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WO2024153067A1 - Dérivé hétérocyclique contenant de l'azote substitué par un hétérocycle, composition pharmaceutique, utilisation et procédé de préparation associé - Google Patents

Dérivé hétérocyclique contenant de l'azote substitué par un hétérocycle, composition pharmaceutique, utilisation et procédé de préparation associé Download PDF

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WO2024153067A1
WO2024153067A1 PCT/CN2024/072518 CN2024072518W WO2024153067A1 WO 2024153067 A1 WO2024153067 A1 WO 2024153067A1 CN 2024072518 W CN2024072518 W CN 2024072518W WO 2024153067 A1 WO2024153067 A1 WO 2024153067A1
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alkyl
halogenated
alkoxy
group
halogen
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PCT/CN2024/072518
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Chinese (zh)
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吴春艳
杨文�
谢婧
周宾山
朱卫星
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Publication of WO2024153067A1 publication Critical patent/WO2024153067A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • 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
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medical technology, and in particular to a heterocyclic substituted nitrogen-containing heterocyclic derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition, and an application and preparation method thereof.
  • Adaptor protein complex 2 (AP-2) is a heterotetramer composed of ⁇ , ⁇ , ⁇ , and ⁇ subunits. Clathrin-mediated endocytosis is initiated by recruiting the AP-2 complex to saturated protease-sensitive sites on the cell membrane. AAK1 was originally discovered as a phosphorylation-regulated kinase of AP-2, and both are involved in the formation of clathrin-coated vesicles.
  • AAK1 changes the molecular conformation of AP-2 by phosphorylating the ⁇ 2 subunit of AP-2, enhancing the affinity of AP-2 for endocytic receptors, accelerating the formation of clathrin-coated vesicles, and thus improving endocytic efficiency.
  • AAK1 is widely expressed in the brain and spinal cord, including dorsal root ganglia. GABA A receptor-related chloride channels are associated with nociception, and it is speculated that reducing the cell surface level of ⁇ 2 containing GABA A receptors and thus reducing endocytosis is related to the analgesic effect of AAK1 inhibitors.
  • AAK1 knockout mice have strong resistance to neuropathic pain, indicating that targeting the adapter-associated kinase 1 (AAK1) gene is a potential therapeutic target for neuropathic pain.
  • LX9211 developed by Lexicon and BMS, which is in Phase II clinical trials.
  • Preclinical studies have shown that in neuropathic pain models, LX9211 shows central nervous system penetration and reduced pain behavior, and does not affect the opioid pathway.
  • previous studies have found that LX9211 is cleared relatively quickly in rats, the in vivo exposure level is not ideal, and there is severe hERG inhibition, which has potential cardiotoxicity. Therefore, it is of great clinical significance to develop AAK1 inhibitors with high activity, better in vivo pharmacokinetic parameters, and weaker hERG inhibition.
  • the purpose of the present invention is to provide a heterocyclic substituted nitrogen-containing heterocyclic derivative which selectively inhibits AAK1 kinase activity, has excellent pharmacokinetic parameters, has a weaker hERG inhibitory effect, and has excellent central nervous system penetration.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • Z 1 and Z 2 are each independently C or N;
  • Ra and Rb are each independently absent, hydrogen, deuterium , -NRa0Rb0 , halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), halogen (preferably fluorine or chlorine), 5- or 6-membered heteroaryl, cyano, hydroxyl, carboxyl, C3-6 cycloalkyl, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), -S1-8 alkyl (preferably -S1-6 alkyl) R 1-8 alkyl (preferably -C ( O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)C 1-8 alkyl (preferably -C(O )OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl , more
