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WO2025225608A1 - Dérivé de tétrahydropyrazolopyridine - Google Patents

Dérivé de tétrahydropyrazolopyridine

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Publication number
WO2025225608A1
WO2025225608A1 PCT/JP2025/015581 JP2025015581W WO2025225608A1 WO 2025225608 A1 WO2025225608 A1 WO 2025225608A1 JP 2025015581 W JP2025015581 W JP 2025015581W WO 2025225608 A1 WO2025225608 A1 WO 2025225608A1
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WO
WIPO (PCT)
Prior art keywords
compound
alkyl
substituted
salt
methyl
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/JP2025/015581
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English (en)
Inventor
Hirotaka Tanaka
Takuya Chiba
Yohei Yuki
Keita IIO
Yasuhiro Menjo
Yusuke AKAO
Akimasa Sato
Shumpei Ishikawa
Masaki Toda
Miho KANEDA
Nasa SAKAMOTO
Koji Sakai
Ayumu Sato
Jinichi Yonemori
Yoshi Nara
Mitsuhiro Ito
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.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
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Publication of WO2025225608A1 publication Critical patent/WO2025225608A1/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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to tetrahydropyrazolopyridine derivatives having AAK1 inhibitory activity.
  • Adaptor-associated kinase 1 also known as AP2-associated protein kinase 1
  • AAK1 is a member of Ark1/Prk1 family of serine/threonine kinase, which is an enzyme involved in clathrin-mediated endocytosis.
  • AAK1 has attracted attention as a promising target for the treatment of various neurological and psychiatric disorders, including schizophrenia, Parkinson's disease, bipolar disorder, Alzheimer's disease, and neuropathic pain, as well as viral infection (Non-Patent Literatures 1 - 12), and the research on its inhibitors has been progressing.
  • NPL 1 Henderson DM, et al. Mol Biol Cell. 2007; 18(7): 2698-2706.
  • NPL 2 Mettlen M, et al. Annu Rev Biochem. 2018: 87: 871-896.
  • NPL 3 Kuai L, et al. Chem Biol. 2011; 18(7): 891-906.
  • NPL 4 Mei L, et al. Nat Rev Neurosci. 2008; 9(6): 437-452.
  • NPL 5 Buonanno A. Brain Res Bull. 2010; 83(3-4): 122-131.
  • NPL 6 Jaaro-Peled H, et al. Schizophr Bull. 2010; 36(2): 301-313.
  • NPL 7 Wen L, et al. Proc Natl Acad Sci U S A. 2010; 107(3): 1211-1216.
  • NPL 8 Latourelle JC, et al. BMC Med Genet. 2009: 10: 98.
  • NPL 9 Zhang Y, et al. Am J Med Genet B Neuropsychiatr Genet. 2005; 137B(1): 5-16.
  • NPL 10 Kostich W, et al. J Pharmacol Exp Ther. 2016; 358(3): 371-386.
  • NPL 11 Karim M, et al. Antiviral Res. 2022: 204: 105367.
  • NPL 12 Neveu G, et al. J Virol. 2015; 89(8): 4387-4404.
  • the purpose of the present invention is to provide a new pharmaceutical compound having a potent AAK1 inhibitory activity, which is expected to have therapeutic effect for schizophrenia, Parkinson's disease, neuropathic pain, bipolar disorder, Alzheimer's disease, viral infection, etc.
  • (Item 12) The compound of any one of Items 1 - 11, wherein R 1 or R 12 is a 4- to 7-membered monocyclic or 7- to 10-membered bicyclic saturated heterocyclyl which includes 1 - 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom as a ring heteroatom, or a salt thereof or a co-crystal thereof.
  • (Item 13) The compound of any one of Items 1 - 11, wherein R 1 or R 12 is a 5- or 6-membered monocyclic or 8- to 10-membered bicyclic aromatic heterocyclyl which includes 1 - 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom as a ring heteroatom, or a salt thereof or a co-crystal thereof.
  • (Item 21) The compound of any one of Items 1 - 20, wherein R 1 or R 12 is (i) azetidinyl, pyrrolidinyl, or piperidinyl, (ii) oxetanyl, oxolanyl, oxanyl, or dioxanyl, (iii) pyrazolyl, imidazolyl, 1,3-oxazolyl, thiazolyl, pyridinyl, pyrazinyl, or 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazinyl, (iv) 8-oxa-3-azabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl, or 2-oxa-5-azabicyclo[2.2.1]heptanyl, (v) 5-azaspiro[2.4]heptanyl, or (vi) morpholinyl, 1,4-oxazepanyl
  • (Item 26) The compound of any one of Items 2 - 25, wherein R 3 is F, Cl, difluoromethyl, hydroxymethyl, -CHO, phenyl, 4-cyanophenyl, 2-methyl-1,3-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-5-yl, 1,2-thiazol-3-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 1-trifluoromethyl-1H-pyrazol-4-yl, pyrrolidin-2-on-1-yl, 3,4-dihydro-2H-pyridin-1-yl, pyridin-2-yl, 2-methylpyridin-4-yl, 3-fluoropyrrolidin-1-yl, 1,3-oxazol-2-yl, 1,3-oxazol-5-yl, 2,3-dihydro-1,4-oxa
  • Item 29 The compound of Item 1, which is selected from the following compounds: or a salt thereof or a co-crystal thereof.
  • (Item 31) A pharmaceutical composition comprising the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof.
  • An inhibitor of AAK1 activity comprising the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof.
  • a pharmaceutical composition for treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection comprising the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof.
  • Item 34 The pharmaceutical composition of Item 33, wherein the acute pain and chronic pain are pain associated with rheumatoid arthritis, or wherein the neuropathic pain is pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), or peripheral neuropathy (such as diabetic neuropathy and postherpetic neuralgia, chemotherapy induced peripheral neuropathy) wherein the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.
  • the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landou
  • (Item 35) The compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof, for use in treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection.
  • (Item 36) The compound of any one of Item 35, or a salt thereof or a co-crystal thereof, wherein the acute pain and chronic pain are pain associated with rheumatoid arthritis, or wherein the neuropathic pain is pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), or peripheral neuropathy (such as diabetic neuropathy and postherpetic neuralgia, chemotherapy induced peripheral neuropathy) wherein the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.
  • the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular
  • (Item 37) Use of the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection.
  • Item 38 The use of Item 37, wherein the acute pain and chronic pain are pain associated with rheumatoid arthritis, or wherein the neuropathic pain is pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), or peripheral neuropathy (such as diabetic neuropathy and postherpetic neuralgia, chemotherapy induced peripheral neuropathy) wherein the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.
