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WO2025149545A1 - Dérivés d'hétéroarylphényl éther - Google Patents

Dérivés d'hétéroarylphényl éther

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Publication number
WO2025149545A1
WO2025149545A1 PCT/EP2025/050384 EP2025050384W WO2025149545A1 WO 2025149545 A1 WO2025149545 A1 WO 2025149545A1 EP 2025050384 W EP2025050384 W EP 2025050384W WO 2025149545 A1 WO2025149545 A1 WO 2025149545A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
phenoxy
carboxamide
indazole
propoxy
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/EP2025/050384
Other languages
English (en)
Inventor
Xingchun Han
Chuanlong HUANG
Mingming Li
Yongqiang Liu
Min Wang
Yongguang Wang
Song Yang
Lei YIN
Chengang ZHOU
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.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche Inc
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Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Publication of WO2025149545A1 publication Critical patent/WO2025149545A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • C07D401/02—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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D491/08—Bridged 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 organic compounds, in particular to CDK8/19 inhibitors, useful for treatment of cancers in a mammal.
  • the present invention relates to CDK8/19 inhibitors that have CDK8/19 inhibition activity, as well as their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.
  • CDK8/19 inhibitors that have CDK8/19 inhibition activity, as well as their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.
  • Cyclin-dependent kinase 8 (CDK8) and its paralog CDK19, in association with cyclin C, are integral parts of the mediator complex that play vital roles in regulating transcription by phosphorylating RNPII and other specific transcription factors (Dannappel et al. Front. Cell Dev. Biol.2019.).
  • CDK8/19 only regulates transcription but not cell cycle or cell proliferation, and in contrast to some other transcriptional CDKs, they only regulate a subset of genes related to cell activation, have minimal impact on basal gene expression (Fant et al. Transcription.2019).
  • the CDK8 ⁇ cyclin C complex directly or indirectly regulates a variety of signaling pathways, including STAT1 (Bancerek et al Immunity.2013), Wnt- ⁇ catenin (Firestein et al. Nature, 2008), Notch, Smads, HIF1 ⁇ , p21/p53, and NF ⁇ B (Li et al. Cells.2019).
  • Objects of the present invention are novel compounds of formula (I), their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) as CDK8/19 inhibitors for the treatment of a broad spectrum of immune mediated diseases.
  • the compounds of formula (I) show superior CDK8/19 inhibition activity.
  • the compounds of formula (I) can also increase expression of Foxp3+ and IL-10 in activated T cells and myeloid cells.
  • Another aspect of the invention pertains to a method for the treatment of immune mediated diseases, which method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • compound(s) of this invention and “compound(s) of the present invention” refers to compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), or formula (Id), and stereoisomers, solvates or salts thereof (e.g., pharmaceutically acceptable salts).
  • substituted denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule.
  • alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene.
  • halogen or “Halo” denotes fluoro, chloro, bromo, or iodo.
  • haloC1-6alkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by same or different halogen atoms, particularly fluoro atoms.
  • Examples of haloC1-6alkyl include monochloro-, difluoro-or trifluoro-methyl, -ethyl or -propyl, for example difluoromethyl.
  • heteroaryl moieties include, but not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quina
  • Heteroaryl can be further substituted by halogen, C 1-6 alkyl, haloC 1-6 alkyl, cyano, C3-7cycloalkyl, (C1-6alkyl)2amino, or C1-6alkoxy.
  • heterocyclyl denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • heterocyclyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • monocyclic saturated heterocyclyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperaz
  • hydroxyC 1-6 alkyl denotes a C 1-6 alkyl group wherein at least one of the hydrogen atoms of the C 1-6 alkyl group has been replaced by a hydroxy group.
  • the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Intermediate A in Scheme 1 can be prepared as compound of formula Intermediate A1 I ntermediate A1 according to the synthetic route outlined in Scheme 3: a) Buchwald-Hartwig or copper catalyzed cyanidation of a compound of formula XVII XVII provides a compound of formula XVIII; X VIII b) Copper catalyzed cross coupling or S N Ar substitution of a compound of formula XVIII with a compound of formula XIX provides a compound of formula XX; c) Hydrogenation of a compound of formula XX with a transitional metal catalyst, for example Pd/C, Pd(OH)2/C, PtO2 or Raney Nickel provides compound of formula XXI; d) Condensation of compound of formula XXI with acid anhydride, for example acetyl anhydride, formic acid/acetyl anhydride mixture and consequential hydrolysis under basic condition provides compound of formula Intermediate A1.
  • a transitional metal catalyst for example P
  • Step 3 methyl 7-(4-hydroxyphenoxy)-1-methyl-indazole-5-carboxylate (Int-1a) To a 100 mL flask were added methyl 7-(4-benzyloxyphenoxy)-1-methyl-indazole-5- carboxylate (420.0 mg, 1.08 mmol), methanol (5 mL) and Pd/C (200 mg, 10% loading) in one portion. The mixture was degassed and purged with H2 three times and then stirred at 20 °C for 2 h under H2 atmosphere (50 psi). The suspension was filtered through a pad of Celite and the cake was washed with methanol. The solvent was removed in vacuum. The residue was purified by prep.
  • Step 4 methyl 8-(4-benzyloxyphenoxy)imidazo[1,5-a]pyridine-6-carboxylate
  • DMF 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride
  • 8-(4-benzyloxyphenoxy)-6-bromo-imidazo[1,5-a]pyridine 350.0 mg, 0.89 mmol
  • triethylamine 0.4 mL, 2.66 mmol
  • Step 3 methyl 2-(aminomethyl)-6-(4-hydroxyphenoxy)pyridine-4-carboxylate To a mixture of methyl 2-(4-benzyloxyphenoxy)-6-cyano-pyridine-4-carboxylate (330.0 mg, 0.92 mmol) and HCl (0.6 mL, 7.01 mmol) in methanol (10 mL) was added Pd/C (50 mg, 10% loading) at 25 °C. The mixture was degassed and purged with H2 (20 psi) three times, stirred at 25 °C for 12 h and filtered through a Celite pad.
  • Step 4 methyl 5-(4-acetoxyphenoxy)imidazo[1,5-a]pyridine-7-carboxylate To a 10 mL round-bottom flask was added acetyl acetate (1.2 mL) followed by formic acid (1 mL). The mixture was warmed up to 50 °C, stirred for 2h and then cooled to 20 °C.
  • Step 2 methyl 2-(4-benzyloxy-2-fluoro-phenoxy)-6-cyano-pyridine-4-carboxylate
  • methyl 2-(4-benzyloxy-2-fluoro-phenoxy)-6-bromo- pyridine-4-carboxylate 3.0 g, 6.94 mmol
  • DMF 30 mL
  • dicyanocopper 4.0 g, 34.83 mmol
  • the mixture was stirred at 80 °C for 12 h, cooled and diluted with water (50 mL).
  • the mixture was extracted with EtOAc.
  • the organic phase was washed with brine, dried over Na2SO4 and filtrated. The filtrate was concentrated in vacuum.
  • Step 3 6-(4-benzyloxyphenoxy)-1-methyl-indazole-5-carboxamide
  • 6-(4-benzyloxyphenoxy)-1-methyl-indazole-5-carboxylic acid (4.61 g, 12.31 mmol) followed by successive addition of DMF (20 mL), NH4Cl (3.3 g, 61.57 mmol), HATU (7.02 g, 18.47 mmol) and DIEA (16.0 g, 123.13 mmol).
  • DMF 20 mL
  • NH4Cl 3.3 g, 61.57 mmol
  • HATU 7.02 g, 18.47 mmol
  • DIEA (16.0 g, 123.13 mmol
  • Step 4 6-(4-hydroxyphenoxy)-1-methyl-indazole-5-carboxamide (Int-4a) To a 250 mL flask were added 6-(4-benzyloxyphenoxy)-1-methyl-indazole-5-carboxamide (4.6 g, 12.32 mmol) and methanol (100 mL) and then Pd/C (920 mg, 10% loading) in one portion.
  • Step 2 2-tetrahydrofuran-3-yloxyethanol (Int-7a) To a 100 mL flask were added 3-(2-benzyloxyethoxy)tetrahydrofuran (2.1 g, 9.76 mmol) and methanol (25 mL). Then Pd/C (0.5 g, 10% loading) was added in one portion under N 2 .
  • Step 2 1-(2-chloroethyl)-3-methyl-imidazolidin-2-one (Int-14a) To a mixture of 1-(2-chloroethyl)imidazolidin-2-one (1.0 g, 6.73 mmol) in THF (10 mL) was added NaH (465.0 mg, 11.63 mmol) in portions over 0.2 h at 0 °C. Iodomethane (1.9 g, 13.46 mmol) was added.
