WO2020036437A1 - Dérivé hétéroaryle substitué, son procédé de production, et composition pharmaceutique destinée à prévenir ou à traiter des maladies liées à la protéine kinase le contenant en tant que principe actif - Google Patents

Dérivé hétéroaryle substitué, son procédé de production, et composition pharmaceutique destinée à prévenir ou à traiter des maladies liées à la protéine kinase le contenant en tant que principe actif Download PDF

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WO2020036437A1
WO2020036437A1 PCT/KR2019/010369 KR2019010369W WO2020036437A1 WO 2020036437 A1 WO2020036437 A1 WO 2020036437A1 KR 2019010369 W KR2019010369 W KR 2019010369W WO 2020036437 A1 WO2020036437 A1 WO 2020036437A1
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cyclopropyl
amino
pyrrolo
cancer
trifluoromethyl
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Korean (ko)
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최환근
고은화
박진희
고이경
강석용
김소영
장보미
이승연
이선화
김다예
이선주
김상범
박종배
남도현
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재단법인 대구경북첨단의료산업진흥재단
국립암센터
사회복지법인 삼성생명공익재단
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Publication of WO2020036437A1 publication Critical patent/WO2020036437A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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

  • Substituted heteroaryl derivatives methods for preparing the same, and pharmaceutical compositions for the prophylaxis or treatment of protein kinase related diseases containing the same as an active ingredient.
  • Protein kinases are enzymes that catalyze the reaction that transfers the terminal phosphate group of adenosine triphosphate (ATP) to specific residues of the protein (tyrosine, serine, threonine) .It is responsible for the activity, growth and differentiation of cells against changes in extracellular mediators and the environment. It is involved in the signal to regulate.
  • ATP adenosine triphosphate
  • Inappropriately high protein kinase activity is directly or indirectly associated with many diseases resulting from abnormal cellular action.
  • disease may be caused by mutations, over-expression, or failure of the proper regulation of kinases involved in inappropriate enzyme activity, or by the production of excess or deficiency of factors involved in signal transduction upstream or downstream of cytokines or kinases.
  • selective inhibition of kinase activity may be a beneficial target of drug development for disease treatment.
  • Brain cancer is a generic term for primary brain cancers that occur in brain tissue and the brain envelope that surrounds the brain, and secondary brain cancers that have metastasized from cancers that occur in the skull or other parts of the body. Such brain cancer is often distinguished from cancers occurring in other organs. First, lung, stomach, and breast cancers occur in one or two types of organs, and their properties are the same and similar. However, the brain develops a wide variety of cancers. For example, glioblastoma multiforme, malignant gliomas, lymphomas, germ cell tumors, metastatic tumors, and the like.
  • Parkinson's disease is the result of chronic progressive degeneration of neurons, but the cause is not yet fully understood. Parkinson's disease is characterized by the degeneration of dopaminergic neurons of substantia nigra (SN), although the main cause is unknown. Melanoma is the brain stem or part of the lower brain that helps control the unconscious movement. Dopamine deficiency in the brain due to the loss of these neurons is known to cause observable symptoms. Clinically, Parkinson's disease appears in the form of major symptoms of resting tremor, rigidity, bradykinesia and postural instability.
  • dopamine agonists eg, rotigotine, pramipexole, bromocriptine, ropinillol, cabergoline, as well as MAO-B inhibitor selegiline and COMT inhibitor entacapone
  • Pergolides e.g., rotigotine, pramipexole, bromocriptine, ropinillol, cabergoline, as well as MAO-B inhibitor selegiline and COMT inhibitor entacapone
  • Pergolides e.g, rotigotine, pramipexole, bromocriptine, ropinillol, cabergoline, as well as MAO-B inhibitor selegiline and COMT inhibitor entacapone
  • Pergolides e.g, rotigotine, pramipexole, bromocriptine, ropinillol, cabergoline, as well as MAO-B inhibitor selegiline and COMT inhibitor entacapone
  • Pergolides e.g
  • LRRK2 leucin-rich repeat kinase-2
  • LRRK2 belongs to the leucin-rich repeat kinase family and consists of 2527 amino acid sequences with high similarity between species. It has both GTPase and Serine-threonine kinase activity.
  • the expressed LRRK2 is observed in various organs and tissues including the brain, and is known to exist in the cytoplasm or cell membrane and mitochondrial outer membrane at the cellular level. Currently, research on the exact in vivo function of LRRK2 is being actively conducted.
