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WO2024125464A1 - Dérivés de tétrahydroisoquinoléinone, leurs procédés de préparation et leurs utilisations médicinales - Google Patents

Dérivés de tétrahydroisoquinoléinone, leurs procédés de préparation et leurs utilisations médicinales Download PDF

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Publication number
WO2024125464A1
WO2024125464A1 PCT/CN2023/137983 CN2023137983W WO2024125464A1 WO 2024125464 A1 WO2024125464 A1 WO 2024125464A1 CN 2023137983 W CN2023137983 W CN 2023137983W WO 2024125464 A1 WO2024125464 A1 WO 2024125464A1
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alkyl
cyano
nitro
alkynyl
alkenyl
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Inventor
Jason Rohde
Jianhua TIAN
Allen CHAO
Hugh Y. Zhu
Wei Zhou
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Hansoh Bio LLC
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Hansoh Bio LLC
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Priority to CN202380085173.5A priority Critical patent/CN120418250A/zh
Publication of WO2024125464A1 publication Critical patent/WO2024125464A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P37/02—Immunomodulators
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • 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
    • C07D471/10—Spiro-condensed systems
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and relates to piperidin-ones derivatives, preparation methods thereof, pharmaceutical compositions comprising the compounds, and medical uses thereof.
  • MK2 Mitogen-activiated protein kinase-activated protein kinase 2
  • TNFa tumor necrosis factor alpha
  • IFNg interleukin 6
  • IFNg interferon gamma
  • MK2 resides in the nucleus of non-stimulated cells and upon stimulation, it translocates to the cytoplasm and phosphorylates and activates tuberin and HSP27. MK2 is also implicated in heart failure, brain ischemic injury, the regulation of stress resistance and the production of TNF-quadrature.
  • X 1 , X 2 , X 3 and X 4 a re each independently selected from bond, CH, N, O or S;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently selected from bond, CH, N, O or S;
  • M 1 , M 2 , M 3 , M 4 , M 5 and M 6 are each independently selected from bond, CH, N, O or S;
  • L is bond, NH, O, S, alkyl, alkoxy, alkyl-N-or -CONH-;
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxyalkyl, cyano-alkyl, oxo, -CONH 2 , alkenyl-C (O) NH-, alkynyl-NH-, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl at each occurrence is independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, alkyl, alkoxy, haloalkyl, hydroxyal
  • R 2 and R 3 together with the C atom to which they are bound form a heterocyclyl, wherein the heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • X 1 , X 2 , X 3 or X 4 is selected from heteroatoms N, it has hydrogen substituents to satisfy the valences;
  • the compound of formula (I-0) or a tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated derivative, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is compound of formula (I) :
  • X 1 , X 2 , X 3 and X 4 are each independently selected from bond, CH, N, NH, O or S;
  • X 1 , X 2 , X 3 or X 4 is selected from heteroatoms N, it has hydrogen substituents to satisfy the valences;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently selected from bond, CH, N, O or S;
  • R 2 and R 3 together with the C atom to which they are bound form a heterocyclyl, wherein the heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, nitro, cyano, hydroxyl, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl;
  • t 0, 1, 2 or 3;
  • L is bond, NH, O, S, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-N-or -CONH-.
  • L is bond, NH, O, S, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-N-or -CONH-.
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, -CONH 2 .
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, -CONH 2 .
  • R 2 and R 3 are each independently selected from hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl.
  • R 2 and R 3 together with the C atom to which they are bound form a 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 4 is independently selected from the group consisting of hydrogen, deuterium, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, amino, F, Cl or Br.
  • R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 2-4 cyano-alkyl, C 2-4 alkoxy-C 1-4 alkyl, C 2-4 alkoxy-deuterated C 1-4 alkyl, oxo, -CONH 2 , C 3-6 alkenyl-C (O) NH-, C 2-4 alkynyl-NH-, -C (O) O-C 1-4 alkyl, -C (O) NH-C 1-4 alkyl,
  • R 6 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl;
  • R 6 is independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl;
  • R 2g , R 3g , R 4g , R 5g are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, deuterated C 1-6 alkyl, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl, deuterated C 1-6 haloalkyl, deuterated C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, -CONH 2 ;
  • R y is selected from the group consisting of hydrogen, deuterium, F, Cl Br, amino, cyano, nitro, deuterated C 1-6 alkyl, deuterated C 2-6 alkenyl, deuterated C 2-6 alkynyl, deuterated C 1-6 haloalkyl, deuterated C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo, and -CONH 2 ;
  • R 2 and R 3 together with the C atom to which they are bound form
  • the compound of formula (I) is compound of formulas (IIa) or (IIb) :
  • L is NH, O, S, C 1-3 alkylene, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH-or -CONH-;
  • L 1 is O, S or NH
  • Y 2 is selected from CH, N, O or S;
  • M 4 is selected from CH, N, O or S;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, oxo and-CONH 2 ;
  • R 2 and R 3 together with the C atom to which they are bound form a C 3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1 or 2 of heteroatoms selected from N or O, C 6-10 aryl and 5-7 membered heteroaryl containing 1 or 2 of heteroatoms selected from N or O;
  • R 7 is together with to form a 9-10 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, 9-10 membered heteroaryl containing 1 2, 3 or 4 of heteroatoms selected from N, O or S;
  • R a is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 3-6 cycloalkyl;
  • R b is independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and 5-6 membered heteroaryl containing 1 or 2 of heteroatoms selected from N, O or S;
  • n 0, 1 or 2;
  • t 0, 1 or 2;
  • s 0, 1, 2 or 3.