  • the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy
  • a method for treating or preventing Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection comprising administering a therapeutically effective amount of the compound of any one of Items 1 - 30, or a salt thereof or a co-crystal thereof to a patient in need thereof.
  • Item 40 The method of Item 39, wherein the acute pain and chronic pain are pain associated with rheumatoid arthritis, or wherein the neuropathic pain is pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), or peripheral neuropathy (such as diabetic neuropathy and postherpetic neuralgia, chemotherapy induced peripheral neuropathy) wherein the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.
  • the muscular dystrophy includes Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy
  • Another embodiment of the present invention includes a method of treating or controlling a disease or disorder, comprising administering a therapeutically or prophylactically effective amount of the AAK1 inhibitor of the present invention to a patient in need thereof, wherein the disease or disorder is Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia (including cognitive impairment in schizophrenia), pain, muscular dystrophy, or viral infection.
  • the disease or disorder is Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia (including cognitive impairment in schizophrenia), pain, muscular dystrophy, or viral infection.
  • Specific types of pain include chronic pain, acute pain, and neuropathic pain.
  • Specific types of acute pain and chronic pain include pain associated with rheumatoid arthritis.
  • muscular dystrophy include Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.
  • neuropathic pain include pain associated with fibromyalgia, central nervus neuropathy, and peripheral neuropathy (such as diabetic neuropathy, postherpetic neuralgia, chemotherapy induced peripheral neuropathy).
  • halogen used herein includes, for example, fluorine, chlorine, bromine, and iodine, and preferably, fluorine and chlorine.
  • C 1-6 alkyl used herein means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, which includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, and their structural isomers.
  • C 1-6 alkoxy used herein means an oxy group substituted with the above “C 1-6 alkyl", which includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.
  • the "C 3-10 cycloalkyl” used herein means a cyclic non-aromatic hydrocarbon group having 3 to 10 carbon atoms.
  • the "C 3-10 cycloalkyl” includes preferably “C 3-6 cycloalkyl”.
  • the "C 3-10 cycloalkyl” includes a bridged one.
  • the "C 3-10 cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl, and bicyclo[1.1.1]pentyl.
  • C 1-6 haloalkyl used herein means a C 1-6 alkyl group substituted with one or more the same or different halogen atoms.
  • the "C 1-6 haloalkyl” includes preferably a C 1-6 alkyl group substituted with 1 to 5 the same or different halogen atoms.
  • C 1-6 haloalkyl includes, for example, mono-, di-, or tri-fluoromethyl; mono-, di-, or tri-chloromethyl; mono-, di-, tri-, tetra-, or penta-fluoroethyl; mono-, di-, tri-, tetra-, or penta-chloroethyl; and 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl.
  • the typical C 1-6 haloalkyl includes trifluoromethyl and difluoromethyl.
  • the "C 1-6 hydroxyalkyl” means a C 1-6 alkyl group substituted with one or more hydroxy groups.
  • the "C 1-6 hydroxyalkyl” includes preferably a C 1-6 alkyl group substituted with 1 to 3 hydroxy groups.
  • the "C 1-6 hydroxyalkyl” includes, for example, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.
  • the "4- to 12-membered saturated or aromatic heterocyclyl” includes a monocyclic one and a polycyclic one such as bicyclic one, and preferably mono-cyclic and bicyclic ones.
  • bicyclic ring includes a bicyclic ring in which one ring is a saturated hetero ring and the other is an aromatic hetero ring, and a bicyclic ring in which one ring is a saturated or aromatic hetero ring and the other is a cycloalkyl or benzene ring.
  • the "4- to 12-membered saturated heterocyclyl” used herein means a 4- to 12-membered saturated ring group containing heteroatom(s), which includes the ring group having partially unsaturated bond(s). It includes 4- to 7-membered mono-cyclic or 7- to 12-membered bi-cyclic saturated hetero ring group containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom; and 4- to 7-membered mono-cyclic or 7- to 10-membered bi-cyclic saturated hetero ring group containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom.
  • It includes, preferably, 4- to 7-membered mono-cyclic saturated hetero ring group containing 1 or 2 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and 7- to 10-membered bi-cyclic saturated hetero ring group containing 1 to 3 the same or different heteroatoms, and more preferably, 4- to 6-membered mono-cyclic or 7- to 8-membered bi-cyclic saturated hetero ring group containing 1 or 2 the same or different heteroatoms selected from the group consisting of nitrogen atom and oxygen atom.
  • the "4- to 12-membered aromatic heterocyclyl” includes 4- to 8-membered mono-cyclic or 7- to 10-membered bi-cyclic aromatic heterocyclyl containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, preferably 5- to 6-membered mono-cyclic aromatic heterocyclyl containing only 1 - 4 nitrogen atoms, or only one oxygen or sulfur atom, or one or two nitrogen atoms and one oxygen atom or sulfur atom, more preferably 5- to 6-membered mono-cyclic aromatic heterocyclyl containing only one or two nitrogen atoms, or one or two nitrogen atoms and one oxygen or sulfur atom.
  • the "4- to 12-membered saturated or aromatic heterocyclyl” is a saturated, partially-unsaturated, or unsaturated, monocyclic or polycyclic heterocyclic ring group containing, as ring-constituting heteroatoms, 1 to 4 heteroatoms independently-selected from the group consisting of nitrogen, oxygen, and sulfur (preferably nitrogen and oxygen), which includes, for example, (a) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered, preferably 4- to 7-membered, more preferably a saturated 5- or 6-membered mono-cyclic heterocyclic ring group containing 1 to 4 nitrogen atoms alone as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, tetrahydropyridine, pyrimidine, pyrazine, pyridazine, triazole, te
  • the polycyclic saturated or aromatic heterocyclyl may be a bridged ring or a spiro ring.
  • R 1 is 4- to 12-membered saturated or aromatic heterocyclyl, preferably R 12 is not a 4- to 12-membered saturated or aromatic heterocyclyl.
  • the "4- to 10-membered saturated heterocyclyl" in R 11 means a 4- to 10-membered saturated ring group containing heteroatom(s), which may include partially unsaturated bond(s). It includes 4- to 7-membered mono-cyclic or 7- to 10-membered bi-cyclic saturated heterocyclyl containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, preferably 4- to 7-membered mono-cyclic saturated heterocyclyl containing one or two the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom.
  • the substituent "4- to 7-membered saturated or aromatic heterocyclyl" with which Ring A is substituted means 4- to 7-membered saturated ring group containing heteroatom(s), which may include partially unsaturated bond(s). It includes 4- to 7-membered mono-cyclic saturated or aromatic heterocyclyl containing, as ring-constituting heteroatoms, 1 to 4 the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, preferably 4- to 6-membered mono-cyclic saturated or aromatic heterocyclyl containing one or two the same or different heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom.
