[go: up one dir, main page]

WO2025135870A1 - Inhibiteur de tyk2 et son utilisation - Google Patents

Inhibiteur de tyk2 et son utilisation Download PDF

Info

Publication number
WO2025135870A1
WO2025135870A1 PCT/KR2024/020810 KR2024020810W WO2025135870A1 WO 2025135870 A1 WO2025135870 A1 WO 2025135870A1 KR 2024020810 W KR2024020810 W KR 2024020810W WO 2025135870 A1 WO2025135870 A1 WO 2025135870A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
oxo
pyrrolo
pyridin
dihydropyridazin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2024/020810
Other languages
English (en)
Korean (ko)
Inventor
박진영
황인수
정희성
김지원
김봉태
김혜정
박찬우
이근호
태양훈
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HK Inno N Corp
Original Assignee
HK Inno N Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by HK Inno N Corp filed Critical HK Inno N Corp
Publication of WO2025135870A1 publication Critical patent/WO2025135870A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to pyrrolopyridine and pyrrolopyrimidine compounds useful for modulating the activity of tyrosine kinase 2 (TYK2), and a method for preparing the same.
  • the present invention also relates to their use in the treatment of diseases mediated by tyrosine kinase 2, particularly autoimmune diseases, inflammatory diseases and cancer.
  • Tyrosine kinase 2 is a non-receptor tyrosine kinase that constitutes the Janus kinase (JAK) family together with Janus kinases 1, 2, and 3.
  • the JAK family forms dimers in various combinations depending on the cytokine that binds to the receptor domain of the cell membrane, and regulates the activity of immune cells through STAT (Signal Transducer and Activator of Transcription) (Prior Art Documents 1 and 2). That is, JAK family dimers activate STAT, and the activated STAT enters the nucleus and promotes the production of new cytokines, thereby inducing the activity of immune cells.
  • TYK2 is activated particularly by interleukin-12, interleukin-23, and type 1 and type 3 interferons, which are inflammatory cytokines that are the main causes of various autoimmune diseases including psoriasis (Prior Art Document 3). Therefore, TYK2 activation is the cause of various diseases.
  • TYK2-deficient mice support this. For example, in an experiment in which psoriasis was induced by IL-23, TYK2-deficient mice showed a reduced skin inflammatory response (Prior Art Document 4). In addition, TYK2-deficient mice showed resistance in models of colitis and multiple sclerosis (Prior Art Documents 5, 6). These research results suggest the importance of the TYK2 mechanism in autoimmune diseases.
  • TYK2 is known to cause or worsen various autoimmune diseases, including: That is, TYK2 is associated with various types of psoriasis (Plaque Psoriasis, Scalp Psoriasis, Nail Psoriasis, Palmoplantar Pustulosis), Psoriatic arthritis, various forms of lupus (Systemic lupus erythematosus, Discoid Lupus Erythematosus, Subacute Cutaneous Lupus Erythematosus), Lupus nephritis, Ulcerative colitis, Crohn’s disease, Alopecia areata, Ankylosing spondylitis, Multiple sclerosis, Sjogren’s syndrome, Type 1 diabetes, Temporal arteritis, Tendonitis, Dermatomyositis, Polymyositis.
  • the inventors of the present invention completed the present invention by studying a novel compound that can act as a TYK2 inhibitor and proving that it can be usefully used for various autoimmune diseases, inflammatory diseases, or cancer.
  • Tyk2 is a therapeutic target for psoriasis-like skin inflammation.
  • Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis. Journal of Immunology, 183(11), 7539-7546.
  • the purpose of the present invention is to provide a novel compound of the following chemical formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, which can be usefully used for the prevention, improvement, or treatment of TYK2-related diseases.
  • a pharmaceutical composition for preventing, improving or treating a TYK2-related disease which comprises a compound of the above chemical formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a use of the compound for the manufacture of a medicament for preventing, improving or treating a TYK2-related disease.
  • Another object of the present invention is to provide a method for preventing, improving or treating a TYK2-related disease by administering the compound.
  • substituents include, for example, deutero, hydroxy, nitro, amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, lower alkyl, halo lower alkyl, lower alkylamino, halo lower alkylamino, lower alkoxy, halo lower alkoxy, lower alkoxyalkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,
  • the substitution can occur within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, etc.) or at the chain terminus (e.g., 2-hydroxyethyl, 3-cyanopropyl, etc.).
  • the substituted substituent can be a straight chain, branched chain, or cyclic arrangement of covalently bonded carbons or heteroatoms. It is to be understood that the above definition is not intended to encompass impermissible substitution patterns (e.g., a methyl substituted with five fluoro groups, or a halogen atom substituted with another halogen atom). Such impermissible substitution patterns are known to those skilled in the art.
  • halo halogen
  • halide(s) as used herein include fluoro, chloro, bromo, and iodo.
  • alkyl refers to an aliphatic hydrocarbon radical, including both linear and branched hydrocarbon radicals.
  • C 1 -C 6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms and can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
  • alkyl means C 1 - 10 alkyl, preferably C 1 - 6 alkyl, C 1 - 4 alkyl, more preferably C 1 - 3 alkyl.
  • haloalkyl as used herein means an alkyl group substituted with one or more, for example, 1 to 3, 1 to 4, halogen atoms, said alkyl group being defined as above.
  • Halo represents F, Cl, Br or I and the term is used interchangeably with the term “halogen”.
  • haloalkyl means fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl and the like.
  • alkenyl refers to a hydrocarbon radical derived from a saturated alkyl having at least one double bond.
  • the alkenyl can be in the E or Z configuration.
  • alkenyl means C 2-10 alkenyl, preferably C 2-6 alkenyl , C 2-4 alkenyl , more preferably C 2-3 alkenyl.
  • alkynyl refers to a hydrocarbon radical derived from a saturated alkyl having at least one triple bond.
  • alkynyl means C 2-10 alkynyl , preferably C 2-6 alkynyl , C 2-4 alkynyl , more preferably C 2-3 alkynyl .
  • alkoxy refers to an -O-alkyl or alkyl-O- group, wherein the alkyl group is defined as above. For example, it can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy.
