WO2020149553A1 - Dérivé d'aryle ou d'hétéroaryle, et composition pharmaceutique le comprenant en tant que principe actif pour le traitement d'une maladie associée à une kinase - Google Patents

Dérivé d'aryle ou d'hétéroaryle, et composition pharmaceutique le comprenant en tant que principe actif pour le traitement d'une maladie associée à une kinase Download PDF

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WO2020149553A1
WO2020149553A1 PCT/KR2019/018834 KR2019018834W WO2020149553A1 WO 2020149553 A1 WO2020149553 A1 WO 2020149553A1 KR 2019018834 W KR2019018834 W KR 2019018834W WO 2020149553 A1 WO2020149553 A1 WO 2020149553A1
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phenyl
carboxamide
substituted
imidazo
ethynyl
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Korean (ko)
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이화
조서현
류희선
김승수
최현진
도우미
김현경
최지은
김대권
손정범
김남두
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주식회사 보로노이
주식회사 보로노이바이오
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Publication of WO2020149553A1 publication Critical patent/WO2020149553A1/fr

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    • 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
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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • 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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • An aryl or heteroaryl derivative, and a pharmaceutical composition for treating a kinase-related disease comprising the same as an active ingredient.
  • Protein kinase is an enzyme that catalyzes the phosphorylation reaction that transfers the gamma-phosphate group of ATP to the hydroxy group of proteins tyrosine, serine and threonine, and is responsible for the metabolism, gene expression, cell growth, differentiation, and cell division of cells. It plays an important role in signal transmission (Non-Patent Document 1, Thomas A. Hamilton, in Encyclopedia of Immunology (Second Edition), 1998, 2028-2033). Protein kinases are classified into tyrosine protein kinase and serine/threonine kinase, of which about 90 or more are tyrosine kinase.
  • Protein kinase is a molecular switch that must smoothly regulate the transition between active and inactive states in cells. If the metastasis between the active and inactive states is abnormally regulated, intracellular signal transduction is excessively activated, leading to uncontrollable cell division and proliferation. In addition, abnormal activation by gene mutation, amplification, and overexpression of protein kinase is related to the development and progression of various tumors, and thus plays a decisive role in the development of various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer.
  • kinases examples include ABL1, ABL2, BRAF, CDK11, CDK8, CDKL2, CIT, CSF1R, DDR1, DDR2, FLT3, KIT, LOK, LTK, MUSK, PAK3, PDGFRA, PDGFRB, RAF1, RIPK1, and the like.
  • Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), an embodiment of a protein kinase, mediates NF- ⁇ B activation, apoptosis and/or necroptosis. It is a multifunctional signal transducer involved in doing this.
  • Non-Patent Document 2 Holler et al., Nat Immunol 2000; 1: 489-495; Non-Patent Document 3, Degterev et al., Nat Chem Biol 2008; 4: 313-321).
  • necroptosis mediated by RIPK1 is associated with various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer.
  • RIP3 knockout mice designed to completely block RIPK1-mediated programmed necrosis are inflammatory bowel disease (including ulcerative colitis and Crohn's disease) (Non-Patent Document 4, (2011) Nature 477, 330-334), Psoriasis (Psoriasis) ) (Non-patent document 5, (2011) Immunity 35, 572-582), retinal-peel-induced photoreceptor necrosis (non-patent document 6, (2010) PNAS 107, 21695-21700), retinitis pigmentosa ) (Non-Patent Document 7, (2012) Proc. Natl. Acad. Sci.
  • Non-Patent Document 8 (2009) Cell 137, 1100-1111
  • SIRS sepsis/systemic inflammatory response syndrome
  • RIPK1 is known to mediate a microglial response in Alzheimer's disease (Non-Patent Document 10, PNAS October 10, 2017. 114 (41) E8788-E8797), so a specific compound is RIPK1. If targeted and can effectively inhibit activity, the compounds include Downs syndrome, Parkinson's disease, Lou Gehrig's disease, dementia, Huntington's disease, multiple sclerosis, proximal lateral sclerosis, stroke, stroke, and mild perception, including Alzheimer's disease It may also be developed as a treatment for degenerative brain diseases such as disorders (ie, degenerative neurological diseases).
  • RIPK1 regulates the production of tumor necrosis factor-alpha (TNF- ⁇ ), and the TNF- ⁇ is involved in cell death and mediation of inflammation in numerous diseases such as rheumatoid arthritis, cancer, etc. Since it is known to be a pro-inflammatory cytokine (Non-Patent Document 11, Cell Death and Disease (2012) 3, e320), if a specific compound can effectively inhibit the activity by targeting RIPK1, the compound is Rheumatoid arthritis ), including rheumatoid polymyalgia, ankylosing spondylitis, motor neurone disease, and autoimmune diseases, or cancer.
  • RIPK1 has been known to induce macrophage-mediated adaptive immune tolerance in pancreatic cancer (non-patent document 12, Cancer Cell 34, 757-774, November 12, 2018). More specifically, RIPK1 inhibition in TAMs results in cytotoxic T cell activation and T helper cell differentiation for mixed Th1/Th17 phenotypes, resulting in tumor immunity in organ type models of mouse and human PDA. It is disclosed to induce.
  • RIPK1 acts synergistically with PD-1 and inducible co-stimulator based immunotherapy, so it can be seen that RIPK1 is a checkpoint kinase that governs tumor immunity. That is, since compounds capable of effectively inhibiting RIPK1 activity are likely to be developed as therapeutic agents for various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer, development of a novel protein kinase inhibitor is required. .