  • L is NH, O, S,
  • L 1 is O, S or NH
  • Y 2 is selected from CH, N, O or S;
  • M 4 is selected from CH, N, O or S;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 hydroxyalkyl;
  • R 2 and R 3 together with the C atom to which they are bound form a C 3-6 cycloalkyl or 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 4 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, oxo and -CONH 2 ;
  • R 5 is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, nitro, hydroxyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, and C 3-6 cycloalkyl;
  • R a is independently selected from the group consisting of hydrogen, deuterium, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, and C 3-6 cycloalkyl;
  • R b is independently selected from the group consisting of hydrogen, deuterium, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and 5-6 membered heteroaryl containing 1 or 2 of heteroatoms selected from N, O or S.
  • the present invention also provides a process for the preparation of a compound of formula (I) , or a pharmaceutically acceptable salt, comprising the step of reacting a compound of formula (Xa) with a compound of formula (Xb) ,
  • X is OH, SH or NH 2 ;
  • Hal is halogen
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , s, and t are defined as formula (I) .
  • the amount of the compound, tautomer, cis- or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated derivative, or pharmaceutically acceptable salts thereof is about 0.1-95%by weight of free base; preferably, is about 5-70%, e.g. 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%.
  • above stated pharmaceutical composition is formulated as a tablet, capsule, liquid form or injection form.
  • the amount of the compound, tautomer, cis- or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated derivative, or pharmaceutically acceptable salts thereof is about 1-1000mg; preferably, is about 1-500mg, more preferably, is about 1mg, 2mg, 3mg, 5mg, 10mg, 20mg, 40mg, 50mg, 60mg, 80mg, 100mg, 200mg, 300mg, 400m or 500mg.
  • the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or deuterated derivative, or pharmaceutically acceptable salts thereof is can be administered by any suitable route of administration, e.g. oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical compositions adapted accordingly.
  • the compound, tautomer, cis-or trans-isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salts is formulated as a soild or liquid form, e.g. syrups, suspension, emulsion, tablets, capsules, powders, granules or lozenges.
  • the present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of any formula (I) - (IV) , or tautomer, or deuterated derivative, or pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention relates to a method of inhibiting MK2 kinase, comprising administering to a subject in need thereof an effective amount of a compound of any formula (I) - (IV) , or a pharmaceutical composition comprising the same.
  • the present invention provides a method for treating a disorder mediated by MK2 kinase, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof.
  • diseases include, but are not limited to, immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases and proliferative diseases.
  • the immune, autoimmune or inflammatory diseases is selected from the group consisting of inflammatory bowel diseases, ulcerative colitis, Crohn′s disease, multiple sclerosis, psoriasis, arthritis, rheumatoid arthritis, osteoarthritis, juvenile arthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, cryopyrin associated periodic syndromes, Muckle-Wells syndrome, familial cold auto-inflammatory syndrome, neonatal-onset multisystem inflammatory disease, TNF receptor associated periodic synderome, acute and chronic pancreatitis, atherosclerosis, gout, ankylosing spondylitis, fibrotic disorders, hepatic fibrosis, idiopathic pulmonary fibrosis, nephropathy, sarcoidosis, scleroderma, anaphylaxis, diabetes, diabetes mellitus type 1, diabetes mellitus type 2, diabetic retinopathy, Still′s disease, vasculitis, sarcoidos
  • graft vs. host disease allograft rejections, acute allograft rejection, chronic allograft rejection, early transplantation rejection, acute allograft rejection, reperfusion injury, pain, acute pain, chronic pain, neuropathic pain, fibromyalgia, chronic infections, meningitis, encephalitis, myocarditis, gingivitis, post surgical trauma, tissue injury, traumatic brain injury, enterocolitis, sinusitis, uveitis, ocular inflammation, optic neuritis, gastric ulcers, esophagitis, peritonitis, periodontitis, dermatomyositis, gastritis, myositis, polymyalgia, pneumonia and bronchitis.
  • Alkyl refers to a saturated aliphatic hydrocarbon group including C 1 -C 20 straight chain and branched chain groups.
  • an alkyl group is an alkyl having 1 to 12, sometimes preferably 1 to 6, sometimes more preferably 1 to 4, carbon atoms.
  • Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • an alkyl group is a lower alkyl having 1 to 6 carbon atoms.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, etc.
  • the alkyl group can be substituted or unsubstituted.
  • the substituent group (s) can be substituted at any available connection point, preferably the substituent group (s) is one or more substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
  • Alkenyl refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc., preferably C 2-20 alkenyl, more preferably C 2-12 alkenyl, and most preferably C 2-6 alkenyl.
  • the alkenyl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
  • Alkynyl refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl etc., preferably C 2-20 alkynyl, more preferably C 2-12 alkynyl, and most preferably C 2-6 alkynyl.
  • the alkynyl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, wherein having 2 residues derived by removing two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms.
  • the straight or branched chain group containing 1 to 20 carbon atoms preferably has 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -) , 1, 1-ethylene (-CH (CH 3 ) -) , 1, 2-ethylene (-CH 2 CH 2 ) -, 1, 1-propylene (-CH (CH 2 CH 3 ) -) , 1, 2-propylene (-CH 2 CH (CH 3 ) -) , 1, 3-propylene (-CH 2 CH 2 CH 2 -) , 1, 4-butylidene (-CH 2 CH 2 CH 2 CH 2 -) etc.