  • R a0 and R b0 are each independently hydrogen, C 1-3 alkyl, -C(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, halogenated C 1-8 alkyl, 5- or 6-membered heteroaryl, -C(O)C 3-6 cycloalkyl, -C(O)NR a1 R b1 or -C(O)-R, R is a 5- or 6-membered heteroaryl; or R a0 , R b0 and the nitrogen atom to which they are connected together form a 4- to 6-membered saturated monocyclic heterocyclic ring; the 5- or 6-membered heteroaryl, the 4- to 6-membered saturated monocyclic heterocyclic ring are each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C
  • R c and R d are each independently hydrogen, deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, -NR a1 R b1 , C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -S 1-8 alkyl (preferably -S 1-6 alkyl, more preferably -S 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy) or C 3-6 cycloalkyl;
  • Ring A is a benzopyrazole ring, a pyrazine ring, a piperidine ring or a benzopyrrole ring;
  • R 1 n represents that the hydrogen on ring A is replaced by n R 1s , n is 0, 1, 2 or 3; each R 1 is the same or different and is independently cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -NR a1 R b1 , C 3-6 cycloalkyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -SC 1-8 alkyl (preferably -SC 1-6 alkyl, more preferably -SC 1-3 alkyl), -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl,
  • R 0 is hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
  • R 2 and R 3 are each independently a C 1-3 alkyl group; or R 2 , R 3 and the carbon atoms to which they are connected together form a C 3-6 cycloalkyl ring;
  • Ra1 and Rb1 are independently hydrogen, C1-3 alkyl or acetyl; or Ra1 , Rb1 and the nitrogen atom to which they are connected together form a 4- to 6-membered saturated monocyclic heterocyclic ring; the 4- to 6-membered saturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, oxo, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-3 alkyl, halogenated C1-3 alkoxy, -SO2C1-3 alkyl, -S (O)C1-3 alkyl , -SC1-3 alkyl, -C(O) NH2 , -C(O)NH( C1-3 alkyl), -C(O)N( C1-3 alkyl) 2 , -C(
  • the compound of formula (I) is a compound of formula (II):
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the structure Select one of the following structures:
  • (R 1 ) n represents that the hydrogen on ring A is replaced by n R 1 , n is 0 or 1; each R 1 is the same or different and is independently C 1-3 alkyl; wherein the C 1-3 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen.
  • each R 1 is the same or different and is independently monofluoromethyl, difluoromethyl, or trifluoromethyl.
  • R 1 is cyano, hydroxyl, carboxyl, halogen (preferably fluorine, chlorine or bromine), -NH 2 , C 1-3 alkyl, C 1-3 alkoxy, -C(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl or -C(O)NH 2 ; wherein the C 1-3 alkyl, the C 1-3 alkoxy are each independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl and carboxyl.
  • halogen preferably fluorine, chlorine or bromine
  • R 1 is halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkoxy.
  • R 1 is fluorine, fluorinated C 1-3 alkyl, or fluorinated C 1-3 alkoxy.
  • R 1 is fluoro, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, or trifluoroethoxy.
  • R 1 is difluoromethyl.
  • R 1 is C 3-6 cycloalkyl.
  • R 1 is cyclopropyl
  • the structure Select one of the following structures:
  • n 1
  • n 0.
  • Z1 and Z2 are both C;
  • Ra is hydrogen, deuterium , -NRa0Rb0 , halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), halogen (preferably fluorine or chlorine), 5- or 6-membered heteroaryl, cyano, hydroxyl, carboxyl, C3-6 cycloalkyl, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), halogenated C1-8 alkoxy (preferably halogenated C1-6 alkoxy, more preferably halogenated C1-3 alkoxy), -C(O) C1-8 alkyl (preferably -C(O) C1-6 alkyl, more preferably -C(O) C1-3 alkyl), -C(O) OC1-8 alkyl (preferably -C(O) OC1-6 alkyl, more preferably -C(O
  • Ra is hydrogen, halogen, C1-8 alkyl, halogenated C1-8 alkyl or C3-6 cycloalkyl;
  • R b is hydrogen, halogen (preferably fluorine or chlorine), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), cyano, hydroxyl, carboxyl, C 3-6 cycloalkyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl
  • R b is hydrogen
  • Z1 and Z2 are both C;
  • Ra is hydrogen, deuterium , -NRa0Rb0 , halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), halogenated C1-8 alkoxy (preferably halogenated C1-6 alkoxy, more preferably halogenated C1-3 alkoxy), halogen (preferably fluorine or chlorine), C3-6 cycloalkyl, -C(O) NRa1Rb1 or 5- or 6-membered heteroaryl; wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-3 alkyl, hal
  • R b is hydrogen or halogen (preferably fluorine or chlorine).