  • hydroxy or "hydroxyl”, as used herein, alone or in combination with other terms, means -OH.
  • amino as used herein means -NH 2 .
  • cycloalkyl refers to a cyclic alkyl which may be substituted or unsubstituted, for example, C 3-20 cycloalkyl refers to a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms.
  • the cycloalkyl group can be monocyclic or polycyclic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • the cycloalkyl can be C 3-8 cycloalkyl or C 3-6 cycloalkyl .
  • cycloalkenyl refers to a group which refers to a cyclic alkene derived from a saturated cycloalkyl having one double bond.
  • the cycloalkenyl group can be monocyclic or polycyclic.
  • Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • the cycloalkenyl can be C 3-8 cycloalkenyl or C 3-6 cycloalkenyl .
  • aryl refers to a monovalent aromatic hydrocarbon having, for example, 6 to 20 carbon atoms (C 6 - 20 ), derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring.
  • Aryl may include a bicyclic radical containing an aromatic ring fused to a saturated or partially unsaturated ring.
  • Exemplary aryl groups may include radicals derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, and the like.
  • aryl means C 6 - 12 aryl, preferably C 6 - 10 aryl.
  • heterocycle refers to an aromatic, saturated or partially unsaturated mono-, bi- or poly-ring system containing the indicated number of ring atoms, which includes one or more heteroatoms selected from N, O and S.
  • the ring members, wherein the heterocyclic ring can be connected to the base molecule via ring atoms (which can be C or N).
  • the bicyclic system can be connected by 1,1-fused (spiro), 1,2-fused (fused) or 1,>2-fused (bridgehead).
  • the 1,1-fused (spiro) is but is not limited to oxaspiro[3.3]heptanyl, oxaspiro[3.4]octanyl, azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, and the like.
  • heteroaryl refers to a monovalent or divalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon containing one or more, preferably 1 to 4, 1 to 3 or 1 to 2, heteroatoms selected from N, O and S.
  • heteroaryl examples include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxazole, 3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl, and the like.
  • bicyclic heteroaryls include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, furopyridinyl and similar groups thereof.
  • heteroaryl is a 4-12 membered heteroaryl, preferably a 4-10 membered heteroaryl, more preferably a 4-7 membered heteroaryl.
  • heterocycloalkyl refers to a monocyclic, bicyclic, tricyclic or higher cyclic alkyl having 3 to 10 carbon ring members containing one or more heteroatoms selected from N, O and S, for example 1 to 4, 1 to 3, or 1 to 2.
  • the heterocycle according to the present invention can also be a fused or bridged heterocycloalkyl.
  • heterocycloalkyl examples include azetidinyl, oxetanyl, tetrahydro, tetrahydrofuran, pyrrolidinyl, imidazolinyl, oxazolinyl, oxazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrazolopyridinyl, morpholinyl, indolinyl, azethiomorpholinyl, and the like.
  • heterocycloalkyl refers to a 4 to 12 membered heterocycloalkyl, preferably a 4 to 10 membered heterocycloalkyl, more preferably a 4 to 7 membered heterocycloalkyl.
  • cyclic substituents e.g., cycloalkyl, cycloalkenyl, aryl, heterocycle, heteroaryl, heterocycloalkyl, etc.
  • cycloalkyl, cycloalkenyl, aryl, heterocycle, heteroaryl, heterocycloalkyl, etc. may be unsubstituted or substituted.
  • the compound according to the present invention and its pharmaceutically acceptable salt have TYK2 inhibitory activity with superior cell activity and enzyme selectivity than existing patented compounds compared to conventional TYK2 inhibitors, and thus can be usefully used for the prevention, improvement or treatment of TYK2-related diseases, specifically, autoimmune diseases, inflammatory diseases, cancer or neurodegenerative diseases.
  • the present invention provides a compound represented by the following chemical formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
  • a 1 , A2, A3, A 4 and A 5 are each independently C, CH, CH 2 or N;
  • R 2 is H, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 8 cycloalkyl, 4-membered-12-membered heterocycloalkyl, OR' or NR'R", wherein said C 1 -C 10 alkyl, C 1 -C 10 alkoxy or 4-membered-12-membered heterocycloalkyl may be unsubstituted or substituted with 1 or more, preferably 1 to 4, substituents selected from the group consisting of halo, cyano, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkoxyC 1 -C 10 alkyl, 4-membered-12-membered heterocycloalkyl, C 6 -C 10 aryl and C 3 -C 8 cycloalkyl,
  • R' and R" are each independently H, C 1 -C 10 alkyl, and at this time, the C 1 -C 10 alkyl may be unsubstituted or substituted with 1 or more, preferably 1 to 4, substituents selected from the group consisting of halo, cyano, 4-12 membered heterocycloalkyl, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl and C 1 -C 10 alkoxy, or
  • R' and R may be taken together with N in said NR'R” to form a 4- to 12-membered heterocycloalkyl, wherein the 4- to 12-membered heterocycloalkyl may be unsubstituted or substituted with halo, C 1 -C 10 alkoxy, or C 1 -C 10 alkoxyC 1 -C 10 alkyl;
  • R 4 is C 1 -C 10 alkyl, C 1 -C 10 deuteroalkyl, or amino, wherein the C 1 -C 10 alkyl, C 1 -C 10 deuteroalkyl, or amino may be unsubstituted or substituted with one or more, preferably 1 to 4, substituents selected from the group consisting of hydroxy and C 1 -C 10 alkyl;
  • R can be H, halo, C 1 -C 10 alkyl, C 1 -C 10 deuteroalkyl, C 1 -C 10 haloalkyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 arylC 1 -C 10 alkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkylC 1 -C 10 alkyl, 4-12 membered heteroaryl or 4-12 membered heteroarylC 1 -C 10 alkyl.
  • R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or a 4- to 10-membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or a 4- to 10-membered heterocycloalkyl may be unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of oxo, fluoro, chloro, bromo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkyl.
  • the C 3 -C 6 cycloalkyl of R 1 can be cyclobutyl, cyclopentyl or cyclohexyl, and the 4- to 10-membered heterocycloalkyl can be oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.
  • the C 1 -C 6 alkyl of R 1 can be methyl, ethyl, propyl, isopropyl, butyl, t-butyl.
  • the C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 3 -C 8 cycloalkyl, or 4- to 12-membered heterocycloalkyl of R 1 may be unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, fluoro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, and methoxy.
  • R 1 may be selected from the following groups:
  • R 2 is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 4-10 membered heterocycloalkyl, OR' or NR'R", wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy or 4-10 membered heterocycloalkyl may be unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of fluoro, chloro, bromo, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl and C 3 -C 6 cycloalkyl,
  • R' and R” are each independently H, C 1 -C 6 alkyl, and at this time, the C 1 -C 6 alkyl may be unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of fluoro, chloro, bromo, cyano, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy.
  • R' and R may be taken together with N in said NR'R” to form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl may be unsubstituted or substituted with fluoro, chloro, bromo, C 1 -C 6 alkoxy, or C 1 -C 6 alkoxyC 1 -C 6 alkyl.
  • R 2 may be selected from the following groups:
  • R 3 may be selected from the following groups:
  • R 4 is C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or amino, wherein the C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, or amino may be unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of hydroxy and C 1 -C 6 alkyl.
  • R 4 is CH 3 , CD 3 , CH 2 OH, NH 2 , or NHCH 3 .
  • R can be H, halo, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 arylC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylC 1 -C 6 alkyl, 4-10 membered heteroaryl or 4-10 membered heteroarylC 1 -C 6 alkyl.
  • the heterocycloalkyl or heteroaryl may contain 1 or more, preferably 1 to 4, more preferably 1 to 3 heteroatoms.
  • the heteroatoms may be selected from the group consisting of N, O and S.
  • the compounds of chemical formula 1 according to the present invention may be one or more selected from the group consisting of compounds 1 to 117 below, but are not limited thereto.
  • Compound 8 N-(1-(3-cyanocyclobutyl)-3-(5-cyclopropyl-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 36 N-(1-cyclobutyl-3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 37 1-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea,
  • Compound 40 N-(3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 48 N-(1-methyl-3-(1-(1-methylcyclobutyl)-5-(oxetan-3-ylmethoxy)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 53 N-(1-Cyclopropyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 64 (S)-N-(1-Cyclopropyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 65 N-(1-Cyclopropyl-3-(5-((R)-2-methoxypropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 70 (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 72 (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3,
  • Compound 80 (S)-N-(1-(cyclopropylmethyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 90 (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-((3-methyloxetan-3-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 100 N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3-fluorocyclobut-2-en-1-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • Compound 110 (S)-N-(1-Cyclopropyl-3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,
  • the chemical formulas or names given in the specification and claims encompass tautomers and all stereo, optical and geometrical isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or mixtures of any of the foregoing in which both isomers and enantiomers exist, and pharmaceutically acceptable salts thereof and salts thereof, including solvates and hydrates of the free compounds or hydrates including solvates and hydrates of salts of the compounds.
  • the compound of the present invention may exist in the form of a pharmaceutically acceptable salt.
  • the salt is useful as an acid addition salt formed by a pharmaceutically acceptable free acid.
  • pharmaceutically acceptable salt of the present invention means any organic or inorganic addition salt of the compound, which has a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and the side effects due to the salt do not reduce the beneficial effects of the compound according to the present invention.
  • Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone or acetonitrile.
  • a water-miscible organic solvent for example, methanol, ethanol, acetone or acetonitrile.
  • Equimolar amounts of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water can be heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered off with suction.
  • organic acids and inorganic acids can be used as the free acid, and inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid can be used, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid can be used, but are not limited thereto.
  • inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid
  • organic acids such as methanes
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • An alkali metal salt or an alkaline earth metal salt is obtained, for example, by dissolving a compound in an excess of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and then evaporating and drying the filtrate.
  • sodium, potassium, or calcium salts are particularly suitable for preparing the metal salt, but are not limited thereto.
  • a corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).
  • Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups which may be present in the compounds described in Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups
  • other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like, and can be prepared by methods for preparing salts known in the art.
  • the pharmaceutically acceptable salt of the compounds of the present invention may be hydrochloride.
  • any salt of the compound described in the chemical formula 1 that is pharmaceutically acceptable and exhibits pharmacological activity equivalent to that of the compound described in the chemical formula 1 may be used without limitation.
  • the compound described in the above formula 1 according to the present invention includes, without limitation, pharmaceutically acceptable salts thereof, as well as solvates such as possible hydrates which can be prepared therefrom, and all possible stereoisomers.
  • All stereoisomers of the present invention including enantiomeric forms and diastereomeric forms (e.g., those which can exist due to the asymmetric carbons in various substituents), are included in the scope of the present invention.
  • the individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers having a specific activity), or may be, for example, racemates or mixed with all other or other selected stereoisomers.
  • the chiral center of the compounds of the present invention may have the S or R configuration as defined by the IUPAC 1974 recommendation.
