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  5. 제 1 항에 있어서, The method of claim 1,
    Y1은 -H, -C1-6알킬, -C1-6할로알킬, 또는 -할로이고, Y2는 -H이고, 또는 Y1 및 Y2는 서로 연결되어 피리미딘 고리와 함께 고리 내 N, O, 및 S 원자 중 하나 이상을 포함하는 이중 고리의 헤테로아릴을 형성할 수 있는 것인 {여기서, 상기 이중 고리의 헤테로아릴의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -CN, 또는 -할로로 치환될 수 있음};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};
    화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  6. 제 1 항에 있어서, The method of claim 1,
    Z1은 -H 또는 -O-C1-6알킬이고;Z 1 is —H or —OC 1-6 alkyl;
    Z2는 -H, -C1-6알킬, 또는 -할로이고;Z 2 is —H, —C 1-6 alkyl, or —halo;
    Z3는 -H인;Z 3 is -H;
    화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  7. 제 1 항에 있어서, The method of claim 1,
    W1 및 W2는 각각 독립적으로 -CRARB-, -NRC-, 또는 -O-이고;W 1 and W 2 are each independently —CR A R B —, —NR C —, or —O—;
    RA 내지 RC는 각각 독립적으로 -H, -C1-6알킬, 또는 -C3-6사이클로알킬, 헤테로사이클로알킬이고 {여기서, 상기 -C3-6사이클로알킬 또는 헤테로사이클로알킬의 하나 이상의 H는 -C1-6알킬 또는 -C3-6사이클로알킬로 치환될 수 있음};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};
    화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  8. 제 1 항에 있어서, The method of claim 1,
    R1은 -H이고;R 1 is —H;
    R2는 -H인;R 2 is -H;
    화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  9. 제 1 항에 있어서,The method of claim 1,
    상기 화학식 1로 표시되는 화합물이 하기 화합물로 이루어진 군으로부터 선택된 것인, 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염: The compound represented by Formula 1 is selected from the group consisting of the following compounds, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
    (1) (R)-(6-((5-브로모-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (1) (R)-(6-((5-bromo-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydro benzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (2) (6-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (2) (6-((5-bromo-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-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) di methylphosphine oxide;
    (3) (6-((5-브로모-2-(((6aR,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (3) (6-((5-bromo-2-(((6aR,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8; 9,10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) di methylphosphine oxide;
    (4) (6-((5-브로모-2-(((6aS,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (4) (6-((5-bromo-2-(((6aS,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8; 9,10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) di methylphosphine oxide;
    (5) (6-((5-브로모-2-(((6aS,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (5) (6-((5-bromo-2-(((6aS,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8; 9,10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) di methylphosphine oxide;
    (6) (R)-(6-((5-브로모-2-((3-(1-에틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (6) (R)-(6-((5-bromo-2-((3-(1-ethylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydro benzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (7) (R)-(6-((5-브로모-2-((10-플루오로-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (7) (R)-(6-((5-bromo-2-((10-fluoro-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a) , 5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide;
    (8) (R)-(6-((5-브로모-2-((3-(1-사이클로프로필피페리딘-4-일)-10-플루오로-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (8) (R)-(6-((5-bromo-2-((3-(1-cyclopropylpiperidin-4-yl)-10-fluoro-1,2,3,4; 4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)di methylphosphine oxide;
    (9) (R)-(6-((5-브로모-2-((10-클로로-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (9) (R)-(6-((5-bromo-2-((10-chloro-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a; 5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine fin oxide;
    (10) (R)-(6-((5-브로모-2-((10-클로로-3-(1-에틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (10) (R)-(6-((5-bromo-2-((10-chloro-3-(1-ethylpiperidin-4-yl)-1,2,3,4,4a; 5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine fin oxide;
    (11) (S)-(6-((5-브로모-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (11) (S)-(6-((5-bromo-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydro benzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (12) (R)-(6-((5-브로모-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (12) (R)-(6-((5-bromo-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-) d][1,4])oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (13) (R)-(6-((5-브로모-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (13) (R)-(6-((5-bromo-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino) [1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (14) (S)-(6-((5-브로모-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (14) (S)-(6-((5-bromo-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-] d][1,4])oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (15) (S)-(6-((5-브로모-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (15) (S)-(6-((5-bromo-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino) [1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (16) (6-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)(이미노)(메틸)-λ6-설파논; (16) (6-((5-bromo-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-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) ( imino)(methyl)-λ 6 -sulfanone;
    (17) (6-((5-브로모-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)(이미노)(메틸)-λ6-설파논; (17) (6-((5-bromo-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) (imino) (methyl )-λ 6 -sulfanone;
    (18) N-(6-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드; (18) N-(6-((5-bromo-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-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl ) methanesulfonamide;
