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WO2020149553A1 - Aryl or heteroaryl derivative, and pharmaceutical composition comprising same as active ingredient for treatment of kinase-related disease - Google Patents

Aryl or heteroaryl derivative, and pharmaceutical composition comprising same as active ingredient for treatment of kinase-related disease Download PDF

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Publication number
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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Prior art keywords
phenyl
carboxamide
substituted
imidazo
ethynyl
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PCT/KR2019/018834
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French (fr)
Korean (ko)
Inventor
이화
조서현
류희선
김승수
최현진
도우미
김현경
최지은
김대권
손정범
김남두
Original Assignee
주식회사 보로노이
주식회사 보로노이바이오
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Publication of WO2020149553A1 publication Critical patent/WO2020149553A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/4353—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
    • 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
    • A61K31/4353—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
    • 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
    • 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

The present invention relates to an aryl or heteroaryl derivative and a pharmaceutical composition comprising same as an active ingredient for treatment of kinase-related disease. An aryl or heteroaryl derivative provided according to an aspect of the present invention exhibits an excellent inhibitory activity against receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and as such, can be used as a therapeutic agent for RIPK1-related disease.

Description

아릴 또는 헤테로아릴 유도체, 및 이를 유효성분으로 포함하는 키나아제 관련 질환 치료용 약학적 조성물Aryl or heteroaryl derivatives, and pharmaceutical compositions for treating kinase-related diseases comprising the same as an active ingredient
아릴 또는 헤테로아릴 유도체, 및 이를 유효성분으로 포함하는 키나아제 관련 질환 치료용 약학적 조성물에 관한 것이다.An aryl or heteroaryl derivative, and a pharmaceutical composition for treating a kinase-related disease comprising the same as an active ingredient.
단백질 키나아제는 ATP의 감마-인산기를 단백질의 타이로신, 세린 및 트레오닌의 하이드록시 그룹에 전달하는 인산화 반응을 촉매하는 효소로서, 세포의 대사, 유전자 발현, 세포 성장, 분화 및 세포 분열 작용을 담당하며 세포 신호 전달에 중요한 역할을 한다(비특허문헌 1, Thomas A. Hamilton, in Encyclopedia of Immunology (Second Edition), 1998, 2028-2033). 단백질 키나아제는 타이로신 단백질 키나아제와 세린/트레오닌 키나아제로 분류되는데, 그 중 약 90 종 이상은 타이로신 키나아제이다.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.
단백질 키나아제는 분자 스위치로 세포 내에서 활성과 비활성 상태 사이의 전이가 원활하게 조절되어야 한다. 만약, 상기 활성과 비활성 상태 사이의 전이가 비정상적으로 조절되면 세포 내 신호 전달을 과도하게 활성화시켜 통제불능의 세포 분열 및 증식을 유도하게 된다. 또한, 단백질 키나아제의 유전자 변이, 증폭 및 과발현에 의한 비정상적인 활성화는 다양한 종양의 발생 및 진행과 관련이 있어 염증성 질환, 퇴행성 뇌질환, 자가면역 질환, 암 등 다양한 질병의 발병에 결정적인 역할을 하게 된다. 이와 관련된 키나아제의 예를 들면 ABL1, ABL2, BRAF, CDK11, CDK8, CDKL2, CIT, CSF1R, DDR1, DDR2, FLT3, KIT, LOK, LTK, MUSK, PAK3, PDGFRA, PDGFRB, RAF1, RIPK1 등이 있다. 단백질 키나아제의 일 구체예인 수용체-상호작용 단백질-1 키나아제(Receptor-interacting serine/threonine-protein kinase 1, RIPK1)는 NF-κB 활성화, 아폽토시스(Apoptosis) 및/또는 네크롭토시스(Necroptosis)를 매개하는데 관여하는 다작용성 신호 전달자이다.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. Examples of related kinases 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-κB activation, apoptosis and/or necroptosis. It is a multifunctional signal transducer involved in doing this.
특히, RIPK1 활성은 괴사 세포사의 카스파제(caspase)-비의존성 경로인 네크롭토시스(Necroptosis)의 매개에 결정적으로 관여하는 것으로 알려져 있다(비특허문헌 2, Holler et al., Nat Immunol 2000; 1: 489-495; 비특허문헌 3, Degterev et al., Nat Chem Biol 2008; 4: 313-321).In particular, RIPK1 activity is known to be critically involved in the mediation of necroptosis, a caspase-independent pathway of necrotic cell death (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).
따라서, RIPK1 활성을 효과적으로 억제할 수 있다면, 종양 괴사 인자 알파(tumor necrosis factor-alpha, TNF-α)에 의한 세포사멸유도 조건에서 세포 보호가 가능하여, 네크롭토시스(Necroptosis)를 차단할 수 있을 것이다. 상기 RIPK1에 의해 매개되는 네크롭토시스(Necroptosis)는 염증성 질환, 퇴행성 뇌질환, 자가면역 질환, 암 등 다양한 질병과 관련이 있음이 보고되어 왔다. 먼저, RIPK1-매개 프로그램화된 괴사가 완전히 차단되도록 설계된 RIP3 녹아웃 마우스는 염증성 장 질환(궤양성 결장염 및 크론병 포함)(비특허문헌 4, (2011) Nature 477, 330-334), 건선(Psoriasis)(비특허문헌 5, (2011) Immunity 35, 572-582), 망막-박리-유도된 광수용체 괴사(비특허문헌 6, (2010) PNAS 107, 21695-21700), 색소성 망막염(Retinitis pigmentosa) (비특허문헌 7, (2012) Proc. Natl. Acad. Sci., 109:36, 14598-14603), 세룰레인-유도된 급성 췌장염(비특허문헌 8, (2009) Cell 137, 1100-1111) 및 패혈증/전신 염증 반응 증후군(SIRS)(비특허문헌 9, (2011) Immunity 35, 908-918)에서 보호성인 것으로 확인된 바 있으므로, 특정 화합물이 RIPK1에 의해 매개되는 네크롭토시스를 차단할 수 있다면, 해당 화합물은 염증성 질환 치료제로 개발될 가능성이 있다.Therefore, if RIPK1 activity can be effectively inhibited, cell protection is possible under apoptosis-inducing conditions by tumor necrosis factor-alpha (TNF-α), and thus, necroptosis can be blocked. will be. It has been reported that necroptosis mediated by RIPK1 is associated with various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer. First, 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. , 109:36, 14598-14603), Cerulein-induced acute pancreatitis (Non-Patent Document 8, (2009) Cell 137, 1100-1111 ) And sepsis/systemic inflammatory response syndrome (SIRS) (non-patent document 9, (2011) Immunity 35, 908-918), so certain compounds block RIPK1 mediated necrosis. If possible, the compound is likely to be developed as a treatment for inflammatory diseases.
또한, RIPK1은 알츠하이머병(Alzheimer's disease)에서 소교 반응 (microglial response)을 매개함이 알려진바 있으므로(비특허문헌 10, PNAS October 10, 2017. 114 (41) E8788-E8797), 특정 화합물이 RIPK1을 표적하여 활성을 효과적으로 억제할 수 있다면, 해당 화합물은 알츠하이머병을 포함하여 다운 신드롬, 파킨슨 질환, 루게릭병, 치매, 헌팅턴 질환, 다발성 경화증(Multiple sclerosis), 근위측성 측삭 경화증, 중풍, 뇌졸중, 경도 인지장애 등의 퇴행성 뇌질환(즉, 퇴행성 신경질환) 치료제로도 개발될 가능성이 있다. 나아가, RIPK1은 종양 괴사 인자 알파(tumor necrosis factor-alpha, TNF-α)의 생산을 조절하고, 상기 TNF-α는 류마티스성 관절염(Rheumatoid arthritis), 암 등 수많은 질병에서 세포 사멸 및 염증 매개에 관여하는 친 염증성 사이토카인임이 알려져 있으므로(비특허문헌 11, Cell Death and Disease (2012) 3, e320), 특정 화합물이 RIPK1을 표적하여 활성을 효과적으로 억제할 수 있다면, 해당 화합물은 류마티스성 관절염(Rheumatoid arthritis)을 포함하여 류마티스성 다발근통, 강직성 척추염, 운동신경원병(Motor neurone disease) 등의 자가면역질환, 또는 암의 치료제로도 개발될 가능성이 있다. 또한, RIPK1은 췌장암(pancreatic cancer)에서 대식세포-매개 적응 면역 내성(Macrophage-Mediated Adaptive Immune Tolerance)을 유도하는 것으로 공지된 바 있다(비특허문헌 12, Cancer Cell 34, 757-774, November 12, 2018). 보다 구체적으로, TAMs에서의 RIPK1 억제는 혼합된 Th1/Th17 표현형(phenotype)에 대한 세포 독성 T 세포 활성화 및 T 헬퍼 세포 분화를 초래하여, 마우스 및 인간 PDA의 기관 유형 모델에서 종양 면역(tumor immunity)을 유도함을 개시하고 있다.In addition, 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). Furthermore, RIPK1 regulates the production of tumor necrosis factor-alpha (TNF-α), and the TNF-α 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. In addition, 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.
이에, RIPK1을 표적으로 하는 것은 PD-1 및 유도성 공동 자극기 기반 면역 요법과 상승적으로 작용하므로, RIPK1은 종양 면역을 통제(governing)하는 체크 포인트(checkpoint) 키나아제임을 알 수 있다. 즉, RIPK1 활성을 효과적으로 억제할 수 있는 화합물은 염증성 질환, 퇴행성 뇌질환, 자가면역 질환, 암 등 다양한 질병의 치료제로 개발될 가능성이 있으므로, 신규한 구조의 단백질 키나아제 억제제에 대한 개발이 요구되고 있다.Thus, targeting 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. .
본 발명의 일 측면에서의 목적은 RIPK1(Receptor-interacting serine/threonine-protein kinase 1)에 대해 우수한 저해활성을 나타내어, 상기 키나아제 관련 질환에 치료 효과를 갖는 신규한 구조의 아릴 또는 헤테로아릴 유도체, 특히 N-(에티닐페닐)이속사졸리딘-2-카복사마이드 유도체, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.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.
본 발명의 다른 일 측면에서의 목적은 상기 N-(에티닐페닐)이속사졸리딘-2-카복사마이드 유도체, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 RIPK1 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.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.
본 발명의 또 다른 일 측면에서의 목적은 상기 N-(에티닐페닐)이속사졸리딘-2-카복사마이드 유도체, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, RIPK1 관련 질환의 치료방법을 제공하는 것이다.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).
본 발명의 다른 일 측면에서의 목적은 RIPK1 관련 질환의 예방 또는 치료에 사용하기 위한, 상기 N-(에티닐페닐)이속사졸리딘-2-카복사마이드 유도체, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.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.
본 발명의 또 다른 일 측면에서의 목적은 RIPK1 관련 질환의 예방 또는 치료에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 N-(에티닐페닐)이속사졸리딘-2-카복사마이드 유도체, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공하는 것이다.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.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명의 일 측면은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공한다:One aspect of the present invention provides a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2019018834-appb-I000001
Figure PCTKR2019018834-appb-I000001
상기 화학식 1에서,In Chemical Formula 1,
E는 질소(N) 또는 탄소(C)이고;E is nitrogen (N) or carbon (C);
L은 직접결합 또는 C1~5 알킬렌기이며;L is a direct bond or a C 1-5 alkylene group;
R1 및 R2는 각각 독립적으로 부존재, 수소, 할로겐 원자, 또는 C1-5의 직쇄 또는 분지쇄 알킬이고;R 1 and R 2 are each independently absent, hydrogen, halogen atom, or C 1-5 straight or branched chain alkyl;
R3은 비치환 또는 치환된 피리디닐, 피리미디닐, 이미다조피리다지닐, 이미다조피리디닐, 이미다조피리미디닐, 피라졸로피리미디닐, 이미다조피라지닐 또는 피라졸로피리디닐이며; 및R 3 is unsubstituted or substituted pyridinyl, pyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl; And
R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-10의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-10의 직쇄 또는 분지쇄 알킬, C1-10의 직쇄 또는 분지쇄 알콕시, 할로알킬 또는 시아노(-CN)로 치환된 것이다.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.
본 발명의 다른 일 측면은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.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
본 발명의 또 다른 일 측면은 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 치료방법을 제공한다.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.
본 발명의 다른 일 측면은 RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 예방 또는 치료에 사용하기 위한, 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다.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).
본 발명의 또 다른 일 측면은 RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 예방 또는 치료에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공한다.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.
본 발명의 일 측면에서 제공하는 N-(에티닐페닐)이속사졸리딘-2-카복사마이드 유도체는 RIPK1(Receptor-interacting serine/threonine-protein kinase 1)에 대해 우수한 억제 활성을 나타내므로, 키나아제 관련 질환의 치료제로 사용 가능한 효과가 있다.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.
이하, 본 발명을 실시 태양으로 예를 들어 상세히 설명한다.Hereinafter, the present invention will be described in detail by way of example.
본 명세서에서, 용어 "비치환 또는 치환된"은 하나 또는 복수의 수소원자가 할로겐 원자(염소(Cl), 요오드(I), 브롬(Br), 플루오르(F)), C1~10 알킬, C2~10 알켄일, C2~10 알킨일, 하이드록실, C1~10 알콕시, 아미노, 니트로, 티올(thiol), 티오에테르, 이민, 시아노, 포스포나토(phosphonato), 포스핀(phosphine), 카르복시, 카르밤오일(carbamoyl), 카르밤산, 아세탈, 요소, 티오카르보닐, 설폰일, 설폰아미드(sulfonamide), 케톤, 알데히드, 에스테르, 아세틸, 이세톡시, 산소(=0), 할로알킬(예를 들어, 트리플루오르메틸), 치환 아미노아실과 아미노알킬, 탄소고리 사이클로 알킬로서 단일 고리이거나 융합 혹은 비융합 다중 고리 (예를 들어, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 또는 사이클로헥실), 혹은 헤테로 사이클로 알킬로서 단일 고리이거나 융합 또는 비융합된 다중 고리 (예를 들어, 피롤리딘일, 피페리딘일딘일, 피페라진일, 모르폴린일, 또는 티아진일), 탄소고리 또는 헤테로 고리, 단일고리 또는 융합 또는 비융합 다중 고리 아릴 (예를 들어, 페닐, 나프틸, 피롤릴(pyrrolyl), 인돌릴, 퓨란일, 티엔일, 이미다졸릴, 옥사졸릴, 이속사졸릴(isoxazolyl), 티아졸릴, 트리아졸릴, 테트라졸릴, 피라졸릴, 피리딘일, 퀴놀린일, 이소퀴놀린일, 아크리딘일(acridinyl), 피라진일, 피리다진일, 피리미딘일, 벤즈이미다졸릴(benzimidazolyl), 벤조티엔일 또는 벤조퓨란일), 아미노(일급, 이급, 또는 삼급), -0-저급알킬, -O-아릴, 아릴, 아릴-저급알킬, CO2CH3, CONH2, OCH2CONH2,NH2, N(C1~4 알킬)2, NHC(O)C1~4알킬, SO2NH2, SO2C1~4알킬, OCHF2, OCF3로 이루어진 군에서 선택되는 하나 이상의 치환기로 치환 또는 치환되지 않은 것을 의미할 수 있다. 또한, 상기 예시된 치환기 각각은 다시 이들 치환기 군에서 선택된 치환기로 비치환 또는 치환된 것일 수 있다. In the present specification, the term "unsubstituted or substituted" means one or more hydrogen atoms are halogen atoms (chlorine (Cl), iodine (I), bromine (Br), fluorine (F)), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hydroxyl, C 1-10 alkoxy, amino, nitro, thiol, thioether, imine, cyano, phosphonato, phosphine ), carboxy, carbamoyl, carbamic acid, acetal, urea, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, acetyl, isethoxy, oxygen (=0), haloalkyl (E.g., trifluoromethyl), substituted aminoacyl and aminoalkyl, monocyclic or fused or non-fused multiple rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) as cycloalkyl, Or as a heterocycloalkyl, a single ring or a fused or unfused multiple ring (e.g., pyrrolidinyl, piperidinyldinyl, piperazinyl, morpholinyl, or thiazinyl), carbon ring or heterocycle, single ring Or fused or non-fused polycyclic aryl (e.g. phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, Triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzo Furanyl), amino (primary, secondary, or tertiary), -0-lower alkyl, -O-aryl, aryl, aryl-lower alkyl, CO 2 CH 3 , CONH 2 , OCH 2 CONH 2 ,NH 2 , N( C 1-4 Alkyl) 2 , NHC(O)C 1-4 Alkyl, SO 2 NH 2 , SO 2 C 1-4 Alkyl, OCHF 2 , OCF 3 One or more substituents selected from the group consisting of substituted or unsubstituted It can mean not. In addition, each of the above-described substituents may be unsubstituted or substituted with a substituent selected from these substituent groups.
본 명세서에서, “할로겐 원자”는 F, Cl, Br, 또는 I 일 수 있다.In the present specification, “halogen atom” may be F, Cl, Br, or I.
본 명세서에서, “할로알킬”은 본원에 정의된 바와 같은 하나 이상의 할로겐 원자로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)를 의미할 수 있다. 상기 할로알킬의 예로는 하나 이상의 할로겐 원자, 예를 들어 F, Cl, Br, I로 독립적으로 치환된 메틸, 에틸, 프로필, 이소프로필, 이소부틸 및 N-부틸을 포함하나, 이에 한정되는 것은 아니다.As used herein, “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 .
본 명세서에서, "알킬”은 탄소원자로 이루어진 직쇄 또는 분지쇄의 비고리형 포화 탄화 수소를 의미할 수 있다. 대표적인 -(C1~8알킬)은 -메틸, -에틸, -N-프로필, -N-부틸, -N-펜틸및 -N-헥실, -N-헵틸과 -N-옥틸을 포함하고; 가지친사슬포화알킬은 -이소프로필, -2급(sec)-부틸, -이소부틸, -3급(tert)-부틸, -이소펜틸, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2,3-디메틸부틸 등을 포함할 수 있다. -(C1~8알킬)은 치환될 수도 치환되지 않을 수도 있다. 예를들어, C1~8 알킬기는 페닐로 치환되어 벤질기를 이룰 수 있다.As used herein, "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 group.
본 명세서에서, "사이클로 알킬" 작용기는 비방향족인 포화 또는 불포화 탄소 고리를 의미할 수 있다. 대표적인 사이클로 알킬에는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로펜타디엔일, 사이클로헥실, 사이클로헥센일, 1,3-사이클로헥사디엔일, 1,4-사이클로헥사디엔일, 사이클로헵틸, 1,3-사이클로헵타디엔일, 1,3,5-사이클로헵타트리엔일, 사이클로옥틸과 사이클로옥타디엔일이 포함되지만 이에 한정되지는 않는다. 사이클로알킬기는 치환될 수도 치환되지 않을 수도 있다. 한 실시 태양에서는 이 사이클로알킬기는 C3~8 사이클로알킬기일 수 있다.As used herein, "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.
본 명세서에서, “헤테로 사이클로 알킬”은 3 내지 10의 전체 수의 고리 원자를 갖고 N, O 및 S로부터 선택된 1 내지 5개의 헤테로 원자를 함유하는 포화된 또는 부분적으로 불포화된 고리형 치환기를 의미할 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬기는 단환식, 이환식, 스피로환식 또는 다환식 고리형일 수 있다. 또한 상기 헤테로사이클로알킬은 하나 이상의 원소로 브릿지된 고리형을 포함할 수 있다. 헤테로사이클로알킬은 하나 이상의 고리 탄소 또는 헤테로 원자를 통해 분자의 나머지에 부착될 수 있다. 헤테로사이클로알킬의 예로는 피롤리딘, 피페리딘, N-메틸피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이미드, 피페리딘, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥산, 모폴린, 티오모폴린, 티오모폴린-S-옥사이드, 티오모폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 티오피란, 피론, 테트라하이드로푸란, 테트라하이드로티오펜, 퀴누클리딘, 트로판, 2-아자스피로[3.3]헵탄, (1R,5S)-3-아자바이사이클로[3.2.1]옥탄, (1s,4s)-2-아자바이사이클로[2.2.2]옥탄, (1R,4R)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함하지만, 이에 한정되지 않는다.As used herein, “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. Examples of heterocycloalkyl 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]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2 .2] octane, and the like.
본 명세서에서, “아릴”은 방향족 탄화수소 고리로부터 하나의 수소가 제거되어 유도된 임의의 작용기 또는 치환기를 의미할 수 있다. 아릴기는 단환식 아릴기 또는 다환식 아릴기일 수 있다. 아릴기의 고리 형성 탄소수는 5 이상 30 이하, 5 이상 20 이하, 또는 5 이상 15 이하일 수 있다. 아릴기의 예로는 페닐기, 나프틸기, 플루오레닐기, 안트라세닐기, 페난트릴기, 바이페닐기, 터페닐기, 쿼터페닐기, 퀸크페닐기, 섹시페닐기, 트리페닐렌기, 피레닐기, 벤조 플루오란테닐기, 크리세닐기 등을 예시할 수 있지만, 이들에 한정되지 않는다.In the present specification, “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. Examples of the aryl group 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.
본 명세서에서, “헤테로 아릴”은 이종 원소로 O, N, P, Si 및 S 중 1개 이상을 포함하는 아릴 고리기일 수 있다. 헤테로아릴기의 고리 형성 탄소수는 2 이상 30 이하 또는 2 이상 20 이하일 수 있다. 헤테로 아릴은 단환식 헤테로 아릴 또는 다환식 헤테로 아릴일 수 있다. 다환식 헤테로 아릴는 예를 들어, 2환 또는 3환 구조를 갖는 것일 수 있다. 헤테로 아릴의 예로는 티에닐, 티오펜, 퓨릴, 피롤릴, 피라졸릴, 이미다졸릴, 티아졸릴, 옥사졸릴, 이소티아졸릴, 옥사디아졸릴, 트리아졸릴, 피리디닐, 비피리딜, 피리미딜, 트리아지닐, 트리아졸릴, 아크리딜기, 피리다지닐기, 피라지닐, 퀴놀리닐, 퀴나졸린, 퀴녹살리닐, 페녹사질, 프탈라지닐, 피리미디닐, 피리도 피리미디닐, 피리도 피라지닐, 피라지노 피라지닐, 이소퀴놀린, 인돌, 카바졸, 이미다조피리다지닐, 이미다조피리디닐, 이미다조피리미디닐, 피라졸로피리미디닐, 이미다조피라지닐 또는 피라졸로피리디닐, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸기, 벤조옥사졸, 벤조이미다졸, 벤조티아졸, 벤조카바졸, 벤조티오펜, 디벤조티오페닐, 티에노티오펜, 벤조퓨라닐, 페난트롤린, 이소옥사졸릴, 옥사디아졸릴, 티아디아졸릴, 벤조티아졸릴, 테트라졸릴, 페노티아지닐, 디벤조실롤 및 디벤조퓨라닐 등이 있으나, 이들에 한정되지 않는다. 본 발명의 일 실시태양에서 헤테로 아릴은 또한 헤테로 사이클로 알킬 고리에 융합된 아릴 고리 또는 사이클로 알킬 고리에 융합된 헤테로 아릴을 포함하는 바이사이클릭 헤테로사이클로-아릴을 포함할 수 있다.In the present specification, “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. Examples of heteroaryl are 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, pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl, N -Arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole group, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophenyl, thienothiophene, benzofuranyl , Phenanthroline, isooxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, tetrazolyl, phenothiazinyl, dibenzosilol and dibenzofuranyl, and the like. In one embodiment of the present invention, 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.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용되는 염을 제공한다:The present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1] [Formula 1]
Figure PCTKR2019018834-appb-I000002
Figure PCTKR2019018834-appb-I000002
상기 화학식 1에서,In Chemical Formula 1,
E는 질소(N) 또는 탄소(C)이고;E is nitrogen (N) or carbon (C);
L은 직접결합 또는 C1~5 알킬렌기이며;L is a direct bond or a C 1-5 alkylene group;
R1 및 R2는 각각 독립적으로 부존재, 수소, 할로겐 원자, 또는 C1-5의 직쇄 또는 분지쇄 알킬이고;R 1 and R 2 are each independently absent, hydrogen, halogen atom, or C 1-5 straight or branched chain alkyl;
R3은 비치환 또는 치환된 피리디닐, 피리미디닐, 이미다조피리다지닐, 이미다조피리디닐, 이미다조피리미디닐, 피라졸로피리미디닐, 이미다조피라지닐 또는 피라졸로피리디닐이고; 및R 3 is unsubstituted or substituted pyridinyl, pyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl; And
R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-10의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-10의 직쇄 또는 분지쇄 알킬, C1-10의 직쇄 또는 분지쇄 알콕시, 할로알킬 또는 시아노(-CN)로 치환된 것일 수 있다.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.
다른 실시 태양에서,In another embodiment,
본 발명은 하기 화학식 2 또는 3으로 표시되는 화합물일 수 있다:The present invention may be a compound represented by Formula 2 or 3 below:
[화학식 2][Formula 2]
Figure PCTKR2019018834-appb-I000003
Figure PCTKR2019018834-appb-I000003
[화학식 3][Formula 3]
Figure PCTKR2019018834-appb-I000004
Figure PCTKR2019018834-appb-I000004
화학식 2 또는 3에서,In Formula 2 or 3,
상기 E, L, R1, R2, R3 및 R4는 상기 정의한 바와 같다.The E, L, R 1 , R 2 , R 3 and R 4 are as defined above.
또 다른 실시 태양에서,In another embodiment,
상기 E는 질소이고;E is nitrogen;
상기 L은 직접 결합 또는 C1~3 알킬렌기이며; 및L is a direct bond or a C 1-3 alkylene group; And
상기 R1 및 R2는 각각 독립적으로 수소, F, Cl, Br, 또는 C1-5의 직쇄 또는 분지쇄 알킬일 수 있다.R 1 and R 2 may be each independently hydrogen, F, Cl, Br, or C 1-5 straight or branched chain alkyl.
구체적으로, 상기 C1-3의 직쇄 알킬로 보다 구체적으로 메틸기일 수 있다.Specifically, the C 1-3 linear alkyl may be more specifically a methyl group.
또 다른 실시 태양에서,In another embodiment,
상기 R3은 ,
Figure PCTKR2019018834-appb-I000005
,
Figure PCTKR2019018834-appb-I000006
,
Figure PCTKR2019018834-appb-I000007
, R 3 is,
Figure PCTKR2019018834-appb-I000005
,
Figure PCTKR2019018834-appb-I000006
,
Figure PCTKR2019018834-appb-I000007
,
Figure PCTKR2019018834-appb-I000008
,
Figure PCTKR2019018834-appb-I000009
,
Figure PCTKR2019018834-appb-I000010
,
Figure PCTKR2019018834-appb-I000011
Figure PCTKR2019018834-appb-I000008
,
Figure PCTKR2019018834-appb-I000009
,
Figure PCTKR2019018834-appb-I000010
,
Figure PCTKR2019018834-appb-I000011
또는
Figure PCTKR2019018834-appb-I000012
로 표시되는 비치환 헤테로 아릴일 수 있다. or
Figure PCTKR2019018834-appb-I000012
It may be unsubstituted heteroaryl represented by.
또한, 상기 R3은
Figure PCTKR2019018834-appb-I000013
,
Figure PCTKR2019018834-appb-I000014
또는
Figure PCTKR2019018834-appb-I000015
로 표시되는 치환된 헤테로 아릴일 수 있다.In addition, R 3 is
Figure PCTKR2019018834-appb-I000013
,
Figure PCTKR2019018834-appb-I000014
or
Figure PCTKR2019018834-appb-I000015
It may be a substituted heteroaryl represented by.
여기서 상기 R5는 수소, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기은 C1-10의 직쇄 또는 분지쇄 알킬, C1-10의 직쇄 또는 분지쇄 알킬카보닐, C3-6의 사이클로알킬카보닐, C1-10의 직쇄 또는 분지쇄 알콕시카보닐, 비치환 또는 치환된 페닐, 비치환 또는 치환된 피라졸릴, C3-6의 사이클로알킬, 또는 산소(O)를 헤테로 원자로 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며, 상기 치환된 페닐 또는 치환된 피라졸릴은 C1-10 알킬 또는 질소(N)를 하나 이상 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것일 수 있다. 구체적으로, 상기 치환된 아미노기는 C1-5의 직쇄 알킬, C1-5의 직쇄 알킬카보닐, C3-4의 사이클로알킬카보닐, C1-5의 직쇄 알콕시카보닐, 비치환 페닐, 비치환 또는 치환된 피라졸릴, C3-4의 사이클로알킬, 또는 하나의 산소(O)를 헤테로 원자로 포함하는 비치환된 6-원 헤테로사이클로알킬로 치환된 것일 수 있다. 보다 구체적으로, 상기 치환된 피라졸릴은 C1-3 알킬 또는 하나의 질소(N)를 포함하고 메틸기로 치환된 6-원 헤테로사이클로알킬로 치환된 것일 수 있다.Wherein R 5 is hydrogen or an unsubstituted or substituted amino group, and 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). It may be substituted with cycloalkyl. Specifically, 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).
또한, 상기 R6은 C1-10의 직쇄 또는 분지쇄 알킬, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-10의 직쇄 또는 분지쇄 알킬, C3-6의 사이클로알킬, C1-10의 하이드록시알킬로 치환된 것일 수 있다. 구체적으로 상기 치환된 아미노기는 C1-5의 분지쇄 알킬, C3-4의 사이클로알킬, C1-5의 하이드록시알킬로 치환된 것일 수 있다.Further, 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 . Specifically, the substituted amino group may be substituted with C 1-5 branched chain alkyl, C 3-4 cycloalkyl, or C 1-5 hydroxyalkyl.
또한, 상기 R7은 C1-10의 직쇄 또는 분지쇄 알킬, C1-10의 직쇄 또는 분지쇄 알콕시 또는 상기 피리디닐의 서로 인접하는 2개의 탄소원자와 융합된 고리기를 형성하는 비치환 또는 치환된 6-원의 헤테로사이클로알킬기일 수 있다. 구체적으로 상기 R7은 C1-5의 알킬, C1-5의 알콕시 또는 상기 피리디닐의 서로 인접하는 2개의 탄소원자와 융합된 고리기를 형성하고 산소(O)로 치환된 6-원의 헤테로사이클로알킬기일 수 있다. Further, 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.
다른 실시 태양에서, In another embodiment,
상기 R3은R 3 is
Figure PCTKR2019018834-appb-I000016
,
Figure PCTKR2019018834-appb-I000017
,
Figure PCTKR2019018834-appb-I000018
,
Figure PCTKR2019018834-appb-I000016
,
Figure PCTKR2019018834-appb-I000017
,
Figure PCTKR2019018834-appb-I000018
,
Figure PCTKR2019018834-appb-I000019
,
Figure PCTKR2019018834-appb-I000020
,
Figure PCTKR2019018834-appb-I000021
,
Figure PCTKR2019018834-appb-I000022
,
Figure PCTKR2019018834-appb-I000019
,
Figure PCTKR2019018834-appb-I000020
,
Figure PCTKR2019018834-appb-I000021
,
Figure PCTKR2019018834-appb-I000022
,
Figure PCTKR2019018834-appb-I000023
,
Figure PCTKR2019018834-appb-I000024
,
Figure PCTKR2019018834-appb-I000025
,
Figure PCTKR2019018834-appb-I000026
,
Figure PCTKR2019018834-appb-I000023
,
Figure PCTKR2019018834-appb-I000024
,
Figure PCTKR2019018834-appb-I000025
,
Figure PCTKR2019018834-appb-I000026
,
Figure PCTKR2019018834-appb-I000027
,
Figure PCTKR2019018834-appb-I000028
,
Figure PCTKR2019018834-appb-I000029
,
Figure PCTKR2019018834-appb-I000030
,
Figure PCTKR2019018834-appb-I000027
,
Figure PCTKR2019018834-appb-I000028
,
Figure PCTKR2019018834-appb-I000029
,
Figure PCTKR2019018834-appb-I000030
,
Figure PCTKR2019018834-appb-I000031
,
Figure PCTKR2019018834-appb-I000032
,
Figure PCTKR2019018834-appb-I000033
,
Figure PCTKR2019018834-appb-I000034
,
Figure PCTKR2019018834-appb-I000031
,
Figure PCTKR2019018834-appb-I000032
,
Figure PCTKR2019018834-appb-I000033
,
Figure PCTKR2019018834-appb-I000034
,
Figure PCTKR2019018834-appb-I000035
,
Figure PCTKR2019018834-appb-I000036
, 또는
Figure PCTKR2019018834-appb-I000037
일 수 있다.
Figure PCTKR2019018834-appb-I000035
,
Figure PCTKR2019018834-appb-I000036
, or
Figure PCTKR2019018834-appb-I000037
Can be
또 다른 실시 태양에서,In another embodiment,
상기 R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-5의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-5의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알콕시, 할로알킬 또는 시아노(-CN)로 치환된 것일 수 있다.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.
구체적으로, 상기 치환된 페닐은 하나 이상의 F, Cl, Br, 또는 C1-3의 알콕시로 치환될 수 있고, 상기 치환된 피리디닐 또는 티아졸릴은 C1-3의 직쇄 알킬, C1-3의 직쇄 알콕시, 트리플루오르알킬(-CF3) 또는 시아노(-CN)로 치환된 것일 수 있다. 보다 구체적으로, 상기 피리디닐은 메틸 또는 시아노로 치환될 수 있고 상기 티아졸릴은 트리플루오르알킬로 치환될 수 있다.Specifically, the substituted phenyl may be substituted with one or more F, Cl, Br, or C 1-3 alkoxy, and 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). More specifically, the pyridinyl may be substituted with methyl or cyano and the thiazolyl may be substituted with trifluoroalkyl.
또한, 상기 R4는In addition, R 4 is
Figure PCTKR2019018834-appb-I000038
,
Figure PCTKR2019018834-appb-I000039
,
Figure PCTKR2019018834-appb-I000040
,
Figure PCTKR2019018834-appb-I000038
,
Figure PCTKR2019018834-appb-I000039
,
Figure PCTKR2019018834-appb-I000040
,
Figure PCTKR2019018834-appb-I000041
,
Figure PCTKR2019018834-appb-I000042
,
Figure PCTKR2019018834-appb-I000043
,
Figure PCTKR2019018834-appb-I000041
,
Figure PCTKR2019018834-appb-I000042
,
Figure PCTKR2019018834-appb-I000043
,
Figure PCTKR2019018834-appb-I000044
,
Figure PCTKR2019018834-appb-I000045
,
Figure PCTKR2019018834-appb-I000046
,
Figure PCTKR2019018834-appb-I000044
,
Figure PCTKR2019018834-appb-I000045
,
Figure PCTKR2019018834-appb-I000046
,
Figure PCTKR2019018834-appb-I000047
,
Figure PCTKR2019018834-appb-I000048
,
Figure PCTKR2019018834-appb-I000049
,
Figure PCTKR2019018834-appb-I000047
,
Figure PCTKR2019018834-appb-I000048
,
Figure PCTKR2019018834-appb-I000049
,
Figure PCTKR2019018834-appb-I000050
,
Figure PCTKR2019018834-appb-I000051
,
Figure PCTKR2019018834-appb-I000052
,
Figure PCTKR2019018834-appb-I000050
,
Figure PCTKR2019018834-appb-I000051
,
Figure PCTKR2019018834-appb-I000052
,
Figure PCTKR2019018834-appb-I000053
,
Figure PCTKR2019018834-appb-I000054
,
Figure PCTKR2019018834-appb-I000055
,
Figure PCTKR2019018834-appb-I000053
,
Figure PCTKR2019018834-appb-I000054
,
Figure PCTKR2019018834-appb-I000055
,
Figure PCTKR2019018834-appb-I000056
,
Figure PCTKR2019018834-appb-I000057
, 또는
Figure PCTKR2019018834-appb-I000058
일 수 있다.
Figure PCTKR2019018834-appb-I000056
,
Figure PCTKR2019018834-appb-I000057
, or
Figure PCTKR2019018834-appb-I000058
Can be
또 다른 실시 태양에서, 상기 E가 질소(N)일 때,In another embodiment, when E is nitrogen (N),
상기 L은 직접 결합 또는 C1~3 알킬렌이며,L is a direct bond or C 1-3 alkylene,
상기 R1 및 R2는 각각 독립적으로 부존재 또는 수소이고,R 1 and R 2 are each independently absent or hydrogen,
상기 R3은
Figure PCTKR2019018834-appb-I000059
이고, 및R 3 is
Figure PCTKR2019018834-appb-I000059
Is, and
상기 R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-3의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-3의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알콕시, 할로알킬 또는 시아노(-CN)로 치환된 것일 수 있다.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).
구체적으로, 상기 R4는 비치환, 또는 F, Cl, 및 Br으로 이루어진 군으로부터 선택되는 하나 이상의 할로겐 원자로 치환된 페닐일 수 있다. 보다 구체적으로 상기 할로겐 원자는 F일 수 있다. Specifically, 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.
또 다른 실시 태양에서, 상기 E가 탄소(C)일 때,In another embodiment, when E is carbon (C),
상기 L은 직접 결합 또는 C1~3 알킬렌기이며,L is a direct bond or a C 1-3 alkylene group,
상기 R1 및 R2는 각각 독립적으로 수소, 할로겐 원자 또는 C1-5의 직쇄 또는 분지쇄 알킬이고,R 1 and R 2 are each independently hydrogen, a halogen atom or C 1-5 straight or branched chain alkyl,
상기 R3은R 3 is
Figure PCTKR2019018834-appb-I000060
,
Figure PCTKR2019018834-appb-I000061
,
Figure PCTKR2019018834-appb-I000062
,
Figure PCTKR2019018834-appb-I000063
,
Figure PCTKR2019018834-appb-I000064
,
Figure PCTKR2019018834-appb-I000065
,
Figure PCTKR2019018834-appb-I000066
또는
Figure PCTKR2019018834-appb-I000067
이고, 여기서 상기 R5는 수소, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-3의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알킬카보닐, C3-4의 사이클로알킬카보닐, C1-3의 직쇄 또는 분지쇄 알콕시카보닐, 비치환 또는 치환된 페닐, 비치환 또는 치환된 피라졸릴, C3-4의 사이클로알킬, 또는 산소(O)를 헤테로 원자로 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며, 상기 치환된 페닐 또는 치환된 피라졸릴은 C1-3 알킬 또는 질소(N)를 하나 이상 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며, 상기 R6은 C1-3의 직쇄 또는 분지쇄 알킬, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-3의 직쇄 또는 분지쇄 알킬, C3-4의 사이클로알킬, C1-5의 하이드록시알킬로 치환된 것이며, 상기 R7 은 C1-3의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알콕시 또는 상기 피리디닐의 서로 인접하는 2개의 탄소원자와 융합된 고리기를 형성하는 비치환 또는 치환된 6-원의 헤테로사이클로알킬기이고; 및
Figure PCTKR2019018834-appb-I000060
,
Figure PCTKR2019018834-appb-I000061
,
Figure PCTKR2019018834-appb-I000062
,
Figure PCTKR2019018834-appb-I000063
,
Figure PCTKR2019018834-appb-I000064
,
Figure PCTKR2019018834-appb-I000065
,
Figure PCTKR2019018834-appb-I000066
or
Figure PCTKR2019018834-appb-I000067
, Wherein 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). -Substituted with a one-membered heterocycloalkyl, wherein 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
R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-3의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-3의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알콕시, 할로알킬 또는 시아노(-CN)로 치환된 것일 수 있다.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.
또한, 상기 L은 직접 결합 또는 메틸렌이며;Further, L is a direct bond or methylene;
상기 R1 및 R2는 각각 독립적으로 수소, F, 또는 C1-3의 직쇄 알킬이고;R 1 and R 2 are each independently hydrogen, F, or C 1-3 straight-chain alkyl;
상기 R3은
Figure PCTKR2019018834-appb-I000068
이며; 및R 3 is
Figure PCTKR2019018834-appb-I000068
Is; And
상기 R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-3의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-3의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알콕시, 트리플루오르화탄소(-CF3) 또는 시아노(-CN)로 치환된 것 일 수 있다.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.
구체적으로 상기 R4는Specifically, R 4 is
Figure PCTKR2019018834-appb-I000069
,
Figure PCTKR2019018834-appb-I000070
,
Figure PCTKR2019018834-appb-I000071
,
Figure PCTKR2019018834-appb-I000072
,
Figure PCTKR2019018834-appb-I000069
,
Figure PCTKR2019018834-appb-I000070
,
Figure PCTKR2019018834-appb-I000071
,
Figure PCTKR2019018834-appb-I000072
,
Figure PCTKR2019018834-appb-I000073
,
Figure PCTKR2019018834-appb-I000074
,
Figure PCTKR2019018834-appb-I000075
,
Figure PCTKR2019018834-appb-I000076
,
Figure PCTKR2019018834-appb-I000073
,
Figure PCTKR2019018834-appb-I000074
,
Figure PCTKR2019018834-appb-I000075
,
Figure PCTKR2019018834-appb-I000076
,
Figure PCTKR2019018834-appb-I000077
,
Figure PCTKR2019018834-appb-I000078
,
Figure PCTKR2019018834-appb-I000079
,
Figure PCTKR2019018834-appb-I000080
,
Figure PCTKR2019018834-appb-I000077
,
Figure PCTKR2019018834-appb-I000078
,
Figure PCTKR2019018834-appb-I000079
,
Figure PCTKR2019018834-appb-I000080
,
Figure PCTKR2019018834-appb-I000081
,
Figure PCTKR2019018834-appb-I000082
,
Figure PCTKR2019018834-appb-I000083
,
Figure PCTKR2019018834-appb-I000084
,
Figure PCTKR2019018834-appb-I000081
,
Figure PCTKR2019018834-appb-I000082
,
Figure PCTKR2019018834-appb-I000083
,
Figure PCTKR2019018834-appb-I000084
,
Figure PCTKR2019018834-appb-I000085
,
Figure PCTKR2019018834-appb-I000086
,
Figure PCTKR2019018834-appb-I000087
,
Figure PCTKR2019018834-appb-I000088
,
Figure PCTKR2019018834-appb-I000085
,
Figure PCTKR2019018834-appb-I000086
,
Figure PCTKR2019018834-appb-I000087
,
Figure PCTKR2019018834-appb-I000088
,
또는
Figure PCTKR2019018834-appb-I000089
일 수 있다.or
Figure PCTKR2019018834-appb-I000089
Can be
또한, 상기 L은 직접 결합이고;Further, L is a direct bond;
상기 R1 및 R2는 수소이며;R 1 and R 2 are hydrogen;
상기 R3은R 3 is
Figure PCTKR2019018834-appb-I000090
,
Figure PCTKR2019018834-appb-I000091
,
Figure PCTKR2019018834-appb-I000092
,
Figure PCTKR2019018834-appb-I000093
,
Figure PCTKR2019018834-appb-I000090
,
Figure PCTKR2019018834-appb-I000091
,
Figure PCTKR2019018834-appb-I000092
,
Figure PCTKR2019018834-appb-I000093
,
Figure PCTKR2019018834-appb-I000094
,
Figure PCTKR2019018834-appb-I000095
또는
Figure PCTKR2019018834-appb-I000096
이고, 여기서 상기 R5는 수소, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-3의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알킬카보닐, C3-4의 사이클로알킬카보닐, C1-3의 직쇄 또는 분지쇄 알콕시카보닐, 비치환 또는 치환된 페닐, 비치환 또는 치환된 피라졸릴, C3-4의 사이클로알킬, 또는 산소(O)를 헤테로 원자로 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며, 상기 치환된 페닐 또는 치환된 피라졸릴은 C1-3 알킬 또는 질소(N)를 하나 이상 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며, 상기 R6은 C1-3의 직쇄 또는 분지쇄 알킬, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-3의 직쇄 또는 분지쇄 알킬, C3-4의 사이클로알킬, C1-3의 하이드록시알킬로 치환된 것이며, 상기 R7 은 C1-3의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알콕시 또는 상기 피리디닐의 서로 인접하는 2개의 탄소원자와 융합된 고리기를 형성하는 비치환 또는 치환된 6-원의 헤테로사이클로알킬기이고; 및
Figure PCTKR2019018834-appb-I000094
,
Figure PCTKR2019018834-appb-I000095
or
Figure PCTKR2019018834-appb-I000096
, Wherein 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). -Substituted with a one-membered heterocycloalkyl, wherein 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
상기 R4는 비치환 페닐일 수 있다.R 4 may be unsubstituted phenyl.