  • Z1 and Z2 are both C;
  • Ra is hydrogen, deuterium , -NRa0Rb0 , halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), halogenated C1-8 alkoxy (preferably halogenated C1-6 alkoxy, more preferably halogenated C1-3 alkoxy), halogen (preferably fluorine or chlorine), C3-6 cycloalkyl, -C(O) NRa1Rb1 , pyrazolyl or thiazolyl; wherein the pyrazolyl and the thiazolyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, C1-3 alkyl and halogenated C1-3 alkyl;
  • R b is hydrogen or halogen (preferably fluorine or chlorine).
  • Z1 and Z2 are both C;
  • Ra is hydrogen, deuterium, halogen, -NH2 , -NHCH3 , -NH-difluoroethyl, difluoromethyl, trifluoromethyl, monofluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, monofluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, -NHCOCH3 , -NHCOOCH3 , -NHCO-cyclopropyl, -NHCO-thiazole, -NHCO- tetrahydropyrrole, -NHCONHCH2CH3 , pyrazolyl, methylpyrazolyl, -NH-methylpyrazole, -NH-thiazole, -NH-methylthi
  • R b is hydrogen, fluorine or chlorine.
  • Z 1 and Z 2 are both C; Ra is hydrogen, halogen, difluoromethyl or cyclopropyl; and R b is hydrogen, fluorine or chlorine.
  • Z 1 and Z 2 are both C; Ra is hydrogen, halogen, or difluoromethyl; and R b is hydrogen, fluorine, or chlorine.
  • Z 1 and Z 2 are both C; Ra is fluoro, chloro, bromo, methyl, cyclopropyl, trifluoromethyl, difluoromethyl, or monofluoromethyl; and R b is hydrogen.
  • Z 1 is C, Z 2 is N;
  • Ra is hydrogen, deuterium , -NRa0Rb0 , halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C3-6 cycloalkyl, C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), C1-8 alkoxy (preferably C1-6 alkoxy, more preferably C1-3 alkoxy), halogenated C1-8 alkoxy (preferably halogenated C1-6 alkoxy, more preferably halogenated C1-3 alkoxy), -C(O) C1-8 alkyl (preferably -C(O) C1-6 alkyl, more preferably -C(O) C1-3 alkyl), -C(O) OC1-8 alkyl (preferably -C(O) OC1-6 alkyl, more preferably -C(O) OC1-3 alkyl), -
  • R b does not exist
  • Ra and Rb and Z1 and Z2 connected thereto form a 5- or 6-membered heteroaryl ring, or a 5- or 6-membered heterocycloalkyl ring; wherein the 5- or 6-membered heteroaryl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-3 alkyl, halogenated C1-3 alkoxy, -NRa1Rb1, -SO2C1-3 alkyl, -S(O)C1-3 alkyl, -C(O)NRa1Rb1, -C(O) OC1-3 alkyl, -OC(O) C1-3 alkyl, -C(O)C1-3 alkyl, -SC1-3 alkyl, C2-4 alkynyl, halogenated C
  • Z 1 is C, Z 2 is N;
  • Z 1 is C, Z 2 is N;
  • Z 1 is C
  • Z 2 is N
  • Ra and R b and Z 1 and Z 2 attached thereto together form a 5-membered heteroaryl ring, which is a pyrazole ring
  • the pyrazole ring is unsubstituted or substituted by 1 or 2 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-3 alkyl, halo-substituted C 1-3 alkoxy and -S 1-3 alkyl ; the C 2-4 alkenyl is substituted by 0, 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine, chlorine or bromine) and halo-substituted C 1-3 alkyl; the C 2-4 alkynyl is substitute
  • Z 1 is C
  • Z 2 is N
  • Ra and R b and Z 1 and Z 2 attached thereto together form a 5-membered heteroaryl ring
  • the 5-membered heteroaryl ring is a pyrazole ring
  • the pyrazole ring is unsubstituted or substituted by 1 or 2 substituents each independently selected from the group consisting of deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy and -S C 1-3 alkyl.
  • Z 1 is C
  • Z 2 is N
  • Ra and R b together with Z 1 and Z 2 attached thereto, form a 5-membered heteroaryl ring, which is a pyrazole ring
  • the pyrazole ring is unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -SCH 3 and -SCH 2 CH 3 .