    (19) N-(6-((5-브로모-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드; (19) N-(6-((5-bromo-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10) -hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;
    (20) (7-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)다이메틸포스핀옥사이드; (20) (7-((5-bromo-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-yl) amino) pyrimidin-4-yl) amino) imidazo [1,2-a ]pyridin-8-yl)dimethylphosphine oxide;
    (21) (7-((5-브로모-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)다이메틸포스핀옥사이드; (21) (7-((5-bromo-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) imidazo [1,2-a] pyridine-8- 1) dimethyl phosphine oxide;
    (22) (6-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (22) (6-((2-(((6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)quinoc salin-5-yl)dimethylphosphine oxide;
    (23) 다이메틸(6-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드; (23) Dimethyl (6-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)quinoxaline-5 -yl) phosphine oxide;
    (24) (7-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)다이메틸포스핀옥사이드; (24) (7-((2-(((6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)imi polyzo[1,2-a]pyridin-8-yl)dimethylphosphine oxide;
    (25) 다이메틸(7-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)포스핀옥사이드; (25) Dimethyl (7-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)imidazo[1 ,2-a]pyridin-8-yl)phosphine oxide;
    (26) (6-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (26) (6-((2-(((6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) quinoxaline- 5-yl) dimethyl phosphine oxide;
    (27) 다이메틸(6-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드; (27) Dimethyl (6-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)quinoxalin-5-yl ) phosphine oxide;
    (28) (7-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)다이메틸포스핀옥사이드; (28) (7-((2-(((6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) imidazo [ 1,2-a]pyridin-8-yl)dimethylphosphine oxide;
    (29) 다이메틸(7-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)이미다조[1,2-a]피리딘-8-일)포스핀옥사이드; (29) Dimethyl (7-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) imidazo [1,2 -a] pyridin-8-yl) phosphine oxide;
    (30) (6-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; (30) (6-((5-chloro-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-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide;
    (31) (7-((5-브로모-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)-4-메틸-3,4-다이하이드로-2H-벤조[b][1,4]옥사진-8-일)다이메틸포스핀옥사이드; (31) (7-((5-bromo-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-yl) amino) pyrimidin-4-yl) amino) -4-methyl-3,4 -dihydro-2H-benzo[b][1,4]oxazin-8-yl)dimethylphosphine oxide;
    (32) (R)-(7-((5-브로모-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)-4-메틸-3,4-다이하이드로-2H-벤조[b][1,4]옥사진-8-일)다이메틸포스핀옥사이드; (32) (R)-(7-((5-bromo-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydro Benzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) -4-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)dimethylphosphine oxide;
    (33) (R)-(3-((5-브로모-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사히드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴놀린-4-일)다이메틸포스핀옥사이드; (33) (R)-(3-((5-bromo-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a) ,5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinolin-4-yl) dimethyl phosphine fin oxide;
    (34) (R)-(6-((5-브로모-2-((10-메틸-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사히드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(34) (R)-(6-((5-bromo-2-((10-methyl-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a; 5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphos fin oxide;
    (35) (R)-(6-((5-브로모-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노) [1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(35) (R)-(6-((5-bromo-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a) ,5-hexahydrobenzo [b] pyrazino) [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) di methylphosphine oxide;
    (36) (S)-(6-((5-브로모-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노)[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(36) (S)-(6-((5-bromo-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a) ,5-hexahydrobenzo [b] pyrazino) [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) di methylphosphine oxide;
    (37) (6-((5-브로모-2-(((6aR,8S)-8-(4-에틸피페라진-1-일)-2-메톡시-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(37) (6-((5-bromo-2-(((6aR,8S)-8-(4-ethylpiperazin-1-yl)-2-methoxy-6,6a,7,8, 9,10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) di methylphosphine oxide;
    (38) (6-((5-브로모-2-(((6aR,8R)-8-(4-에틸피페라진-1-일)-2-메톡시-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(38) (6-((5-bromo-2-(((6aR,8R)-8-(4-ethylpiperazin-1-yl)-2-methoxy-6,6a,7,8, 9,10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) di methylphosphine oxide;
    (39) (6-((5-브로모-2-(((6aR,8S)-8-(4-사이클로프로필피페라진-1-일)-2-메톡시-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(39) (6-((5-bromo-2-(((6aR,8S)-8-(4-cyclopropylpiperazin-1-yl)-2-methoxy-6,6a,7,8) , 9,10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide;
    (40) (6-((5-브로모-2-(((6aR,8S)-8-(4-아이소프로필피페라진-1-일)-2-메톡시-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(40) (6-((5-bromo-2-(((6aR,8S)-8-(4-isopropylpiperazin-1-yl)-2-methoxy-6,6a,7,8) , 9,10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide;
