WO2021096112A1 - Dérivé de composé pyrrolopyrimidine, pyrrolopyridine et d'indazole, et composition pharmaceutique thérapeutique le contenant - Google Patents

Dérivé de composé pyrrolopyrimidine, pyrrolopyridine et d'indazole, et composition pharmaceutique thérapeutique le contenant Download PDF

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WO2021096112A1
WO2021096112A1 PCT/KR2020/014806 KR2020014806W WO2021096112A1 WO 2021096112 A1 WO2021096112 A1 WO 2021096112A1 KR 2020014806 W KR2020014806 W KR 2020014806W WO 2021096112 A1 WO2021096112 A1 WO 2021096112A1
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compound
methylphenyl
group
pyrrolo
pyridin
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PCT/KR2020/014806
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Korean (ko)
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심태보
신인재
남윤주
데바브라타부니아
박찬중
허우영
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한국과학기술연구원
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Publication of WO2021096112A1 publication Critical patent/WO2021096112A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention is a novel pyrrolopyrimidine, pyrrolopyridine, indazole derivatives having protein kinase inhibitory activity and a pharmaceutically acceptable salt thereof, a hydrate thereof, a compound selected from a solvate thereof or a stereoisomer thereof, and the compound It relates to a pharmaceutical composition for preventing, alleviating or treating cancer, including.
  • Chronic myelogenous leukemia is a type of blood cancer caused by abnormal expansion of a clone of a hematopoietic stem cell with a Philadelphia chromosome.
  • the Philadelphia chromosome is caused by the formation and continuous activity of the Bcr-Abl fusion protein, which is the causative protein of CML.
  • More than 90% of patients with chronic myelogenous leukemia (CML) and about 40% of patients with acute lymphoblastic leukemia (ALL) express this abnormal Bcr-Abl protein, and the sustained activity of Bcr-Abl further promotes leukemia. .
  • Bcr-Abl tyrosine kinase has been considered a promising drug target for CML.
  • Imatinib as a treatment drug for chronic myelogenous leukemia is commercialized and marketed as Gleevec, but various point mutant species resistant to Gleevec have been recently reported.
  • T315I known as a gatekeeper mutant
  • Many studies have been conducted to overcome these gatekeeper mutant species, but until now, only ponatinib has been reported as the only drug approved for limited clinical use.
  • Ponatinib has been reported to strongly inhibit wild type Bcr-Abl and T315I-Bcr-Abl in vitro and in vivo, and phase 1 clinical trials in patients with chronic myelogenous leukemia with T315I ( NCT00660920) and clinical phase 2 (NCT01207440) showed excellent efficacy.
  • ponatinib is active on various kinases such as VEGFR2, PDGFR, KIT, FLT3, and FGFR at the same time, thereby causing side effects such as myelosuppression and pancreatitis due to low selectivity of the kinase. (Cortes JE et al. , N. Engl. J. Med.
  • Patent Document 1 Korean Patent Registration No. 10-1116756
  • Non-Patent Document 1 Cortes JE et al., N. Engl. J. Med. 367:2075-2088, 2012
  • An object of the present invention is to provide a compound selected from a compound represented by [Formula 1] having inhibitory activity of protein kinase, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof.
  • Another object of the present invention is a cancer comprising a compound selected from a compound represented by [Chemical Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof as an active ingredient, specifically hematologic cancer, in particular It is to provide a pharmaceutical composition for preventing, alleviating or treating chronic myelogenous leukemia.
  • the present invention provides a compound selected from a compound represented by the following [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof:
  • X 1 , X 2 and X 3 are each independently hydrogen or nitrogen
  • L is -NR 5 -; -NR 5 CH 2 -; -NHR 5 -; -NR 5 C(O)-; -C(O)NR 5 -; -NR 5 C(O)NR 5 -; -S(O) 2 -; -NR 5 S(O) 2 -; And -S(O) 2 NR 5 -is selected from the group consisting of;
  • A is a C 6 -C 10 aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms;
  • R 3 is hydrogen; halogen; C 1 -C 13 alkyl group; Or a C 3 -C 10 cyclyl group;
  • R 4 is hydrogen; Hydroxy group; Halogen group; Amino group; Nitro group; Cyano group; C 1 -C 6 alkyl group; C 1 -C 6 alkenyl group; C 6 -C 10 aryl group; C 1 -C 6 alkoxy group; C 3 -C 10 heteroaryl group; Or a C 3 -C 10 heterocyclyl group;
  • R 5 is hydrogen; C 1 -C 6 alkyl group; And oxazole group; is selected from the group consisting of;
  • n 1 to 3
  • the C 1 -C 6 alkyl group, C 1 -C 13 alkyl group or C 3 -C 10 cyclyl group, hydrogen; Hydroxy group; Halogen group; C 1 -C 13 alkyl group; C 1 -C 6 alkoxy group; An amide group (-(C O)NR 6 R 7 ); C 6 -C 10 aryl group; C 3 -C 10 heteroaryl group; And one or more substituents selected from the group consisting of C 3 -C 10 heterocyclyl groups,
  • R 6 above And R 7 is hydrogen; C 1 -C 6 alkyl group; C 1 -C 6 alkenyl group; C 1 -C 6 alkynyl group; C 6 -C 10 aryl group; C 3 -C 10 heteroaryl group; And one or more selected from the group consisting of a C 3 -C 10 heterocyclyl group,
  • the C 3 -C 10 heteroaryl group and the C 3 -C 10 heterocyclyl group include at least one heteroatom selected from the group consisting of N, O, and S.