  • it includes the following groups.
  • C 6-10 aryl used herein means an aromatic hydrocarbon group having 6 - 10 carbon atoms, which includes, more preferably, phenyl.
  • the "C 6-10 aromatic hydrocarbon group” includes, for example, phenyl, 1-naphthyl, and 2-naphthyl.
  • the "thieno[3,2-b]pyridine” or “[1,2]thiazolo[4,5-b]pyridine” has the structures shown below, and the binding position is bondable carbon atom or nitrogen atom in the ring. And, “an N-oxide thereof” means a N-oxide form of the nitrogen atom which constitutes the ring. Preferably, the binding position is as shown below.
  • the “salt” used herein means a pharmaceutically acceptable acid addition salt or base addition salt.
  • the pharmaceutically acceptable salt includes, but not to be limited thereto, acid addition salts such as acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, malonate, lactate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonate, para-toluenesulfonate (tosylate), laurylsulfate, malate, ascorbate, mandelate, saccharin, xinafoate, pamoate, cinnamate, adipate, cysteine salt, N-acetylcysteine salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide,
  • co-crystal used herein means a complex crystal composed of the present compound and an ingredient (coformer) that exist in the same crystal lattice interacting nonionically each other in a molar ratio.
  • the co-crystal can exist as multiple crystal forms (also referred to herein as "crystalline polymorphs").
  • the present compound forming a co-crystal may be in any crystal form or a mixture thereof, and may be amorphous.
  • the coformer includes, for example, the compounds listed below, but not to be limited thereto. And, Examples 12, 30, 41, etc. shown below are exemplified as co-crystals.
  • the present compound or a salt thereof and the coformer may coexist in various proportions, for example, 1/10, 1/5, 1/4, 1/3, 1/2, 2/3, 3/4, 1, 1.5, 2, 3, etc.
  • the compound of the present invention encompasses various hydrates, solvates, and crystalline polymorphs of Compound [1] or a salt thereof or a co-crystal thereof.
  • the hydrates or solvates of Compound [1] or a salt thereof or a co-crystal thereof may be present in various proportions, for example, 1/10, 1/5, 1/4, 1/3, 1/2, 2/3, 3/4, 1, 1.5, 2, 3, etc.
  • the compound of the present invention or a salt thereof or a co-crystal thereof also includes compounds in which one or more atoms are replaced by one or more isotope atoms.
  • isotope atoms include deuterium ( 2 H or D), tritium ( 3 H), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 35 S, 36 Cl, 37 Cl, 18 F, 123 I, 125 I, and the like.
  • Compound [I], or a salt thereof or a co-crystal thereof may be useful as a Positron Emission Topography (PET) tracer, preferably a PET imaging agent, that may be useful for in vitro, exo vivo, in vivo, or clinical trial tests and diagnostic imaging in humans and/or non-humans.
  • PET Positron Emission Topography
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O, and 13 N, can be useful in PET studies for examining target occupancy.
  • compounds labeled with 11 C or 18 F may be used for a PET tracer.
  • the compound [1] of the present invention includes pharmaceutically acceptable prodrugs.
  • substituents that can be modified to make prodrugs include reactive functional groups such as -OH, -COOH, and amino.
  • the modifying groups of these functional groups can be selected appropriately from the "substituents" in the present specification.
  • the functional groups may be modified with any group(s) selected appropriately from the protecting groups of hydroxy, carboxy, and amino.
  • R includes H, C 1-6 alkyl, and halogen, preferably H, methyl, F, and Cl, and more preferably H.
  • R 1 includes C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 12-membered saturated heterocyclyl, 4- to 12-membered aromatic heterocyclyl, -O-R 11 , and -N(R 11a )(R 11b ), wherein the saturated and aromatic heterocyclyls may be substituted with oxo to give an oxide or dioxide form, and any one or more hydrogen atoms in R 1 may be substituted with the same or different R 12 .
  • the above C 1-6 alkyl includes, preferably methyl, ethyl, propyl, isopropyl, 2-methylpropyl, tert-butyl, 2-methylbutyl, 3-methylbutyl, and hexyl, more preferably methyl, ethyl, propyl, 2-methylpropyl, 2-methylbutyl, and 3-methylbutyl.
  • the above C 3-10 cycloalkyl includes, preferably cyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentyl.
  • the above 4- to 12-membered saturated heterocyclyl includes, preferably azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, morpholinyl, oxazepanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, hexahydrofuro[3,4-c]pyrrolyl, dihydro-4H-pyrazolo[1,5-a]pyrazinyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, and azaspiro[2.4]heptanyl.
  • the above 4- to 12-membered aromatic heterocyclyl includes, preferably pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, and pyrazinyl, and the above aromatic heterocyclyl substituted with oxo includes pyridin-2(1H)-one.
  • R 11 , R 11a , and R 11b include H, C 1-6 alkyl, C 3-8 cycloalkyl, and 4- to 10-membered saturated heterocyclyl.
  • the above C 1-6 alkyl includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and their structural isomers, preferably methyl, ethyl, propyl, and tert-butyl, more preferably methyl, ethyl, and tert-butyl.
  • the above C 3-8 cycloalkyl includes, preferably cyclopropyl, cyclobutyl, and cyclopentyl.
  • the above 4- to 10-membered saturated heterocyclyl includes, preferably oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.
  • the above halogen includes, preferably fluoro and chloro, more preferably fluoro.
  • the above C 1-6 alkyl includes, preferably methyl and ethyl.
  • the above C 1-6 haloalkyl includes, preferably trifluoromethyl, difluoromethyl, and 2,2,2-trifluoroethyl, more preferably trifluoromethyl.
  • the above C 1-6 alkoxy-C 1-6 alkyl includes, preferably methoxymethyl, ethoxymethyl, and methoxyethyl, more preferably methoxymethyl.
  • the above C 6-10 aryl includes, preferably phenyl and naphthyl, more preferably phenyl.
  • the above C 3-10 cycloalkyl includes, preferably cyclopropyl, cyclobutyl, and cyclopentyl, more preferably cyclopropyl.
  • the above 4- to 12-membered saturated or aromatic heterocyclyl includes, preferably oxazolyl, tetrahydrofuranyl, morpholinyl, and pyrazolyl.
  • the above C 1-6 alkyl includes, preferably methyl and ethyl, more preferably methyl.
  • the above C 1-6 alkoxy-C 1-6 alkyl includes, preferably 2-methoxyethyl.
  • R 2 includes C 1-6 alkyl, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, and their structural isomers, and more preferably methyl.