  • Step 3 methyl 2-[(tert-butoxycarbonylamino)methyl]-5-[4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]pyridine-4-carboxylate
  • a mixture of methyl 2-cyano-5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]pyridine- 4-carboxylate (850.0 mg, 2.31 mmol) and Boc 2 O (1.9 g, 8.53 mmol) in methanol (30 mL) was added Pd/C (170 mg, 10% loading). The mixture was degassed and purged with H2 three times, stirred at 20 °C for 14 h under H2 ballon and filtered through a Celite pad.
  • Step 2 methyl 2-methyl-3-tetrahydropyran-4-yloxy-propanoate
  • methyl 2-(tetrahydropyran-4-yloxymethyl)prop-2-enoate 3.4 g, 17.0 mmol
  • methanol 30 mL
  • Pd/C 0.7 g, 10% loading
  • the suspension was degassed and purged with H2 three times.
  • the resulting mixture was stirred at 20 °C for 12 h under H2 balloon and filtered through a pad of Celite. The cake was washed with MeOH.
  • Step 2 3-[4-(5-carbamoyl-1-methyl-indazol-6-yl)oxyphenoxy]propanoic acid (Int-22a) To a 250 mL flask were added benzyl (E)-3-[4-(5-carbamoyl-1-methyl-indazol-6- yl)oxyphenoxy]prop-2-enoate (800 mg, 1.80 mmol) and methanol (150 mL). Pd/C (400 mg, 10% loading) was added in one portion. The suspension was degassed and purged with H 2 three times. The resulting mixture was stirred at 20 °C for 12 h under H 2 balloon and filtered through a pad of Celite.
  • Step 4 (3-tetrahydropyran-4-yloxycyclobutyl) 4-methylbenzenesulfonate (Int-37a)
  • TEA 3.0 g, 30.00 mmol
  • the mixture was stirred at rt for 14 h and diluted with water (40 mL).
  • the mixture was extracted with DCM.
  • the combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuum.
  • Step 2 [3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoro-propyl]trifluoromethanesulfonate (Int- 38a) To a 100 mL flask were added 3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoro-propan-1-ol (4.8 g, 13.7 mmol) and DCM (50 mL).2,6-lutidine (1.6 mL, 13.7 mmol) and trifluoromethanesulfonic anhydride (3.9 g, 13.7 mmol) were added at -10 °C.
  • Step 3 4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenol
  • N-[(E)-dimethylaminomethyleneamino]-5-(4- hydroxyphenoxy)imidazo[1,5-a]pyridine-7-carboxamide 590 mg, 1.74 mmol
  • acetic acid 2 mL
  • acetonitrile 10 mL
  • ethylamine hydrochloride 7.83 mg, 8.69 mmol
  • Step 2 7-bromo-1-methyl-indazole-5-carbohydrazide
  • methyl 7-bromo-1- methyl-indazole-5-carboxylate 10.0 g, 37.16 mmol
  • ethanol 150 mL
  • NHNH•HO 25.0 g, 499.4 mmol
  • Step 3 1-methyl-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole-5-carboxamide (Example 1)
  • compound 1.2 0.4 g, 1.0 mmol
  • HATU 0.42 g, 1.1 mmol
  • NH 4 Cl 0.27 g, 5.09 mmol
  • DIEA 0.26 g, 2.01 mmol
  • the mixture was stirred at 20 °C for 2 h and filtered. The filtrate was concentrated in vacuum. The residue was purified by reverse-phase chromatography to give Example 1 (70.0 mg) as colorless oil.
  • MS [M+H] + 398.2.
  • Step 2 7-[4-[2-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]ethoxy]phenoxy]-1-methyl- indazole-5-carboxylic acid (compound 2.2)
  • compound 2.1 60.0 mg, 0.11 mmol
  • LiOH•H2O 15.0 mg, 0.37 mmol
  • water 0.2 mL
  • Step 3 tert-butyl 4-[2-[4-(5-carbamoyl-1-methyl-indazol-7-l)oxyphenoxy]ethoxy]piperidine- 1-carboxylate (compound 2.3)
  • NH 4 Cl 180 mg, 3.42 mmol
  • HATU 520 mg, 1.37 mmol
  • DIEA 180 mg, 1.37 mmol
  • the mixture was stirred at 20 °C for 1 h and filtered. The filtrate was concentrated in vacuum. The residue was purified by prep-TLC to give compound 2.3 (0.35 g) as brown oil.
  • Example 3 1-methyl-7-[4-[2-[(1-methyl-4-piperidyl)oxy]ethoxy]phenoxy]indazole-5-carboxamide
  • the titled compound was synthesized from Example 2 according to the following scheme: To a solution of Example 2 (50.0 mg, 0.12 mmol) in methanol were added polyformaldehyde (7.31 mg, 0.24 mmol) and NaBH3CN (30 mg, 0.37 mmol). The mixture was stirred at 20 °C for 2 h and filtered. The filtrate was concentrated in vacuum. The residue was purified by reversed-phase chromatography to give Example 3 (6.4 mg) as colorless oil. MS [M+H] + : 425.2.
  • Example 6 5-[4-(2-tetrahydrofuran-3-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridine-7-carboxamide
  • Example 6 was prepared in analogy to Example 1, by replacing Int-1a with Int-3a in step 1.
  • MS [M+H] + 384.2.
  • Example 11 7-[4-(cyclopropylmethoxy)phenoxy]-1-methyl-indazole-5-carboxamide 7-[4-(cyclopropylmethoxy)phenoxy]-1-methyl-indazole-5-carboxamide (Example 11) was prepared in analogy to Example 9, by replacing Int-8a and Int-1b with iodomethylcyclopropane and Int-1a in step 1. White solid, MS [M+H] + : 338.3.
  • Example 17 1-methyl-7-[4-[2-(2-oxopyrrolidin-1-yl)ethoxy]phenoxy]indazole-5-carboxamide
  • Example 17 was prepared in analogy to Example 9, by replacing Int-8a and Int-1b with Int-8e and Int- 1a in step 1.
  • Example 18 1-methyl-7-[4-[3-(2-oxopyrrolidin-1-yl)propoxy]phenoxy]indazole-5-carboxamide
  • Example 18 was prepared in analogy to Example 9, by replacing Int-8a and Int-1b with Int- 8f and Int-1a in step 1.
  • Example 21 7-[3-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide 7-[3-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide (Example 21) was prepared in analogy to Example 9, by replacing Int-1b and Int- 8a with Int-1c and Int-8a in step 1. White solid, MS [M+H] + : 430.2.
  • Example 23 5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridine-7-carboxamide 5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridine-7-carboxamide (Example 23) was prepared in analogy to Example 9, by replacing Int-1b and Int-8a with Int- 3a and Int-8a in step 1. Off-white solid, MS [M+H] + : 398.1.
  • Example 28 5-[4-[3-(3-methylmorpholin-4-yl)propoxy]phenoxy]imidazo[1,5-a]pyridine-7-carboxamide
  • the titled compound was synthesized from Int-6b according to the following scheme: Step 1: methyl 5-[4-[3-(3-methylmorpholin-4-yl)propoxy]phenoxy]imidazo[1,5-a]pyridine- 7-carboxylate (compound 28.1)
  • Int-6b (120.0 mg, 0.33 mmol)
  • DMF (1 mL
  • 3- methylmorpholine 240.0 mg, 2.37 mmol
  • K 2 CO 3 144.0 mg, 1.04 mmol
  • KI 60.0 mg, 0.36 mmol.
  • Example 33 5-[4-[3-(3-oxomorpholin-4-yl)propoxy]phenoxy]imidazo[1,5-a]pyridine-7-carboxamide 5-[4-[3-(3-oxomorpholin-4-yl)propoxy]phenoxy]imidazo[1,5-a]pyridine-7-carboxamide (Example 33) was prepared in analogy to Example 31, by replacing 3,3-dimethylmorpholine with morpholin-3-one in step 1. MS [M+H] + : 411.2.
  • Example 36 7-[4-[3-(2-benzyloxyethoxy)azetidin-1-yl]phenoxy]-1-methyl-indazole-5-carboxamide
  • the titled compound was synthesized from Int-6a and Int-10a according to the following scheme: Step 1: methyl 7-(4-bromophenoxy)-1-methyl-indazole-5-carboxylate (compound 36.1)
  • DMF 10 mL
  • CuI 17. mg, 0.93 mmol
  • K2CO3 770.4 mg, 5.57 mmol
  • 4- bromophenol 643.0 mg, 3.72 mmol
  • BPPO BPPO
  • Step 2 methyl 7-[4-[3-(2-benzyloxyethoxy)azetidin-1-yl]phenoxy]-1-methyl-indazole-5- carboxylate (compound 36.2)
  • Int-10a 80.0 mg, 0.39 mmol
  • Cs 2 CO 3 378.9 mg, 1.16 mmol
  • t BuXPhos Pd G3 30.8 mg, 0.04 mmol
  • Example 38 7-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1H-indazole-5-carboxamide 7-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1H-indazole-5-carboxamide (Example 38) was prepared in analogy to Example 2, by replacing Int-1a and tert-butyl 4-(2- hydroxyethoxy)piperidine-1-carboxylate with Int-1e and Int-7b in step 1; HCl with TFA in step 4. MS [M+H] +: 398.1.