  • the present invention is a pharmaceutical for preventing, reducing or treating cancer comprising a compound selected from the compound represented by [Chemical Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof as an active ingredient
  • a pharmaceutically acceptable salt thereof a hydrate thereof, a solvate thereof, and a stereoisomer thereof as an active ingredient
  • the composition is provided.
  • the compounds according to the present invention have excellent ability to inhibit the activity of Bcr-Abl tyrosine kinase and drug-resistant mutant T315I-Bcr-Abl tyrosine kinase. Therefore, it can be used for the purpose of overcoming drug resistance and at the same time treating, preventing, and alleviating cancer caused by abnormal cell growth.
  • the compound according to the present invention does not have inhibitory activity against VEGFR2 protein kinase. Therefore, by selectively inhibiting the activity of Bcr-Abl tyrosine kinase and T315I mutant Bcr-Abl tyrosine kinase, the occurrence of drug side effects such as inducing cardiovascular disease in patients taking Bcr-Abl or T315I mutant Bcr-Abl tyrosine kinase inhibitory drugs. It has the effect of reducing.
  • the compound according to the present invention can be usefully used as a target therapeutic agent capable of treating hematologic cancer, particularly chronic myelogenous leukemia (CML), while significantly reducing drug resistance and side effects.
  • CML chronic myelogenous leukemia
  • variable includes all values within the stated range, including the stated endpoints of the range.
  • a range of “5 to 10” includes values of 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc.
  • Inclusive and it will be understood to include any values between integers that are reasonable in the scope of the stated range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like.
  • the range of "10% to 30%” is 10% to 15%, 12% to 10%, 11%, 12%, 13%, etc., as well as all integers including up to 30%. It will be understood to include any subranges, such as 18%, 20% to 30%, and the like, and include any values between reasonable integers within the scope of the stated range, such as 10.5%, 15.5%, 25.5%, and the like.
  • the present inventors continued research to develop a compound effective for the targeted treatment, prevention and alleviation of chronic myelogenous leukemia (CML), which can be fatal among tumor diseases.
  • CML chronic myelogenous leukemia
  • Bcr-Abl the causative gene of CML.
  • the present invention was completed by selecting a novel compound that has excellent ability to inhibit the activity of tyrosine kinase and the drug-resistant mutant T315I-Bcr-Abl tyrosine kinase and does not have inhibitory activity against VEGFR2 protein kinase.
  • One aspect of the present invention provides a compound selected from a compound represented by the following [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof:
  • X 1 , X 2 and X 3 are each independently hydrogen or nitrogen, and L is -NR 5 -; -NR 5 CH 2 -; -NHR 5 -; -NR 5 C(O)-; -C(O)NR 5 -; -NR 5 C(O)NR 5 -; -S(O) 2 -; -NR 5 S(O) 2 -; And -S(O) 2 NR 5 -; is selected from the group consisting of, A is a C 6 -C 10 aryl group; Or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms; R 1 is hydrogen; C 1 -C 13 alkyl group; C 6 -C 10 aryl group; C 3 -C 10 cyclyl group; C 3 -C 10 heteroaryl group; C 3 -C 10 heterocyclyl group; -C(O)-(C 1
  • L is -NHC(O)-; -C(O)NH-; And -NHC(O)NH-, wherein R 3 is CH 3 , and A may be any one of benzene, thiophene, furan, cyazole, oxazole, pyrazole, and pyridine.