  • R 3 includes F, Cl, difluoromethyl, hydroxymethyl, -CHO, phenyl, 4-cyanophenyl, 2-methyl-1,3-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-5-yl, 1,2-thiazol-3-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-5-yl, 1-trifluoromethyl-1H-pyrazol-4-yl, pyrrolidin-2-on-1-yl, 3,4-dihydro-2H-pyridin-1-yl, pyridin-2-yl, 2-methylpyridin-4-yl, 3-fluoropyrrolidin-1-yl, 1,3-oxazol-2-yl, 1,3-oxazol-5-yl, 2,3-dihydro-1,4-oxazin-4-yl, pyrimidin-5-yl,
  • m includes 0, 1, and 2, and preferably 1.
  • the compound of formula [1] can be prepared, for example, based on the general processes shown below, but is not limited thereto.
  • starting material compounds a commercially available one may be used, or it may be synthesized according to a known method or a method analogous thereto.
  • the solvents, acids, bases, protecting groups, and leaving groups which are used as needed in the production of the compound of formula [1] are not particularly limited as long as they are commonly used in the field of organic synthetic chemistry.
  • each product can be used in the next reaction as a reaction solution including it or as its crude product, or it can be also isolated from the reaction mixture according to a conventional method, or can be also easily purified by conventional separation means.
  • Conventional separation means include, for example, filtration, extraction, concentration, solvent removal, crystallization, recrystallization, reprecipitation, distillation, chromatography, and optical resolution.
  • these reactions are themselves performed by known methods.
  • the above conventionally-used methods and reagents are disclosed, for example, in ORGANIC FUNCTIONAL GROUP PREPARATIONS Second Edition, ACADEMIC PRESS, INC. 1989; Comprehensive Organic Transformations VCH Publishers Inc., 1989, P. G. M. Wuts; T. W.
  • Compound [1] may be manufactured, but is not limited thereto, based on the methods described in the General syntheses and Examples below. Unless otherwise specified, reaction temperatures may be optionally adjusted depending on reactants, solvents, and other conditions used in each reaction herein.
  • An alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction etherification reaction, nucleophilic substitution reaction, addition reaction, oxidation reaction, reduction reaction, and the like in the General syntheses may be performed in accordance with any known methods. Examples of such methods include the methods described in Experimental Chemistry (Fifth Edition, edited by The Chemical Society of Japan, Maruzen Co., Ltd.); Organic Functional Group Preparations Second Edition, Academic Press, Inc., 1989; Comprehensive Organic Transformations, VCH Publishers, Inc., 1989; and P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (Fourth Edition, 2006), and the like.
  • C 1-18 alkanesulfonyl is a linear or branched alkanesulfonyl having 1 to 18 carbon atoms (C 1-18 ), and examples thereof include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, and the like.
  • lower alkanesulfonyloxy is a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C 1-6 ), and examples thereof include methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy, and the like.
  • arylsulfonyloxy is phenylsulfonyloxy, naphthylsulfonyloxy, and the like, that is optionally substituted with 1 to 3 groups selected from the group consisting of a linear or branched alkyl having 1 to 6 carbon atoms (C 1-6 ), a linear or branched alkoxy having 1 to 6 carbon atoms (C 1-6 ), nitro, and halogen, on the benzene or naphthalene ring.
  • phenylsulfonyloxy optionally having substituent(s) include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and the like.
  • naphthylsulfonyloxy include ⁇ -naphthylsulfonyloxy, ⁇ -naphthylsulfonyloxy, and the like.
  • aralkylsulfonyloxy is a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C 1-6 ) that is substituted with phenyl optionally substituted with 1 to 3 groups selected from the group consisting of a linear or branched alkyl having 1 to 6 carbon atoms (C 1-6 ), a linear or branched alkoxy having 1 to 6 carbon atoms (C 1-6 ), nitro, and halogen on the benzene ring; or a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C 1-6 ) that is substituted with naphthyl, and the like.
  • alkanesulfonyloxy substituted with phenyl examples include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and the like.
  • alkanesulfonyloxy substituted with naphthyl include ⁇ -naphthylmethylsulfonyloxy, ⁇ -naphthylmethylsulfonyloxy, and the like.
  • perhaloalkanesulfonyloxy examples include trifluoromethanesulfonyloxy and the like.
  • sulfonio examples include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, di-(2-cyanoethyl)sulfonio, di-(2-nitroethyl)sulfonio, di-(aminoethyl)sulfonio, di-(2-methylaminoethyl)sulfonio, di-(2-dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio, di-(3-hydroxypropyl)sulfonio, di-(2-methoxyethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(
  • solvent may be an inert solvent in a reaction described herein, and examples thereof include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether), hydrocarbons, halogenated hydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, and carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, and xylene), alcohols (e.g., methanol, ethanol, and isopropanol), esters, ketones, amides, nitriles, sulfoxides, and polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (DMF), N-methylpyrroli
  • solvents may be used alone or as a mixture of any two or more of them with optional ratios.
  • hydrocarbons include, for example, aliphatic hydrocarbons such as hexane and pentane; alicyclic hydrocarbons such as cyclopentane and cyclohexane; and aromatic hydrocarbons such as benzene and toluene.
  • alcohols include, for example, methanol, ethanol, 2-propanol, propanol, and tert-butanol.
  • ethers herein include, for example, chained ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, and diphenyl ether; and circular ethers such as 1,4-dioxane and tetrahydrofuran.
  • esters herein include, for example, ethyl acetate and ethyl propionate.
  • ketones herein include, for example, acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • amides herein include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone.
  • nitriles herein include, for example, acetonitrile and propionitrile.
  • sulfoxides herein include, for example, dimethyl sulfoxide.
  • catalyst to be used in reduction reactions is not particularly limited to examples used herein, but examples thereof include palladium on carbon (Pd/C), platinum on carbon (Pt/C), platinum oxide (PtO 2 ), and the like.
  • halogenating agent is not particularly limited to examples used herein, but examples thereof include fluorinating agents, chlorinating agents, brominating agents, and iodinating agents, such as potassium fluoride, tetrabutylammonium fluoride, (diethylamino)sulfur trifluoride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, trichlorophosphoric acid, bromine, phosphorus oxybromide, phosphorus tribromide, iodine, sodium iodide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and the like.
  • fluorinating agents such as potassium fluoride, tetrabutylammonium fluoride, (diethylamino)sulfur trifluoride, phosphorus oxychloride
  • the term "acid” is not particularly limited to examples used herein, but includes an inorganic acid, an organic acid, and the like.
  • examples of the “inorganic acid” include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, and the like.
  • examples of the “organic acid” include acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and the like. These acids may be used alone or as a mixture of any two or more of them.