  • Parkinson's disease occurs sporadically, but 5-10% of patients have a family history, and studies of these patient samples have revealed the locus of PARK 1-16 to date, and mutations in several loci have led to Parkinson's disease.
  • the gene causing the disease has been identified. Parkinson's disease-causing genes caused by mutations are known as parkin, PINK1, DJ-1, ⁇ -synuclein, and LRRK2 (leucine-rich repeat kinase 2). Of these, the LRRK2 gene was first reported in 2004 as a dominant gene of homologous chromosomes like ⁇ -synuclein.
  • Parkinson's disease patients with LRRK2 mutations unlike other Parkinson's disease genes, have very similar symptoms to sporadic Parkinson's disease patients.
  • the LRRK2 mutation is found in 1-2% of sporadic Parkinson's disease patients, as well as in patients with family history of Parkinson's disease. Identifying the mechanism of Parkinson's disease caused by mutations in this gene can be helpful in understanding the pathogenesis of Parkinson's disease and in developing therapeutics. .
  • LRRK2 is implicated in the imputation of mild cognitive impairment associated with Alzheimer's disease, L-Dopa induced dyskinesia, CNS disorders associated with neuronal progenitor differentiation, cancers such as brain cancer, kidney cancer, breast cancer, prostate cancer, blood cancer and lung cancer, and Compounds and compositions that are known to be associated with acute myeloid leukemia, papillary kidney and thyroid carcinoma, multiple myeloma, amyotrophic lateral sclerosis, rheumatoid arthritis and ankylosing spondylitis, are effective in controlling LRRK2 activity, including neurodegenerative diseases, CNS Therapeutic effects such as disorders, cancer, acute myeloid leukemia and multiple myeloma, and inflammatory diseases.
  • One object of the present invention is to provide substituted heteroaryl derivatives.
  • Another object of the present invention is to provide a method for preparing a substituted heteroaryl derivative.
  • Another object of the present invention to provide a pharmaceutical composition for the prophylaxis or treatment of protein kinase-related diseases.
  • a 1 is CH or N;
  • R 1 and R 2 are independently hydrogen or straight or branched C 1-6 alkyl, or R 1 and R 2 together with the carbon atom to which they are attached may form pyrrole, wherein said alkyl is halogen May be substituted with one or more, and the pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF 3 ;
  • R 3 is straight or branched C 1-10 alkyl, straight or branched C 2-10 alkenyl, straight or branched C 2-10 alkynyl or C 3-7 cycloalkyl, said alkyl, al Kenyl and alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C 1-6 alkoxy, respectively;
  • heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S, wherein the heteroaryl is straight or branched C 1-6 alkyl or alkoxy; And 3 to 8 atoms of heterocycloalkyl or heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of N, O, and S, and may be substituted with one or more substituents selected from the group consisting of , Wherein the alkyl and alkoxy may be substituted with one or more CN, and the heterocycloalkyl and heterocycloalkylcarbonyl are halogenated and 3 to 6 atoms including one or more heteroatoms selected from the group consisting of N, O and S May be substituted with one or more substituents selected from the group consisting of heterocycloalkyl of
  • R a and R b are independently 3-8 membered heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of hydrogen, halogen or N, O and S, wherein the heterocycloalkylcarbon Neyl may be substituted with one or more substituents selected from the group consisting of halogen and 3 to 6 membered heterocycloalkyl including one or more heteroatoms selected from the group consisting of N, O and S, or R a and R b may form an unsubstituted or substituted heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atoms to which they are attached, wherein the substituted heterocycloalkyl is a straight chain Or one or more substituents selected from the group consisting of branched C 1-6 alkyl and oxo ( ⁇ O).
  • R c is hydrogen, halogen or straight or branched C 1-6 alkoxy).
  • a pharmaceutical composition for the prophylaxis or treatment of protein kinase-related diseases containing a compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a health functional food for the prevention or improvement of protein kinase-related diseases containing the compound represented by the formula (1), the optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a protein kinase comprising administering to a subject in need thereof a pharmaceutical composition or a nutraceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition containing the same as an active ingredient is a protein It can be usefully used for the treatment or prevention of kinase related diseases.
  • FIG. 1 and 2 are photographs showing the results of the inhibition of LRRK2 phosphorylation in 448T cell line of the compounds according to the present invention.