  • the compound represented by [Chemical Formula 1] provides a compound selected from the group consisting of the following compound numbers 1 to 66:
  • substitution' refers to the introduction of a hydrogen atom instead of a hydrogen atom when a derivative is formed by replacing one or more hydrogen atoms in an organic compound with another atomic group
  • substitution' refers to the introduced atomic group
  • the substituent is, for example, a halogen atom, a halogen atom, a C 1 -C 20 alkyl group substituted with a halogen atom (eg, CCF 3 , CHCF 2 , CH 2 F, CCl 3, etc.), C 1 -C 20 alkoxy, C 2 -C 20 alkoxyalkyl, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or salt thereof, sulfonyl group, sulfamoyl group, sulfonic acid group or salt thereof, phosphoric acid or its Salt, or C 1 -C 20 alkyl group, C 2 -C 20 alkenyl group, C 2 -C 20 alkynyl group, C 1 -C 20 heteroalkyl group, C 6 -C 20 aryl group, C 6 -C 20 arylalkyl group, It may be a C 6
  • alkyl means an aliphatic hydrocarbon radical.
  • Alkyl may be “saturated alkyl” that does not include an alkenyl or alkynyl moiety, or may be “unsaturated alkyl” that includes at least one alkenyl or alkynyl moiety.
  • Alkenyl means a group containing at least one carbon-carbon double bond
  • alkynyl means a group containing at least one carbon-carbon triple bond.
  • Alkyl when used alone or in combination, may each be cyclic, branched or straight chain.
  • aryl alone or in combination with other radicals, is a carbocyclic containing 6 carbon atoms, which may be further fused with a second 5 or 6 membered carbocyclic group which may be aromatic, saturated or unsaturated. It means an aromatic monocyclic group.
  • aryl include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, teprahiadronaphthyl, and the like.
  • Aryl can be linked with other groups at appropriate positions on the aromatic ring.
  • alkoxy' refers to an alkyl group (ie, -O-alkyl) linked to another group through an oxygen atom.
  • the alkoxy group may be unsubstituted or substituted with one or more suitable substituents.
  • suitable substituents include (C 1 -C 6 ) alkoxy groups such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O -2-Methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl -1-propyl, -O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O -3-Met
  • phenoxy' refers to a phenyl group (ie, -O-aryl) linked to another group through an oxygen atom.
  • the phenoxy group is unsubstituted or one or more halogens; Alkyl group; It may be substituted with an aryl group and a hetero aryl group, but is not limited thereto.
  • amino group' refers to an alkyl group (ie -NH- or -N-alkyl) linked to another group through a nitrogen atom.
  • the amino group may be unsubstituted or substituted with one or more suitable substituents.
  • amino groups include (C1-C6) amino groups such as -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH-2-methyl -2-propyl, -NH-2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2-dimethyl-1-propyl , -NH-2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, -NH-2-methyl-2-pentyl, -NH-3-methyl -2-pentyl, -NH-4-methyl-2-pentyl, -NH-2,2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2-ethyl-1-butyl , -NH-butyl
  • halogen atom' refers to an atom of group 7 of the periodic table.
  • Halogen atoms include fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the like.
  • heterocycle group' refers to a heteroaromatic compound containing at least one hetero atom selected from the group consisting of N, O, and S.
  • the heterocyclyl group may include a pyrrolidine, a furan group, a morpholine group, a piperazine and a piperidine group, more preferably a pyrrolidine group, a piperidine group, a piperazine group, and a mole It may include a foreign group, but is not limited thereto.
  • heteroaryl group' refers to a heteroaromatic compound containing at least one hetero atom selected from the group consisting of N, O, and S.
  • the heteroaryl group is a pyridine group, a pyrazine group, a pyrimidine group, a pyridazine group, a pyrazole group, an imidazole group, a triazole group, an indole group, an oxadiazole group, a thiadiazole group, a quinoline, an isoquinoline group, It may include an isoxazole group, an oxazole group, a thiazole group, and a pyrrole group, but is not limited thereto.
  • the term'derivative' refers to a compound obtained by substituting a part of the structure of the compound with another atom or group of atoms.
  • stereoisomer' refers to a compound having the same molecular formula and connection method of members, but different spatial arrangements between atoms.
  • the stereoisomer may be a diasteromer or an enantiomer.
  • the enantiomer refers to an isomer that does not overlap with the mirror image, such as the relationship between the left hand and the right hand, and is also called an optical isomer. Enantiomers are classified into R (Rectus: clockwise) and S (sinister: counterclockwise) when four or more substituents are different on the chiral central carbon.
  • Diastereoisomers refer to stereoisomers that are not in an enantiomeric relationship, and can be divided into cis-trans isomers due to differences in the spatial arrangement of atoms.
  • the compound of [Formula 1] may be used in the form of a pharmaceutically acceptable salt derived from inorganic or organic acids, and preferred salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid , Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, It may be one or more selected from the group consisting of salicylic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.