  • the term "base” is not particularly limited to examples used herein, but includes an inorganic base, an organic base, and the like.
  • the “inorganic base” include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, and barium hydroxide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, and barium carbonate), alkali metal carboxylates (e.g., sodium acetate, potassium acetate, and sodium butyrate), alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate), alkali metal phosphates (e.g., sodium phosphate, potassium phosphate, and ce
  • organic base examples include aromatic amines (e.g., pyridine and lutidine), trialkylamines (e.g., trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine (DIPEA)), cyclohexyldimethylamine, 4-dimethylaminopyridine (DMAP), N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorphiline, tetramethylethylenediamine, tetramethylpropylenediamine, picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), dialkylamine (e.g., diethylamine and diisopropylamine), metal
  • palladium catalyst is not particularly limited to examples used herein, and examples thereof include tetravalent palladium catalysts such as sodium hexachloropalladium (IV) acid tetrahydrate and potassium hexachloropalladium (IV) acid; divalent palladium catalysts such as [1,1’-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct (PdCl 2 (dppf).DCM), (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium (II) methanesulfonate (XPhos Pd G3), palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palla
  • the term "leaving group” is not particularly limited to examples used herein, and examples thereof include halogen (e.g., fluorine, chlorine, bromine, and iodine), C 1-18 alkylsulfonyl, alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy, and trifluoromethylsulfonyloxy), phenyloxy (e.g., 4-nitrophenyloxy), arylsulfonyloxy (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, and 4-nitrobenzenesulfonyloxy), aralkylsulfonyloxy, perhaloalkanesulfonyloxy, sulf
  • condensation agent examples include, but not limited to: T3P; PyBOP; DMT-MM; COMU; HBTU; HATU; DCC; N-cyclohexyl-N’-morpholinoethylcarbodiimide; N-cyclohexyl-N’-(4-diethylaminocyclohexyl)carbodiimide; N,N’-diethylcarbodiimide; N,N’-diisopropylcarbodiimide; N,N-diisopropylethylamine; WSC or a hydrochloride salt thereof; N,N’-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene, 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;
  • a condensation accelerator may be added.
  • a condensation accelerator used herein include, but not limited to, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzotriazole (HOAt), and hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt).
  • Examples of a reducing agent used herein include, but not limited to, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium triethylborohydride, lithium triethylborohydride, lithium aluminum hydride, sodium dihydridobis(2-methoxyethoxy)aluminate, borane-tetrahydrofuran complex, diisobutylaluminium hydride, and hydrosilane such as triethylsilane and phenylsilane.
  • Examples of a reducing agent for the reductive amination reaction herein include, but not limited to: sodium borohydride (NaBH 4 ), lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride (NaBH(OAc) 3 ), sodium triethylborohydride, lithium triethylborohydride, lithium aluminum hydride, sodium dihydridobis(2-methoxyethoxy)-aluminate, borane-tetrahydrofuran complex, diisobutylaluminium hydride, formic acid, sodium formate, ammonium formate, and phenylsilane.
  • sodium borohydride NaBH 4
  • lithium borohydride lithium borohydride
  • sodium cyanoborohydride sodium triacetoxyborohydride (NaBH(OAc) 3 )
  • sodium triethylborohydride lithium triethylborohydride
  • lithium aluminum hydride sodium dihydridobis(2-me
  • Examples of a catalyst for the reductive amination reaction herein include, but not limited to: Iridium catalysts such as chloro(pentamethylcyclopentadienyl)(8-quinolinolato)iridium (III), chlorido(8-quinolinolato- ⁇ 2N,O)( ⁇ 5-pentamethylcyclopentadienyl)iridium (III), [5,5'-bis(trifluoromethyl)-2,2'-bipyridine- ⁇ N, ⁇ N]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl- ⁇ N]phenyl] iridium hexafluorophosphate and (4,4'-Di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-kappaN)phenyl-kappaC] irid
  • Examples of a "protecting group of hydroxy” used herein include, but not limited to, any protecting groups of hydroxy used in the field of synthetic organic chemistry, and include, for example, alkyl groups (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, acetylmethyl); alkenyl groups (e.g., ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl); alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl); formyl; alkyl (alkenyl) carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, chloroacet
  • Examples of a “protecting group of carboxy” used herein include, but not limited to, any protecting groups of carboxy used in the field of synthetic organic chemistry, and include, for example, the “alkyl groups”, “alkenyl groups”, “alkynyl groups”, “aralkyl groups”, and “silyl groups” as above listed in the examples of the "protecting group of hydroxy” and similar groups thereof.
  • Examples of a “protecting group of amino” used herein include, but not limited to, any protecting groups of amino used in the field of synthetic organic chemistry, and include, for example, the “alkyl (alkenyl) carbonyl groups", “arylcarbonyl groups”, “alkoxycarbonyl groups”, “silyl groups”, “aralkyl groups”, “alkenyloxycarbonyl groups”, and “aralkyloxycarbonyl groups” as above listed in the "protecting group of hydroxy” and similar groups thereof.
  • the reaction temperature in each step in the General syntheses herein typically ranges from -80 to 150°C.
  • the reaction time in each step typically ranges from 0.1 to 200 hours.
  • the compound [1a] may be prepared by the reaction of compound [P1] with compound [P2] in the presence of a condensation reagent and a base in an inert solvent.
  • Step 1 The compound [P3] may be prepared by the reaction of compound [P2'] with SOCl 2 in an inert solvent.
  • Step 2 The compound [1] may be prepared by the reaction of compound [P1] with compound [P3] in the presence of a base in an inert solvent.
  • the compound [1a] may be prepared by the reaction of compound [P1] with compound [P5] in an inert solvent.
  • the compound [1a] may be also prepared by the reaction of compound [P6] with compound [P4] in the presence of MeI or MsOH in an inert solvent.
  • the compound [1b] may be prepared by the reaction of compound [P7] with compound [P8] in the presence of base in an inert solvent.
  • the compound [1e] may be prepared by the reaction of compound (P1) with compound [P9] in the presence of a base in an inert solvent.
  • the compound [1] may be prepared by the reaction of compound [P10] with compound [P11] in the presence of a palladium catalyst (e.g. Xphos-Pd-G3) and a fluoride ion (e.g. CsF) in an inert solvent.
  • a palladium catalyst e.g. Xphos-Pd-G3
  • a fluoride ion e.g. CsF
  • the compound [1] may be prepared by the deprotection reaction of compound (P12)
  • R 1 is amine
  • Q 1 is an "protecting group of amino" described herein.
  • the deprotection herein comprises any suitable deprotection reactions, the conditions of which depend upon the nature of a protecting group used.