    (41) (R)-(6-((5-브로모-2-((3-(1-아이소프로필피페리딘-4-일))-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(41) (R)-(6-((5-bromo-2-((3-(1-isopropylpiperidin-4-yl))-1,2,3,4,4a,5- Hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide ;
    (42) (R)-(6-((5-브로모-2-((3-(1-사이클로프로필피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(42) (R)-(6-((5-bromo-2-((3-(1-cyclopropylpiperidin-4-yl)-1,2,3,4,4a,5-hexa hydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (43) (6-((5-브로모-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(43) (6-((5-bromo-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa hydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (44) (R)-(6-((5-브로모-2-((10-클로로-3-(1-아이소프로필피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(44) (R)-(6-((5-bromo-2-((10-chloro-3-(1-isopropylpiperidin-4-yl)-1,2,3,4,4a) , 5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide;
    (45) (R)-(6-((5-브로모-2-((10-클로로-3-(1-사이클로프로필피페리딘-4-일))-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(45) (R)-(6-((5-bromo-2-((10-chloro-3-(1-cyclopropylpiperidin-4-yl))-1,2,3,4, 4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)di methylphosphine oxide;
    (46) (R)-(6-((5-브로모-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(46) (R)-(6-((5-bromo-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyra) zino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (47) (S)-(6-((5-브로모-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(47) (S)-(6-((5-bromo-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyra) zino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (48) (R)-(6-((5-브로모-2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(48) (R)-(6-((5-bromo-2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyra) zino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (49) (S)-(6-((5-브로모-2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(49) (S)-(6-((5-bromo-2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyra) zino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (50) (R)-(6-((5-브로모-2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(50) (R)-(6-((5-bromo-2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino) [1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (51) (S)-(6-((5-브로모-2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(51) (S)-(6-((5-bromo-2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino) [1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (52) (R)-(6-((5-브로모-2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(52) (R)-(6-((5-bromo-2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino) [4,3-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (53) (S)-(6-((5-브로모-2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(53) (S)-(6-((5-bromo-2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino) [4,3-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (54) (R)-(6-((5-브로모-2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(54) (R)-(6-((5-bromo-2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-) d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (55) (S)-(6-((5-브로모-2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(55) (S)-(6-((5-bromo-2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-] d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (56) (R)-(6-((5-브로모-2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(56) (R)-(6-((5-bromo-2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2) -d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (57) (S)-(6-((5-브로모-2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]))옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(57) (S)-(6-((5-bromo-2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2) -d][1,4]))oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (58) (R)-(6-((5-브로모-2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(58) (R)-(6-((5-bromo-2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-] d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (59) (S)-(6-((5-브로모-2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(59) (S)-(6-((5-bromo-2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-] d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (60) (R)-(6-((5-브로모-2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(60) (R)-(6-((5-bromo-2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2) -d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (61) (S)-(6-((5-브로모-2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;(61) (S)-(6-((5-bromo-2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2) -d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
    (62) (R)-다이메틸(6-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드;(62) (R)-dimethyl (6-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [ 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)quinoxalin-5-yl)phosphine oxide;
    (63) (R)-다이메틸(6-((2-((3-(1-메틸피페리딘-4-일))-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드;(63) (R)-dimethyl(6-((2-((3-(1-methylpiperidin-4-yl))-1,2,3,4,4a,5-hexahydrobenzo[ b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)quinoxaline-5 -yl) phosphine oxide;
    (64) (R)-다이메틸(6-((2-((3-(1-메틸피페리딘-4-일))-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)티에노[3,2-d]피리미딘-4-일)아미노)퀴녹살린-5-일)포스핀옥사이드;(64) (R)-dimethyl(6-((2-((3-(1-methylpiperidin-4-yl))-1,2,3,4,4a,5-hexahydrobenzo[ b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) quinoxalin-5-yl) phosphine oxide;