  • Step 3 methyl 1-methyl-7-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole-5- carboxylate (compound 39.3)
  • a mixture of cesium carbonate (126.0 mg, 0.39 mmol), iodomethane (28.0 mg, 0.2 mmol) and compound 39.2 (80.0 mg, 0.19 mmol) in DMF (3.0 mL) was stirred at 20 °C for 4 h.
  • the mixture was diluted with EtOAc, washed with water and brine successively, dried over Na 2 SO 4 and concentrated in vacuum.
  • the residue was purified by flash chromatography to give compound 39.3 (70.0 mg) as light yellow solid.
  • Step 2 methyl 3-methyl-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5- a]pyridine-7-carboxylate (compound 44.2)
  • POCl 3 18.0 mg, 1.20 mmol
  • the resulting solution was stirred at 100 °C for 1 h, cooled to rt and quenched with sat. NaHCO3 at 0 °C.
  • the aqueous phase was extracted with EtOAc.
  • the combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum.
  • Example 47 1-methyl-7-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridine-6- carboxamide
  • the titled compound was synthesized from methyl 6-bromo-1H-indazole-5-carboxylate according to the following scheme: Step 1: methyl 6-bromo-1-ethyl-indazole-5-carboxylate (compound 47.1) To a suspension of methyl 6-bromo-1H-indazole-5-carboxylate (1.0 g, 3.92 mmol) and Cs 2 CO 3 (2.6 g, 7.84 mmol) in ACN (30 mL) was added iodoethane (734 mg, 4.70 mmol).
  • Step 4 1-methyl-7-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridine- 6-carboxamide (Example 47) To a 20 mL vial were added compound 47.3 (302.8 mg, 0.71 mmol), DMF (10 mL), NH4Cl (189.0 mg, 3.52 mmol), HATU (405.0 mg, 1.07 mmol) and DIEA (918 mg, 7.10 mmol).
  • Example 49 1-methyl-6-[4-(2-tetrahydrofuran-3-yloxyethoxy)phenoxy]indazole-5-carboxamide
  • the titled compound was synthesized from Int-4a according to the following scheme: To a solution of Int-4a (200.0 mg, 0.71 mmol) and Int-8g (404 mg, 1.42 mmol) in DMF (3 mL) was added K 2 CO 3 (293.0 mg, 2.11 mmol). The mixture was stirred at 80 °C for 16 h, cooled to rt and filtered through a pad of Celite. The cake was washed with DCM. The filtrate was concentrated in vacuum. The residue was purified by prep. HPLC to give Example 49 (121.0 mg) as white solid.
  • Example 51 (6.3 mg), slower fraction, white solid. MS [M+H] + : 398.1.
  • Example 52 6-[4-[2-(cyclopropoxy)ethoxy]phenoxy]-1-methyl-indazole-5-carboxamide 6-[4-[2-(cyclopropoxy)ethoxy]phenoxy]-1-methyl-indazole-5-carboxamide (Example 52) was prepared in analogy to Example 49, by replacing Int-8g with 2-(cyclopropoxy)ethyl 4- methylbenzenesulfonate in step 1. MS [M+H] + : 368.1.
  • Example 53 1-methyl-6-[4-(3-morpholinopropoxy)phenoxy]indazole-5-carboxamide
  • Example 53 was prepared in analogy to Example 49, by replacing Int-8g with 4-(3-bromopropyl)morpholine; hydrobromide in step 1.
  • MS [M+H] + 411.1.
  • Example 57 6-[4-(3-methoxy-3-methyl-butoxy)phenoxy]-1-methyl-indazole-5-carboxamide 6-[4-(3-methoxy-3-methyl-butoxy)phenoxy]-1-methyl-indazole-5-carboxamide (Example 57) was prepared in analogy to Example 49, by replacing Int-8g with Int-8i in step 1. MS [M+H] + : 384.1.
  • Example 58 1-methyl-6-[4-[3-(2-oxopyrrolidin-1-yl)propoxy]phenoxy]indazole-5-carboxamide
  • Example 58 was prepared in analogy to Example 49, by replacing Int-8g with Int-8f in step 1.
  • MS [M+H] + : 409.1.
  • Example 59 1-methyl-6-[4-[3-(2-methyl-5-oxo-pyrrolidin-1-yl)propoxy]phenoxy]indazole-5- carboxamide
  • Example 59 was prepared in analogy to Example 49, by replacing Int-8g with Int-19a in step 1.
  • MS [M+H] + 423.1.
  • Example 60 1-methyl-6-[4-(3-tetrahydropyran-4-yloxypropoxy)phenoxy]indazole-5-carboxamide
  • Example 60 was prepared in analogy to Example 49, by replacing Int-8g with Int-8j in step 1.
  • MS [M+H] + 426.1.
  • Example 68 1-methyl-6-[4-(3-morpholino-3-oxo-propoxy)phenoxy]indazole-5-carboxamide
  • the titled compound was synthesized from Int-22a according to the following scheme: To a 20 mL vial were added Int-22a (580.0 mg, 1.63 mmol), DMF (10 mL), morpholine (214.0 mg, 2.45 mmol), HATU (932.0 mg, 2.45 mmol) and DIEA (632.0 mg, 4.89 mmol). The resulting mixture was stirred at 20 °C for 2 h, diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified directly by prep.
  • Example 69 6-[2-fluoro-4-[3-oxo-3-(3-oxopiperazin-1-yl)propoxy]phenoxy]-1-methyl-indazole-5- carboxamide 6-[2-fluoro-4-[3-oxo-3-(3-oxopiperazin-1-yl)propoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 69) was prepared in analogy to Example 68, by replacing morpholine and Int-22a with piperazin-2-one and Int-22b in step 1. MS [M+H] + : 456.1.
  • Example 70 6-[2-fluoro-4-[3-(4-hydroxy-1-piperidyl)-3-oxo-propoxy]phenoxy]-1-methyl-indazole-5- carboxamide 6-[2-fluoro-4-[3-(4-hydroxy-1-piperidyl)-3-oxo-propoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 70) was prepared in analogy to Example 68, by replacing morpholine and Int-22a with piperidin-4-ol hydrochloride and Int-22b in step 1. MS [M+H] + : 457.1.
  • Example 71 1-methyl-6-[4-(2-tetrahydropyran-3-yloxyethoxy)phenoxy]indazole-5-carboxamide
  • Example 71 was prepared in analogy to Example 49, by replacing Int-8g with Int-8m in step 1.
  • MS [M+H] + 412.1.
  • Example 72 and Example 73 1-methyl-6-[4-[2-[(3S)-tetrahydropyran-3-yl]oxyethoxy]phenoxy]indazole-5-carboxamide and 1-methyl-6-[4-[2-[(3R)-tetrahydropyran-3-yl]oxyethoxy]phenoxy]indazole-5- carboxamide 1-methyl-6-[4-[2-[(3S)-tetrahydropyran-3-yl]oxyethoxy]phenoxy]indazole-5-carboxamide and 1-methyl-6-[4-[2-[(3R)-tetrahydropyran-3-yl]oxyethoxy]phenoxy]indazole-5-carboxamide (Example 72 and Example 73) were prepared in analogy to Example 4 and Example 5 by SFC.
  • Example 74 6-[2-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide 6-[2-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide (Example 74) was prepared in analogy to Example 47, by replacing iodoethane with iodomethane in step 1; Int-9a with Int-9b in step 2. MS [M+H] + : 430.1.
  • Example 76 6-[2,6-difluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide 6-[2,6-difluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide (Example 76) was prepared in analogy to Example 47, by replacing iodoethane with iodomethane in step 1; Int-9a with Int-9c in step 2. MS [M+H] + : 448.0.
  • Example 77 1-methyl-6-[2-methyl-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole-5- carboxamide
  • Example 77 was prepared in analogy to Example 47, by replacing iodoethane with iodomethane in step 1; Int-9a with Int-9d in step 2.
  • MS [M+H] + 426.1.