  • Q 1 is a tert-butoxycarbonyl
  • the tert-butoxycarbonyl may be deprotected to the corresponding amine by hydrolysis with a suitable aqueous inorganic acid (e.g. hydrochloric acid).
  • Any solvents may be used in this reaction, and the solvent preferably used herein includes water, an organic solvent, and a mixed solvent of water and any of the organic co-solvents herein.
  • reaction product may be used in the next reaction either as is in the form dissolved in the reaction solution or as a crude product, but it may also be isolated from the reaction mixture by ordinary methods and easily purified by ordinary separation techniques. Examples of ordinary separation techniques include recrystallization, distillation, and chromatography.
  • Any starting compounds, intermediate compounds, and product compounds in each of the above steps and Compound [1] include geometric isomers, stereoisomers, optical isomers, and tautomers thereof. Respective isomers may be separated by ordinary optical resolution methods. They may also be manufactured from raw material compounds having suitable optical activity.
  • Compound [1] may be manufactured according to any of the above synthetic schemes, or analogous methods thereof.
  • any starting compounds used in the manufacture of Compound [1] are commercially available, or may be produced by known methods or analogous methods thereof.
  • Any starting compounds and product compounds in each step above may be used in the form of appropriate salts thereof.
  • Examples of such salts include salts similar to those listed for salts of Compound [1].
  • any compounds obtained in each step or commercially available compounds used herein are in the free form, they may be converted to corresponding salts by known methods.
  • any compounds obtained in each step or commercially available compounds used herein are in the salt form, they may be converted to corresponding free forms or into other salts by known methods.
  • the pharmaceutical composition comprising the compound [1] or a salt thereof or a co-crystal thereof as an active ingredient is a general formulation of pharmaceutical compositions, which can be formed with the compound [1] or a salt thereof or a co-crystal thereof, as well as a generally-used carrier, diluent and/or excipient, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants (also referred to as "pharmaceutically acceptable carrier").
  • Such a pharmaceutical composition can be selected from various forms according to the therapeutic objective, and examples thereof include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, emulsions, suspensions, etc.), and the like.
  • a wide range of known carriers may be used when molding the preparation in the form of a tablet, and examples thereof include excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; disintegration inhibitors such as white sugar, stearin, cocoa butter, and hydrogenated oil; absorption aids such as quaternary ammonium salt and sodium lauryl sulfate; humec
  • the tablet may as necessary be made into a tablet with an ordinary coating, such as a sugar-coated tablet, gelatin-coated tablet, enteric coated tablet, film-coated tablet, double tablet or multilayer tablet.
  • an ordinary coating such as a sugar-coated tablet, gelatin-coated tablet, enteric coated tablet, film-coated tablet, double tablet or multilayer tablet.
  • a wide range of known carriers may be used when molding the preparation in the form of a pill, and examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; and disintegrants such as laminaran, and agar.
  • excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc
  • binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol
  • disintegrants such as laminaran, and agar.
  • a wide range of known carriers may be used when forming the preparation as a suppository, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, ester of higher alcohol, gelatin, and semi-synthetic glyceride.
  • the liquid, the emulsion or the suspension is preferably sterilized, and is also preferably isotonic with blood.
  • diluents can be used for forming these liquid, emulsion, and suspension, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • sufficient amounts of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and a conventional solubilizing agent, buffer, soothing agent, etc. may be included, and further a coloring agent, preservative, etc., and/or one or more other pharmaceuticals may be also included as necessary.
  • the amount of Compound [1] or a salt thereof or a co-crystal thereof that is contained in the pharmaceutical composition is not particularly limited and may be selected appropriately from a wide range, but generally Compound [1] or a salt thereof or a co-crystal thereof is preferably contained in the amount of 1% to 70% of the pharmaceutical composition.
  • the method for administering the pharmaceutical composition of the present invention is not particularly limited, and it can be administered by a method suited to the dosage form, the age and sex of the patient (in particular, human), the disease status and other conditions.
  • it can be administered orally when it is in the form of a tablet, pill, liquid, suspension, emulsion, granules or capsules.
  • it can be administered intravenously either alone or in a mixture with an ordinary replacement fluid such as glucose or amino acids, or else it can be administered by itself intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary.
  • a suppository it can be administered in the rectum.
  • the dose of the pharmaceutical composition may be selected according to the administration method, the age and sex of the patient (in particular, human), the severity of the disease and other conditions, but generally 0.001 to 100 mg or preferably 0.001 to 50 mg of Compound [1] per 1 kg of body weight can be administered per day in one to several administrations.
  • the dose herein is also referred to as effective amount. This dose is affected by various conditions, and in some cases a dose below the aforementioned range may be sufficient, while in others a dose above the aforementioned range may be necessary.
  • the compound [1] or a salt thereof or a co-crystal thereof has a potent AAK1 inhibitory activity, which is expected to have therapeutic and/or prophylactical effect for a disease/disorder associated with AAK1. Specifically, it is expected to have therapeutic and/or prophylactical effect for Alzheimer's disease, bipolar disorder, Parkinson disease, schizophrenia, cognitive impairment in schizophrenia, acute pain, chronic pain, neuropathic pain, muscular dystrophy, or a disease associated with viral infection, and the like. Specific types of pain include chronic pain, acute pain, and neuropathic pain. Specific types of acute pain and chronic pain include pain associated with rheumatoid arthritis.
  • neuropathic pain include pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), and peripheral neuropathy (such as diabetic neuropathy, postherpetic neuralgia, chemotherapy induced peripheral neuropathy).
  • specific types of muscular dystrophy include Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy, Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy, Mytonic dystrophy, congenital muscular dystrophy.
  • Another embodiment of the invention includes a method of treating or controlling a disease or disorder, comprising administering a therapeutically or prophylactically effective amount of the AAK1 inhibitor of the invention to a patient in need thereof, wherein the disease or disorder is Alzheimer's disease, bipolar disorder, pain, Parkinson disease, schizophrenia (including cognitive impairment in schizophrenia), or viral infection.
  • Specific types of pain include chronic pain, acute pain, and neuropathic pain.
  • Specific types of acute pain and chronic pain include pain associated with rheumatoid arthritis.
  • Specific types of neuropathic pain include pain associated with fibromyalgia, central nervus neuropathy (such as spinal cord injury related pain), and peripheral neuropathy (such as diabetic neuropathy, postherpetic neuralgia, chemotherapy induced peripheral neuropathy).
  • room temperature generally indicates from about 10°C to about 35°C.
  • the ratios indicated for mixed solvents are volume ratios unless otherwise specified. Percentages indicate weight% unless otherwise specified.