  • the alkylene group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Alkenylene refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C 2-20 alkenylene, more preferably C 2-12 alkenylene, and most preferably C 2-6 alkenylene.
  • the alkenylene group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Alkynylene refers to an alkynyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, preferably C 2-20 alkynylene, more preferably C 2-12 alkynylene, and most preferably C 2-6 alkynylene.
  • alkenylene groups include, but are not limited to, -CH ⁇ CH-, -CH ⁇ CHCH 2 -, -CH ⁇ CHCH 2 CH 2 -, -CH 2 CH ⁇ CHCH 2 -etc.
  • the alkynylene group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Cycloalkyl refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms.
  • Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.
  • Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.
  • “Spiro Cycloalkyl” refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom) , wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a spiro cycloalkyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl.
  • Representative examples of spiro cycloalkyl include, but are not limited to the following substituents:
  • “Fused Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a fused cycloalkyl group is 6 to 14 membered, more preferably 7 to 10 membered.
  • fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and preferably refers to a bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused cycloalkyl.
  • Representative examples of fused cycloalkyls include, but are not limited to, the following substituents:
  • “Bridged Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings can have one or more double bonds, but have no completely conjugated pi-electron system.
  • a bridged cycloalkyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl.
  • Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents:
  • the cycloalkyl can be fused to the ring of an aryl, heteroaryl or heterocyclic alkyl, wherein the ring bound to the parent structure is cycloalkyl.
  • Representative examples include, but are not limited to indanylacetic, tetrahydronaphthalene, benzocycloheptyl and so on.
  • the cycloalkyl is optionally substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
  • Heterocyclyl refers to a 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) m (wherein m is 0, 1, or 2) as ring atoms, but excluding -O-O-, -O-S-or -S-S-in the ring, the remaining ring atoms being C.
  • heterocyclyl is a 3 to 12 membered having 1 to 4 heteroatoms; more preferably a 3 to 10 membered having 1 to 3 heteroatoms; more preferably a 4 to 8 membered having 1 to 3 heteroatoms; most preferably a 5 to 6 membered having 1 to 2 heteroatoms.
  • monocyclic heterocyclyls include, but are not limited to, oxetanyl, azabutyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and so on.
  • Polycyclic heterocyclyl includes the heterocyclyl having a spiro ring, fused ring or bridged ring.
  • “Spiro heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom) , wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) m (wherein m is 0, 1 or 2) as ring atoms, the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a spiro heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl.
  • Representative examples of spiro heterocyclyl include, but are not limited to the following substituents:
  • “Fused Heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with the other ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S (O) p (wherein p is 0, 1, or 2) as ring atoms, the remaining ring atoms being C.
  • a fused heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably refers to bicyclic or tricyclic fused heterocyclyl, more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclyl.
  • fused heterocyclyl include, but are not limited to, the following substituents:
  • “Bridged Heterocyclyl” refers to a 5 to 14 membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, the rings can have one or more double bonds, but have no completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O, and S (O) m (wherein m is 0, 1, or 2) as ring atoms, the remaining ring atoms being C.
  • a bridged heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered.
  • bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl.
  • Representative examples of bridged heterocyclyl include, but are not limited to, the following substituents:
  • the ring of said heterocyclyl can be fused to the ring of an aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl.
  • Representative examples include, but are not limited to the following substituents:
  • the heterocyclyl is optionally substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group (s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio.
  • Aryl refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi-electron system.
  • aryl is 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl.
  • the aryl can be fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl. Representative examples include, but are not limited to, the following substituents:
  • the aryl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • Heteroaryl refers to an aryl system having 1 to 4 heteroatoms selected from the group consisting of O, S and N as ring atoms and having 5 to 14 annular atoms.
  • a heteroaryl is 5-to 10-membered, more preferably 5-or 6-membered, for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. Representative examples include, but are not limited to, the following substituents:
  • the heteroaryl group can be substituted or unsubstituted.
  • the substituent group (s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio and -NR 9 R 10 .
  • Alkoxy refers to both an -O- (alkyl) and an -O- (unsubstituted cycloalkyl) group, wherein the alkyl is defined as above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxyl can be substituted or unsubstituted.
  • the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
  • “Bond” refers to a covalent bond using a sign of “-” .
  • Hydroalkyl refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • Haldroxy refers to an -OH group.
  • Halogen refers to fluoro, chloro, bromo or iodo atoms.
  • Amino refers to a -NH 2 group.
  • Cyano refers to a -CN group.
  • Niro refers to a -NO 2 group.
  • Carboxyl refers to a -C (O) OH group.
  • Alkoxycarbonyl refers to a -C (O) O (alkyl) or (cycloalkyl) group, wherein the alkyl and cycloalkyl are defined as above.
  • deuterated derivative refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ( “D” ) . It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivatives described herein. Thus, unless otherwise stated, when a reference is made to a “deuterated derivative” of a compound of the invention, at least one hydrogen is replaced with deuterium at well above its natural isotopic abundance (which is typically about 0.015%) .
  • the deuterated derivatives of the invention have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5%deuterium incorporation at each designated deuterium) at least 4500, (67.5%deuterium incorporation) , at least 5000 (75%deuterium incorporation) at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at lease 6333.3 (95%deuterium incorporation, at least 6466.7 (97%deuterium incorporation, or at least 6600 (99%deuterium incorporation) .
  • heterocyclic group optionally substituted by an alkyl means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.
  • “Substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. It goes without saying that the substituents exist in their only possible chemical position. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the invention, such salts being safe and effective when used in a mammal and have corresponding biological activity.