    (65) (R)-(2-((2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (65) (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)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (66) (R)-(2-((2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드;(66) (R)-(2-((2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-] d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (67) (2-((2-(((6aR,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (67) (2-((2-(((6aR,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[ 1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (68) (2-((2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (68) (2-((2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[ 1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (69) (2-((2-(((6aS,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (69) (2-((2-(((6aS,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[ 1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (70) (2-((2-(((6aS,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (70) (2-((2-(((6aS,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[ 1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (71) (2-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (71) (2-((2-(((6aR,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl ) dimethyl phosphine oxide;
    (72) (2-((2-(((6aS,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (72) (2-((2-(((6aS,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl ) dimethyl phosphine oxide;
    (73) (2-((2-(((6aR,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (73) (2-((2-(((6aR,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl ) dimethyl phosphine oxide;
    (74) (2-((2-(((6aS,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (74) (2-((2-(((6aS,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl ) dimethyl phosphine oxide;
    (75) (R)-(2-((2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (75) (R)-(2-((2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1] ,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (76) (R)-(2-((2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (76) (R)-(2-((2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2) -d][1,4])oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (77) (S)-다이메틸(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (77) (S)-dimethyl (2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [ 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphineoxide;
    (78) (R)-(2-((5-클로로-2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (78) (R)-(2-((5-chloro-2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [ 1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (79) (R)-(2-((5-클로로-2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (79) (R)-(2-((5-chloro-2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-] d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (80) (R)-(2-((5-클로로-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (80) (R)-(2-((5-chloro-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino) [1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (81) (S)-다이메틸(2-((2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (81) (S)-dimethyl (2-((2-((3- (1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide ;
    (82) (S)-4-((2-(다이메틸포스포릴)페닐)아미노)-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴; (82) (S)-4-((2-(dimethylphosphoryl)phenyl)amino)-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b] pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile;
    (83) (S)-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4])옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (83) (S)-(2-((5-chloro-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d) ][1,4])oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (84) (R)-4-((2-(다이메틸포스포릴)페닐)아미노)-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴; (84) (R)-4-((2-(dimethylphosphoryl)phenyl)amino)-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexa hydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile;
    (85) (R)-(2-((5-클로로-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (85) (R)-(2-((5-chloro-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[ 1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (86) (2-((5-클로로-2-(((6aS,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (86) (2-((5-chloro-2-(((6aS,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b] ]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphos fin oxide;
    (87) (2-((5-클로로-2-(((6aS,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (87) (2-((5-chloro-2-(((6aS,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b] ]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphos fin oxide;
    (88) (2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (88) (2-((5-chloro-2-(((6aR,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b] ]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphos fin oxide;
    (89) (2-((5-클로로-2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (89) (2-((5-chloro-2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b] ]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphos fin oxide;
    (90) (2-((5-클로로-2-(((6aR,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (90) (2-((5-chloro-2-(((6aR,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9) , 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl ) amino) phenyl) dimethyl phosphine oxide;
    (91) (2-((5-클로로-2-(((6aS,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (91) (2-((5-chloro-2-(((6aS,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9) , 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl ) amino) phenyl) dimethyl phosphine oxide;