  • the racemic forms may be analyzed by physical methods such as separation by chiral column chromatography or separation or crystallization of diastereomeric derivatives, fractional shape crystallization.
  • Individual optical isomers can be obtained from the racemate by any suitable method including, but not limited to, salt formation with an optically active acid followed by crystallization.
  • Solvates and stereoisomers of the compound of formula 1 can be prepared from the compound using methods known in the art.
  • the compound of formula 1 according to the present invention can be prepared in a crystalline or amorphous form, and when prepared in a crystalline form, can be optionally hydrated or solvated.
  • the present invention may include not only stoichiometric hydrates of the compound described in formula 1, but also compounds containing various amounts of water.
  • the solvates of the compound of formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.
  • the activity of TYK2 JH2, JAK1 JH1, JAK2 JH1, JAK3 JH1, and TYK2 JH1 enzymes was evaluated for the compound represented by the chemical formula 1 according to the present invention, and excellent activity and selectivity were confirmed.
  • excellent activity of IC 50 ⁇ 50 nM was exhibited in TYK2/JAK1 cell activity.
  • the compound according to the present invention and its pharmaceutically acceptable salt can be usefully used for the prevention, improvement or treatment of TYK2-related diseases, specifically, autoimmune diseases, inflammatory diseases or cancer.
  • the present invention relates to a method for producing the novel compound.
  • the compounds of the present invention can be prepared from commercially available starting materials using the general methods illustrated herein.
  • Schemes 1-5 depicted below provide routes for synthesizing compounds of formula 1 as well as key intermediates. For more detailed descriptions of individual reaction steps, see the Examples section below. Those skilled in the art will recognize that other synthetic routes are available and can be used.
  • specific starting materials and reagents are depicted in the schemes and described below, other starting materials and reagents can be substituted to provide a variety of derivatives and/or reaction conditions.
  • many of the compounds prepared by the methods described below can be further modified in light of the present disclosure using conventional chemistries known to those skilled in the art.
  • the manufacturing method is:
  • It includes a first step of producing a compound represented by the chemical formula 1 by borylating a compound represented by the chemical formula 3 below and then performing a Suzuki reaction or Ullmann reaction with a compound corresponding to the chemical formula 2.
  • the compound represented by the chemical formula 3 was dissolved in 1,4-dioxane, and then bis(pinacolato)diboron, potassium acetate, Pd(dba) 2 , and 0.6 M PCy 3 in toluene were added as reaction reagents. Toluene) is used. Stir at 90 ⁇ 110°C for 1 hour to overnight, then filter. Dissolve the reactant and the compound represented by chemical formula 2 in 1,4-dioxane and water, and use Pd(dppf) 2 Cl 2 . DCM and K 3 PO 4 as reaction reagents. Stir at 70 ⁇ 80°C for 1 hour to overnight, then prepare chemical formula 1.
  • a 1 , A 2 , A 3 , A 4 , A 5 , R 1 , R 2 , R 3 , R 4 , R 5 and the dotted line are as defined in the chemical formula 1 above,
  • X is halo, preferably fluoro, chloro, bromo or iodo.
  • the above manufacturing method can be represented by the following reaction scheme 1.
  • a 1 , A 2 , A 3 , A 4 , A 5 , R 1 , R 2 , R 3 , R 4 , R 5 and the dotted line are as defined in the chemical formula 1 above,
  • X is halo, preferably fluoro, chloro, bromo or iodo.
  • the compound of the above chemical formula 2 can be prepared by a preparation method comprising the following steps:
  • a second step of producing a compound represented by the following chemical formula 5 by reacting a compound represented by the following chemical formula 4 with NBS or NIS;
  • a third step of producing a compound represented by the following chemical formula 6 by subjecting a compound represented by the following chemical formula 5 to an SN 2 reaction or a Chan-Lam reaction;
  • a fourth step of producing a compound represented by the chemical formula 2 by deacetylating the compound represented by the chemical formula 6 below with an acid, for example, hydrochloric acid, and then reacting it with isocyanate or acetyl chloride.
  • an acid for example, hydrochloric acid
  • the compound represented by the chemical formula 4 is dissolved in an appropriate solvent, for example, N,N-dimethylformamide, and then NBS or NIS as a halogen donor is added dropwise and stirred at room temperature overnight.
  • an appropriate solvent for example, N,N-dimethylformamide
  • the compound represented by the chemical formula 5 is dissolved in acetonitrile or N,N-dimethylformamide, and then cesium carbonate is used as a base and dimethyl sulfate or a halogenated alkyl or mesyl alcohol is used as a reaction reagent.
  • the chemical formula 6 is prepared by stirring at room temperature or 80°C overnight.
  • Mesyl alcohol is prepared by dissolving the alcohol corresponding to R 3 in dimethyl chloride, then adding triethylamine and methanesulfonyl chloride dropwise at 0°C, and stirring at room temperature for 2 to 4 hours.
  • R 3 B(OH) 2 , 2,2'-bipyridyl, anhydrous copper (II) acetate, and sodium carbonate are used as reaction reagents for the Chan-Lam reaction, and N,N-dimethylformamide is used as a solvent.
  • the chemical formula 6 is prepared by stirring at 70°C overnight.
  • the compound represented by the chemical formula 6 is dissolved in methanol, 4N HCl in 1,4-dioxane is added dropwise, and the mixture is stirred at 80°C for 5 hours.
  • the reactant is concentrated and dissolved in dimethyl chloride, and N,N-diisopropylethylamine and 2,2,2-trichloroacetyl isocyanate are added dropwise at 0°C.
  • the mixture is stirred at room temperature for 30 minutes and concentrated.
  • the reactant is dissolved in methanol, and a saturated sodium bicarbonate aqueous solution is added dropwise. The mixture is stirred at room temperature for 1 to 4 hours to produce chemical formula 2.
  • the above manufacturing method can be represented by the following reaction scheme 2.
  • a 2 , A 3 , A 4 , A 5 , R 3 , R 4 and the dotted line are as defined in the chemical formula 1 above,
  • X is halo, preferably fluoro, chloro, bromo or iodo.
  • the compound of formula 3 wherein R 5 is H and R 2 is 4-12 membered heterocycloalkyl, OR' or NR'R" can be prepared by a preparation method comprising the following steps:
  • a disilicide compound NaHMDS
  • an alcohol compound corresponding to R 2 such as HOR'
  • an amine compound corresponding to R 2 such as HNR'R
  • the compound represented by the chemical formula 7 is dissolved in N,N-dimethylformamide, and then cesium carbonate and an alkyl halide are added dropwise. The mixture is stirred at room temperature overnight to prepare the chemical formula 8.
  • the compound represented by the chemical formula 7 is dissolved in tetrahydrofuran, and then R 1 OH, PhOPPh 2 or PPh 3 , and DIAD or DEAD are added dropwise, and then stirred at room temperature overnight to prepare the chemical formula 8.
  • step 6 can be performed by dissolving a compound represented by chemical formula 8 in 1,4-dioxane or tetrahydrofuran, and then adding dropwise 2N NaHMDS in tetrahydrofuran and an alcohol (HOR') or amine (HNR'R”) corresponding to R 2. Stirring is performed at room temperature or 50° C. for 1 to 4 hours to prepare chemical formula 3.
  • a method for preparing a compound of the above chemical formula 3, wherein R 5 is H and R 2 is 4-12 membered heterocycloalkyl, OR' or NR'R" can be represented by the following reaction scheme 3.
  • a 1 , R 1 and R 2 are as defined in the chemical formula 1 above,
  • X is halo, preferably fluoro, chloro, bromo or iodo.
  • the compound of formula 3, wherein R 5 is H and R 2 is H, C 1 -C 10 alkyl, C 1 -C 10 alkoxy or C 3 -C 8 cycloalkyl can be prepared by a preparation method comprising the following steps:
  • the compound represented by the chemical formula 9 is dissolved in N,N-dimethylformamide, and then cesium carbonate and an alkyl halide are added dropwise. The mixture is stirred at room temperature overnight to produce the chemical formula 8.
  • the compound represented by the chemical formula 9 is dissolved in tetrahydrofuran, and then R 1 OH, PhOPPh 2 or PPh 3 , and DIAD or DEAD are added dropwise, and then stirred at room temperature overnight to produce the chemical formula 8.
  • a method for preparing a compound of the above formula 3, wherein R 5 is H and R 2 is H, C 1 -C 10 alkyl, C 1 -C 10 alkoxy or C 3 -C 8 cycloalkyl can be represented by the following reaction scheme 4.
  • a 1 , R 1 and R 2 are as defined in the chemical formula 1 above,
  • X is halo, preferably fluoro, chloro, bromo or iodo.
  • the compound of the above chemical formula 1 can also be prepared by a preparation method comprising the following steps:
  • a first step of producing a compound represented by chemical formula 10 by subjecting a compound represented by chemical formula 3 to a Suzuki reaction or an Ulmann reaction with a compound corresponding to chemical formula 6, which is a borylated compound;
  • an acid for example, hydrochloric acid
  • the compound represented by the chemical formula 3 was dissolved in 1,4-dioxane, and then bis(pinacolato)diboron, potassium acetate, Pd(dba) 2 , and 0.6 M PCy 3 in toluene were added as reaction reagents. Toluene) is used. Stir at 90 ⁇ 110°C for 1 hour to overnight, then filter. Dissolve the reactant and the compound represented by chemical formula 6 in 1,4-dioxane and water, and use Pd(dppf) 2 Cl 2 . DCM and K 3 PO 4 as reaction reagents. Stir at 70 ⁇ 80°C for 1 hour to overnight, then prepare chemical formula 10.
  • the compound represented by the chemical formula 10 synthesized in the '1st step' is dissolved in methanol, 4N HCl in 1,4-dioxane is added dropwise, and the mixture is stirred at 80°C for 5 hours.
  • the reactant is concentrated, dissolved in dimethyl chloride, and acetoxyacetyl chloride and pyridine are added dropwise.
  • the mixture is stirred at room temperature for 3 hours and concentrated.
  • the reactant is dissolved in methanol, and potassium carbonate is added dropwise. The mixture is stirred at room temperature for 15 minutes to produce chemical formula 1.
  • the deacetylated reactant is concentrated, dissolved in tetrahydrofuran, and triphosgene is added dropwise at 0°C and stirred for 1 hour. Methylamine is added dropwise to the reactant at room temperature and stirred to produce chemical formula 1.
  • the above manufacturing method can be represented by the following reaction scheme 5.
  • a 1 , A 2 , A 3 , A 4 , A 5 , R 1 , R 2 , R 3 , R 4 , R 5 and the dotted line are as defined in the chemical formula 1 above,
  • X is halo, preferably fluoro, chloro, bromo or iodo.
  • the compounds of the present invention may be suitable for preventing, improving or treating various diseases caused by TYK2 activity due to their biological properties.
  • the present invention relates to a pharmaceutical composition for preventing, improving or treating various diseases related to TYK2, comprising a compound of the above chemical formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a disease associated with TYK2 may include any disease, disorder or condition that is directly or indirectly linked to the expression or activity of TYK2, including overexpression and/or abnormal activity levels.
  • the abnormal activity level may be determined by comparing the activity level in a normal healthy tissue or cell with the activity level in a diseased cell.
  • a disease mediated by TYK2 may also include any disease, disorder or condition that can be prevented, ameliorated, inhibited or cured by modulating TYK2 activity.
  • Diseases mediated by TYK2 that can be treated using the compound of the present invention may be autoimmune diseases, inflammatory diseases, cancer, or neurodegenerative diseases.
  • parenteral administration is preferred as the administration methods of the pharmaceutical composition.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • composition comprising the compound of chemical formula 1 of the present invention or a salt thereof can be formulated and used in the form of oral formulations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, liquid solutions, emulsions, syrups, external preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods.
  • the pharmaceutical composition according to the present invention may be in the form of a sterile injectable preparation as a sterile aqueous or oily suspension for injection.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic, parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Acceptable vehicles and solvents include mannitol, water, Ringer's solution, or isotonic sodium chloride solution.
  • a sterile fixed oil is typically used as a solvent or suspending medium.
  • any fixed oil having little irritation including synthetic mono- or diglycerides, may be used.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in injectable preparations, as are pharmaceutically acceptable natural oils (e.g., olive oil or castor oil), especially their polyoxyethylated forms.