  • Z 1 is C
  • Z 2 is N
  • Ra and R b and Z 1 and Z 2 connected thereto together form a 5-membered heteroaryl ring
  • the 5-membered heteroaryl ring is a pyrazole ring
  • the pyrazole ring is unsubstituted or substituted by 1 or 2 substituents each independently selected from the following group: bromine, difluoromethyl, trifluoromethyl.
  • Z 1 is C
  • Z 2 is N
  • Ra and R b and Z 1 and Z 2 attached thereto together form a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring is a pyrazole ring; the pyrazole ring is unsubstituted or substituted with 1 substituent each independently selected from the group consisting of bromine and trifluoromethyl.
  • each occurrence of R s1 is independently deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, halo C 1-3 alkoxy, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -NC(O)(CH 2 ) 3 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -SC 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, -C(O)C 1-3 alkyl or C 3-6 cycloalkyl; said C The
  • n1 0, 1, or 2.
  • each occurrence of Rs1 is independently deuterium, halogen, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 alkynyl, halo- C1-3 alkyl, halo -C1-3 alkoxy , -NH2 , -NHC1-3 alkyl, -N( C1-3 alkyl ) 2 , -NC(O)( CH2 ) 3 , -SO2C1-3 alkyl, -S(O) C1-3 alkyl, -SC1-3 alkyl, -C(O) NH2 , -C(O)NH( C1-3 alkyl), -C(O)N( C1-3 alkyl) 2 , -C(O) OC1-3 alkyl, -OC(O) C1-3 alkyl, -C(O) C1-3 alkyl
  • the C 2-4 alkenyl group is substituted by 0, 1 , 2 or 3 substituent
  • n1 0, 1, or 2.
  • each occurrence of R is independently deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, ethynyl, propynyl, butynyl, vinyl, 1-fluorovinyl, 1-trifluoromethylvinyl, 2,2-difluorovinyl, -SCH 3 , -SC 2 H 5 , -SC 3 H 7 , -SCH(CH 3 ) 2 , methoxy, ethoxy, n-propoxy, isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, difluor
  • n1 0, 1, or 2.
  • each occurrence of Rs1 is independently deuterium, halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy;
  • n1 0, 1, or 2.
  • each occurrence of R s1 is independently bromo or trifluoromethyl
  • n1 0, 1, or 2.
  • Z 1 is C
  • Z 2 is N
  • Ra is hydrogen, deuterium, -NR a0 R b0 , haloC 1-3 alkyl, halogen, cyano, hydroxy, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, -C(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, or -OC(O)C 1-3 alkyl ;
  • R a0 and R b0 are each independently hydrogen, C 1-3 alkyl, -C(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, halogenated C 1-3 alkyl, -C(O)N R a1 R b1 ;
  • Ra is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, monofluoropropoxy, difluoropropoxy or trifluoropropoxy;
  • Ra is hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl;
  • Ra is hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.
  • Z 1 is C
  • Z 2 is N
  • Ra is hydrogen, deuterium, halogen, fluorinated C 1-3 alkyl, C 1-3 alkyl, fluorinated C 1-3 alkoxy, cyclopropyl, or C 1-3 alkoxy.
  • Z 1 is C
  • Z 2 is N
  • Ra is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, monofluoropropoxy, difluoropropoxy, or trifluoropropoxy.
  • Z 1 is C
  • Z 2 is N
  • Ra is methyl, cyclopropyl, trifluoromethyl, difluoromethyl or monofluoromethyl.
  • the structure A structure selected from one of the following groups:
  • the structure A structure selected from one of the following groups:
  • the structure A structure selected from one of the following groups:
  • the structure A structure selected from one of the following groups:
  • the 5- to 10-membered heteroaryl groups in each group are independently selected from: pyridyl, indazolyl, thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl), tetrazolyl, isoxazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazine d]pyrimidinyl, pyr
  • the saturated or partially unsaturated 3-7 membered monocyclic heterocycles in each group are independently selected from: propylene oxide, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxolanyl, dioxane, morpholinyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, azetidin-2-one, oxacyclopentyl, butane-2-onyl, pyrrolidine-2-onyl, pyrrolidine-2,5-dione, piperidin-2-onyl, dihydrofuran-2(3H)-onyl, dihydrofuran-2,
  • the 5- or 6-membered heteroaryl (ring) in each group is independently selected from: thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl), isoxazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl.