  • the compound of [Formula 1] or a pharmaceutically acceptable salt thereof according to the present invention may include hydrates and solvates.
  • the hydrate may mean that the compound of [Formula 1] is formed by bonding with water molecules.
  • Another aspect of the present invention is the prevention and reduction of cancer comprising a compound selected from the compound represented by [Formula 1] according to the present invention as an active ingredient, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof Or it provides a pharmaceutical composition for treatment.
  • the pharmaceutical composition according to the present invention has excellent ability to inhibit the activity of protein kinase.
  • the protein kinases are ABL1, ABL2, ALK, ARAF, BRAF, BRK, MER, SRC, CSK, DDR1, DDR2, EPHA1-8, EPHB1-4, ERBB2, ERBB4, FGFR1, FGFR2, FGR, FMS, FRK, GCK, HCK, JAK1, JAK2, LCK, LIMK1, LIMK2, LOK, LYN, LYNB, MLCK2, MUSK, P38a, P38b, P70S6K, PDGFR, PEAK1, PKA, PYK2, RAF1, RET, RIPK3, RS1K4, RIPK3, RIPK4, RSK2, SLK, STK21, TAOK1, TAOK2, TAOK3, TESK1, TIE2, TNK1, TYK1, TYRO3, YES, and ZAK may be included.
  • the MER kinase whose activity is inhibited by the compound of the present invention is a tyrosine kinase belonging to the TAM (Tyro3, Axl and Mer) family along with TYRO3 and AXL, and is known to be associated with cancer progression, metastasis, and drug resistance.
  • TAM Tethyrosine kinase
  • TYRO3 and AXL tyrosine kinase belonging to the TAM (Tyro3, Axl and Mer) family along with TYRO3 and AXL
  • the pharmaceutical composition of the present invention can be used for the purpose of treating, preventing, and alleviating cancer caused by abnormal cell growth.
  • Cancers that can be prevented, treated or alleviated by the treatment of the pharmaceutical composition of the present invention include hematologic cancer, lymphoma, bladder cancer, breast cancer, melanoma, endometrial cancer, gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer.
  • the blood cancer may be chronic myelogenous leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, or acute lymphocytic leukemia.
  • the pharmaceutical composition of the present invention inhibits the activity of Bcr-Abl tyrosine kinase or T315I-Bcr-Abl tyrosine kinase, and does not inhibit the activity of VEGFR2 kinase, that is, Bcr-Abl tyrosine kinase or T315I-Bcr-Abl tyrosine. Since kinase selectively exhibits excellent inhibitory activity, it can be usefully used as a therapeutic agent for the prevention, alleviation or treatment of hematologic cancer, especially chronic myelogenous leukemia (CML).
  • CML chronic myelogenous leukemia
  • the novel pyrrolopyrimidine, pyrrolopyridine, and indazole compounds represented by [Chemical Formula 1] inhibit Bcr-Abl, the causative protein of chronic myelogenous leukemia (CML). Since it has an activity, it is not only useful as a target drug for CML, but also has a strong inhibitory activity against the mutant species T315I-Bcr-Abl, so it can be seen that drug resistance is also excellent.
  • the novel compound represented by [Chemical Formula 1] has excellent inhibitory activity against Bcr-Abl, a causative gene of chronic myelogenous leukemia, and its point mutant T315I-Bcr-Abl, while having an excellent inhibitory activity against VEGFR2 kinase. Since it does not exhibit inhibitory activity, it has been demonstrated that it can be used as a useful pharmaceutical composition for the treatment, prevention and alleviation of chronic myelogenous leukemia that simultaneously reduces drug resistance and side effects.
  • the pharmaceutical composition provides a pharmaceutical composition for preventing, reducing or treating cancer, characterized in that it is administered to a patient having a Bcr-Abl gene or a T315I-Bcr-Abl gene.
  • the pharmaceutical composition may be applied to laboratory animals such as mice, rabbits, rats, guinea pigs, or hamsters, or primates including humans, but is not limited thereto, and may be preferably applied to primates including humans, more preferably humans.
  • treatment refers to relief or improvement of symptoms, reduction of the range of the disease, delay or alleviation of disease progression, improvement, alleviation or stabilization, partial or complete recovery, prolongation of survival, and other beneficial treatment results, etc. It can be used in a sense that includes all of.
  • cancer in the present specification means treatment for all cancer cells, and cancer includes angiogenesis of endothelial cells and mitosis thereof (solid tumor, tumor metastasis, and benign tumor).