  • composition according to the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions.
  • compositions of the present invention may also be administered in the form of suppositories for rectal administration.
  • These compositions may be prepared by mixing the compounds of the present invention with suitable non-irritating excipients that are solid at room temperature but liquid at the rectal temperature.
  • suitable non-irritating excipients include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.
  • Oral administration of the pharmaceutical composition according to the present invention is particularly useful when the desired treatment involves a site or organ easily accessible by topical application.
  • the pharmaceutical composition When applied topically to the skin, the pharmaceutical composition should be formulated as a suitable ointment containing the active ingredient suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water.
  • the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical composition of the present invention may also be applied topically to the lower intestinal tract by rectal suppositories and as a suitable enema. Topically applied transdermal patches are also encompassed by the present invention.
  • compositions of the present invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well known in the art of pharmacy and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other solubilizing or dispersing agents known in the art.
  • the novel compound described above is contained in the pharmaceutical composition of the present invention in a therapeutically effective amount or a prophylactically effective amount.
  • the preferred dosage of the compound according to the present invention varies depending on the patient's condition and weight, the degree of the disease, the drug form, the administration route and period, but can be appropriately selected by those skilled in the art.
  • the compound of chemical formula 1 of the present invention can be administered once or several times a day in an amount of 0.0001 to 1000 mg/kg, preferably 0.01 to 500 mg/kg.
  • the compound of chemical formula 1 may be blended in an amount of 0.0001 to 50 wt% based on the total weight of the entire composition.
  • the present invention relates to a method for preventing, improving or treating various diseases caused by the activity of TYK2, comprising a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compound of chemical formula 1 of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not causing side effects, and the effective dosage level can be determined according to factors including the patient's health condition, the type and severity of the disease, the activity of the drug, the sensitivity to the drug, the administration method, the administration time, the administration route and the excretion rate, the treatment period, the drug used in combination or simultaneously, and other factors well known in the medical field.
  • composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects by considering all of the above factors, and this can be easily determined by those skilled in the art.
  • the dosage may increase or decrease depending on the route of administration, severity of disease, gender, weight, age, etc., and thus the dosage does not limit the scope of the present invention in any way.
  • the preferred dosage of the compound of the present invention varies depending on the patient's condition and weight, the degree of disease, the form of the drug, the route and period of administration, but can be appropriately selected by those skilled in the art.
  • the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them may be used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents).
  • Combination therapy may, for example, combine two therapies, or may combine three therapies (e.g., triple therapy with three therapeutic agents) or more.
  • the dosage of one or more of the additional therapies e.g., non-pharmacological or therapeutic agents
  • the compounds of the present invention, the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, may be administered before, after, or simultaneously with one or more such additional therapies.
  • the compound of formula 1 may be combined with an additional therapeutic compound having anti-inflammatory or anti-hyperproliferative properties, or useful in the treatment of an autoimmune disease, an inflammatory disease, or a cancer.
  • the additional therapeutic agent may be an NSAID or other anti-inflammatory agent.
  • the additional therapeutic agent may be a chemotherapeutic agent.
  • the compounds of the invention are administered with any anti-IBD agent, including but not limited to an anti-inflammatory drug, such as sulfasalazine, mesalamine, or a corticosteroid, such as budesonide, prednisone, cortisone, or hydrocortisone, an immunosuppressant, such as azathioprine, mercaptopurine, infliximab, adalimumab, certolizumab pegol, methotrexate, cyclosporine, or natalizumab, an antibiotic, such as metronidazole or ciprofloxacin, an antidiarrheal agent, such as psyllium powder, loperamide or methylcellulose, lazatib, an analgesic, such as an NSAID or acetaminophen, iron supplements, vitamin B supplements, vitamin D supplements, and any combination of the foregoing.
  • an anti-inflammatory drug such as sulfas
  • the compounds of the invention are coadministered with any antipsoriatic agent, including but not limited to topical corticosteroids, vitamin D analogues such as calcipotriene or calcitriol, anthralin, topical retinoids such as tazarotene, calcineurin inhibitors such as tacrolimus or pimecrolinus, salicylic acid, coal tar, NSAIDs, moisturizing creams and ointments, oral or injectable retinoids such as acitretin, methotrexate, cyclosporine, hydroxyurea, immunomodulatory drugs such as alefacept, etanercept, infliximab or ustekinumab, thioguanine, and any combination of the foregoing.
  • any antipsoriatic agent including but not limited to topical corticosteroids, vitamin D analogues such as calcipotriene or calcitriol, anthralin, topical retin
  • the compounds of the invention can be administered together with other antipsoriatic treatments, such as phototherapy, sunlight therapy, UVB therapy, narrow-band UVB therapy, Goeckerman therapy, photochemotherapy, such as psoralen plus ultraviolet A (PUVA), excimer and pulsed dye laser therapy, or any combination (e.g., before, during or after) of antipsoriatic agents and antipsoriatic treatments.