  • the 3- to 6-membered heterocycloalkyl group in each group is a 4- to 6-membered heterocycloalkyl group, each independently selected from the group consisting of azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxane, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, pyrrolidin-2-one, dihydrofuran-2(3H)-one, morpholine-3-one, piperazine-2-one and piperidine-2-one.
  • the 5- or 6-membered heterocycloalkyl ring formed by Ra and Rb together with Z1 and Z2 attached thereto is independently selected from a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, a morpholine ring, and a tetrahydropyran ring.
  • the 4- to 6-membered saturated monocyclic heterocyclic ring is independently selected from: an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide and a tetrahydropyran ring.
  • R c is hydrogen, halogen, -NR a1 R b1 or halogenated C 1-3 alkyl. Further, R c is hydrogen, chlorine, fluorine, amino or difluoromethyl.
  • R d is hydrogen or halogen. Further, R d is hydrogen, fluorine or chlorine.
  • R c , R d are each independently hydrogen, fluoro, or chloro.
  • R c is hydrogen
  • Rd is hydrogen
  • R 0 is hydrogen or C 1-3 alkyl. Further, R 0 is hydrogen or methyl.
  • R2 is methyl
  • R 3 is methyl
  • R 2 , R 3 and the carbon atom to which they are attached together form a cyclopropyl ring.
  • the compound of formula (I) is any one of the following compounds:
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of an AAK1 activity inhibitor.
  • the AAK1 activity inhibitor is used to treat or manage a disease or condition associated with or mediated by AAK1 activity.
  • the disease or condition is pain.
  • the pain is neuropathic pain.
  • the neuropathic pain is fibromyalgia or peripheral neuropathy.
  • a fourth aspect of the present invention provides a method for treating or controlling a disease or condition mediated by AAK1 activity, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the disease or condition is pain.
  • the pain is neuropathic pain.
  • the neuropathic pain is fibromyalgia or peripheral neuropathy.
  • the fifth aspect of the present invention provides a compound represented by formula (III), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • Z 1 , Z 2 , Ra , R b , R c , and R d are as described in the specification;
  • R 4 is OH, OTs, OMs, C 1-6 alkoxy or halogen
  • the compound of formula (III) is any one of the following compounds:
  • the sixth aspect of the present invention provides a method for preparing a compound represented by formula (IV), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the following steps:
  • Z 1 , Z 2 , Ring A, Ra, Rb, Rc, Rd, (R 1 ) n , and R 4 are as described in the specification;
  • RG1 and RG2 are a pair of groups that can undergo coupling reaction.
  • step S100 can be modified by methods well known in the art (such as modifying the amino group by acylation reaction, or converting the halogen into the amino group, or alkylating the amino group, etc.).
  • the modification method is not particularly limited, as long as it does not conflict with the purpose of the invention of this application, and it should be understood that it is within the scope of protection of this application.
  • step S100 can be modified with respect to R 4 by methods well known in the art, for example, converting -OH to halogen, converting alkoxy to hydroxyl, activating hydroxyl to convert to sulfonate, etc.
  • the modification method is not particularly limited, as long as it does not conflict with the purpose of the invention of the present application, and it should be understood that it is within the scope of protection of the present application.
  • R G1 and R G2 are a pair of groups that can undergo Suzuki coupling reaction.
  • one of R G1 and R G2 is a halogen and one is (HO) 2 B- or a borate group (including a pinacol borate group).
  • R G1 is Br, Cl, or I; and R G2 is (HO) 2 B- or a boronate group (including a pinacol boronate group).
  • R G2 is Br, Cl, or I; and R G1 is (HO) 2 B- or a boronate group (including a pinacol boronate group).
  • R G1 and R G2 are a pair of groups that can undergo Stille coupling reaction.
  • one of R G1 and R G2 is halogen and one is -SnBu 3 or -SnMe 3 .
  • RG1 is Br, Cl or I; RG2 is -SnBu3 or -SnMe3 .
  • RG2 is Br, Cl or I; RG1 is -SnBu3 or -SnMe3 .