구체적으로 상기 R3은 Specifically, R 3 is
Figure PCTKR2019018834-appb-I000097
,
Figure PCTKR2019018834-appb-I000098
,
Figure PCTKR2019018834-appb-I000099
,
Figure PCTKR2019018834-appb-I000097
,
Figure PCTKR2019018834-appb-I000098
,
Figure PCTKR2019018834-appb-I000099
,
Figure PCTKR2019018834-appb-I000100
,
Figure PCTKR2019018834-appb-I000101
,
Figure PCTKR2019018834-appb-I000102
,
Figure PCTKR2019018834-appb-I000100
,
Figure PCTKR2019018834-appb-I000101
,
Figure PCTKR2019018834-appb-I000102
,
Figure PCTKR2019018834-appb-I000103
,
Figure PCTKR2019018834-appb-I000104
,
Figure PCTKR2019018834-appb-I000105
,
Figure PCTKR2019018834-appb-I000103
,
Figure PCTKR2019018834-appb-I000104
,
Figure PCTKR2019018834-appb-I000105
,
Figure PCTKR2019018834-appb-I000106
,
Figure PCTKR2019018834-appb-I000107
,
Figure PCTKR2019018834-appb-I000108
,
Figure PCTKR2019018834-appb-I000106
,
Figure PCTKR2019018834-appb-I000107
,
Figure PCTKR2019018834-appb-I000108
,
Figure PCTKR2019018834-appb-I000109
,
Figure PCTKR2019018834-appb-I000110
,
Figure PCTKR2019018834-appb-I000111
,
Figure PCTKR2019018834-appb-I000109
,
Figure PCTKR2019018834-appb-I000110
,
Figure PCTKR2019018834-appb-I000111
,
Figure PCTKR2019018834-appb-I000112
,
Figure PCTKR2019018834-appb-I000113
,
Figure PCTKR2019018834-appb-I000114
,
Figure PCTKR2019018834-appb-I000112
,
Figure PCTKR2019018834-appb-I000113
,
Figure PCTKR2019018834-appb-I000114
,
Figure PCTKR2019018834-appb-I000115
,
Figure PCTKR2019018834-appb-I000116
, 또는
Figure PCTKR2019018834-appb-I000117
일 수 있다.
Figure PCTKR2019018834-appb-I000115
,
Figure PCTKR2019018834-appb-I000116
, or
Figure PCTKR2019018834-appb-I000117
Can be
다른 실시 태양에서, 상기 화학식 2 또는 3으로 표시되는 화합물은 각각 하기 화학식 2', 2'', 3' 또는 3''로 표시되는 화합물일 수 있다:In another embodiment, the compound represented by Formula 2 or 3 may be a compound represented by Formula 2', 2'', 3'or 3'', respectively:
[화학식 2'][Formula 2']
Figure PCTKR2019018834-appb-I000118
Figure PCTKR2019018834-appb-I000118
[화학식 2''][Formula 2'']
Figure PCTKR2019018834-appb-I000119
Figure PCTKR2019018834-appb-I000119
[화학식 3'][Formula 3']
Figure PCTKR2019018834-appb-I000120
Figure PCTKR2019018834-appb-I000120
[화학식 3''][Formula 3'']
Figure PCTKR2019018834-appb-I000121
Figure PCTKR2019018834-appb-I000121
상기 화학식 2', 2'', 3' 또는 3''에서,In the formula 2', 2'', 3'or 3'',
상기 E, L, R1, R2, R3 및 R4는 상기 정의한 바와 같다.The E, L, R 1 , R 2 , R 3 and R 4 are as defined above.
다른 일 실시태양에서,In another embodiment,
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나의 화합물 또는 이들의 약학적으로 허용가능한 염일 수 있다.The compound represented by Formula 1 may be any one compound selected from the following group of compounds, or a pharmaceutically acceptable salt thereof.
(1)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (2)(S)-3-(3,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)이소옥사졸리딘-2-카복사마이드; (3)(S)-3-(3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)이소옥사졸리딘-2-카복사마이드; (4)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (5)(R)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐아이소옥사졸리딘-2-카복사마이드; (6)(S)-3-(3,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (7)(R)-3-(3,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (8)(S)-3-(3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (9)(R)-3-(3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (10)(S)-3-(4-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (11)(S)-3-(4-클로로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (12)(S)-3-(4-브로모페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (13)(S)-3-(3,4-다이클로로-2-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (14)(S)-3-(4-클로로-3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (15)(S)-3-(3-클로로-4-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (16)(S)-3-(2,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (17)(S)-3-(3-클로로-2-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (18)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(3-메톡시페닐)이소옥사졸리딘-2-카복사마이드; (19)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(6-메틸피리딘-3-일)이소옥사졸리딘-2-카복사마이드; (20)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(피리딘-3-일)이소옥사졸리딘-2-카복사마이드; (21)(S)-N-(4-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카르복사마이드; (22)(S)-3-(5-사이아노피리딘-3-일)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (23)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(4-(트리플루오로메틸)티아졸-2-일)이소옥사졸리딘-2-카복사마이드; (24)(R)-3-벤질-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (25)(S)-3-벤질-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(1)( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-phenylisooxazolidine-2-carboxamide ; (2)( S )-3-(3,5-difluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)iso Oxazolidine-2-carboxamide; (3)( S )-3-(3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)isooxazolidine -2-carboxamide; (4) (S) - N- (3- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (5) (R) - N- (3- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3-phenyl-iso-oxazolidine-2-carboxamide; (6)( S )-3-(3,5-difluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine -2-carboxamide; (7) (R) -3- ( 3,5- difluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin-isopropyl -2-carboxamide; (8)( S )-3-(3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2- Carboxamide; (9) (R) -3- (3-fluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin-2-isopropyl Carboxamide; (10)( S )-3-(4-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2- Carboxamide; (11) (S) -3- ( 4- chlorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin-2-isopropyl car Radiation amide; (12)( S )-3-(4-Bromophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2- Carboxamide; (13) (S) -3- (3,4-dichloro-2-fluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) Isooxazolidine-2-carboxamide; (14)( S )-3-(4-Chloro-3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazoli Dean-2-carboxamide; (15) (S) -3- ( 3- chloro-4-fluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin iso Dean-2-carboxamide; (16) (S) -3- ( 2,5- difluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin-isopropyl -2-carboxamide; (17) (S) -3- (3-chloro-2-fluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin iso Dean-2-carboxamide; (18)( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(3-methoxyphenyl)isooxazolidine-2- Carboxamide; (19) (S) - N- (3- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3- (6-methylpyridin-3-yl) oxazolidin-isopropyl -2-carboxamide; (20)( S )- N- (3-(imidazo[1,2-b]pyridazin-3-ylethynyl)phenyl)-3-(pyridin-3-yl)isooxazolidine-2- Carboxamide; (21) (S) - N- (4- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (22)( S )-3-(5-Cyanopyridin-3-yl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazoli Dean-2-carboxamide; (23) (S) - N- (3- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3- (4- (trifluoromethyl) thiazol-2 1) isooxazolidine-2-carboxamide; (24)( R )-3-benzyl- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide; (25)( S )-3-benzyl- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide;
(26)(S)-N-(2-(이미다조[1,2-b]피리다진-3- 일에티닐)피리딘-4-일)-3-페닐이소옥사졸리딘-2-카복사마이드; (27)(R)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-yl)-3-페닐이소옥사졸리딘-2-카복사마이드; (28)(S)-3-(3,5-다이플루오로페닐)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-일)이소옥사졸리딘-2-카복사마이드; (29)(S)-3-(3-플루오로페닐)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-일)이소옥사졸리딘-2-카복사마이드; (30)(S)-N-(4-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (31)(S)-N-(2-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (32)(S)-N-(2-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(피리딘-3-일)이소옥사졸리딘-2-카복사마이드; (33)(S)-N-(2,4-다이플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (34)(S)-N-(2,4-다이플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(피리딘-3-일)이소옥사졸리딘-2-카복사마이드; (35)(S)-N-(3-((8-아미노이미다조 [1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (36)(S)-N-(3-((8-(사이클로프로페인카복사미도)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (37)(S)-N-(3-((8-(에틸아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (38)(S)-3-페닐-N-(3-((8-((테트라하이드로-2H-피란-4-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (39)(S)-메틸-3-((3-(3-페닐이소옥사졸리딘-2-카복사미도)페닐)에티닐)이미다조[1,2-a]피리딘-8-일카바메이트; (40)(S)-N-(3-((8-((5-메틸-1H-피라졸-3-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (41)(S)-N-(3-((8-((1-메틸-1H-피라졸-3-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (42)(S)-N-(3-((8-((1-메틸-1H-피라졸-4-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (43)(S)-N-(3-((8-(사이클로프로필아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (44)(S)-3-페닐-N-(3-((8-(페닐아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (45)(S)-N-(3-((8-((1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (46)(S)-N-(3-(이미다조[1,2-a]피리딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (47)(S)-3-페닐-N-(3-(피라졸로[1,5-a]피리미딘-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (48)(S)-N-(3-(이미다조[1,2-a]피라진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (49)(S)-N-(3-(이미다조[1,2-a]피리미딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (50)(R)-N-(3-(이미다조[1,2-a]피리딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (51)(R)-3-페닐-N-(3-(피라졸로[1,5-a]피리미딘-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (52)(R)-N-(3-(이미다조[1,2-a]피라진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (53)(R)-N-(3-(이미다조[1,2-a]피리미딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (54)(S)-N-(3-((6-메틸피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (55)(S)-N-(3-((5-메톡시피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (56)(S)-N-(3-((1H-피라졸로[3,4-b]피리딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (57)(S)-N-(3-((7-옥소-5,6,7,8-테트라하이드로-1,8-나프티리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (58)(S)-N-(3-((2-아미노피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (59)(S)-N-(3-((2-(사이클로프로필아미노)피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (60)(S)-N-(3-((2-((3-하이드록시프로필)아미노)피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; 및 (61)(S)-N-(3-((2-(이소부틸아미노)피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드. (26) (S) - N- (2- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) pyridin-4-yl) -3-phenyl-2-isopropyl-oxazolidine-carboxamide Mide; (27) (R) - N- (2- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) pyridin -4-yl) -3- isopropyl-phenyl oxazolidin-2-carboxamide Mide; (28) (S) -3- ( 3,5- difluorophenyl) - N- (2- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) pyridin-4-yl) Isooxazolidine-2-carboxamide; (29) (S) -3- (3-fluorophenyl) - N- (2- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) pyridin-4-yl) oxazolidin iso Dean-2-carboxamide; (30)( S )- N- (4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-car Radiation amide; (31)( S )- N- (2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-car Radiation amide; (32) (S) - N- (2- fluoro-3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3- (pyridin-3-yl) -isoxazol Zolidine-2-carboxamide; (33) (S) - N- (2,4- difluoro-3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3-phenyl-oxazolidine-isopropyl- 2-carboxamide; (34) (S) - N- (2,4- difluoro-3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3- (pyridin-3-yl )Isooxazolidine-2-carboxamide; (35) (S) - N- (3 - ((8- amino-imidazo [1,2-a] pyridin-ethynyl-3-yl)) phenyl) -3-phenyl-2-isopropyl-oxazolidine-carboxamide Mide; (36)( S )- N- (3-((8-(cyclopropanecarboxamido)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxa Zolidine-2-carboxamide; (37)( S )- N- (3-((8-(ethylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2 -Carboxamide; (38)( S )-3-phenyl- N- (3-((8-((tetrahydro-2H-pyran-4-yl)amino)imidazo[1,2-a]pyridin-3-yl) Ethynyl)phenyl)isooxazolidine-2-carboxamide; (39)( S )-methyl-3-((3-(3-phenylisooxazolidine-2-carboxamido)phenyl)ethynyl)imidazo[1,2-a]pyridine-8-ylcarba Mate; (40)( S )- N- (3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl )Phenyl)-3-phenylisooxazolidine-2-carboxamide; (41) (S) - N- (3 - ((8 - ((1- methyl -1H- pyrazol-3-yl) amino) imidazo [1,2-a] ethynyl-3-yl) )Phenyl)-3-phenylisooxazolidine-2-carboxamide; (42) (S) - N- (3 - ((8 - ((1- methyl -1H- pyrazol-4-yl) amino) imidazo [1,2-a] ethynyl-3-yl) )Phenyl)-3-phenylisooxazolidine-2-carboxamide; (43)( S )- N- (3-((8-(cyclopropylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine- 2-carboxamide; (44)( S )-3-phenyl- N- (3-((8-(phenylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)isooxazolidine-2 -Carboxamide; (45)( S )- N- (3-((8-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)imidazo[1,2 -a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide; (46) (S) - N- (3- ( already ethynyl-imidazo [1,2-a] pyridin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (47)( S )-3-phenyl- N- (3-(pyrazolo[1,5-a]pyrimidin-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide; (48) (S) - N- (3- ( already ethynyl-imidazo [1,2-a] pyrazin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (49) (S) - N- (3- ( already ethynyl-imidazo [1,2-a] pyrimidin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (50) (R) - N- (3- ( already ethynyl-imidazo [1,2-a] pyridin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (51)( R )-3-phenyl- N- (3-(pyrazolo[1,5-a]pyrimidin-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide; (52) (R) - N- (3- ( already ethynyl-imidazo [1,2-a] pyrazin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (53) (R) - N- (3- ( already ethynyl-imidazo [1,2-a] pyrimidin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (54) (S) - N- (3 - ((6- methylpyridin-3-yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (55) (S) - N- (3 - ((5- methoxypyridin-3- yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (56) (S) - N- (3 - ((1H- pyrazolo [3,4-b] pyridin-ethynyl-5-yl)) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide ; (57)( S )- N- (3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethynyl)phenyl)-3-phenyliso Oxazolidine-2-carboxamide; (58) (S) - N- (3 - ((2- amino-pyrimidin-5-yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (59) (S) - N- (3 - ((2- ( cyclopropyl) pyrimidin-5-yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide; (60)( S )- N- (3-((2-((3-hydroxypropyl)amino)pyrimidin-5-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-car Radiant amide; And (61) (S) - N- (3 - ((2- ( isobutyl amino) pyrimidin-5-yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide.
본 발명에서 상기 화합물의 약학적으로 허용가능한 염은 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염일 수 있다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. In the present invention, 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. Get from
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 입체 이성질체, 수화물 등을 모두 포함할 수 있으며, 상기 입체 이성질체는 구체적으로 거울상 이성질체일 수 있다.Furthermore, 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.
상기 화학식 1로 표시되는 화합물은 하기 반응식 1에 나타난 바와 같이,The compound represented by Formula 1, as shown in Scheme 1 below,
화학식 4로 표시되는 화합물로부터, 화학식 5으로 표시되는 화합물을 제조하는 단계(단계 1);Preparing a compound represented by Chemical Formula 5 from a compound represented by Chemical Formula 4 (Step 1);
상기 단계 1에서 제조한 화학식 5으로 표시되는 화합물로부터, 화학식 6으로 표시되는 화합물을 제조하는 단계(단계 2);Preparing a compound represented by Formula 6 from the compound represented by Formula 5 prepared in Step 1 (Step 2);
상기 단계 2에서 제조한 화학식 6으로 표시되는 화합물과 화학식 7로 표시되는 화합물을 반응시켜, 화학식 8로 표시되는 화합물을 제조하는 단계(단계 3); 및Reacting the compound represented by Formula 6 and the compound represented by Formula 7 prepared in Step 2 to prepare a compound represented by Formula 8 (Step 3); And
상기 단계 3에서 제조한 화학식 8로 표시되는 화합물과 N,N'-다이석시니미딜 카보네이트 및 화학식 9로 표시되는 화합물을 반응시켜, 화학식 1로 표시되는 화합물을 제조하는 단계(단계 4)를 통해 제조될 수 있다.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.
[반응식 1][Scheme 1]
Figure PCTKR2019018834-appb-I000122
Figure PCTKR2019018834-appb-I000122
상기 반응식 1에서,In Reaction Scheme 1,
R1, R2, R3, R4 및 E는 독립적으로 상기 정의된 바와 같고;R 1 , R 2 , R 3 , R 4 and E are independently as defined above;
상기 PG는 트리(C1-C6알킬)실릴기, C1-C6알킬 카르보닐기, 벤조일기, 및 페닐아세틸기로부터 선택되는 보호기일 수 있고, 구체적으로, 트리메틸실릴(TMS)일 수 있으며; 및The 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); And
상기 X1 및 X2는 독립적으로 할로겐 원자이다.X 1 and X 2 are independently a halogen atom.
이하, 상기 화학식 1로 표시되는 화합물의 제조방법을 단계별로 상세히 설명한다.Hereinafter, a method for preparing the compound represented by Chemical Formula 1 will be described in detail step by step.
상기 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 1은 화학식 2로 표시되는 화합물로부터, 화학식 3으로 표시되는 화합물을 제조하는 단계이다. 보다 구체적으로, 화학식 2로 표시되는 화합물의 X1이 결합되어 있는 위치에, 보호기가 말단에 치환된 아세틸렌, 하나의 구체예로는 트리메틸실릴아세틸렌을 치환시켜, 화학식 3으로 표시되는 화합물을 제조하는 단계이다. 반응 용매로는 특별한 제한은 없으나 아세토나이트릴 등을 사용할 수 있고, 반응 온도는 70 내지 90℃의 범위에서 수행할 수 있다.In the method for preparing a compound represented by Chemical Formula 1, 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.
상기 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 2는 상기 단계 1에서 제조한 화학식 3으로 표시되는 화합물로부터, 화학식 4로 표시되는 화합물을 제조하는 단계이다. 본 단계에서 보호기의 제거는, 도입된 보호기의 종류에 따라, 해당 보호기의 제거방법으로 공지된 방법을 제한 없이 채용하여 수행할 수 있다. 만약, 하나의 구체예로 도입된 보호기가 트리메틸실릴(Trimethylsilyl, TMS)일 경우, 메탄올 용매 하에 탄산칼륨을 처리하여 트리메틸실릴을 제거할 수 있다.In the method for preparing a compound represented by Formula 1, step 2 is a step of preparing a compound represented by Formula 4 from the compound represented by Formula 3 prepared in Step 1. In this step, 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.
상기 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 3은 상기 단계 2에서 제조한 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜, 화학식 6으로 표시되는 화합물을 제조하는 단계이다. 이때 반응은 에틸아세테이트에서 수행될 수 있으며, 반응온도는 30 내지 70℃ 범위에서 수행할 수 있다. 반응 시간은 특별히 제한되는 것은 아니나, 1시간 내지 3시간 동안 수행할 수 있다.In the method for preparing a compound represented by Formula 1, 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. At this time, the reaction can be carried out in ethyl acetate, the reaction temperature can be carried out in the range of 30 to 70 ℃. The reaction time is not particularly limited, but may be performed for 1 hour to 3 hours.
상기 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 4는 상기 단계 3에서 제조한 화학식 6으로 표시되는 화합물과 N,N'-다이석시니미딜 카보네이트 및 화학식 7로 표시되는 화합물을 반응시켜, 화학식 1로 표시되는 화합물을 제조하는 단계이다. 본 단계는 피리딘 존재하에 다이메틸포름아마이드 용매에서 화학식 6으로 표시되는 화합물과 N,N'-다이석시니미딜 카보네이트를 먼저 반응시키고(이때 반응 온도는 약 0 내지 10℃, 반응 시간은 1 내지 3시간 동안 수행할 수 있으나, 이에 특별히 제한되는 것은 아니다), 이후 화학식 7로 표시되는 화합물을 반응시켜, 화학식 1로 표시되는 화합물을 제조할 수 있다.In the method for preparing the compound represented by Chemical Formula 1, 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). In this step, in the presence of pyridine, 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).
본 발명의 다른 측면은,Another aspect of the invention,
상기 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다. Provided is a pharmaceutical composition for the prevention or treatment of RIPK1 (Receptor-interacting serine/threonine-protein kinase 1) related disease containing the compound, its stereoisomer or its pharmaceutically acceptable salt as an active ingredient.
일 측면에서, 상기 RIPK1 관련 질환은,In one aspect, the RIPK1-related disease,
프로그램화된 괴사, 아폽토시스 또는 염증성 시토카인의 생산에 의해 적어도 부분적으로 조절될 수 있는 질환/장애, 특히 염증성 장질환(크론병 및 궤양성 결장염 포함), 건선, 망막 박리 (및 변성), 색소성 망막염, 황반 변성, 췌장염, 아토피성 피부염, 관절염(류마티스 관절염, 척추관절염, 통풍, 소아 특발성 관절염(전신 발병 소아 특발성 관절염(SoJIA)), 건선성 관절염 포함), 전신 홍반성 루푸스(SLE), 쇼그렌 증후군, 전신 경피증, 항-인지질 증후군(APS), 혈관염, 골관절염, 간 상해/질환(비-알콜 지방간염, 알콜 지방간염, 자가면역 간염, 자가면역 간담도 질환, 원발성 경화성 담관염(PSC), 아세트아미노펜 독성, 간독성), 신장 상해/손상(신염, 신장 이식, 수술, 신독성 약물 예를 들어 시스플라틴의 투여, 급성 신장 손상(AKI)), 복강 질환, 자가면역 특발성 혈소판감소성 자반증(자가면역 ITP), 이식 거부(이식 기관, 조직 및 세포의 거부), 실질 기관의 허혈 재관류 손상, 패혈증, 전신 염증 반응 증후군(SIRS), 뇌혈관 사고(CVA, 졸중), 심근경색(MI), 아테롬성동맥경화증, 헌팅턴병, 알츠하이머병, 파킨슨병, 근위축성 측삭 경화증(ALS), 신생아 저산소성 뇌 손상, 허혈성 뇌 손상, 외상성 뇌 손상 알레르기성 질환(천식 및 아토피성 피부염 포함), 화상, 다발성 경화증, 제I형 당뇨병, 베게너 육아종증, 폐 사르코이드증, 베체트병, 인터류킨-1 전환 효소(ICE, 또한 카스파제-1로서 공지됨) 연관 열 증후군, 만성 폐쇄성 폐질환(COPD), 담배 연기-유발 상해, 낭성 섬유증, 종양 괴사 인자 수용체-연관 주기성 증후군(TRAPS), 신생물성 종양, 치주염, NEMO-돌연변이(NF-카파-B 필수 조정제 유전자 (또한 IKK 감마 또는 IKKG로서 공지됨)의 돌연변이), 특히, NEMO-결핍 증후군, HOIL-1 결핍 ((또한 RBCK1로서 공지됨) 헴-산화된 IRP2 유비퀴틴 리가제-1 결핍), 선형 유비퀴틴 쇄 어셈블리 복합적(LUBAC) 결핍 증후군, 혈액 및 실질 기관 악성종양, 박테리아 감염 및 바이러스 감염 (예컨대 인플루엔자, 스타필로코쿠스, 및 미코박테리움(결핵)), 및 리소솜 축적 질환(특히, 고셔병, 및 GM2 강글리오시드증, 알파-만노시드축적증, 아스파르틸글루코사민뇨, 콜레스테릴 에스테르 축적 질환, 만성 헥소사미니다제 A 결핍, 시스틴축적증, 다논병, 파브리병, 파버병, 푸코시드축적증, 갈락토시알산증, GM1 강글리오시드증, 점액지질증, 영아 유리 시알산 축적 질환, 소아 헥소사미니다제 A 결핍, 크라베병, 리소솜 산 리파제 결핍, 이염성 백질이영양증, 뮤코폴리사카라이드증 장애, 다발성 술파테이스 결손증, 니만-픽병, 신경 세로이드 리포푸신증, 폼페병, 농축이골증, 샌드호프병, 쉰들러병, 시알산 축적 질환, 테이-작스 및 월만병 포함), 스티븐스-존슨 증후군, 녹내장, 척수 손상, 췌장관 선암종, 간세포성암종, 중피종, 흑색종, 급성 간부전 등 일 수 있다.Diseases/disorders that can be at least partially regulated by the production of programmed necrosis, apoptosis or inflammatory cytokines, particularly inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment (and degeneration), retinitis pigmentosa , Macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondylitis, gout, childhood idiopathic arthritis (systemic onset childhood idiopathic arthritis (SoJIA)), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome , Systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver injury/disease (non-alcoholic steatohepatitis, alcoholic hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen Toxicity, hepatotoxicity), kidney injury/damage (nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP) , Transplant rejection (implantation of organs, tissues and cells), ischemic reperfusion injury of parenchymal organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury allergic diseases (including asthma and atopic dermatitis), burns, multiple sclerosis, type I diabetes , Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), tobacco smoke-induced injury, cystic fibrosis , Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, periodontitis, NEMO-mutations (mutations of the NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), in particular NEMO-deficiency Syndrome, HOIL-1 deficiency (also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assemble Ly complex (LUBAC) deficiency syndrome, blood and parenchymal organ malignancies, bacterial infections and viral infections (such as influenza, Staphylococcus, and Mycobacterium (tuberculosis)), and lysosomal storage diseases (especially Gaucher's disease, and GM2 Gangliosidosis, alpha-mannoside accumulation, aspartylglucosamineuria, cholesteryl ester accumulation disease, chronic hexosaminidase A deficiency, cystine accumulation, Dannon disease, Fabry disease, Faber disease, fucoside accumulation , Galactosialosis, GM1 gangliosidosis, mucolipidemia, infant free sialic acid accumulation disease, pediatric hexosaminidase A deficiency, Krabe's disease, lysosomal acid lipase deficiency, inflammatory white matter dystrophy, mucopolysaccharideosis Disorders, multiple sulfatase deficiencies, Niemann-Pick disease, neuroseroid lipofuscinosis, Pompe disease, adenomyosis, Sandhoff disease, Schindler's disease, sialic acid accumulation disease, including Tay-Sachs and Wolman's disease), Stevens-Johnson Syndrome, glaucoma, spinal cord injury, pancreatic duct adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, acute liver failure, and the like.
상기 본 발명의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물은 개별 치료제로 투여하거나, 사용중인 다른 항암제와 병용투여하여 사용할 수 있다.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. .
본 발명의 약학적 조성물은 부형제, 붕해제, 감미제, 활택제, 향미제 등을 추가로 포함함으로써 통상적인 방법에 의해 정제, 캅셀제, 산제, 과립제, 현탁제, 유제, 시럽제, 기타 액제로 제형화될 수 있다.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.
구체적으로, 본 발명의 약학적 조성물은 전신 및/또는 국부로 작용할 수 있고, 경구 및 비경구, 즉, 폐, 비강, 설하, 설측, 협측, 직장, 피부, 경피 또는 결막 등 다양한 경로를 통해 대상에 투여될 수 있으므로, 투여 경로에 적합한 형태로 제형화될 수 있다. Specifically, 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.
예를 들면, 경구 투여에 적합한 제형은, 결정질 및/또는 무정형 및/또는 용해된 형태의 본 발명의 화합물을 함유하는 것들로, 예를 들어 정제 (비코팅 또는 코팅된 정제, 예를 들어 본 발명의 화합물의 방출을 제어하는 위액-내성 또는 지연-용해 또는 불용성 코팅을 사용함), 구강 내에서 신속하게 붕해되는 정제 또는 필름/오블레이트, 필름/동결건조물, 캡슐(예를 들어 경질 또는 연질 젤라틴 캡슐), 당-코팅된 정제, 츄어블제 (예를 들어 연질 츄어블제), 과립, 펠릿, 분말, 에멀젼, 현탁액, 에어로졸 또는 용액일 수 있다.For example, 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.
비경구 투여는 흡수 단계를 회피하면서 (예를 들어 정맥내, 동맥내, 심장내, 척수내 또는 요추내 경로에 의함) 또는 흡수를 포함하면서 (예를 들어 근육내, 피부, 피하, 피내, 경피 또는 복강내 경로에 의함) 달성될 수 있다. 비경구 투여에 적합한 제형은 용액, 현탁액, 에멀젼, 동결건조물 또는 멸균 분말 형태의 주사 및 주입을 위한 제제를 포함할 수 있다. 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.
본 발명의 다른 일 측면은 상기 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 또는 이들을 포함하는 약학적 조성물을 필요로 하는 대상(subject)에게 약학적으로 유효한 양으로 투여하는 단계를 포함하는, 키나아제 관련 질환의 치료방법을 제공한다.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.
본 명세서에서 용어, "투여"는 어떠한 적절한 방법으로 상기 질환의 의심 대상에게 본 발명의 약학적 조성물을 도입하는 것을 의미하며, 투여 경로는 목적 조직에 도달할 수 있는 한 다양한 경로를 통하여 투여될 수 있다.As used herein, 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.
본 명세서에서 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 투여 용량은, 환자의 상태, 연령, 성별 및 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다.As used herein, the term “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. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect in a minimal amount without side effects, and can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention 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.
본 발명의 또 다른 일 측면은 RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 예방 또는 치료에 사용하기 위한, 상기 N-(에티닐페닐)이속사졸리딘-2-카복사마이드 유도체, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다.Another aspect of the present invention for use in the prevention or treatment of RIPK1 (Receptor-interacting serine/threonine-protein kinase 1) related diseases, the N- (ethynylphenyl) isoxazolidine-2-carboxamide Derivatives, stereoisomers thereof, or pharmaceutically acceptable salts thereof are provided.
본 발명의 다른 일 측면은 RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 예방 또는 치료에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 N-(에티닐페닐)이속사졸리딘-2-카복사마이드 유도체, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공한다.Another aspect of the present 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 N- (ethynylphenyl) Provides the use of sazolidine-2-carboxamide derivatives, stereoisomers thereof or pharmaceutically acceptable salts thereof.
본 발명의 일 측면에서 제공하는 N-(에티닐페닐)이속사졸리딘-2-카복사마이드 유도체는 RIPK1(Receptor-interacting serine/threonine-protein kinase 1)에 대해 우수한 억제 활성을 나타내므로, RIPK1 관련 질환의 치료제로 사용 가능한 효과가 있으며, 이는 후술하는 실험예에 의해 뒷받침된다.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), 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) 관련 질환은 전술한 바와 동일하므로, 중복 설명을 피하기 위하여 구체적인 설명은 생략한다.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.
이하, 본 발명을 실시예 및 실험예에 의하여 상세히 설명한다.Hereinafter, the present invention will be described in detail by examples and experimental examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 한정되는 것은 아니다.However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited thereto.
본 발명의 실시예에서 합성된 화합물은 다음의 HPLC 조건에 의해 정제하거나 또는 구조 분석을 실시하였다: 정제용 중압액체크로마토그래피(Medium pressure liquid chromatography; MPLC); 중압액체크로마토그래피는 TELEEDYNE ISCO사의 CombiFlash Rf +UV을 사용하였다.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.
분석용 HPLC 조건 (ACQUITY UPLC H-Class Core System)Analytical HPLC conditions (ACQUITY UPLC H-Class Core System)
Waters사 제조 UPLC system (ACQUITY UPLC PDA Detector)에 Waters사 제조 mass QDA Detector가 장착된 장비를 사용하였다. 사용 컬럼은 Waters사의 ACQUITY UPLC®BEH C18 (1.7　㎛, 2.1X50 mm)였으며 컬럼온도는 30℃에서 진행하였다.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㎛, 2.1X50 mm) from Waters, and the column temperature was performed at 30°C.
이동상 A는 0.1% 개미산이 포함된 물, 이동상 B는 0.1%의 개미산이 포함된 아세토니트릴을 사용하였다.Mobile phase A used water containing 0.1% formic acid and mobile phase B used acetonitrile containing 0.1% formic acid.
Gradient condition(10-100% B로 3분, 이동속도=0.6ml/min)Gradient condition (3 minutes at 10-100% B, moving speed = 0.6ml/min)
정제용 Prep-LCMS (Preparative-Liquid chromatography mass spectrometry)Preparative-Liquid chromatography mass spectrometry (Prep-LCMS) for purification
Waters사 제조 Autopurification HPLC system(2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector)에 Waters사 제조 mass QDA Detector가 장착된 장비를 사용하였다. 사용 컬럼은 Waters사의 SunFire®Prep C18 OBDTM(5　㎛, 19X50 mm)였으며 컬럼온도는 실온에서 진행하였다.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 μm, 19×50 mm) from Waters, and the column temperature was performed at room temperature.
이동상 A는 0.035% 트리플루오로아세트산이 포함된 물, 이동상 B는 0.035%의 트리플루오로아세트산이 포함된 메탄올을 사용하였다.Mobile phase A used water containing 0.035% trifluoroacetic acid, and mobile phase B used methanol containing 0.035% trifluoroacetic acid.
Gradient condition(15-100% B로 10분, 이동속도=25ml/min)Gradient condition (15-100% B for 10 minutes, moving speed=25ml/min)
정제용 Prep-150 LC System(Preparative-Liquid chromatography UV spectrometry)Prep-150 LC System(Preparative-Liquid chromatography UV spectrometry) for purification
Waters사 제조 Prep 150 LC system(2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector Ⅲ)에 Waters사 제조 장비를 사용하였다. 사용 컬럼은 Waters사의 XTERRA®Prep RP18 OBDTM(10　㎛, 30X300 mm)였으며 컬럼온도는 실온에서 진행하였다.Waters manufactured equipment was used in the Prep 150 LC system (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III) manufactured by Waters. The column used was Waters' XTERRA®Prep RP18 OBD TM (10 μm, 30X300 mm), and the column temperature was performed at room temperature.
Gradient condition(3-100% B로 120분, 이동속도=40ml/min)Gradient condition (120 minutes at 3-100% B, moving speed = 40ml/min)
사용된 시판 시약은 추가 정제 없이 사용하였다. 본 발명에서 실온이란 20~25℃ 정도의 온도를 말한다. 감압하 농축 또는 용매 증류 제거는, 회전식 증발기(rotary evaporator)를 사용하였다.The commercial reagents used were used without further purification. In the present invention, room temperature refers to a temperature of about 20 to 25°C. For concentration under reduced pressure or removal of solvent, a rotary evaporator was used.
<제조예 1> (<Production Example 1> ( SS )-3-페닐이소옥사졸리딘의 제조)-3-phenylisooxazolidine Preparation
Figure PCTKR2019018834-appb-I000123
Figure PCTKR2019018834-appb-I000123
단계 1: Step 1: terttert -부틸 (-Butyl ( RR )-(3-하이드록시-3-페닐프로폭시)카바메이트의 제조)-(3-hydroxy-3-phenylpropoxy)carbamate preparation
tert-부틸 하이드록시카바메이트(7.8 g, 58.6 mmol)를 다이메틸폼아마이드 (140 mL)에 녹인 후 0℃에서 수소화나트륨(2.58 g, 64.5 mmol)을 첨가하고 30분 동안 반응하였다. 그리고 다이메틸폼아마이드(10 mL)에 녹인 (R)-3-클로로-1-페닐프로판-1-올(5 g, 29.3 mmol)을 0℃에서 10분간 천천히 적가하고 상온에서 72시간 교반하였다. 반응 혼합물에 염화암모늄 수용액을 넣어 반응을 종결시키고 에틸아세테이트 및 소금물로 추출하여 유기층을 합하였다. 유기층을 황산나트륨으로 건조한 후 감압하여 농축 후 중압액체크로마토그래피(에틸아세테이트/n-헥산)으로 정제하여 목적 화합물 tert-부틸 (R)-(3-하이드록시-3-페닐프로폭시)카바메이트 (2.8 g, 68%)을 수득하였다. After tert -butyl hydroxycarbamate (7.8 g, 58.6 mmol) was dissolved in dimethylformamide (140 mL), sodium hydride (2.58 g, 64.5 mmol) was added at 0° C. and reacted for 30 minutes. And ( R )-3-chloro-1-phenylpropan-1-ol (5 g, 29.3 mmol) dissolved in dimethylformamide (10 mL) was slowly added dropwise at 0° C. for 10 minutes and stirred at room temperature for 72 hours. The reaction mixture was added with an aqueous ammonium chloride solution to terminate the reaction, and extracted with ethyl acetate and brine to combine the organic layers. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain the desired compound tert -butyl ( R )-(3-hydroxy-3-phenylpropoxy)carbamate (2.8 g, 68%).
MS (m/z): 150.17 [M+1]+, UPLC r. t. (min) : 1.51MS (m/z): 150.17 [M+1] + , UPLC rt (min): 1.51
1H NMR (400 MHz, CDCl3) δ = 7.43 - 7.39 (m, 2H), 7.38 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 5.05 - 4.97 (m, 1H), 4.15 - 4.08 (m, 1H), 4.07 - 4.00 (m, 1H), 2.10 - 1.93 (m, 2H), 1.54 - 1.48 (m, 9H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.43-7.39 (m, 2H), 7.38-7.32 (m, 2H), 7.27-7.24 (m, 1H), 5.05-4.97 (m, 1H), 4.15- 4.08 (m, 1H), 4.07-4.00 (m, 1H), 2.10-1.93 (m, 2H), 1.54-1.48 (m, 9H)
단계 2: Step 2: terttert -부틸 (-Butyl ( SS )-3-페닐아이소옥사졸리딘-2-카복시레이트의 제조)-3-phenylisooxazolidine-2-carboxylate preparation
상기 제조예 1의 단계 1에서 얻어진 화합물 tert-부틸 (R)-(3-하이드록시-3-페닐프로폭시)카바메이트(2.55 g, 9.54 mmol)와 트리에틸아민(3.13 ml, 22.44 mmol)을 다이클로로메탄(250 ml)에 녹인 후 0℃로 냉각하였다. 그리고 메탄설포닐클로라이드(1 ml, 13 mmol)을 적가하고 0℃에서 2시간 반응하였다. 반응 혼합물을 소금물 및 다이클로로메탄으로 추출하여 유기층을 합하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 목적 화합물 ter-부틸 3-페닐아이소옥사졸리딘-2-카복시레이트를 얻어 정제없이 다음 반응에 사용하였다.Compound tert -butyl ( R )-(3-hydroxy-3-phenylpropoxy)carbamate (2.55 g, 9.54 mmol) and triethylamine (3.13 ml, 22.44 mmol) obtained in Step 1 of Preparation Example 1 were prepared. It was dissolved in dichloromethane (250 ml) and cooled to 0°C. Then, methanesulfonyl chloride (1 ml, 13 mmol) was added dropwise and reacted at 0°C for 2 hours. The reaction mixture was extracted with brine and dichloromethane, and the organic layers were combined. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound ter -butyl 3-phenylisooxazolidine-2-carboxylate, which was used in the next reaction without purification.
MS (m/z): 194.13 [M+1]+, UPLC r. t. (min) : 1.69MS (m/z): 194.13 [M+1] + , UPLC rt (min): 1.69
1H NMR (400 MHz, CDCl3) δ = 7.29 - 7.23 (m, 4H), 7.18 - 7.17 (m, 1H), 5.12 - 5.11 (m, 1H), 4.10 - 4.03 (m, 1H), 3.82- 3.80 (m, 1H), 2.75 - 2.65 (m, 1H), 2.29 - 2.15 (m, 1H), 1.37 (s, 9H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.29-7.23 (m, 4H), 7.18-7.17 (m, 1H), 5.12-5.11 (m, 1H), 4.10-4.03 (m, 1H), 3.82- 3.80 (m, 1H), 2.75-2.65 (m, 1H), 2.29-2.15 (m, 1H), 1.37 (s, 9H)
단계 3: (Step 3: ( SS )-3-페닐이소옥사졸리딘의 제조)-3-phenylisooxazolidine Preparation
상기 제조예 1의 단계 2에서 얻어진 화합물 3-페닐아이소옥사졸리딘-2-카복시레이트(2.3 g)을 다이클로로메탄(90 mL)에 녹인 후 트리플루오로아세트산(14 mL)을 첨가하고 상온에서 1시간 동안 반응하였다. 반응 혼합물을 중탄산나트륨 수용액으로 중화시킨 뒤 유기층을 합하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 중압액체크로마토그래피(테트라하이드로퓨란/n-헥산)로 정제하여 목적 화합물 3-페닐이소옥사졸리딘(1.3 g, 94%)를 수득하였다.After dissolving the compound 3-phenylisooxazolidine-2-carboxylate (2.3 g) obtained in Step 2 of Preparation Example 1 in dichloromethane (90 mL), trifluoroacetic acid (14 mL) was added and at room temperature. It reacted for 1 hour. The reaction mixture was neutralized with an aqueous sodium bicarbonate solution, and then the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (tetrahydrofuran/n - hexane) to obtain the target compound 3-phenylisooxazolidine (1.3 g, 94%).