  • each compound was identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS) .
  • NMR chemical shifts ( ⁇ ) were given in 10 -6 (ppm) .
  • NMR was determined by Varian Mercury 300 MHz Bruker Avance III 400MHz machine.
  • the solvents used were deuterated-dimethyl sulfoxide (DMSO-d 6 ) , deuterated-chloroform (CDCl 3 ) and deuterated-methanol (CD 3 OD) .
  • HPLC High performance liquid chromatography
  • LCMS Liquid Chromatography Mass Spectrometry
  • the average rates of ATPase inhibition, and the IC 50 values were determined by Victor Nivo multimode plate reader (PerkinElmer, USA) .
  • the thin-layer silica gel plates used in thin-layer chromatography were Yantai Xinnuo silica gel plate.
  • the dimension of the plates used in TLC was 0.15 mm to 0.2 mm, and the dimension of the plates used in thin-layer chromatography for product purification was 0.4 mm to 0.5 mm.
  • the known starting material of the invention can be prepared by the conventional synthesis method in the prior art, or can be purchased from ABCR GmbH &Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari chemical Company, etc.
  • argon atmosphere or “nitrogen atmosphere” means that a reaction flask was equipped with a balloon having 1 L of argon or nitrogen.
  • hydrogen atmosphere means that a reaction flask was equipped with a balloon having 1 L of hydrogen.
  • Step 3 6- (1- (3-Aminophenyl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (INT-001) , To a solution of tert-butyl N- [3- [3-nitro-4- (1-oxo-3, 4-dihydro-2H-isoquinolin-6-yl) pyrazol-1-yl] phenyl] carbamate 7 (406 mg, 90.33 ⁇ mol, 1.0 equiv) in CH2Cl2 (5 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at room temperature for 2 h.
  • Step 1 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (INT-003) , To a solution of6-bromo-3, 4-dihydroisoquinolin-1 (2H) -one 1 (4 g, 17.69 mmol, 1.0 equiv) in 1, 4-dioxane (40 mL) was added 4, 4, 4’, 4’, 5, 5, 5’, 5’-octamethyl-2, 2’-bi-1, 3, 2-dioxaborolane 2 (6.74 g, 26.54 mmol, 1.5 equiv) and Pd (dppf) Cl2 ⁇ CH2Cl2 (1.43 g, 1.77 mmol, 0.1 equiv) .
  • 2-chloro-4- (1-ethoxyvinyl) pyrimidine A mixture of 2, 4-dichloropyrimidine (2 g, 13.42 mmol, 1.0 equiv) , tributyl (1-ethoxyvinyl) stannane (7.27 g, 20.14 mmol, 1.5 equiv) and Pd (PPh 3 ) 2 Cl 2 (471 mg, 0.67 mmol, 0.05 equiv) inDMF (20 mL) was stirred under N 2 at 80 °C overnight.
  • 2-bromo-1- (2-chloropyrimidin-4-yl) ethan-1-one To a solution of 2-chloro-4- (1-ethoxyvinyl) pyrimidine (1.53 g, 8.29 mmol, 1.0 equiv) in THF (27 mL) and water (3 mL) was added NBS (1.62 g, 9.12 mmol, 1.1 equiv) at room temperature. The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3) .
  • Test Method A Titank C183u 50*2.1mm; Mobile phase: A: 0.1%formic acid in water; B: acetonitrile.
  • Test Method B XBRIDGE C18 2.1*50mm, 3.5um; Mobile phase: H 2 O (0.05%TFA) -ACN (0.05%TFA) ACN from 0%to 60%over 7 minutes, 7-8min, ACN from 60%to 100%.
  • Test Method C CHIRALPAK IA 4.6*250mm, 5 ⁇ m; Mobile phase: 40%Acetonitrile, H2O (0.1%FA) .
  • Test Method D XBRIDGE C18 2.1*50mm, 3.5um; Mobile phase: H 2 O (0.05%TFA) , ACN (0.05%TFA) ; 7 min., ACN from 10-100%; Flow rate: 1.0 mL/min; Column temperature: 45°C.
  • Test Method E Gemini 5u C19 150*21.2mm; Mobile phase: H 2 O (0.5%NH 4 OH) , ACN; 10.5 min., ACN from 2-95%; Flow rate: 20 mL/min; Column temperature: 20°C.
  • Test Method F XBRIDGE C18 2.12*150mm, 5um; H 2 O (0.1%FA) -CAN; ACN from 2%to 95%over 16 minutes; Flow rate: 20.0 mL/min; Column temperature 45°C.
  • Example 9 and 10 were also being prepared in a manner depicted below Synthesis of Example 9 and 10
  • Step 2 6- (1- (1H-indol-6-yl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 3 6- (1- (1- (2-chloroacetyl) -1H-indol-6-yl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 4 6- (3-amino-1- (1- (2-chloroacetyl) -1H-indol-6-yl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one, Example 151
  • Step 1 N- (3- (3- (methylamino) -4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (Example 152) and N- (3- (3- (dimethylamino) -4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (Example 153)
  • the mixture was dissolved in anhydrous THF (2 mL, 0.01 M) and treated with formaldehyde (0.001 g, 0.1 mmol, 1.5 equiv) , then AcOH (0.001 mg, 0.02 mmol, 1.0 equiv) and let stir at room temperature for 24 hours.
  • the reaction mixture was then diluted with EtOAc, washed with one volume of brine, dried with Na2SO4, then concentrated.