  • step S100 includes the following steps:
  • the solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, ethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, propanol, isopropanol, butanol, water and combinations thereof.
  • the solvent is a mixed solvent of 1,4-dioxane and water; further, the volume ratio of 1,4-dioxane and water is about (2-12):1; further, the volume ratio of 1,4-dioxane and water can be 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1 or 12:1.
  • the catalyst is a palladium catalyst; further, the palladium catalyst is selected from: palladium carbon, tris(dibenzylideneacetone)dipalladium ( Pd2 (dba) 3 ), tetrakis(triphenylphosphine)palladium (Pd( PPh3 ) 4 ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium ( PddppfCl2 ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, XPhos Pd G2, palladium acetate, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(
  • the base is an inorganic base or an organic base; further, the base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, N-methylmorpholine, pyridine and combinations thereof; further, the base is potassium carbonate, sodium carbonate, potassium acetate or cesium carbonate.
  • DBU 1,8-diazabicyclo[5,4,0]-7-undecene
  • the reaction temperature is 0-180°C; further, the reaction temperature is 20°C-150°C; further, the reaction temperature is 30-120°C.
  • step S110 is reacted under microwave conditions.
  • the seventh aspect of the present invention provides a method for preparing the compound of formula (I) according to the first aspect of the present invention, comprising the following steps:
  • Z 1 , Z 2 , Ring A, Ra , R b , R c , R d , (R 1 ) n , R 0 , R 2 , and R 3 are as described in the specification.
  • R5 is an amino protecting group
  • Z 1 , Z 2 , Ring A, Ra , R b , R c , R d , (R 1 ) n , R 0 , R 2 , and R 3 are as described in the specification;
  • R5 is an amino protecting group.
  • the compound of formula (V) obtained in step S210 can be modified by methods well known in the art (such as modifying the amino group by acylation reaction (such as converting the amino group into an amide, or modifying the carboxyl group into an amide by acylation reaction, or converting the halogen into an amino group, or alkylating the amino group, etc.), and the modification method is not particularly limited, as long as it does not conflict with the purpose of the invention of the present application, and it should be understood that it is within the scope of protection of the present application.
  • methods well known in the art such as modifying the amino group by acylation reaction (such as converting the amino group into an amide, or modifying the carboxyl group into an amide by acylation reaction, or converting the halogen into an amino group, or alkylating the amino group, etc.)
  • the modification method is not particularly limited, as long as it does not conflict with the purpose of the invention of the present application, and it should be understood that it is within the scope of protection of the present
  • the amino protecting group is a common amino protecting group commonly used by those skilled in the art, including but not limited to -Cbz, -Boc, and the like.
  • step S210 the compound of formula (IV) reacts with a suitable intermediate (such as intermediate a, intermediate b, intermediate d, intermediate e, intermediate f, etc.) in the presence of a base to obtain a compound of formula (V).
  • a suitable intermediate such as intermediate a, intermediate b, intermediate d, intermediate e, intermediate f, etc.
  • the base is an inorganic base or an organic base; further, the base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, N-methylmorpholine, pyridine, sodium hydride and combinations thereof; further, the base is potassium carbonate, sodium carbonate, potassium acetate, sodium hydride or cesium carbonate.
  • DBU 1,8-diazabicyclo[5,4,0]-7-undecene
  • the reaction temperature is -20-150°C; further -10-130°C; further Further, it is 70-120°C or -10-40°C.
  • the reaction in step S310 is a common reaction of removing the amino protecting group (for example, when the amino protecting group is -Cbz, the condition for removing the protecting group is H 2 /Pd-C; when the amino protecting group is -Boc, the condition for removing the protecting group is to react in the presence of TFA).
  • the method of removing the protecting group is not particularly limited, as long as it does not conflict with the purpose of the invention of the present application, and it should be understood that it is within the scope of protection of the present application.
  • the eighth aspect of the present invention provides a compound of formula (I) prepared by the method for preparing the compound of formula (I) according to the seventh aspect of the present invention.
  • this type of heterocyclic substituted nitrogen-containing heterocyclic derivatives have significant selective inhibition of AAK1 kinase activity and excellent in vivo pharmacokinetic activity, and this type of compound has a weaker hERG inhibitory effect and better central nervous system penetration. Therefore, this series of compounds is expected to be developed into AAK1 kinase inhibitors and used to treat or control related diseases or conditions mediated by AAK1 activity. On this basis, the inventors completed the present invention.