  • other antipsoriatic treatments such as phototherapy, sunlight therapy, UVB therapy, narrow-band UVB therapy, Goeckerman therapy, photochemotherapy, such as psoralen plus ultraviolet A (PUVA), excimer and pulsed dye laser therapy, or any combination (e.g., before, during or after) of antipsoriatic agents and antipsoriatic treatments.
  • PUVA psoralen plus ultraviolet A
  • the compounds of the invention are coadministered with any antiasthmatic agent, including but not limited to ⁇ 2-adrenergic agonists, inhaled and oral corticosteroids, leukotriene receptor antagonists, and omalizumab.
  • the compounds of the invention can be coadministered with an antiasthmatic agent selected from a combination of an NSAID, fluticasone and salmeterol, a combination of budesonide and formoterol, omalizumab, lebrikizumab, and a corticosteroid selected from fluticasone, budesonide, mometasone, flunisolide, and beclomethasone.
  • the manufacturing examples below are examples of compounds represented by the chemical formula 1 of the above reaction scheme 1, and can be appropriately changed according to the structure of the example to be prepared.
  • N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (10 g, 54.23 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and then NBS (12.19 g, 81.34 mmol) was added dropwise. The mixture was stirred at room temperature until the reaction was complete, and then 100 mL of water and 100 mL of ethyl acetate were added dropwise. The organic layer, extracted with 200 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained compound was proceeded to the next reaction without any purification step.
  • the title compound was prepared using the same method as in step 2 of Manufacturing Example 1.
  • N-(3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide (2500 mg, 9.32 mmol) was dissolved in 10 mL of methanol, and 4N HCl (11 mL, 46.6 mmol) was added dropwise. After reaction at 80°C for 1 hour, the mixture was concentrated under reduced pressure. The reaction mixture was dissolved in 10 mL of dimethyl chloride, and 4.61 mL of N,N-diisopropylethylamine and 2.78 mL of 2,2,2-trichloroacetyl isocyanate were slowly added dropwise at 0°C. The mixture was stirred at room temperature until the reaction was complete, and the reaction mixture was concentrated under reduced pressure.
  • the reaction mixture was dissolved in 10 mL of methanol, and 10 mL of a saturated aqueous sodium bicarbonate solution was added dropwise, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was filtered and dried to obtain the target compound. (2200 mg, 88%)
  • 6-(6-chloro-3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one 10 mg (0.029 mmol), acetamide 3.5 mg (0.058 mmol), Brettphos Pd(II) G3 2.7 mg (0.0029 mmol), cesium carbonate 28 mg (0.087 mmol) were dissolved in 2 mL of tert -butanol and stirred at 130°C for 3 hours. After lowering the temperature to room temperature, celite was used for filtration. The target compound was obtained by separation using Prep-HPLC. (1.5 mg, 14%)
  • N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (5 g, 28.54 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NIS (7.7 g, 34.25 mmol) was added dropwise. The mixture was stirred at room temperature until the reaction was complete, and then 100 mL of water and 100 mL of ethyl acetate were added dropwise. The organic layer, extracted with 200 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained compound was proceeded to the next reaction without purification.
  • 3-Hydroxycyclobutanecarbonitrile 631 mg (6.50 mmol) was dissolved in 7 mL of dimethyl chloride, and then 1.09 mL (7.80 mmol) of triethylamine and 0.550 mL (7.15 mmol) of methanesulfonyl chloride were slowly added dropwise at -10°C. After stirring for 4 hours at 0°C, 20 mL of water and 20 mL of ethyl acetate were added dropwise, and the mixture was washed with a saturated aqueous sodium bicarbonate solution. The organic layer, extracted with 200 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • 3-Methoxyazetidine hydrochloride (97 mg (0.79 mmol)) was dissolved in 1 mL of 1,4-dioxane, N,N-diisopropylethylamine (0.22 mL (1.31 mmol)) was added dropwise, and the mixture was stirred at room temperature for 15 minutes.
  • 4-bromo-6-chloro-2-(2,2,2-trifluoro-1-methyl-ethyl)pyridazin-3-one 200 mg (0.65 mmol)
  • 2 M NaHMDS (0.42 mL (0.85 mmol
  • Step 3 Preparation of N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Step 2 Preparation of 4-(2,2-difluoroethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]pyridazin-3-one
  • N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide 50 mg (0.20 mmol), 4-(2,2-difluoroethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]pyridazin-3-one 94 mg (0.24 mmol), Pd(dppf) 2 Cl 2 .
  • Step 2 Preparation of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetamide
  • Step 2 Preparation of (S)-1-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea
  • Example 58 Synthesis of (S)-N-(1-cyclopropyl-3-(6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 62 Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 65 Synthesis of N-(1-cyclopropyl-3-(5-((R)-2-methoxypropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 72 Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3
  • Example 76 Synthesis of (S)-N-(1-ethyl-3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 77 Synthesis of (S)-N-(1-cyclopropyl-3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 78 Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 80 Synthesis of (S)-N-(1-(cyclopropylmethyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 81 Synthesis of (S)-N-(1-((3,3-difluorocyclobutyl)methyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 82 Synthesis of (S)-N-(1-(2-fluoro-2-methylpropyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2 -yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 83 Synthesis of (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-methylallyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 84 Synthesis of (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 88 Synthesis of (S)-N-(1-(3-cyanopropyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne : un composé représenté par la formule chimique 1 selon la présente invention, un isomère optique, un stéréoisomère, un solvate, un tautomère ou un sel pharmaceutiquement acceptable de celui-ci ; et une composition pharmaceutique le comprenant. Le composé ou le sel pharmaceutiquement acceptable de celui-ci selon la présente invention peut être efficacement utilisé pour prévenir, soulager ou traiter des maladies associées à TYK2.
PCT/KR2024/020810 2023-12-20 2024-12-20 Inhibiteur de tyk2 et son utilisation Pending WO2025135870A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2023-0187651 2023-12-20
KR20230187651 2023-12-20