  • the crude mixture was purified by prep-HPLC, 5-95%MeCN/H2O + 0.05%formic acid to give at least 0.002 g (24%and 23%yield) of desired products as white solids.
  • Step 1 2, 2-trifluoro-N- (3- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acetamide
  • Step 1 N- (3- (4- (2-methyl-1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -3-nitro-1H-pyrazol-1-yl) phenyl) acrylamide
  • Step 1 N- (3- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) methacrylamide
  • Step 1 methyl 4-bromo-2- (3- ( (tert-butyldimethylsilyl) oxy) -1-cyanopropyl) benzoate
  • Step 3 4- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 4 N- (3- (4- (4- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -3-nitro-1H-pyrazol-1-yl) phenyl) acrylamide
  • N- (3- (3-amino-4- (4- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -1-oxo-1, 2, 3, 4-tetrahydrois oquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide 10 mg, 0.02 mmol, 1.0 equiv
  • DMF 0.5 mL
  • CSF 9 mg, 0.06 mmol, 3.0 equiv
  • Step 1 8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydrobenzo [f] [1, 4] oxazepin-5 (2H) -one
  • Step 4 N- (3- (4- (4-ethyl-1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -3-nitro-1H-pyrazol-1-yl) phenyl) acrylamide
  • Step 1 tert-butyl (3- (4-bromo-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) carbamate
  • the title compound (1.05 g, 55%yield) was prepared following the Chan-Lam coupling procedure described for INT 001, substituting 4-bromo-3- (trifluoromethyl) -1H-pyrazole (1.0 g, 4.65 mmol, 1.0 equiv) .
  • LCMS-ESI (m/z) [M-H] -calc'd for C15H15BrF3N3O2, 404.03; found, 404.17.
  • Step 3 6- (1- (3-aminophenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 4 N- (3- (4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) acrylamide,
  • the title compound (18 mg, 29%yield) was prepared following the acrylamide formation procedure described for Example 10, substituting 6- (1- (3-aminophenyl) -3- (triluoromethyl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (54 mg, 145 ⁇ mol, 1.0 equiv) .
  • Step 1 2-chloro-5, 6, 7, 8-tetrahydropyrido [2, 3-d] pyrimidine: To a solution of 2-chloropyrido [2, 3-d] pyrimidine (250 mg, 1.51 mmol, 1.0 equiv. ) in ethyl acetate (10 mL) was added 10%Pd-C (125 mg) , the reaction was stirred in H 2 at room temperature overnight. The mixture was filtered and concentrated to give 2-chloro-5, 6, 7, 8-tetrahydropyrido [2, 3-d] pyrimidine (197 mg, 1.16 mmol, 77%) as a white solid.
  • LCMS-ESI (m/z) [M+H] + calc'd for C 7 H 8 ClN 3 , 170.04; found, 170.09.
  • Step 2 8- (4-bromopyridin-2-yl) -2-chloro-5, 6, 7, 8-tetrahydropyrido [2, 3-d] pyrimidine: To a solution of 2-chloro-5, 6, 7, 8-tetrahydropyrido [2, 3-d] pyrimidine (134 mg, 0.79 mmol, 1.0 equiv. ) and 4-bromo-2-fluoropyridine in DMAc (2 mL) was added potassium tert-butoxide (180 mg, 1.58 mmol, 4.0 equiv. ) , the reaction was stirred at 90 °C overnight.
  • Step 3 2- (2- (2-chloro-6, 7-dihydropyrido [2, 3-d] pyrimidin-8 (5H) -yl) pyridin-4-yl) -1, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one
  • Example 173 To a solution of 8- (4-bromopyridin-2-yl) -2-chloro-5, 6, 7, 8-tetrahydropyrido [2, 3-d] pyrimidine (60 mg, 0.18 mmol, 1.0 equiv. ) and Int-005 (121 mg, 0.45 mmol, 2.5 equiv.
  • Step 1 methyl (3- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) carbamate
  • Step 1 tert-butyl 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-4H-benzo [b] [1, 4] oxa zine-4-carboxylate,
  • the title compound (320 mg, 92%yield) was prepared following the Miyaura borylation procedure described for INT-003, using tert-butyl 6-bromo-2, 3-dihydro-4H-benzo [b] [1, 4] oxazine-4-carboxylate (300 mg, 954.9 ⁇ mol, 1.0 equiv) .
  • Step 2 (4- (tert-butoxycarbonyl) -3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) boronic acid, To a solution of tert-butyl 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-4H-benzo [b] [1, 4] oxazine -4-carboxylate (320 mg, 885.8 ⁇ mol, 1.0 equiv) in acetone (9 mL) at room temperature were added sodium periodate (568.4 mg, 2.66 mmol, 3.0 equiv) , NH 4 OAc (150.2 mg, 1.95 mmol, 2.2 equiv) , and water (9 mL) .
  • Step 7 6- (1- (4-acryloyl-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) -3-amino-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (Example 175)
  • Step 1 tert-butyl (4- (4-bromo-3-nitro-1H-pyrazol-1-yl) phenyl) carbamate, the title compound (1.24 g, 62%yield) was prepared following the Chan-Lam coupling procedure described for INT-001, using (4- ( (tert-butoxycarbonyl) amino) phenyl) boronic acid (1.48 g, 6.25 mmol, 1.2 equiv) .
  • LCMS-ESI (m/z) [M-H] -calc'd for C14H14BrN4O4, 381.03; found, 381.24.