  • Example 78 6-[2-chloro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide 6-[2-chloro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide (Example 78) was prepared in analogy to Example 47, by replacing iodoethane with iodomethane in step 1; Int-9a with Int-9e in step 2. MS [M+H] + : 446.0.
  • Example 79 1-methyl-6-[4-[2-(8-oxabicyclo[3.2.1]octan-3-yloxy)ethoxy]phenoxy]indazole-5- carboxamide
  • Example 79 was prepared in analogy to Example 49, by replacing Int-8g with Int-8n in step 1.
  • Example 83 1-methyl-6-[4-[2-(2-methyltetrahydropyran-4-yl)oxyethoxy]phenoxy]indazole-5- carboxamide
  • Example 83 was prepared in analogy to Example 49, by replacing Int-8g with Int-8r in step 1.
  • MS [M+H] + 426.1.
  • Example 94 2-[2-fluoro-4-[3-(2-oxooxazolidin-3-yl)propoxy]phenoxy]-5-methyl-4-(4-methyl-1,2,4- triazol-3-yl)benzamide 2-[2-fluoro-4-[3-(2-oxooxazolidin-3-yl)propoxy]phenoxy]-5-methyl-4-(4-methyl-1,2,4- triazol-3-yl)benzamide (Example 94) was prepared in analogy to Example 65, by replacing Example 64 with Example 93 in step 1. MS [M+H] + : 470.2.
  • Example 95 7-[2-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide 7-[2-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide (Example 95) was prepared in analogy to Example 9, by replacing Int-8a and Int- 1b with Int-1h and Int-8a in step 1. MS [M+H] + : 430.2.
  • Example 97 1-methyl-7-[4-[3-(3-oxomorpholin-4-yl)propoxy]phenoxy]indazole-5-carboxamide
  • Example 97 was prepared in analogy to Example 31, by replacing Int-6c and 3,3- dimethylmorpholine with Int-6e and morpholin-3-one in step 1.
  • MS [M+H] + 425.2.
  • Example 98 1-methyl-7-[4-[3-(4-methyl-2-oxo-piperazin-1-yl)propoxy]phenoxy]indazole-5-carboxamide
  • Example 98 was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6e and 4-methylpiperazin-2-one in step 1.
  • Example 99 1-methyl-7-[4-[3-(4-methyl-3-oxo-piperazin-1-yl)propoxy]phenoxy]indazole-5-carboxamide
  • Example 99 was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6e and 1-methylpiperazin-2-one in step 1.
  • MS [M+H] + 438.2.
  • Step 2 1-methyl-7-[4-[3-(3-oxopiperazin-1-yl)propoxy]phenoxy]indazole-5-carboxamide (Example 100) To a 40 mL flask were added compound 100.1 (50.0 mg, 0.1 mmol) and 2 M HCl(g) in dioxane (5.0 mL, 10.0 mmol). The mixture was stirred at 25 °C for 2 h and concentrated in vacuum. The residue was purified by prep.
  • Example 102 7-[2-chloro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide 7-[2-chloro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide (Example 102) was prepared in analogy to Example 9, by replacing Int-8a and Int-1b with Int-1i and Int-8a in step 1. Off-white solid, MS [M+H] + : 446.1.
  • Example 103 5-(4-ethyl-1,2,4-triazol-3-yl)-1-methyl-7-[4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]indazole
  • the titled compound was synthesized from Int-27f according to the following scheme:
  • Int-27f 100.0 mg, 0.23 mmol
  • DMF ⁇ DMA 40.0 mg, 0.34 mmol
  • ACN 2 mL
  • Example 104 5-[2-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridine-7- carboxamide 5-[2-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridine-7- carboxamide (Example 104) was prepared in analogy to Example 9, by replacing Int-8a and Int-1b with Int-3c and Int-8a in step 1. Light yellow solid, MS [M+H] + : 416.2.
  • Example 105 7-[2-fluoro-4-[3-(2-oxooxazolidin-3-yl)propoxy]phenoxy]-1-methyl-indazole-5-carboxamide 7-[2-fluoro-4-[3-(2-oxooxazolidin-3-yl)propoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 105) was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6f and oxazolidin-4-one in step 1. MS [M+Na] + : 451.2.
  • Example 106 7-[2-fluoro-4-[3-(4-methyl-3-oxo-piperazin-1-yl)propoxy]phenoxy]-1-methyl-indazole-5- carboxamide 7-[2-fluoro-4-[3-(4-methyl-3-oxo-piperazin-1-yl)propoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 106) was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6f and 1-methylpiperazin-2-one in step 1. MS [M+H] + :456.1.
  • Example 108 and Example 109 7-[2-fluoro-4-[2-[(3S)-tetrahydrofuran-3-yl]oxyethoxy]phenoxy]-1-methyl-indazole-5- carboxamide and 7-[2-fluoro-4-[2-[(3R)-tetrahydrofuran-3-yl]oxyethoxy]phenoxy]-1- methyl-indazole-5-carboxamide
  • the titled compound was synthesized according to the following scheme Example 108 & Example 109 Step 1: 7-[2-fluoro-4-(2-tetrahydrofuran-3-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide 7-[2-fluoro-4-(2-tetrahydrofuran-3-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carboxamide (Compound 108.1) was prepared in analogy to Example 30, by replacing Int-5a and 3-(2-chloroethyl)o
  • Example 132 6-[4-[3-(diethylamino)-3-oxo-propoxy]phenoxy]-1-methyl-indazole-5-carboxamide 6-[4-[3-(diethylamino)-3-oxo-propoxy]phenoxy]-1-methyl-indazole-5-carboxamide (Example 132) was prepared in analogy to Example 68, by replacing morpholine with N- ethylethanamine in step 1. MS [M+H] + : 411.1.
  • Example 136 1-methyl-6-[4-[3-(2-oxooxazolidin-3-yl)propoxy]phenoxy]indazole-5-carboxamide
  • Example 136 was prepared in analogy to Example 47, by replacing iodoethane with iodomethane in step 1; Int-9a with Int-21c in step 2.
  • MS [M+H] + 411.2.
  • Step 3 6-[4-[2-[(3-hydroxybicyclo[1.1.1]pentane-1-carbonyl)amino]ethoxy]phenoxy]-1- methyl-indazole-5-carboxamide (Example 137)
  • 3- hydroxybicyclo[1.1.1]pentane-1-carboxylic acid 96.0 mg, 0.75 mmol
  • HATU 286.0 mg, 0.75 mmol
  • DIEA 324.0 mg, 2.50 mmol
  • Example 138 1-methyl-2-oxo-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indoline-5-carboxamide
  • the titled compound was synthesized from 138.1 according to the following scheme: Step 1: 6-bromo-5-(2-chloroacetyl)-1-methyl-indolin-2-one (compound 138.1) To a suspension of 6-bromo-1-methyl-indolin-2-one (2.5 g, 11.06 mmol) and aluminum chloride (5.2 g, 38.71 mmol) in 1,2-dichloroethane (40.0 mL) was added dropwise 2- chloroacetyl chloride (2.6 g, 23.22 mmol) at 0 °C.
  • Step 2 6-bromo-1-methyl-2-oxo-indoline-5-carboxylic acid (compound 138.2) A mixture of compound 138.1 (3.22 g, 10.65 mmol) and pyridine (30 mL, 371 mmol) was heated at 90 °C for 2.5 h.
  • Step 3 methyl 6-bromo-1-methyl-2-oxo-indoline-5-carboxylate (compound 138.3)
  • H2SO4 0.42 mL, 7.80 mmol
  • the mixture was stirred at 90 °C for 16 h, cooled to rt, and concentrated in vacuum. The residue was neutralized with sat. sodium bicarbonate. The precipitate was collected, washed with water and dried in vacuum to give compound 138.3 (2.0 g).
  • MS [M+H] + 283.9.
  • Step 4 methyl 6-bromo-1-methyl-2,3-dioxo-indoline-5-carboxylate (compound 138.4)
  • DMSO dimethyl sulfoxide
  • SeO 2 1.2 g, 10.60 mmol
  • Step 5 methyl 1-methyl-2,3-dioxo-6-[4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]indoline-5-carboxylate (compound 138.5)
  • a flask was dried by heating with a heat gun in vacuum.
  • To this flask were added successively Int-9a (572.0 mg, 2.40 mmol), compound 138.4 (600.0 mg, 2.00 mmol), CuI (40.0 mg, 0.20 mmol), BMPPO (Accela ChemBio; 70.0 mg, 0.20 mmol), K3PO4 (850.0 mg, 4.00 mmol) and DMSO (2.5 mL).