MS (m/z): 150.08 [M+1]+, UPLC r. t. (min) : 0.72MS (m/z): 150.08 [M+1] + , UPLC rt (min): 0.72
1H NMR (400 MHz, DMSO-d 6) δ = 7.59 - 7.52 (m, 2H), 7.50 - 7.39 (m, 3H), 5.01 - 4.93 (m, 1H), 2.93 - 2.82 (m, 1H), 2.62 - 2.53 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.59-7.52 (m, 2H), 7.50-7.39 (m, 3H), 5.01-4.93 (m, 1H), 2.93-2.82 (m, 1H), 2.62-2.53 (m, 2H)
<제조예 2> (<Production Example 2> ( SS )-3-(3-플루오로페닐)이소옥사졸리딘)-3-(3-fluorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000124
Figure PCTKR2019018834-appb-I000124
단계 1: 3-플루오로-Step 1: 3-fluoro- N-N- 메톡시-Methoxy- N-N- 메틸벤자마이드의 제조Preparation of methylbenzamide
3-플루오로벤조익산(90 g, 642.35 mmol, 1 eq)을 피리딘(150 mL)에 녹인 후, N,O-다이메틸하이드록실아민 염산염(75.19 g, 770.81 mmol, 1.2 eq)을 첨가한다. 그 후 15°C에서 EDCI(147.77 g, 770.81 mmol, 1.2 eq)를 첨가하였다. 반응 혼합물을 50°C에서 30분 동안 교반한다. TLC 분석결과(PE:EA = 3:1), 출발물질이 모두 사라졌으며 낮은 극성을 가지는 새로운 스팟이 검출되었다. 감압 농축하여 피리딘 용매를 제거하고, DCM(500mL)과 HCl(500mL, 2N), 소금물(200mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 황색 오일의 목적 화합물 3-플루오로-N-메톡시-N-메틸벤자마이드(110 g, 600.50 mmol, 93.49% yield)를 수득하였다.After 3-fluorobenzoic acid (90 g, 642.35 mmol, 1 eq ) is dissolved in pyridine (150 mL), N,O -dimethylhydroxylamine hydrochloride (75.19 g, 770.81 mmol, 1.2 eq ) is added. Then EDCI (147.77 g, 770.81 mmol, 1.2 eq ) was added at 15°C. The reaction mixture is stirred at 50°C for 30 minutes. As a result of TLC analysis (PE:EA = 3:1), all of the starting materials disappeared and a new spot having a low polarity was detected. 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.
단계 2: 1-(3-플루오로페닐)프로프-2-엔-1-원의 제조Step 2: Preparation of 1-(3-fluorophenyl)prop-2-en-1-one
상기 제조예 2의 단계 1에서 얻어진 3-플루오로-N-메톡시-N-메틸-벤자마이드 (110 g, 600.50 mmol, 1 eq)를 THF(1 L)에 녹인 후, 0°C에서 브로모(비닐)마그네슘(1 M, 630.53 mL, 1.05 eq)를-78°C에서 한 방울씩 적가하였다. 그 후, 반응 혼합물을 0°C에서 30분 동안 교반하였다. TLC 분석 결과 (PE:EA=4:1), 출발 물질이 모두 사라졌으며, 낮은 극성을 가지는 새로운 스팟이 검출되었다. HCl(4N, 500 mL)을 첨가하여 반응을 종결한 후, MTBE(2000 mL)와 소금물(500 mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후, 감압 농축하였다. 농축한 화합물을 크로마토그래피(석유 에테르/에틸 아세테이트=30/1)을 이용해 정제하여 황색 오일 상태의 목적 화합물 1-(3-플루오로페닐)프로프-2-엔-1-원(80 g, 532.80 mmol, 88.73% yield)을 수득하였다.After dissolving 3-fluoro- N -methoxy- N- methyl-benzamide (110 g, 600.50 mmol, 1 eq ) obtained in Step 1 of Preparation Example 2 in THF (1 L), broke at 0°C. Parent (vinyl) magnesium (1 M, 630.53 mL, 1.05 eq ) was added dropwise at -78°C dropwise. Thereafter, the reaction mixture was stirred at 0°C for 30 minutes. As a result of TLC analysis (PE:EA=4:1), all of the starting material disappeared, and a new spot with low polarity was detected. After the reaction was terminated by adding HCl (4N, 500 mL), the organic layer was extracted with MTBE (2000 mL) and brine (500 mL). The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The concentrated compound was purified by chromatography (petroleum ether/ethyl acetate=30/1) to obtain the desired compound 1-(3-fluorophenyl)prop-2-ene-1-one (80 g, in yellow oil). 532.80 mmol, 88.73% yield).
단계 3: 3-클로로-1-(3-플루오로페닐)프로판-1-원의 제조Step 3: Preparation of 3-chloro-1-(3-fluorophenyl)propane-1-one
상기 제조예 2의 단계 2에서 얻어진 1-(3-플루오로페닐) 프로프-2-엔-1-원 (71 g, 472.86 mmol, 1.0 eq)을 DCM(71 mL)에 녹인 후, 0°C에서 HCl/dioxane(4 M, 295.54 mL, 2.5 eq)을 첨가하였다. 그 후, 반응 혼합물을 15°C에서 1.5시간 동안 교반하였다. TLC 분석 결과 (PE:EA=10:1), 출발 물질은 모두 사라졌으며, 목적 화합물이 검출 되었다. 반응 혼합물을 감압 하에 농축하였고, DCM(450 mL)과 물 (200 mL * 5)을 첨가하여 유기층을 추출하였고, 황산나트륨으로 건조한 후 감압 농축하여 황색의 고체의 목적 화합물 3-클로로-1-(3-플루오로페닐)프로판-1-원 (73 g, 391.19 mmol, 82.73% yield)을 수득하였다.After dissolving 1-(3-fluorophenyl) prop-2-ene-1-one (71 g, 472.86 mmol, 1.0 eq ) obtained in Step 2 of Preparation Example 2 in DCM (71 mL), 0° HCl/dioxane (4 M, 295.54 mL, 2.5 eq ) in C was added. Thereafter, the reaction mixture was stirred at 15°C for 1.5 hours. As a result of TLC analysis (PE:EA=10:1), all of the starting material disappeared, and the target compound was detected. The reaction mixture was concentrated under reduced pressure, and the organic layer was extracted by adding DCM (450 mL) and water (200 mL * 5), dried over sodium sulfate, and then concentrated under reduced pressure to give the desired compound as a yellow solid, 3-chloro-1-(3 -Fluorophenyl)propane-1-one (73 g, 391.19 mmol, 82.73% yield) was obtained.
1H NMR (400MHz, CDCl3) δ = 7.78 - 7.72 (m, 1H), 7.69 - 7.60 (m, 1H), 7.53 - 7.44 (m, 1H), 7.37 - 7.24 (m, 1H), 3.93 (t, J=6.8 Hz, 2H), 3.46 (t, J=6.8 Hz, 2H) 1 H NMR (400MHz, CDCl 3 ) δ = 7.78-7.72 (m, 1H), 7.69-7.60 (m, 1H), 7.53-7.44 (m, 1H), 7.37-7.24 (m, 1H), 3.93 (t , J =6.8 Hz, 2H), 3.46 (t, J =6.8 Hz, 2H)
단계4: (Step 4: ( RR )-3-클로로-1-(3-플루오로페닐)프로판-1-올의 제조)-3-Chloro-1-(3-fluorophenyl)propan-1-ol
(S)-1-메틸-3,3-다이페닐테트라하이드로-1H,3H-피롤로[1,2-c][1,3,2]옥사자보롤(8.61 g, 31.08 mmol, 9.27 mL, 0.1 eq)을 THF(380 mL)에 녹인 후, BH3.THF(1 M, 186.48 mL, 0.6 eq)를 0°C에서 질소기류 하에 한 방울씩 첨가하였다. 반응 혼합물을 0°C에서 30분간 교반하였다. 그 후, 반응 혼합물에 THF(390 mL)에 희석한 상기 제조예 2의 단계 3에서 얻어진 3-클로로-1-(3-플루오로페닐)프로판-1-원(70g, 375.11 mmol, 1 eq)을 0°C에서 한 방울씩 적가하였다. 반응 혼합물을 0°C에서 30분 동안 교반하였다. TLC 분석 결과 (PE:EA=5:1), 출발물질이 모두 사라졌으며, 목적 화합물 스팟이 검출되었다. 0°C에서 MeOH (100mL)를 첨가하여 반응을 종결한 후, 용매를 감압 하에 날려주었다. 농축한 화합물을 DCM(100mL * 3)과 NH4Cl 용액(300mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하였다. 농축한 화합물을 실리카겔 크로마토그래피 (PE:EA=50:1 to 5:1)를 사용해 정제하여 무색의 오일 (R)-3-클로로-1-(3-플루오로페닐)프로판-1-올(55 g, 286.33 mmol, 92.13% yield, 98.2% purity, 54.1% e.e.)를 수득하였다.( S )-1-methyl-3,3-diphenyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazabolol (8.61 g, 31.08 mmol, 9.27 mL, 0.1 eq ) was dissolved in THF (380 mL), and BH 3 .THF (1 M, 186.48 mL, 0.6 eq ) was added dropwise at 0°C under a nitrogen stream. The reaction mixture was stirred at 0°C for 30 minutes. Then, 3-chloro-1-(3-fluorophenyl)propane-1-one (70 g, 375.11 mmol, 1 eq ) obtained in Step 3 of Preparation Example 2 diluted in THF (390 mL) in the reaction mixture. Was added dropwise at 0°C dropwise. The reaction mixture was stirred at 0°C for 30 minutes. As a result of TLC analysis (PE:EA=5:1), all starting materials disappeared, and a target compound spot was detected. After the reaction was terminated by adding MeOH (100 mL) at 0°C, the solvent was blown off under reduced pressure. The concentrated compound was extracted with an organic layer using DCM (100 mL * 3) and NH 4 Cl solution (300 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (PE:EA=50:1 to 5:1) to give a colorless oil ( R )-3-chloro-1-(3-fluorophenyl)propan-1-ol ( 55 g, 286.33 mmol, 92.13% yield, 98.2% purity, 54.1% ee).
MS (m/z): 135.2 [M-56+H]＋ MS (m/z): 135.2 [M-56 + H] +
1H NMR (400 MHz, CDCl3) δ = 7.35 - 7.28 (m, 1H), 7.19 - 7.04 (m, 2H), 7.01 - 6.91 ( m, 1H), 5.00 - 4.88 (m, 1H), 3.76 - 3.70 (m, 1H), 3.60 - 3.51 (m, 1H), 2.24 - 2.13 (m, 1H), 2.12 - 1.98 (m, 2H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.35-7.28 (m, 1H), 7.19-7.04 (m, 2H), 7.01-6.91 (m, 1H), 5.00-4.88 (m, 1H), 3.76- 3.70 (m, 1H), 3.60-3.51 (m, 1H), 2.24-2.13 (m, 1H), 2.12-1.98 (m, 2H)
단계5: Step 5: terttert -부틸 (-Butyl ( RR )-(3-(3-플루오로페닐)-3-하이드록시프로폭시)카바메이트의 제조)-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate preparation
tert-부틸 하이드록시카바메이트(40.76 g, 306.16 mmol, 1.05 eq)를 DMF(400 mL)에 녹인 후, 0°C에서 질소기류 하에 NaH (12.83 g, 320.74 mmol, 60% purity, 1.1 eq)를 첨가하였다. 반응 혼합물을 10°C에서 1시간 동안 교반하고, DMF(150 mL)에 희석된 상기 제조예 2의 단계 4에서 얻어진 (1R)-3-클로로-1-(3-플루오로페닐)프로판-1-올(55 g, 291.58 mmol, 1 eq)를 0°C에서 한 방울씩 첨가하고 10°C에서 16시간 동안 교반하였다. TLC 분석 결과 (PE:EA=2:1), 출발 물질은 모두 사라졌으며, 목적 화합물이 검출되었다. 물(800mL)을 첨가하여 반응을 종결한 후, 생성된 고체를 필터해주었다. 회수한 고체를 에틸아세테이트(800mL)와 물(100mL), 소금물(100mL)를 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 밝은 황색 고체의 tert-부틸 (R)-(3-(3-플루오로페닐)-3-하이드록시프로폭시)카바메이트(72 g, 189.57 mmol, 65.01% yield, 75.12% purity)를 수득하였다. After tert -butyl hydroxycarbamate (40.76 g, 306.16 mmol, 1.05 eq ) was dissolved in DMF (400 mL), NaH (12.83 g, 320.74 mmol, 60% purity, 1.1 eq ) was added under nitrogen flow at 0°C. Was added. The reaction mixture was stirred at 10°C for 1 hour, and (1 R )-3-chloro-1-(3-fluorophenyl)propane- obtained in Step 4 of Preparation Example 2 diluted in DMF (150 mL) 1-ol (55 g, 291.58 mmol, 1 eq ) was added dropwise at 0°C and stirred at 10°C for 16 hours. As a result of TLC analysis (PE:EA=2:1), all of the starting material disappeared, and the target compound was detected. After the reaction was terminated by adding water (800 mL), the resulting solid was filtered. The recovered solid was extracted with an organic layer using ethyl acetate (800 mL), water (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give tert -butyl ( R )-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate (72 g, 189.57 mmol, 65.01% yield) as a light yellow solid. , 75.12% purity).
MS (m/z):167.9 [M-118]＋ MS (m/z): 167.9 [M-118] +
1H NMR (400 MHz, CDCl3) δ = 7.17 - 7.06 (m, 1H), 7.01 - 6.93 (m, 2H), 6.80 - 6.73 (m, 1H), 4.89 - 4.79 (m, 1H), 3.95 - 3.89 (m, 1H), 3.88 - 3.82 (m, 1H), 1.89 - 1.81 (m, 1H), 1.80 - 1.69 (m, 1H), 1.32 (s, 9H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.17-7.06 (m, 1H), 7.01-6.93 (m, 2H), 6.80-6.73 (m, 1H), 4.89-4.79 (m, 1H), 3.95- 3.89 (m, 1H), 3.88-3.82 (m, 1H), 1.89-1.81 (m, 1H), 1.80-1.69 (m, 1H), 1.32 (s, 9H)
단계6: Step 6: terttert -부틸 (-Butyl ( SS )-3-(3-플루오로페닐)이소옥사졸리딘-2-카복실레이트의 제조)-3-(3-fluorophenyl)isooxazolidine-2-carboxylate preparation
상기 제조예 2의 단계 5에서 얻어진 tert-부틸 (R)-(3-(3-플루오로페닐)-3-하이드록시프로폭시)카바메이트(72g, 252.36mmol, 1 eq)와 Et3N (76.61 g, 757.07 mmol, 105.38 mL, 3 eq)를 DCM (700 mL)에 녹인 후, 0°C에서 메탄설폰산 무수물 (65.94 g, 378.53 mmol, 1.5 eq)을 천천히 첨가하였다. 반응 혼합물을 20°C에서 12시간 동안 교반하였다. TLC 분석결과(PE:EA=3:1), 출발물질은 모두 사라졌으며, 새로운 스팟이 검출되었다. 물(1000mL)을 첨가하여 반응을 종결한 후, DCM(200 mL * 3)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하였다. 농축한 화합물을 크로마토그래피(PE:EA=50:1 to 5:1)로 정제하여 57.7% e.e 값을 가지는 목적화합물 35g을 추출하였다. 목적화합물을 SFC(column: DAICEL CHIRALPAK AD-H(250mm*30mm,5um); mobile phase: [Neu-MeOH]; B%: 15 %, 2.9 min;760 min)을 통해 정제하여 밝은 황색의 고체 tert-부틸 (S)-3-(3-플루오로페닐)이소옥사졸리딘-2-카복실레이트(25 g, 92.00 mmol, 36.17% yield, 98.37% purity,100% e.e.)와 tert-부틸 (R)-3-(3-플루오로페닐)이소옥사졸리딘-2-카복실레이트(6.5 g, 22.16 mmol, 8.71% yield, 91.13% purity, 100% e.e.)를 수득하였다. Tert -butyl ( R )-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate (72 g, 252.36 mmol, 1 eq ) and Et 3 N (obtained in Step 5 of Preparation Example 2) 76.61 g, 757.07 mmol, 105.38 mL, 3 eq ) was dissolved in DCM (700 mL), and methanesulfonic anhydride (65.94 g, 378.53 mmol, 1.5 eq ) was slowly added at 0°C. The reaction mixture was stirred at 20°C for 12 hours. As a result of TLC analysis (PE:EA=3:1), all starting materials disappeared, and a new spot was detected. After the reaction was terminated by adding water (1000 mL), the organic layer was extracted using DCM (200 mL * 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The concentrated compound was purified by chromatography (PE:EA=50:1 to 5:1) to extract 35 g of the target compound having a value of 57.7% ee. 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.
MS (m/z): 212.2 [M-56+H]＋ MS (m/z): 212.2 [M-56+H] +
1H NMR (400 MHz, CDCl3) δ = 7.34 - 7.27 (m, 1H), 7.17 - 7.05 (m, 2H), 6.99 - 6.91 (m, 1H), 5.20 (dd, J=5.6, 8.8 Hz, 1H), 4.22 - 4.14 (m, 1H), 3.94 - 3.84 (m, 1H), 2.84 - 2.73 (m, 1H), 2.34 - 2.22 (m, 1H), 1.47 (s, 9H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.34-7.27 (m, 1H), 7.17-7.05 (m, 2H), 6.99-6.91 (m, 1H), 5.20 (dd, J =5.6, 8.8 Hz, 1H), 4.22-4.14 (m, 1H), 3.94-3.84 (m, 1H), 2.84-2.73 (m, 1H), 2.34-2.22 (m, 1H), 1.47 (s, 9H)
단계7: (Step 7: ( SS )-3-(3-플루오로페닐)이소옥사졸리딘의 제조)-3-(3-fluorophenyl)isooxazolidine preparation
tert-부틸 (3S)-3-(3-플루오로페닐)이소옥사졸리딘-2-카복실레이트(25g, 93.53 mmol, 1 eq)를 EA(50mL)에 녹인 후, 0°C에서 HCl/EtOAc(4M, 250mL)를 첨가하였다. 그 후, 반응 혼합물을 10°C에서 1시간 동안 교반하였다. LCMS 분석 결과, 출발물질이 모두 사라졌고 목적 화합물 96.97%가 검출되었다. 고체를 얻기 위해 감압 농축하여 백색 고체의 (S)-3-(3-플루오로페닐)이소옥사졸리딘(19.12g, 86.71mmol, 92.71% yield, 92.35% purity, HCl, 99.91% e.e.)를 수득하였다. tert - butyl in (3 S) -3- were dissolved (3-fluorophenyl) oxazolidin-isopropyl-2-carboxylate (25g, 93.53 mmol, 1 eq ) in EA (50mL), 0 ° C HCl / EtOAc (4M, 250 mL) was added. Thereafter, the reaction mixture was stirred at 10°C for 1 hour. As a result of LCMS analysis, all starting materials disappeared and 96.97% of the target compound was detected. Concentration under reduced pressure to obtain a solid yielded ( S )-3-(3-fluorophenyl)isooxazolidine (19.12g, 86.71mmol, 92.71% yield, 92.35% purity, HCl, 99.91% ee) as a white solid. Did.
MS (m/z): 168.3 [M+H]＋ MS (m/z): 168.3 [M+H] +
1H NMR (400 MHz, DMSO-d 6) δ = 12.51 (br s, 1H), 7.55 - 7.44 (m, 2H), 7.44 - 7.37 (m, 1H), 7.32 - 7.22 (m, 1H), 5.03 (t, J=8.0 Hz, 1H), 4.54 - 4.43 (m, 1H), 4.34 - 4.24 (m, 1H), 2.95 - 2.83 (m, 1H), 2.64 - 2.52 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 12.51 (br s, 1H), 7.55-7.44 (m, 2H), 7.44-7.37 (m, 1H), 7.32-7.22 (m, 1H), 5.03 (t, J =8.0 Hz, 1H), 4.54-4.43 (m, 1H), 4.34-4.24 (m, 1H), 2.95-2.83 (m, 1H), 2.64-2.52 (m, 1H)
상기 제조예 1, 2와 유사한 방법으로 제조예 3 내지 20을 제조하였으며, 제조예 3 내지 20의 화합물명, 화학구조식, UPLC 및 NMR분석 결과를 아래에 나타내었고 이하 실시예의 제조시 사용하였다.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.
<제조예 3> (<Production Example 3> ( RR )-3-페닐이소옥사졸리딘의 제조)-3-phenylisooxazolidine Preparation
Figure PCTKR2019018834-appb-I000125
Figure PCTKR2019018834-appb-I000125
MS (m/z): 150.08 [M+1]+ MS (m/z): 150.08 [M+1] +
1H NMR (400 MHz, DMSO-d 6) δ = 7.59 - 7.53 (m, 2H), 7.51 - 7.41 (m, 3H), 5.02 - 4.93 (m, 1H), 4.52 - 4.43 (m, 1H), 4.33 - 4.23 (m, 1H), 2.93 - 2.83 (m, 1H), 2.62 - 2.55 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.59-7.53 (m, 2H), 7.51-7.41 (m, 3H), 5.02-4.93 (m, 1H), 4.52-4.43 (m, 1H), 4.33-4.23 (m, 1H), 2.93-2.83 (m, 1H), 2.62-2.55 (m, 1H)
<제조예 4>(<Production Example 4> ( RR )-3-(3-플루오로페닐)이소옥사졸리딘)-3-(3-fluorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000126
Figure PCTKR2019018834-appb-I000126
1H NMR (400 MHz, DMSO-d 6) δ = 12.31 (br s, 1H), 7.55 - 7.43 (m, 2H), 7.43 - 7.37 ( m, 1H), 7.32 - 7.22 (m, 1H), 5.04 - 5.00 (t, J = 7.6 Hz, 1H), 4.51 - 4.43 (m, 1H), 4.32 - 4.23 (m, 1H), 2.95 - 2.82 (m, 1H), 2.63 - 2.51 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 12.31 (br s, 1H), 7.55-7.43 (m, 2H), 7.43-7.37 (m, 1H), 7.32-7.22 (m, 1H), 5.04 -5.00 (t, J = 7.6 Hz, 1H), 4.51-4.43 (m, 1H), 4.32-4.23 (m, 1H), 2.95-2.82 (m, 1H), 2.63-2.51 (m, 1H)
<제조예 5>(<Production Example 5> ( SS )-3-(3,5-다이플루오로페닐)이소옥사졸리딘)-3-(3,5-difluorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000127
Figure PCTKR2019018834-appb-I000127
1H NMR (400 MHz, DMSO-d 6) δ = 7.36 - 7.28 (m, 3H), 5.04 - 4.98 (t, J = 7.6 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.25 - 4.19 (dd, J = 7.6, 15.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.36-7.28 (m, 3H), 5.04-4.98 (t, J = 7.6 Hz, 1H), 4.47-4.38 (m, 1H), 4.25-4.19 ( dd, J = 7.6, 15.2 Hz, 1H), 2.89-2.81 (m, 1H), 2.58-2.51 (m, 1H)
<제조예 6>(<Production Example 6> ( RR )-3-(3,5-다이플루오로페닐)이소옥사졸리딘)-3-(3,5-difluorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000128
Figure PCTKR2019018834-appb-I000128
1H NMR (400 MHz, DMSO-d 6) δ = 7.36 - 7.27 (m, 3H), 5.04 - 4.98 (t, J = 7.6 Hz, 1H), 4.46 - 4.36 (m, 1H), 4.25 - 4.19 (dd, J = 7.6, 15.2 Hz, 1H), 2.90 - 2.78 (m, 1H), 2.56 - 2.51 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.36-7.27 (m, 3H), 5.04-4.98 (t, J = 7.6 Hz, 1H), 4.46-4.36 (m, 1H), 4.25-4.19 ( dd, J = 7.6, 15.2 Hz, 1H), 2.90-2.78 (m, 1H), 2.56-2.51 (m, 1H)
<제조예 7>(<Production Example 7> ( SS )-3-(4-클로로페닐)이소옥사졸리딘)-3-(4-chlorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000129
Figure PCTKR2019018834-appb-I000129
1H NMR (400 MHz, MeOD) δ = 7.58 - 7.52 (m, 4H), 5.19 - 5.15 (t, J = 7.6 Hz, 1H), 4.71 - 4.66 (m, 1H), 4.48 - 4.42 (m, 1H), 3.04 - 3.0 (m, 1H), 2.81 - 2.75 (m, 1H) 1 H NMR (400 MHz, MeOD) δ = 7.58-7.52 (m, 4H), 5.19-5.15 (t, J = 7.6 Hz, 1H), 4.71-4.66 (m, 1H), 4.48-4.42 (m, 1H) ), 3.04-3.0 (m, 1H), 2.81-2.75 (m, 1H)
<제조예 8>(<Production Example 8> ( SS )-3-(4-브로모페닐)이소옥사졸리딘)-3-(4-bromophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000130
Figure PCTKR2019018834-appb-I000130
1H NMR (400 MHz, MeOD) δ = 7.69 - 7.65 (d, J = 8.6 Hz, 2H), 7.48 - 7.46 (d, J = 8.6 Hz, 2H), 5.16 - 5.12 (m, 1H), 4.67 - 4.63 (m, 1H), 4.46 - 4.40 (m, 1H), 3.02 - 2.98 (m, 1H), 2.78 - 2.72 (m, 1H) 1 H NMR (400 MHz, MeOD ) δ = 7.69 - 7.65 (d, J = 8.6 Hz, 2H), 7.48 - 7.46 (d, J = 8.6 Hz, 2H), 5.16 - 5.12 (m, 1H), 4.67 - 4.63 (m, 1H), 4.46-4.40 (m, 1H), 3.02-2.98 (m, 1H), 2.78-2.72 (m, 1H)
<제조예 9>(<Production Example 9> ( SS )-3-(3,4-다이클로로-2-플루오로페닐)이소옥사졸리딘)-3-(3,4-dichloro-2-fluorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000131
Figure PCTKR2019018834-appb-I000131
1H NMR (400 MHz, DMSO-d 6) δ = 7.64 - 7.58 (m, 2H), 5.16 - 5.06 (dd, J = 6.4, 8.0 Hz, 1H), 4.44 - 4.32 (m, 1H), 4.20 - 4.10 (dd, J = 7.6, 15.2 Hz, 1H), 2.91 - 2.76 (m, 1H), 2.57 - 2.51 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.64-7.58 (m, 2H), 5.16-5.06 (dd, J = 6.4, 8.0 Hz, 1H), 4.44-4.32 (m, 1H), 4.20- 4.10 (dd, J = 7.6, 15.2 Hz, 1H), 2.91-2.76 (m, 1H), 2.57-2.51 (m, 1H)
<제조예 10>(<Production Example 10> ( SS )-3-(4-클로로-3-플루오로페닐)이소옥사졸리딘)-3-(4-chloro-3-fluorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000132
Figure PCTKR2019018834-appb-I000132
1H NMR (400MHz, DMSO-d 6) δ = 7.78 - 7.63 (m, 2H), 7.43 - 7.40 (dd, J = 1.6, 8.0 Hz, 1H), 5.03 - 4.99 (t, J = 7.6 Hz, 1H), 4.47 - 4.40 (m, 1H), 4.26 - 4.20 (q, J = 7.6 Hz, 1H), 2.90 - 2.82 (m, 1H), 2.58 - 2.52 (m, 1H) 1 H NMR (400MHz, DMSO- d 6 ) δ = 7.78-7.63 (m, 2H), 7.43-7.40 (dd, J = 1.6, 8.0 Hz, 1H), 5.03-4.99 (t, J = 7.6 Hz, 1H ), 4.47-4.40 (m, 1H), 4.26-4.20 (q, J = 7.6 Hz, 1H), 2.90-2.82 (m, 1H), 2.58-2.52 (m, 1H)
<제조예 11>(<Production Example 11> ( SS )-3-(3-클로로-4-플루오로페닐)이소옥사졸리딘)-3-(3-chloro-4-fluorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000133
Figure PCTKR2019018834-appb-I000133
1H NMR (400 MHz, DMSO-d 6) δ = 7.80 - 7.87 (dd, J = 2.0,7.2 Hz, 1H), 7.55 - 7.50 (m, 2H), 4.98 - 4.94 (t, J = 8.0 Hz, 1H), 4.43 - 4.39 (m, 1H), 4.22 - 4.18 (m, 1H), 2.85 - 2.81(m, 1H), 2.54 - 2.53 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.80-7.87 (dd, J = 2.0,7.2 Hz, 1H), 7.55-7.50 (m, 2H), 4.98-4.94 (t, J = 8.0 Hz, 1H), 4.43-4.39 (m, 1H), 4.22-4.18 (m, 1H), 2.85-2.81 (m, 1H), 2.54-2.53 (m, 1H)
<제조예 12>(<Production Example 12> ( SS )-3-(2,5-다이플루오로페닐)이소옥사졸리딘)-3-(2,5-difluorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000134
Figure PCTKR2019018834-appb-I000134
1H NMR (400MHz, DMSO-d 6) δ = 7.55 - 7.49 (m, 1H), 7.39 - 7.30 (m, 2H), 5.13 - 5.10 (t, J = 7.2 Hz, 1H), 4.47 - 4.39 (m, 1H), 4.22 - 4.17 (q, J = 7.6 Hz, 1H), 2.93 - 2.82 (m, 1H), 2.59 - 2.52 (m, 1H) 1 H NMR (400MHz, DMSO- d 6 ) δ = 7.55-7.49 (m, 1H), 7.39-7.30 (m, 2H), 5.13-5.10 (t, J = 7.2 Hz, 1H), 4.47-4.39 (m , 1H), 4.22-4.17 (q, J = 7.6 Hz, 1H), 2.93-2.82 (m, 1H), 2.59-2.52 (m, 1H)
<제조예 13>(<Production Example 13> ( SS )-3-(3-클로로-2-플루오로페닐)이소옥사졸리딘)-3-(3-chloro-2-fluorophenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000135
Figure PCTKR2019018834-appb-I000135
1H NMR (400 MHz, DMSO-d 6) δ = 7.49 - 7.43 (m, 2H), 7.20 - 7.16 (m, 1H), 6.56 (s, 1H), 4.65 (s, 1H), 3.96 - 3.91 (m, 1H), 3.67 - 3.65 (m, 1H), 2.66 - 2.61 (m, 1H), 2.08 - 2.01 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.49-7.43 (m, 2H), 7.20-7.16 (m, 1H), 6.56 (s, 1H), 4.65 (s, 1H), 3.96-3.91 ( m, 1H), 3.67-3.65 (m, 1H), 2.66-2.61 (m, 1H), 2.08-2.01 (m, 1H)
<제조예 14> (<Production Example 14> ( SS )-3-(3-메톡시페닐)이소옥사졸리딘)-3-(3-methoxyphenyl)isooxazolidine
Figure PCTKR2019018834-appb-I000136
Figure PCTKR2019018834-appb-I000136
1H NMR (400 MHz, DMSO-d 6) δ = 7.37 (t, J = 8.0 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 8.3, 2.5 Hz, 1H), 4.96 (t, J = 8.1 Hz, 1H), 4.49 (td, J = 8.1, 4.0 Hz, 1H), 4.30 (q, J = 7.7 Hz, 1H), 3.79 (s, 3H), 2.88 (dtd, J = 11.5, 7.4, 4.0 Hz, 1H), 2.58 (dq, J = 12.5, 8.5 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.37 (t, J = 8.0 Hz, 1H), 7.23-7.20 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.01 (dd , J = 8.3, 2.5 Hz, 1H), 4.96 (t, J = 8.1 Hz, 1H), 4.49 (td, J = 8.1, 4.0 Hz, 1H), 4.30 (q, J = 7.7 Hz, 1H), 3.79 (s, 3H), 2.88 (dtd, J = 11.5, 7.4, 4.0 Hz, 1H), 2.58 (dq, J = 12.5, 8.5 Hz, 1H)
<제조예 15>(<Production Example 15> SS )-3-(6-메틸피리딘-3-일)이소옥사졸리딘)-3-(6-methylpyridin-3-yl)isooxazolidine
Figure PCTKR2019018834-appb-I000137
Figure PCTKR2019018834-appb-I000137
1H NMR (400 MHz, MeOD) δ = 8.98 (d, J = 2.0 Hz, 1H), 8.71-8.68 (dd, J = 2.0, 8.4 Hz, 1H), 8.09 - 8.07 (d, J = 8.4 Hz, 1H), 5.53 - 5.49 (dd, J = 6.8, 8.0 Hz, 1H), 4.79-4.75 (m, 1H), 4.49 - 4.43 (m, 1H), 3.17 - 3.11 (m, 1H), 2.94 - 2.78 (m, 4H) 1 H NMR (400 MHz, MeOD) δ = 8.98 (d, J = 2.0 Hz, 1H), 8.71-8.68 (dd, J = 2.0, 8.4 Hz, 1H), 8.09-8.07 (d, J = 8.4 Hz, 1H), 5.53-5.49 (dd, J = 6.8, 8.0 Hz, 1H), 4.79-4.75 (m, 1H), 4.49-4.43 (m, 1H), 3.17-3.11 (m, 1H), 2.94-2.78 ( m, 4H)
<제조예 16>(<Production Example 16> SS )-3-(피리딘-3-일)이소옥사졸리딘)-3-(pyridin-3-yl)isooxazolidine
Figure PCTKR2019018834-appb-I000138
Figure PCTKR2019018834-appb-I000138
1H NMR (400 MHz, DMSO-d 6) δ = 9.09 - 9.08 (d, J = 1.6 Hz, 1H), 8.96 - 8.95 (d, J = 5.2 Hz 1H), 8.76 - 8.74 (m, 1H), 8.15 - 8.12 (dd, J = 5.6 Hz, 8.0 Hz, 1H), 5.34 -5.30 (m, 1H), 4.52 - 4.48 (m, 1H), 4.29 - 4.25 (m, 1H), 2.94 - 2.91 (m, 1H), 2.69 - 2.66 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.09-9.08 (d, J = 1.6 Hz, 1H), 8.96-8.95 (d, J = 5.2 Hz 1H), 8.76-8.74 (m, 1H), 8.15-8.12 (dd, J = 5.6 Hz, 8.0 Hz, 1H), 5.34 -5.30 (m, 1H), 4.52-4.48 (m, 1H), 4.29-4.25 (m, 1H), 2.94-2.91 (m, 1H), 2.69-2.66 (m, 1H)
<제조예 17>(<Production Example 17> ( SS )-5-(아이소옥사졸리딘-3-일)니코티노나이트릴)-5-(isooxazolidin-3-yl)nicotinonitrile
Figure PCTKR2019018834-appb-I000139
Figure PCTKR2019018834-appb-I000139
1H NMR (400 MHz, CDCl3) δ = 8.79 - 8.76 (dd, J = 2.0, 12.4 Hz, 2H), 8.09 (s, 1H), 5.58 (br s, 1H), 4.67 - 4.66 (m, 1H), 4.19 - 4.14 (m, 1H), 3.84 - 3.82 (m, 1H), 2.82 - 2.77 (m, 1H), 2.29 - 2.25 (m, 1H) 1 H NMR (400 MHz, CDCl 3 ) δ = 8.79-8.76 (dd, J = 2.0, 12.4 Hz, 2H), 8.09 (s, 1H), 5.58 (br s, 1H), 4.67-4.66 (m, 1H ), 4.19-4.14 (m, 1H), 3.84-3.82 (m, 1H), 2.82-2.77 (m, 1H), 2.29-2.25 (m, 1H)
<제조예 18>(<Production Example 18> ( SS )-3-(4-(트리플루오로메틸)싸이아졸-2-일)이소옥사졸리딘)-3-(4-(trifluoromethyl)thiazol-2-yl)isooxazolidine
Figure PCTKR2019018834-appb-I000140
Figure PCTKR2019018834-appb-I000140
1H NMR (400 MHz, CDCl3) δ = 7.71 (s, 1H), 5.76 (br d, J = 4.4 Hz, 1H), 4.91 - 4.88 (m, 1H), 4.20 - 4.15 (m, 1H), 3.80 (m, 1H), 2.81 - 2.76 (m, 2H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.71 (s, 1H), 5.76 (br d, J = 4.4 Hz, 1H), 4.91-4.88 (m, 1H), 4.20-4.15 (m, 1H), 3.80 (m, 1H), 2.81-2.76 (m, 2H)
<제조예 19>(<Production Example 19> RR )-3-벤질이소옥사졸리딘)-3-benzylisooxazolidine
Figure PCTKR2019018834-appb-I000141
Figure PCTKR2019018834-appb-I000141
1H NMR (400 MHz, MeOD) δ = 7.38 - 7.31 (m, 5H), 4.45 - 4.42 (m, 1H), 4.31 - 4.23 (m, 2H), 3.18 - 3.09 (m, 2H), 2.62 - 2.58 (m, 1H), 2.36 - 2.30 (m, 1H) 1 H NMR (400 MHz, MeOD) δ = 7.38-7.31 (m, 5H), 4.45-4.42 (m, 1H), 4.31-4.23 (m, 2H), 3.18-3.09 (m, 2H), 2.62-2.58 (m, 1H), 2.36-2.30 (m, 1H)
<제조예 20>(<Production Example 20> ( SS )-3-벤질이소옥사졸리딘)-3-benzylisooxazolidine
Figure PCTKR2019018834-appb-I000142
Figure PCTKR2019018834-appb-I000142
1H NMR (400 MHz, MeOD) δ = 7.38 - 7.30 (m, 5H), 4.45 - 4.42 (m, 1H), 4.31 - 4.24 (m, 2H), 3.20 - 3.11 (m, 2H), 2.60 - 2.59 (m, 1H), 2.36 - 2.31 (m, 1H) 1 H NMR (400 MHz, MeOD) δ = 7.38-7.30 (m, 5H), 4.45-4.42 (m, 1H), 4.31-4.24 (m, 2H), 3.20-3.11 (m, 2H), 2.60-2.59 (m, 1H), 2.36-2.31 (m, 1H)
<제조예 21>(<Production Example 21> ( SS )-)- N-N- (3-에티닐페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(3-ethynylphenyl)-3-phenylisooxazolidine-2-carboxamide
Figure PCTKR2019018834-appb-I000143
Figure PCTKR2019018834-appb-I000143
단계 1: (Step 1: ( SS )-)- N-N- (3-에티닐페닐)-3-페닐이소옥사졸리딘-2-카복사마이드의 제조Preparation of (3-ethynylphenyl)-3-phenylisooxazolidine-2-carboxamide
3-에티닐아닐린(15.8g, 134.87mmol, 1 eq), TEA(68.24g, 674.36mmol, 93.86mL, 5 eq)를 DCM(300mL)에 녹인 후, -10°C에서 DSC(38.01g, 148.36mmol, 1.1 eq)를 첨가하였다. 반응 혼합물을 -20°C에서 30분간 교반하였다. 그 후, 상기 제조예 1에서 얻어진(S)-3-페닐이소옥사졸리딘 염산염(30g, 160.62mmol, 1.19 eq)를 첨가하였다. LC-MS 분석 결과, 출발물질이 모두 사라졌으며, 목적 화합물 69%가 검출되었다. HCl(1 N, 300mL)을 첨가하여 반응을 종결한 후, 물(400mL*2), 소금물(300mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 오일 상태의 목적화합물을 얻었다. 화합물을 크로마토그래피(석유 에테르/에틸아세테이트=15/1 to 10/1)를 사용해 정제하여 황색의 목적화합물 (S)-N-(3-에티닐페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(17g, 58.15mmol, 43.11% yield, 100% purity， 96.63% e.e.)를 수득하였다.After dissolving 3-ethynylaniline (15.8g, 134.87mmol, 1 eq ), TEA (68.24g, 674.36mmol, 93.86mL, 5 eq ) in DCM (300mL), DSC (38.01g, 148.36 at -10°C) mmol, 1.1 eq ) was added. The reaction mixture was stirred at -20°C for 30 minutes. Thereafter, ( S )-3-phenylisooxazolidine hydrochloride (30 g, 160.62 mmol, 1.19 eq ) obtained in Preparation Example 1 was added. As a result of LC-MS analysis, all starting materials disappeared and 69% of the target compound was detected. After the reaction was terminated by adding HCl (1 N, 300 mL), the organic layer was extracted with water (400 mL*2) and brine (300 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain an oily target compound. The compound purified by chromatography (petroleum ether / ethyl acetate = 15/1 to 10/1) the desired compound as a yellow (S) purified using a - N- -3- phenylisothiazol-oxazolidin-2 (3-ethynyl-phenyl) -Carboxamide (17g, 58.15mmol, 43.11% yield, 100% purity, 96.63% ee) was obtained.
MS (m/z): 293.1 [M+H]＋ MS (m/z): 293.1 [M+H] +
1H NMR (400 MHz, DMSO-d 6) δ = 9.52 (s, 1H), 7.82 (1, 1H), 7.71 - 7.68 (d, J = 8.0 Hz, 1H), 7.38 - 7.37 (m, 4H), 7.34 - 7.28 (m, 2H), 7.4 (m, 1H), 5.43 - 5.40 (m, 1H), 4.27 - 4.24 (m, 1H), 4.15 (s, 1H), 3.89 - 3.87 (m, 1H), 2.86 - 2.85 (m, 1H), 2.24 - 2.23(m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.52 (s, 1H), 7.82 (1, 1H), 7.71-7.68 (d, J = 8.0 Hz, 1H), 7.38-7.37 (m, 4H) , 7.34-7.28 (m, 2H), 7.4 (m, 1H), 5.43-5.40 (m, 1H), 4.27-4.24 (m, 1H), 4.15 (s, 1H), 3.89-3.87 (m, 1H) , 2.86-2.85 (m, 1H), 2.24-2.23 (m, 1H)
<실시예 1> <Example 1> N-N- (3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)-3-페닐이소옥사졸리딘-2-카복사마이드 트리플루오르아세트산염의 제조Preparation of (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-phenylisooxazolidine-2-carboxamide trifluoroacetate
Figure PCTKR2019018834-appb-I000144
Figure PCTKR2019018834-appb-I000144
단계 1: 3-((트리메틸실릴)에티닐)이미다조[1,2-b]피리다진의 제조Step 1: Preparation of 3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine
3-브로모이미다조[1,2-b]피리다진(10g, 50.5mmol), Pd(PPh3)4(2.92g, 2.52mmol)과 CuI(0.962g, 5.05mmol)를 넣고 아세토나이트릴(50.5ml)를 첨가하여 희석 후 질소를 흘리면서 5분 동안 초음파 처리하여 가스를 제거하였다. 반응혼합물에 트리메틸실릴아세틸렌(7.44g, 76mmol)과 트리에틸아민(28.2mL, 202mmol)을 첨가한 후, 80℃에서 1시간 동안 반응시켰다. 반응 후 반응혼합물을 셀라이트로 여과하여 얻어진 여과액을 회전식 증발기를 이용하여 감압하에 농축한 후 3-((트리메틸실릴)에티닐)이미다조[1,2-b]피리다진(11g, 100%)을 얻었으며, 정제없이 다음 반응에 사용하였다.3-Bromoimidazo[1,2-b]pyridazine (10g, 50.5mmol), Pd(PPh 3 ) 4 (2.92g, 2.52mmol) and CuI (0.962g, 5.05mmol) and acetonitrile ( 50.5 ml) was added and diluted and then nitrogen was flowed to remove the gas by ultrasonic treatment for 5 minutes. After adding trimethylsilylacetylene (7.44 g, 76 mmol) and triethylamine (28.2 mL, 202 mmol) to the reaction mixture, the mixture was reacted at 80° C. for 1 hour. After the reaction, the reaction mixture was filtered through celite, and the filtrate obtained was concentrated under reduced pressure using a rotary evaporator, and then 3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (11g, 100%) ) Was obtained and used for the next reaction without purification.