  • One aspect of the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • a 1 is CH or N;
  • R 1 and R 2 are independently hydrogen or straight or branched C 1-6 alkyl, or R 1 and R 2 together with the carbon atom to which they are attached may form pyrrole, wherein said alkyl is halogen May be substituted with one or more, and the pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF 3 ;
  • R 3 is straight or branched C 1-10 alkyl, straight or branched C 2-10 alkenyl, straight or branched C 2-10 alkynyl or C 3-7 cycloalkyl, said alkyl, al Kenyl and alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C 1-6 alkoxy, respectively;
  • heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S, wherein the heteroaryl is straight or branched C 1-6 alkyl or alkoxy; And 3 to 8 atoms of heterocycloalkyl or heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of N, O, and S, and may be substituted with one or more substituents selected from the group consisting of , Wherein the alkyl and alkoxy may be substituted with one or more CN, and the heterocycloalkyl and heterocycloalkylcarbonyl are halogenated and 3 to 6 atoms including one or more heteroatoms selected from the group consisting of N, O and S May be substituted with one or more substituents selected from the group consisting of heterocycloalkyl of
  • R a and R b are independently 3-8 membered heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of hydrogen, halogen or N, O and S, wherein the heterocycloalkylcarbon Neyl may be substituted with one or more substituents selected from the group consisting of halogen and 3 to 6 membered heterocycloalkyl including one or more heteroatoms selected from the group consisting of N, O and S, or R a and R b may form an unsubstituted or substituted heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S together with the carbon atoms to which they are attached, wherein the substituted heterocycloalkyl is a straight chain Or one or more substituents selected from the group consisting of branched C 1-6 alkyl and oxo ( ⁇ O).
  • R c is hydrogen, halogen or straight or branched C 1-6 alkoxy.
  • a 1 is CH or N
  • R 1 and R 2 are independently hydrogen or straight or branched C 1-4 alkyl, or R 1 and R 2 may form pyrrole with the carbon atoms to which they are attached, wherein said alkyl is halogen May be substituted with one or more, and the pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF 3 ;
  • R 3 is straight or branched C 1-6 alkyl, straight or branched C 2-6 alkenyl, straight or branched C 2-6 alkynyl or C 3-5 cycloalkyl, said alkyl, al Kenyl and alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C 1-4 alkoxy, respectively;
  • R d , R f , R g , R i , R j , R l , R r and R x are independently hydrogen, halogen or straight or branched C 1-6 alkyl or alkoxy, wherein said alkyl and Alkoxy may be substituted one or more with CN,
  • R e , R h and R k are independently 5 or 6 membered heterocycloalkyl or heterocycloalkylcarbonyl including one or more heteroatoms selected from the group consisting of N, O and S, wherein said hetero Cycloalkyl and heterocycloalkylcarbonyl may be substituted with one or more substituents selected from the group consisting of halogen and 3 to 6 membered heterocycloalkyl including one or more heteroatoms selected from the group consisting of N, O and S There is,
  • R m , R n , R o , R p , R s , R t , R v , and R w are each hydrogen or straight or branched C 1-6 alkyl, or R m , R n , R o Two of which are bonded to the same carbon of R p , R s , R t , R v , and R w may form carbonyl with the carbon to which they are attached,
  • R q and R u can be independently hydrogen or straight or branched C 1-6 alkyl.
  • a 1 is CH or N
  • R 1 and R 2 are independently hydrogen or straight or branched C 1-2 alkyl, or R 1 and R 2 may form pyrrole with the carbon atom to which they are attached, wherein said alkyl is halogen One or more may be substituted, and said pyrrole may be substituted with one or more substituents selected from the group consisting of halogen, CN and CF 3 ;
  • R 3 is straight or branched C 1-4 alkyl, straight or branched C 2-4 alkenyl, straight or branched C 2-4 alkynyl, cyclopropyl or cyclobutyl, said alkyl, alkenyl And alkynyl may be substituted one or more with a substituent selected from the group consisting of hydroxyl and straight or branched C 1-2 alkoxy, respectively;
  • R d , R f , R g , R i , R j , R l , R r and R x are independently hydrogen, halogen or straight or branched C 1-3 alkyl or alkoxy, wherein said alkyl and Alkoxy may be substituted one or more with CN,
  • R e , R h and R k are independently morpholinyl, piperidinyl, morpholinylcarbonyl, piperazinylcarbonyl or piperidinylcarbonyl, wherein the morpholinyl, piperidinyl, Morpholinylcarbonyl piperazinylcarbonyl and piperidinylcarbonyl may be substituted with one or more substituents selected from the group consisting of halogen, morpholinyl and oxetanyl,
  • R m , R n , R o , R p , R s , R t , R v , and R w are each hydrogen or straight or branched C 1-3 alkyl, or R m , R n , R o Two of which are bonded to the same carbon of R p , R s , R t , R v , and R w may form carbonyl with the carbon to which they are attached,
  • R q and R u can be independently hydrogen or straight or branched C 1-3 alkyl.