  • Step 7 1-methyl-2,3-dioxo-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indoline-5- carboxamide (compound 138.7)
  • compound 138.6 370.8 mg, 0.84 mmol
  • DMF 8 mL
  • NH4Cl 225.0 mg, 4.20 mmol
  • HATU 480.0 mg, 1.26 mmol
  • DIEA (1.09 g, 8.40 mmol).
  • Step 2 6-[2-fluoro-4-[3-(3-oxomorpholin-4-yl)propoxy]phenoxy]-1-methyl-indazole-5- carboxylic acid (compound 144.2)
  • compound 144.1 300 mg, 655.81 ⁇ mol
  • methanol 8 mL
  • water 2 mL
  • lithium hydroxide monohydrate 82.55 mg, 1.97 mmol
  • the mixture was extracted with DCM.
  • the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuum to give crude compound 144.2 (280 mg) as yellow oil.
  • Example 145 7-(4-ethyl-1,2,4-triazol-3-yl)-5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5- a]pyridine 7-(4-ethyl-1,2,4-triazol-3-yl)-5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5- a]pyridine was prepared in analogy to Example 103, by replacing Int-27f with Int-27a in step 1. MS [M+H] + : 450.2.
  • Example 147 7-(4-cyclopropyl-1,2,4-triazol-3-yl)-5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy] imidazo[1,5-a]pyridine 7-(4-cyclopropyl-1,2,4-triazol-3-yl)-5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy] imidazo[1,5-a]pyridine was prepared in analogy to Example 145, by replacing by replacing Int-27f with Int-27a in step 1; ethylamine hydrochloride with cyclopropylamine in step 2. MS [M+H] + : 462.2.
  • Example 148 7-[4-(2-methoxyethyl)-1,2,4-triazol-3-yl]-5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy] imidazo[1,5-a]pyridine 7-[4-(2-methoxyethyl)-1,2,4-triazol-3-yl]-5-[4-(2-tetrahydropyran-4-yloxyethoxy) phenoxy]imidazo[1,5-a]pyridine was prepared in analogy to Example 103, by replacing by replacing Int-27f with Int-27a in step 1; ethylamine hydrochloride with 2-methoxyethylamine in step 2.
  • Example 149 2-[5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridin-7-yl]-1,3,4- oxadiazole 2-[5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridin-7-yl]-1,3,4- oxadiazole was prepared in analogy to Example 103, by replacing by replacing Int-27f with Int- 27a in step 1 and removing ethylamine hydrochloride in step 2. MS [M+H] + : 423.3.
  • Example 150 5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-7-(4H-1,2,4-triazol-3-yl)imidazo[1,5- a]pyridine
  • the titled compound was synthesized from 7-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol- 3-yl]-5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridine(compound 150.1) according to the following scheme:
  • the compound 150.1 was prepared in analogy to Example 103, by replacing Int-27f with Int-27a in step 1; ethylamine hydrochloride with 4-methoxybenzylamine in step 2.
  • Example 151 2-[5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridin-7-yl]-1,3,4- thiadiazole
  • Step 1 2-[5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo[1,5-a]pyridin-7-yl]- 1,3,4-thiadiazole
  • Example 151 A solution of Int-27a (90 mg, 218.21 ⁇ mol) in ethyl formate (1.62 g, 1.78 mL, 21.82 mmol) was stirred for 48 h at 100 o C, cooled to rt and concentrated in vacuum to give compound 151.1 (90 mg) which was used in the next step without purification.
  • Example 152 7-(4,5-dimethyl-1,2,4-triazol-3-yl)-5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]imidazo [1,5-a]pyridine
  • Step 1 7-(4,5-dimethyl-1,2,4-triazol-3-yl)-5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy] imidazo[1,5-a]pyridine (Example 152)
  • Example 153 3-[4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propan-1-ol 3-[4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propan-1-ol was prepared in analogy to Example 103, by replacing Int-27f with Int-27b in step 1. MS [M+H] + : 380.1.
  • Example 157 2-[2-[4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]ethoxy]ethanol 2-[2-[4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5- yl]oxyphenoxy]ethoxy]ethanol was prepared in analogy to Example 145, by replacing Int-27f with Int-27e in step 1. MS [M+H] + : 410.1.
  • Example 158 7-(4-ethyl-1,2,4-triazol-3-yl)-5-[4-(3-methoxypropoxy)phenoxy]imidazo[1,5-a]pyridine
  • the titled compound was synthesized from Example 153 according to the following scheme: E xample 153
  • sodium hydride (16.87 mg, 421.71 ⁇ mol) at 0 o C.
  • Example 159 5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-7-[4-(trideuteriomethyl)-1,2,4-triazol-3- yl]imidazo[1,5-a]pyridine
  • 5-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-7-[4-(trideuteriomethyl)-1,2,4-triazol-3- yl]imidazo[1,5-a]pyridine was prepared in analogy to Example 103, by replacing by replacing Int-27f with Int-27a in step 1; ethylamine hydrochloride with trideuteriomethylamine hydrochloride in step 2.
  • Example 160 4-[3-[4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propyl]-1- methyl-piperazin-2-one
  • the titled compound was synthesized from Example 153 according to the following scheme: Step 1: 3-[4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propyl 4- methylbenzenesulfonate (compound 160.1)
  • DCM 4 mL
  • Step 2 4-[3-[4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5- yl]oxyphenoxy]propyl]-1-methyl-piperazin-2-one (Example 160)
  • 1-methylpiperazin-2-one (15.4 mg, 134.93 ⁇ mol)
  • potassium carbonate 31.08 mg, 224.89 ⁇ mol
  • Example 161 N-[3-[4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propyl] tetrahydrofuran-3-amine N-[3-[4-[7-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propyl] tetrahydrofuran-3-amine (Example 161) was prepared in analogy to Example 160, by replacing 1-methylpiperazin-2-one with tetrahydrofuran-3-ylamine in step 2. MS [M+H] + : 449.2.
  • Example 162 6-[3-[4-[7-(1,3,4-oxadiazol-2-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propyl]-3-oxa-6- azabicyclo[3.1.1]heptane 6-[3-[4-[7-(1,3,4-oxadiazol-2-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propyl]-3-oxa-6- azabicyclo[3.1.1]heptane (Example 162) was prepared in analogy to Example 160, by replacing Example 153 with Example 154 in step 1; 1-methylpiperazin-2-one with 3-oxa-6- azabicyclo[3.1.1]heptane hydrochloride in step 2.
  • Example 163 1-[4-[3-[4-[7-(1,3,4-oxadiazol-2-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propyl]piperazin -1-yl]ethanone 1-[4-[3-[4-[7-(1,3,4-oxadiazol-2-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propyl] piperazin-1-yl]ethanone (Example 163) was prepared in analogy to Example 160, by replacing Example 153 with Example 154 in step 1; 1-methylpiperazin-2-one with 1- piperazinoethanone in step 2. MS [M+H] + : 463.2.
  • Example 164 1-methyl-4-[3-[4-[7-(1,3,4-oxadiazol-2-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]propyl] piperazin-2-one
  • Example 164 was prepared in analogy to Example 160, by replacing Example 153 with Example 154 in step 1; MS [M+H] + : 449.2.
  • Example 168 7-[2-fluoro-4-[2-(4-piperidyloxy)ethoxy]phenoxy]-1-methyl-indazole-5-carboxamide The titled compound was synthesized from Int-5c and Int-8t according to the following scheme:
  • Int-5c 60.0 mg, 0.20 mmol
  • ACN 0.5 mL
  • K 2 CO 3 55.0 mg, 0.40 mmol
  • Example 168 (50.0 mg) as light yellow oil.
  • Example 169 7-[4-[2-[(1-acetyl-4-piperidyl)oxy]ethoxy]-2-fluoro-phenoxy]-1-methyl-indazole-5- carboxamide
  • the titled compound was synthesized from Example 168 according to the following scheme: Step 1: 7-[4-[2-[(1-acetyl-4-piperidyl)oxy]ethoxy]-2-fluoro-phenoxy]-1-methyl-indazole-5- carboxamide (Example 169)
  • DIEA 21.0 mg, 0.16 mmol
  • Example 170 1-methyl-5-(4-methyl-1,2,4-triazol-3-yl)-7-[4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]indazole 1-methyl-5-(4-methyl-1,2,4-triazol-3-yl)-7-[4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]indazole (Example 170) was prepared in analogy to Example 103, by replacing ethylamine hydrochloride with methylamine hydrochloride in step 2. MS [M+H] + : 450.2.
  • Example 171 5-(4-cyclopropyl-1,2,4-triazol-3-yl)-1-methyl-7-[4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]indazole
  • 5-(4-cyclopropyl-1,2,4-triazol-3-yl)-1-methyl-7-[4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]indazole (Example 171) was prepared in analogy to Example 103, by replacing ethylamine hydrochloride with cyclopropanamine in step 2.