  • the objective in one aspect of the present invention is to show excellent inhibitory activity against RIPK1 (Receptor-interacting serine/threonine-protein kinase 1), a novel structured aryl or heteroaryl derivative having a therapeutic effect on the kinase-related disease, in particular It provides an N- (ethynylphenyl) isoxazolidine-2-carboxamide derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • RIPK1 Receptor-interacting serine/threonine-protein kinase 1
  • An object of another aspect of the present invention is a RIPK1-related disease containing the N- (ethynylphenyl) isoxazolidine-2-carboxamide derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for the prevention or treatment of.
  • An object in another aspect of the present invention is the N- (ethynylphenyl) isoxazolidine-2-carboxamide derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the object in need thereof ( To provide a treatment method for RIPK1-related diseases, comprising administering to a subject).
  • An object in another aspect of the present invention is for use in the prevention or treatment of RIPK1-related diseases, the N- (ethynylphenyl) isoxazolidine-2-carboxamide derivatives, stereoisomers thereof or pharmaceuticals thereof It is to provide an acceptable salt.
  • An object in another aspect of the present invention is the N- (ethynylphenyl) isoxazolidine-2-carboxa for use in the manufacture of a medicament for use in the prevention or treatment of RIPK1-related diseases. It is to provide the use of a amide derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • One aspect of the present invention provides a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • E is nitrogen (N) or carbon (C);
  • L is a direct bond or a C 1-5 alkylene group
  • R 1 and R 2 are each independently absent, hydrogen, halogen atom, or C 1-5 straight or branched chain alkyl;
  • R 3 is unsubstituted or substituted pyridinyl, pyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl;
  • R 4 is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl or thiazolyl, where substituted phenyl is substituted with one or more halogen atoms or C 1-10 straight or branched chain alkoxy, where substituted pyridinyl or thiazolyl is substituted with a C 1-10 linear or branched alkyl, straight-chain or branched alkoxy, haloalkyl, or cyano (-CN) of C 1-10.
  • Another aspect of the present invention is a pharmaceutical composition for the prevention or treatment of RIPK1 (Receptor-interacting serine/threonine-protein kinase 1) related diseases containing the compound, stereoisomers thereof or pharmaceutically acceptable salts thereof as an active ingredient gives
  • Another aspect of the present invention comprises the step of administering the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof to a subject in need thereof, RIPK1 (Receptor-interacting serine/threonine-protein) kinase 1) It provides a treatment method for related diseases.
  • RIPK1 Receptor-interacting serine/threonine-protein
  • Another aspect of the present invention provides a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease related to RIPK1 (Receptor-interacting serine/threonine-protein kinase 1).
  • Another aspect of the invention for use in the manufacture of a medicament for use in the prevention or treatment of RIPK1 (Receptor-interacting serine/threonine-protein kinase 1) related disease, the compound, stereoisomer thereof, or Provides the use of pharmaceutically acceptable salts.
  • RIPK1 Receptor-interacting serine/threonine-protein kinase 1
  • the N- (ethynylphenyl)isoxazolidine-2-carboxamide derivative provided in one aspect of the present invention exhibits excellent inhibitory activity against RIPK1 (Receptor-interacting serine/threonine-protein kinase 1), thus it is a kinase. There is an effect that can be used as a treatment for a related disease.
  • RIPK1 Receptor-interacting serine/threonine-protein kinase 1
  • halogen atom may be F, Cl, Br, or I.
  • haloalkyl may mean straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halogen atoms as defined herein.
  • examples of the haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and N -butyl independently substituted with one or more halogen atoms, for example F, Cl, Br, I .
  • alkyl may refer to a saturated acyclic hydrocarbon consisting of carbon atoms straight-chain or branched representative -.
  • (C 1 ⁇ 8-alkyl) is -methyl, -ethyl, - N- propyl-N -butyl, - N- cyclopentyl and - N- cyclohexyl-N- heptyl with - N- and include octyl; branched chain saturated alkyl-isopropyl-sec (sec) butyl, - isobutyl, - Tert-butyl, -isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • -(C 1-8 alkyl) may be substituted It may or may not be substituted, for example, a C 1-8 alkyl group may be substituted with phenyl to form a benzyl
  • cycloalkyl functional group may mean a non-aromatic saturated or unsaturated carbon ring.
  • Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3- Cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl and cyclooctadienyl.
  • the cycloalkyl group may or may not be substituted. In one embodiment, this cycloalkyl group may be a C 3-8 cycloalkyl group.
  • hetero cycloalkyl means a saturated or partially unsaturated cyclic substituent having a total number of ring atoms of 3 to 10 and containing 1 to 5 hetero atoms selected from N, O and S. Can. Unless otherwise stated, heterocycloalkyl groups can be monocyclic, bicyclic, spirocyclic or polycyclic cyclic. In addition, the heterocycloalkyl may include a cyclic bridge with one or more elements. Heterocycloalkyl can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms.
  • heterocycloalkyl examples include pyrrolidine, piperidine, N -methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, Phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropan, 2-azaspiro[3.3]heptane, (1R, 5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2
  • aryl may mean any functional group or substituent derived by removing one hydrogen from an aromatic hydrocarbon ring.
  • the aryl group may be a monocyclic aryl group or a polycyclic aryl group.