    (92) (2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (92) (2-((5-chloro-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-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl ) amino) phenyl) dimethyl phosphine oxide;
    (93) (2-((5-클로로-2-(((6aS,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (93) (2-((5-chloro-2-(((6aS,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9) , 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl ) amino) phenyl) dimethyl phosphine oxide;
    (94) (R)-(2-((2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (94) (R)-(2-((2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1] ,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (95) (R)-(2-((5-클로로-2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (95) (R)-(2-((5-chloro-2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-) d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (96) (R)-(2-((2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (96) (R)-(2-((2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2) -d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (97) (R)-(2-((5-클로로-2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (97) (R)-(2-((5-chloro-2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino) [1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (98) (R)-(2-((2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (98) (R)-(2-((2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1, 4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (99) (R)-(2-((5-클로로-2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (99) (R)-(2-((5-chloro-2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d) ][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;
    (100) 다이메틸(2-((2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (100) Dimethyl (2-((2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydrobenzo[ b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide;
    (101) (R)-(2-((2-((10-플루오로-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (101) (R)-(2-((2-((10-fluoro-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydro benzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl) dimethyl phosphine oxide;
    (102) (R)-(2-((2-((3-(1-사이클로프로필피페리딘-4-일)-10-플루오로-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (102) (R)-(2-((2-((3-(1-cyclopropylpiperidin-4-yl)-10-fluoro-1,2,3,4,4a,5-hexa Hydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl ) dimethyl phosphine oxide;
    (103) (R)-(2-((2-((10-클로로-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (103) (R)-(2-((2-((10-chloro-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo [b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)di methylphosphine oxide;
    (104) (R)-(2-((2-((3-(1-에틸피페리딘-4-일)-10-플루오로-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (104) (R)-(2-((2-((3-(1-ethylpiperidin-4-yl)-10-fluoro-1,2,3,4,4a,5-hexahydro benzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl) dimethyl phosphine oxide;
    (105) (S)-다이메틸(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-5-(트라이플루오로메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (105) (S)-dimethyl (2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [ 1,4]oxazin-8-yl)amino)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphineoxide;
    (106) (R)-(2-((2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-5-(트라이플루오로메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (106) (R)-(2-((2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-] d][1,4]oxazin-8-yl)amino)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide;
    (107) 4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴; (107) 4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9 , 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidine-5-car bonitrile;
    (108) 4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aS,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴; (108) 4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aS,8S)-2-methoxy-8-morpholino-6,6a,7,8,9 , 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidine-5-car bonitrile;
    (109) 4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aS,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴; (109) 4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aS,8R)-2-methoxy-8-morpholino-6,6a,7,8,9 , 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidine-5-carbohydrate bonitrile;
    (110) 4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aR,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴; (110) 4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aR,8S)-2-methoxy-8-morpholino-6,6a,7,8,9 , 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3-d] pyrimidine-5-carbohydrate bonitrile;
    (111) 4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴; (111) 4-((2-(dimethylphosphoryl)phenyl)amino)-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-yl) amino) -7H-pyrrolo [2,3- d]pyrimidine-5-carbonitrile;
    (112) 4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aR,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴; (112) 4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aR,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6 , 6a, 7, 8, 9, 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3- d]pyrimidine-5-carbonitrile;
    (113) 4-((2-(다이메틸포스포릴)페닐)아미노)-2-(((6aS,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-5-카르보나이트릴; (113) 4-((2-(dimethylphosphoryl)phenyl)amino)-2-(((6aS,8S)-2-methoxy-8-(4-methylpiperazin-1-yl)-6 , 6a, 7, 8, 9, 10-hexahydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) -7H-pyrrolo [2,3- d]pyrimidine-5-carbonitrile;