  • a 1 is CH or N
  • R 1 and R 2 are independently hydrogen or CF 3, or R 1 and R 2 may form pyrrole with the carbon atom to which they are attached, wherein pyrrole is from the group consisting of F, Cl, CN and CF 3 May be substituted with one or more substituents selected;
  • R 3 is straight or branched C 1-4 alkyl, vinyl, ethynyl or cyclopropyl, said alkyl substituted with one or more substituents selected from the group consisting of hydroxyl and straight or branched C 1-2 alkoxy Can be;
  • R d , R f , R g , R i , R j , R l , R r and R x are independently hydrogen, F, Cl, OMe or ego,
  • R e , R h and R k are independently , , or ego,
  • R m , R n , R o , R p , R s , R t , R v , and R w are each hydrogen or methyl, or R m , R n , R o , R p , R s , R t , R two of the v , and R w bonded to the same carbon may form carbonyl together with the carbon to which they are attached,
  • R q and R u can be independently hydrogen or methyl.
  • a 1 is CH or N
  • R 1 and R 2 are independently hydrogen or CF 3, or R 1 and R 2 together with the carbon atom to which they are attached , , or Can form;
  • R 3 is methyl, ethyl, i-propyl, t-butyl, i-butyl, hydroxyethyl, methoxyethyl, vinyl, ethynyl or cyclopropyl;
  • Examples of the compound represented by Formula 1 according to the present invention include the following compounds:
  • the compound represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexane-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlor
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid.
  • the solvent may be prepared by filtration and drying, or the solvent and the excess acid may be distilled under reduced pressure, dried and then crystallized under an organic solvent.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
  • the present invention includes not only the compound represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.
  • the preparation method represented by Scheme 1 of the present invention is a step of reacting a substituted heteroaryl derivative represented by Chemical Formula 2 with a compound represented by Chemical Formula 3, specifically, halogen of the compound represented by Chemical Formula 2 and Chemical Formula 3
  • the amine of the compound represented by the reaction is a step of preparing a compound represented by the formula (1).
  • the reaction may be performed using the compound represented by the formula (2), the compound represented by the formula (3), and the base, and in some cases, a palladium catalyst may be further used as the metal catalyst.
  • the base includes inorganic bases such as cesium carbonate, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and sodium hydride; Or N, N-diisopropylethylamine (DIPEA), 1, 8-diazabicyclo [5. 4. 0] -7-untetene (DBU), pyridine, triethylamine and other organic bases; and the like or equivalent, can be used alone or in combination.
  • DIPEA N-diisopropylethylamine
  • DBU 1, 8-diazabicyclo [5. 4. 0] -7-untetene
  • pyridine triethylamine and other organic bases
  • the palladium catalyst may include tris (dibenzylideneacetone) palladium (Pd 2 (dba) 3 ), tetrakis (triphenylphosphine) palladium (Pd (Ph 3 P) 4 ), and palladium char (Pd-C).
  • reaction solvents include toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride, dichloroethane, water, ethyl acetate, acetonitrile; Lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; Ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1, 2-dimethoxyethane and the like; Etc., and these may be used alone or in combination.
  • DMA dimethylacetamide
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • methylene chloride dichloroethane
  • Lower alcohols including isopropanol, methanol, ethanol, propanol and butanol
  • Ether solvents including tetrahydrofuran (THF), dioxane, ethyl
  • Another aspect of the present invention provides a pharmaceutical composition for the prophylaxis or treatment of a protein kinase related disease containing the compound represented by Formula 1, the optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the protein kinase is AAK1, ABL1 (E255K) -phosphorylated.