MS (m/z): 216. 15[M+1]+, UPLC r. t. (min) : 1.63MS (m/z): 216. 15[M+1] + , UPLC rt (min): 1.63
단계 2: 3-에티닐이미다조[1,2-b]피리다진의 제조Step 2: Preparation of 3-ethynylimidazo[1,2-b]pyridazine
상기 실시예 1의 단계 1에서 얻어진 화합물 3-((트리메틸실릴)에티닐)이미다조[1,2-b]피리다진(11g, 51.1mmol)과 탄산칼륨 (21.18g, 153mmol)을 메탄올(51.1 mL)에 첨가하여 녹인 후, 1시간 동안 교반 하였다. 반응 후 반응 혼합물을 여과하여 얻어진 여과액을 회전식 증발기를 이용하여 감압하에 농축한 후, 중압액체크로마토그래피(다이클로메탄/에틸아세테이트)로 정제하여 고체의 목적화합물 3-에티닐이미다조[1,2-b]피리다진(5.78g, 80%)을 수득하였다.Compound 3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (11g, 51.1mmol) and potassium carbonate (21.18g, 153mmol) obtained in step 1 of Example 1 above are methanol (51.1 mL) and dissolved for 1 hour. After the reaction, the reaction mixture was filtered, and the filtrate obtained was concentrated under reduced pressure using a rotary evaporator, and then purified by medium pressure liquid chromatography (diclomethane/ethyl acetate) to obtain a solid target compound 3-ethynylimidazo[1 ,2-b]pyridazine (5.78 g, 80%).
MS (m/z): 144.03 [M+1]+, UPLC r. t. (min) : 0.87MS (m/z): 144.03 [M+1] + , UPLC rt (min): 0.87
1H NMR(400 MHz, DMSO-d 6) δ 8.66 (dd, J = 4.4, 1.5 Hz, 3H), 7.70 - 7.61 (m, 6H), 7.59 - 7.51 (m, 5H), 4.96 (s, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.66 (dd, J = 4.4, 1.5 Hz, 3H), 7.70-7.61 (m, 6H), 7.59-7.51 (m, 5H), 4.96 (s, 2H ).
단계 3: 3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸아닐린의 제조Step 3: Preparation of 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylaniline
상기 실시예 1의 단계 2에서 얻어진 화합물 3-에티닐이미다조[1,2-b]피리다진 (400mg, 2.79mmol), 3-아이오도-4-메틸아닐린(715mg, 3.07mmol)을 에틸아세테이트 (9.3mL)에 첨가하여 녹인 후 질소를 흘리면서 5분 동안 초음파 처리하였다. 반응혼합물에 Pd(PPh3)4(161mg, 0.140mmol), CuI(53.2mg, 0.279mmol)와 DIPEA(976μL, 5.59mmol)를 첨가한 후 50℃에서 2시간 동안 교반하였다. 반응 혼합물을 셀라이트로 여과하고, 에틸아세테이트로 씻어주었다. 얻어진 여과액을 감압하에 농축한 후, 중압 액체 크로마토그래피(다이클로메탄/에틸아세테이트)로 정제하여 고체의 목적화합물 3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸아닐린(555mg, 80%)을 수득하였다.Compound 3-ethynylimidazo[1,2-b]pyridazine (400mg, 2.79mmol), 3-iodo-4-methylaniline (715mg, 3.07mmol) obtained in Step 2 of Example 1 was ethyl It was added to acetate (9.3 mL), dissolved, and sonicated for 5 minutes while flowing nitrogen. Pd(PPh 3 ) 4 (161 mg, 0.140 mmol), CuI (53.2 mg, 0.279 mmol) and DIPEA (976 μL, 5.59 mmol) were added to the reaction mixture, followed by stirring at 50° C. for 2 hours. The reaction mixture was filtered through celite, and washed with ethyl acetate. 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.
MS (m/z): 249.16 [M+1]+, UPLC r. t. (min) : 1.12MS (m/z): 249.16 [M+1] + , UPLC rt (min): 1.12
1H NMR(400 MHz, DMSO-d 6) δ 8.69 (dd, J = 4.4, 1.2 Hz, 1H), 8.29 - 8.07 (m, 2H), 7.36 (dd, J = 9.2, 4.4 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 8.2, 2.4 Hz, 1H), 5.08 (s, 2H), 2.35 (s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.69 (dd, J = 4.4, 1.2 Hz, 1H), 8.29-8.07 (m, 2H), 7.36 (dd, J = 9.2, 4.4 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 8.2, 2.4 Hz, 1H), 5.08 (s, 2H), 2.35 (s, 3H ).
단계 4: Step 4: N-N- (3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)-3-페닐이소옥사졸리딘-2-카복사마이드 트리플루오르아세트산염의 제조Preparation of (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-phenylisooxazolidine-2-carboxamide trifluoroacetate
상기 실시예 1의 단계 3에서 얻어진 화합물(100mg, 0.4mmol)과 피리딘 (0.14mL, 1.7mmol)을 다이메틸포름아마이드(2mL)에 첨가하여 녹인 후 0℃에서 N,N'-다이석시니미딜 카보네이트(127mg, 0.785mmol)을 첨가하였다. 0℃에서 2시간 동안 교반하였다. 제조예 1에서 얻어진 화합물 3-페닐아이소옥사졸리딘(0.09mL, 0.6mmol)을 천천히 적가한 뒤 60℃에서 2시간 동안 교반하였다. 반응 종결 뒤 에틸아세테이트 및 소금물로 추출하여 유기층을 합한다. 유기층을 황산나트륨으로 건조한 후 감압하여 농축 후 Prep-150 장치를 이용하여 정제한 후 목적 화합물 N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)-3-페닐이소옥사졸리딘-2-카복사마이드 트리플루오르아세트산염(178mg, 70% purity; 94.4% e.e.)을 얻었다The compound (100mg, 0.4mmol) and pyridine (0.14mL, 1.7mmol) obtained in Step 3 of Example 1 were added to dimethylformamide (2mL) to dissolve and then N,N'-disuccinimi at 0°C. Dill carbonate (127 mg, 0.785 mmol) was added. Stir at 0° C. for 2 hours. Compound 3-phenylisooxazolidine (0.09 mL, 0.6 mmol) obtained in Preparation Example 1 was slowly added dropwise and stirred at 60° C. for 2 hours. After completion of the reaction, extract with ethyl acetate and brine, and combine the organic layers. After drying the organic layer over sodium sulfate and then concentrated under reduced pressure and purified using a Prep-150 unit the objective compound N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) -4-methylphenyl )-3-phenylisooxazolidine-2-carboxamide trifluoroacetate (178mg, 70% purity; 94.4% ee) was obtained.
MS (m/z): 424.32 [M+1]+, UPLC r. t. (min) : 1.73MS (m/z): 424.32 [M+1] + , UPLC rt (min): 1.73
1H NMR (400 MHz, DMSO-d6) δ = 9.50 (s, 1H), 8.78 (dd, J = 4.5, 1.6 Hz, 1H), 8.34 - 8.28 (m, 2H), 7.93 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.4, 2.3 Hz, 1H), 7.48 (dd, J = 9.2, 4.5 Hz, 1H), 7.41 - 7.34 (m, 4H), 7.29 - 7.24 (m, 2H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.25 (td, J = 7.9, 3.1 Hz, 1H), 3.89 (dt, J = 9.1, 7.2 Hz, 1H), 2.90 - 2.80 (m, 1H), 2.46 (s, 3H), 2.28 - 2.17 (m, 1H) 1 H NMR (400 MHz, DMSO-d6) δ = 9.50 (s, 1H), 8.78 (dd, J = 4.5, 1.6 Hz, 1H), 8.34-8.28 (m, 2H), 7.93 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.4, 2.3 Hz, 1H), 7.48 (dd, J = 9.2, 4.5 Hz, 1H), 7.41-7.34 (m, 4H), 7.29-7.24 (m, 2H) , 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.25 (td, J = 7.9, 3.1 Hz, 1H), 3.89 (dt, J = 9.1, 7.2 Hz, 1H), 2.90-2.80 (m, 1H ), 2.46 (s, 3H), 2.28-2.17 (m, 1H)
상기 실시예 1과 유사한 방법으로 실시예 2 내지 25를 제조하였으며, 실시예 1 내지 25의 화합물명, 화학구조식, NMR 및 UPLC 분석 결과를 하기 표 1에 정리하여 나타내었다.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.
실시예Example 구조rescue 화합물명Compound name UPLC[M+1]+; r.t. (min)UPLC[M+1] + ; rt (min) 1H NMR 1 H NMR
1One
Figure PCTKR2019018834-appb-I000145
Figure PCTKR2019018834-appb-I000145
 		(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)-3-페닐이소옥사졸리딘-2-카복사마이드염산염( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-phenylisooxazolidine-2-carboxamide hydrochloride 424.4; 1.74424.4; 1.74 1H NMR (400 MHz, DMSO-d 6) δ = 9.50 (s, 1H), 8.78 (dd, J = 4.5, 1.6 Hz, 1H), 8.34 - 8.28 (m, 2H), 7.93 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.4, 2.3 Hz, 1H), 7.48 (dd, J = 9.2, 4.5 Hz, 1H), 7.41 - 7.34 (m, 4H), 7.29 - 7.24 (m, 2H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.25 (td, J = 7.9, 3.1 Hz, 1H), 3.89 (dt, J = 9.1, 7.2 Hz, 1H), 2.90 - 2.80 (m, 1H), 2.46 (s, 3H), 2.28 - 2.17 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.50 (s, 1H), 8.78 (dd, J = 4.5, 1.6 Hz, 1H), 8.34-8.28 (m, 2H), 7.93 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.4, 2.3 Hz, 1H), 7.48 (dd, J = 9.2, 4.5 Hz, 1H), 7.41-7.34 (m, 4H), 7.29-7.24 (m, 2H ), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.25 (td, J = 7.9, 3.1 Hz, 1H), 3.89 (dt, J = 9.1, 7.2 Hz, 1H), 2.90-2.80 (m, 1H), 2.46 (s, 3H), 2.28-2.17 (m, 1H)
22
Figure PCTKR2019018834-appb-I000146
Figure PCTKR2019018834-appb-I000146
 		(S)-3-(3,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)이소옥사졸리딘-2-카복사마이드 트리플루오르아세트산염( S )-3-(3,5-difluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)isooxazolidine -2-carboxamide trifluoroacetate 460.2; 1.81460.2; 1.81 1H NMR (400 MHz, DMSO-d 6) δ = 9.56 (s, 1H), 8.72 (dd, J = 4.5, 1.6 Hz, 1H), 8.29 - 8.19 (m, 2H), 7.91 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.4, 2.3 Hz, 1H), 7.39 (dd, J = 9.2, 4.5 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.19 - 7.08 (m, 3H), 5.45 (dd, J = 8.7, 5.8 Hz, 1H), 4.24 (dt, J = 7.9, 4.0 Hz, 1H), 3.90 (dd, J = 8.1, 1.8 Hz, 1H), 2.93 - 2.85 (m, 1H), 2.46 (s, 3H), 2.29 - 2.20 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.56 (s, 1H), 8.72 (dd, J = 4.5, 1.6 Hz, 1H), 8.29-8.19 (m, 2H), 7.91 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.4, 2.3 Hz, 1H), 7.39 (dd, J = 9.2, 4.5 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.19-7.08 ( m, 3H), 5.45 (dd, J = 8.7, 5.8 Hz, 1H), 4.24 (dt, J = 7.9, 4.0 Hz, 1H), 3.90 (dd, J = 8.1, 1.8 Hz, 1H), 2.93-2.85 (m, 1H), 2.46 (s, 3H), 2.29-2.20 (m, 1H)
33
Figure PCTKR2019018834-appb-I000147
Figure PCTKR2019018834-appb-I000147
 		(S)-3-(3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)이소옥사졸리딘-2-카복사마이드 트리플루오르아세트산염( S )-3-(3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)isooxazolidine-2- Carboxamide trifluoroacetate 442.2; 1.77442.2; 1.77 1H NMR (400 MHz, DMSO-d 6) δ = 9.53 (s, 1H), 8.73 (dd, J = 4.4, 1.5 Hz, 1H), 8.26 (dd, J = 9.2, 1.6 Hz, 1H), 8.23 (s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.44 - 7.37 (m, 2H), 7.27 (d, J = 8.7 Hz, 2H), 7.19 (s, 1H), 7.11 (d, J = 2.7 Hz, 1H), 5.44 (dd, J = 8.6, 5.8 Hz, 1H), 4.25 (d, J = 3.1 Hz, 1H), 3.90 (dd, J = 8.1, 1.9 Hz, 1H), 2.87 (dddd, J = 12.0, 8.6, 7.0, 3.1 Hz, 1H), 2.47 (s, 3H), 2.29 - 2.19 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.53 (s, 1H), 8.73 (dd, J = 4.4, 1.5 Hz, 1H), 8.26 (dd, J = 9.2, 1.6 Hz, 1H), 8.23 (s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.63-7.57 (m, 1H), 7.44-7.37 (m, 2H), 7.27 (d, J = 8.7 Hz, 2H), 7.19 ( s, 1H), 7.11 (d, J = 2.7 Hz, 1H), 5.44 (dd, J = 8.6, 5.8 Hz, 1H), 4.25 (d, J = 3.1 Hz, 1H), 3.90 (dd, J = 8.1 , 1.9 Hz, 1H), 2.87 (dddd, J = 12.0, 8.6, 7.0, 3.1 Hz, 1H), 2.47 (s, 3H), 2.29-2.19 (m, 1H)
44
Figure PCTKR2019018834-appb-I000148
Figure PCTKR2019018834-appb-I000148
 		(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 410.3; 1.67410.3; 1.67 1HNMR (400 MHz, CDCl3) δ = 8.44 - 8.38 (m, 1H), 7.98 - 7.84 (m, 3H), 7.72 - 7.67 (m, 1H), 7.53 - 7.46 (m, 1H), 7.38 - 7.33 (m, 2H), 7.32 - 7.24 (m, 4H), 7.23 - 7.20 (m, 1H), 7.08 - 6.99 (m, 1H), 5.52 - 5.44 (m, 1H), 4.25 - 4.15 (m, 1H), 3.97 - 3.84 (m, 1H), 2.83 - 2.71 (m, 1H), 2.45 - 2.31 (m, 1H) 1 HNMR (400 MHz, CDCl 3 ) δ = 8.44-8.38 (m, 1H), 7.98-7.84 (m, 3H), 7.72-7.67 (m, 1H), 7.53-7.46 (m, 1H), 7.38-7.33 (m, 2H), 7.32-7.24 (m, 4H), 7.23-7.20 (m, 1H), 7.08-6.99 (m, 1H), 5.52-5.44 (m, 1H), 4.25-4.15 (m, 1H) , 3.97-3.84 (m, 1H), 2.83-2.71 (m, 1H), 2.45-2.31 (m, 1H)
55
Figure PCTKR2019018834-appb-I000149
Figure PCTKR2019018834-appb-I000149
 		(R)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐아이소옥사졸리딘-2-카복사마이드 트리플루오르아세트산염 (R) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3-phenyl-iso-oxazolidine-2-carboxamide trifluoroacetic acid salt 410.3; 1.63410.3; 1.63 1H NMR (400 MHz, DMSO-d 6) δ = 9.59 (s, 1H), 8.72 (d, J = 4.4 Hz, 1H), 8.47 - 8.12 (m, 2H), 7.98 (t, J = 1.9 Hz, 1H), 7.72 (dd, J = 8.3, 2.2 Hz, 1H), 7.43 - 7.34 (m, 6H), 7.30 - 7.23 (m, 2H), 5.42 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 1H), 3.90 (dt, J = 9.3, 7.4 Hz, 1H), 2.92 - 2.80 (m, 1H), 2.30 - 2.18 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.59 (s, 1H), 8.72 (d, J = 4.4 Hz, 1H), 8.47-8.12 (m, 2H), 7.98 (t, J = 1.9 Hz , 1H), 7.72 (dd, J = 8.3, 2.2 Hz, 1H), 7.43-7.34 (m, 6H), 7.30-7.23 (m, 2H), 5.42 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 1H), 3.90 (dt, J = 9.3, 7.4 Hz, 1H), 2.92-2.80 (m, 1H), 2.30-2.18 (m, 1H)
66
Figure PCTKR2019018834-appb-I000150
Figure PCTKR2019018834-appb-I000150
 		(S)-3-(3,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(3,5-difluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2- Carboxamide trichloroacetate 446.2; 1.73446.2; 1.73 1H NMR (400 MHz, DMSO-d 6) δ = 9.65 (s, 1H), 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.24 (dd, J = 9.3, 1.6 Hz, 1H), 8.19 (s, 1H), 7.97 (t, J = 1.9 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.41 - 7.35 (m, 2H), 7.26 (dt, J = 7.6, 1.3 Hz, 1H), 7.16 (dt, J = 9.2, 2.4 Hz, 1H), 7.13 - 7.08 (m, 2H), 5.46 (dd, J = 8.7, 5.8 Hz, 1H), 4.25 (td, J = 7.9, 3.0 Hz, 1H), 3.96 - 3.84 (m, 1H), 2.87 (dtt, J = 9.7, 7.1, 3.5 Hz, 1H), 2.24 (dddd, J = 12.2, 9.3, 7.8, 5.6 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.65 (s, 1H), 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.24 (dd, J = 9.3, 1.6 Hz, 1H), 8.19 (s, 1H), 7.97 (t, J = 1.9 Hz, 1H), 7.74-7.69 (m, 1H), 7.41-7.35 (m, 2H), 7.26 (dt, J = 7.6, 1.3 Hz, 1H), 7.16 (dt, J = 9.2, 2.4 Hz, 1H), 7.13-7.08 (m, 2H), 5.46 (dd, J = 8.7, 5.8 Hz, 1H), 4.25 (td, J = 7.9, 3.0 Hz, 1H) , 3.96-3.84 (m, 1H), 2.87 (dtt, J = 9.7, 7.1, 3.5 Hz, 1H), 2.24 (dddd, J = 12.2, 9.3, 7.8, 5.6 Hz, 1H)
77
Figure PCTKR2019018834-appb-I000151
Figure PCTKR2019018834-appb-I000151
 		(R)-3-(3,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플루오르아세트산염 (R) -3- (3,5- difluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin-2-isopropyl Carboxamide trifluoroacetate 446.3;1.77446.3;1.77 1H NMR (400 MHz, DMSO-d 6) δ = 9.65 (s, 1H), 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.25 (dd, J = 9.2, 1.6 Hz, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.72 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.62 (m, 2H), 7.56 (m, 1H), 7.38 (m, 2H), 7.27 (dt, J = 7.7, 1.3 Hz, 1H), 7.16 (m, 1H), 5.47 (dd, J = 8.7, 5.8 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 1H), 3.91 (m, 1H), 2.88 (m, 1H), 2.24 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.65 (s, 1H), 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.25 (dd, J = 9.2, 1.6 Hz, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.72 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.62 (m, 2H), 7.56 (m, 1H), 7.38 (m, 2H), 7.27 ( dt, J = 7.7, 1.3 Hz, 1H), 7.16 (m, 1H), 5.47 (dd, J = 8.7, 5.8 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 1H), 3.91 (m , 1H), 2.88 (m, 1H), 2.24 (m, 1H)
88
Figure PCTKR2019018834-appb-I000152
Figure PCTKR2019018834-appb-I000152
 		(S)-3-(3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide Trichloroacetate 428.3; 1.66428.3; 1.66 1H NMR (400 MHz, DMSO-d 6) δ = 9.62 (s, 1H), 8.70 (dd, J = 4.5, 1.6 Hz, 1H), 8.24 (dd, J = 9.2, 1.6 Hz, 1H), 8.19 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.71 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.45 - 7.34 (m, 3H), 7.26 (ddd, J = 8.0, 3.6, 2.4 Hz, 2H), 7.20 (dt, J = 10.3, 2.2 Hz, 1H), 7.11 (td, J = 8.4, 2.5 Hz, 1H), 5.45 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 1H), 3.90 (dt, J = 9.1, 7.3 Hz, 1H), 2.88 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.24 (dddd, J = 12.1, 9.5, 7.9, 5.9 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.62 (s, 1H), 8.70 (dd, J = 4.5, 1.6 Hz, 1H), 8.24 (dd, J = 9.2, 1.6 Hz, 1H), 8.19 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.71 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.45-7.34 (m, 3H), 7.26 (ddd, J = 8.0 , 3.6, 2.4 Hz, 2H), 7.20 (dt, J = 10.3, 2.2 Hz, 1H), 7.11 (td, J = 8.4, 2.5 Hz, 1H), 5.45 (dd, J = 8.6, 5.9 Hz, 1H) , 4.26 (td, J = 7.9, 3.0 Hz, 1H), 3.90 (dt, J = 9.1, 7.3 Hz, 1H), 2.88 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.24 (dddd , J = 12.1, 9.5, 7.9, 5.9 Hz, 1H)
99
Figure PCTKR2019018834-appb-I000153
Figure PCTKR2019018834-appb-I000153
 		(R)-3-(3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플루오르아세트산염( R )-3-(3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide Trifluoroacetate 428.3; 1.73428.3; 1.73 1H NMR (400 MHz, DMSO-d 6) δ = 9.62 (s, 1H), 8.70 (dd, J = 4.5, 1.6 Hz, 1H), 8.25 (dd, J = 9.2, 1.6 Hz, 1H), 8.20 (s, 1H), 7.98 (t, J = 1.7 Hz, 1H), 7.72 (m, 1H), 7.43 (m, 1H), 7.37 (m, 2H), 7.26 (m, 2H), 7.20 (dt, J = 10.3, 2.2 Hz, 1H), 7.11 (td, J = 8.6, 2.7 Hz, 1H), 5.45 (dd, J = 8.7, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 2.9 Hz, 1H), 3.91 (q, J = 7.7 Hz, 1H), 2.88 (m, 1H), 2.24 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.62 (s, 1H), 8.70 (dd, J = 4.5, 1.6 Hz, 1H), 8.25 (dd, J = 9.2, 1.6 Hz, 1H), 8.20 (s, 1H), 7.98 (t, J = 1.7 Hz, 1H), 7.72 (m, 1H), 7.43 (m, 1H), 7.37 (m, 2H), 7.26 (m, 2H), 7.20 (dt, J = 10.3, 2.2 Hz, 1H), 7.11 (td, J = 8.6, 2.7 Hz, 1H), 5.45 (dd, J = 8.7, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 2.9 Hz, 1H) ), 3.91 (q, J = 7.7 Hz, 1H), 2.88 (m, 1H), 2.24 (m, 1H)
1010
Figure PCTKR2019018834-appb-I000154
Figure PCTKR2019018834-appb-I000154
 		(S)-3-(4-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드( S )-3-(4-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide 428.3; 1.69428.3; 1.69 1H NMR (400 MHz, DMSO-d 6) δ = 9.59 (s, 1H), 8.70 (dd, J = 4.5, 1.6 Hz, 1H), 8.24 (dd, J = 9.2, 1.6 Hz, 1H), 8.19 (s, 1H), 7.97 (t, J = 1.9 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.45 - 7.40 (m, 2H), 7.40 - 7.35 (m, 2H), 7.25 (dt, J = 7.6, 1.3 Hz, 1H), 7.22 - 7.16 (m, 2H), 5.42 (dd, J = 8.5, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 1H), 3.90 (dt, J = 9.1, 7.6 Hz, 1H), 2.85 (dtt, J = 9.6, 7.0, 3.5 Hz, 1H), 2.22 (dddd, J = 12.1, 9.5, 7.8, 5.9 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.59 (s, 1H), 8.70 (dd, J = 4.5, 1.6 Hz, 1H), 8.24 (dd, J = 9.2, 1.6 Hz, 1H), 8.19 (s, 1H), 7.97 (t, J = 1.9 Hz, 1H), 7.74-7.68 (m, 1H), 7.45-7.40 (m, 2H), 7.40-7.35 (m, 2H), 7.25 (dt, J = 7.6, 1.3 Hz, 1H), 7.22-7.16 (m, 2H), 5.42 (dd, J = 8.5, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 1H), 3.90 (dt, J = 9.1, 7.6 Hz, 1H), 2.85 (dtt, J = 9.6, 7.0, 3.5 Hz, 1H), 2.22 (dddd, J = 12.1, 9.5, 7.8, 5.9 Hz, 1H)
1111
Figure PCTKR2019018834-appb-I000155
Figure PCTKR2019018834-appb-I000155
 		(S)-3-(4-클로로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(4-chlorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide triple Lauroacetate 444.3; 1.78444.3; 1.78 1H NMR (400 MHz, DMSO-d 6) δ = 9.62 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.25 (dd, J = 9.2, 1.3 Hz, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.72 (dd, J = 8.3, 1.1 Hz, 1H), 7.45 - 7.36 (m, 6H), 7.27 (d, J = 7.7 Hz, 1H), 5.43 (dd, J = 8.5, 6.0 Hz, 1H), 4.26 (td, J = 7.8, 2.8 Hz, 1H), 3.91 (dd, J = 16.8, 7.8 Hz, 1H), 2.87 (dtd, J = 9.8, 7.2, 2.9 Hz, 1H), 2.22 (dtd, J = 12.3, 9.3, 7.9 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.62 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.25 (dd, J = 9.2, 1.3 Hz, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.72 (dd, J = 8.3, 1.1 Hz, 1H), 7.45-7.36 (m, 6H), 7.27 (d, J = 7.7 Hz, 1H), 5.43 ( dd, J = 8.5, 6.0 Hz, 1H), 4.26 (td, J = 7.8, 2.8 Hz, 1H), 3.91 (dd, J = 16.8, 7.8 Hz, 1H), 2.87 (dtd, J = 9.8, 7.2, 2.9 Hz, 1H), 2.22 (dtd, J = 12.3, 9.3, 7.9 Hz, 1H)
1212
Figure PCTKR2019018834-appb-I000156
Figure PCTKR2019018834-appb-I000156
 		(S)-3-(4-브로모페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(4-Bromophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide Trichloroacetate 490.2; 1.90490.2; 1.90 1H NMR (400 MHz, DMSO-d 6) δ = 9.62 (s, 2H), 8.70 (dd, J = 4.4, 1.4 Hz, 2H), 8.25 (dd, J = 9.2, 1.5 Hz, 2H), 8.20 (s, 2H), 7.98 (s, 2H), 7.72 (dd, J = 8.3, 1.1 Hz, 2H), 7.57 (d, J = 8.4 Hz, 4H), 7.41 - 7.34 (m, 8H), 7.27 (d, J = 7.7 Hz, 2H), 5.41 (dd, J = 8.4, 6.0 Hz, 2H), 4.26 (td, J = 7.8, 2.8 Hz, 2H), 3.91 (dd, J = 16.7, 7.8 Hz, 2H), 2.92 - 2.82 (m, 3H), 2.21 (dtd, J = 12.3, 9.3, 7.9 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.62 (s, 2H), 8.70 (dd, J = 4.4, 1.4 Hz, 2H), 8.25 (dd, J = 9.2, 1.5 Hz, 2H), 8.20 (s, 2H), 7.98 (s, 2H), 7.72 (dd, J = 8.3, 1.1 Hz, 2H), 7.57 (d, J = 8.4 Hz, 4H), 7.41-7.34 (m, 8H), 7.27 ( d, J = 7.7 Hz, 2H), 5.41 (dd, J = 8.4, 6.0 Hz, 2H), 4.26 (td, J = 7.8, 2.8 Hz, 2H), 3.91 (dd, J = 16.7, 7.8 Hz, 2H) ), 2.92-2.82 (m, 3H), 2.21 (dtd, J = 12.3, 9.3, 7.9 Hz, 2H)
1313
Figure PCTKR2019018834-appb-I000157
Figure PCTKR2019018834-appb-I000157
 		(S)-3-(3,4-다이클로로-2-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(3,4-dichloro-2-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazoli Dean-2-carboxamide trifluoroacetate 496.3; 2.00496.3; 2.00 1H NMR (400 MHz, DMSO-d 6) δ = 9.70 (s, 1H), 8.73 (d, J = 4.3 Hz, 1H), 8.27 (d, J = 9.5 Hz, 2H), 7.98 (s, 1H), 7.72 (dd, J = 8.3, 1.0 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.50 - 7.36 (m, 3H), 7.28 (d, J = 7.7 Hz, 1H), 5.62 (dd, J = 8.5, 6.1 Hz, 1H), 4.30 (td, J = 7.8, 2.5 Hz, 1H), 3.99 - 3.91 (m, 1H), 2.98 - 2.87 (m, 1H), 2.29 - 2.16 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.70 (s, 1H), 8.73 (d, J = 4.3 Hz, 1H), 8.27 (d, J = 9.5 Hz, 2H), 7.98 (s, 1H ), 7.72 (dd, J = 8.3, 1.0 Hz, 1H), 7.57-7.52 (m, 1H), 7.50-7.36 (m, 3H), 7.28 (d, J = 7.7 Hz, 1H), 5.62 (dd, J = 8.5, 6.1 Hz, 1H), 4.30 (td, J = 7.8, 2.5 Hz, 1H), 3.99-3.91 (m, 1H), 2.98-2.87 (m, 1H), 2.29-2.16 (m, 1H)
1414
Figure PCTKR2019018834-appb-I000158
Figure PCTKR2019018834-appb-I000158
 		(S)-3-(4-클로로-3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(4-Chloro-3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2 -Carboxamide trichloroacetate 462.3; 1.89462.3; 1.89 1H NMR (400 MHz, DMSO-d 6) δ = 9.65 (s, 1H), 8.71 (dd, J = 4.4, 1.4 Hz, 1H), 8.25 (dd, J = 9.2, 1.5 Hz, 1H), 8.21 (s, 1H), 7.98 (t, J = 1.6 Hz, 1H), 7.72 (dd, J = 8.3, 1.1 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.40 (ddd, J = 13.7, 9.0, 2.0 Hz, 3H), 7.28 (dd, J = 10.3, 4.5 Hz, 2H), 5.46 (dd, J = 8.5, 5.9 Hz, 1H), 4.27 (td, J = 7.9, 2.9 Hz, 1H), 3.92 (dd, J = 16.7, 7.9 Hz, 1H), 2.88 (dtd, J = 9.9, 7.1, 3.0 Hz, 1H), 2.30 - 2.15 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.65 (s, 1H), 8.71 (dd, J = 4.4, 1.4 Hz, 1H), 8.25 (dd, J = 9.2, 1.5 Hz, 1H), 8.21 (s, 1H), 7.98 (t, J = 1.6 Hz, 1H), 7.72 (dd, J = 8.3, 1.1 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.40 (ddd, J = 13.7, 9.0, 2.0 Hz, 3H), 7.28 (dd, J = 10.3, 4.5 Hz, 2H), 5.46 (dd, J = 8.5, 5.9 Hz, 1H), 4.27 (td, J = 7.9, 2.9 Hz, 1H) ), 3.92 (dd, J = 16.7, 7.9 Hz, 1H), 2.88 (dtd, J = 9.9, 7.1, 3.0 Hz, 1H), 2.30-2.15 (m, 1H)
1515
Figure PCTKR2019018834-appb-I000159
Figure PCTKR2019018834-appb-I000159
 		(S)-3-(3-클로로-4-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(3-chloro-4-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2 -Carboxamide trichloroacetate 462.3; 1.88462.3; 1.88 1H NMR (400 MHz, DMSO-d 6) δ = 9.64 (s, 1H), 8.72 (dd, J = 4.4, 1.3 Hz, 1H), 8.26 (dd, J = 9.2, 1.3 Hz, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.72 (dd, J = 8.3, 1.0 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.45 - 7.35 (m, 4H), 7.27 (d, J = 7.7 Hz, 1H), 5.45 (dd, J = 8.4, 6.0 Hz, 1H), 4.27 (td, J = 7.8, 2.8 Hz, 1H), 3.92 (dd, J = 16.8, 7.8 Hz, 1H), 2.88 (ddd, J = 11.8, 10.8, 2.9 Hz, 1H), 2.31 - 2.18 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.64 (s, 1H), 8.72 (dd, J = 4.4, 1.3 Hz, 1H), 8.26 (dd, J = 9.2, 1.3 Hz, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.72 (dd, J = 8.3, 1.0 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.45-7.35 (m, 4H), 7.27 ( d, J = 7.7 Hz, 1H), 5.45 (dd, J = 8.4, 6.0 Hz, 1H), 4.27 (td, J = 7.8, 2.8 Hz, 1H), 3.92 (dd, J = 16.8, 7.8 Hz, 1H) ), 2.88 (ddd, J = 11.8, 10.8, 2.9 Hz, 1H), 2.31-2.18 (m, 1H)
1616
Figure PCTKR2019018834-appb-I000160
Figure PCTKR2019018834-appb-I000160
 		(S)-3-(2,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(2,5-difluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2- Carboxamide trichloroacetate 446.3; 1.80446.3; 1.80 1H NMR (400 MHz, DMSO-d 6) δ = 9.69 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.26 (dd, J = 9.2, 1.4 Hz, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.72 (dd, J = 8.3, 1.1 Hz, 1H), 7.40 (td, J = 7.6, 3.1 Hz, 2H), 7.34 - 7.26 (m, 2H), 7.25 - 7.17 (m, 2H), 5.60 (dd, J = 8.5, 6.0 Hz, 1H), 4.31 (td, J = 7.9, 2.7 Hz, 1H), 3.97-3.91 (m, 1H), 2.97 - 2.85 (m, 1H), 2.26 - 2.13 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.69 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.26 (dd, J = 9.2, 1.4 Hz, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.72 (dd, J = 8.3, 1.1 Hz, 1H), 7.40 (td, J = 7.6, 3.1 Hz, 2H), 7.34-7.26 (m, 2H), 7.25-7.17 (m, 2H), 5.60 (dd, J = 8.5, 6.0 Hz, 1H), 4.31 (td, J = 7.9, 2.7 Hz, 1H), 3.97-3.91 (m, 1H), 2.97-2.85 ( m, 1H), 2.26-2.13 (m, 1H)
1717
Figure PCTKR2019018834-appb-I000161
Figure PCTKR2019018834-appb-I000161
 		(S)-3-(3-클로로-2-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(3-chloro-2-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2 -Carboxamide trichloroacetate 462.3; 1.88462.3; 1.88 1H NMR (400 MHz, DMSO-d 6) δ = 9.68 (s, 2H), 8.72 (dd, J = 4.4, 1.4 Hz, 2H), 8.26 (dd, J = 9.2, 1.4 Hz, 2H), 8.22 (s, 2H), 7.98 (s, 2H), 7.72 (dd, J = 8.3, 1.1 Hz, 2H), 7.57 - 7.49 (m, 2H), 7.48 - 7.42 (m, 2H), 7.42 - 7.36 (m, 4H), 7.26 (t, J = 8.2 Hz, 4H), 5.64 (dd, J = 8.5, 6.2 Hz, 2H), 4.31 (td, J = 7.9, 2.5 Hz, 3H), 3.95 (dd, J = 17.0, 7.7 Hz, 2H), 2.99 - 2.87 (m, 2H), 2.28 - 2.14 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.68 (s, 2H), 8.72 (dd, J = 4.4, 1.4 Hz, 2H), 8.26 (dd, J = 9.2, 1.4 Hz, 2H), 8.22 (s, 2H), 7.98 (s, 2H), 7.72 (dd, J = 8.3, 1.1 Hz, 2H), 7.57-7.49 (m, 2H), 7.48-7.42 (m, 2H), 7.42-7.36 (m , 4H), 7.26 (t, J = 8.2 Hz, 4H), 5.64 (dd, J = 8.5, 6.2 Hz, 2H), 4.31 (td, J = 7.9, 2.5 Hz, 3H), 3.95 (dd, J = 17.0, 7.7 Hz, 2H), 2.99-2.87 (m, 2H), 2.28-2.14 (m, 2H)
1818
Figure PCTKR2019018834-appb-I000162
Figure PCTKR2019018834-appb-I000162
 		(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(3-메톡시페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(3-methoxyphenyl)isooxazolidine-2-carboxamide Trichloroacetate 440.3; 1.75440.3; 1.75 1H NMR (400 MHz, DMSO-d 6) δ = 9.61 (s, 2H), 8.71 (dd, J = 4.4, 1.2 Hz, 2H), 8.25 (dd, J = 9.2, 1.3 Hz, 2H), 8.21 (s, 2H), 8.00 (s, 2H), 7.73 (dd, J = 8.3, 1.1 Hz, 2H), 7.42 - 7.34 (m, 4H), 7.32 - 7.24 (m, 4H), 6.96 (dd, J = 10.5, 4.9 Hz, 4H), 6.85 (dd, J = 8.1, 2.4 Hz, 2H), 5.41 (dd, J = 8.5, 5.9 Hz, 2H), 4.26 (td, J = 7.8, 2.9 Hz, 2H), 3.90 (dd, J = 16.9, 7.7 Hz, 3H), 3.77 (s, 6H), 2.86 (ddd, J = 15.4, 9.5, 3.0 Hz, 2H), 2.30 - 2.17 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.61 (s, 2H), 8.71 (dd, J = 4.4, 1.2 Hz, 2H), 8.25 (dd, J = 9.2, 1.3 Hz, 2H), 8.21 (s, 2H), 8.00 (s, 2H), 7.73 (dd, J = 8.3, 1.1 Hz, 2H), 7.42-7.34 (m, 4H), 7.32-7.24 (m, 4H), 6.96 (dd, J = 10.5, 4.9 Hz, 4H), 6.85 (dd, J = 8.1, 2.4 Hz, 2H), 5.41 (dd, J = 8.5, 5.9 Hz, 2H), 4.26 (td, J = 7.8, 2.9 Hz, 2H) , 3.90 (dd, J = 16.9, 7.7 Hz, 3H), 3.77 (s, 6H), 2.86 (ddd, J = 15.4, 9.5, 3.0 Hz, 2H), 2.30-2.17 (m, 2H)
1919
Figure PCTKR2019018834-appb-I000163
Figure PCTKR2019018834-appb-I000163
 		(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(6-메틸피리딘-3-일)이소옥사졸리딘-2-카복사마이드( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(6-methylpyridin-3-yl)isooxazolidine-2- Carboxamide 425.3; 1.14425.3; 1.14 1H NMR (400 MHz, DMSO-d 6) δ = 9.64 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.51 (s, 1H), 8.25 (dd, J = 9.2, 1.4 Hz, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.76 (dd, J = 8.1, 2.2 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.41 - 7.35 (m, 2H), 7.33 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 5.47 (dd, J = 8.3, 6.0 Hz, 1H), 4.28 (td, J = 7.9, 3.0 Hz, 1H), 3.94 (dd, J = 16.6, 7.9 Hz, 1H), 2.92 - 2.82 (m, 1H), 2.49 (s, 3H), 2.34 - 2.21 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.64 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.51 (s, 1H), 8.25 (dd, J = 9.2, 1.4 Hz, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.76 (dd, J = 8.1, 2.2 Hz, 1H), 7.74-7.70 (m, 1H), 7.41-7.35 (m, 2H ), 7.33 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 5.47 (dd, J = 8.3, 6.0 Hz, 1H), 4.28 (td, J = 7.9, 3.0 Hz , 1H), 3.94 (dd, J = 16.6, 7.9 Hz, 1H), 2.92-2.82 (m, 1H), 2.49 (s, 3H), 2.34-2.21 (m, 1H)
2020
Figure PCTKR2019018834-appb-I000164
Figure PCTKR2019018834-appb-I000164
 		(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(피리딘-3-일)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(pyridin-3-yl)isooxazolidine-2-carboxamide Trichloroacetate 411.2; 1.13411.2; 1.13 1H NMR (400 MHz, DMSO-d 6) δ = 9.64 (s, 1H), 8.71 (ddd, J = 11.3, 4.5, 1.6 Hz, 1H), 8.61 (dd, J = 5.2, 2.3 Hz, 1H), 8.50 (d, J = 4.8 Hz, 1H), 8.27 - 8.22 (m, 1H), 8.19 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.79 (dt, J = 8.7, 2.6 Hz, 1H), 7.46 - 7.34 (m, 3H), 7.30 - 7.23 (m, 1H), 5.47 (ddd, J = 14.5, 8.6, 5.8 Hz, 1H), 4.30 (dtd, J = 11.0, 8.0, 6.9, 3.1 Hz, 1H), 3.99 - 3.89 (m, 1H), 2.90 (dtt, J = 11.8, 7.5, 3.7 Hz, 1H), 2.34 - 2.23 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.64 (s, 1H), 8.71 (ddd, J = 11.3, 4.5, 1.6 Hz, 1H), 8.61 (dd, J = 5.2, 2.3 Hz, 1H) , 8.50 (d, J = 4.8 Hz, 1H), 8.27-8.22 (m, 1H), 8.19 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.79 (dt, J = 8.7, 2.6 Hz, 1H), 7.46-7.34 (m, 3H), 7.30-7.23 (m, 1H), 5.47 (ddd, J = 14.5, 8.6, 5.8 Hz, 1H), 4.30 (dtd, J = 11.0, 8.0, 6.9 , 3.1 Hz, 1H), 3.99-3.89 (m, 1H), 2.90 (dtt, J = 11.8, 7.5, 3.7 Hz, 1H), 2.34-2.23 (m, 1H)
2121
Figure PCTKR2019018834-appb-I000165
Figure PCTKR2019018834-appb-I000165
 		(S)-N-(4-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카르복사마이드 트리플루오로아세트산염( S )- N- (4-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide trifluoroacetate 410.2; 1.69410.2; 1.69 1H NMR (400 MHz, DMSO-d 6) δ = 9.66 (s, 1H), 8.69 (dd, J = 4.5, 1.6 Hz, 1H), 8.23 (dd, J = 9.2, 1.6 Hz, 1H), 8.15 (s, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.41 - 7.34 (m, 5H), 7.30 - 7.25 (m, 1H), 5.43 (dd, J = 8.6, 5.8 Hz, 1H), 4.27 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 2.90 - 2.83 (m, 1H), 2.24 (ddt, J = 9.8, 5.9, 3.2 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.66 (s, 1H), 8.69 (dd, J = 4.5, 1.6 Hz, 1H), 8.23 (dd, J = 9.2, 1.6 Hz, 1H), 8.15 (s, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.41-7.34 (m, 5H), 7.30-7.25 (m, 1H), 5.43 ( dd, J = 8.6, 5.8 Hz, 1H), 4.27 (d, J = 3.1 Hz, 1H), 3.92-3.87 (m, 1H), 2.90-2.83 (m, 1H), 2.24 (ddt, J = 9.8, 5.9, 3.2 Hz, 1H)
2222
Figure PCTKR2019018834-appb-I000166
Figure PCTKR2019018834-appb-I000166
 		(S)-3-(5-사이아노피리딘-3-일)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드( S )-3-(5-Cyanopyridin-3-yl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2 -Carboxamide 436.3; 1.44436.3; 1.44 1H NMR (400 MHz, DMSO-d 6) δ = 9.70 (s, 1H), 8.94 (dd, J = 25.4, 2.0 Hz, 2H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.31 (t, J = 1.8 Hz, 1H), 8.25 (dd, J = 9.2, 1.4 Hz, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.75 - 7.68 (m, 1H), 7.42 - 7.34 (m, 2H), 7.28 (d, J = 7.7 Hz, 1H), 5.57 (dd, J = 8.4, 5.9 Hz, 1H), 4.31 (td, J = 7.8, 3.0 Hz, 1H), 3.97 (dd, J = 16.4, 8.0 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.42 - 2.29 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.70 (s, 1H), 8.94 (dd, J = 25.4, 2.0 Hz, 2H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.31 (t, J = 1.8 Hz, 1H), 8.25 (dd, J = 9.2, 1.4 Hz, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.75-7.68 (m, 1H), 7.42- 7.34 (m, 2H), 7.28 (d, J = 7.7 Hz, 1H), 5.57 (dd, J = 8.4, 5.9 Hz, 1H), 4.31 (td, J = 7.8, 3.0 Hz, 1H), 3.97 (dd , J = 16.4, 8.0 Hz, 1H), 2.97-2.85 (m, 1H), 2.42-2.29 (m, 1H)
2323
Figure PCTKR2019018834-appb-I000167
Figure PCTKR2019018834-appb-I000167
 		(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(4-(트리플루오로메틸)티아졸-2-일)이소옥사졸리딘-2-카복사마이드( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(4-(trifluoromethyl)thiazol-2-yl)iso Oxazolidine-2-carboxamide 485.2; 1.69485.2; 1.69 1H NMR (400 MHz, DMSO-d 6) δ = 9.80 (s, 1H), 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.47 (d, J = 1.0 Hz, 1H), 8.25 (dd, J = 9.2, 1.6 Hz, 1H), 8.20 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.43 - 7.36 (m, 2H), 7.30 (dt, J = 7.7, 1.3 Hz, 1H), 5.76 (dd, J = 8.9, 5.2 Hz, 1H), 4.32 (td, J = 8.1, 3.0 Hz, 1H), 3.95 (q, J = 8.2 Hz, 1H), 2.94 - 2.92 (m, 1H), 2.66 - 2.58 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.80 (s, 1H), 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.47 (d, J = 1.0 Hz, 1H), 8.25 (dd , J = 9.2, 1.6 Hz, 1H), 8.20 (s, 1H), 7.98 (t, J = 1.9 Hz, 1H), 7.76-7.70 (m, 1H), 7.43-7.36 (m, 2H), 7.30 ( dt, J = 7.7, 1.3 Hz, 1H), 5.76 (dd, J = 8.9, 5.2 Hz, 1H), 4.32 (td, J = 8.1, 3.0 Hz, 1H), 3.95 (q, J = 8.2 Hz, 1H) ), 2.94-2.92 (m, 1H), 2.66-2.58 (m, 1H)
2424
Figure PCTKR2019018834-appb-I000168
Figure PCTKR2019018834-appb-I000168
 		(R)-3-벤질-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( R )-3-benzyl- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide triloacetate 424.4; 1.74424.4; 1.74 1H NMR (400 MHz, DMSO-d 6) δ = 9.48 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.25 (dd, J = 9.2, 1.4 Hz, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.68 (dd, J = 8.3, 1.1 Hz, 1H), 7.42 - 7.19 (m, 8H), 4.68 - 4.57 (m, 1H), 4.17 (td, J = 8.0, 3.6 Hz, 1H), 3.80 (q, J = 8.2 Hz, 1H), 2.94 (dd, J = 13.7, 7.2 Hz, 1H), 2.77 (dd, J = 13.7, 7.3 Hz, 1H), 2.35 - 2.24 (m, 1H), 2.07 - 1.94 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.48 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.25 (dd, J = 9.2, 1.4 Hz, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.68 (dd, J = 8.3, 1.1 Hz, 1H), 7.42-7.19 (m, 8H), 4.68-4.57 (m, 1H), 4.17 (td, J = 8.0, 3.6 Hz, 1H), 3.80 (q, J = 8.2 Hz, 1H), 2.94 (dd, J = 13.7, 7.2 Hz, 1H), 2.77 (dd, J = 13.7, 7.3 Hz, 1H), 2.35 -2.24 (m, 1H), 2.07-1.94 (m, 1H)
2525
Figure PCTKR2019018834-appb-I000169
Figure PCTKR2019018834-appb-I000169
 		(S)-3-벤질-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-benzyl- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide trichloroacetate 424.4; 1.97424.4; 1.97 1H NMR (400 MHz, DMSO-d 6) δ = 9.48 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.25 (dd, J = 9.2, 1.3 Hz, 1H), 8.21 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.68 (dd, J = 8.3, 1.1 Hz, 1H), 7.41 - 7.19 (m, 8H), 4.63 (qd, J = 7.4, 4.7 Hz, 1H), 4.17 (td, J = 7.9, 3.5 Hz, 1H), 3.83 - 3.77 (m, 1H), 2.94 (dd, J = 13.7, 7.2 Hz, 1H), 2.77 (dd, J = 13.7, 7.3 Hz, 1H), 2.35 - 2.23 (m, 1H), 2.06 - 1.94 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.48 (s, 1H), 8.71 (dd, J = 4.4, 1.3 Hz, 1H), 8.25 (dd, J = 9.2, 1.3 Hz, 1H), 8.21 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.68 (dd, J = 8.3, 1.1 Hz, 1H), 7.41-7.19 (m, 8H), 4.63 (qd, J = 7.4, 4.7 Hz, 1H), 4.17 (td, J = 7.9, 3.5 Hz, 1H), 3.83-3.77 (m, 1H), 2.94 (dd, J = 13.7, 7.2 Hz, 1H), 2.77 (dd, J = 13.7, 7.3 Hz, 1H), 2.35-2.23 (m, 1H), 2.06-1.94 (m, 1H)
<실시예 26> (<Example 26> ( SS )-)- N-N- (2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-일)-3-페닐아이소옥사졸리딘-2-카복사마이드의 제조Preparation of (2-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-4-yl)-3-phenylisooxazolidine-2-carboxamide
Figure PCTKR2019018834-appb-I000170
Figure PCTKR2019018834-appb-I000170
단계 1: 2-아이오도피리딘-4-아민의 제조Step 1: Preparation of 2-iodopyridin-4-amine
2-브로모피리딘-4-아민(400mg, 2.312mmol), CuI(881mg, 4.62mmol)과 KI(1.92g, 11.56mmol)을 1,4-디옥산(7.7mL)에 첨가하여 녹인 후, 질소를 흘리면서 10분동안 초음파 처리하여 가스를 제거하여 130℃에서 밤새 교반하였다. 반응 혼합물을 셀라이트로 여과하고, 과량의 에틸아세테이트에 녹여 소금물로 닦아준 뒤, 유기층을 황산나트륨으로 건조 후 감압하에서 농축한다. 얻어진 여과액을 농축하여 목적화합물인 2-아이오도피리딘-4-아민(105.1mg, 83%)을 얻었으며, 정제없이 다음 반응에 사용하였다.2-Bromopyridin-4-amine (400mg, 2.312mmol), CuI (881mg, 4.62mmol) and KI (1.92g, 11.56mmol) were added to 1,4-dioxane (7.7mL), dissolved, and then nitrogen The gas was removed by ultrasonic treatment for 10 minutes while flowing, and stirred at 130°C overnight. The reaction mixture was filtered through celite, dissolved in excess ethyl acetate, wiped with brine, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained filtrate was concentrated to obtain 2-iodopyridin-4-amine (105.1 mg, 83%) as a target compound, which was used in the next reaction without purification.