    (114) (R)-(2-((5-클로로-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (114) (R)-(2-((5-chloro-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo [b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)di methylphosphine oxide;
    (115) (R)-(2-((5-클로로-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (115) (R)-(2-((5-chloro-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a; 5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino)phenyl)dimethylphosphine oxide;
    (116) (R)-다이메틸(2-((2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d])[1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (116) (R)-dimethyl (2-((2-((3- (1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d])[1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide;
    (117) (R)-(2-((2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (117) (R)-(2-((2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydro benzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl) dimethyl phosphine oxide;
    (118) (S)-(2-((2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (118) (S)-(2-((2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydro benzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl) dimethyl phosphine oxide;
    (119) (R)-(2-((2-((3-(1-아이소프로필피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (119) (R)-(2-((2-((3-(1-isopropylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;
    (120) (R)-(2-((2-((10-플루오로-3-(1-아이소프로필피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (120) (R)-(2-((2-((10-fluoro-3-(1-isopropylpiperidin-4-yl)-1,2,3,4,4a,5-hexa Hydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl ) dimethyl phosphine oxide;
    (121) (R)-(2-((2-((3-(1-에틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (121) (R)-(2-((2-((3-(1-ethylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyra) Zino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide ;
    (122) (R)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (122) (R)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][) 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphineoxide;
    (123) (S)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (123) (S)-dimethyl (2-((2-((1,2,4a,5-tetrahydro-4H-benzo [b] [1,4] oxazino [4,3-d] [ 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphineoxide;
    (124) (R)-(2-((2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (124) (R)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-] d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (125) (S)-(2-((2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (125) (S)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3- d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (126) (R)-(2-((2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-5-(트라이플루오로메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (126) (R)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3- d][1,4]oxazin-8-yl)amino)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethyl phosphine oxide;
    (127) (R)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (127) (R)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][) 1,4]oxazin-8-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide;
    (128) (S)-(2-((2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (128) (S)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-] d][1,4]oxazin-8-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;
    (129) (2-((2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (129) (2-((2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo[b]pyrido[ 1,2-d][1,4]oxazin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;
    (130) (2-((2-(((6aS,8R)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (130) (2-((2-(((6aS,8R)-2-methoxy-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexa Hydrobenzo [b] pyrido [1,2-d] [1,4] oxazin-3-yl) amino) thieno [3,2-d] pyrimidin-4-yl) amino) phenyl) di methylphosphine oxide;
    (131) (R)-다이메틸(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (131) (R)-dimethyl (2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [ 1,4]oxazin-8-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide;
    (132) (S)-다이메틸(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (132) (S)-dimethyl (2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [ 1,4]oxazin-8-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide;
    (133) (S)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)싸이에노[3,2-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (133) (S)-dimethyl (2-((2-((1,2,4a,5-tetrahydro-4H-benzo [b] [1,4] oxazino [4,3-d] [ 1,4]oxazin-8-yl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide;
    (134) (R)-(2-((2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조 [b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)싸이에노[2,3-d]피리미딘-4-일)아미노)페닐)다이메틸포스핀옥사이드; (134) (R)-(2-((2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo [b] [1,4] oxazino [4,3- d][1,4]oxazin-8-yl)amino)thieno[2,3-d]pyrimidin-4-yl)amino)phenyl)dimethylphosphineoxide;
    (135) (R)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)싸이에노[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (135) (R)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][) 1,4]oxazin-8-yl)amino)thieno[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide;
    (136) (R)-다이메틸(2-((2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)-5-(트라이플루오로메틸)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)포스핀옥사이드; (136) (R)-dimethyl(2-((2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][) 1,4]oxazin-8-yl)amino)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphineoxide;