  • the number of ring-forming carbon atoms of the aryl group may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less.
  • aryl group examples include a phenyl group, a naphthyl group, a fluorenyl group, anthracenyl group, a phenanthryl group, a biphenyl group, a terphenyl group, a quarterphenyl group, a quenkyphenyl group, a sexyphenyl group, a triphenylene group, a pyrenyl group, a benzo fluoranthenyl group, Although a chrysenyl group etc. can be illustrated, it is not limited to these.
  • heteroaryl may be an aryl ring group containing one or more of O, N, P, Si and S as heterogeneous elements.
  • the number of ring-forming carbon atoms of the heteroaryl group may be 2 or more and 30 or less, or 2 or more and 20 or less.
  • Heteroaryl can be monocyclic heteroaryl or polycyclic heteroaryl.
  • the polycyclic heteroaryl may be, for example, a bicyclic or tricyclic structure.
  • heteroaryl examples include thienyl, thiophene, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridinyl, bipyridyl, pyrimidyl, Triazinyl, triazolyl, acridil group, pyridazinyl group, pyrazinyl, quinolinyl, quinazolin, quinoxalinyl, phenoxazil, phthalazinyl, pyrimidinyl, pyrido pyrimidinyl, pyridopyra Genyl, pyrazino pyrazinyl, isoquinoline, indole, carbazole, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidin
  • hetero aryl may also include a bicyclic heterocyclo-aryl comprising an aryl ring fused to a hetero cycloalkyl ring or hetero aryl fused to a cyclo alkyl ring.
  • the present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • E is nitrogen (N) or carbon (C);
  • L is a direct bond or a C 1-5 alkylene group
  • R 1 and R 2 are each independently absent, hydrogen, halogen atom, or C 1-5 straight or branched chain alkyl;
  • R 3 is unsubstituted or substituted pyridinyl, pyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl;
  • R 4 is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl or thiazolyl, where substituted phenyl is substituted with one or more halogen atoms or C 1-10 straight or branched chain alkoxy, where substituted pyridinyl or thiazolyl group may be one substituted with a C 1-10 linear or branched alkyl, straight-chain or branched alkoxy, haloalkyl, or cyano (-CN) of C 1-10.
  • the present invention may be a compound represented by Formula 2 or 3 below:
  • the E, L, R 1 , R 2 , R 3 and R 4 are as defined above.
  • L is a direct bond or a C 1-3 alkylene group
  • R 1 and R 2 may be each independently hydrogen, F, Cl, Br, or C 1-5 straight or branched chain alkyl.
  • the C 1-3 linear alkyl may be more specifically a methyl group.
  • R 3 is, , , ,
  • R 3 is , or It may be a substituted heteroaryl represented by.
  • R 5 is hydrogen or an unsubstituted or substituted amino group
  • the substituted amino group is C 1-10 straight or branched chain alkyl, C 1-10 straight or branched chain alkylcarbonyl, C 3-6 cyclo Alkylcarbonyl, C 1-10 straight or branched chain alkoxycarbonyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyrazolyl, C 3-6 cycloalkyl, or oxygen (O) as a hetero atom
  • Unsubstituted or substituted 6-membered heterocycloalkyl, and the substituted phenyl or substituted pyrazolyl is unsubstituted or substituted 6-membered hetero containing one or more C 1-10 alkyl or nitrogen (N).
  • the substituted amino group is C 1-5 straight-chain alkyl, C 1-5 straight-chain alkylcarbonyl, C 3-4 cycloalkylcarbonyl, C 1-5 straight-chain alkoxycarbonyl, unsubstituted phenyl, It may be substituted with unsubstituted or substituted pyrazolyl, C 3-4 cycloalkyl, or unsubstituted 6-membered heterocycloalkyl containing one oxygen (O) as a hetero atom. More specifically, the substituted pyrazolyl may be C 1-3 alkyl or 6-membered heterocycloalkyl substituted with a methyl group and substituted with one nitrogen (N).
  • R 6 is C 1-10 linear or branched chain alkyl, or unsubstituted or substituted amino group, and the substituted amino group is C 1-10 linear or branched alkyl, C 3-6 cycloalkyl, It may be substituted with hydroxyalkyl of C 1-10 .
  • the substituted amino group may be substituted with C 1-5 branched chain alkyl, C 3-4 cycloalkyl, or C 1-5 hydroxyalkyl.
  • R 7 is C 1-10 straight or branched chain alkyl, C 1-10 straight or branched alkoxy, or unsubstituted or substituted to form a ring group fused with two adjacent carbon atoms of the pyridinyl. 6-membered heterocycloalkyl group. Specifically, R 7 is C 1-5 alkyl, C 1-5 alkoxy, or a 6-membered hetero substituted with oxygen (O) forming a ring group fused with two adjacent carbon atoms of the pyridinyl It may be a cycloalkyl group.
  • R 4 is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl or thiazolyl, wherein substituted phenyl is substituted with one or more halogen atoms or C 1-5 straight or branched chain alkoxy, where substituted pyridinyl or thiazolyl group may be one substituted with straight or branched alkyl, straight-chain or branched alkoxy, haloalkyl, or cyano (-CN) of a C 1-5 of C 1-5.
  • the substituted phenyl may be substituted with one or more F, Cl, Br, or C 1-3 alkoxy
  • the substituted pyridinyl or thiazolyl is C 1-3 straight-chain alkyl, C 1-3 It may be substituted with a straight chain alkoxy, trifluoroalkyl (-CF 3 ) or cyano (-CN).