MS (m/z) : 220.95 [M+1]+, UPLC r. t. (min) : 0.22MS (m/z): 220.95 [M+1] + , UPLC rt (min): 0.22
1H NMR (400 MHz, CDCl3) δ = 7.94 - 7.87 (m, 1H), 6.99 - 6.94 (m, 1H), 6.50 - 6.43 (m, 1H), 4.32 - 4.14 (m, 2H)1H NMR (400 MHz, CDCl 3 ) δ = 7.94-7.87 (m, 1H), 6.99-6.94 (m, 1H), 6.50-6.43 (m, 1H), 4.32-4.14 (m, 2H)
단계 2: (Step 2: ( SS )-)- N-N- (2-아이오도피리딘-4-일)-3-페닐아이소옥사졸리딘-2-카복사마이드의 제조Preparation of (2-iodopyridin-4-yl)-3-phenylisooxazolidine-2-carboxamide
상기 실시예 26의 단계 1에서 얻어진 화합물 2-아이오도피리딘-4-아민(350mg, 1.591mmol), N,N′'-다이석시니미딜 카보네이트(509mg, 1.989mmol)과 피리딘(0.515mL, 6.36mmol)을 DMF(7mL)에 첨가하여 녹인 후, 6시간 동안 교반 하고, 상기 제조예 1에서 얻어진 (S)-3-페닐이소옥사졸리딘(350μL, 2.386mmol)을 첨가하여 2시간 동안 교반 한다. 반응 종결 뒤 에틸아세테이트 및 소금물로 추출하여 유기층을 합한다. 유기층을 황산나트륨으로 건조한 후 감압하여 농축 후 중압액체크로마토그래피(테트라하이드로퓨란/n-헥산)로 정제하여 고체의 목적화합물 (S)-N-(2-아이오도피리딘-4-일)-3-페닐아이소옥사졸리딘-2-카복사마이드(470mg, 74 %)를 수득하였다Compound 2-iodopyridin-4-amine (350mg, 1.591mmol), N , N ''-disuccinimidyl carbonate (509mg, 1.989mmol) and pyridine (0.515mL, obtained in Step 1 of Example 26 above) 6.36 mmol) was added to DMF (7 mL) to dissolve, stirred for 6 hours, and (S)-3-phenylisooxazolidine (350 μL, 2.386 mmol) obtained in Preparation Example 1 was added and stirred for 2 hours. do. After completion of the reaction, extract with ethyl acetate and brine, and combine the organic layers. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then purified by medium-pressure liquid chromatography (tetrahydrofuran/n-hexane) to obtain a target compound as a solid ( S )- N- (2-iodopyridin-4-yl)-3- Phenylisooxazolidine-2-carboxamide (470 mg, 74%) was obtained.
MS (m/z): 396.3 [M+1]+, UPLC r. t. (min) : 1.77MS (m/z): 396.3 [M+1] + , UPLC rt (min): 1.77
**1H NMR (400 MHz, CDCl3) δ = 8.20 - 8.17 (m, 1H), 7.98 - 7.96 (m, 1H), 7.94 - 7.89 (m, 1H), 7.43 - 7.40 (m, 1H), 7.39 - 7.37 (m, 3H), 7.32 - 7.28 (m, 1H), 5.51 - 5.44 (m, 1H), 4.34 - 4.25 (m, 1H), 4.01 - 3.91 (m, 1H), 2.93 - 2.81 (m, 1H), 2.51 - 2.40 (m, 1H)** 1 H NMR (400 MHz, CDCl 3 ) δ = 8.20-8.17 (m, 1H), 7.98-7.96 (m, 1H), 7.94-7.89 (m, 1H), 7.43-7.40 (m, 1H), 7.39-7.37 (m, 3H), 7.32-7.28 (m, 1H), 5.51-5.44 (m, 1H), 4.34-4.25 (m, 1H), 4.01-3.91 (m, 1H), 2.93-2.81 (m , 1H), 2.51-2.40 (m, 1H)
단계 3: (Step 3: ( SS )-)- N-N- (2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-일)-3-페닐아이소옥사졸리딘-2-카복사마이드 트리플루오로아세트산염의 제조Preparation of (2-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-4-yl)-3-phenylisooxazolidine-2-carboxamide trifluoroacetic acid salt
상기 실시예 26의 단계 2에서 얻어진 화합물 (S)-N-(2-아이오도피리딘-4-일)-3-페닐아이소옥사졸리딘-2-카복사마이드(470mg, 1.189mmol), 상기 실시예 1의 단계 2에서 얻어진 3-에티닐이미다조[1,2-b]피리다진(213mg, 1.487mmol), Pd(PPh3)4(68.7mg, 0.059mmol), CuI(22.65mg, 0.119mmol)와 트리에틸아민(332μL, 2.379mmol)를 아세토나이트릴(11mL)에 첨가하여 녹인 후, 50℃에서 밤새 가열한 후, 온도를 실온으로 낮추어 반응을 종료하였다. 반응 혼합물을 회전식 증발기를 이용하여 감압하에 농축한 후, Prep-150 장치를 이용하여 정제한 후 목적 화합물 (S)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-일)-3-페닐아이소옥사졸리딘-2-카복사마이드 트리플루오로산염(155mg, 29%)을 얻었다.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 μL, 2.379 mmol) were added to acetonitrile (11 mL) to dissolve, followed by heating at 50° C. overnight, after which the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, Prep-150 was purified using the device the desired compound (S) - N- (2- (imidazo [1,2-b] pyridazin-3 Iethynyl)pyridin-4-yl)-3-phenylisooxazolidine-2-carboxamide trifluoro acid salt (155 mg, 29%) was obtained.
MS (m/z): 411.3 [M+1]+, UPLC r. t. (min) : 1.34MS (m/z): 411.3 [M+1] + , UPLC rt (min): 1.34
1H NMR (400 MHz, CDCl3) δ = 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 - 2.33 (m, 1H) 1 H NMR (400 MHz, CDCl3) δ = 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), 2.44-2.33 (m, 1H)
상기 실시예 26과 유사한 방법으로 실시예 27 내지 29를 제조하였으며, 실시예 26 내지 29의 화합물명, 화학구조식, NMR 및 UPLC 분석 결과를 하기 표 2에 정리하여 나타내었다.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.
실시예Example 구조rescue 화합물명Compound name UPLC[M+1]+; r.t. (min)UPLC[M+1] + ; rt (min) 1H NMR 1 H NMR
2626
Figure PCTKR2019018834-appb-I000171
Figure PCTKR2019018834-appb-I000171
 		(S)-N-(2-(이미다조[1,2-b]피리다진-3- 일에티닐)피리딘-4-일)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (2-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-4-yl)-3-phenylisooxazolidine-2-carboxamide 411.3; 1.36411.3; 1.36 1HNMR (400 MHz, CDCl3) δ = 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 - 2.33 (m, 1H) 1 HNMR (400 MHz, CDCl 3 ) δ = 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), 2.44-2.33 (m, 1H)
2727
Figure PCTKR2019018834-appb-I000172
Figure PCTKR2019018834-appb-I000172
 		(R)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-yl)-3-페닐이소옥사졸리딘-2-카복사마이드( R )- N- (2-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-4-yl)-3-phenylisooxazolidine-2-carboxamide 411.2; 1.36411.2; 1.36 1H NMR (400 MHz, DMSO-d 6) δ = 9.97 (s, 1H), 8.72 (dd, J = 4.5, 1.6 Hz, 1H), 8.44 (d, J = 5.7 Hz, 1H), 8.30 - 8.23 (m, 2H), 8.07 (d, J = 2.1 Hz, 1H), 7.71 (dd, J = 5.7, 2.2 Hz, 1H), 7.38 (q, J = 2.6 Hz, 4H), 7.28 (dp, J = 8.5, 2.8 Hz, 1H), 5.41 (dd, J = 8.6, 6.2 Hz, 1H), 4.30 (td, J = 7.9, 2.8 Hz, 1H), 3.92 (ddd, J = 9.6, 8.1, 6.8 Hz, 1H), 2.89 (tdt, J = 9.3, 6.9, 2.8 Hz, 1H), 2.24 (dddd, J = 12.1, 9.8, 7.7, 6.2 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.97 (s, 1H), 8.72 (dd, J = 4.5, 1.6 Hz, 1H), 8.44 (d, J = 5.7 Hz, 1H), 8.30-8.23 (m, 2H), 8.07 (d, J = 2.1 Hz, 1H), 7.71 (dd, J = 5.7, 2.2 Hz, 1H), 7.38 (q, J = 2.6 Hz, 4H), 7.28 (dp, J = 8.5, 2.8 Hz, 1H), 5.41 (dd, J = 8.6, 6.2 Hz, 1H), 4.30 (td, J = 7.9, 2.8 Hz, 1H), 3.92 (ddd, J = 9.6, 8.1, 6.8 Hz, 1H ), 2.89 (tdt, J = 9.3, 6.9, 2.8 Hz, 1H), 2.24 (dddd, J = 12.1, 9.8, 7.7, 6.2 Hz, 1H)
2828
Figure PCTKR2019018834-appb-I000173
Figure PCTKR2019018834-appb-I000173
 		(S)-3-(3,5-다이플루오로페닐)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-일)이소옥사졸리딘-2-카복사마이드 염산염( S )-3-(3,5-difluorophenyl)- N- (2-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-4-yl)isooxazoli Dean-2-carboxamide hydrochloride 447.2; 1.44447.2; 1.44 1H NMR (400 MHz, DMSO-d 6) δ = 10.78 (s, 1H), 8.77 (dd, J = 4.5, 1.5 Hz, 1H), 8.59 (d, J = 6.8 Hz, 1H), 8.42 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.32 (dd, J = 9.2, 1.5 Hz, 1H), 8.07 (dd, J = 6.8, 2.3 Hz, 1H), 7.50 (dd, J = 9.3, 4.5 Hz, 1H), 7.08 - 7.04 (m, 2H), 5.40 (dd, J = 8.6, 6.4 Hz, 1H), 4.29 (td, J = 7.8, 2.6 Hz, 1H), 3.94(ddd, J = 9.8, 8.0, 6.6 Hz, 1H), 2.90 (dddd, J = 11.9, 9.0, 6.4, 2.5 Hz, 1H), 2.22 (tt, J = 9.7, 7.3 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.78 (s, 1H), 8.77 (dd, J = 4.5, 1.5 Hz, 1H), 8.59 (d, J = 6.8 Hz, 1H), 8.42 (s , 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.32 (dd, J = 9.2, 1.5 Hz, 1H), 8.07 (dd, J = 6.8, 2.3 Hz, 1H), 7.50 (dd, J = 9.3, 4.5 Hz, 1H), 7.08-7.04 (m, 2H), 5.40 (dd, J = 8.6, 6.4 Hz, 1H), 4.29 (td, J = 7.8, 2.6 Hz, 1H), 3.94 (ddd, J = 9.8, 8.0, 6.6 Hz, 1H), 2.90 (dddd, J = 11.9, 9.0, 6.4, 2.5 Hz, 1H), 2.22 (tt, J = 9.7, 7.3 Hz, 1H)
2929
Figure PCTKR2019018834-appb-I000174
Figure PCTKR2019018834-appb-I000174
 		(S)-3-(3-플루오로페닐)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-일)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )-3-(3-fluorophenyl)- N- (2-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-4-yl)isooxazolidine-2 -Carboxamide trichloroacetate 429.3; 1.37429.3; 1.37 1H NMR (400 MHz, DMSO-d 6) δ = 10.58 (s, 1H), 8.78 (dd, J = 4.5, 1.6 Hz, 1H), 8.59 (d, J = 6.4 Hz, 1H), 8.41 (s, 1H), 8.37 - 8.30 (m, 2H), 8.00 (dd, J = 6.5, 2.3 Hz, 1H), 7.50 (dd, J = 9.2, 4.5 Hz, 1H), 7.43 (td, J = 8.0, 6.0 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.20 (dt, J = 10.3, 2.2 Hz, 1H), 7.13 (td, J = 8.5, 2.7 Hz, 1H), 5.44 (dd, J = 8.5, 6.4 Hz, 1H), 4.35 (td, J = 7.8, 2.6 Hz, 2H), 3.97 (ddd, J = 9.9, 8.0, 6.7 Hz, 1H), 2.94 (dddd, J = 11.8, 9.0, 6.6, 2.6 Hz, 1H), 2.28 (ddt, J = 14.1, 12.0, 4.9 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.58 (s, 1H), 8.78 (dd, J = 4.5, 1.6 Hz, 1H), 8.59 (d, J = 6.4 Hz, 1H), 8.41 (s , 1H), 8.37-8.30 (m, 2H), 8.00 (dd, J = 6.5, 2.3 Hz, 1H), 7.50 (dd, J = 9.2, 4.5 Hz, 1H), 7.43 (td, J = 8.0, 6.0 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.20 (dt, J = 10.3, 2.2 Hz, 1H), 7.13 (td, J = 8.5, 2.7 Hz, 1H), 5.44 (dd, J = 8.5, 6.4 Hz, 1H), 4.35 (td, J = 7.8, 2.6 Hz, 2H), 3.97 (ddd, J = 9.9, 8.0, 6.7 Hz, 1H), 2.94 (dddd, J = 11.8, 9.0, 6.6 , 2.6 Hz, 1H), 2.28 (ddt, J = 14.1, 12.0, 4.9 Hz, 1H)
<실시예 30> (<Example 30> ( SS )-)- N-N- (4-플루오르-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드 트리플루오르아세트산염의 제조Preparation of (4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide trifluoroacetate
Figure PCTKR2019018834-appb-I000175
Figure PCTKR2019018834-appb-I000175
단계 1: 3-((2-플루오르-5-나이트로페닐)에티닐)이미다조[1,2-b]피리다진의 제조Step 1: Preparation of 3-((2-fluoro-5-nitrophenyl)ethynyl)imidazo[1,2-b]pyridazine
상기 실시예 1의 단계 2에서 얻어진 화합물 3-에티닐이미다조[1,2-b]피리다진 (400mg, 2.79mmol), 1-플루오르-2-아이오도-4-나이트로벤젠(746mg, 2.79mmol)에 에틸아세테이트(9.3mL)에 첨가하여 녹인 후 질소를 흘리면서 5분 동안 초음파 처리하였다. 반응혼합물에 Pd(PPh3)4(161mg, 0.140mmol), CuI(53.2mg, 0.279mmol)와 DIPEA(976μL, 5.59mmol)를 첨가한 후 50℃에서 16시간 동안 교반하였다. 반응 혼합물을 셀라이트로 여과하고, 에틸아세테이트로 씻어주었다. 얻어진 여과액을 감압하에 농축한 후, 중압액체크로마토그래피 (다이클로메탄/에틸아세테이트)로 정제하여 고체의 목적화합물 3-((2-플루오르-5-나이트로페닐)에티닐)이미다조[1,2-b]피리다진(619mg, 78%)을 수득하였다.Compound 3-ethynylimidazo[1,2-b]pyridazine (400mg, 2.79mmol), 1-fluor-2-iodo-4-nitrobenzene (746mg, obtained in Step 2 of Example 1 above) 2.79mmol) was dissolved in ethyl acetate (9.3mL) and then sonicated for 5 minutes while flowing nitrogen. Pd(PPh 3 ) 4 (161 mg, 0.140 mmol), CuI (53.2 mg, 0.279 mmol) and DIPEA (976 μL, 5.59 mmol) were added to the reaction mixture, followed by stirring at 50° C. for 16 hours. The reaction mixture was filtered through celite, and washed with ethyl acetate. 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%).
MS (m/z): 283.14 [M+1]+, UPLC r. t. (min) : 1.43MS (m/z): 283.14 [M+1] + , UPLC rt (min): 1.43
단계 2: 4-플루오르-3-(이미다조[1,2-b]피리다진-3-일에티닐)아닐린의 제조Step 2: Preparation of 4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)aniline
상기 실시예 30의 단계 1에서 얻어진 화합물 3-((2-플루오르-5-나이트로페닐)에티닐)이미다조[1,2-b]피리다진(619mg, 2.193mmol), Fe(612mg, 10.97 mmol)과 염화암모늄(1173mg, 21.93mmol)을 에탄올/H2O(비율 4/1)의 혼합용액에 첨가하여 녹인 후, 80℃에서 1시간 30분 동안 가열한 후, 온도를 실온으로 낮추어 반응을 종료하였다. 반응 혼합물을 셀라이트로 여과하고, 여과액을 농축하여 클로로폼과 증류수를 이용하여 추출한 후, 황산나트륨으로 건조하였다. 얻어진 여과액을 회전식 증발기를 이용하여 감압하에 농축하여 목적화합물4-플루오르-3-(이미다조[1,2-b]피리다진-3-일에티닐)아닐린(535mg, 97%)을 수득하였다Compound 3-((2-fluoro-5-nitrophenyl)ethynyl)imidazo[1,2-b]pyridazine (619mg, 2.193mmol), Fe (612mg, 10.97) obtained in Step 1 of Example 30 above. mmol) and ammonium chloride (1173mg, 21.93mmol) were added to a mixed solution of ethanol/H 2 O (ratio 4/1), dissolved, heated at 80°C for 1 hour and 30 minutes, and then lowered to room temperature. Ended. The reaction mixture was filtered through celite, and the filtrate was concentrated, extracted with chloroform and distilled water, and dried over sodium sulfate. 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%).
MS (m/z): 253.1 [M+1]+, UPLC r. t. (min) : 1.26MS (m/z): 253.1 [M+1] + , UPLC rt (min): 1.26
단계 3: Step 3: N-N- (4-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-5-페닐-4,5-다이하이드로-1H-피리졸-1-카복사마이드 트리플루오로아세트산염의 제조(4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-5-phenyl-4,5-dihydro-1H-pyrisol-1-carboxa Preparation of amide trifluoroacetate
상기 실시예 30의 단계 2에서 얻어진 화합물 4-플루오르-3-(이미다조[1,2-b]피리다진-3-일에티닐)아닐린(100mg, 0.396mmol), 1,1'-카보닐다이이미다졸(96mg, 0.595mmol)과 DIPEA(277μL, 1.586mmol)을 DMF(1.321mL)에 첨가하여 녹인 후, 1시간 30분 동안 교반 하고, 5-페닐-4,5-다이하이드로-1H-피라졸(103μL, 0.595mmol)을 첨가하여 1시간 동안 교반한다. 반응 후 반응 혼합물을 디클로로메탄 및 증류수로 추출하여 유기층을 합한다. 유기층을 황산나트륨으로 건조한 후 감압하여 농축 후 Prep-150 장치를 이용하여 정제한 후 목적화합물 N-(4-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-5-페닐-4,5-다이하이드로-1H-피리졸-1-카복사마이드 트리플루오로아세트산염(119mg, 56%)을 수득하였다.Compound 4-fluor-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)aniline (100mg, 0.396mmol), 1,1'-carbonyldiyl obtained in Step 2 of Example 30 above. imidazole (96mg, 0.595mmol) and DIPEA (277μL, 1.586mmol) was dissolved was added to DMF (1.321mL), 1 hour and 30 minutes stirring, 5-phenyl-4,5-dihydro -1 for H - Pyrazole (103 μL, 0.595 mmol) was added and stirred for 1 hour. After the reaction, the reaction mixture was extracted with dichloromethane and distilled water, and the organic layers were combined. 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.
MS (m/z): 438.2 [M+1]+, UPLC r. t. (min) : 1.85MS (m/z): 438.2 [M+1] + , UPLC rt (min): 1.85
1H NMR (400 MHz, DMSO-d 6) δ = 9.65 (s, 1H), 8.71 (dd, J = 4.5, 1.5 Hz, 1H), 8.29 - 8.21 (m, 2H), 8.00 (dd, J = 6.4, 2.7 Hz, 1H), 7.73 (ddd, J = 9.1, 4.7, 2.8 Hz, 1H), 7.43 - 7.33 (m, 6H), 7.30 (d, J = 9.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 2H), 2.93 - 2.78 (m, 1H), 2.23 (dddd, J = 12.0, 9.6, 7.8, 5.8 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.65 (s, 1H), 8.71 (dd, J = 4.5, 1.5 Hz, 1H), 8.29-8.21 (m, 2H), 8.00 (dd, J = 6.4, 2.7 Hz, 1H), 7.73 (ddd, J = 9.1, 4.7, 2.8 Hz, 1H), 7.43-7.33 (m, 6H), 7.30 (d, J = 9.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 2H), 2.93-2.78 (m, 1H), 2.23 (dddd, J = 12.0, 9.6, 7.8, 5.8 Hz, 1H)
상기 실시예 30과 유사한 방법으로 실시예 31 내지 34를 제조하였으며, 실시예 30 내지 34의 화합물명, 화학구조식, NMR 및 UPLC 분석 결과를 하기 표 3에 정리하여 나타내었다.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.
실시예Example 구조rescue 화합물명Compound name UPLC[M+1]+; r.t. (min)UPLC[M+1] + ; rt (min) 1H NMR 1 H NMR
3030
Figure PCTKR2019018834-appb-I000176
Figure PCTKR2019018834-appb-I000176
 		(S)-N-(4-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )- N- (4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide triple Lauroacetate 428.3; 1.85428.3; 1.85 1H NMR (400 MHz, DMSO-d 6) δ = 9.65 (s, 1H), 8.71 (dd, J = 4.5, 1.5 Hz, 1H), 8.29 - 8.21 (m, 2H), 8.00 (dd, J = 6.4, 2.7 Hz, 1H), 7.73 (ddd, J = 9.1, 4.7, 2.8 Hz, 1H), 7.43 - 7.33 (m, 6H), 7.30 (d, J = 9.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 2H), 2.93 - 2.78 (m, 1H), 2.23 (dddd, J = 12.0, 9.6, 7.8, 5.8 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.65 (s, 1H), 8.71 (dd, J = 4.5, 1.5 Hz, 1H), 8.29-8.21 (m, 2H), 8.00 (dd, J = 6.4, 2.7 Hz, 1H), 7.73 (ddd, J = 9.1, 4.7, 2.8 Hz, 1H), 7.43-7.33 (m, 6H), 7.30 (d, J = 9.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (td, J = 7.9, 3.0 Hz, 2H), 2.93-2.78 (m, 1H), 2.23 (dddd, J = 12.0, 9.6, 7.8, 5.8 Hz, 1H)
3131
Figure PCTKR2019018834-appb-I000177
Figure PCTKR2019018834-appb-I000177
 		(S)-N-(2-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )- N- (2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide triple Lauroacetate 428.3; 1.71428.3; 1.71
3232
Figure PCTKR2019018834-appb-I000178
Figure PCTKR2019018834-appb-I000178
 		(S)-N-(2-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(피리딘-3-일)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )- N- (2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(pyridin-3-yl)isooxazolidine- 2-carboxamide trichloroacetate 429.3;1.14429.3;1.14 1H NMR (400 MHz, DMSO-d 6) δ = 9.35 (s, 1H), 8.80 (s, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 1.7 Hz, 2H), 8.24 (d, J = 2.6 Hz, 1H), 7.81 (dd, J = 8.1, 5.1 Hz, 2H), 7.65 (td, J = 7.8, 1.7 Hz, 1H), 7.48 (ddd, J = 8.0, 6.3, 1.7 Hz, 1H), 7.40 (ddd, J = 9.3, 7.8, 4.5 Hz, 2H), 7.26 (t, J = 7.9 Hz, 1H), 6.89 - 6.73 (m, 1H), 5.59 (dd, J = 8.7, 5.8 Hz, 1H), 4.30 (dd, J = 8.1, 3.2 Hz, 7H), 4.05 - 3.97 (m, 5H), 2.94 (dddd, J = 15.5, 11.8, 7.0, 3.6 Hz, 2H), 2.41 - 2.28 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.35 (s, 1H), 8.80 (s, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 1.7 Hz, 2H ), 8.24 (d, J = 2.6 Hz, 1H), 7.81 (dd, J = 8.1, 5.1 Hz, 2H), 7.65 (td, J = 7.8, 1.7 Hz, 1H), 7.48 (ddd, J = 8.0, 6.3, 1.7 Hz, 1H), 7.40 (ddd, J = 9.3, 7.8, 4.5 Hz, 2H), 7.26 (t, J = 7.9 Hz, 1H), 6.89-6.73 (m, 1H), 5.59 (dd, J = 8.7, 5.8 Hz, 1H), 4.30 (dd, J = 8.1, 3.2 Hz, 7H), 4.05-3.97 (m, 5H), 2.94 (dddd, J = 15.5, 11.8, 7.0, 3.6 Hz, 2H), 2.41-2.28 (m, 1H)
3333
Figure PCTKR2019018834-appb-I000179
Figure PCTKR2019018834-appb-I000179
 		(S)-N-(2,4-다이플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )- N- (2,4-difluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-car Radiamide trifluoroacetate 446.2; 1.59446.2; 1.59
3434
Figure PCTKR2019018834-appb-I000180
Figure PCTKR2019018834-appb-I000180
 		(S)-N-(2,4-다이플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(피리딘-3-일)이소옥사졸리딘-2-카복사마이드 트리플로오르아세트산염( S )- N- (2,4-difluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(pyridin-3-yl)isooxa Zolidine-2-carboxamide trichloroacetate 447.2; 1.16447.2; 1.16 1H NMR (400 MHz, DMSO-d 6) δ = 9.39 (s, 1H), 8.73 (dd, J = 4.5, 1.5 Hz, 1H), 8.33 - 8.22 (m, 3H), 8.07 (d, J = 8.0 Hz, 1H), 7.70 - 7.56 (m, 2H), 7.42 (dd, J = 9.2, 4.4 Hz, 1H), 7.31 - 7.25 (m, 1H), 5.53 (dd, J = 8.6, 5.7 Hz, 1H), 4.31 (td, J = 8.0, 3.1 Hz, 2H), 3.54 - 3.45 (m, 1H), 2.99 - 2.87 (m, 1H), 2.37 - 2.25 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.39 (s, 1H), 8.73 (dd, J = 4.5, 1.5 Hz, 1H), 8.33-8.22 (m, 3H), 8.07 (d, J = 8.0 Hz, 1H), 7.70-7.56 (m, 2H), 7.42 (dd, J = 9.2, 4.4 Hz, 1H), 7.31-7.25 (m, 1H), 5.53 (dd, J = 8.6, 5.7 Hz, 1H ), 4.31 (td, J = 8.0, 3.1 Hz, 2H), 3.54-3.45 (m, 1H), 2.99-2.87 (m, 1H), 2.37-2.25 (m, 2H)
<실시예 35>(<Example 35> ( SS )-)- N-N- (3-((8-아미노이미다조 [1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(3-((8-aminoimidazo [1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide
Figure PCTKR2019018834-appb-I000181
Figure PCTKR2019018834-appb-I000181
단계 1: Step 1: terttert -부틸(-Butyl ( terttert -부톡시카보닐)(이미다조[1,2-a]피리딘-8-일)카바메이트의 제조-Butoxycarbonyl) (imidazo[1,2-a]pyridin-8-yl)carbamate preparation
이미다조[1,2-a]피리딘-8-아민(9g, 67.59mmol, 1 eq), DMAP(1.65g, 13.52mmol, 0.2 eq)과 TEA(28.22ml, 202.78mmol, 3 eq)를 THF(100mL)에 첨가하여 녹인 후, (Boc)2O(32.45g, 148.70mmol, 34.16mL, 2.2 eq)를 첨가하였다. 혼합물을 25°C에서 1시간동안 교반하였다. LC-MS 분석 결과, 출발물질이 모두 사라졌으며 목적 화합물 66%가 검출되었다. 반응 혼합물을 감압하에 농축한 후, 크로마토그래피(SiO2, 석유 에테르/에틸아세테이트=5/1 to 1/1)를 사용해 정제하여 황색 고체의 목적화합물 tert-부틸(tert-부톡시카보닐)(이미다조[1,2-a]피리딘-8-일)카바메이트(12.5g, 37.49mmol, 55.47% yield, 100% purity)를 수득하였다.Imidazo[1,2-a]pyridin-8-amine (9g, 67.59mmol, 1 eq ), DMAP (1.65g, 13.52mmol, 0.2 eq ) and TEA (28.22ml, 202.78mmol, 3 eq ) THF ( 100 mL) to dissolve, followed by (Boc) 2 O (32.45 g, 148.70 mmol, 34.16 mL, 2.2 eq ). The mixture was stirred at 25°C for 1 hour. As a result of LC-MS analysis, all starting materials disappeared and 66% of the target compound was detected. The reaction mixture was concentrated under reduced pressure, and then purified using chromatography (SiO 2 , petroleum ether/ethyl acetate=5/1 to 1/1) to give the target compound tert-butyl (tert-butoxycarbonyl) as a yellow solid ( Imidazo[1,2-a]pyridin-8-yl)carbamate (12.5g, 37.49mmol, 55.47% yield, 100% purity) was obtained.
MS (m/z): 334.2 [M+H]+ MS (m/z): 334.2 [M+H] +
1H NMR (400 MHz, CDCl3) δ = 8.09 (dd, J = 1.0, 6.8 Hz, 1H), 7.61 (dd, J = 1.2, 15.6 Hz, 2H), 7.04 (dd, J = 1.0, 7.2 Hz, 1H), 6.77 (t, J = 7.0 Hz, 1H), 1.42 (s, 18H) 1 H NMR (400 MHz, CDCl 3 ) δ = 8.09 (dd, J = 1.0, 6.8 Hz, 1H), 7.61 (dd, J = 1.2, 15.6 Hz, 2H), 7.04 (dd, J = 1.0, 7.2 Hz , 1H), 6.77 (t, J = 7.0 Hz, 1H), 1.42 (s, 18H)
단계 2: Step 2: terttert -부틸(-Butyl ( terttert -부톡시카보닐)(3-아이오도이미다조[1,2-a]피리딘-8-일)카바메이트의 제조-Butoxycarbonyl)(3-iodoimidazo[1,2-a]pyridin-8-yl) Preparation of carbamate
상기 실시예 35의 단계 1에서 얻어진tert-부틸(tert-부톡시카보닐)(이미다조[1,2-a]피리딘-8-일)카바메이트(12.5g, 37.49mmol, 1 eq)와 NIS (9.28g, 41.24mmol, 1.1 eq)를 CH3CN(100mL)에 첨가하여 녹인 후, 25°C에서 1시간 동안 반응시켰다. TLC 분석 결과 (PE/EA=1:3), 출발물질 중 5%가 남았으며 더 낮은 극성을 가지는 새로운 스팟이 검출되었다. 그 후 혼합물을 필터하였고, CH3CN(10mL)로 씻어주었다. 회수한 고체를 감압하에 건조하여 백색 고체의 목적화합물 tert-부틸(tert-부톡시카보닐)(3-아이오도이미다조[1,2-a]피리딘-8-일)카바메이트(14g, 30.09mmol, 80.24% yield, 98.79% purity)를 수득하였다. Tert -butyl ( tert -butoxycarbonyl) (imidazo[1,2-a]pyridin-8-yl)carbamate (12.5 g, 37.49 mmol, 1 eq ) and NIS obtained in step 1 of Example 35 above (9.28g, 41.24mmol, 1.1 eq ) was added to CH 3 CN (100mL) to dissolve and reacted at 25°C for 1 hour. As a result of TLC analysis (PE/EA=1:3), 5% of the starting material remained and a new spot with a lower polarity was detected. The mixture was then filtered and washed with CH 3 CN (10 mL). 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).
MS (m/z): 460.3 [M+H]+ MS (m/z): 460.3 [M+H] +
1H NMR (400 MHz, MeOD) δ = 8.35 (dd, J = 1.0, 6.8 Hz, 1H), 7.66 (s, 1H), 7.32 - 7.31 (dd, J = 1.0, 7.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 1.34 (s, 18H) 1 H NMR (400 MHz, MeOD) δ = 8.35 (dd, J = 1.0, 6.8 Hz, 1H), 7.66 (s, 1H), 7.32-7.31 (dd, J = 1.0, 7.2 Hz, 1H), 7.13 ( t, J = 7.2 Hz, 1H), 1.34 (s, 18H)
단계 3: Step 3: terttert -부틸(-Butyl ( SS )-()-( terttert -부톡시카보닐)(3-((3-(3-페닐이소옥사졸리딘-2-카복사미도)페닐)에티닐)이미다조[1,2-a]피리딘-8-일)카바메이트의 제조-Butoxycarbonyl)(3-((3-(3-phenylisooxazolidine-2-carboxamido)phenyl)ethynyl)imidazo[1,2-a]pyridin-8-yl)carbamate Manufacturing
상기 실시예 35의단계 2에서 얻어진tert-부틸(tert-부톡시카보닐)(3-아이오도이미다조[1,2-a]피리딘-8-일)카바메이트(2.36g, 5.13mmol, 1 eq), 상기 제조예 21에서 얻어진(S)-N-(3-에티닐페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(1.5g, 5.13mmol, 1 eq)와 TEA(1.56g, 15.39mmol, 2.14mL, 3 eq)를 DMF(15mL)에 첨가하여 녹인 후, Pd(PPh3)4 (1.19g, 1.03mmol, 0.2 eq)와 CuI(293.17mg, 1.54mmol, 0.3 eq)를 첨가하였다. 질소 기류 하에 혼합물을 25°C에서 3시간 동안 교반하였다. TLC 분석 결과 (PE/EA=1:1), 출발물질이 모두 사라졌으며 더 높은 극성을 가지는 새로운 스팟이 검출되었다. 반응 종결 후, 에탈아세테이트 및 소금물을 사용하여 유기층을 추출하고 감압 농축하였다. 농축한 화합물을 크로마토그래피(SiO2, 석유에테르/에틸아세테이트=4/1 to 2/1)를 사용해 정제하여 황백색의 목적화합물 tert-부틸(S)-(tert-부톡시카보닐)(3-((3-(3-페닐이소옥사졸리딘-2-카복사미도)페닐)에티닐)이미다조[1,2-a]피리딘-8-일)카바메이트(4.3g, 4.48mmol, 61.50% yield, 65% purity)를 수득하였다. Tert -butyl ( tert -butoxycarbonyl) (3-iodoimidazo[1,2-a]pyridin-8-yl)carbamate (2.36g, 5.13mmol, 1) obtained in Step 2 of Example 35 above. eq), (S) obtained in Preparation example 21 - N- (phenyl) 3-ethynyl-3-isopropyl-phenyl oxazolidin-2-carboxamide (1.5g, 5.13mmol, 1 eq) and TEA (1.56 g, 15.39mmol, 2.14mL, 3 eq ) was added to DMF (15mL) to dissolve, Pd(PPh 3 ) 4 (1.19g, 1.03mmol, 0.2 eq ) and CuI (293.17mg, 1.54mmol, 0.3 eq ) Was added. The mixture was stirred at 25°C for 3 hours under a nitrogen stream. As a result of TLC analysis (PE/EA=1:1), all starting materials disappeared and a new spot having a higher polarity was detected. After the completion of the reaction, the organic layer was extracted with ethanol acetate and brine, and concentrated under reduced pressure. The concentrated compound was purified by chromatography (SiO 2 , petroleum ether/ethyl acetate=4/1 to 2/1) to obtain an off-white target compound tert -butyl( S )-( tert -butoxycarbonyl)(3- ((3-(3-phenylisooxazolidine-2-carboxamido)phenyl)ethynyl)imidazo[1,2-a]pyridin-8-yl)carbamate (4.3g, 4.48mmol, 61.50% yield, 65% purity).