  • Step 3 6- (1- (4-aminophenyl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • the title compound (400 mg, 90%yield) was prepared following the acidolysis procedure described for INT-001, using tert-butyl (4- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) carbamate (500 mg, 1.3 mmol, 1.0 equiv) .
  • LCMS-ESI (m/z) [M+H] + calc'd for C18H16N5O3, 350.12; found, 350.03.
  • Step 4 N- (4- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide, the title compound (400 mg, 98%yield) was prepared following the acrylamide formation procedure described for Example 9, using 6- (1- (4-aminophenyl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (350 mg, 1.0 mmol, 1.0 equiv) .
  • LCMS-ESI (m/z) [M+H] + calc'd for C21H18N5O4, 404.13; found, 404.04.
  • Step 5 N- (4- (3-amino-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide, The title compound (70 mg, 37%yield) was prepared following the nitro reduction procedure described for Example 9, using N- (4- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) ac rylamide (200 mg, 0.495 mmol, 1.0 equiv) .
  • Step 1 N- (3- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) propiolamide
  • 3- (trimethylsilyl) propioloyl chloride 92 mg, 0.572 mmol, 2.0 equiv
  • K 2 CO 3 198 mg, 1.43 mmol, 5.0 equiv
  • LCMS-ESI (m/z) [M+H] + calc'd for C21H16N5O4, 402.11; found, 401.98.
  • Step 3 1- (3-aminophenyl) -4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazole-3-carbonitrile
  • Step 4 N- (3- (3-cyano-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide
  • Step 1 1- (3-acrylamidophenyl) -4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazole-3-carboxamide
  • Step 1 6- (3-nitro-1- (3- (prop-2-yn-1-ylamino) phenyl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 2 6- (3-amino-1- (3- (prop-2-yn-1-ylamino) phenyl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 4 N- (3- (3-amino-4- (8-fluoro-1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide
  • Step 3 8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxab orolan-2-yl) -1, 2, 3, 4-tetrahydro-5H-benzo [e] [1, 4] diazepin-5-one
  • Step 1 6- (3-nitro-1- (3- (2-oxo-2, 5-dihydro-1H-pyrrol-1-yl) phenyl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 2 6- (3-amino-1- (3- (2-oxo-2, 5-dihydro-1H-pyrrol-1-yl) phenyl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 1 7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinazoline-2, 4 (1H, 3H) -dione
  • the title compound (810 mg, 67%yield) was prepared following the Miyaura borylation procedure described for INT-003, using 7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinazoline-2, 4 (1H, 3H) -dione (1 g, 4.15 mmol, 1.0 equiv) and stirring at 95 °C for 16 h.
  • LCMS-ESI (m/z) [M+H+CH3CN] + calc'd for C16H21BN3O4, 330.15; found, 329.85.
  • Step 2 N- (3- (3-m ethyl-4- (1-oxo-1, 2, 3, 4-tetrahydroiso quinolin-6-yl) -1H-pyr azol-1-yl) phenyl) acrylamide
  • Step 1 4- (1- (3-acrylamidophenyl) -3-nitro-1H-pyrazol-4-yl) -2-fluorobenzamide
  • the title compound (84 mg, 47%yield) was prepared following the Suzuki coupling procedure described for Example 158, using (4-carbamoyl-3-fluorophenyl) boronic acid (98 mg, 0.53 mmol, 1.2 equiv) and stirring at 100 °C for 1 h.
  • LCMS-ESI (m/z) [M+H] + calc'd for C19H15FN5O4, 396.10; found, 396.61.
  • Step 2 4- (1- (3-acrylamidophenyl) -3-amino-1H-pyrazol-4-yl) -2-fluorobenzamide
  • the title compound (1.0 mg, 2%yield) was prepared following the nitro reduction procedure described for Example 9, using 4- (1- (3-acrylamidophenyl) -3-nitro-1H-pyrazol-4-yl) -2-fluorobenzamide (65 mg, 0.16 mmol, 1.0 equiv) .
  • Step 1 N- (3- (4-cyano-3, 5-difluorophenyl) -3-nitro-1H-pyrazol-1-yl) phenyl) acrylamide
  • N- (3- (4-bromo-3-nitro-1H-pyrazol-1-yl) phenyl) acrylamide (0.20 g, 0.59 mmol, 1.0 equiv)
  • (4-cyano-3, 5-difluorophenyl) boronic acid (0.16 g, 0.89 mmol, 1.5 equiv.
  • Step 1 N- (3- (4- (4-cyano-3-methoxyphenyl) -3-nitro-1H-pyrazol-1-yl) phenyl) acrylamide
  • the title compound (45 mg, 52%yield) was prepared following the Suzuki coupling procedure described for Example 370, using (4-cyano-3-methoxyphenyl) boronic acid (63 mg, 0.36 mmol, 1.2 equiv) and stirring at 120 °C for 1 h.
  • LCMS-ESI (m/z) [M-H+HCOOH] - calc'd for C21H16N5O6, 434.11; found, 423.95.
  • Step 2 N- (3- (3-amino-4- (4-cyano-3-methoxyphenyl) -1H-pyrazol-1-yl) phenyl) acrylamide
  • the title compound (46 mg, 70%yield) was prepared following the nitro reduction procedure described for Example 9, using N- (3- (4- (4-cyano-3-methoxyphenyl) -3-nitro-1H-pyrazol-1-yl) phenyl) acrylamide (70 mg, 0.18 mmol, 1.0 equiv) .