  • the pyridinyl may be substituted with methyl or cyano and the thiazolyl may be substituted with trifluoroalkyl.
  • R 4 is
  • L is a direct bond or C 1-3 alkylene
  • R 1 and R 2 are each independently absent or hydrogen
  • R 3 is Is
  • R 4 is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl or thiazolyl, where substituted phenyl is substituted with one or more halogen atoms or straight or branched chain alkoxy of C 1-3 , where substituted
  • the pyridinyl or thiazolyl may be substituted with C 1-3 linear or branched alkyl, C 1-5 linear or branched alkoxy, haloalkyl or cyano (-CN).
  • R 4 may be unsubstituted or substituted with one or more halogen atoms selected from the group consisting of F, Cl, and Br. More specifically, the halogen atom may be F.
  • L is a direct bond or a C 1-3 alkylene group
  • R 1 and R 2 are each independently hydrogen, a halogen atom or C 1-5 straight or branched chain alkyl,
  • R 5 is hydrogen, or an unsubstituted or substituted amino group, and the substituted amino group is C 1-3 straight or branched chain alkyl, C 1-3 straight or branched chain alkylcarbonyl, C 3- Heteroalkyl of 4 cycloalkylcarbonyl, C 1-3 straight or branched alkoxycarbonyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyrazolyl, C 3-4 cycloalkyl, or oxygen (O) Which is an unsubstituted or substituted 6-membered heterocycloalkyl containing an atom, and the substituted phenyl or substituted pyrazolyl is unsubstituted or substituted 6 containing one or more C 1-3 alkyl or nitrogen (N).
  • R 6 is C 1-3 straight or branched chain alkyl, or unsubstituted or substituted amino group, and the substituted amino group is C 1-3 straight or branched chain alkyl, C 3-4 cycloalkyl, substituted with C 1-5 hydroxyalkyl, wherein R 7 is C 1-3 straight or branched chain alkyl, C 1-3 straight or branched alkoxy, or pyridinyl Is an unsubstituted or substituted 6-membered heterocycloalkyl group forming a fused ring group with two carbon atoms adjacent to each other; And
  • R 4 is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl or thiazolyl, where substituted phenyl is substituted with one or more halogen atoms or straight or branched chain alkoxy of C 1-3 , wherein substituted pyridinyl or thiazolyl group may be one substituted with straight or branched alkyl, straight-chain or branched alkoxy, haloalkyl, or cyano (-CN) of a C 1-3 of C 1-3.
  • L is a direct bond or methylene
  • R 1 and R 2 are each independently hydrogen, F, or C 1-3 straight-chain alkyl
  • R 3 is Is
  • R 4 is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridinyl or thiazolyl, where substituted phenyl is substituted with one or more halogen atoms or straight or branched chain alkoxy of C 1-3 , where substituted pyridinyl or thiazolyl group may be substituted is a straight or branched alkyl, straight-chain or branched alkoxy, tri fluorocarbon of C 1-3 (-CF 3) or cyano (-CN) C 1-3 of have.
  • R 4 is
  • L is a direct bond
  • R 1 and R 2 are hydrogen
  • R 5 is hydrogen, or an unsubstituted or substituted amino group, and the substituted amino group is C 1-3 straight or branched chain alkyl, C 1-3 straight or branched chain alkylcarbonyl, C 3- Heteroalkyl of 4 cycloalkylcarbonyl, C 1-3 straight or branched alkoxycarbonyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyrazolyl, C 3-4 cycloalkyl, or oxygen (O) which is an unsubstituted or substituted 6-membered heterocycloalkyl containing an atom, and the substituted phenyl or substituted pyrazolyl is unsubstituted or substituted 6 containing one or more C 1-3 alkyl or nitrogen (N).
  • R 6 is C 1-3 straight or branched chain alkyl, or unsubstituted or substituted amino group, and the substituted amino group is C 1-3 straight or branched chain alkyl, C 3-4 cycloalkyl, substituted with C 1-3 hydroxyalkyl, wherein R 7 is C 1-3 straight or branched chain alkyl, C 1-3 straight or branched chain alkoxy, or pyridinyl Is an unsubstituted or substituted 6-membered heterocycloalkyl group forming a fused ring group with two carbon atoms adjacent to each other; And
  • R 4 may be unsubstituted phenyl.
  • R 3 is
  • the compound represented by Formula 2 or 3 may be a compound represented by Formula 2', 2'', 3'or 3'', respectively:
  • the E, L, R 1 , R 2 , R 3 and R 4 are as defined above.
  • the compound represented by Formula 1 may be any one compound selected from the following group of compounds, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of the compound may be an acid addition salt formed by a pharmaceutically acceptable free acid.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., 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, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.
  • the present invention may include all of the compounds represented by Formula 1 and pharmaceutically acceptable salts thereof, as well as solvates, stereoisomers, hydrates, etc., which can be prepared therefrom. It can be an enantiomer.
  • Step 1 Preparing a compound represented by Chemical Formula 5 from a compound represented by Chemical Formula 4 (Step 1);
  • Step 2 Preparing a compound represented by Formula 6 from the compound represented by Formula 5 prepared in Step 1 (Step 2);
  • step 4 The step of preparing a compound represented by the formula (1) by reacting the compound represented by the formula (8) and the N,N'- disuccinimidyl carbonate and the compound represented by the formula (9) prepared in step 3 (step 4) Can be manufactured through.