    (137) N-(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (137) N-(2-((5-chloro-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-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (138) (R)-N-(2-((5-클로로-2-((9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (138) (R)-N-(2-((5-chloro-2-((9-methoxy-1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxa) zino[4,3-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (139) N-(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)-N-메틸프로판-2-설폰아마이드; (139) N-(2-((5-chloro-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-yl) amino) pyrimidin-4-yl) amino) phenyl) -N-methylpropane -2-sulfonamide;
    (140) (R)-N-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (140) (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)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (141) (R)-N-(2-((5-클로로-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (141) (R)-N-(2-((5-chloro-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyra) zino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (142) (R)-N-(2-((5-클로로-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (142) (R)-N-(2-((5-chloro-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4, 4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (143) (R)-N-(2-((5-클로로-2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)-N-메틸프로판-2-설폰아마이드; (143) (R)-N-(2-((5-chloro-2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4, 4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylpropane- 2-sulfonamide;
    (144) (S)-N-(2-((5-클로로-2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (144) (S)-N-(2-((5-chloro-2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3) -d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (145) (R)-N-(2-((5-클로로-2-((1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (145) (R)-N-(2-((5-chloro-2-((1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3) -d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (146) (R)-N-(2-((5-클로로-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (146) (R)-N-(2-((5-chloro-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexa hydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (147) (R)-N-(2-((5-클로로-2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)-N-메틸프로판-2-설폰아마이드; (147) (R)-N-(2-((5-chloro-2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexa hydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylpropane-2-sulfonamide;
    (148) (S)-N-(2-((5-클로로-2-((3-에틸-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (148) (S)-N-(2-((5-chloro-2-((3-ethyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyra) zino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (149) (S)-N-(2-((5-클로로-2-((3-에틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (149) (S)-N-(2-((5-chloro-2-((3-ethyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2) -d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (150) (S)-N-(2-((5-클로로-2-((9-메톡시-3-(테트라하이드로-2H-피란-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (150) (S)-N-(2-((5-chloro-2-((9-methoxy-3-(tetrahydro-2H-pyran-4-yl)-1,2,3,4, 4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (151) (S)-N-(2-((5-클로로-2-((3-아이소프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (151) (S)-N-(2-((5-chloro-2-((3-isopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b] pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (152) (S)-N-(2-((5-클로로-2-((3-아이소프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (152) (S)-N-(2-((5-chloro-2-((3-isopropyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1, 2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (153) (S)-N-(2-((5-클로로-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (153) (S)-N-(2-((5-chloro-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b] pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (154) (S)-N-(2-((5-클로로-2-((3-사이클로프로필-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (154) (S) -N- (2-((5-chloro-2-((3-cyclopropyl-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1, 2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (155) N-(2-((5-클로로-2-(((6aS,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (155) N-(2-((5-chloro-2-(((6aS,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo [b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (156) N-(2-((5-클로로-2-(((6aR,8R)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (156) N-(2-((5-chloro-2-(((6aR,8R)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo [b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (157) N-(2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (157) N-(2-((5-chloro-2-(((6aR,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo [b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (158) N-(2-((5-클로로-2-(((6aS,8S)-2-메톡시-8-모르폴리노-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (158) N-(2-((5-chloro-2-(((6aS,8S)-2-methoxy-8-morpholino-6,6a,7,8,9,10-hexahydrobenzo [b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (159) (S)-5-클로로-N4-(2-(메틸설포닐)페닐)-N2-(1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)피리미딘-2,4-다이아민; (159) (S)-5-chloro-N4-(2-(methylsulfonyl)phenyl)-N2-(1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxa zino[4,3-d][1,4]oxazin-8-yl)pyrimidine-2,4-diamine;
    (160) (R)-5-클로로-N4-(2-(메틸설포닐)페닐)-N2-(1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)피리미딘-2,4-다이아민; (160) (R)-5-chloro-N4-(2-(methylsulfonyl)phenyl)-N2-(1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxa zino[4,3-d][1,4]oxazin-8-yl)pyrimidine-2,4-diamine;