  • Step 4 (1- (3-bromophenyl) -3- ( (4-methoxybenzyl) oxy) -1H-pyrazol-4-yl) -3, 4-dihydroiso quinolin-1 (2H) -one
  • Step 6 (1- (3-aminophenyl) -3- ( (4-methoxybenzyl) oxy) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 7 N- (3- (3- ( (4-methoxybenzyl) oxy) -4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide
  • Step 8 N- (3- (3-hydroxy-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide
  • N- (3- (3- ( (4-methoxybenzyl) oxy) -4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide 160 mg, 0.10 mmol, 1.0 equiv
  • TFA 1 mL
  • the resulting mixture was stirred for 1 h, then was filtered.
  • the filtrate was concentrated and purified by Prep-HPLC using a gradient of water (0.1%FA) /ACN (Flow rate: 20 ml/min; Wavelength: 214 nm/254 nm.
  • N- (5- (4-bromo-3-nitro-1H-pyrazol-1-yl) pyridin-3-yl) acrylamide (1 g, 0.003 mol, 1.0 equiv) in dioxane (12 mL) /water (3 mL) at room temperature were added 6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydro-2H-isoquinolin-1-one (1.64 g, 0.006 mol, 2.0 equiv) , Pd (dppf) Cl 2 (0.22 g, 0.0003 mol, 0.1 equiv) , K 2 CO 3 (1.24 g, 0.009 mol, 3.0 equiv) .
  • Step 2 6- (1- (6-aminopyridin-2-yl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 4 N- (3-amino-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) -4-methylphenyl) acrylamide
  • the title compound (15.9 mg, 11%yield) was prepared following the nitro reduction procedure described for Example 193, using N- (4-methyl-3- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (160 mg, 0.38 mmol, 1.0 equiv) .
  • Step 1 N- (3- (4-bromo-5-nitro-1H-pyrazol-1-yl) -5-methylphenyl) acrylamide (A1) and N- (3- (4-bromo-3-nitro-1H-pyrazol-1-yl) -5-methylphenyl) acrylamide (A2)
  • Step 2 N- (3-methyl-5- (5-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (B1) and N- (3-methyl-5- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (B2)
  • Step 3 N- (3- (5-amino-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) -5-methylphenyl) acrylamide (Eaxmple451) and N- (3- (3-amino-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) -5-methylphenyl) acrylamide (Example 195)
  • Example 194 (1.34 mg, 2%yield) and Example 195 (1.82 mg, 6.4%yield) were prepared following the nitro reduction procedure described for Example 192, using N- (3-methyl-5- (5-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide B1 (70 mg, 0.17 mmol, 1.0 equiv) and N- (3-methyl-5- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide B2 (30 mg, 0.072 mmol, 1.0 equiv) respectively.
  • Step 2 N- (2-methyl-5- (5-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (D1) and N- (2-methyl-5- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (D2)
  • Example 196 (2.38 mg, 17%yield) and Example 197 (1.11 mg, 8%yield) were prepared following the nitro reduction procedure described for Example 192, using N- (2-methyl-5- (5-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide D1 (14 mg, 0.034 mmol, 1.0 equiv) and N- (2-methyl-5- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide D2 (14 mg, 0.034 mmol, 1.0 equiv) respectively.
  • N- (2-fluoro-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acrylamide 700 mg, 2.4 mmol, 1.0 equiv
  • Acetone/H2O 2.5 mL/2.5 mL
  • NalO 4 (1.19 g, 5.5 mmol, 2.3 equiv)
  • NH 4 OAc (426 mg, 5.5 mmol, 2.3 equiv)
  • the mixture was stirred at 25°C under N 2 atmosphere for 16 h, then was concentrated under vacuo.
  • the aqueous layer was extracted with EtOAc (10 mLx3) .
  • Step 4 N- (3- (hydroxymethyl) -5- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide
  • Step 1 N- (3- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) -5- (pyrrolidin-1-ylmethyl) phenyl) acrylamide
  • Step 3 6- (1- (3-aminophenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • reaction mixture was then treated with 6- (1- (3-aminophenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (0.050 g, 0.13 mmol, 1.0 equiv) , warmed to 40°C and stirred for 24 h. Afterward, the mixture was cooled to room temperature, diluted with EtOAc, washed with one volume of brine, dried (Na 2 SO 4 ) , and concentrated. The crude mixture was purified by silica gel column chromatography (0-100%EtOAc/Heptane, then 0-20%MeOH/CH 2 Cl 2 ) .