  • cancer is breast cancer, ovarian cancer, cervical cancer, prostate cancer, testis cancer, urogenital organ cancer, esophageal cancer, laryngeal cancer, glioblastoma, gastric cancer, skin cancer, keratoblastoma, lung cancer, squamous cell carcinoma, large cell carcinoma, Small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, undifferentiated cancer, papillary cancer, seminoma, melanoma, sarcoma, bladder cancer, liver and biliary duct cancer, kidney cancer, myeloid disease, lymphoid Disease, Hodgkin's disease, hair cell
  • the content of a compound selected from the compound represented by [Formula 1] as an active ingredient, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof is It may be appropriately adjusted and used according to the choice of those skilled in the art.
  • the pharmaceutical composition is 0.1 to 10% by weight based on the total weight of a compound selected from the compound represented by [Chemical Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof, and further Preferably, it may be included in an amount of 0.5 to 5% by weight.
  • a compound selected from the compound represented by [Chemical Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof may be included alone in the pharmaceutical composition, or other pharmacologically acceptable carriers, excipients, It may also be included with a diluent or accessory ingredient.
  • Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , Dextrin, calcium carbonate, propylene glycol, liquid paraffin, and one or more selected from the group consisting of physiological saline, but are not limited thereto, and conventional carriers, excipients, or diluents may all be used.
  • the pharmaceutical composition may include conventional fillers, extenders, binders, disintegrants, anti-aggregating agents, lubricants, wetting agents, pH adjusters, nutrients, vitamins, electrolytes, alginic acid and salts thereof, pectic acid and salts thereof, protective colloids, glycerin , Fragrances, emulsifiers or preservatives, etc. may additionally be included.
  • a compound selected from a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof of the compound of [Chemical Formula 1] according to the present invention is administered in combination with other anticancer agents for treating cancer or tumor. You can enhance the effect.
  • the pharmaceutical composition may further include at least one other anticancer agent or other therapeutic agent known to be effective in the treatment or prevention of cancer in addition to the active ingredient, and may be used as a combination therapy applied at the same time or at the same time.
  • Other anticancer or other therapeutic agents that can be applied to the combination therapy include, for example, Gleevec ® , imatinib, Sutent ® , sunitinib, Herceptin ® , Trastuzumab, and Velcade ® , Bortezomib), dexamethasone (dexamethasone), Nexavar (Nexavar ®, Sorafenib), an aromatase inhibitor, or, but may include at least one compound selected from the group consisting of kinase inhibitors is not limited thereto.
  • the method of administering the pharmaceutical composition may be oral or parenteral, and for example, it may be administered through various routes including oral, transdermal, subcutaneous, intravenous, or intramuscular.
  • the formulation of the composition may vary depending on the method of use, and is formulated using a method well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. Can be.
  • solid preparations for oral administration include tablets, pills, soft or hard capsules (CAPSULES), pills (PILLS), powders (POWDERS), and granules (GRANULES), and such preparations include one or more.
  • it may be prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin, and the like.
  • lubricants such as magnesium stearate and talc may also be used.
  • Liquid preparations for oral use include suspensions (SUSTESIONS), solvents, emulsions (EMULSIONS), and syrups (SYRUPS).
  • various excipients such as humectants Sweeteners, fragrances, preservatives, and the like may be included.
  • Forms for parenteral administration are Cream, Lotions, Ointments, PLASTERS, LIQUIDS AND SOULTIONS, Aerosols, FRUIDEXTRACTS, Elixir. It may be in the form of (ELIXIR), INFUSIONS, SACHET, PATCH, or INJECTIONS, and preferably in the form of an isotonic aqueous solution or suspension in the case of a formulation for injection. .
  • the pharmaceutical composition may further contain adjuvants such as sterilizers, preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, and conventional mixing and granulation Alternatively, it may be formulated according to a coating method, and in addition, it may be formulated using a suitable method known in the art.
  • adjuvants such as sterilizers, preservatives, stabilizers, hydrating agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, and conventional mixing and granulation
  • it may be formulated according to a coating method, and in addition, it may be formulated using a suitable method known in the art.
  • the dosage of the pharmaceutical composition can be determined in consideration of the method of administration, the age, sex of the taker, the severity of the patient, the condition, the absorption of the active ingredient in the body, the inactivation rate, and the drug to be used together, and can be determined once or several times. Can be administered separately.
  • an active ingredient of the pharmaceutical composition it is preferably administered orally or parenterally to mammals including humans in an amount of 0.001 to 100 mg/kg body weight, preferably 0.01 to 35 mg/kg body weight, once a day or divided. It can be administered by the old route.
  • Another embodiment of the present invention comprises the step of administering a therapeutically effective amount of a compound selected from a compound represented by [Formula 1], a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, and a stereoisomer thereof. It provides a method of treating cancer.