MS (m/z): 424.3 [M+H]+ MS (m/z): 424.3 [M+H] +
1H NMR (400 MHz, CDCl3) δ = 8.32 (dd, J = 1.0, 6.8 Hz, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.86 (t, J = 1.6 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.50 - 7.43 (m, 4H), 7.40 - 7.34 (m, 2H), 7.31 - 7.28 (m, 1H), 5.55 (dd, J = 5.8, 8.4 Hz, 1H), 4.33 - 4.20 (m, 1H), 4.04 - 3.92 (m, 1H), 2.91 - 2.79 (m, 1H), 2.53 - 2.35 (m, 1H), 1.42 (s, 18H) 1 H NMR (400 MHz, CDCl 3 ) δ = 8.32 (dd, J = 1.0, 6.8 Hz, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.86 (t, J = 1.6 Hz, 1H ), 7.72-7.64 (m, 2H), 7.50-7.43 (m, 4H), 7.40-7.34 (m, 2H), 7.31-7.28 (m, 1H), 5.55 (dd, J = 5.8, 8.4 Hz, 1H) ), 4.33-4.20 (m, 1H), 4.04-3.92 (m, 1H), 2.91-2.79 (m, 1H), 2.53-2.35 (m, 1H), 1.42 (s, 18H)
단계 4: (Step 4: ( SS )-)- N-N- (3-((8-아미노이미다조 [1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드의 제조Preparation of (3-((8-aminoimidazo [1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide
상기 실시예 35의단계 3에서 얻어진tert-부틸(S)-(tert-부톡시카보닐)(3-((3-(3-페닐이소옥사졸리딘-2-카복사미도)페닐)에티닐)이미다조[1,2-a]피리딘-8-일)카바메이트(3.9g, 6.25mmol, 1 eq)를 EtOAc(10mL)에 녹인 후, HCl/EtOAc (4M, 30mL, 19.19 eq)를 첨가한다. 혼합물을 25°C에서 12시간 동안 교반하였다. LC-MS 분석 결과, 출발물질이 모두 사라졌으며, 목적 화합물 80%가 검출되었다. 반응 종료 후, 감압 농축하여 갈색의 목적화합물(S)-N-(3-((8-아미노이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(2.4g, 5.67mmol, 90.64% yield)를 얻었다. 300mg의 목적화합물을 prep-HPLC (column: Xtimate C18 150 * 40mm * 10μm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 40% - 70%, 10 min]; B%: 40% - 70%, 10min)을 통해 정제하여 백색 고체의 목적화합물 (S)-N-(3-((8-아미노이미다조 [1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(45mg, 100% purity, 96.82% e.e.)를 얻었다. Tert -Butyl( S )-( tert -butoxycarbonyl)(3-((3-(3-phenylisooxazolidine-2-carboxamido)phenyl)ethynyl obtained in Step 3 of Example 35 above. )Imidazo[1,2-a]pyridin-8-yl)carbamate (3.9g, 6.25mmol, 1 eq ) was dissolved in EtOAc (10mL), and HCl/EtOAc (4M, 30mL, 19.19 eq ) was added. do. The mixture was stirred at 25°C for 12 hours. As a result of LC-MS analysis, all starting materials disappeared, and 80% of the target compound was detected. After completion of the reaction, concentrated under reduced pressure to an object of the brown compound (S) - N- (3 - ((8- amino-imidazo [1,2-a] pyridin-3-yl) ethynyl) phenyl) -3-phenyl iso Oxazolidine-2-carboxamide (2.4 g, 5.67 mmol, 90.64% yield) was obtained. 300mg of the target compound was prep-HPLC (column: Xtimate C18 150 * 40mm * 10μm; 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.
MS (m/z): 424.3 [M+H]+ MS (m/z): 424.3 [M+H] +
1H NMR (400 MHz, MeOD) δ = 7.89 - 7.87 (dd, J = 0.8, 6.4 Hz, 1H), 7.85 - 7.84 (m, 1H), 7.74 (s, 1H), 7.57 - 7.54 (m, 1H), 7.43 - 7.41 (m, 2H), 7.37 - 7.32 (m, 3H), 7.31 - 7.28 (m, 1H), 7.27 - 7.23 (m, 1H), 6.92 - 6.88 (dd, J = 6.8, 7.6 Hz, 1H), 6.57 - 6.55 (dd, J = 1.2, 7.6 Hz, 1H), 5.48 - 5.45 (dd, J = 6.0, 8.4 Hz, 1H), 4.30 - 4.25 (m, 1H), 4.01 - 3.95 (m, 1H), 2.93 - 2.85 (m, 1H), 2.38 - 2.29 (m, 1H) 1 H NMR (400 MHz, MeOD) δ = 7.89-7.87 (dd, J = 0.8, 6.4 Hz, 1H), 7.85-7.84 (m, 1H), 7.74 (s, 1H), 7.57-7.54 (m, 1H ), 7.43-7.41 (m, 2H), 7.37-7.32 (m, 3H), 7.31-7.28 (m, 1H), 7.27-7.23 (m, 1H), 6.92-6.88 (dd, J = 6.8, 7.6 Hz , 1H), 6.57-6.55 (dd, J = 1.2, 7.6 Hz, 1H), 5.48-5.45 (dd, J = 6.0, 8.4 Hz, 1H), 4.30-4.25 (m, 1H), 4.01-3.95 (m , 1H), 2.93-2.85 (m, 1H), 2.38-2.29 (m, 1H)
<실시예 36>(<Example 36> ( SS )-)- N-N- (3-((8-(사이클로프로페인카복사미도)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(3-((8-(cyclopropanecarboxamido)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide
Figure PCTKR2019018834-appb-I000182
Figure PCTKR2019018834-appb-I000182
단계 1: (Step 1: ( SS )-)- N-N- (3-((8-(사이클로프로페인카복사미도)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드의 제조(3-((8-(Cyclopropanecarboxamido)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide Produce
상기 실시예 35에서 얻어진 화합물 (S)-N-(3-((8-아미노이미다조 [1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(200mg, 472.29 umol, 1 eq)를 DCM(1mL)에 녹인 후, 상온에서 TEA(143.37mg, 1.42mmol, 197.21uL, 3 eq)를 첨가한다. 그 후, DCM(1mL)에 희석되어 있는 사이클로프로페인카보닐 클로라이드(43.36μL, 477.02μmol, 1.01 eq)를 0°C에서 첨가하고, 혼합물을 0°C에서 1시간 동안 교반한 뒤, 25°C에서 1시간 동안 교반하였다. LC-MS 분석 결과, 출발물질 중 4%가 남았으며 목적화합물 73.65% 검출되었다. 반응 혼합물을 감압 농축한 후, prep-HPLC(column: Unisil 3-100 C18 Ultra 150*50mm*3 um; mobile phase: [water (0.225%FA)-ACN]; B%: 50%-80%, 10min)을 통해 정제하여 적색 고체의 목적화합물 (S)-N-(3-((8-(사이클로프로페인카복사미도)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(68mg, 138.34μmol, 29.29% yield, 100% purity, 98.85% e.e.)를 수득하였다.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. Thereafter, cyclopropanecarbonyl chloride (43.36 μL, 477.02 μmol, 1.01 eq ) diluted in DCM (1 mL) was added at 0° C., and the mixture was stirred at 0° C. for 1 hour, followed by 25° Stir at C for 1 hour. As a result of LC-MS analysis, 4% of the starting material remained and 73.65% of the target compound was detected. After concentration of the reaction mixture under reduced pressure, prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um; mobile phase: [water (0.225%FA)-ACN]; B%: 50%-80%, 10min) to give the target compound as a red solid (S) - N- (3 - ((8- ( cyclopropanecarboxylic carboxamide shown) imidazo [1,2-a] ethynyl-3-yl)) from Phenyl)-3-phenylisooxazolidine-2-carboxamide (68mg, 138.34μmol, 29.29% yield, 100% purity, 98.85% ee) was obtained.
MS (m/z): 492.5 [M+H]＋ MS (m/z): 492.5 [M+H] +
1H NMR (400 MHz, DMSO-d 6) δ = 10.43 (s, 1H), 9.56 (s, 1H), 8.30 - 8.28 (dd, J = 0.8, 7.6 Hz, 1H), 8.11 - 8.09 (m, 1H), 8.03 (s, 1H), 7.99 - 7.98 (m, 1H), 7.72 - 7.69 (m, 1H), 7.41 - 7.32 (m, 6H), 7.30 - 7.25 (m, 1H), 7.1 - 7.09 (t, J = 4.0 Hz, 1H), 5.44 - 5.40 (m, 1H), 4.29 - 4.24 (m, 1H), 2.89 - 2.85 (m, 1H), 2.35 - 2.32 (m, 1H), 2.29 - 2.2 (m, 1H), 0.86 - 0.8.0 (m, 4H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.43 (s, 1H), 9.56 (s, 1H), 8.30-8.28 (dd, J = 0.8, 7.6 Hz, 1H), 8.11-8.09 (m, 1H), 8.03 (s, 1H), 7.99-7.98 (m, 1H), 7.72-7.69 (m, 1H), 7.41-7.32 (m, 6H), 7.30-7.25 (m, 1H), 7.1-7.09 ( t, J = 4.0 Hz, 1H), 5.44-5.40 (m, 1H), 4.29-4.24 (m, 1H), 2.89-2.85 (m, 1H), 2.35-2.32 (m, 1H), 2.29-2.2 ( m, 1H), 0.86-0.8.0 (m, 4H)
상기 나열된 방법으로 실시예 35, 36을 제조하였고, 실시예 36과 유사한 방법으로 실시예 37 내지 39를 제조하였으며, 실시예 35 내지 39의 화합물명, 화학구조식, NMR 및 UPLC 분석 결과를 하기 표 4에 정리하여 나타내었다.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.
실시예Example 구조rescue 화합물명Compound name UPLC[M+1]+ UPLC[M+1] + 1H NMR 1 H NMR
3535
Figure PCTKR2019018834-appb-I000183
Figure PCTKR2019018834-appb-I000183
 		(S)-N-(3-((8-아미노이미다조 [1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((8-aminoimidazo [1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 424.3424.3 1H NMR (400 MHz, MeOD) δ= 7.89 - 7.87 (dd, J = 0.8, 6.4 Hz, 1H), 7.85 - 7.84 (m, 1H), 7.74 (s, 1H), 7.57 - 7.54 (m, 1H), 7.43 - 7.41 (m, 2H), 7.37 - 7.32 (m, 3H), 7.31 - 7.28 (m, 1H), 7.27 - 7.23 (m, 1H), 6.92 - 6.88 (dd, J = 6.8, 7.6 Hz, 1H), 6.57 - 6.55 (dd, J = 1.2, 7.6 Hz, 1H), 5.48 - 5.45 (dd, J = 6.0, 8.4 Hz, 1H), 4.30 - 4.25 (m, 1H), 4.01 - 3.95 (m, 1H), 2.93 - 2.85 (m, 1H), 2.38 - 2.29 (m, 1H) 1 H NMR (400 MHz, MeOD) δ= 7.89-7.87 (dd, J = 0.8, 6.4 Hz, 1H), 7.85-7.84 (m, 1H), 7.74 (s, 1H), 7.57-7.54 (m, 1H ), 7.43-7.41 (m, 2H), 7.37-7.32 (m, 3H), 7.31-7.28 (m, 1H), 7.27-7.23 (m, 1H), 6.92-6.88 (dd, J = 6.8, 7.6 Hz , 1H), 6.57-6.55 (dd, J = 1.2, 7.6 Hz, 1H), 5.48-5.45 (dd, J = 6.0, 8.4 Hz, 1H), 4.30-4.25 (m, 1H), 4.01-3.95 (m , 1H), 2.93-2.85 (m, 1H), 2.38-2.29 (m, 1H)
3636
Figure PCTKR2019018834-appb-I000184
Figure PCTKR2019018834-appb-I000184
 		(S)-N-(3-((8-(사이클로프로페인카복사미도)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((8-(cyclopropanecarboxamido)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine- 2-carboxamide 492.5492.5 1H NMR (400 MHz, DMSO-d 6) δ = 10.43 (s, 1H), 9.56 (s, 1H), 8.30 - 8.28 (dd, J = 0.8, 7.6 Hz, 1H), 8.11 - 8.09 (m, 1H), 8.03 (s, 1H), 7.99 - 7.98 (m, 1H), 7.72 - 7.69 (m, 1H), 7.41 - 7.32 (m, 6H), 7.30 - 7.25 (m, 1H), 7.1 - 7.09 (t, J = 4.0 Hz, 1H), 5.44 - 5.40 (m, 1H), 4.29 - 4.24 (m, 1H), 2.89 - 2.85 (m, 1H), 2.35 - 2.32 (m, 1H), 2.29 - 2.2 (m, 1H), 0.86 - 0.8.0 (m, 4H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.43 (s, 1H), 9.56 (s, 1H), 8.30-8.28 (dd, J = 0.8, 7.6 Hz, 1H), 8.11-8.09 (m, 1H), 8.03 (s, 1H), 7.99-7.98 (m, 1H), 7.72-7.69 (m, 1H), 7.41-7.32 (m, 6H), 7.30-7.25 (m, 1H), 7.1-7.09 ( t, J = 4.0 Hz, 1H), 5.44-5.40 (m, 1H), 4.29-4.24 (m, 1H), 2.89-2.85 (m, 1H), 2.35-2.32 (m, 1H), 2.29-2.2 ( m, 1H), 0.86-0.8.0 (m, 4H)
3737
Figure PCTKR2019018834-appb-I000185
Figure PCTKR2019018834-appb-I000185
 		(S)-N-(3-((8-(에틸아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((8-(ethylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxa Mide 452.3452.3 1H NMR (400 MHz, MeOD) δ = 7.85 - 7.82 (m, 2H), 7.72 (s, 1H), 7.57 - 7.54 (m, 1H), 7.45 - 7.40 (m, 2H), 7.38 - 7.32 (m, 3H), 7.31 - 7.29 (m, 1H), 7.28 - 7.23 (m, 1H), 6.97 - 6.94 (dd, J = 6.4, 7.2 Hz, 1H), 6.37 - 6.35 (d, J = 7.2 Hz, 1H), 5.59 - 5.45 (dd, J = 6.0, 8.4 Hz, 1H), 4.58 (s, 1H), 4.30 - 4.26 (m, 1H), 4.02 - 3.96 (m, 1H), 3.35 - 3.32 (m, 2H), 2.93 - 2.88 (m, 1H), 2.39 - 2.30 (m, 1H), 1.38 - 1.34 (t, J = 7.2 Hz, 3H) 1 H NMR (400 MHz, MeOD) δ = 7.85-7.82 (m, 2H), 7.72 (s, 1H), 7.57-7.54 (m, 1H), 7.45-7.40 (m, 2H), 7.38-7.32 (m , 3H), 7.31-7.29 (m, 1H), 7.28-7.23 (m, 1H), 6.97-6.94 (dd, J = 6.4, 7.2 Hz, 1H), 6.37-6.35 (d, J = 7.2 Hz, 1H ), 5.59-5.45 (dd, J = 6.0, 8.4 Hz, 1H), 4.58 (s, 1H), 4.30-4.26 (m, 1H), 4.02-3.96 (m, 1H), 3.35-3.32 (m, 2H) ), 2.93-2.88 (m, 1H), 2.39-2.30 (m, 1H), 1.38-1.34 (t, J = 7.2 Hz, 3H)
3838
Figure PCTKR2019018834-appb-I000186
Figure PCTKR2019018834-appb-I000186
 		(S)-3-페닐-N-(3-((8-((테트라하이드로-2H-피란-4-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)이소옥사졸리딘-2-카복사마이드( S )-3-phenyl- N- (3-((8-((tetrahydro-2H-pyran-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl) Phenyl)isooxazolidine-2-carboxamide 508.5508.5 1H NMR (400 MHz, DMSO-d 6) δ = 9.56 (s, 1H), 7.96 - 7.95 (m, 1H), 7.86 (s, 1H), 7.82 - 7.80 (m, 1H), 7.71 - 7.68 (m, 1H), 7.41 - 7.35 (m, 5H), 7.31 - 7.26 (m, 2H), 8.95 - 8.91 (t, J = 16.0 Hz, 1H), 6.42 - 6.41 (m, 1H), 5.91 - 5.89 (d, J = 8.0 Hz, 1H), 5.44 - 5.4 (m, 1H), 3.93 - 3.87 (m, 3H), 3.73 - 3.66 (m, 1H), 3.48 - 3.42 (m, 2H), 2.9 - 2.85 (m, 1H), 2.26 - 2.3 (m, 1H), 1.94 - 1.9 (m, 2H), 1.65 - 1.55 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.56 (s, 1H), 7.96-7.95 (m, 1H), 7.86 (s, 1H), 7.82-7.80 (m, 1H), 7.71-7.68 ( m, 1H), 7.41-7.35 (m, 5H), 7.31-7.26 (m, 2H), 8.95-8.91 (t, J = 16.0 Hz, 1H), 6.42-6.41 (m, 1H), 5.91-5.89 ( d, J = 8.0 Hz, 1H), 5.44-5.4 (m, 1H), 3.93-3.87 (m, 3H), 3.73-3.66 (m, 1H), 3.48-3.42 (m, 2H), 2.9-2.85 ( m, 1H), 2.26-2.3 (m, 1H), 1.94-1.9 (m, 2H), 1.65-1.55 (m, 2H)
3939
Figure PCTKR2019018834-appb-I000187
Figure PCTKR2019018834-appb-I000187
 		(S)-메틸 3-((3-(3-페닐이소옥사졸리딘-2-카복사미도)페닐)에티닐)이미다조[1,2-a]피리딘-8-일카바메이트( S )-Methyl 3-((3-(3-phenylisooxazolidine-2-carboxamido)phenyl)ethynyl)imidazo[1,2-a]pyridine-8-ylcarbamate 482.4482.4 1H NMR (400 MHz, DMSO-d 6) δ = 9.56 (s, 1H), 9.4 (s, 1H), 8.30 - 8.28 (dd, J = 0.8, 6.8 Hz, 1H), 8.0 - 7.98 (m, 2H), 7.78 - 7.76 (m, 1H), 7.72 - 7.69 (m, 1H), 7.41 - 7.32 (m, 6H), 7.29 - 7.25 (m, 1H), 7.14 - 7.10 (t, J = 16.0 Hz, 1H), 5.44 - 5.4 (m, 1H), 4.29 - 4.24 (m, 1H), 3.93 - 3.87 (m, 1H), 3.73 (s, 3H), 2.89 - 2.84 (m, 1H), 2.26 - 2.21 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.56 (s, 1H), 9.4 (s, 1H), 8.30-8.28 (dd, J = 0.8, 6.8 Hz, 1H), 8.0-7.98 (m, 2H), 7.78-7.76 (m, 1H), 7.72-7.69 (m, 1H), 7.41-7.32 (m, 6H), 7.29-7.25 (m, 1H), 7.14-7.10 (t, J = 16.0 Hz, 1H), 5.44-5.4 (m, 1H), 4.29-4.24 (m, 1H), 3.93-3.87 (m, 1H), 3.73 (s, 3H), 2.89-2.84 (m, 1H), 2.26-2.21 ( m, 1H)
<실시예 40>(<Example 40> ( SS )-)- N-N- (3-((8-((5-메틸-1H-피라졸-3-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxa Zolidine-2-carboxamide
Figure PCTKR2019018834-appb-I000188
Figure PCTKR2019018834-appb-I000188
단계 1: 8-브로모-3-아이오도이미다조[1,2-a]피리딘의 제조Step 1: Preparation of 8-bromo-3-iodoimidazo[1,2-a]pyridine
8-브로모이미다조[1,2-a]피리딘(4.8g, 24.36mmol, 1 eq)과 NIS(5.76g, 25.58mmol, 1.05 eq)를 아세토나이트릴(100mL)에 녹인 후, 25°C에서 10시간 동안 교반하였다. LCMS를 통해 출발 물질 모두 반응이 진행되었음을 확인하였으며, 목적화합물 97.84%가 검출되었다. 물(500mL)을 첨가하여 반응을 종결한 후, 이로부터 생성된 노란색의 고체 목적화합물 8-브로모-3-아이오도이미다조[1,2-a]피리딘(6.9g, 21.37mmol, 87.71% yield)을 수득하였다.8-bromoimidazo[1,2-a]pyridine (4.8g, 24.36mmol, 1 eq ) and NIS (5.76g, 25.58mmol, 1.05 eq ) are dissolved in acetonitrile (100mL), then 25°C The mixture was stirred for 10 hours. Through LCMS, it was confirmed that all the starting materials had progressed, and 97.84% of the target compound was detected. After the reaction was terminated by adding water (500 mL), the resulting yellow solid target compound 8-bromo-3-iodoimidazo[1,2-a]pyridine (6.9g, 21.37mmol, 87.71%) yield).
MS (m/z): 332.8 [M+H]＋ MS (m/z): 332.8 [M+H] +
1H NMR (400MHz, DMSO-d 6) δ = 8.37 (d, J = 6.4 Hz, 1H), 7.85 - 7.75 (m, 1H), 7.69 (d, J = 6.8 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H) 1 H NMR (400MHz, DMSO- d 6 ) δ = 8.37 (d, J = 6.4 Hz, 1H), 7.85-7.75 (m, 1H), 7.69 (d, J = 6.8 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H)
단계 2: (Step 2: ( SS )-)- N-N- (3-((8-브로모이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드의 제조Preparation of (3-((8-bromoimidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide
상기 제조예 21에서 얻어진(S)-N-(3-에티닐페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(2g, 6.84mmol, 1eq), 상기 실시예 40의단계 1에서 얻어진8-브로모-3-아이오도이미다조[1,2-a]피리딘(2.61g, 8.07mmol, 1.18 eq), Pd(PPh3)4 (830.11mg, 718.20μmol, 0.105 eq), TEA (4.76mL, 34.20mmol, 5 eq)와 CuI(299.68mg, 1.57mmol, 0.23 eq)를 에틸아세테이트(20mL)에 녹인 후, 세 차례 질소 치환하였다. 이후 반응 혼합물을 질소 조건하에 25°C에서 2시간 동안 교반하였다. TLC (PE:EA = 1:1)를 통해 출발 물질 모두 반응이 진행되어 새로운 물질이 생성되었음을 확인하였다. 반응 혼합물을 회전식 증발기를 이용하여 감압하에 농축한 후 역상 컬럼으로 정제하여 노란색 고체의 목적화합물 (S)-N-(3-((8-브로모이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(2.5g, 5.09mmol, 74.48% yield, 99.31% purity, 96.57% e.e.)을 수득하였다.The prepared (S) obtained in Example 21 - N- (3-ethynyl-phenyl) -3-phenyl-2-isopropyl-oxazolidine-carboxamide (2g, 6.84mmol, 1eq), in step 1 of Example 40 Obtained 8-bromo-3-iodoimidazo[1,2-a]pyridine (2.61g, 8.07mmol, 1.18 eq), Pd(PPh 3 ) 4 (830.11mg, 718.20μmol, 0.105 eq ), TEA ( 4.76 mL, 34.20 mmol, 5 eq ) and CuI (299.68 mg, 1.57 mmol, 0.23 eq ) were dissolved in ethyl acetate (20 mL), followed by nitrogen substitution three times. Then the reaction mixture was stirred for 2 hours at 25 °C under nitrogen conditions. Through TLC (PE:EA = 1:1), all of the starting materials were reacted to confirm that new materials were formed. 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.
MS (m/z): 489.0 [M+H]＋ MS (m/z): 489.0 [M+H] +
1H NMR (400 MHz, DMSO-d 6) δ = 9.57 (s, 1H), 8.63 (dd, J = 0.8, 6.8 Hz, 1H), 8.08 (s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.79 (dd, J = 0.8, 7.6 Hz, 1H), 7.73 - 7.70 (m, 1H), 7.42 - 7.33 (m, 6 H), 7.31 - 7.24 (m, 1 H), 7.07 (t, J = 7.2 Hz, 1H), 5.42 (dd, J = 6.0, 7.4 Hz, 1H), 4.30 - 4.25 (m, 2.93 Hz, 1H), 3.96 - 3.85 (m, 1H), 2.94- 2.79 (m, 1H), 2.30 - 2.16 (m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.57 (s, 1H), 8.63 (dd, J = 0.8, 6.8 Hz, 1H), 8.08 (s, 1H), 8.00 (d, J = 1.6 Hz , 1H), 7.79 (dd, J = 0.8, 7.6 Hz, 1H), 7.73-7.70 (m, 1H), 7.42-7.33 (m, 6 H), 7.31-7.24 (m, 1 H), 7.07 (t , J = 7.2 Hz, 1H), 5.42 (dd, J = 6.0, 7.4 Hz, 1H), 4.30-4.25 (m, 2.93 Hz, 1H), 3.96-3.85 (m, 1H), 2.94-2.79 (m, 1H), 2.30-2.16 (m, 1H).
단계 3: (Step 3: ( SS )-)- N-N- (3-((8-((5-메틸-1H-피라졸-3-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드의 제조(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
상기 실시예 40의 단계 2에서 얻어진(S)-N-(3-((8-브로모이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(200mg, 410.39μmol, 1 eq)와 5-메틸-1H-피라졸-3-아민(59.78mg, 615.58μmol, 1.5 eq)를 다이옥세인(40mL)에 녹인 후, KOAc(120.83mg, 1.23mmol, 3 eq), Pd2(dba)3 (75.16mg, 82.08μmol, 0.2 eq)와 di-tert-부틸-[2-(2,4,6-트리아이소프로필페닐)페닐]포스페인(52.28mg, 123.12μmol, 0.3 eq)를 첨가하였다. 반응 혼합물은 100 °C에서 10시간 동안 교반하였다. TLC (PE:EA = 2:5)를 통해 출발 물질 모두 반응이 진행되어 여러 개의 새로운 물질이 생성되었음을 확인하였다. 반응 후 반응 혼합물을 여과하여 얻어진 여과액을 회전식 증발기를 이용하여 감압하에 농축한 후, Prep-TLC (PE:EA = 2:5)를 이용하여 1차 정제하였다. 이후 Prep-HPLC(column: Waters Xbridge 150 * 25mm * 5μm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 50%-80%, 10 min)로 2차 정제하여 황백색 고체의 목적화합물 (S)-N-(3-((8-((5-메틸-1H-피라졸-3-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(15mg, 28.87μmol, 7.04% yield, 96.92% purity, 100% e.e.)를 수득하였다.Example 40 (S) obtained in the step 2 of the - N- (3 - ethynyl ((8-bromo feeders microporous crude [1,2-a] pyridin-3-yl)) phenyl) -3-phenyl -isoxazol Zolidine-2-carboxamide (200mg, 410.39μmol, 1 eq ) and 5-methyl- 1H -pyrazol-3-amine (59.78mg, 615.58μmol, 1.5 eq ) were dissolved in dioxane (40mL). , KOAc (120.83mg, 1.23mmol, 3 eq ), Pd 2 (dba) 3 (75.16mg, 82.08μmol, 0.2 eq ) and di- tert -butyl-[2-(2,4,6-triisopropylphenyl) )Phenyl]phospain (52.28 mg, 123.12 μmol, 0.3 eq ) was added. The reaction mixture was stirred at 100 °C for 10 hours. It was confirmed through TLC (PE:EA = 2:5) that the reaction of all starting materials produced several new materials. After the reaction, the reaction mixture was filtered and the filtrate obtained was concentrated under reduced pressure using a rotary evaporator, followed by primary purification using Prep-TLC (PE:EA = 2:5). Then, prep-HPLC (column: Waters Xbridge 150 * 25mm * 5μm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 50%-80%, 10 min) Target compound of yellowish white solid ( S )- N- (3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyridin-3-yl) Ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide (15mg, 28.87μmol, 7.04% yield, 96.92% purity, 100% ee) was obtained.
MS (m/z): 504.2 [M+H]＋ MS (m/z): 504.2 [M+H] +
1H NMR (400 MHz, DMSO-d 6) δ = 11.81 (d, J = 1.6 Hz, 1H), 9.54 (s, 1H), 8.67 (s, 1H), 7.95 - 7.92 (m, 2H), 7.91 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.40 - 7.32 (m, 5H), 7.31 - 7.22 (m, 2H), 6.99 (dd, J = 6.8, 7.6 Hz, 1H), 5.91 (s, 1H), 5.40 (dd, J = 6.0, 8.4 Hz, 1H), 4.257 - 4.22 (m, 1H), 3.92 - 3.83 (m, 1H), 2.90 - 2.79 (m, 1H), 2.28 - 2.20 (m, 1H), 2.18 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.81 (d, J = 1.6 Hz, 1H), 9.54 (s, 1H), 8.67 (s, 1H), 7.95-7.92 (m, 2H), 7.91 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.70-7.66 (m, 1H), 7.40-7.32 (m, 5H), 7.31-7.22 (m, 2H), 6.99 (dd, J = 6.8, 7.6 Hz, 1H), 5.91 (s, 1H), 5.40 (dd, J = 6.0, 8.4 Hz, 1H), 4.257-4.22 (m, 1H), 3.92-3.83 (m, 1H), 2.90- 2.79 (m, 1H), 2.28-2.20 (m, 1H), 2.18 (s, 3H)
상기 실시예 40과 유사한 방법으로 실시예 41 내지 45를 제조하였으며, 실시예 40 내지 45의 화합물명, 화학구조식, NMR 및 UPLC 분석 결과를 하기 표 5에 정리하여 나타내었다.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.
실시예Example 구조rescue 화합물명Compound name UPLC[M+1]+ UPLC[M+1] + 1H NMR 1 H NMR
4040
Figure PCTKR2019018834-appb-I000189
Figure PCTKR2019018834-appb-I000189
 		(S)-N-(3-((8-((5-메틸-1H-피라졸-3-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl) -3-phenylisooxazolidine-2-carboxamide 504.2504.2 1H NMR (400 MHz, DMSO-d 6) δ = 11.81 (d, J = 1.6 Hz, 1H), 9.54 (s, 1H), 8.67 (s, 1H), 7.95 - 7.92 (m, 2H), 7.91 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.40 - 7.32 (m, 5H), 7.31 - 7.22 (m, 2H), 6.99 (dd, J = 6.8, 7.6 Hz, 1H), 5.91 (s, 1H), 5.40 (dd, J = 6.0, 8.4 Hz, 1H), 4.257 - 4.22 (m, 1H), 3.92 - 3.83 (m, 1H), 2.90 - 2.79 (m, 1H), 2.28 - 2.20 (m, 1H), 2.18 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.81 (d, J = 1.6 Hz, 1H), 9.54 (s, 1H), 8.67 (s, 1H), 7.95-7.92 (m, 2H), 7.91 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.70-7.66 (m, 1H), 7.40-7.32 (m, 5H), 7.31-7.22 (m, 2H), 6.99 (dd, J = 6.8, 7.6 Hz, 1H), 5.91 (s, 1H), 5.40 (dd, J = 6.0, 8.4 Hz, 1H), 4.257-4.22 (m, 1H), 3.92-3.83 (m, 1H), 2.90- 2.79 (m, 1H), 2.28-2.20 (m, 1H), 2.18 (s, 3H)
4141
Figure PCTKR2019018834-appb-I000190
Figure PCTKR2019018834-appb-I000190
 		(S)-N-(3-((8-((1-메틸-1H-피라졸-3-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((8-((1-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl) -3-phenylisooxazolidine-2-carboxamide 504.2504.2 1H NMR (400MHz, DMSO-d 6) δ = 9.56 (s, 1H), 8.85 (s, 1H), 8.00 - 7.96 (m, 2H), 7.95 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.43 - 7.35 (m, 5H), 7.34 - 7.25 (m, 2H), 7.07 - 7.02 (m, 1H), 6.12 (d, J=2.2 Hz, 1H), 5.43 (dd, J = 6.2, 8.6 Hz, 1H), 4.32 - 4.22 (m, 1H), 3.96 - 3.86 (m, 1H), 2.92 - 2.82 (m, 1H), 2.30 - 2.19 (m, 1H) 1 H NMR (400MHz, DMSO- d 6 ) δ = 9.56 (s, 1H), 8.85 (s, 1H), 8.00-7.96 (m, 2H), 7.95 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.43-7.35 (m, 5H), 7.34-7.25 (m, 2H), 7.07-7.02 (m, 1H), 6.12 (d, J=2.2 Hz, 1H), 5.43 (dd, J = 6.2, 8.6 Hz, 1H), 4.32-4.22 (m, 1H), 3.96-3.86 (m, 1H), 2.92-2.82 (m, 1H), 2.30-2.19 (m, 1H)
4242
Figure PCTKR2019018834-appb-I000191
Figure PCTKR2019018834-appb-I000191
 		(S)-N-(3-((8-((1-메틸-1H-피라졸-4-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((8-((1-methyl-1H-pyrazol-4-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl) -3-phenylisooxazolidine-2-carboxamide 504.2504.2 1H NMR (400 MHz, DMSO-d 6) δ = 9.55 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.93 - 7.87 (m, 2H), 7.81 (s, 1H), 7.70 (br d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.43 - 7.34 (m, 5H), 7.33 - 7.24 (m, 2H), 6.94 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.42 (dd, J = 6.0, 8.0 Hz, 1H), 4.32 - 4.22 (m, 1H), 3.94 - 3.86 (m, 1H), 3.83 (s, 3H), 2.92 - 2.81 (m, 1H), 2.29 - 2.19 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.55 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.93-7.87 (m, 2H), 7.81 (s, 1H) , 7.70 (br d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.43-7.34 (m, 5H), 7.33-7.24 (m, 2H), 6.94 (t, J = 7.2 Hz, 1H) , 6.57 (d, J = 7.6 Hz, 1H), 5.42 (dd, J = 6.0, 8.0 Hz, 1H), 4.32-4.22 (m, 1H), 3.94-3.86 (m, 1H), 3.83 (s, 3H ), 2.92-2.81 (m, 1H), 2.29-2.19 (m, 1H)
4343
Figure PCTKR2019018834-appb-I000192
Figure PCTKR2019018834-appb-I000192
 		(S)-N-(3-((8-(사이클로프로필아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((8-(cyclopropylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-ka Radiation Mind 464.4464.4 1H NMR (400 MHz, MeOD) δ = 7.90 - 7.88 (dd, J = 0.8, 6.8 Hz, 1H), 7.85 - 7.84 (m, 1H), 7.71 (s, 1H), 7.57 - 7.54 (m, 1H), 7.43 - 7.42 (m, 2H), 7.37 - 7.33 (m, 3H), 7.31 - 7.29 (m, 1H), 7.27 - 7.24 (m, 1H), 7.01 - 6.97 (dd, J = 6.8, 7.6 Hz, 1H), 6.74 - 6.72 (dd, J = 0.8, 7.6 Hz, 1H), 5.49 - 5.45 (dd, J = 6.0, 8.8 Hz, 1H), 4.58 (s, 2H), 4.30 - 4.26 (m, 1H), 4.02 - 3.96 (m, 1H), 2.94 - 2.88 (m, 1H), 2.61 - 2.56 (m, 1H), 2.39 - 2.30 (m, 1H), 0.88 - 0.83 (m, 2H), 0.63 - 0.59 (m, 2H) 1 H NMR (400 MHz, MeOD) δ = 7.90-7.88 (dd, J = 0.8, 6.8 Hz, 1H), 7.85-7.84 (m, 1H), 7.71 (s, 1H), 7.57-7.54 (m, 1H ), 7.43-7.42 (m, 2H), 7.37-7.33 (m, 3H), 7.31-7.29 (m, 1H), 7.27-7.24 (m, 1H), 7.01-6.97 (dd, J = 6.8, 7.6 Hz , 1H), 6.74-6.72 (dd, J = 0.8, 7.6 Hz, 1H), 5.49-5.45 (dd, J = 6.0, 8.8 Hz, 1H), 4.58 (s, 2H), 4.30-4.26 (m, 1H ), 4.02-3.96 (m, 1H), 2.94-2.88 (m, 1H), 2.61-2.56 (m, 1H), 2.39-2.30 (m, 1H), 0.88-0.83 (m, 2H), 0.63-0.59 (m, 2H)
4444
Figure PCTKR2019018834-appb-I000193
Figure PCTKR2019018834-appb-I000193
 		(S)-3-페닐-N-(3-((8-(페닐아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)이소옥사졸리딘-2-카복사마이드( S )-3-phenyl- N- (3-((8-(phenylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)isooxazolidine-2-carboxa Mide 500.3500.3 1H NMR (400MHz, DMSO-d 6) δ = 9.57 (s, 1H), 8.50 (s, 1H), 8.04 (dd, J = 1.6, 6.0 Hz, 1H), 8.00 - 7.95 (m, 2H), 7.71 (br d, J = 8.6 Hz, 1H), 7.43 - 7.32 (m, 10H), 7.31 - 7.25 (m, 1H), 7.05 - 6.96 (m, 3H), 5.43 (dd, J = 6.0, 8.4 Hz, 1H), 4.32 - 4.22 (m, 1H), 3.96 - 3.86 (m, 1H), 2.96 - 2.80 (m, 1H), 2.32 - 2.17 (m, 1H) 1 H NMR (400MHz, DMSO- d 6 ) δ = 9.57 (s, 1H), 8.50 (s, 1H), 8.04 (dd, J = 1.6, 6.0 Hz, 1H), 8.00-7.95 (m, 2H), 7.71 (br d, J = 8.6 Hz, 1H), 7.43-7.32 (m, 10H), 7.31-7.25 (m, 1H), 7.05-6.96 (m, 3H), 5.43 (dd, J = 6.0, 8.4 Hz , 1H), 4.32-4.22 (m, 1H), 3.96-3.86 (m, 1H), 2.96-2.80 (m, 1H), 2.32-2.17 (m, 1H)
4545
Figure PCTKR2019018834-appb-I000194
Figure PCTKR2019018834-appb-I000194
 		(S)-N-(3-((8-((1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((8-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)imidazo[1,2-a] Pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 587.3587.3 1H NMR (400MHz, MeOD) δ = 7.84 (dd, J = 0.8, 6.8 Hz, 1H), 7.77 (t, J = 1.6 Hz, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.50 (d, J = 0.6 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.35 - 7.31 (m, 2H), 7.29 - 7.21 (m, 4H), 7.21 - 7.14 (m, 1H), 6.85 (dd, J = 6.8, 7.6 Hz, 1H), 6.53 (dd, J = 0.8, 7.6 Hz, 1H), 5.37 (dd, J = 6.0, 8.4 Hz, 1H), 4.32 (m, 1H), 4.18 (m, 1H), 3.89 (m, 1H), 3.33 (m, 2H), 2.88 - 2.75 (m, 3H), 2.63 (s, 3H), 2.28 - 2.16 (m, 2H), 2.24 - 2.15 (m, 4H) 1 H NMR (400MHz, MeOD) δ = 7.84 (dd, J = 0.8, 6.8 Hz, 1H), 7.77 (t, J = 1.6 Hz, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.50 (d, J = 0.6 Hz, 1H), 7.48-7.43 (m, 1H), 7.35-7.31 (m, 2H), 7.29-7.21 (m, 4H), 7.21-7.14 (m, 1H), 6.85 ( dd, J = 6.8, 7.6 Hz, 1H), 6.53 (dd, J = 0.8, 7.6 Hz, 1H), 5.37 (dd, J = 6.0, 8.4 Hz, 1H), 4.32 (m, 1H), 4.18 (m , 1H), 3.89 (m, 1H), 3.33 (m, 2H), 2.88-2.75 (m, 3H), 2.63 (s, 3H), 2.28-2.16 (m, 2H), 2.24-2.15 (m, 4H) )
<실시예 46>(<Example 46> ( SS )-)- N-N- (3-(이미다조[1,2-a]피리딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(3-(imidazo[1,2-a]pyridin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide
Figure PCTKR2019018834-appb-I000195
Figure PCTKR2019018834-appb-I000195
단계 1: (Step 1: ( SS )-)- N-N- (3-(이미다조[1,2-a]피리딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드의 제조Preparation of (3-(imidazo[1,2-a]pyridin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide
3-아이오도이미다조[1,2-a]피리딘(200mg, 819.56μmol, 1 eq)을 DMF(7mL)에 녹인 후, CuI(46.83mg, 245.87μmol, 0.3 eq), Pd(PPh3)4(189.41mg, 163.91μmol, 0.2 eq)과 TEA(570.37μL, 4.10mmol, 5 eq)를 25°C에서 질소기류 하에 첨가한다. 그 후, DMF(3mL)에 희석된 상기 제조예 21에서 얻어진(S)-N-(3-에티닐페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(150mg, 513.12μmol, 0.6 eq)를 천천히 적가하고 반응혼합물을 25°C에서 2시간 동안 교반하였다. LC-MS 분석 결과, 출발물질이 모두 사라졌으며, 목적 화합물 49.5%가 검출되었다. 물(20mL)와 NH3·H2O(20mL)를 첨가하여 반응을 종결한 후 EtOAc(40mL*2)와 소금물(100mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하였다. 화합물을 prep-HPLC(column: Xtimate C18 150*40mm*10um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 44%-74%,10min)을 통해 정제하여 백색 고체의 목적화합물 (S)-N-(3-(이미다조[1,2-a]피리딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드(125mg, 302.24μmol, 36.88% yield, 98.76% purity, 96.68% e.e.)를 수득하였다.3-Iodoimidazo[1,2-a]pyridine (200mg, 819.56μmol, 1 eq ) was dissolved in DMF (7mL), CuI (46.83mg, 245.87μmol, 0.3 eq ), Pd(PPh 3 ) 4 (189.41 mg, 163.91 μmol, 0.2 eq ) and TEA (570.37 μL, 4.10 mmol, 5 eq ) are added under nitrogen flow at 25°C. Then, obtained in the Preparative Example 21 was diluted in DMF (3mL) (S) - N- ( 3-ethynyl-phenyl) -3-phenyl-2-isopropyl-oxazolidine-carboxamide (150mg, 513.12μmol, 0.6 eq ) was slowly added dropwise and the reaction mixture was stirred at 25°C for 2 hours. As a result of LC-MS analysis, all starting materials disappeared, and 49.5% of the target compound was detected. After the reaction was terminated by adding water (20 mL) and NH 3 ·H 2 O (20 mL), the organic layer was extracted with EtOAc (40 mL*2) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The compound was purified by prep-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 44%-74%, 10min) to white Solid target compound ( S )- N- (3-(imidazo[1,2-a]pyridin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide (125mg, 302.24 μmol, 36.88% yield, 98.76% purity, 96.68% ee).