    (161) (R)-5-클로로-N2-(9-메톡시-1,2,4a,5-테트라하이드로-4H-벤조[b][1,4]옥사지노[4,3-d][1,4]옥사진-8-일)-N4-(2-(메틸설포닐)페닐)피리미딘-2,4-다이아민; (161) (R)-5-chloro-N2- (9-methoxy-1,2,4a,5-tetrahydro-4H-benzo [b] [1,4] oxazino [4,3-d] [1,4]oxazin-8-yl)-N4-(2-(methylsulfonyl)phenyl)pyrimidine-2,4-diamine;
    (162) (R)-N-(2-((5-클로로-2-((3-사이클로프로필-9-메톡시-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; (162) (R)-N-(2-((5-chloro-2-((3-cyclopropyl-9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b] pyrazino[1,2-d][1,4]oxazin-8-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (163) (2-((5-클로로-2-(((R)-9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)(이미노)(메틸)-λ6-설파논; (163) (2-((5-chloro-2-(((R)-9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a; 5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) phenyl) (imino) (methyl) - λ 6 -sulfanone;
    (164) (2-((5-클로로-2-(((R)-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)피리미딘-4-일)아미노)페닐)(이미노)(메틸)-λ6-설파논; (164) (2-((5-chloro-2-(((R)-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) pyrimidin-4-yl) amino) phenyl) (imino) (methyl) -λ 6 -sulfanone ;
    (165) (2-((5-클로로-2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)(이미노)(메틸)-λ6-설파논; (165) (2-((5-chloro-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-yl) amino) pyrimidin-4-yl) amino) phenyl) (imino) (methyl) -λ 6 -sulfanone;
    (166) (2-((5-클로로-2-(((6aR,8S)-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)피리미딘-4-일)아미노)페닐)(이미노)(메틸)-λ6-설파논; (166) (2-((5-chloro-2-(((6aR,8S)-8-(4-methylpiperazin-1-yl)-6,6a,7,8,9,10-hexahydro Benzo[b]pyrido[1,2-d][1,4]oxazin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)(imino)(methyl)-λ 6 -sulfa rice paddy;
    (167) (R)-N-(2-((5-클로로-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드;(167) (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)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (168) N-(2-((2-(((6aR,8S)-2-메톡시-8-(4-메틸피페라진-1-일)-6,6a,7,8,9,10-헥사하이드로벤조[b]피리도[1,2-d][1,4]옥사진-3-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드;(168) N-(2-((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-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino )phenyl)methanesulfonamide;
    (169) (R)-N-(2-((2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드;(169) (R)-N-(2-((2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][) 1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (170) (R)-N-(2-((2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드;(170) (R)-N-(2-((2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1, 2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (171) (R)-N-(2-((2-((9-메톡시-3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드;(171) (R)-N-(2-((2-((9-methoxy-3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5- Hexahydrobenzo [b] pyrazino [1,2-d] [1,4] oxazin-8-yl) amino) -7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) phenyl)methanesulfonamide;
    (172) (R)-N-(2-((5-시아노-2-((3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드;(172) (R)-N-(2-((5-cyano-2-((3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1, 2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
    (173) (R)-N-(2-((2-((3-(1-메틸피페리딘-4-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드; 및(173) (R)-N-(2-((2-((3-(1-methylpiperidin-4-yl)-1,2,3,4,4a,5-hexahydrobenzo[b] ]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide ; and
    (174) (R)-N-(2-((5-클로로-2-((9-메톡시-3-메틸-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-일)아미노)-7H-피롤로[2,3-d]피리미딘-4-일)아미노)페닐)메탄설폰아마이드.(174) (R)-N-(2-((5-chloro-2-((9-methoxy-3-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyra) Zino[1,2-d][1,4]oxazin-8-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide.
  10. 제 1 항 내지 제 9 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 암의 치료 또는 예방용 약학적 조성물.A pharmaceutical composition for the treatment or prevention of cancer, comprising the compound according to any one of claims 1 to 9, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  11. 제 10 항에 있어서,11. The method of claim 10,
    EGFR을 억제하는 것인, 약학적 조성물.Inhibiting EGFR, the pharmaceutical composition.
  12. 제 11 항에 있어서,12. The method of claim 11,
    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, 및 EGFR Exon20 ins ASV로 이루어진 군으로부터 선택된 어느 하나 이상을 억제하는 것인, 약학적 조성물.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 SV Inhibiting any one or more, the pharmaceutical composition.
  13. 제 10 항에 있어서,11. The method of claim 10,
    상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인, 약학적 조성물.The cancer is 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 carcinoma, Ovarian 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 ; Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma malignant, mesothelioma malignant, melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilm Breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma , pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymus At least one selected from the group consisting of cancer, a pharmaceutical composition.
  14. 암의 치료 또는 예방에 사용하기 위한 약제의 제조에 사용하기 위한, 제 1 항 내지 제 10 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도.11. Use of a compound according to any one of claims 1 to 10, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of cancer.
  15. 제 1 항 내지 제 10 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는, 암을 치료 또는 예방하는 방법.11. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 10, an optical isomer thereof, or a pharmaceutically acceptable salt thereof How to treat or prevent.
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