  • the treatment method may further include the step of identifying a patient in need of prevention or treatment of the cancer prior to the administering step.
  • the “therapeutically effective amount” of the present invention refers to an amount of an active ingredient for mammals that is effective for the prevention or treatment of cancer, and the therapeutically effective amount is the type of disease, the severity of the disease, the active ingredient and other ingredients contained in the composition. It can be adjusted according to various factors, including the type and content of, the type of formulation and the patient's age, weight, general health status, sex and diet, administration time, route of administration and blood clearance of the composition, treatment period, and drugs used simultaneously. However, preferably, as described above, in an amount of 0.001 to 100 mg/kg body weight, preferably 0.01 to 35 mg/kg body weight on a daily basis, administered once a day or divided into oral or parenteral routes. can do.
  • the pyrrolopyrimidine, pyrrolopyridine, and indazole compounds represented by [Chemical Formula 1] according to the present invention are newly synthesized compounds based on the compounds disclosed in Korean Patent No. 10-1116756, wherein the [Chemical Formula 1]
  • the novel compound represented by 1] can be easily synthesized and used based on the manufacturing method disclosed in Korean Patent No. 10-1116756 or a method known in the art.
  • the present invention can prepare the target compound by various methods based on the structure of [Chemical Formula 1], and all of these methods are included in the scope of the present invention. It must be interpreted. That is, the compound of the present invention can be prepared by arbitrarily combining the synthesis methods specifically described in the following examples or various synthesis methods disclosed in the prior art, which is understood to be within the scope of the present invention, and the preparation of the compound of the present invention The method is not limited by the specific examples below.
  • 6-bromo-1 H -indole 500 mg, 2.36 mmol was added, and 1,2-dimethoxyethane (8 mL) was added to dissolve it. Then, 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborane (930 mg, 3.54 mmol), Pd(PPh 3 ) 4 (1.64 g, 1.42 mmol), 2 M aqueous sodium carbonate solution (5.9 mL, 11.8 mmol) was added. After stirring at 100° C. for 6 hours, when the reaction was completed, it was filtered through Celite.
  • Step 3 1-(6-chloropyrimidin-4-yl)-6-(2-methyl-5-nitrophenyl)-1 H -Pyrrolo[3,2-c]pyridine
  • Step 5 6-(6-(5-amino-2-methylphenyl)-1 H -Pyrrolo[3,2-c]pyridin-1-yl)pyrimidin-4-amine
  • Step 6 N -(3-(1-(6-aminopyridin-4-yl)-1) H -Pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide
  • 6-(6-(5-amino-2-methylphenyl)-1 H -pyrrolo[3,2-c]pyridin-1-yl)pyrimidin-4-amine 40 mg, 0.127 mmol
  • 3-(trifluoromethyl)benzoic acid 36 mg, 0.191 mmol
  • HATU 97 mg, 0.254 mmol
  • dimethylformamide 1.3 mL
  • diethylisopropylamine (0.06 mL, 0.318 mmol) was added. After stirring at room temperature for 2 hours, when the reaction was complete, it was diluted with ethyl acetate.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • Example 35 N -(3-(1-(6-aminopyrimidin-4-yl)-1) H -Pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-((2-(dimethylamino)ethyl)(methyl)amino)-3-(trifluoromethyl)benzamide (Compound No. 35)
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • Example 36 N -(3-(1-(6-aminopyrimidin-4-yl)-1) H -Pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-4-(2,4-dimethyl-1 H -Imidazol-1-yl)-3-(trifluoromethyl)benzamide (Compound No. 36)
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • Example 42 tert-butyl-4-(4-((3-(1-(6-aminopyrimidin-4-yl)-1) H -Pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)carbamoyl)-2-(trifluoromethyl)benzyl)piperazine-1-carboxylate (Compound No. 42)
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 6 of Example 1 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • Example 22 The experimental method as in Example 22 was the same as in Example 22, except that the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution in Step 4 of Example 1.
  • Example 28 The experimental method as in Example 28 was the same, except that the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution in Step 4 of Example 1.
  • Example 22 The experimental method as in Example 22 was the same as in Example 22, except that the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution in Step 4 of Example 1.
  • Example 54 N-(3-(1-(6-((furan-2-ylmethyl)amino)pyrimidin-4-yl)-1 H -Pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 54)
  • Example 22 The experimental method as in Example 22 was the same as in Example 22, except that the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution in Step 4 of Example 1.