  • Dom. 2, S808G GRK1, GRK2, GRK3, GRK4, GRK7, GSK3A, GSK3B, HASPIN, HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HUNK, ICK, IGF1R, IKK-alpha, IKK-beta, IKK-epson , INSR, INSRR, IRAK1, IRAK3, IRAK4, ITK, JAK1 (JH1domain-catalytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT (V559D, V654
  • PFPK5 P. falciparum
  • PFTAIRE2 PFTK1, PHKG1, PHKG2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA (C420R), PIK3CA (E542K), PIK3CA (E545A), PIK3CA (47545) (K5453) (H1047Y), PIK3CA (I800L), PIK3CA (M1043I), PIK3CA (Q546K), PIK3CB, PIK3CD, PIK3CG, PIK4CB, PIKFYVE, PIM1, PIM2, PIM3, PIP5K1A, PIP5K2C, PIPK-K2C, PIP5-K2-C , PKMYT1, PKN1, PKN2, M.
  • PKNB tuberculosis
  • RPS6KA5 Kin. Dom. 2-C-terminal
  • RSK1 Kin. Dom. 1
  • N-terminal N-terminal
  • RSK1 Kin. Dom. 2-C-terminal
  • RSK2 Kin. Dom. 1-N-terminal
  • RSK2 Kin. Dom. 2-C-terminal
  • RSK3 Kin. Dom 1-N-terminal
  • RSK3 Kin. Dom. 2-C-terminal
  • RSK4 Kin. Dom. 1-N-terminal
  • RSK4 Kin. Dom. 1-N-terminal
  • the protein kinase-related disease may be at least one selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease.
  • the degenerative brain disease may be at least one selected from the group consisting of Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, dementia, Huntington's disease, multiple sclerosis, proximal lateral sclerosis, stroke, stroke, and mild cognitive impairment.
  • the inflammatory diseases include dermatitis, allergy, gastric ulcer, duodenal ulcer, hepatitis, esophagitis, gastritis, enteritis, pancreatitis, colitis, nephritis, systemic edema, local edema, arthritis, keratitis, bronchitis, pleurisy, peritonitis, spondylitis, inflammatory pain, urethritis, At least one member selected from the group consisting of cystitis, periodontitis, and gingivitis.
  • the cancer may be brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroma, intracranial carcinoma, epithelial cell tumor, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal / sinus cancer, nasopharyngeal cancer , Salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary cancer, pancreatic cancer, small intestine Cancer, colorectal cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer,
  • the compound is ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (Q252H) -nonphosphorylated, ALK, ALK (C1156Y), ALK (L1196M), ASK1, BRSK1, BUB1, CAMK1B, CAMKK2A, CAM2, CLK1, CLK2, CLK4, CSF1R-autoinhibited, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, EPHA7, EPHALT, EPHALT3 (ITD, F691L), GAK, GCN2 (Kin.Dom.
  • RPS6KA5 Kin. Dom. 2-C-terminal
  • RSK3 Kin. Dom. 2-C-terminal
  • Compound represented by the formula (1) of the present invention shows excellent inhibitory activity against LRRK2, LRRK2 (G2019S), DYRK1A, CLK1 kinase (see Experimental Example 1), so that the disease associated with LRRK2, LRRK2 (G2019S), DYRK1A, CLK1 kinase It can be usefully used as a pharmaceutical composition for treatment or prophylaxis.
  • the compound represented by Formula 1 of the present invention is ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (Q252H) -nonphosphorylated, ALK, ALK (C1156Y), ALK (L1196M), ASK1, BRSK1, BUB1 , CAMK1B, CAMK2A, CAMKK2, CHEK2, CLK1, CLK2, CLK4, CSF1R-autoinhibited, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK1, EPBHA, EPBHA, EPAKHA , FER, FLT3 (D835V), FLT3 (ITD, F691L), GAK, GCN2 (Kin.Dom.
  • the compound represented by the formula (1) according to the present invention can effectively be used as a pharmaceutical composition for the treatment or prevention of LRRK2-related diseases by effectively inhibiting LRRK2 phosphorylation in 448T cell line derived from brain tumor patients, in particular, brain cancer Or it may be usefully used as a pharmaceutical composition for treating or preventing Parkinson's disease.
  • the pharmaceutical composition of the present invention When used in the treatment of cancer, the pharmaceutical composition of the present invention may be administered as a separate therapeutic agent or in combination with other anticancer agents in use.
  • Another aspect of the present invention the prevention of a disease selected from the group consisting of cancer, inflammatory diseases and degenerative brain diseases containing the compound represented by the formula (1), optical isomers thereof, or a pharmaceutically acceptable salt thereof as an active ingredient Or it provides a pharmaceutical composition for treatment.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various formulations, oral and parenteral, during clinical administration.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used.
  • Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid form preparations include at least one excipient such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin.
  • lubricants such as magnesium stearate, talc and the like are also used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like can be used.
  • compositions comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration may be administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how to do it.
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, which is an ampule or vial unit dosage form. It can be prepared by.
  • the composition may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt, etc. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt, etc. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
  • a health functional food for the prevention or improvement of protein kinase-related diseases containing the compound represented by the formula (1), the optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound represented by Chemical Formula 1 according to the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement).
  • the amount of the compound in the health food can be added from 0.1 to 90 parts by weight of the total food weight.
  • the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
  • the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents such as, tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of said natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
  • the compound represented by Chemical Formula 1 according to the present invention may be used in various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors such as flavoring agents, colorants and neutralizing agents (cheese, chocolate, etc.), pect Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
  • the compound represented by the formula (1) of the present invention may contain a fruit flesh for the production of natural fruit juice and fruit juice beverage and vegetable beverage.
  • a protein kinase comprising administering to a subject in need thereof a pharmaceutical composition or a nutraceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • Step 1 Preparation of 2, 4-dichloro-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d] pyrimidine
  • Step 3 (4-((4-cyclopropyl-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d] pyri) Preparation of midin-2-yl) amino) methoxyphenyl) (morpholino) methanone
  • Step 4 (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) ( Preparation of morpholino) methanone
  • Examples 2 to 28 were prepared in a similar manner to Example 1, and the chemical structures of Examples 1 to 28 are shown in Table 1 below, compound names, mass and UPLC analysis results are summarized in Table 2 below.
  • Example Chemical structure Example Chemical structure One 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
  • Example Compound name 1 H NMR, MS yield(%) HPLC r.t. (min) (analysis condition) One (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino Methanone 1 H NMR (400 MHz, TFA salt, MeOD-d 4 ) ⁇ 8.67 (d, J 8.28 Hz, 1H), 7.70 (s, 1H), 7.10 (s, 1H), 7.07-7.05 (m, 1H) , 3.99 (s, 3H), 3.79-3.59 (m, 8H), 2.53-2.48 (m, 1H), 1.38-1.35 (m, 2H), 1.28-1.25 (m, 2H); 462 [M + H] + 35 6.95 / 100% / (A) 2 (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-
  • Step 1 Preparation of 4-chloro-3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine
  • Step 2 Preparation of 4-chloro-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine
  • reaction was carried out with CuI (5.0 equiv) and KF (5.0 equiv) maintaining the temperature at 150 ° C. for 2 hours under reduced pressure close to vacuum. After the reaction was cooled to room temperature, trimethyl (trifluoromethyl) silane (5.0 equiv) was dissolved in DMF and NMP (1: 1 ratio, 0.2 M total) under nitrogen, and then put through a syringe.
  • Step 3 Preparation of 4-cyclopropyl-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine
  • Step 4 4- (cyclopropyl-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine-7-oxide
  • Step 5 of 6-chloro-4-cyclopropyl-3- (trifluoromethyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b] pyridine Produce
  • Step 6 (4-((4-cyclopropyl-5- (trifluoromethyl) -7-((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d] pyridine Preparation of -2-yl) amino) methoxyphenyl) (morpholino) methanone
  • Step 7 (4-((4-cyclopropyl-5- (trifluoromethyl) -7H-pyrrolo [2, 3-d] pyridin-2-yl) amino) -3-methoxyphenyl) (parent Preparation of polyno) methanone
  • Examples 31 to 54 were prepared in a similar manner to Example 30, and the chemical structures of Examples 30 to 54 are shown in Table 3 below, the compound names, mass and UPLC analysis results are summarized in Table 4 below.
  • Example Chemical structure Example Chemical structure 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
  • Step 1 Preparation of (4-((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone
  • Step 2 Preparation of (4-((4-cyclopropyl-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) (morpholino) methanone
  • Examples 56 to 58 were prepared in a similar manner to Example 55, and the chemical structures of Examples 55 to 58 are shown in Table 5 below, the compound names, mass and UPLC analysis results are summarized in Table 6 below.
  • the substrate was treated with basic reaction buffer (20 mM Hepes, pH 7.5), 10 mM MgCl 2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na 3 VO 4, 2 mM DTT, 1%. DMSO) and then added the cofactor necessary for the reaction.