  • MS [M+H] + 476.2.
  • Example 172 7-[2-fluoro-4-(2-pyrrolidin-3-yloxyethoxy)phenoxy]-1-methyl-indazole-5-carboxamide 7-[2-fluoro-4-(2-pyrrolidin-3-yloxyethoxy)phenoxy]-1-methyl-indazole-5-carboxamide (Example 172) was prepared in analogy to Example 168, by replacing Int-8t with Int-8u in step 1. MS [M+H] + : 415.1.
  • Example 173 7-[4-[2-(1-acetylpyrrolidin-3-yl)oxyethoxy]-2-fluoro-phenoxy]-1-methyl-indazole-5- carboxamide 7-[4-[2-(1-acetylpyrrolidin-3-yl)oxyethoxy]-2-fluoro-phenoxy]-1-methyl-indazole-5- carboxamide (Example 173) was prepared in analogy to Example 169, by replacing Example168 with Example 172 in step 1. MS [M+H] + : 457.2.
  • Example 174 7-[2-fluoro-4-[3-(3-oxomorpholin-4-yl)propoxy]phenoxy]-1-methyl-indazole-5- carboxamide 7-[2-fluoro-4-[3-(3-oxomorpholin-4-yl)propoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 174) was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6f and morpholin-3-one in step 1. MS [M+H] + : 443.2.
  • Example 175 7-[2-fluoro-4-[3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)propoxy]phenoxy]-1-methyl-indazole- 5-carboxamide 7-[2-fluoro-4-[3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)propoxy]phenoxy]-1-methyl- indazole-5-carboxamide (Example 175) was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6f and 2-oxa-5-azabicyclo[2.2.2]octane;oxalic acid in step 1. MS [M+H] + : 455.2.
  • Example 176 7-[4-[3-(3-ethylmorpholin-4-yl)propoxy]-2-fluoro-phenoxy]-1-methyl-indazole-5- carboxamide 7-[4-[3-(3-ethylmorpholin-4-yl)propoxy]-2-fluoro-phenoxy]-1-methyl-indazole-5- carboxamide (Example 176) was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6f and 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride in step 1. MS [M+H] + : 441.2.
  • Example 177 7-[2-fluoro-4-[3-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)propoxy]phenoxy]-1-methyl- indazole-5-carboxamide 7-[2-fluoro-4-[3-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)propoxy]phenoxy]-1-methyl- indazole-5-carboxamide (Example 177) was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6f and 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride in step 1. MS [M+H] + : 441.1.
  • Example 178 7-[2-fluoro-4-[3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)propoxy]phenoxy]-1-methyl- indazole-5-carboxamide 7-[2-fluoro-4-[3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)propoxy]phenoxy]-1-methyl- indazole-5-carboxamide (Example 178) was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6f and 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride in step 1. MS [M+H] + : 441.2.
  • Example 179 7-[2-fluoro-4-[3-[2-(hydroxymethyl)morpholin-4-yl]propoxy]phenoxy]-1-methyl-indazole- 5-carboxamide 7-[2-fluoro-4-[3-[2-(hydroxymethyl)morpholin-4-yl]propoxy]phenoxy]-1-methyl-indazole- 5-carboxamide (Example 179) was prepared in analogy to Example 31, by replacing Int-6c and 3,3-dimethylmorpholine with Int-6f and morpholin-2-ylmethanol in step 1. MS [M+H] + : 459.2.
  • Example 180 5-imidazol-1-yl-1-methyl-7-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole
  • the titled compound was synthesized from Int-29b according to the following scheme: I nt-29b Step 1: 5-imidazol-1-yl-1-methyl-7-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole (Example 180) To an 8 mL vial was added Int-29b (100.0 mg, 0.20 mmol) and DMSO (1 mL).
  • Example 181 1-methyl-5-(3-methylimidazol-4-yl)-7-[4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]indazole
  • the titled compound was synthesized from Int-29b according to the following scheme: Int-29b Step 1: 1-methyl-5-(3-methylimidazol-4-yl)-7-[4-(2-tetrahydropyran-4-yloxyethoxy) phenoxy]indazole (Example 181)
  • Int-29b 70.0 mg, 0.14 mmol
  • 1,4-dioxane (1 mL)
  • water 0.2 mL
  • 1-methyl-1H-imidazole-5-boronic acid pinacol ester 35.0 mg, 0.17 mmol
  • K2CO3 39.4 mg, 0.29 mmol
  • Pd(dppf)Cl2 1.0 mg, 0.01 mmol
  • Example 187 5-[3-[4-[5-(4-ethyl-1,2,4-triazol-3-yl)-1-methyl-indazol-7-yl]oxyphenoxy]propyl]-2-oxa-5- azabicyclo[2.2.2]octane
  • the titled compound was synthesized from Int-6i according to the following scheme: Step 1: methyl 1-methyl-7-[4-[3-(3-propylmorpholin-4-yl)propoxy]phenoxy]indazole-5- carboxylate (compound 187.1) To an 8 mL vial were added Int-6i (200.0 mg, 0.53 mmol) and DMF (2 mL).
  • Step 2 1-methyl-7-[4-[3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)propoxy]phenoxy]indazole-5- carbohydrazide (compound 187.2)
  • compound 187.1 60.0 mg, 0.13 mmol
  • hydrazine hydrate 54.0 mg, 1.08 mmol
  • ethanol 0.8 mL
  • the mixture was stirred at 80 °C for 2 h, cooled to rt and concentrated in vacuum.
  • the residue was purified by reversed-phase chromatography to give compound 187.2 (45.0 mg) as brown gum.
  • MS [M+H] + 452.2.
  • Step 3 5-[3-[4-[5-(4-ethyl-1,2,4-triazol-3-yl)-1-methyl-indazol-7-yl]oxyphenoxy]propyl]-2- oxa-5-azabicyclo[2.2.2]octane (Example 187)
  • compound 187.2 35.0 mg, 0.08 mmol
  • ACN 1 mL
  • acetic acid 0.1 mL
  • ethanamine hydrochloride 8.8 mg, 0.11 mmol, 1.38 eq
  • DMFDMA (12.3 mg, 0.1 mmol, 1.33 eq
  • Example 188 5-[3-[4-[5-(4-ethyl-1,2,4-triazol-3-yl)-1-methyl-indazol-7-yl]oxyphenoxy]propyl]-2-oxa-5- azabicyclo[2.2.1]heptane 5-[3-[4-[5-(3-ethylimidazol-4-yl)-1-methyl-indazol-7-yl]oxyphenoxy]propyl]-2-oxa-5- azabicyclo[2.2.1]heptane (Example 188) was prepared in analogy to Example 187, by replacing 2-oxa-5-azabicyclo[2.2.2]octane;oxalic acid with 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride in step 1.
  • Example 189 3-[3-[4-[5-(4-ethyl-1,2,4-triazol-3-yl)-1-methyl-indazol-7-yl]oxyphenoxy]propyl]-6-oxa-3- azabicyclo[3.1.1]heptane 3-[3-[4-[5-(3-ethylimidazol-4-yl)-1-methyl-indazol-7-yl]oxyphenoxy]propyl]-6-oxa-3- azabicyclo[3.1.1]heptane (Example 189) was prepared in analogy to Example 187, by replacing 2-oxa-5-azabicyclo[2.2.2]octane;oxalic acid with 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride in step 1.
  • Step 2 methyl 6-[4-(6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl)phenoxy]-1-methyl- indazole-5-carboxylate (compound 191.2) 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (23.33 mg, 189.43 umol), compound 191.1 (50 mg, 157.86 umol), RuPhos Pd G4 (Sigma-Aldrich; 268 mg, 316 umol) and Cs 2 CO 3 (309 mg, 947.2 umol) were evacuated and backfilled with nitrogen for 5 times.
  • Step 3 6-[4-(6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl)phenoxy]-1-methyl-indazole-5- carboxylic acid (compound 191.3)
  • Compound 191.1 100 mg, 0.248 mmol
  • NaOH 29.74 mg, 743.62 umol
  • methanol 619.69 uL
  • water 619.69 uL
  • Sodium bisulfate hydrate 102.68 mg, 743.62 umol
  • the compound 191.3 (90 mg) was collected by filtration as yellow solid and used in the next step without further purification.
  • MS [M+H] + 390.1.
  • Step 4 6-[4-(6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl)phenoxy]-1-methyl-indazole-5- carboxamide (Example 191)
  • Compound 191.3 100 mg, 256.8 umol
  • ammonium chloride 41.21 mg, 770.4 umol
  • DIEA 165.94 mg, 1.28 mmol
  • HATU 97.64 mg, 256.8 umol
  • Example 191 (29 mg) as white powder. [M+H] + : 389.1.