Publications (1)

Publication Number Publication Date
WO2025135870A1 true WO2025135870A1 (fr) 2025-06-26

Family

ID=96137567

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2024/020810 Pending WO2025135870A1 (fr) 2023-12-20 2024-12-20 Inhibiteur de tyk2 et son utilisation

Country Status (2)

Country Link
KR (1) KR20250096635A (fr)
WO (1) WO2025135870A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080109841A (ko) * 2006-03-10 2008-12-17 뉴로젠 코포레이션 피페라지닐 옥소알킬 테트라히드로이소퀴놀린 및 관련유사체
KR20150028999A (ko) * 2012-06-27 2015-03-17 에프. 호프만-라 로슈 아게 5-아자인다졸 화합물 및 이의 사용 방법
WO2022204235A1 (fr) * 2021-03-23 2022-09-29 Nido Biosciences, Inc. Composés bicycliques en tant que modulateurs du récepteur des androgènes
WO2022242697A1 (fr) * 2021-05-19 2022-11-24 南京药石科技股份有限公司 Inhibiteur sélectif de tyk2 et son utilisation
WO2023220046A1 (fr) * 2022-05-10 2023-11-16 Biogen Ma Inc. Inhibiteurs de tyk2

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080109841A (ko) * 2006-03-10 2008-12-17 뉴로젠 코포레이션 피페라지닐 옥소알킬 테트라히드로이소퀴놀린 및 관련유사체
KR20150028999A (ko) * 2012-06-27 2015-03-17 에프. 호프만-라 로슈 아게 5-아자인다졸 화합물 및 이의 사용 방법
WO2022204235A1 (fr) * 2021-03-23 2022-09-29 Nido Biosciences, Inc. Composés bicycliques en tant que modulateurs du récepteur des androgènes
WO2022242697A1 (fr) * 2021-05-19 2022-11-24 南京药石科技股份有限公司 Inhibiteur sélectif de tyk2 et son utilisation
WO2023220046A1 (fr) * 2022-05-10 2023-11-16 Biogen Ma Inc. Inhibiteurs de tyk2

Also Published As

Publication number Publication date
KR20250096635A (ko) 2025-06-27

Similar Documents

Publication Publication Date Title
WO2018208132A1 (fr) Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif
WO2022139304A1 (fr) Nouveau composé dérivé de quinazoline en tant qu'inhibiteur de sos1, et son utilisation
WO2020149723A1 (fr) Dérivé de pyrrolopyrimidine et composition pharmaceutique pour la prévention ou le traitement d'une maladie liée à la protéine kinase le comprenant en tant que principe actif
EP3166945A2 (fr) Nouveaux dérivés triazolopyrimidinone ou triazolopyridinone et leur utilisation
WO2018004258A1 (fr) Nouveau dérivé hétérocyclique et son utilisation
WO2016006974A2 (fr) Nouveaux dérivés triazolopyrimidinone ou triazolopyridinone et leur utilisation
WO2016006975A2 (fr) Nouveaux dérivés imidazotriazinone ou imidazopyrazinone et leur utilisation
WO2023080732A1 (fr) Composé ayant une activité de dégradation de la protéine btk, et utilisations médicales associées
WO2020060112A1 (fr) Nouveaux dérivés de thiazole et sels pharmaceutiquement acceptables de ceux-ci
WO2020262998A1 (fr) Nouveau dérivé de quinazoline ayant une activité antitumorale et composition pharmaceutique le comprenant
EP4658662A1 (fr) Composés d'aminopyridine macrocycliques en tant qu'inhibiteurs d'egfr
WO2025135870A1 (fr) Inhibiteur de tyk2 et son utilisation
WO2023195773A1 (fr) Dérivé hétéroaryle et son utilisation
WO2022270881A1 (fr) Nouveau composé en tant qu'inhibiteur de protéine kinase
WO2022114812A1 (fr) Composé hétérocyclique en tant qu'inhibiteur de la diacylglycérol kinase et son utilisation
WO2022211573A1 (fr) Dérivé de pyrimidine ayant une activité inhibitrice de protéine kinase, et composition pharmaceutique thérapeutique le comprenant
WO2021201576A1 (fr) Composé dérivé de benzothiazole
WO2021112626A1 (fr) Nouveau dérivé d'indirubine et son utilisation
WO2020060268A1 (fr) Nouveau dérivé de sulfonamide présentant un squelette de pyrimidine fusionné, ayant un effet inhibiteur de mutation du récepteur du facteur de croissance épidermique
WO2024205311A1 (fr) Dérivés de composés sultam substitués et leur utilisation pharmaceutique
WO2023027515A1 (fr) Composés aminopyridine substitués en tant qu'inhibiteurs d'egfr
WO2025037870A1 (fr) Composé benzofurane et composition pharmaceutique le comprenant pour prévenir ou traiter des maladies cancéreuses et des métastases cancéreuses
WO2022169248A1 (fr) Nouveau composé utilisé comme inhibiteur de protéine kinase
WO2024181803A1 (fr) Dérivé hétéroaryle et son utilisation
WO2023244059A1 (fr) Méthodes de traitement du cancer utilisant un composé double inhibiteur du récepteur des androgènes et de la pde5

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24908152

Country of ref document: EP

Kind code of ref document: A1