  • the 1 H-NMR proto nuclear magnetic resonance spectrum
  • the 1 H-NMR was measured by Fourier-transform type NMR (any one of Bruker AVANCE III 400 (400 MHz), Bruker AVANCE III HD (500 MHz), RUKER AVANCE 400 (400 MHz), and BRUKER AVANCE III 300N (300 MHz)).
  • the spectra were analyzed with MestReNova version:14.1.2 (Mestrelab Research) or ACD/Spectrus Processor TM (ACD).
  • Mass spectrum was measured by LC/MS (either of ACQUITY UPLC H-Class and Shimadzu LCMS-2020). As an ionization method, ESI method was used. The data indicate actual measured values (found). Generally, molecular ion peaks ([M+H]+, [M-H]-, etc.) were observed. In the case of a salt, a molecular ion peak or fragment ion peak of free form was generally observed. In silica gel column chromatography, when denoted as basic, aminopropylsilane-bonded silica gel was used.
  • the absolute configuration of the compound was determined by known X-ray crystal structure analysis methods (for example, Shigeru Oba and Shigenobu Yano, "Basic Course for Chemists 12, X-ray Crystal Structure Analysis” (First Edition, 1999)), or estimated from empirical rules of Shi asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401. Yuanming Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).
  • the resulting precipitate was collected on a filter. To the obtained precipitate were added water (50 mL) and aqueous saturated sodium bicarbonate (300 mL), and the mixture was stirred at 25°C for one hour. The resulting precipitate was collected on a filter and dried in vacuo. The residue was triturated in methanol, and the precipitate was collected on a filter and dried in vacuo to give the title compound (5.90 g).
  • the reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrated was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to givethe title compound as a crude product (part 1).
  • the temperature of the oil bath was set to 135°C, and the reaction mixture was stirred for 2 hours.
  • the reaction mixture was cooled to room temperature, and water (20 ml) and conc. hydrochloric acid (9.8 ml) were added to the reaction mixture.
  • the mixture was stirred at 50°C for 30 minutes.
  • the mixture was extracted with AcOEt, concentrated, and re-crystalized with heptane-EtOH to give the title compound (2.2 g).
  • Example 9 [(7S)-7-Methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(2R*)-piperidin-2-yl]methanone dihydrochloride
  • the titled compound was prepared from the corresponding starting material in the same manner as Example 1. The purification was carried out by SFC preparative separation (CHIRALPAK IH, CO 2 : MeOH + 0.1 % DEA), and the compound that came out later was designated as Example 9.
  • Example 13 62.7 mg
  • Example 14 61.8 mg
  • Example 15 [(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(2R*)-2-methyloxolan-2-yl]methanone
  • Example 16 [(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(2S*)-2-methyloxolan-2-yl]methanone
  • the titled compound was prepared from Reference example 18 and the corresponding starting material in the same manner as Example 13. The purification was carried out by SFC preparative separation (CHIRALPAK IH, CO 2 : MeOH + 0.1 %DEA), and the compound that came out first was designated as Example 15, and the compound that came out later
  • Example 17 [(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(3S)-oxan-3-yl]methanone
  • Example 18 [(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[(3R)-oxan-3-yl]methanone
  • the titled compound was prepared from Reference example 18 and the corresponding starting material in the same manner as Example 10. The purification was carried out by SFC preparative separation (CHIRALPAK IB N-5, CO 2 : MeOH + 0.1 %DEA), and the compound that came out first was designated as Example 17, and the compound that came out later was designated as Example 18.
  • Example 70 (3,3-Difluoropyrrolidin-1-yl)-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanethione 1,1’-Thiocarbonylimidazole (69 mg) was dissolved in DMF (1 ml), and a solution of the salt-free form of Reference example 20 (100 mg) in DMF (1 ml) was added to the solution at room temperature.
  • the racemic mixture (100 mg) was purified by chiral SFC (DAICEL CHIRALPAK AS-H, 0.1 % NH 3 H 2 O MeOH, CO 2 ) to give the title compound (compound with longer retention time, 23.0 mg).
  • Example 149 and (Example 150) (3-Fluorooxolan-3-yl)[(7S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]methanone
  • the titled compound was prepared from the corresponding starting material in the same manner as Example 8.
  • Example 149 the compound that came out first was designated as Example 149, and the compound that came out later was designated as Example 150 (the absolute structures at the fluorooxolane moiety are undetermined).
  • Example 152 2-Methoxy-1-[(7S)-7-methyl-2-(thieno[3,2-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]propan-1-one
  • the titled compound was prepared from the corresponding starting material in the same manner as Example 8.
  • Example 157 and (Example 158) 1-[(7S)-2-(2-Fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]-2-(oxolan-3-yl)ethan-1-one
  • the titled compound was prepared from the corresponding starting material in the same manner as Example 8. The purification was carried out by HPLC (CHIRALPAK IC, Ethanol) to give two single isomers, and the compound that came out first was designated as Example 157, and the compound that came out later was designated as Example 158 (the absolute structures at the oxolanylethane moiety are undetermined).
  • the titled compound was prepared from the corresponding starting material in the same manner as Example 8. The purification was carried out by HPLC (CHIRALPAK IG, Ethanol) to give two single isomers, and the compound that came out first was designated as Example 159, and the compound that came out later was designated as Example 160 (the absolute structures at the oxetanylmethanone moiety are undetermined).
  • Example 164 and (Example 165) (3-Fluorooxolan-3-yl)[(7S)-2-(2-fluorothieno[3,2-b]pyridin-7-yl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]methanone
  • the titled compound was prepared from the corresponding starting material in the same manner as Example 8. The purification was carried out with HPLC (CHIRALPAK IA, Ethanol) to give two single isomers, and the compound that came out first was designated as Example 164, and the compound that came out later was designated as Example 165 (the absolute structures at the fluorooxolane moiety are undetermined).
  • Example 199 [2-(Difluoromethyl)morpholin-4-yl]-[(7S)-7-methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]methanone
  • methyl iodide 0.083 mL
  • Example 200 [(7S)-7-Methyl-2-([1,2]thiazolo[4,5-b]pyridin-7-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl]-[2-(trifluoromethyl)morpholin-4-yl]methanone
  • methanesulfonic acid 0.036 mL
  • Test example 1 in vitro AAK1 inhibitory activity (1) Preparation of AAK1-His protein Sf9 cells (Thermo, Catalog No. 514002) were infected with baculovirus into which AAK1 gene sequence had been introduced with Entry clone pENTR-D-TOPO/hAAK1-His, and cultured in 2L of medium [PSFM-J1 Medium, 5% FBS, 100 units/mL Penicillin, 100 ⁇ g/mL Streptomycin (PSFM-J1 Medium; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 160-25851, FBS; Biowest, Catalog No.