  • Example 192 1-methyl-6-[4-(2-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)phenoxy]indazole-5- carboxamide
  • Example 192 was prepared in analogy to Example 191, by replacing 5,6,7,8- tetrahydroimidazo[1,5-a]pyrazine with 2-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine in step 2.
  • Example 193 7-[4-[3-(2-ethylmorpholin-4-yl)-3-oxo-propoxy]phenoxy]-1-methyl-indazole-5-carboxamide 7-[4-[3-(2-ethylmorpholin-4-yl)-3-oxo-propoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 193) was prepared in analogy to Example 68, by replacing morpholine and Int-22a with 6-oxa-3-azabicyclo[3.1.1]heptane;4-methylbenzenesulfonic acid and Int-22c in step 1. MS [M+H] + : 437.3.
  • Example 194 3-chloro-1-methyl-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole-5- carboxamide 3-chloro-1-methyl-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole-5- carboxamide (Example 194) was prepared in analogy to Example 144, by replacing 6-bromo-1- methyl-indazole-5-carboxylate and Int-21d with Int-30a and Int-9a in step 1. MS [M+H] + : 446.1.
  • Example 195 7-[2-fluoro-4-(3-morpholino-3-oxo-propoxy)phenoxy]-1-methyl-indazole-5-carboxamide 7-[2-fluoro-4-(3-morpholino-3-oxo-propoxy)phenoxy]-1-methyl-indazole-5-carboxamide (Example 195) was prepared in analogy to Example 68, by replacing Int-22a with Int-22d in step 1. MS [M+H] + : 443.1.
  • Example 196 7-[2-fluoro-4-[3-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-3-oxo-propoxy]phenoxy]-1-methyl- indazole-5-carboxamide 7-[2-fluoro-4-[3-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-3-oxo-propoxy]phenoxy]-1- methyl-indazole-5-carboxamide (Example 196) was prepared in analogy to Example 68, by replacing morpholine and Int-22a with 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride and Int- 22d in step 1.
  • Example 197 7-[2-fluoro-4-[3-(4-hydroxy-1-piperidyl)-3-oxo-propoxy]phenoxy]-1-methyl-indazole-5- carboxamide 7-[2-fluoro-4-[3-(4-hydroxy-1-piperidyl)-3-oxo-propoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 197) was prepared in analogy to Example 68, by replacing morpholine and Int-22a with piperidin-4-ol hydrochloride and Int-22d in step 1. MS [M+H] + : 457.1.
  • Example 198 3-fluoro-1-methyl-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole-5- carboxamide 3-fluoro-1-methyl-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole-5- carboxamide (Example 198) was prepared in analogy to Example 144, by replacing 6-bromo-1- methyl-indazole-5-carboxylate and Int-21d with Int-31a and Int-9a in step 1. MS [M+H] + : 430.1.
  • Example 199 1-isopropyl-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole-5-carboxamide
  • Example 199 was prepared in analogy to Example 47, by replacing iodoethane with 2- iodopropane in step 1.
  • MS [M+H] + : 440.2.
  • Example 200 1-cyclopropyl-6-[4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]indazole-5-carboxamide
  • Example 200 was prepared in analogy to Example 144, by replacing 6-bromo-1-methyl- indazole-5-carboxylate and Int-21d with Int-32a and Int-9a in step 1.
  • MS [M+H] + : 438.2.
  • Example 201 6-[4-[2-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]oxy]ethoxy]phenoxy]-1-methyl-indazole-5- carboxamide 6-[4-[2-[[(1S,5R)-8-azabicyclo[3.2.1]octan-3-yl]oxy]ethoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 201) was prepared in analogy to Example 168, by replacing Int-5c and Int-8t with Int-4a and Int-8v, K2CO3 and ACN with Cs2CO3 and DMF in step 1. MS [M+H] + : 437.2.
  • Example 202 6-[4-[2-[[(1R,5S)-8-acetyl-8-azabicyclo[3.2.1]octan-3-yl]oxy]ethoxy]phenoxy]-1-methyl- indazole-5-carboxamide 6-[4-[2-[[(1R,5S)-8-acetyl-8-azabicyclo[3.2.1]octan-3-yl]oxy]ethoxy]phenoxy]-1-methyl- indazole-5-carboxamide (Example 202) was prepared in analogy to Example 141, by replacing Example 140 with Example 202 in step 1. MS [M+H] + : 479.2.
  • Example 203 1-methyl-6-[4-[2-[[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3- yl]oxy]ethoxy]phenoxy]indazole-5-carboxamide
  • the titled compound was synthesized from Example 201 according to the following scheme: To a solution of Example 201 (260.0 mg, 0.60 mmol) in methanol were added formalin (1 mL), HOAc (72.0 mg, 1.20 mmol) and NaBH3CN (188.5 mg, 3.00 mmol). The mixture was stirred at 20 °C for 2 h, quenched with sat. NaHCO3 and extracted with DCM.
  • Example 203 (100.6 mg) as white powder. MS [M+H] + : 451.2.
  • Example 204 6-[4-[2-[[(1R,5S)-8-(2-methoxyacetyl)-8-azabicyclo[3.2.1]octan-3-yl]oxy]ethoxy]phenoxy]-1- methyl-indazole-5-carboxamide
  • the titled compound was synthesized from Example 201 according to the following scheme: To a 20 mL vial were added Example 201 (120.0 mg, 0.28 mmol), DMF (3 mL), methoxyacetic acid (38.0 mg, 0.42 mmol), HATU (157.0 mg, 0.42 mmol) and DIEA (107.0 mg, 0.83 mmol). The resulting mixture was stirred at 20 °C for 2 h, diluted with water and extracted with DCM.
  • Example 204 (52.0 mg) as white solid. MS [M+H] + : 509.2.
  • Example 206 6-[4-[2-[[1-(2-methoxyacetyl)-4-piperidyl]oxy]ethoxy]phenoxy]-1-methyl-indazole-5- carboxamide 6-[4-[2-[[1-(2-methoxyacetyl)-4-piperidyl]oxy]ethoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 206) was prepared in analogy to Example 204, by replacing Example 201 with Example 140 in step 1. MS [M+H] + : 483.1.
  • Example 212 6-[4-[2-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxyethoxy]phenoxy]-1-methyl-indazole-5- carboxamide 6-[4-[2-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxyethoxy]phenoxy]-1-methyl-indazole-5- carboxamide (Example 212) was prepared in analogy to Example 208, by replacing Example 140 with Int-33a in step 1. MS [M+H] + : 451.1.
  • Step 2 7-[2-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-indazole-5- carbohydrazide (compound 220.2)
  • compound 220.1 200.0 mg, 0.45 mmol
  • N 2 H 4 •H 2 O 67.6 mg, 1.35 mmol
  • ethanol 3 mL
  • the crude product was purified by reversed-phase chromatography to give compound 220.2 (80.0 mg) as yellow solid.
  • MS [M+H] + 445.2.
  • Step 3 7-[2-fluoro-4-(2-tetrahydropyran-4-yloxyethoxy)phenoxy]-1-methyl-5-(4-methyl- 1,2,4-triazol-3-yl)indazole (Example 220) and 2-[7-[2-fluoro-4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]-1-methyl-indazol-5-yl]-1,3,4-oxadiazole (Exampe 221) To a 8 mL vial were added compound 220.2 (70.0 mg, 0.16 mmol), ACN (1 mL) and acetic acid (0.1 mL).
  • Example 220 (22.4 mg, 0.05 mmol) as yellow gum and Example 221 (14.3 mg) as yellow solid.
  • Example 224 1-methyl-7-[4-[3-(2-oxopiperazin-1-yl)propoxy]phenoxy]indazole-5-carboxamide
  • Example 224 was prepared in analogy to Example 100, by replacing tert-butyl 2- oxopiperazine-1-carboxylate with tert-butyl 3-oxopiperazine-1-carboxylate in step 1.
  • Step 2 1-methyl-5-pyridazin-3-yl-7-[4-(2-tetrahydropyran-4- yloxyethoxy)phenoxy]indazole (Example 225)
  • compound 225.1 (45.0 mg, 0.09 mmol)
  • 1,4-dioxane (1 mL)
  • water 0.1 mL
  • CataCXium Ad-G2 (received from Sigma-Aldrich; 0.6 mg, 0.01 mmol) and K2CO3 (25.0 mg, 0.18 mmol) were added.
  • the mixture was purged with N2 for 1 minute and stirred at 80 °C for 16 h.
  • the reaction mixture was cooled and filtrated.