  • R 1 , R 2 , R 3 , R 4 and E are independently as defined above;
  • the PG may be a tri(C 1 -C 6 alkyl) silyl group, a C 1 -C 6 alkyl carbonyl group, a benzoyl group, and a protecting group selected from phenylacetyl groups, specifically, trimethylsilyl (TMS);
  • TMS trimethylsilyl
  • X 1 and X 2 are independently a halogen atom.
  • step 1 is a step of preparing a compound represented by Chemical Formula 3 from a compound represented by Chemical Formula 2. More specifically, in a position where X 1 of the compound represented by Formula 2 is bonded, a protecting group is substituted with acetylene substituted at the terminal, and in one embodiment, trimethylsilylacetylene is substituted to prepare a compound represented by Formula 3 It is a step.
  • the reaction solvent is not particularly limited, but acetonitrile or the like may be used, and the reaction temperature may be performed in a range of 70 to 90°C.
  • step 2 is a step of preparing a compound represented by Formula 4 from the compound represented by Formula 3 prepared in Step 1.
  • the removal of the protecting group may be performed by employing a method known as a removing method of the protecting group without limitation, depending on the type of the protecting group introduced. If the protecting group introduced in one embodiment is trimethylsilyl (TMS), trimethylsilyl may be removed by treating potassium carbonate under a methanol solvent.
  • TMS trimethylsilyl
  • step 3 is a step of preparing a compound represented by Formula 6 by reacting the compound represented by Formula 4 and the compound represented by Formula 5 prepared in Step 2 to be.
  • the reaction can be carried out in ethyl acetate, the reaction temperature can be carried out in the range of 30 to 70 °C.
  • the reaction time is not particularly limited, but may be performed for 1 hour to 3 hours.
  • step 4 reacts the compound represented by Chemical Formula 6 prepared in Step 3 with the compound represented by N,N'-disuccinimidyl carbonate and Chemical Formula 7 It is a step of preparing a compound represented by the formula (1).
  • a compound represented by Chemical Formula 6 and N,N'-disuccinimidyl carbonate are first reacted in a dimethylformamide solvent (reaction temperature is about 0 to 10°C, reaction time is 1 to 1). It can be carried out for 3 hours, but is not particularly limited to this), and then reacting the compound represented by the formula (7) to prepare a compound represented by the formula (1).
  • RIPK1 Receptor-interacting serine/threonine-protein kinase 1
  • RIPK1 Receptor-interacting serine/threonine-protein kinase 1
  • the RIPK1-related disease in one aspect, the RIPK1-related disease,
  • the pharmaceutical composition for preventing or treating cancer containing the compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent or in combination with other anticancer agents in use. .
  • the pharmaceutical composition of the present invention is formulated into tablets, capsules, powders, granules, suspensions, emulsions, syrups, other liquids by conventional methods by further including excipients, disintegrants, sweeteners, lubricants, flavoring agents, etc. Can be.
  • the pharmaceutical composition of the present invention can act systemically and/or locally, and is subject to various routes such as oral and parenteral, i.e., lung, nasal, sublingual, lingual, buccal, rectal, skin, transdermal or conjunctival. Since it can be administered in, it can be formulated in a form suitable for the route of administration.
  • oral and parenteral i.e., lung, nasal, sublingual, lingual, buccal, rectal, skin, transdermal or conjunctival. Since it can be administered in, it can be formulated in a form suitable for the route of administration.
  • formulations suitable for oral administration are those containing the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example the invention Gastric-resistant or delayed-dissolving or insoluble coatings to control the release of the compound of the present), tablets or films/oblates that disintegrate rapidly in the oral cavity, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules) ), sugar-coated tablets, chewables (eg soft chewables), granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example the invention Gastric-resistant or delayed-dissolving or insoluble coatings to control the release of the compound of the present
  • tablets or films/oblates that disintegrate rapidly in the oral cavity films/lyophilisates
  • capsules e.g. hard or soft gelatin capsules
  • sugar-coated tablets e.g. hard or soft
  • Parenteral administration avoids the absorption phase (e.g., by intravenous, intraarterial, intracardiac, intrathecal or lumbar routes) or includes absorption (e.g. intramuscular, skin, subcutaneous, intradermal, transdermal) Or by an intraperitoneal route).
  • Formulations suitable for parenteral administration may include solutions, suspensions, emulsions, lyophilisates or preparations for injection and infusion in sterile powder form.
  • Another aspect of the present invention comprises the step of administering a pharmaceutically effective amount to a subject in need of the compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • Kinase-related diseases are provided.
  • the term “administration” refers to introducing the pharmaceutical composition of the present invention to a suspected subject of the disease in any suitable way, and the route of administration can be administered through various routes as long as the target tissue can be reached. have.
  • the term “pharmaceutically effective amount” refers to an amount sufficient to treat the disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level refers to the individual type and severity, age, sex, and disease. It can be determined according to the type, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and discharge, the duration of treatment, the factors including the drugs used simultaneously, and other factors well known in the medical field.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered single or multiple.
  • the dosage of the pharmaceutical composition of the present invention can be determined by a specialist according to various factors such as the patient's condition, age, sex and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used in more than the determined dosage.
  • RIPK1 Receptor-interacting serine/threonine-protein kinase 1
  • N- (ethynylphenyl) isoxazolidine-2-carboxamide Derivatives, stereoisomers thereof, or pharmaceutically acceptable salts thereof are provided.