  • Step 2 (4-(6-(2-methyl-5-nitrophenyl)-1 H -Pyrrolo[3,2-c]pyridin-1-yl)-7 H -Pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate
  • step 6 N -(3-(1-(7 H -Pyrrolo[2,3-d]pyrimidin-4-yl)-1 H -Pyrrolo[3,2-c]pyridin-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide
  • Step 2 7-(6-chloropyrimidin-4-yl)-2-(2-methyl-5-nitrophenyl)-7 H -Pilolo[2,3-d]pyrimidine
  • Step 3 6-(2-(2-methyl-5-nitrophenyl)-7 H -Pyrrolo[2,3-d]pyrimidin-7-yl)pyrimidin-4-amine
  • Step 4 6-(2-(5-amino-2-methylphenyl)-7 H -Pyrrolo[2,3-d]pyrimidin-7-yl)pyrimidin-4-amine
  • Step 5 N -(3-(7-(6-aminopyrimidin-4-yl)-7 H -Pyrrolo[2,3-d]pyrimidin-2-yl)-4-methylphenyl)-3-(4-methyl-1 H -Imidazol-1-yl)-5-(fluoromethyl)benzamide
  • Step 1 6-(2-methyl-5-nitrophenyl)-1 H -Indazole
  • 6-bromo-1H-indazole 200 mg, 1.02 mmol
  • 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3, 2-dioxaborane 348 mg, 1.326 mmol
  • cesium carbonate 998 mg, 3.06 mmol
  • Pd(PPh 3 ) 4 236 mg, 0.204 mmol
  • 1,4-dioxane:water 10: 1, 10 mL
  • Step 2 1-(6-chloropyrimidin-4-yl)-6-(2-methyl-5-nitrophenyl)-1 H -Indazole
  • Step 3 6-(6-(2-methyl-5-nitrophenyl)-1 H -Indazol-1-yl)pyrimidin-4-amine
  • Step 4 6-(6-(5-amino-2-methylphenyl)-1 H -Indazol-1-yl)pyrimidin-4-amine
  • Step 5 N -(3-(1-(6-aminopyrimidin-4-yl)-1) H -Indazol-6-yl)-4-methylphenyl)-3-(4-methyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide
  • step 5 of Example 57 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 5 of Example 57 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 5 of Example 57 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • step 5 of Example 57 the experimental method was the same except that the corresponding acid derivative was used instead of 3-(trifluoromethyl)benzoic acid.
  • Example 62 N -(3-(1-(6-aminopyrimidin-4-yl)-1) H -Indazol-6-yl)-4-methylphenyl)-3-(2,4-dimethyl-1 H -Imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 62)
  • Example 57 The experimental method as in Example 57 was the same as in Example 57, except that the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution in Step 3 of Example 57.
  • LCMS (ESI) m/z 583 [M + H] + .
  • Example 63 The experimental method as in Example 63 was the same as in Example 63, except that the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution in Step 3 of Example 57.
  • LCMS (ESI) m/z 597 [M + H] + .
  • Example 64 3-(2,4-dimethyl-1 H -Imidazol-1-yl)- N -(3-(1-(6-((2-hydroxyethyl)amino)pyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide (Compound No. 64)
  • Example 63 The experimental method as in Example 63 was the same as in Example 63, except that the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution in Step 3 of Example 57.
  • LCMS (ESI) m/z 627 [M + H] + .
  • Example 65 3-(2,4-dimethyl-1 H -Imidazol-1-yl)- N -(3-(1-(6-((furan-2-ylmethyl)amino)pyrimidin-4-yl)-1 H -Indazol-6-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide (Compound No. 65)
  • Example 63 The experimental method as in Example 63 was the same as in Example 63, except that the corresponding amine derivative was used instead of the 2 M ammonia isopropanol solution in Step 3 of Example 57.
  • LCMS (ESI) m/z 663 [M + H] + .
  • a biochemical assay was performed in a kinase panel composed of 369 kinases.
  • -Methyl-1H -imidazol-1-yl)-5-(trifluoromethyl)benzamide (Compound No. 57) was used.
  • Example 57 was treated with a single concentration of 1 ⁇ M to measure the inhibitory effect of the kinase, and the residual enzyme activity value (%) was calculated.
  • Table 1 shows a list of kinases whose residual enzyme activity value (%) calculated when the compound of Example 57 was treated with a single concentration of 1 ⁇ M was 30% or less, that is, 70% or more.
  • the compounds of the present invention are protein kinases, specifically ABL1, ABL2, ALK, ARAF, BRAF, BRK, MER, SRC, CSK, DDR1, DDR2, EPHA1-8, EPHB1-4, ERBB2, ERBB4, FGFR1, FGFR2, FGR, FMS, FRK, GCK, HCK, JAK1, JAK2, LCK, LIMK1, LIMK2, LOK, LYN, LYNB, MLCK2, MUSK, P38a, P38b, P70S6K, PDGFR, PYK2, PKA It was found that the ability to inhibit the activities of RAF1, RET, RIPK3, RIPK4, ROS, RSK1, RSK2, SLK, STK21, TAOK1, TAOK2, TAOK3, TESK1, TIE2, TNK1, TYK1, TYRO3, YES, and ZAK was excellent. .