  • Example 226 7-[4-(2,2-difluoro-3-morpholino-propoxy)phenoxy]-1-methyl-indazole-5-carboxamide
  • the titled compound was synthesized from Int-38a and Int-1a according to the following scheme: Step 1: methyl 7-[4-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoro-propoxy]phenoxy]-1- methyl-indazole-5-carboxylate (compound 226.1) To a mixture of K2CO3 (560.0 mg, 4.06 mmol) and Int-1a (400.0 mg, 1.34 mmol) in acetone (5 mL) was added Int-38a (0.98 g, 2.02 mmol).
  • Example 232 2-[4-[7-(4-cyclopropyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5-yl]oxyphenoxy]ethanol 2-[4-[7-(4-cyclopropyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-5- yl]oxyphenoxy]ethanol(Example 232) was prepared in analogy to Example 103, by replacing Int-27f with Int-27g in step 1; ethylamine hydrochloride with cyclopropanamine in step 2. MS [M+H] + : 378.2.
  • Example 238 1-cyclopropyl-3-[4-[5-(4-ethyl-1,2,4-triazol-3-yl)-1-methyl-indazol-7- yl]oxyphenyl]imidazolidin-2-one
  • 1-cyclopropyl-3-[4-[5-(4-ethyl-1,2,4-triazol-3-yl)-1-methyl-indazol-7- yl]oxyphenyl]imidazolidin-2-one (Example 238) was prepared in analogy to Example 233, by replacing Int-40a with Int-43d in step 3.
  • MS [M+H] + 444.3.
  • Example 245 1-(cyclopropylmethyl)-3-[4-[6-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-8- yl]oxyphenyl]imidazolidin-2-one
  • 1-(cyclopropylmethyl)-3-[4-[6-(4-ethyl-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-8- yl]oxyphenyl]imidazolidin-2-one (Example 245) was prepared in analogy to Example 234, by replacing Int-40b with Int-44b in step 1. MS [M+H] + : 444.2.
  • Example 246 3-[1-methyl-7-[4-(3-methyl-2-oxo-imidazol-1-yl)phenoxy]indazol-5-yl]triazole-4- carboxamide
  • the titled compound was synthesized from Int-29c according to the following scheme: Step 1: 3-[1-methyl-7-[4-(3-methyl-2-oxo-imidazol-1-yl)phenoxy]indazol-5-yl]triazole-4- carbonitrile (compound 246.1)
  • Int-29c 500.0 mg, 1.49 mmol
  • 3-(dimethylamino)acrylonitrile 17.5.0 mg, 1.82 mmol
  • TsNHNH 2 380.0 mg, 2.26 mmol
  • DMSO 5 mL
  • Example 246 (3.28 mg) as white solid.
  • Example 247 1-[4-[5-(4-ethyl-1,2,4-triazol-3-yl)-1-methyl-indazol-7-yl]oxyphenyl]-3-(1- methylcyclopropyl)imidazol-2-one 1-[4-[5-(4-ethyl-1,2,4-triazol-3-yl)-1-methyl-indazol-7-yl]oxyphenyl]-3-(1- methylcyclopropyl)imidazol-2-one (Example 247) was prepared in analogy to Example 233, by replacing Int-40a with Int-45b in step 3. MS [M+H] + : 456.2.
  • Example 251 1-cyclopropyl-6-[4-[3-(4-methylpiperazin-1-yl)propoxy]phenoxy]indazole-5-carboxamide
  • Example 251 was prepared in analogy to Example 31, by replacing Int-6c with Int-6f, 3,3- dimethylmorpholine with 1-methylpiperazine in step 1.
  • MS [M+H] + 450.1.
  • RNA polymerase II C-terminal domain(Ser5)-biotin [CTD(Ser5)-biotin]peptide, Europium-anti- phospho-C-terminal domain (Ser5) [Eu-anti-pCTD(Ser5)] and Streptavidin-XL665 (SA-XL665) were obtained from HTRF CDKs kinase kit (cisbio, cat# 63ADK000CB13PEH).
  • reaction buffer 50 mM HEPES, 10 mM MgCl2, 1 mM EGTA, 0.1 mg/ml BSA, 1 mM DTT and 0.01% Tween20
  • Example B2 IL-10 expression analysis in THP-1 cells
  • THP-1 cells (ATCC) were suspended in RPMI 1640 (Invitrogen) containing 2% heat- inactivated FBS and 100 ⁇ M penicillin-streptomycin at a concentration of 1 x 10 6 cells/mL and incubated with diluted compound followed by stimulation with 5 ⁇ M R848 (1-[4-amino-2- (ethoxymethyl)imidazo[4,5-c]quinolin-1-yl]-2-methyl-propan-2-ol, working concentration) in 96-well plates for overnight culture (5 vol% CO 2 , 37°C).

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Abstract

La présente invention concerne de nouveaux composés de formule générale (I) dans laquelle R1 à R2, L1 à L5, A1 à A4 sont tels que décrits dans la description, ou un sel pharmaceutiquement acceptable de ceux-ci, des compositions comprenant les composés et des procédés d'utilisation des composés.
PCT/EP2025/050384 2024-01-11 2025-01-09 Dérivés d'hétéroarylphényl éther Pending WO2025149545A1 (fr)

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US4625048A (en) * 1982-08-13 1986-11-25 Hoffmann-La Roche Inc. Carbamic acid esters
EP0669874A1 (fr) * 1992-11-23 1995-09-06 C.G. Bretting Manufacturing Co., Inc. Systeme de transfert pour repliage de panneaux multiples
WO2003090751A1 (fr) * 2002-04-26 2003-11-06 Pfizer Products Inc. Inhibiteurs de metalloproteinase a base de pyrimidine-2, 4, 6-trione
WO2016041618A1 (fr) * 2014-09-15 2016-03-24 Merck Patent Gmbh Indazoles substitués et hétérocycles associés
CN107189048A (zh) * 2017-06-06 2017-09-22 四川大学 基于芳腈结构的低烟阻燃抗熔滴共聚酯及其制备方法
WO2020011810A1 (fr) * 2018-07-09 2020-01-16 Abivax Dérivés de phényl-n-quinoléine pour le traitement d'une infection par un virus à arn
CN115141373A (zh) * 2022-08-04 2022-10-04 齐鲁工业大学 一种环氧基邻苯二甲腈/聚硅氧烷共聚树脂的制备方法
WO2022266458A1 (fr) * 2021-06-17 2022-12-22 Black Diamond Therapeutics, Inc. Dérivés de 6-hétérocycloalkyle-quinazoline et leurs utilisations

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US4625048A (en) * 1982-08-13 1986-11-25 Hoffmann-La Roche Inc. Carbamic acid esters
EP0669874A1 (fr) * 1992-11-23 1995-09-06 C.G. Bretting Manufacturing Co., Inc. Systeme de transfert pour repliage de panneaux multiples
WO2003090751A1 (fr) * 2002-04-26 2003-11-06 Pfizer Products Inc. Inhibiteurs de metalloproteinase a base de pyrimidine-2, 4, 6-trione
WO2016041618A1 (fr) * 2014-09-15 2016-03-24 Merck Patent Gmbh Indazoles substitués et hétérocycles associés
CN107189048A (zh) * 2017-06-06 2017-09-22 四川大学 基于芳腈结构的低烟阻燃抗熔滴共聚酯及其制备方法
WO2020011810A1 (fr) * 2018-07-09 2020-01-16 Abivax Dérivés de phényl-n-quinoléine pour le traitement d'une infection par un virus à arn
WO2022266458A1 (fr) * 2021-06-17 2022-12-22 Black Diamond Therapeutics, Inc. Dérivés de 6-hétérocycloalkyle-quinazoline et leurs utilisations
CN115141373A (zh) * 2022-08-04 2022-10-04 齐鲁工业大学 一种环氧基邻苯二甲腈/聚硅氧烷共聚树脂的制备方法

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MICHAEL F. T. KOEHLER ET AL: "Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells", ACS MEDICINAL CHEMISTRY LETTERS, vol. 7, no. 3, 10 March 2016 (2016-03-10), US, pages 223 - 228, XP055336410, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.5b00278 *
SERGIO H SZAJNMAN WEN YAN BRIAN N BAILEY ROBERTO DOCAMPO ELEONORA ELHALEM JUAN B RODRIGUEZ: "Design and Synthesis of Aryloxyethyl Thiocyanate Derivatives as Potent Inhibitors of Trypanosoma cruzi Proliferation", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 43, no. 9, 4 May 2000 (2000-05-04), pages 1826 - 1840, XP008182415, ISSN: 0022-2623, [retrieved on 20000414], DOI: 10.1021/JM9905007 *

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