MS (m/z): 409.4 [M+H]＋ MS (m/z): 409.4 [M+H] +
1H NMR (400 MHz, DMSO-d 6) δ = 9.56 (s, 1H), 8.60 - 8.58 (d, J = 1.2 Hz, 1H), 8.03 (s, 1H), 7.99 - 7.98 (s, 1H), 7.74 - 7.69 (m, 2H), 7.46 - 7.42 (m, 1H), 7.41 -7.37 (m, 4H), 7.40 - 7.39 (m, 2H), 7.38 (m, 1 H), 7.17 - 7.14 (m, 1H), 5.44 - 5.41 (m, 1H), 4.30 - 5.41 (m, 1H), 3.93 - 3.87 (m, 1H), 2.89 - 2.86 (m, 1H), 2.27 - 2.23 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.56 (s, 1H), 8.60-8.58 (d, J = 1.2 Hz, 1H), 8.03 (s, 1H), 7.99-7.98 (s, 1H) , 7.74-7.69 (m, 2H), 7.46-7.42 (m, 1H), 7.41 -7.37 (m, 4H), 7.40-7.39 (m, 2H), 7.38 (m, 1 H), 7.17-7.14 (m , 1H), 5.44-5.41 (m, 1H), 4.30-5.41 (m, 1H), 3.93-3.87 (m, 1H), 2.89-2.86 (m, 1H), 2.27-2.23 (m, 1H)
상기 실시예 46과 유사한 방법으로 실시예 47 내지 61을 제조하였으며, 실시예 46 내지 61의 화합물명, 화학구조식, NMR 및 UPLC 분석 결과를 하기 표 6에 정리하여 나타내었다.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.
실시예Example 구조rescue 화합물명Compound name UPLC[M+1]+ UPLC[M+1] + 1H NMR 1 H NMR
4646
Figure PCTKR2019018834-appb-I000196
Figure PCTKR2019018834-appb-I000196
 		(S)-N-(3-(이미다조[1,2-a]피리딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-(imidazo[1,2-a]pyridin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 409.4409.4 1H NMR (400 MHz, DMSO-d 6) δ = 9.56 (s, 1H), 8.60 - 8.58 (d, J = 1.2 Hz, 1H), 8.03 (s, 1H), 7.99 - 7.98 (s, 1H), 7.74 - 7.69 (m, 2H), 7.46 - 7.42 (m, 1H), 7.41 -7.37 (m, 4H), 7.40 - 7.39 (m, 2H), 7.38 (m, 1 H), 7.17 - 7.14 (m, 1H), 5.44 - 5.41 (m, 1H), 4.30 - 5.41 (m, 1H), 3.93 - 3.87 (m, 1H), 2.89 - 2.86 (m, 1H), 2.27 - 2.23 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.56 (s, 1H), 8.60-8.58 (d, J = 1.2 Hz, 1H), 8.03 (s, 1H), 7.99-7.98 (s, 1H) , 7.74-7.69 (m, 2H), 7.46-7.42 (m, 1H), 7.41 -7.37 (m, 4H), 7.40-7.39 (m, 2H), 7.38 (m, 1 H), 7.17-7.14 (m , 1H), 5.44-5.41 (m, 1H), 4.30-5.41 (m, 1H), 3.93-3.87 (m, 1H), 2.89-2.86 (m, 1H), 2.27-2.23 (m, 1H)
4747
Figure PCTKR2019018834-appb-I000197
Figure PCTKR2019018834-appb-I000197
 		(S)-3-페닐-N-(3-(피라졸로[1,5-a]피리미딘-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드( S )-3-phenyl- N- (3-(pyrazolo[1,5-a]pyrimidin-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide 410.3410.3 1H NMR (400 MHz, DMSO-d 6) δ = 9.54 (s, 1H), 9.22 - 9.21 (d, J = 5.6 Hz, 1H), 8.70 - 8.69 (m, 1H), 8.52 (s, 1H), 7.91 (s, 1H), 7.67 - 7.64 (m, 1H), 7.41 - 7.31 (m, 5H), 7.20 (m, 1H), 7.20 - 7.18 (m, 2H), 5.44 - 5.41 (m, 1H), 4.28 - 4.24 (m, 1H), 3.93 - 3.87 (m, 1H), 2.87 - 2.84 (m, 1H), 2.26 - 2.21 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.54 (s, 1H), 9.22-9.21 (d, J = 5.6 Hz, 1H), 8.70-8.69 (m, 1H), 8.52 (s, 1H) , 7.91 (s, 1H), 7.67-7.64 (m, 1H), 7.41-7.31 (m, 5H), 7.20 (m, 1H), 7.20-7.18 (m, 2H), 5.44-5.41 (m, 1H) , 4.28-4.24 (m, 1H), 3.93-3.87 (m, 1H), 2.87-2.84 (m, 1H), 2.26-2.21 (m, 1H)
4848
Figure PCTKR2019018834-appb-I000198
Figure PCTKR2019018834-appb-I000198
 		(S)-N-(3-(이미다조[1,2-a]피라진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-(imidazo[1,2-a]pyrazin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 410.3410.3 1H NMR (400 MHz, DMSO-d 6) δ = 9.59 (s, 1H), 9.19 (s, 1H), 8.67 - 8.66 (m, 1H), 8.24 (s, 1H), 8.12 - 8.11 (d, J = 4.8 Hz, 1H), 8.02 (s, 1H), 7.74 - 7.71 (m, 1H), 7.40 - 7.36 (m, 6H), 7.30 - 7.26 (m, 1H), 5.45 - 5.41 (m, 1H), 4.30 - 4.26 (m, 1H), 3.94 - 3.88 (m, 1H), 2.91 - 2.84 (m, 1H), 2.29 - 2.22 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.59 (s, 1H), 9.19 (s, 1H), 8.67-8.66 (m, 1H), 8.24 (s, 1H), 8.12-8.11 (d, J = 4.8 Hz, 1H), 8.02 (s, 1H), 7.74-7.71 (m, 1H), 7.40-7.36 (m, 6H), 7.30-7.26 (m, 1H), 5.45-5.41 (m, 1H) , 4.30-4.26 (m, 1H), 3.94-3.88 (m, 1H), 2.91-2.84 (m, 1H), 2.29-2.22 (m, 1H)
4949
Figure PCTKR2019018834-appb-I000199
Figure PCTKR2019018834-appb-I000199
 		(S)-N-(3-(이미다조[1,2-a]피리미딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-(imidazo[1,2-a]pyrimidin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 410.4410.4 1H NMR (400 MHz, DMSO-d 6) δ = 9.56 (s, 1H), 9.05 - 9.04 (d, J = 2.0 Hz, 1H), 8.69 - 8.67 (m, 1H), 8.18 (s, 1H), 8.0 (s, 1H), 7.71 - 7.69 (m, 1H), 7.40 - 7.34 (m, 6H), 7.27 - 7.25 (m, 2H), 5.43 - 5.40 (m, 1H), 4.29 - 4.24 (m, 1H), 3.93 - 3.86 (m, 1H), 2.90 - 2.82 (m, 1H), 2.28 - 2.19 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.56 (s, 1H), 9.05-9.04 (d, J = 2.0 Hz, 1H), 8.69-8.67 (m, 1H), 8.18 (s, 1H) , 8.0 (s, 1H), 7.71-7.69 (m, 1H), 7.40-7.34 (m, 6H), 7.27-7.25 (m, 2H), 5.43-5.40 (m, 1H), 4.29-4.24 (m, 1H), 3.93-3.86 (m, 1H), 2.90-2.82 (m, 1H), 2.28-2.19 (m, 1H)
5050
Figure PCTKR2019018834-appb-I000200
Figure PCTKR2019018834-appb-I000200
 		(R)-N-(3-(이미다조[1,2-a]피리딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( R )- N- (3-(imidazo[1,2-a]pyridin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 409.4409.4 1H NMR (400 MHz, DMSO-d 6) δ = 9.54 (s, 1H), 8.59 - 8.57 (d, J = 6.8 Hz, 1H), 8.01 (s, 1H), 7.98 - 7.97 (t, J = 4 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.45 - 7.31 (m, 7H), 7.29 - 7.25 (m, 1H),7.16 - 7.12 (m, 1H), 5.43 - 5.4 (dd, J = 6.0, 8.8 Hz, 1H), 4.28 - 4.23 (m, 1H), 3.92 - 3.86 (m, 1H), 2.88 - 2.84 (m, 1H), 2.25 - 2.22(m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.54 (s, 1H), 8.59-8.57 (d, J = 6.8 Hz, 1H), 8.01 (s, 1H), 7.98-7.97 (t, J = 4 Hz, 1H), 7.73-7.67 (m, 2H), 7.45-7.31 (m, 7H), 7.29-7.25 (m, 1H), 7.16-7.12 (m, 1H), 5.43-5.4 (dd, J = 6.0, 8.8 Hz, 1H), 4.28-4.23 (m, 1H), 3.92-3.86 (m, 1H), 2.88-2.84 (m, 1H), 2.25-2.22 (m, 1H)
5151
Figure PCTKR2019018834-appb-I000201
Figure PCTKR2019018834-appb-I000201
 		(R)-3-페닐-N-(3-(피라졸로[1,5-a]피리미딘-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드( R )-3-phenyl- N- (3-(pyrazolo[1,5-a]pyrimidin-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide 410.3410.3 1H NMR (400 MHz, DMSO-d 6) δ = 9.53 (s, 1H), 9.22 - 9.20 (m, 1H), 8.70 - 8.68 (m, 1H), 8.52(s, 1H), 7.91 (s, 1H), 7.66 - 7.64 (d, J = 8.0, 1H), 7.41 - 7.31 (m, 5H), 7.29 - 7.26 (m, 1H), 7.21 - 7.18 (m, 2H), 5.44 - 5.40 (m, 1H), 3.93 - 3.87 (m, 1H), 2.90 - 2.82 (m, 1H), 2.28 - 2.21 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.53 (s, 1H), 9.22-9.20 (m, 1H), 8.70-8.68 (m, 1H), 8.52(s, 1H), 7.91 (s, 1H), 7.66-7.64 (d, J = 8.0, 1H), 7.41-7.31 (m, 5H), 7.29-7.26 (m, 1H), 7.21-7.18 (m, 2H), 5.44-5.40 (m, 1H) ), 3.93-3.87 (m, 1H), 2.90-2.82 (m, 1H), 2.28-2.21 (m, 1H)
5252
Figure PCTKR2019018834-appb-I000202
Figure PCTKR2019018834-appb-I000202
 		(R)-N-(3-(이미다조[1,2-a]피라진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( R )- N- (3-(imidazo[1,2-a]pyrazin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 410.3410.3 1H NMR (400 MHz, DMSO-d 6) δ = 9.59 (s, 1H), 9.20 - 9.19 (d, J = 1.6 Hz, 1H), 8.68 - 8.66 (m, 1H), 8.24 (s, 1H), 8.12 - 8.10 (d, J = 4.8 Hz, 1H), 8.03 (m, 1H), 7.74 - 7.71 (m, 1H), 7.42 - 7.35 (m, 6H), 7.30 - 7.26 (m, 1H), 5.44 - 5.40 (m, 1H), 4.30 - 4.25 (m, 1H), 3.93 - 3.87 (m, 1H), 2.91 - 2.83 (m, 1H), 2.29 - 2.23 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.59 (s, 1H), 9.20-9.19 (d, J = 1.6 Hz, 1H), 8.68-8.66 (m, 1H), 8.24 (s, 1H) , 8.12-8.10 (d, J = 4.8 Hz, 1H), 8.03 (m, 1H), 7.74-7.71 (m, 1H), 7.42-7.35 (m, 6H), 7.30-7.26 (m, 1H), 5.44 -5.40 (m, 1H), 4.30-4.25 (m, 1H), 3.93-3.87 (m, 1H), 2.91-2.83 (m, 1H), 2.29-2.23 (m, 1H)
5353
Figure PCTKR2019018834-appb-I000203
Figure PCTKR2019018834-appb-I000203
 		(R)-N-(3-(이미다조[1,2-a]피리미딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( R )- N- (3-(imidazo[1,2-a]pyrimidin-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 410.4410.4 1H NMR (400 MHz, DMSO-d 6) δ = 9.56 (s, 1H), 9.05 - 9.03 (m, 1H), 8.69 - 8.67 (dd, J = 1.6, 5.6 Hz, 1H), 8.18 (s, 1H), 8.0 (s, 1H), 7.71 - 7.69 (m, 1H), 7.40 - 7.34 (m, 6H), 7.29 - 7.25 (m, 2H), 5.43 - 5.40 (m, 1H), 4.29 - 4.25 (m, 1H), 3.93 - 3.87 (m, 1H), 2.87 - 2.85 (m, 1H), 2.26 - 2.22 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.56 (s, 1H), 9.05-9.03 (m, 1H), 8.69-8.67 (dd, J = 1.6, 5.6 Hz, 1H), 8.18 (s, 1H), 8.0 (s, 1H), 7.71-7.69 (m, 1H), 7.40-7.34 (m, 6H), 7.29-7.25 (m, 2H), 5.43-5.40 (m, 1H), 4.29-4.25 ( m, 1H), 3.93-3.87 (m, 1H), 2.87-2.85 (m, 1H), 2.26-2.22 (m, 1H)
5454
Figure PCTKR2019018834-appb-I000204
Figure PCTKR2019018834-appb-I000204
 		(S)-N-(3-((6-메틸피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((6-methylpyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 384.1384.1 1H NMR (400 MHz, DMSO-d 6) δ = 9.55 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 7.92 (t, J = 1.6 Hz, 1H), 7.85 (dd, J = 2.4, 8.0 Hz, 1H), 7.68 (dd, J = 1.2, 8.4 Hz, 1H), 7.42 - 7.18 (m, 8H), 5.41 (dd, J = 6.0, 8.4 Hz, 1H), 4.26 (dt, J = 2.8, 8.0 Hz, 1H), 3.94 - 3.84 (m, 1H), 3.32 - 3.32 (m, 3H), 2.94 - 2.77 (m, 1H), 2.30 - 2.16 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.55 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 7.92 (t, J = 1.6 Hz, 1H), 7.85 (dd, J = 2.4, 8.0 Hz, 1H), 7.68 (dd, J = 1.2, 8.4 Hz, 1H), 7.42-7.18 (m, 8H), 5.41 (dd, J = 6.0, 8.4 Hz, 1H), 4.26 (dt, J = 2.8, 8.0 Hz, 1H), 3.94-3.84 (m, 1H), 3.32-3.32 (m, 3H), 2.94-2.77 (m, 1H), 2.30-2.16 (m, 1H)
5555
Figure PCTKR2019018834-appb-I000205
Figure PCTKR2019018834-appb-I000205
 		(S)-N-(3-((5-메톡시 피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((5-methoxypyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 400.1400.1 1H NMR (400 MHz, DMSO-d 6) δ = 9.53 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.94 -7.82 (m, 2H), 7.66 (dd, J = 1.2, 8.4 Hz, 1H), 7.42 -7.30 (m, 5H), 7.30 -7.24 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.90 - 6.88 (d, J = 8.4 Hz, 1H), 4.25 (td, J = 2.8, 8.0 Hz, 1H), 3.97 -3.84 (m, 4H), 2.94 -2.77 (m, 1H), 2.29 -2.16 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.53 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.94 -7.82 (m, 2H), 7.66 (dd, J = 1.2, 8.4 Hz, 1H), 7.42 -7.30 (m, 5H), 7.30 -7.24 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.90-6.88 (d, J = 8.4 Hz, 1H), 4.25 (td, J = 2.8, 8.0 Hz, 1H), 3.97 -3.84 (m, 4H), 2.94 -2.77 (m, 1H), 2.29 -2.16 (m, 1H)
5656
Figure PCTKR2019018834-appb-I000206
Figure PCTKR2019018834-appb-I000206
 		(S)-N-(3-((1H-피라졸로[3,4-b]피리딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 410.1410.1 1H NMR (400 MHz, DMSO-d 6) δ = 13.90 (br s, 1H), 9.55 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 7.94 (t, J = 1.6 Hz, 1H), 7.68 (dt, J = 1.2, 7.2 Hz, 1H), 7.44 -7.32 (m, 5H), 7.30 -7.22 (m, 2H), 5.42 (dd, J = 2.4, 8.4 Hz, 1H), 4.26 (td, J = 2.8, 8.0 Hz, 1H), 4.00 -3.78 (m, 1H), 2.92 -2.81 (m, 1H), 2.30 -2.18 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 13.90 (br s, 1H), 9.55 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 7.94 (t, J = 1.6 Hz, 1H), 7.68 (dt, J = 1.2, 7.2 Hz, 1H), 7.44 -7.32 (m, 5H), 7.30 -7.22 (m , 2H), 5.42 (dd, J = 2.4, 8.4 Hz, 1H), 4.26 (td, J = 2.8, 8.0 Hz, 1H), 4.00 -3.78 (m, 1H), 2.92 -2.81 (m, 1H), 2.30 -2.18 (m, 1H)
5757
Figure PCTKR2019018834-appb-I000207
Figure PCTKR2019018834-appb-I000207
 		(S)-N-(3-((7-옥소-5,6,7,8-테트라하이드로-1,8-나프티리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine -2-carboxamide 439.0439.0 1H NMR (400 MHz, DMSO-d 6) δ = 10.70 (s, 1H), 9.54 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.90 (t, J = 1.6 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.69 -7.64 (m, 1H), 7.42 -7.24 (m, 6H), 7.22 -7.17 (m, 1H), 5.41 (dd, J = 5.6, 8.4 Hz, 1H), 4.26 (td, J = 2.8, 8.0 Hz, 1H), 3.89 (m, 1H), 2.97 -2.81 (m, 3H), 2.55 (br s, 2H), 2.29 -2.17 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.70 (s, 1H), 9.54 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.90 (t, J = 1.6 Hz, 1H ), 7.79 (d, J = 1.2 Hz, 1H), 7.69 -7.64 (m, 1H), 7.42 -7.24 (m, 6H), 7.22 -7.17 (m, 1H), 5.41 (dd, J = 5.6, 8.4 Hz, 1H), 4.26 (td, J = 2.8, 8.0 Hz, 1H), 3.89 (m, 1H), 2.97 -2.81 (m, 3H), 2.55 (br s, 2H), 2.29 -2.17 (m, 1H) )
5858
Figure PCTKR2019018834-appb-I000208
Figure PCTKR2019018834-appb-I000208
 		(S)-N-(3-((2-아미노피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((2-aminopyrimidin-5-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 386.1386.1 1H NMR (400 MHz, DMSO-d 6) δ = 9.52 (s, 1H), 8.42 (s, 2H), 7.86 (t, J = 1.6 Hz, 1H), 7.66 - 7.61 (m, 1H), 7.42 (m, 6H), 7.19 - 7.11 (m, 3H), 5.41 (dd, J = 6.0, 8.4 Hz, 1H), 4.28 - 4.23 (m, 1H), 3.92 - 3.86 (m, 1H), 2.92 - 2.78 (m, 1H), 2.31 - 2.16 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.52 (s, 1H), 8.42 (s, 2H), 7.86 (t, J = 1.6 Hz, 1H), 7.66-7.61 (m, 1H), 7.42 (m, 6H), 7.19-7.11 (m, 3H), 5.41 (dd, J = 6.0, 8.4 Hz, 1H), 4.28-4.23 (m, 1H), 3.92-3.86 (m, 1H), 2.92-2.78 (m, 1H), 2.31-2.16 (m, 1H)
5959
Figure PCTKR2019018834-appb-I000209
Figure PCTKR2019018834-appb-I000209
 		(S)-N-(3-((2-(사이클로프로필아미노)피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((2-(cyclopropylamino)pyrimidin-5-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 426.3426.3 1H NMR (400 MHz, DMSO-d 6) δ = 9.52 (s, 1H), 8.48 (s, 2H), 7.91 - 7.81 (m, 2H), 7.63 (dd, J = 1.2, 8.4 Hz, 1H), 7.40 - 7.25 (m, 6H), 7.15 (d, J = 7.6 Hz, 1H), 5.40 (dd, J = 6.0, 8.4 Hz, 1H), 4.27 - 4.22 (m, 1H), 3.95 - 3.80 (m, 1H), 2.88 - 2.81 (m, 1H), 2.77 - 2.71 (m, 1H), 2.28 - 2.16 (m, 1H), 0.70 - 0.66 (m, 2H), 0.52 - 0.47 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.52 (s, 1H), 8.48 (s, 2H), 7.91-7.81 (m, 2H), 7.63 (dd, J = 1.2, 8.4 Hz, 1H) , 7.40-7.25 (m, 6H), 7.15 (d, J = 7.6 Hz, 1H), 5.40 (dd, J = 6.0, 8.4 Hz, 1H), 4.27-4.22 (m, 1H), 3.95-3.80 (m , 1H), 2.88-2.81 (m, 1H), 2.77-2.71 (m, 1H), 2.28-2.16 (m, 1H), 0.70-0.66 (m, 2H), 0.52-0.47 (m, 2H)
6060
Figure PCTKR2019018834-appb-I000210
Figure PCTKR2019018834-appb-I000210
 		(S)-N-(3-((2-((3-하이드록시프로필)아미노)피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((2-((3-hydroxypropyl)amino)pyrimidin-5-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 444.1444.1 1H NMR (400 MHz, DMSO-d 6) δ = 9.52 (s, 1H), 8.45 (br d, J = 11.0 Hz, 2H), 7.85 (s, 1H), 7.69 -7.60 (m, 2H), 7.40 -7.24 (m, 6H), 7.15 (d, J = 8 Hz, 1H), 5.41 (dd, J = 2.4, 8.4 Hz, 1H), 4.47 (t, J = 5.2 Hz, 1H), 4.25 (td, J = 2.8, 8.0 Hz, 1H), 3.96 -3.79 (m, 1H), 3.47 (q, J = 6.0 Hz, 2H), 3.35 (br s, 2H), 2.90 -2.80 (m, 1H), 2.28 -2.17 (m, 1H), 1.68 (quin, J = 6.8 Hz, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.52 (s, 1H), 8.45 (br d, J = 11.0 Hz, 2H), 7.85 (s, 1H), 7.69 -7.60 (m, 2H), 7.40 -7.24 (m, 6H), 7.15 (d, J = 8 Hz, 1H), 5.41 (dd, J = 2.4, 8.4 Hz, 1H), 4.47 (t, J = 5.2 Hz, 1H), 4.25 (td , J = 2.8, 8.0 Hz, 1H), 3.96 -3.79 (m, 1H), 3.47 (q, J = 6.0 Hz, 2H), 3.35 (br s, 2H), 2.90 -2.80 (m, 1H), 2.28 -2.17 (m, 1H), 1.68 (quin, J = 6.8 Hz, 2H)
6161
Figure PCTKR2019018834-appb-I000211
Figure PCTKR2019018834-appb-I000211
 		(S)-N-(3-((2-(이소부틸아미노)피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드( S )- N- (3-((2-(isobutylamino)pyrimidin-5-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide 442.1442.1 1H NMR (400 MHz, DMSO-d 6) δ = 9.52 (s, 1H), 8.44 (br d, J = 5.2 Hz, 2H), 7.85 (s, 1H), 7.76 (br t, J = 6.0 Hz, 1H), 7.66 -7.61 (m, 1H), 7.41 -7.24 (m, 6H), 7.15 (br d, J = 7.6 Hz, 1H), 5.41 (dd, J = 6.0, 8.4 Hz, 1H), 4.25 (td, J = 2.8, 8.0 Hz, 1H), 3.94 -3.82 (m, 1H), 3.12 (t, J = 6.4 Hz, 2H), 2.90 -2.80 (m, 1H), 2.29 -2.18 (m, 1H), 1.91 -1.78 (m, 1H), 0.88 (d, J = 6.8 Hz, 6H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.52 (s, 1H), 8.44 (br d, J = 5.2 Hz, 2H), 7.85 (s, 1H), 7.76 (br t, J = 6.0 Hz , 1H), 7.66 -7.61 (m, 1H), 7.41 -7.24 (m, 6H), 7.15 (br d, J = 7.6 Hz, 1H), 5.41 (dd, J = 6.0, 8.4 Hz, 1H), 4.25 (td, J = 2.8, 8.0 Hz, 1H), 3.94 -3.82 (m, 1H), 3.12 (t, J = 6.4 Hz, 2H), 2.90 -2.80 (m, 1H), 2.29 -2.18 (m, 1H) ), 1.91 -1.78 (m, 1H), 0.88 (d, J = 6.8 Hz, 6H)
<실험예 1> 본 발명에 따른 화합물의 RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 저해 활성 평가<Experimental Example 1> Evaluation of RIPK1 (Receptor-interacting serine/threonine-protein kinase 1) inhibitory activity of the compound according to the present invention
본 발명에 따른 화합물의 RIPK1 저해 활성을 평가하기 위해 하기와 같은 실험을 수행하였다.The following experiment was performed to evaluate the RIPK1 inhibitory activity of the compound according to the present invention.
구체적으로, 본 발명의 실시예 화합물 중, 선별된 실시예 4에 대하여, DiscoverX 사에 의뢰하여 효소(kinase) 선택성을 측정하기로 하고, scanMAXTM Kinase 분석용 패널을 사용하여 실험을 진행하였다.Specifically, among the example compounds of the present invention, the selected Example 4 was commissioned by DiscoverX to measure enzyme selectivity, and experiments were performed using a scanMAX TM Kinase analysis panel.
이때, 효소에 처리되는 약물의 농도는 DMSO에 1μM로 하였고, 하기 식 1과 같은 방법으로 조절 백분율(% control)을 정하였고, 그 결과를 하기 표 7에 나타내었다.At this time, the concentration of the drug to be treated with enzyme was 1 μM in DMSO, the control percentage (% control) was determined in the same manner as in Equation 1 below, and the results are shown in Table 7 below.
[식 1][Equation 1]
(실시예 화합물 - 양성 대조군)/(음성 대조군- 양성 대조군) x 100(Example compound-positive control) / (negative control-positive control) x 100
여기서, 상기 양성 대조군은 0%의 조절 백분율을 나타내는 화합물을 말하며, 음성 대조군은 DMSO로 100%의 조절 백분율을 나타낸다. 또한, 본 발명의 효소 선택성은 효소에 대하여 조절 백분율이 <35% (즉 35% 미만)이면 해당 효소에 대하여 활성을 갖는 것으로 판단하였다.Here, the positive control refers to a compound showing a control percentage of 0%, and the negative control shows a control percentage of 100% with DMSO. In addition, 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%).
키나아제Kinase 실시예 4Example 4
RIPK1RIPK1 00
상기 표 7에서 확인할 수 있듯이, 본 발명에 따른 실시예 화합물은 RIPK1에 대하여 조절 백분율 35%보다 작은 값을 가지므로, RIPK1에 대하여 활성을 가짐을 알 수 있다. 이는 본 발명에 따른 실시예 화합물을 RIPK1 관련 질환에 사용할 경우 유용한 효과가 있음을 암시하는 것이며, 따라서, RIPK1 관련 질환의 치료 또는 예방용 조성물로 유용하게 사용할 수 있다.As can be seen from Table 7, 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. This implies that the exemplary compounds according to the present invention have useful effects when used in RIPK1-related diseases, and thus, can be usefully used as a composition for treating or preventing RIPK1-related diseases.
<실험예 2> RIPK1(Receptor-interacting serine/threonine protein kinase 1) 효소 저해능 평가<Experimental Example 2> Evaluation of RIPK1 (Receptor-interacting serine/threonine protein kinase 1) enzyme inhibitory ability
본 발명에 따른 실시예 화합물의 RIPK1(Receptor-interacting serine/threonine protein kinase 1) 효소에 대한 저해 활성을 평가하기 위해 하기와 같은 실험을 수행하였다.The following experiment was performed to evaluate the inhibitory activity of the Example compound according to the present invention for the enzyme RIPK1 (Receptor-interacting serine/threonine protein kinase 1).
본 발명에 따른 실시예 화합물을 정제된 human GST-RIPK1(1-375, signalchem) 효소와 반응하여 하기와 같은 방법으로 효소 저해능을 평가하였다. 반응 버퍼는 40mM Tris-HCl pH 7.4, 20mM MgCl2, 0.5mg/mL BSA, 및 0.5uM DTT 조성을 사용하였으며, 모든 시험물은 반응 버퍼상에서 반응을 수행하였다. 시험시 human GST-RIPK1(1-375, 10ng)효소, 정제된 ATP(50uM), 및 특이적인 기질용액을 25℃ 상에서 4시간 반응시킨 후 효소활성은 in vitro ADP-GloTM kinase assay(promega)을 이용하여 확인하였다. 2:2:1 비율로 효소활성반응액, ADP-Glo 반응액, 및 효소능 detection 용액을 반응시켜서 Luminoscence를 측정하였다. 화합물을 처리하지 않은 용매대조군 효소활성의 형광도를 기준으로 각 화합물들의 처리 농도에 따른 효소활성 저해 정도를 산출하였으며, 이때 효소활성 저해를 50% 억제하는 각 화합물의 농도를 IC50(nM) 값으로 결정하였다. 각 화합물의 IC50는 3개씩의 데이터 세트로 결정하였고, 프리즘(버전 7.01, 그래프패드) 소프트웨어를 이용하여 구하였다.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. After the test, 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.
그 결과를 아래 표 8에 나타내었다.The results are shown in Table 8 below.
<실험예 3> 세포사멸유도 조건에서의 세포 보호효과 평가<Experimental Example 3> Evaluation of cell protection effect under apoptosis-inducing conditions
본 발명에 따른 화합물이 TNF-α에 따른 세포사멸유도 조건에서 세포 보호 효과능을 나타내는지 MTS 분석을 통해 확인하였다. 세포 외부에서 TNF-α와 같은 세포사멸유도인자를 처리하고, FADD가 결핍된 사람 Jurkat T세포(I2.I Cell)의 세포사멸을 유도하고 본 발명에 따른 실시예 화합물을 처리하였을 때 세포 보호효과가 있는지 여부를 하기와 같은 분석을 통해 확인하였다. FADD가 결핍된 Jurkat T 세포주는 10% FBS를 포함하는 RPMI 배지(Hyclone)를 이용하여 세포배양을 하며, 시험 수행시에는 세포주에 맞는 배지가 들어있는 96-웰 플레이트에 각각 10,000 세포/웰의 농도로 분주한 후, 5% CO2 및 37℃ 조건에서 24시간 동안 배양하였다. 그 후, 각 웰에 TNF-α를 40 ng이 되게 처리하고, 상기 실시예에서 제조한 화합물들을 각각 1 μM을 최고농도로 하여 3배 농도구배를 주어 처리하였으며, 용매 대조군으로 디메틸설폭사이드(DMSO)를 화합물 처리시 사용한 것과 동일한 0.05 %(v/v)의 농도로 처리하였다. 그 후, 각 세포를 50시간 동안 배양하였다. 세포의 생존 정도를 확인하기 위하여, 상기 각 배양된 세포의 배지에 CellTiter-Glo® Luminescent Cell Viability Assay Kit(Promega)에서 제공되는 혼합물을 첨가하고, 37℃ 조건에서 30분 동안 추가로 배양하였다. 그 후, Luminoscence 형광도를 측정하였다. 화합물을 처리하지 않은 용매대조군 세포의 형광도를 기준으로 각 화합물들의 처리 농도에 따른 세포사멸유도 저해 정도를 산출하였으며, 이때 저해능이 50%인 농도를 EC50 (μM) 값으로 결정하였고 프리즘(버전 7.01, 그래프패드) 소프트웨어를 이용하여 구하였다.It was confirmed through MTS analysis that the compound according to the present invention exhibits a cell protective effect under apoptosis-inducing conditions according to TNF-α. Cell protective effect when treating apoptosis inducers such as TNF-α 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. After dispensing with 5% CO 2 and cultured for 24 hours at 37 ℃ conditions. Thereafter, TNF-α was treated in each well to be 40 ng, and the compounds prepared in the above Examples were treated with a concentration of 1 μM 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. Thereafter, 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 (μM) value and prism (version 7.01, GraphPad).
그 결과를 아래 표 8에 나타내었다.The results are shown in Table 8 below.
실시예Example Enzyme IC50 (nM)Enzyme IC 50 (nM) I2.I Cell EC50 (nM)I2.I Cell EC 50 (nM) 실시예Example Enzyme IC50 (nM)Enzyme IC 50 (nM) I2.I Cell EC50 (nM)I2.I Cell EC 50 (nM)
1One 30.230.2 0.20.2 3232 27.927.9 3.53.5
22 316316 0.60.6 3333 40.340.3 10.210.2
33 7.47.4 0.30.3 3434 52.852.8 >1000>1000
44 5.15.1 0.60.6 3535 5.65.6 1.21.2
55 268268 17.617.6 3636 3.43.4 1.21.2
66 9.69.6 0.480.48 3737 5.75.7 1.831.83
77 -- -- 3838 13.113.1 0.90.9
88 33 0.050.05 3939 6.96.9 1.31.3
99 >1000>1000 651651 4040 16.316.3 0.20.2
1010 10.710.7 1.11.1 4141 13.613.6 0.060.06
1111 1.81.8 0.640.64 4242 7.17.1 0.50.5
1212 1.51.5 1.41.4 4343 10.310.3 0.70.7
1313 10.510.5 0.130.13 4444 10.410.4 1.41.4
1414 5.75.7 0.50.5 4545 6.26.2 0.20.2
1515 11.811.8 3.53.5 4646 4.54.5 66
1616 18.718.7 1.41.4 4747 1.531.53 3.233.23
1717 17.817.8 10.710.7 4848 1.381.38 2.182.18
1818 14.214.2 1.21.2 4949 2.242.24 41.941.9
1919 683683 19.819.8 5050 >1000>1000 179179
2020 9.89.8 6.76.7 5151 664664 >1000>1000
2121 >1000>1000 >1000>1000 5252 >1000>1000 >1000>1000
2222 1.81.8 7.17.1 5353 >1000>1000 >1000>1000
2323 357357 >1000>1000 5454 6.66.6 257257
2424 5.925.92 9.49.4 5555 13.213.2 77.377.3
2525 >1000>1000 >1000>1000 5656 8.98.9 0.50.5
2626 16.416.4 2.32.3 5757 1.81.8 22
2727 304304 163163 5858 12.612.6 3.13.1
2828 12.312.3 0.170.17 5959 1.031.03 0.30.3
2929 3.83.8 0.070.07 6060 1.51.5 1.31.3
3030 22.722.7 0.30.3 6161 13.513.5 22
3131 27.727.7 3.63.6
상기 표 8는 RIPK1 효소활성능과 FADD가 결핍된 Jurkat T 세포에 대한 각 실험화합물의 세포사멸유도 조건에서의 세포 보호효과를 측정한 결과를 나타낸다.상기 표 8에서 확인할 수 있듯이, 본 발명에 따른 실시예 화합물은 효소활성능과 세포 보호효과 모두에양호한 활성을 나타낸다. 따라서, 본 발명에 따른 화합물은 상기 실험에서 확인한 바와 같이, 세포 사멸유도조건에서 세포보호 활성이 우수함을 알 수 있다.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. As can be seen in Table 8, according to the present invention 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.

Claims (23)

  1. 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체 또는 이의 약학적으로 허용되는 염:A compound represented by Formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2019018834-appb-I000212
    Figure PCTKR2019018834-appb-I000212
    상기 화학식 1에서,In Chemical Formula 1,
    E는 질소(N) 또는 탄소(C)이고;E is nitrogen (N) or carbon (C);
    L은 직접결합 또는 C1~5 알킬렌기이며;L is a direct bond or a C 1-5 alkylene group;
    R1 및 R2는 각각 독립적으로 부존재, 수소, 할로겐 원자, 또는 C1-5의 직쇄 또는 분지쇄 알킬이고;R 1 and R 2 are each independently absent, hydrogen, halogen atom, or C 1-5 straight or branched chain alkyl;
    R3은 비치환 또는 치환된 피리디닐, 피리미디닐, 이미다조피리다지닐, 이미다조피리디닐, 이미다조피리미디닐, 피라졸로피리미디닐, 이미다조피라지닐 또는 피라졸로피리디닐이며; 및R 3 is unsubstituted or substituted pyridinyl, pyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl; And
    R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-5의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-5의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알콕시, 할로알킬 또는 시아노(-CN)로 치환된 것이다. 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 1-5 straight or branched chain alkoxy, where substituted pyridinyl or thiazolyl is substituted with a linear or branched alkyl, straight-chain or branched alkoxy, haloalkyl, or cyano (-CN) of a C 1-5 of C 1-5.