  • IC 50 value by measuring the inhibitory ability against the two kinases wt (wild type)-BCR-ABL, T315I-BCR-ABL for the compounds of compound number 1, compound number 16, compound number 22 to 25, compound number 28 to 34 was calculated.
  • the calculated IC 50 values are shown in Table 2 below.
  • the compounds of the present invention inhibit the BCR-ABL tyrosine kinase and the point mutation of BCR-ABL, specifically the point mutant enzyme activity of T315I-Bcr-AbL, and the effect is remarkable. there was. Accordingly, it was found that the compounds of the present invention inhibit the activation of BCR-ABL tyrosine kinase and its mutation, and thus can be used as a therapeutic agent for BCR-ABL tyrosine kinase activity and cancer caused by its mutation, especially chronic myelogenous leukemia.
  • the Ba/F3 cell line a popular cell line model, was used to evaluate the cancer cell proliferation inhibitory activity. Specifically, Ba/F3 cell lines in which wild-type (wt)-Bcr-Abl, T315I-Bcr-Abl and VEGFR2 (vascular endothelial growth factor receptor 2) kinase were injected into parental Ba/F3 cell lines, respectively, namely wt-Bcr -Abl Ba/F3, T315I-Bcr-Abl Ba/F3, VEGFR2 Ba/F3 In the cell lines, the proliferation inhibitory ability of the compounds of the present invention (Compound Nos. 1 to 57, and Compound No. 66) was measured to calculate the GI 50 value. . The calculated GI 50 values are shown in Table 3 below. At this time, imatinib and ponatinib were used as
  • GI 50 values calculated by measuring the proliferation inhibitory ability of Ba/F3 cell lines injected with wt-BCR-ABL and T315I-BCR-ABL were expressed in three steps as follows.
  • the ponatinib drug strongly inhibited the proliferation of the wild type Bcr-Abl-injected Ba/F3 cell line and the T315I-Bcr-Abl-injected Ba/F3 cell line and at the same time VEGFR2 kinase. It was confirmed that the injected Ba/F3 cell line also had a strong proliferation inhibitory activity.
  • the compounds of the present invention have inhibitory activity against Bcr-Abl, which is the causative protein of CML, so that they are not only useful as target drugs for chronic myelogenous leukemia (CML), but also mutant species. It was found that drug resistance was also excellent because it had a strong inhibitory activity against T315I-Bcr-Abl. At the same time, it was found that the inhibitory activity against VEGFR2 kinase was low, so that drug side effects could be alleviated.
  • Bcr-Abl is the causative protein of CML
  • novel compound represented by Formula 1 according to the present invention can be formulated in various forms depending on the purpose.
  • the following exemplifies some formulation methods in which the compound represented by Formula 1 according to the present invention is contained as an active ingredient, and the present invention is not limited thereto.
  • Formulation Example 2 Tablet (wet granulation)
  • An injection was prepared by containing 100 mg as an active ingredient, in addition to 180 mg of mannitol, 26 mg of Na 2 HPO 4 ⁇ 12H 2 O and 2974 mg of distilled water.

Abstract

La présente invention concerne : un composé choisi parmi un nouveau dérivé de pyrrolopyrimidine, de pyrrolopyridine et d'indazole ayant une activité inhibitrice de protéine kinase, et un sel pharmaceutiquement acceptable, un hydrate, un solvate ou un stéréoisomère de celui-ci ; et une composition pharmaceutique pour prévenir, soulager ou traiter le cancer, contenant le composé. Un composé selon la présente invention a une excellente aptitude à inhiber l'activation de la tyrosine kinase Bcr-Abl et la tyrosine kinase T315I-Bcr-Abl, qui est une espèce mutante résistante aux médicaments, mais n'a pas d'activité inhibitrice contre la protéine kinase VEGFR2, et peut ainsi réduire de manière considérable la résistance aux médicaments et les effets secondaires et peut être utilisé de manière efficace dans la prévention, le soulagement ou le traitement du cancer, en particulier le cancer du sang, notamment la leucémie myéloïde chronique.
PCT/KR2020/014806 2019-11-14 2020-10-28 Dérivé de composé pyrrolopyrimidine, pyrrolopyridine et d'indazole, et composition pharmaceutique thérapeutique le contenant WO2021096112A1 (fr)

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