  • LRRK2, LRRK2 (G2019S), DYRK1A, and CLK1 kinase were added and mixed, and then each of the compound examples was added using Acoustic technology (Echo550; nanoliter range). After standing at room temperature for 20 minutes, the reaction was started by adding 33SYK P-ATP (specific activity 10 mCi / ml). After reacting for 2 hours at room temperature, the P81 exchange paper was spotted. After the reaction, kinase activity was detected using a filter-binding method.
  • Table 7 below shows the inhibitory activities of LRRK2, LRRK2 (G2019S), DYRK1A, and CLK1 of Example compounds.
  • IC 50 values of the measured kinases are classified as Class A when less than 10 nM, Class C when 10 to 100 nM, and Class B above 100 nM.
  • NA means no activity. As shown in Table 7,
  • Example compounds of the present invention was confirmed to exhibit excellent inhibitory activity against LRRK2, LRRK2 (G2019S), DYRK1A, CLK1 kinase.
  • Example compounds of the nickname Examples 1, 12, 30, and 43 selected from the company were determined to measure the enzyme (kinase) selectivity by DiscoverX, and the experiment was conducted using a panel for the scanMAX TM Kinase assay. At this time, the concentration of the drug treated with the enzyme was set to 1 ⁇ M in DMSO, and the percentage control was determined by the same method as in Equation 1 below, and the results are shown in Table 8-10.
  • the positive control refers to a compound exhibiting a control percentage of 0%
  • the negative control indicates a control percentage of 100% with DMSO.
  • the enzyme selectivity of the present invention was determined to have activity for that enzyme if the percentage control for each enzyme was ⁇ 35% (ie less than 35%).
  • the exemplary compound of the present invention is ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (Q252H) -nonphosphorylated, ALK, ALK (C1156Y), ALK (L1196M), ASK1, BRSK1, BUB1, CAMK1B, CAMK2A, CAMKK2, CHEK2, CLK1, CLK2, CLK4, CSF1R-autoinhibited, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G3, DAPK1, DAPK2, DAPK2, DRKKDAK EPHA7, EPHA8, FAK, FER, FLT3 (D835V), FLT3 (ITD, F691L), GAK, GCN2 (Kin.Dom.2, S808G), HIPK2, HIPK3, HIPK4, HUNK, ICK,
  • the compound represented by Formula 1 is ABL1 (F317L) -phosphorylated, ABL1 (H396P) -nonphosphorylated, ABL1 (Q252H) -nonphosphorylated, ALK, ALK (C1156Y), ALK (L1196M), ASK1, BRSK1, BUB1, CAMK1B, CAMK2A, CAMKK2, CHEK2, CLK1, CLK2, CLK4, CSF1R-autoinhibited, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G3, DAPK1, DAPK2, DAPK1, DRAK1, DRK1RK8, DRAK1RK FAK, FER, FLT3 (D835V), FLT3 (ITD, F691L), GAK, GCN2 (Kin.Dom.2, S808G), HIPK2, HIPK3, HIPK4, HUNK, ALK, ALK (C
  • FIG. 1 and 2 are photographs showing the results of the inhibition of LRRK2 phosphorylation in 448T cell line of the compounds according to the present invention.
  • the compound represented by Formula 1 according to the present invention effectively inhibits LRRK2 phosphorylation in cancer-causing cells, and thus may be usefully used as a pharmaceutical composition for the treatment or prevention of LRRK2-related diseases, in particular for the treatment of brain cancer or Parkinson's disease. It can be useful.
  • the compound represented by Formula 1, the optical isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention may be usefully used for the treatment or prevention of a protein kinase related disease.

Abstract

La présente invention concerne : un dérivé hétéroaryle substitué ; un procédé de production de celui-ci ; et une composition pharmaceutique le contenant en tant que principe actif pour la prévention ou le traitement de maladies liées à la protéine kinase. Le dérivé hétéroaryle substitué a une excellente activité inhibitrice vis-à-vis de diverses protéines kinases y compris LRRK2, la composition pharmaceutique contenant le dérivé hétéroaryle substitué en tant que principe actif peut ainsi être utile dans le traitement ou la prévention de maladies liées à la protéine kinase.
PCT/KR2019/010369 2018-08-16 2019-08-14 Dérivé hétéroaryle substitué, son procédé de production, et composition pharmaceutique destinée à prévenir ou à traiter des maladies liées à la protéine kinase le contenant en tant que principe actif WO2020036437A1 (fr)

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