  • Step 2 6- (1- (3-hydroxyphenyl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 3 6- (1- (3- ( (2-chloro-5- (ethoxymethyl) pyrimidin-4-yl) oxy) phenyl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 4 6- (3-amino-1- (3- ( (2-chloro-5- (ethoxymethyl) pyrimidin-4-yl) oxy) phenyl) -1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (Example 117)
  • Step 1 N- (3- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) cyclopent-1-ene-1-carboxamide
  • Step 1 4-bromo-2- (1- (tert-butoxycarbonyl) -3-cyanoazetidin-3-yl) benzoic acid
  • Step 4 4- (1- (3- (N-ethylacrylamido) phenyl) -3-fluoro-1H-pyrazol-4-yl) -2-methoxybenzam ide and 4- (1- (3- (N-ethylacrylamido) phenyl) -5-fluoro-1H-pyrazol-4-yl) -2-methoxybenzam ide (Example 218 and 219)
  • Step 1 N- (3- (4-bromo-3-fluoro-1H-pyrazol-1-yl) phenyl) -N- (2-methoxyethyl) acrylamide
  • Step 1 tert-butyl N-acryloyl-N- (3- (4-bromo-3-fluoro-1H-pyrazol-1-yl) phenyl) glycinate
  • Step 1 6- (3-bromo-1-methyl-1H-pyrazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 4 3-difluoro-6′- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2′, 3′-dihydro-1′H-spiro[cyclobutane-1, 4′-isoquinolin] -1′-one
  • Step 1 4- (1- (3-aminophenyl) -3-fluoro-1H-pyrazol-4-yl) -2-methoxybenzamide
  • Step 2 tert-butyl 2, 2-dimethyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-4H-ben zo[bl [1, 4] oxazine-4-carboxylate,A mixtureof tert-butyl 6-bromo-2, 2-dimethyl-3H-1, 4-benzoxazine-4-carboxylate (245 mg, 715.90 ⁇ mol, 1.0 equiv) , 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (272.69 mg, 1.07 mmol, 1.5 equiv) , cyclopentyl (diphenyl) phosphane; dichloropalladium; iron (52.38 mg, 71.59 ⁇ mol, 0.1 equiv) , and KOA
  • Step 3 (4- (tert-butoxycarbonyl) -2, 2-dimethyl-3, 4-dihydro-2H-benzo [bl [1, 4] oxazin-6-yl) boronic acid, To a solution of tert-butyl 2, 2-dimethyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3H-1, 4-benzoxazine-4-c arboxylate (278.69 mg, 715.9 ⁇ mol, 1.0 equiv) inacetone (15 mL) at rt were added Water (9 mL) , NH 4 OAc (121.40 mg, 1.57 mmol, 2.2 equiv) , and Sodium periodate (459.37 mg, 2.15 mmol, 3.0 equiv) .
  • Step 6 (1- (2, 2-dimethyl-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 7 6- (1- (4-acryloyl-2, 2-dimethyl-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) -3-nitro-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
  • Step 8 (1- (4-acryloyl-2, 2-dimethyl-3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-6-yl) -3-amino-1H-pyrazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (Example 225)
  • Step 2 N- (3-nitro-4- (5-oxo-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (F1) and N- (3- (5-nitro-4- (5-oxo-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (F2)
  • Step 3 The title compound 72 (1.3 mg, 7.5%yield) and 72a (0.49 mg, 3.2%yield) were prepared following the nitro reduction procedure described for Example 10, using a mixture N- (3- (3-nitro-4- (5-oxo-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -1H-pyrazol-1-yl) phe nyl) acrylamide (F1) and N- (3- (5-nitro-4- (5-oxo-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -1H-pyrazol-1-yl) phe nyl) acrylamide (F2) (15.0 mg, 37 ⁇ mol, 1.0 equiv) , and the reaction mixture was stirred in EtOH (1 mL) for 2 h.
  • Step 4 N- (3- (2-methoxyethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ac rylamide
  • Step 6 N- (3- (4-bromo-3-nitro-1H-pyrazol-1-yl) -5- (2-methoxyethoxy) phenyl) acrylamide (G1) and N- (3- (4-bromo-5-nitro-1H-pyrazol-1-yl) -5- (2-methoxyethoxy) phenyl) acrylamide (G2)
  • Step 7 N- (3- (2-methoxyethoxy) -5- (5-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (H1) and N- (3- (2-methoxyethoxy) -5- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (H2)
  • Step 8 The title compounds (483) (45.7 mg, 32.5%yield) and (484) (2.84 mg, 2%yield) were prepared following the nitro reduction procedure described for Example 002, using a mixture of N- (3- (2-methoxyethoxy) -5- (5-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1 H-pyrazol-1-yl) phenyl) acrylamide (H1) and N- (3- (2-methoxyethoxy) -5- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1 H-pyrazol-1-yl) phenyl) acrylamide (H2) (150.0 mg, 0.31 mmol, 1.0 equiv) .
  • Step 4 N- (2- (2-methoxyethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acrylamide
  • Step 6 N- (5- (5-amino-4-bromo-1H-pyrazol-1-yl) -2- (2-methoxyethoxy) phenyl) acrylamide (I1) and N- (5- (3-amino-4-bromo-1H-pyrazol-1-yl) -2- (2-methoxyethoxy) phenyl) acrylamide (I2)
  • Step 7 N- (2- (2-methoxyethoxy) -5- (5-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (J1) and N- (2- (2-methoxyethoxy) -5- (3-nitro-4- (1-oxo-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) -1H-pyrazol-1-yl) phenyl) acrylamide (J2)

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  • Oncology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés de tétrahydroisoquinoléinone de formule (I) utiles en tant qu'inhibiteurs de MK2, leur procédé de préparation, des compositions pharmaceutiques comprenant les composés, et leurs utilisations pharmaceutiques pour le traitement de maladies ou de troubles médiés par MK2.
PCT/CN2023/137983 2022-12-11 2023-12-11 Dérivés de tétrahydroisoquinoléinone, leurs procédés de préparation et leurs utilisations médicinales Ceased WO2024125464A1 (fr)

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US202363486094P 2023-02-21 2023-02-21
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US202363490291P 2023-03-15 2023-03-15
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US202363493354P 2023-03-31 2023-03-31
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US202363503253P 2023-05-19 2023-05-19
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PCT/CN2023/137983 Ceased WO2024125464A1 (fr) 2022-12-11 2023-12-11 Dérivés de tétrahydroisoquinoléinone, leurs procédés de préparation et leurs utilisations médicinales

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