  • a dissolution buffer having the following composition was used: 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM DTT, 5 U/mL Benzonase Nuclease (Tris; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 201-06273, HCl; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 081-05435, NaCl; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 195-01663, DTT; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 049-08972, Benzonase Nuclease; Merck, Catalog No. 71205).
  • the purification was carried out using Ni-NTA affinity column (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 141-09764), and HiLoad TM 26/600 Superdex TM 200 pg (Cytiva, Catalog No. 28989336).
  • the final buffer for AAK1 protein had the following composition: 1 x TBS, 5%(w/v) Glycerol, 1 mM DTT (TBS; Takara Bio, Catalog No. T9141, Glycerol; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 075-00611, DTT; FUJIFILM Wako Pure Chemical Corporation, Catalog No. 049-08972).
  • TR-FRET signal was detected (Ex 337 nm, Em 665/620 nm) using EnVision plate reader (PerkinElmer, Catalog No. 2104-0020) and IC 50 was calculated. ⁇ Measurement parameters> TR-FRET ratio is used for values of Sample, High control, and Low control.
  • IC 50 is calculated with XLfit (fit model 204 : 4 Parameter Logistic Model, IDBS Ltd.).
  • Test example 2 in vitro Cell activity
  • Cell assay T-REx-293 cells (Thermo, Catalog No. R71007) were seeded to Corning TM BioCoat TM Collagen I Coat Flask (Corning, Catalog No. 356485), and cultured at 37°C overnightin 5 % CO 2 .
  • the culture medium had the following composition.
  • DMEM 10% FBS, 100 units/mL Penicillin, 100 ⁇ g/mL Streptomycin, 10 ⁇ g/mL Blasticidin S HCl
  • DMEM high glucose
  • FUJIFILM Wako Pure Chemical Corporation Catalog No. 043-30085, FBS; Corning, Catalog No.
  • the culture medium was treated with TrypLE Express Enzyme (1X) and no phenol red (Thermo, Catalog No. 12604013) at room temperature for 5 minutes, and the cells were collected from the culture medium and seeded to a 96-well plate.
  • the compound solution dissolved in Doxycycline (Takara-Bio, Catalog No. 631311, final concentration: 1 ⁇ g/mL) and DMSO (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 043-07216, final concentration: 0.1%) was diluted with the culture medium and added to the well plate.
  • Lysis buffer [1 ⁇ Lysis buffer, 1/1000 ⁇ Protease inhibitor cocktail, 1/1000 ⁇ Phosphatase inhibitor cocktail (10 ⁇ Lysis buffer; CST, Catalog No. 9803S, Protease inhibitor cocktail; Sigma, Catalog No. P8340-1ML, Phosphatase inhibitor cocktail; Sigma, Catalog No. P5726-1ML)].
  • Lysis buffer [1 ⁇ Lysis buffer, 1/1000 ⁇ Protease inhibitor cocktail, 1/1000 ⁇ Phosphatase inhibitor cocktail (10 ⁇ Lysis buffer; CST, Catalog No. 9803S, Protease inhibitor cocktail; Sigma, Catalog No. P8340-1ML, Phosphatase inhibitor cocktail; Sigma, Catalog No. P5726-1ML)].
  • the phosphorylation state of the substrate AP2M1 was detected by ELISA.
  • a plate washer Biotek, Catalog No. 405TSUVSQ
  • a coating antibody Anti-HA Rat IgG, Roche, Catalog No.
  • 11867423001 was diluted 3000 times with PBS (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 045-29795) and added to a plate (Maxisorp 96 plate, Nunc, Catalog No. 437111). The plate was left standing at 4°C overnight, and the coating antibody was removed. Then, a blocking solution [0.5 ⁇ Block Ace (Megmilk Snow Brand, Catalog No. UKB40), 1/2000 ⁇ ProClin 300 (Sigma, Catalog No. 48912-U)] was added to the plate. The plate was left standing at 4°C overnight, and washed with TBST three times. Immuno-enhancer Reagent A solution (FUJIFILM Wako Pure Chemical Corporation, Catalog No.
  • Inhibition rate (1 - (Sample-Low control)/(High control - Low control)) ⁇ 100 Low control is a well without Doxycycline, High control is a well with Doxycycline.
  • Test example 3 PD assay An administration solution of the test substance was orally administered to C57BL/6J mice (CLEA Japan) at a dose of 0.1 to 3 mg/10 mL/kg. 0.5% Methylcellulose (FUJIFILM Wako Pure Chemical Corporation, Catalog No. 133-17815) was used as the solvent for the administration solution. 0.5 to 4 hours after the administration, the mice were decapitated without anesthesia. The cerebral cortex was cut out from the brain tissue. The weight of the cerebral cortex was measured, and it was placed in an Eppendorf tube (Eppendorf, catalog No. 0030120094). Five times the weight ( ⁇ L) of Cell Lysis Buffer (Cell Signaling Technology, Catalog No.
  • AP2M1 was detected on the membrane after the transcription, using Anti-AP2M1 (phospho T156) antibody (Cell Signaling Technology, Catalog No. 7399S), Anti-AP2M1 antibody (OriGene, Catalog No. AP50202PU-N), ECL rabbit IgG, and HRP-linked F(ab')2 Fragment (from Donkey) (Cytiva, Catalog No. NA9340-1ML).
  • Anti-AP2M1 (phospho T156) antibody and Anti-AP2M1 antibody were diluted 1,000 times with Can Get Signal Solution 1 (TOYOBO, Catalog No.
  • ECL rabbit IgG, HRP-linked F(ab')2 Fragment was diluted 20,000 times with Can Get Signal Solution 2 (TOYOBO, Catalog No. NKB-301), and reacted at room temperature for one hour.
  • ECL Prime Western Blotting Detection Reagent (Cytiva, Catalog No. RPN2236) was used as a detection reagent. The luminescence due to the antibody and the detection reagent was detected using LAS-4000 mini (GE healthcare). The relative protein amount was estimated from the density of the band detected using ImageQuant TL (Cytiva, ver. 7.0), and the AP2M1 phosphorylation status between the samples was compared.
  • Example compounds inhibited AP2M1 phosphorylation with a significant difference at doses of 0.3 to 3 mg/kg: Examples 8, 12, 18, 19, 20, 25, 30, 32, 34, 38, 47, 81, 135, 141, and 156.

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Abstract

La présente invention concerne des dérivés de tétrahydropyrazolopyridine ayant une activité inhibitrice de AAK1.
PCT/JP2025/015581 2024-04-23 2025-04-22 Dérivé de tétrahydropyrazolopyridine Pending WO2025225608A1 (fr)

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