  • N- (ethynylphenyl) Provides the use of sazolidine-2-carboxamide derivatives, stereoisomers thereof or pharmaceutically acceptable salts thereof.
  • N- (ethynylphenyl) isoxazolidine-2-carboxamide derivative provided in one aspect of the present invention exhibits excellent inhibitory activity against RIPK1 (Receptor-interacting serine/threonine-protein kinase 1), so RIPK1 There is an effect that can be used as a therapeutic agent for a related disease, which is supported by experimental examples described below.
  • RIPK1 Receptor-interacting serine/threonine-protein kinase 1
  • RIPK1 Receptor-interacting serine/threonine-protein kinase 1 related diseases are the same as described above, so a detailed description is omitted to avoid overlapping explanations.
  • the compound synthesized in the Examples of the present invention was purified or structural analysis was performed by the following HPLC conditions: medium pressure liquid chromatography (MPLC); For medium pressure liquid chromatography, CombiFlash Rf + UV from TELEEDYNE ISCO was used.
  • MPLC medium pressure liquid chromatography
  • CombiFlash Rf + UV from TELEEDYNE ISCO was used.
  • the equipment equipped with mass QDA Detector manufactured by Waters was used in the UPLC system (ACQUITY UPLC PDA Detector) manufactured by Waters.
  • the column used was ACQUITY UPLC®BEH C18 (1.7s ⁇ m, 2.1X50 mm) from Waters, and the column temperature was performed at 30°C.
  • Mobile phase A used water containing 0.1% formic acid and mobile phase B used acetonitrile containing 0.1% formic acid.
  • the equipment equipped with mass QDA Detector manufactured by Waters was used for the Autopurification HPLC system (2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector) manufactured by Waters.
  • the column used was SunFire® Prep C18 OBD TM (5 ⁇ m, 19 ⁇ 50 mm) from Waters, and the column temperature was performed at room temperature.
  • Mobile phase A used water containing 0.035% trifluoroacetic acid
  • mobile phase B used methanol containing 0.035% trifluoroacetic acid.
  • Prep 150 LC system 2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III
  • the column used was Waters' XTERRA®Prep RP18 OBD TM (10 ⁇ m, 30X300 mm), and the column temperature was performed at room temperature.
  • room temperature refers to a temperature of about 20 to 25°C.
  • a rotary evaporator was used for concentration under reduced pressure or removal of solvent.
  • Step 1 tert -Butyl ( R )-(3-hydroxy-3-phenylpropoxy)carbamate preparation
  • Step 2 tert -Butyl ( S )-3-phenylisooxazolidine-2-carboxylate preparation
  • the pyridine solvent was removed by concentration under reduced pressure, and the organic layer was extracted using DCM (500 mL), HCl (500 mL, 2N), and brine (200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound 3-fluoro- N -methoxy- N- methylbenzamide (110 g, 600.50 mmol, 93.49% yield) as a yellow oil.
  • Step 4 ( R )-3-Chloro-1-(3-fluorophenyl)propan-1-ol
  • Step 5 tert -Butyl ( R )-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate preparation
  • Step 6 tert -Butyl ( S )-3-(3-fluorophenyl)isooxazolidine-2-carboxylate preparation
  • the target compound was purified by SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 um); mobile phase: [Neu-MeOH]; B%: 15 %, 2.9 min; 760 min) and light yellow solid tert -Butyl ( S )-3-(3-fluorophenyl)isooxazolidine-2-carboxylate (25 g, 92.00 mmol, 36.17% yield, 98.37% purity, 100% ee) and tert -butyl ( R ) -3-(3-fluorophenyl)isooxazolidine-2-carboxylate (6.5 g, 22.16 mmol, 8.71% yield, 91.13% purity, 100% ee) was obtained.
  • Step 7 ( S )-3-(3-fluorophenyl)isooxazolidine preparation
  • Preparation Examples 3 to 20 were prepared in a similar manner to Preparation Examples 1 and 2, and the compound names, chemical structural formulas, UPLC and NMR analysis results of Preparation Examples 3 to 20 are shown below, and were used in the preparation of Examples below.
  • Step 1 ( S )- N- Preparation of (3-ethynylphenyl)-3-phenylisooxazolidine-2-carboxamide
  • the obtained filtrate was concentrated under reduced pressure, and then purified by medium pressure liquid chromatography (diclomethane/ethyl acetate) to obtain a solid target compound 3-(imidazo[1,2-b]pyridazine-3-ylethynyl). 4-methylaniline (555 mg, 80%) was obtained.
  • Step 4 N- Preparation of (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-phenylisooxazolidine-2-carboxamide trifluoroacetate
  • Examples 2 to 25 were prepared in a similar manner to Example 1, and the compound names, chemical structural formulas, NMR and UPLC analysis results of Examples 1 to 25 are summarized in Table 1 below.
  • Step 2 ( S )- N- Preparation of (2-iodopyridin-4-yl)-3-phenylisooxazolidine-2-carboxamide
  • Step 3 ( S )- N- Preparation of (2-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-4-yl)-3-phenylisooxazolidine-2-carboxamide trifluoroacetic acid salt
  • Example Compound (S) obtained in the step 2 of 26 - N- (2- iodo-4-yl) -3-phenyl-iso-oxazolidine-2-carboxamide (470mg, 1.189mmol)
  • the above-described 3-Ethynylimidazo[1,2-b]pyridazine (213mg, 1.487mmol)
  • Pd(PPh 3 ) 4 (68.7mg, 0.059mmol)
  • CuI(22.65mg, 0.119) obtained in Step 2 of Example 1 mmol) and triethylamine (332 ⁇ L, 2.379 mmol) were added to acetonitrile (11 mL) to dissolve, followed by heating at 50° C.