  2. 제1항에 있어서,According to claim 1,
    상기 화합물이 하기 화학식 2 또는 3으로 표시되는 것인, The compound is represented by the following formula 2 or 3,
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염:A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof:
    [화학식 2][Formula 2]
    Figure PCTKR2019018834-appb-I000213
    Figure PCTKR2019018834-appb-I000213
    [화학식 3][Formula 3]
    Figure PCTKR2019018834-appb-I000214
    Figure PCTKR2019018834-appb-I000214
  3. 제 1항에 있어서,According to claim 1,
    상기 R3이
    Figure PCTKR2019018834-appb-I000215
    ,
    Figure PCTKR2019018834-appb-I000216
    ,
    Figure PCTKR2019018834-appb-I000217
    ,
    Figure PCTKR2019018834-appb-I000218
    ,
    Figure PCTKR2019018834-appb-I000219
    ,
    Figure PCTKR2019018834-appb-I000220
    ,
    Figure PCTKR2019018834-appb-I000221
    또는
    Figure PCTKR2019018834-appb-I000222
    이고,    R 3 is
    Figure PCTKR2019018834-appb-I000215
    ,
    Figure PCTKR2019018834-appb-I000216
    ,
    Figure PCTKR2019018834-appb-I000217
    ,
    Figure PCTKR2019018834-appb-I000218
    ,
    Figure PCTKR2019018834-appb-I000219
    ,
    Figure PCTKR2019018834-appb-I000220
    ,
    Figure PCTKR2019018834-appb-I000221
    or
    Figure PCTKR2019018834-appb-I000222
    ego,
    상기 R5는 수소, 또는 비치환 또는 치환된 아미노기이며, 상기 치환된 아미노기는 C1-10의 직쇄 또는 분지쇄 알킬, C1-10의 직쇄 또는 분지쇄 알킬카보닐, C3-6의 사이클로알킬카보닐, C1-10의 직쇄 또는 분지쇄 알콕시카보닐, 비치환 또는 치환된 페닐, 비치환 또는 치환된 피라졸릴, C3-6의 사이클로알킬, 또는 산소(O)를 헤테로 원자로 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이고, 상기 치환된 페닐 또는 치환된 피라졸릴은 C1-10 알킬 또는 질소(N)를 하나 이상 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며; R 5 is hydrogen or an unsubstituted or substituted amino group, and 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). Cycloalkyl;
    상기 R6은 C1-10의 직쇄 또는 분지쇄 알킬, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-10의 직쇄 또는 분지쇄 알킬, C3-6의 사이클로알킬, C1-10의 하이드록시알킬로 치환된 것이며; R 6 is C 1-10 straight or branched chain alkyl, or unsubstituted or substituted amino group, and the substituted amino group is C 1-10 straight or branched chain alkyl, C 3-6 cycloalkyl, C 1 Substituted with -10 hydroxyalkyl;
    상기 R7 은 C1-10의 직쇄 또는 분지쇄 알킬, C1-10의 직쇄 또는 분지쇄 알콕시 또는 상기 피리디닐의 서로 인접하는 2개의 탄소원자와 융합된 고리기를 형성하는 비치환 또는 치환된 6-원의 헤테로사이클로알킬기인,R 7 is C 1-10 straight-chain or branched-chain alkyl, C 1-10 straight-chain or branched alkoxy, or unsubstituted or substituted 6 which forms a ring group fused with two adjacent carbon atoms of the pyridinyl. -The original heterocycloalkyl group,
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  4. 제 1항에 있어서, According to claim 1,
    상기 R3은 R 3 is
    Figure PCTKR2019018834-appb-I000223
    ,
    Figure PCTKR2019018834-appb-I000224
    ,
    Figure PCTKR2019018834-appb-I000225
    ,
    Figure PCTKR2019018834-appb-I000226
    ,
    Figure PCTKR2019018834-appb-I000227
    ,
    Figure PCTKR2019018834-appb-I000228
    ,
    Figure PCTKR2019018834-appb-I000229
    ,
    Figure PCTKR2019018834-appb-I000230
    Figure PCTKR2019018834-appb-I000231
    ,
    Figure PCTKR2019018834-appb-I000232
    ,
    Figure PCTKR2019018834-appb-I000233
    ,
    Figure PCTKR2019018834-appb-I000234
    ,
    Figure PCTKR2019018834-appb-I000235
    ,
    Figure PCTKR2019018834-appb-I000236
    ,
    Figure PCTKR2019018834-appb-I000237
    ,
    Figure PCTKR2019018834-appb-I000238
    ,
    Figure PCTKR2019018834-appb-I000223
    ,
    Figure PCTKR2019018834-appb-I000224
    ,
    Figure PCTKR2019018834-appb-I000225
    ,
    Figure PCTKR2019018834-appb-I000226
    ,
    Figure PCTKR2019018834-appb-I000227
    ,
    Figure PCTKR2019018834-appb-I000228
    ,
    Figure PCTKR2019018834-appb-I000229
    ,
    Figure PCTKR2019018834-appb-I000230
    Figure PCTKR2019018834-appb-I000231
    ,
    Figure PCTKR2019018834-appb-I000232
    ,
    Figure PCTKR2019018834-appb-I000233
    ,
    Figure PCTKR2019018834-appb-I000234
    ,
    Figure PCTKR2019018834-appb-I000235
    ,
    Figure PCTKR2019018834-appb-I000236
    ,
    Figure PCTKR2019018834-appb-I000237
    ,
    Figure PCTKR2019018834-appb-I000238
    ,
    Figure PCTKR2019018834-appb-I000239
    ,
    Figure PCTKR2019018834-appb-I000240
    ,
    Figure PCTKR2019018834-appb-I000241
    ,
    Figure PCTKR2019018834-appb-I000242
    ,
    Figure PCTKR2019018834-appb-I000239
    ,
    Figure PCTKR2019018834-appb-I000240
    ,
    Figure PCTKR2019018834-appb-I000241
    ,
    Figure PCTKR2019018834-appb-I000242
    ,
    Figure PCTKR2019018834-appb-I000243
    , 또는
    Figure PCTKR2019018834-appb-I000244
    인,
    Figure PCTKR2019018834-appb-I000243
    , or
    Figure PCTKR2019018834-appb-I000244
    sign,
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  5. 제 1항에 있어서,According to claim 1,
    상기 R4는 R 4 is
    Figure PCTKR2019018834-appb-I000245
    ,
    Figure PCTKR2019018834-appb-I000246
    ,
    Figure PCTKR2019018834-appb-I000247
    ,
    Figure PCTKR2019018834-appb-I000248
    ,
    Figure PCTKR2019018834-appb-I000245
    ,
    Figure PCTKR2019018834-appb-I000246
    ,
    Figure PCTKR2019018834-appb-I000247
    ,
    Figure PCTKR2019018834-appb-I000248
    ,
    Figure PCTKR2019018834-appb-I000249
    ,
    Figure PCTKR2019018834-appb-I000250
    ,
    Figure PCTKR2019018834-appb-I000251
    ,
    Figure PCTKR2019018834-appb-I000252
    ,
    Figure PCTKR2019018834-appb-I000249
    ,
    Figure PCTKR2019018834-appb-I000250
    ,
    Figure PCTKR2019018834-appb-I000251
    ,
    Figure PCTKR2019018834-appb-I000252
    ,
    Figure PCTKR2019018834-appb-I000253
    ,
    Figure PCTKR2019018834-appb-I000254
    ,
    Figure PCTKR2019018834-appb-I000255
    ,
    Figure PCTKR2019018834-appb-I000256
    ,
    Figure PCTKR2019018834-appb-I000253
    ,
    Figure PCTKR2019018834-appb-I000254
    ,
    Figure PCTKR2019018834-appb-I000255
    ,
    Figure PCTKR2019018834-appb-I000256
    ,
    Figure PCTKR2019018834-appb-I000257
    ,
    Figure PCTKR2019018834-appb-I000258
    ,
    Figure PCTKR2019018834-appb-I000259
    ,
    Figure PCTKR2019018834-appb-I000260
    ,
    Figure PCTKR2019018834-appb-I000257
    ,
    Figure PCTKR2019018834-appb-I000258
    ,
    Figure PCTKR2019018834-appb-I000259
    ,
    Figure PCTKR2019018834-appb-I000260
    ,
    Figure PCTKR2019018834-appb-I000261
    ,
    Figure PCTKR2019018834-appb-I000262
    ,
    Figure PCTKR2019018834-appb-I000263
    ,
    Figure PCTKR2019018834-appb-I000264
    ,
    Figure PCTKR2019018834-appb-I000261
    ,
    Figure PCTKR2019018834-appb-I000262
    ,
    Figure PCTKR2019018834-appb-I000263
    ,
    Figure PCTKR2019018834-appb-I000264
    ,
    또는
    Figure PCTKR2019018834-appb-I000265
    인,     or
    Figure PCTKR2019018834-appb-I000265
    sign,
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  6. 제1항에 있어서,According to claim 1,
    상기 E는 질소(N)이고;E is nitrogen (N);
    상기 L은 직접결합 또는 C1~3 알킬렌기이며;L is a direct bond or a C 1-3 alkylene group;
    R1 및 R2는 각각 독립적으로 부존재 또는 수소이고;R 1 and R 2 are each independently absent or hydrogen;
    상기 R3은
    Figure PCTKR2019018834-appb-I000266
    이며; 및    R 3 is
    Figure PCTKR2019018834-appb-I000266
    Is; And
    상기 R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-3의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-3의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알콕시, 할로알킬 또는 시아노(-CN)로 치환된 것인, 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 substituted with C 1-3 straight or branched chain alkyl, C 1-5 straight or branched alkoxy, haloalkyl or cyano (-CN),
    화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  7. 제 6항에 있어서, The method of claim 6,
    상기 R4는 비치환, 또는 F, Cl, 및 Br로 이루어진 군으로부터 선택되는 하나 이상의 할로겐 원자로 치환된 페닐인 것인, R 4 is unsubstituted, or phenyl substituted with one or more halogen atoms selected from the group consisting of F, Cl, and Br,
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  8. 제1항에 있어서,According to claim 1,
    상기 E는 탄소(C)이고;E is carbon (C);
    상기 L은 직접 결합 또는 C1~3 알킬렌기이며;L is a direct bond or a C 1-3 alkylene group;
    상기 R1 및 R2는 각각 독립적으로 수소, 할로겐 원자 또는 C1-3의 직쇄 또는 분지쇄 알킬이고;R 1 and R 2 are each independently hydrogen, a halogen atom or C 1-3 straight or branched chain alkyl;
    상기 R3은R 3 is
    Figure PCTKR2019018834-appb-I000267
    ,
    Figure PCTKR2019018834-appb-I000268
    ,
    Figure PCTKR2019018834-appb-I000269
    ,
    Figure PCTKR2019018834-appb-I000267
    ,
    Figure PCTKR2019018834-appb-I000268
    ,
    Figure PCTKR2019018834-appb-I000269
    ,
    Figure PCTKR2019018834-appb-I000270
    ,
    Figure PCTKR2019018834-appb-I000271
    ,
    Figure PCTKR2019018834-appb-I000272
    ,
    Figure PCTKR2019018834-appb-I000270
    ,
    Figure PCTKR2019018834-appb-I000271
    ,
    Figure PCTKR2019018834-appb-I000272
    ,
    Figure PCTKR2019018834-appb-I000273
    또는
    Figure PCTKR2019018834-appb-I000274
    이며; 여기서 상기 R5는 수소, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-5의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알킬카보닐, C3-4의 사이클로알킬카보닐, C1-5의 직쇄 또는 분지쇄 알콕시카보닐, 비치환 또는 치환된 페닐, 비치환 또는 치환된 피라졸릴, C3-4의 사이클로알킬, 또는 산소(O)를 헤테로 원자로 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며, 상기 치환된 페닐 또는 치환된 피라졸릴은 C1-5 알킬 또는 질소(N)를 하나 이상 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며; 상기 R6은 C1-5의 직쇄 또는 분지쇄 알킬, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-5의 직쇄 또는 분지쇄 알킬, C3-4의 사이클로알킬, C1-5의 하이드록시알킬로 치환된 것이며; 상기 R7 은 C1-5의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알콕시 또는 상기 피리디닐의 서로 인접하는 2개의 탄소원자와 융합된 고리기를 형성하는 비치환 또는 치환된 6-원의 헤테로사이클로알킬기이고; 및
    Figure PCTKR2019018834-appb-I000273
    or
    Figure PCTKR2019018834-appb-I000274
    Is; Wherein R 5 is hydrogen, or an unsubstituted or substituted amino group, and the substituted amino group is C 1-5 linear or branched alkyl, C 1-5 linear or branched alkylcarbonyl, C 3-4 Cycloalkylcarbonyl, C 1-5 straight or branched chain alkoxycarbonyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyrazolyl, C 3-4 cycloalkyl, or oxygen (O) as hetero atom To unsubstituted or substituted 6-membered heterocycloalkyl, wherein the substituted phenyl or substituted pyrazolyl is unsubstituted or substituted 6-membered containing one or more C 1-5 alkyl or nitrogen (N) Substituted with heterocycloalkyl; R 6 is C 1-5 straight or branched chain alkyl, or unsubstituted or substituted amino group, and the substituted amino group is C 1-5 straight or branched chain alkyl, C 3-4 cycloalkyl, C 1 Substituted with -5 hydroxyalkyl; R 7 is C 1-5 straight-chain or branched-chain alkyl, C 1-5 straight-chain or branched alkoxy, or unsubstituted or substituted 6 forming a ring group fused with two adjacent carbon atoms of the pyridinyl. -The original heterocycloalkyl group; And
    R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-3의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-3의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알콕시, 할로알킬 또는 시아노(-CN)로 치환된 것인, 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 is substituted with C 1-3 straight or branched chain alkyl, C 1-5 straight or branched alkoxy, haloalkyl or cyano (-CN),
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  9. 제8항에 있어서,The method of claim 8,
    상기 L은 직접 결합 또는 C1~2 알킬렌기이며;L is a direct bond or a C 1-2 alkylene group;
    상기 R1 및 R2는 각각 독립적으로 수소, 할로겐 원자 또는 C1-3의 직쇄 또는 분지쇄 알킬이고;R 1 and R 2 are each independently hydrogen, a halogen atom or C 1-3 straight or branched chain alkyl;
    상기 R3은
    Figure PCTKR2019018834-appb-I000275
    이며; 및    R 3 is
    Figure PCTKR2019018834-appb-I000275
    Is; And
    상기 R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-3의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-3의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알콕시, 트리플루오르화탄소(-CF3) 또는 시아노(-CN)로 치환된 것인, 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 substituted with C 1-3 straight or branched chain alkyl, C 1-3 straight or branched alkoxy, trifluorocarbon (-CF 3 ) or cyano (-CN),
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  10. 제 9항에 있어서,The method of claim 9,
    상기 R4는 R 4 is
    Figure PCTKR2019018834-appb-I000276
    ,
    Figure PCTKR2019018834-appb-I000277
    ,
    Figure PCTKR2019018834-appb-I000278
    ,
    Figure PCTKR2019018834-appb-I000276
    ,
    Figure PCTKR2019018834-appb-I000277
    ,
    Figure PCTKR2019018834-appb-I000278
    ,
    Figure PCTKR2019018834-appb-I000279
    ,
    Figure PCTKR2019018834-appb-I000280
    ,
    Figure PCTKR2019018834-appb-I000281
    ,
    Figure PCTKR2019018834-appb-I000279
    ,
    Figure PCTKR2019018834-appb-I000280
    ,
    Figure PCTKR2019018834-appb-I000281
    ,
    Figure PCTKR2019018834-appb-I000282
    ,
    Figure PCTKR2019018834-appb-I000283
    ,
    Figure PCTKR2019018834-appb-I000282
    ,
    Figure PCTKR2019018834-appb-I000283
    ,
    Figure PCTKR2019018834-appb-I000284
    ,
    Figure PCTKR2019018834-appb-I000285
    ,
    Figure PCTKR2019018834-appb-I000286
    ,
    Figure PCTKR2019018834-appb-I000284
    ,
    Figure PCTKR2019018834-appb-I000285
    ,
    Figure PCTKR2019018834-appb-I000286
    ,
    Figure PCTKR2019018834-appb-I000287
    ,
    Figure PCTKR2019018834-appb-I000288
    ,
    Figure PCTKR2019018834-appb-I000289
    ,
    Figure PCTKR2019018834-appb-I000287
    ,
    Figure PCTKR2019018834-appb-I000288
    ,
    Figure PCTKR2019018834-appb-I000289
    ,
    Figure PCTKR2019018834-appb-I000290
    ,
    Figure PCTKR2019018834-appb-I000291
    ,
    Figure PCTKR2019018834-appb-I000292
    ,
    Figure PCTKR2019018834-appb-I000290
    ,
    Figure PCTKR2019018834-appb-I000291
    ,
    Figure PCTKR2019018834-appb-I000292
    ,
    Figure PCTKR2019018834-appb-I000293
    ,
    Figure PCTKR2019018834-appb-I000294
    ,
    Figure PCTKR2019018834-appb-I000295
    ,
    Figure PCTKR2019018834-appb-I000293
    ,
    Figure PCTKR2019018834-appb-I000294
    ,
    Figure PCTKR2019018834-appb-I000295
    ,
    또는
    Figure PCTKR2019018834-appb-I000296
    인,     or
    Figure PCTKR2019018834-appb-I000296
    sign,
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  11. 제8항에 있어서,The method of claim 8,
    상기 L은 직접 결합 또는 C1~2 알킬렌기이며;L is a direct bond or a C 1-2 alkylene group;
    상기 R1 및 R2는 수소이고;R 1 and R 2 are hydrogen;
    상기 R3은
    Figure PCTKR2019018834-appb-I000297
    ,
    Figure PCTKR2019018834-appb-I000298
    ,
    Figure PCTKR2019018834-appb-I000299
    ,
    Figure PCTKR2019018834-appb-I000300
    ,
    Figure PCTKR2019018834-appb-I000301
    ,
    Figure PCTKR2019018834-appb-I000302
    또는
    Figure PCTKR2019018834-appb-I000303
    이며, 여기서 상기 R5는 수소, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-3의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알킬카보닐, C3-6의 사이클로알킬카보닐, C1-3의 직쇄 또는 분지쇄 알콕시카보닐, 비치환 또는 치환된 페닐, 비치환 또는 치환된 피라졸릴, C3-4의 사이클로알킬, 또는 산소(O)를 헤테로 원자로 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며, 상기 치환된 페닐 또는 치환된 피라졸릴은 C1-3 알킬 또는 질소(N)를 하나 이상 포함하는 비치환 또는 치환된 6-원 헤테로사이클로알킬로 치환된 것이며; 상기 R6은 C1-3의 직쇄 또는 분지쇄 알킬, 또는 비치환 또는 치환된 아미노기이고, 상기 치환된 아미노기는 C1-3의 직쇄 또는 분지쇄 알킬, C3-4의 사이클로알킬, C1-3의 하이드록시알킬로 치환된 것이며; 상기 R7 은 C1-3의 직쇄 또는 분지쇄 알킬, C1-3의 직쇄 또는 분지쇄 알콕시 또는 상기 피리디닐의 서로 인접하는 2개의 탄소원자와 융합된 고리기를 형성하는 비치환 또는 치환된 6-원의 헤테로사이클로알킬기이고; 및    R 3 is
    Figure PCTKR2019018834-appb-I000297
    ,
    Figure PCTKR2019018834-appb-I000298
    ,
    Figure PCTKR2019018834-appb-I000299
    ,
    Figure PCTKR2019018834-appb-I000300
    ,
    Figure PCTKR2019018834-appb-I000301
    ,
    Figure PCTKR2019018834-appb-I000302
    or
    Figure PCTKR2019018834-appb-I000303
    Wherein 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- Heterocycloalkylcarbonyl of 6 , straight or branched alkoxycarbonyl of C 1-3 , unsubstituted or substituted phenyl, unsubstituted or substituted pyrazolyl, cycloalkyl of C 3-4 , or oxygen (O) hetero 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). -Substituted with a one heterocycloalkyl; R 6 is C 1-3 straight chain or branched chain alkyl, or unsubstituted or substituted amino group, and the substituted amino group is C 1-3 straight chain or branched chain alkyl, C 3-4 cycloalkyl, C 1 Substituted with -3 hydroxyalkyl; R 7 is C 1-3 straight chain or branched chain alkyl, C 1-3 straight chain or branched chain alkoxy, or unsubstituted or substituted 6 to form a ring group fused with two adjacent carbon atoms of the pyridinyl -The original heterocycloalkyl group; And
    상기 R4는 비치환 또는 치환된 페닐인, R 4 is unsubstituted or substituted phenyl,
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  12. 제 11항에 있어서, The method of claim 11,
    상기 R3은R 3 is
    Figure PCTKR2019018834-appb-I000304
    ,
    Figure PCTKR2019018834-appb-I000305
    ,
    Figure PCTKR2019018834-appb-I000306
    ,
    Figure PCTKR2019018834-appb-I000307
    ,
    Figure PCTKR2019018834-appb-I000304
    ,
    Figure PCTKR2019018834-appb-I000305
    ,
    Figure PCTKR2019018834-appb-I000306
    ,
    Figure PCTKR2019018834-appb-I000307
    ,
    Figure PCTKR2019018834-appb-I000308
    ,
    Figure PCTKR2019018834-appb-I000309
    ,
    Figure PCTKR2019018834-appb-I000310
    Figure PCTKR2019018834-appb-I000311
    ,
    Figure PCTKR2019018834-appb-I000308
    ,
    Figure PCTKR2019018834-appb-I000309
    ,
    Figure PCTKR2019018834-appb-I000310
    Figure PCTKR2019018834-appb-I000311
    ,
    Figure PCTKR2019018834-appb-I000312
    ,
    Figure PCTKR2019018834-appb-I000313
    ,
    Figure PCTKR2019018834-appb-I000314
    ,
    Figure PCTKR2019018834-appb-I000312
    ,
    Figure PCTKR2019018834-appb-I000313
    ,
    Figure PCTKR2019018834-appb-I000314
    ,
    Figure PCTKR2019018834-appb-I000315
    ,
    Figure PCTKR2019018834-appb-I000316
    ,
    Figure PCTKR2019018834-appb-I000317
    ,
    Figure PCTKR2019018834-appb-I000315
    ,
    Figure PCTKR2019018834-appb-I000316
    ,
    Figure PCTKR2019018834-appb-I000317
    ,
    Figure PCTKR2019018834-appb-I000318
    ,
    Figure PCTKR2019018834-appb-I000319
    ,
    Figure PCTKR2019018834-appb-I000320
    ,
    Figure PCTKR2019018834-appb-I000318
    ,
    Figure PCTKR2019018834-appb-I000319
    ,
    Figure PCTKR2019018834-appb-I000320
    ,
    Figure PCTKR2019018834-appb-I000321
    ,
    Figure PCTKR2019018834-appb-I000322
    ,
    Figure PCTKR2019018834-appb-I000323
    ,
    Figure PCTKR2019018834-appb-I000321
    ,
    Figure PCTKR2019018834-appb-I000322
    ,
    Figure PCTKR2019018834-appb-I000323
    ,
    또는
    Figure PCTKR2019018834-appb-I000324
    인,     or
    Figure PCTKR2019018834-appb-I000324
    sign,
    화합물, 이의 입체이성질체 또는 이의 약학적으로 허용가능한 염.A compound, stereoisomer thereof or pharmaceutically acceptable salt thereof.
  13. 제1항에 있어서,According to claim 1,
    상기 화학식 1로 표시되는 화합물이 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는, Characterized in that the compound represented by Formula 1 is any one selected from the following group of compounds,
    화합물, 이의 입체 이성질체, 또는 이의 약학적으로 허용 가능한 염:A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof:
    (1)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(1)( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-phenylisooxazolidine-2-carboxamide ;
    (2)(S)-3-(3,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)이소옥사졸리딘-2-카복사마이드(2)( S )-3-(3,5-difluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)iso Oxazolidine-2-carboxamide
    (3)(S)-3-(3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)-4-메틸페닐)이소옥사졸리딘-2-카복사마이드;(3)( S )-3-(3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)isooxazolidine -2-carboxamide;
    (4)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (4) (S) - N- (3- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (5)(R)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐아이소옥사졸리딘-2-카복사마이드; (5) (R) - N- (3- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3-phenyl-iso-oxazolidine-2-carboxamide;
    (6)(S)-3-(3,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(6)( S )-3-(3,5-difluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine -2-carboxamide;
    (7)(R)-3-(3,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (7) (R) -3- ( 3,5- difluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin-isopropyl -2-carboxamide;
    (8)(S)-3-(3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(8)( S )-3-(3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2- Carboxamide;
    (9)(R)-3-(3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(9) (R) -3- (3-fluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin-2-isopropyl Carboxamide;
    (10)(S)-3-(4-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(10)( S )-3-(4-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2- Carboxamide;
    (11)(S)-3-(4-클로로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (11) (S) -3- ( 4- chlorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin-2-isopropyl car Radiation amide;
    (12)(S)-3-(4-브로모페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(12)( S )-3-(4-Bromophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2- Carboxamide;
    (13)(S)-3-(3,4-다이클로로-2-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(13) (S) -3- (3,4-dichloro-2-fluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) Isooxazolidine-2-carboxamide;
    (14)(S)-3-(4-클로로-3-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(14)( S )-3-(4-Chloro-3-fluorophenyl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazoli Dean-2-carboxamide;
    (15)(S)-3-(3-클로로-4-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (15) (S) -3- ( 3- chloro-4-fluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin iso Dean-2-carboxamide;
    (16)(S)-3-(2,5-다이플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드; (16) (S) -3- ( 2,5- difluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin-isopropyl -2-carboxamide;
    (17)(S)-3-(3-클로로-2-플루오로페닐)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(17) (S) -3- (3-chloro-2-fluorophenyl) - N- (3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) oxazolidin iso Dean-2-carboxamide;
    (18)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(3-메톡시페닐)이소옥사졸리딘-2-카복사마이드;(18)( S )- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(3-methoxyphenyl)isooxazolidine-2- Carboxamide;
    (19)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(6-메틸피리딘-3-일)이소옥사졸리딘-2-카복사마이드; (19) (S) - N- (3- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3- (6-methylpyridin-3-yl) oxazolidin-isopropyl -2-carboxamide;
    (20)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(피리딘-3-일)이소옥사졸리딘-2-카복사마이드;(20)( S )- N- (3-(imidazo[1,2-b]pyridazin-3-ylethynyl)phenyl)-3-(pyridin-3-yl)isooxazolidine-2- Carboxamide;
    (21)(S)-N-(4-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카르복사마이드; (21) (S) - N- (4- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (22)(S)-3-(5-사이아노피리딘-3-일)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(22)( S )-3-(5-Cyanopyridin-3-yl)- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazoli Dean-2-carboxamide;
    (23)(S)-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(4-(트리플루오로메틸)티아졸-2-일)이소옥사졸리딘-2-카복사마이드; (23) (S) - N- (3- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3- (4- (trifluoromethyl) thiazol-2 1) isooxazolidine-2-carboxamide;
    (24)(R)-3-벤질-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(24)( R )-3-benzyl- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide;
    (25)(S)-3-벤질-N-(3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(25)( S )-3-benzyl- N- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide;
    (26)(S)-N-(2-(이미다조[1,2-b]피리다진-3- 일에티닐)피리딘-4-일)-3-페닐이소옥사졸리딘-2-카복사마이드; (26) (S) - N- (2- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) pyridin-4-yl) -3-phenyl-2-isopropyl-oxazolidine-carboxamide Mide;
    (27)(R)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-yl)-3-페닐이소옥사졸리딘-2-카복사마이드; (27) (R) - N- (2- ( ethynyl-imidazo [1,2-b] pyridazin-3-yl) pyridin -4-yl) -3- isopropyl-phenyl oxazolidin-2-carboxamide Mide;
    (28)(S)-3-(3,5-다이플루오로페닐)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-일)이소옥사졸리딘-2-카복사마이드; (28) (S) -3- ( 3,5- difluorophenyl) - N- (2- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) pyridin-4-yl) Isooxazolidine-2-carboxamide;
    (29)(S)-3-(3-플루오로페닐)-N-(2-(이미다조[1,2-b]피리다진-3-일에티닐)피리딘-4-일)이소옥사졸리딘-2-카복사마이드;(29) (S) -3- (3-fluorophenyl) - N- (2- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) pyridin-4-yl) oxazolidin iso Dean-2-carboxamide;
    (30)(S)-N-(4-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(30)( S )- N- (4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-car Radiation amide;
    (31)(S)-N-(2-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(31)( S )- N- (2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-phenylisooxazolidine-2-car Radiation amide;
    (32)(S)-N-(2-플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(피리딘-3-일)이소옥사졸리딘-2-카복사마이드; (32) (S) - N- (2- fluoro-3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3- (pyridin-3-yl) -isoxazol Zolidine-2-carboxamide;
    (33)(S)-N-(2,4-다이플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(33) (S) - N- (2,4- difluoro-3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3-phenyl-oxazolidine-isopropyl- 2-carboxamide;
    (34)(S)-N-(2,4-다이플루오로-3-(이미다조[1,2-b]피리다진-3-일에티닐)페닐)-3-(피리딘-3-일)이소옥사졸리딘-2-카복사마이드; (34) (S) - N- (2,4- difluoro-3- (ethynyl-imidazo [1,2-b] pyridazin-3-yl) phenyl) -3- (pyridin-3-yl )Isooxazolidine-2-carboxamide;
    (35)(S)-N-(3-((8-아미노이미다조 [1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (35) (S) - N- (3 - ((8- amino-imidazo [1,2-a] pyridin-ethynyl-3-yl)) phenyl) -3-phenyl-2-isopropyl-oxazolidine-carboxamide Mide;
    (36)(S)-N-(3-((8-(사이클로프로페인카복사미도)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(36)( S )- N- (3-((8-(cyclopropanecarboxamido)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxa Zolidine-2-carboxamide;
    (37)(S)-N-(3-((8-(에틸아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(37)( S )- N- (3-((8-(ethylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2 -Carboxamide;
    (38)(S)-3-페닐-N-(3-((8-((테트라하이드로-2H-피란-4-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(38)( S )-3-phenyl- N- (3-((8-((tetrahydro-2H-pyran-4-yl)amino)imidazo[1,2-a]pyridin-3-yl) Ethynyl)phenyl)isooxazolidine-2-carboxamide;
    (39)(S)-메틸 3-((3-(3-페닐이소옥사졸리딘-2-카복사미도)페닐)에티닐)이미다조[1,2-a]피리딘-8-일카바메이트;(39)( S )-methyl 3-((3-(3-phenylisooxazolidine-2-carboxamido)phenyl)ethynyl)imidazo[1,2-a]pyridine-8-ylcarbamate ;
    (40)(S)-N-(3-((8-((5-메틸-1H-피라졸-3-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(40)( S )- N- (3-((8-((5-methyl-1H-pyrazol-3-yl)amino)imidazo[1,2-a]pyridin-3-yl)ethynyl )Phenyl)-3-phenylisooxazolidine-2-carboxamide;
    (41)(S)-N-(3-((8-((1-메틸-1H-피라졸-3-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (41) (S) - N- (3 - ((8 - ((1- methyl -1H- pyrazol-3-yl) amino) imidazo [1,2-a] ethynyl-3-yl) )Phenyl)-3-phenylisooxazolidine-2-carboxamide;
    (42)(S)-N-(3-((8-((1-메틸-1H-피라졸-4-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (42) (S) - N- (3 - ((8 - ((1- methyl -1H- pyrazol-4-yl) amino) imidazo [1,2-a] ethynyl-3-yl) )Phenyl)-3-phenylisooxazolidine-2-carboxamide;
    (43)(S)-N-(3-((8-(사이클로프로필아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(43)( S )- N- (3-((8-(cyclopropylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine- 2-carboxamide;
    (44)(S)-3-페닐-N-(3-((8-(페닐아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(44)( S )-3-phenyl- N- (3-((8-(phenylamino)imidazo[1,2-a]pyridin-3-yl)ethynyl)phenyl)isooxazolidine-2 -Carboxamide;
    (45)(S)-N-(3-((8-((1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)아미노)이미다조[1,2-a]피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(45)( S )- N- (3-((8-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)imidazo[1,2 -a]pyridin-3-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-carboxamide;
    (46)(S)-N-(3-(이미다조[1,2-a]피리딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (46) (S) - N- (3- ( already ethynyl-imidazo [1,2-a] pyridin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (47)(S)-3-페닐-N-(3-(피라졸로[1,5-a]피리미딘-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(47)( S )-3-phenyl- N- (3-(pyrazolo[1,5-a]pyrimidin-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide;
    (48)(S)-N-(3-(이미다조[1,2-a]피라진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (48) (S) - N- (3- ( already ethynyl-imidazo [1,2-a] pyrazin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (49)(S)-N-(3-(이미다조[1,2-a]피리미딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (49) (S) - N- (3- ( already ethynyl-imidazo [1,2-a] pyrimidin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (50)(R)-N-(3-(이미다조[1,2-a]피리딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (50) (R) - N- (3- ( already ethynyl-imidazo [1,2-a] pyridin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (51)(R)-3-페닐-N-(3-(피라졸로[1,5-a]피리미딘-3-일에티닐)페닐)이소옥사졸리딘-2-카복사마이드;(51)( R )-3-phenyl- N- (3-(pyrazolo[1,5-a]pyrimidin-3-ylethynyl)phenyl)isooxazolidine-2-carboxamide;
    (52)(R)-N-(3-(이미다조[1,2-a]피라진-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (52) (R) - N- (3- ( already ethynyl-imidazo [1,2-a] pyrazin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (53)(R)-N-(3-(이미다조[1,2-a]피리미딘-3-일에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (53) (R) - N- (3- ( already ethynyl-imidazo [1,2-a] pyrimidin-3-yl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (54)(S)-N-(3-((6-메틸피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (54) (S) - N- (3 - ((6- methylpyridin-3-yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (55)(S)-N-(3-((5-메톡시 피리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (55) (S) - N- (3 - ((5- methoxypyridin-3- yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (56)(S)-N-(3-((1H-피라졸로[3,4-b]피리딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (56) (S) - N- (3 - ((1H- pyrazolo [3,4-b] pyridin-ethynyl-5-yl)) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide ;
    (57)(S)-N-(3-((7-옥소-5,6,7,8-테트라하이드로-1,8-나프티리딘-3-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드;(57)( S )- N- (3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethynyl)phenyl)-3-phenyliso Oxazolidine-2-carboxamide;
    (58)(S)-N-(3-((2-아미노피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (58) (S) - N- (3 - ((2- amino-pyrimidin-5-yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (59)(S)-N-(3-((2-(사이클로프로필아미노)피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; (59) (S) - N- (3 - ((2- ( cyclopropyl) pyrimidin-5-yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide;
    (60)(S)-N-(3-((2-((3-하이드록시프로필)아미노)피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드; 및(60)( S )- N- (3-((2-((3-hydroxypropyl)amino)pyrimidin-5-yl)ethynyl)phenyl)-3-phenylisooxazolidine-2-car Radiant amide; And
    (61)(S)-N-(3-((2-(이소부틸아미노)피리미딘-5-일)에티닐)페닐)-3-페닐이소옥사졸리딘-2-카복사마이드. (61) (S) - N- (3 - ((2- ( isobutyl amino) pyrimidin-5-yl) ethynyl) phenyl) -3-phenyl-isopropyl-oxazolidin-2-carboxamide.
  14. 화학식 4로 표시되는 화합물로부터, 화학식 5으로 표시되는 화합물을 제조하는 단계(단계 1);Preparing a compound represented by Chemical Formula 5 from a compound represented by Chemical Formula 4 (Step 1);
    상기 단계 1에서 제조한 화학식 5으로 표시되는 화합물로부터, 화학식 6으로 표시되는 화합물을 제조하는 단계(단계 2);Preparing a compound represented by Formula 6 from the compound represented by Formula 5 prepared in Step 1 (Step 2);
    상기 단계 2에서 제조한 화학식 6으로 표시되는 화합물과 화학식 7로 표시되는 화합물을 반응시켜, 화학식 8로 표시되는 화합물을 제조하는 단계(단계 3); 및Reacting the compound represented by Formula 6 and the compound represented by Formula 7 prepared in Step 2 to prepare a compound represented by Formula 8 (Step 3); And
    상기 단계 3에서 제조한 화학식 8로 표시되는 화합물과 N,N'-다이석시니미딜 카보네이트 및 화학식 9로 표시되는 화합물을 반응시켜, 화학식 1로 표시되는 화합물을 제조하는 단계(단계 4); 를 포함하는 화학식 1로 표시되는 화합물의 제조방법:Preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 8 prepared in Step 3 with a compound represented by N,N'-disuccinimidyl carbonate and Chemical Formula 9 (Step 4); Method for preparing a compound represented by Formula 1 comprising:
    [반응식 1][Scheme 1]
    Figure PCTKR2019018834-appb-I000325
    Figure PCTKR2019018834-appb-I000325
    상기 반응식 1에서,In Reaction Scheme 1,
    E는 질소(N) 또는 탄소(C)이고;E is nitrogen (N) or carbon (C);
    L은 직접결합 또는 C1~5 알킬렌기이며;L is a direct bond or a C 1-5 alkylene group;
    R1 및 R2는 각각 독립적으로 부존재, 수소, 할로겐 원자, 또는 C1-5의 직쇄 또는 분지쇄 알킬이고;R 1 and R 2 are each independently absent, hydrogen, halogen atom, or C 1-5 straight or branched chain alkyl;
    R3은 비치환 또는 치환된 피리디닐, 피리미디닐, 이미다조피리다지닐, 이미다조피리디닐, 이미다조피리미디닐, 피라졸로피리미디닐, 이미다조피라지닐 또는 피라졸로피리디닐이며; R 3 is unsubstituted or substituted pyridinyl, pyrimidinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazopyrazinyl or pyrazolopyridinyl;
    R4는 비치환 또는 치환된 페닐, 또는 비치환 또는 치환된 피리디닐 또는 티아졸릴이고, 여기서 치환된 페닐은 하나 이상의 할로겐 원자 또는 C1-3의 직쇄 또는 분지쇄 알콕시로 치환되며, 여기서 치환된 피리디닐 또는 티아졸릴은 C1-3의 직쇄 또는 분지쇄 알킬, C1-5의 직쇄 또는 분지쇄 알콕시, 할로알킬 또는 시아노(-CN)로 치환된 것이고;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 is substituted with C 1-3 straight or branched chain alkyl, C 1-5 straight or branched alkoxy, haloalkyl or cyano (-CN);
    상기 PG는 보호기이며; 및The PG is a protecting group; And
    상기 X1 및 X2는 독립적으로 할로겐 원자이다.X 1 and X 2 are independently a halogen atom.
  15. 제 14항에 있어서, The method of claim 14,
    상기 보호기는 트리(C1-C6알킬)실릴기, C1-C6 알킬 카르보닐기, 벤조일기, 및 페닐아세틸기 중에서 선택되는 것인 제조방법.The protecting group is a tri (C 1 -C 6 alkyl) silyl group, C 1 -C 6 alkyl carbonyl group, benzoyl group, and phenyl acetyl group is selected from the manufacturing method.
  16. 제1항 내지 제13항 중 어느 한 항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 예방 또는 치료용 약학적 조성물.Prevention or treatment of a disease related to Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) containing the compound of any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. Dragon pharmaceutical composition.
  17. 제16항에 있어서,The method of claim 16,
    상기 RIPK1 관련 질환은,The RIPK1-related diseases,
    염증성 장 질환, 크론병, 궤양성 결장염, 건선, 망막 박리, 색소성 망막염, 황반 변성, 췌장염, 아토피성 피부염, 류마티스 관절염, 척추관절염, 통풍, 쇼그렌 증후군, 전신 경피증, 항-인지질 증후군, 혈관염, 골관절염, 비-알콜 지방간염, 알콜 지방간염, 원발성 경화성 담관염, 신염, 복강 질환, 이식 거부, 패혈증, 전신 염증 반응 증후군, 심근경색, 헌팅턴병, 알츠하이머병, 파킨슨병, 알레르기성 질환, 천식, 아토피성 피부염, 다발성 경화증, 제I형 당뇨병, 베게너 육아종증, 폐 사르코이드증, 베체트병, 운동신경원병(Motor neurone disease), 만성 폐쇄성 폐질환, 암 및 치주염으로 이루어지는 군으로부터 선택되는 질환인 것을 특징으로 하는, Inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, arthritis, gout, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, Osteoarthritis, non-alcoholic steatohepatitis, alcoholic hepatitis, primary sclerosing cholangitis, nephritis, celiac disease, transplant rejection, sepsis, systemic inflammatory response syndrome, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic Dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, motor neurone disease, chronic obstructive pulmonary disease, disease selected from the group consisting of cancer and periodontitis doing,
    RIPK1 관련 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for the prevention or treatment of RIPK1-related diseases.
  18. 제 1항 내지 제 13항 중 어느 한 항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 치료방법. Receptor-interacting serine/threonine of RIPK1, comprising administering the compound of any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof to a subject in need thereof. -protein kinase 1) How to treat related diseases.
  19. 제 18항에 있어서,The method of claim 18,
    상기 RIPK1 관련 질환은,The RIPK1-related diseases,
    염증성 장 질환, 크론병, 궤양성 결장염, 건선, 망막 박리, 색소성 망막염, 황반 변성, 췌장염, 아토피성 피부염, 류마티스 관절염, 척추관절염, 통풍, 쇼그렌 증후군, 전신 경피증, 항-인지질 증후군, 혈관염, 골관절염, 비-알콜 지방간염, 알콜 지방간염, 원발성 경화성 담관염, 신염, 복강 질환, 이식 거부, 패혈증, 전신 염증 반응 증후군, 심근경색, 헌팅턴병, 알츠하이머병, 파킨슨병, 알레르기성 질환, 천식, 아토피성 피부염, 다발성 경화증, 제I형 당뇨병, 베게너 육아종증, 폐 사르코이드증, 베체트병, 운동신경원병(Motor neurone disease), 만성 폐쇄성 폐질환, 암 및 치주염으로 이루어지는 군으로부터 선택되는 질환인 것을 특징으로 하는 RIPK1 관련 질환의 치료방법.Inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, arthritis, gout, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, Osteoarthritis, non-alcoholic steatohepatitis, alcoholic hepatitis, primary sclerosing cholangitis, nephritis, celiac disease, transplant rejection, sepsis, systemic inflammatory response syndrome, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic Dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, motor neurone disease, chronic obstructive pulmonary disease, disease selected from the group consisting of cancer and periodontitis Treatment method of RIPK1-related diseases.
  20. RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 예방 또는 치료에 사용하기 위한, 제 1항 내지 제 13항 중 어느 한 항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염.A compound according to any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of RIPK1 (Receptor-interacting serine/threonine-protein kinase 1) related disease.
  21. 제20항에 있어서,The method of claim 20,
    상기 RIPK1 관련 질환은,The RIPK1-related diseases,
    염증성 장 질환, 크론병, 궤양성 결장염, 건선, 망막 박리, 색소성 망막염, 황반 변성, 췌장염, 아토피성 피부염, 류마티스 관절염, 척추관절염, 통풍, 쇼그렌 증후군, 전신 경피증, 항-인지질 증후군, 혈관염, 골관절염, 비-알콜 지방간염, 알콜 지방간염, 원발성 경화성 담관염, 신염, 복강 질환, 이식 거부, 패혈증, 전신 염증 반응 증후군, 심근경색, 헌팅턴병, 알츠하이머병, 파킨슨병, 알레르기성 질환, 천식, 아토피성 피부염, 다발성 경화증, 제I형 당뇨병, 베게너 육아종증, 폐 사르코이드증, 베체트병, 운동신경원병(Motor neurone disease), 만성 폐쇄성 폐질환, 암 및 치주염으로 이루어지는 군으로부터 선택되는 질환인 것을 특징으로 하는 제 1항 내지 제 13항 중 어느 한 항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염.Inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, arthritis, gout, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, Osteoarthritis, non-alcoholic steatohepatitis, alcoholic hepatitis, primary sclerosing cholangitis, nephritis, celiac disease, transplant rejection, sepsis, systemic inflammatory response syndrome, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic Dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, motor neurone disease, chronic obstructive pulmonary disease, disease selected from the group consisting of cancer and periodontitis A compound according to any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  22. RIPK1(Receptor-interacting serine/threonine-protein kinase 1) 관련 질환의 예방 또는 치료에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 제 1항 내지 제 13항 중 어느 한 항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 용도(use).A compound according to any one of claims 1 to 13, a stereoisomer thereof, 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 Or the use of a pharmaceutically acceptable salt thereof.
  23. 제22항에 있어서,The method of claim 22,
    상기 RIPK1 관련 질환은,The RIPK1-related diseases,
    염증성 장 질환, 크론병, 궤양성 결장염, 건선, 망막 박리, 색소성 망막염, 황반 변성, 췌장염, 아토피성 피부염, 류마티스 관절염, 척추관절염, 통풍, 쇼그렌 증후군, 전신 경피증, 항-인지질 증후군, 혈관염, 골관절염, 비-알콜 지방간염, 알콜 지방간염, 원발성 경화성 담관염, 신염, 복강 질환, 이식 거부, 패혈증, 전신 염증 반응 증후군, 심근경색, 헌팅턴병, 알츠하이머병, 파킨슨병, 알레르기성 질환, 천식, 아토피성 피부염, 다발성 경화증, 제I형 당뇨병, 베게너 육아종증, 폐 사르코이드증, 베체트병, 운동신경원병(Motor neurone disease), 만성 폐쇄성 폐질환, 암 및 치주염으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는, 제 1항 내지 제 13항 중 어느 한 항의 화합물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염의 용도(use).Inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, arthritis, gout, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, Osteoarthritis, non-alcoholic steatohepatitis, alcoholic hepatitis, primary sclerosing cholangitis, nephritis, celiac disease, transplant rejection, sepsis, systemic inflammatory response syndrome, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic Dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, motor neurone disease, chronic obstructive pulmonary disease, characterized by being selected from the group consisting of cancer and periodontitis, Use of the compound of any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113876778A (en) * 2021-11-05 2022-01-04 中日友好医院(中日友好临床医学研究所) Application of KW2449 in preparation of medicine for improving rheumatoid arthritis
WO2023018643A1 (en) * 2021-08-10 2023-02-16 Abbvie Inc. Nicotinamide ripk1 inhibitors
WO2023187471A1 (en) * 2022-03-30 2023-10-05 Voronoi Inc. Heteroaryl derivative compounds, and uses thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022015051A1 (en) * 2020-07-14 2022-01-20 주식회사 보로노이바이오 Aryl or heteroaryl derivative, and pharmaceutical composition comprising same as active ingredient for prevention or treatment of kinase-related disease
WO2023068881A1 (en) * 2021-10-22 2023-04-27 주식회사 보로노이바이오 Aryl or heteroaryl derivative, and pharmaceutical composition comprising same as active ingredient for prevention or treatment of kinase-related diseases

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029117A1 (en) * 1996-12-31 1998-07-09 Guilford Pharmaceuticals Inc. N-linked ureas and carbamates of heterocyclic thioesters
WO2008048589A2 (en) * 2006-10-13 2008-04-24 Xtl Biopharmaceuticals Ltd Compounds and methods for treatment of hcv
US20170305920A1 (en) * 2015-01-13 2017-10-26 Si Chuan University 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
US20180353480A1 (en) * 2015-12-04 2018-12-13 Denali Therapeutics Inc. Isoxazolidine derived inhibitors of receptor interacting protein kinase 1 (ripk1)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998029117A1 (en) * 1996-12-31 1998-07-09 Guilford Pharmaceuticals Inc. N-linked ureas and carbamates of heterocyclic thioesters
WO2008048589A2 (en) * 2006-10-13 2008-04-24 Xtl Biopharmaceuticals Ltd Compounds and methods for treatment of hcv
US20170305920A1 (en) * 2015-01-13 2017-10-26 Si Chuan University 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
US20180353480A1 (en) * 2015-12-04 2018-12-13 Denali Therapeutics Inc. Isoxazolidine derived inhibitors of receptor interacting protein kinase 1 (ripk1)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HARRIS, P. A. ET AL.: "Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. 2013", MED. CHEM. LETT., vol. 4, pages 1238 - 1243, XP055123759, DOI: 10.1021/ml400382p *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023018643A1 (en) * 2021-08-10 2023-02-16 Abbvie Inc. Nicotinamide ripk1 inhibitors
US11767310B2 (en) 2021-08-10 2023-09-26 Abbvie Inc. Nicotinamide RIPK1 inhibitors
JP2023549007A (en) * 2021-08-10 2023-11-22 アッヴィ・インコーポレイテッド Nicotinamide RIPK1 inhibitor
KR20230163568A (en) * 2021-08-10 2023-11-30 애브비 인코포레이티드 Nicotinamide RIPK1 inhibitor
JP7406672B2 (en) 2021-08-10 2023-12-27 アッヴィ・インコーポレイテッド Nicotinamide RIPK1 inhibitor
KR102707109B1 (en) 2021-08-10 2024-09-20 애브비 인코포레이티드 Nicotinamide RIPK1 inhibitor
CN113876778A (en) * 2021-11-05 2022-01-04 中日友好医院(中日友好临床医学研究所) Application of KW2449 in preparation of medicine for improving rheumatoid arthritis
CN113876778B (en) * 2021-11-05 2023-04-14 中日友好医院(中日友好临床医学研究所) Application of KW2449 in preparation of medicine for improving rheumatoid arthritis
WO2023187471A1 (en) * 2022-03-30 2023-10-05 Voronoi Inc. Heteroaryl derivative compounds, and uses thereof

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