  • Examples 27 to 29 were prepared in a similar manner to Example 26, and the compound names, chemical structural formulas, NMR and UPLC analysis results of Examples 26 to 29 are summarized in Table 2 below.
  • Example rescue Compound name UPLC[M+1] + ; rt (min) 1 H NMR 26 ( S )- N- (2-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-4-yl)-3-phenylisooxazolidine-2-carboxamide 411.3; 1.36 1 HNMR (400 MHz, CDCl 3 ) ⁇ 8.44-8.42 (m, 1H), 8.42-8.39 (m, 1H), 8.03-8.01 (m, 1H), 7.96-7.92 (m, 2H), 7.74-7.71 (m, 1H), 7.43-7.39 (m, 1H), 7.37-7.28 (m, 4H), 7.25-7.21 (m, 1H), 7.10-7.03 (m, 1H), 5.48-5.40 (m, 1H) , 4.29-4.17 (m, 1H), 3.96-3.85 (m, 1H), 2.86-2.75 (m, 1H), 2.44
  • Step 1 Preparation of 3-((2-fluoro-5-nitrophenyl)ethynyl)imidazo[1,2-b]pyridazine
  • the obtained filtrate was concentrated under reduced pressure, and then purified by medium pressure liquid chromatography (diclomethane/ethyl acetate) to obtain a target compound of solid 3-((2-fluoro-5-nitrophenyl)ethynyl)imidazo[1 ,2-b]pyridazine (619 mg, 78%).
  • the obtained filtrate was concentrated under reduced pressure using a rotary evaporator to obtain the target compound 4-fluor-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)aniline (535mg, 97%).
  • Step 3 N- (4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-5-phenyl-4,5-dihydro-1H-pyrisol-1-carboxa Preparation of amide trifluoroacetate
  • the organic layer was dried over sodium sulfate, concentrated under reduced pressure, purified using a Prep-150 device, and then the target compound N- (4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl) )Phenyl)-5-phenyl-4,5-dihydro-1 H -pyrizol-1-carboxamide trifluoroacetic acid salt (119 mg, 56%) was obtained.
  • Examples 31 to 34 were prepared in a similar manner to Example 30, and the compound names, chemical structural formulas, NMR and UPLC analysis results of Examples 30 to 34 are summarized in Table 3 below.
  • Step 1 tert -Butyl ( tert -Butoxycarbonyl) (imidazo[1,2-a]pyridin-8-yl)carbamate preparation
  • the recovered solid was dried under reduced pressure to obtain a target compound of white solid tert -butyl ( tert -butoxycarbonyl) (3-iodoimidazo[1,2-a]pyridin-8-yl)carbamate (14g, 30.09 mmol, 80.24% yield, 98.79% purity).
  • Step 3 tert -Butyl ( S )-( tert -Butoxycarbonyl)(3-((3-(3-phenylisooxazolidine-2-carboxamido)phenyl)ethynyl)imidazo[1,2-a]pyridin-8-yl)carbamate Manufacturing
  • Step 4 ( S )- N- Preparation of (3-((8-aminoimidazo [1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide
  • 300mg of the target compound was prep-HPLC (column: Xtimate C18 150 * 40mm * 10 ⁇ m; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 40%-70%, 10 min]; B%: purified through 40%-70%, 10min) to the target compound ( S )- N- (3-((8-aminoimidazo [1,2-a]pyridin-3-yl) as a white solid) Thynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide (45mg, 100% purity, 96.82% ee) was obtained.
  • Step 1 ( S )- N- (3-((8-(Cyclopropanecarboxamido)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide Produce
  • Example 35 The compound obtained in (S) - N- (3 - (phenyl (8-amino already ethynyl-imidazo [1,2-a] pyridin-3-yl))) -3-phenyl-oxazolidine-isopropyl- After dissolving 2-carboxamide (200mg, 472.29 umol, 1 eq ) in DCM (1mL), TEA (143.37mg, 1.42mmol, 197.21uL, 3 eq ) is added at room temperature.
  • Examples 35 and 36 were prepared by the methods listed above, and Examples 37 to 39 were prepared by a method similar to that of Example 36. It is shown in summary.
  • Step 2 ( S )- N- Preparation of (3-((8-bromoimidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide
  • the reaction mixture was concentrated under reduced pressure using a rotary evaporator, and then purified by a reverse phase column to obtain a yellow solid target compound ( S )- N- (3-((8-bromoimidazo[1,2-a]pyridine-3) -Yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide (2.5 g, 5.09 mmol, 74.48% yield, 99.31% purity, 96.57% ee) was obtained.
  • Step 3 ( S )- N- (3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxa Preparation of zolidine-2-carboxamide
  • Examples 41 to 45 were prepared in a similar manner to Example 40, and the compound names, chemical structural formulas, NMR and UPLC analysis results of Examples 40 to 45 are summarized in Table 5 below.
  • Step 1 ( S )- N- Preparation of (3-(imidazo[1,2-a]pyridin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide
  • Examples 47 to 61 were prepared in a similar manner to Example 46, and the compound names, chemical structural formulas, NMR and UPLC analysis results of Examples 46 to 61 are summarized in Table 6 below.
  • Example 4 was commissioned by DiscoverX to measure enzyme selectivity, and experiments were performed using a scanMAX TM Kinase analysis panel.
  • the concentration of the drug to be treated with enzyme was 1 ⁇ M in DMSO
  • the control percentage was determined in the same manner as in Equation 1 below, and the results are shown in Table 7 below.
  • the positive control refers to a compound showing a control percentage of 0%
  • the negative control shows a control percentage of 100% with DMSO.
  • the enzyme selectivity of the present invention was determined to have activity against the enzyme if the control percentage for the enzyme is ⁇ 35% (i.e. less than 35%).
  • the example compound according to the present invention has a value smaller than the control percentage of 35% relative to RIPK1, and thus it can be seen that it has activity against RIPK1.
  • the example compounds according to the present invention were reacted with purified human GST-RIPK1 (1-375, signalchem) enzyme to evaluate the enzyme inhibitory ability in the following manner.
  • As a reaction buffer 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg/mL BSA, and 0.5 uM DTT composition were used, and all test samples were reacted on the reaction buffer.
  • human GST-RIPK1 (1-375, 10 ng) enzyme, purified ATP (50 uM), and specific substrate solution were reacted for 4 hours at 25°C, and the enzyme activity was determined in vitro ADP-Glo TM kinase assay (promega) It was confirmed using.
  • Luminoscence was measured by reacting enzymatic activity reaction solution, ADP-Glo reaction solution, and enzymatic activity detection solution in a 2:2:1 ratio. Relative to the fluorescence of the vehicle control group enzymatic activity which is not treated with the compounds were calculated to inhibit enzyme activity degree of the concentration of each compound, where the enzyme activity inhibition 50% inhibition for each compound concentration of the IC 50 (nM) value for which Decided. The IC 50 of each compound was determined by three data sets and was obtained using Prism (version 7.01, Graphpad) software.
  • the compound according to the present invention exhibits a cell protective effect under apoptosis-inducing conditions according to TNF- ⁇ .
  • Cell protective effect when treating apoptosis inducers such as TNF- ⁇ from outside the cell, inducing apoptosis of human Jurkat T cells (I2.I Cells) deficient in FADD, and treating the example compounds according to the present invention Whether or not was confirmed through the following analysis.
  • FADD-deficient Jurkat T cell lines are cultured using RPMI medium (Hyclone) containing 10% FBS, and when performing the test, each cell has a concentration of 10,000 cells/well in a 96-well plate containing medium suitable for the cell line.
  • TNF- ⁇ was treated in each well to be 40 ng, and the compounds prepared in the above Examples were treated with a concentration of 1 ⁇ M at the highest concentration, giving a three-fold concentration gradient, and dimethyl sulfoxide (DMSO) as a solvent control. ) was treated at the same concentration as 0.05% (v/v) used for compound treatment. Then, each cell was cultured for 50 hours. To confirm the viability of the cells, the mixture provided in the CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega) was added to the culture medium of each cultured cell, and further cultured at 37°C for 30 minutes.
  • DMSO dimethyl sulfoxide
  • Luminoscence fluorescence was measured.
  • the degree of inhibition of apoptosis induction according to the treatment concentration of each compound was calculated based on the fluorescence of the cells in which the compound was not treated, and the concentration at which the inhibitory capacity was 50% was determined as an EC 50 ( ⁇ M) value and prism (version 7.01, GraphPad).
  • Example Enzyme IC 50 (nM) I2.I Cell EC 50 (nM) Example Enzyme IC 50 (nM) I2.I Cell EC 50 (nM)
  • Table 8 shows the results of measuring the cell protective effect under the apoptosis-inducing condition of each experimental compound for the RIPK1 enzyme activity and FADD-deficient Jurkat T cells.
  • Table 8 shows the results of measuring the cell protective effect under the apoptosis-inducing condition of each experimental compound for the RIPK1 enzyme activity and FADD-deficient Jurkat T cells.
  • the example compound exhibits good activity for both enzyme activity and cell protective effect. Therefore, it can be seen that the compound according to the present invention has excellent cell protective activity under the conditions of cell death induction, as confirmed in the above experiment.

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Abstract

La présente invention concerne un dérivé aryle ou hétéroaryle et une composition pharmaceutique le comprenant en tant que principe actif pour le traitement d'une maladie associée à une kinase. Un dérivé aryle ou hétéroaryle selon un aspect de la présente invention présente une excellente activité inhibitrice contre la sérine/thréonine protéine kinase 1 interagissant avec des récepteurs (RIPK1) et, ainsi, peut être utilisé en tant qu'agent thérapeutique pour une maladie associée à RIPK1.
PCT/KR2019/018834 2019-01-15 2019-12-31 Dérivé d'aryle ou d'hétéroaryle, et composition pharmaceutique le comprenant en tant que principe actif pour le traitement d'une maladie associée à une kinase WO2020149553A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
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KR20230058292A (ko) * 2021-10-22 2023-05-03 보로노이바이오 주식회사 아릴 또는 헤테로아릴 유도체, 및 이를 유효성분으로 포함하는 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물

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WO2023018643A1 (fr) * 2021-08-10 2023-02-16 Abbvie Inc. Inhibiteurs de nicotinamide ripk1
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