  • Alkyl refers to a straight chain or branched saturated aliphatic hydrocarbon group.
  • C1-8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, preferably a C1-6 alkyl group, more preferably a C1-6 alkyl group.
  • alkyl examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 1,2-dimethylprop
  • C2-8alkenyl refers to an alkenyl group having 2 to 8 carbon atoms, preferably a C2-6 alkenyl group, more preferably a C2-4 alkenyl group, and the definition is similar; non-limiting examples of alkenyl include ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl and the like.
  • Alkynyl refers to a straight chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon triple bonds; " C2-8alkynyl " refers to an alkynyl group having 2 to 8 carbon atoms, preferably a C2-6alkynyl group, more preferably a C2-4alkynyl group, and the definition is similar; non-limiting examples of alkynyl include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl and the like.
  • Cycloalkyl and “cycloalkyl ring” are used interchangeably and refer to saturated monocyclic, bicyclic or polycyclic hydrocarbon groups, which may be fused with aryl or heteroaryl groups.
  • the cycloalkyl ring may be optionally substituted.
  • the cycloalkyl ring contains one or more carbonyl groups, such as oxo groups.
  • C 3-8 cycloalkyl refers to a monocyclic cycloalkyl group having 3 to 8 carbon atoms
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc.
  • C 3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclopentanone.
  • C 8-10 cycloalkyl refers to a fused bicyclic cyclic hydrocarbon group having 8 to 10 ring atoms. Non-limiting examples of C 8-10 cycloalkyl include
  • Heterocycloalkyl and “heterocycloalkyl ring” are used interchangeably, and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, which group may be fused with an aryl or heteroaryl group.
  • the heterocycloalkyl ring may be optionally substituted.
  • the heterocycloalkyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thio.
  • 3 to 8 membered heterocycloalkyl refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, preferably 4 to 8 membered heterocycloalkyl. More preferably, 3 to 6 membered heterocycloalkyls have 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. More preferably, 4 to 6 membered heterocycloalkyls have 4 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxane, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, azetidin-2-onyl, oxetan-2-onyl, dihydrofuran-2(3H)-onyl, pyrrolidine-2-onyl, pyrrolidine-2,5-dione, dihydrofuran-2,5-dione, piperidin-2-onyl, tetrahydro-2H-pyran-2-onyl, piperazin-2-onyl, morpholin-3-on
  • 6- to 12-membered heterocycloalkyl and “6- to 12-membered fused heterocycloalkyl” are used interchangeably and refer to fused bicyclic cyclic hydrocarbon groups having 6 to 12 ring atoms, wherein 1, 2 or 3 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • 8- to 10-membered heterocycloalkyl and “8- to 10-membered fused heterocycloalkyl” are used interchangeably and refer to fused bicyclic cyclic hydrocarbon groups having 8 to 10 ring atoms, wherein 1, 2 or 3 of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples include hexahydro-1H-furano[3,4-c]pyrrole, octahydro-1H-cyclopenta[c]pyridine, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, octahydropyrrolo[1,2-a]pyrazine, hexahydropyrrolo[1,2-a]pyrazine-4(1H)-one, octahydrocyclopenta[c]pyrrole, and the like.
  • the point of attachment may be either a carbon or nitrogen atom as valence permits.
  • the bicyclic heterocycloalkyl systems may include one or more heteroatoms in one or both rings.
  • Aryl and “aryl ring” and “aromatic ring” are used interchangeably, and all refer to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated ⁇ electron system, which group may be fused with a cycloalkyl ring, a heterocycloalkyl ring, a cycloalkenyl ring, a heterocycloalkenyl ring or a heteroaryl group.
  • C 6-10 aryl refers to a monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms, and non-limiting examples of aryl include phenyl, naphthyl, etc.
  • Heteroaryl and “heteroaryl ring” and “heteroaromatic ring” are used interchangeably and refer to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings.
  • heteroaryl ring may be optionally substituted.
  • "5 to 10 membered heteroaryl” refers to a monocyclic or bicyclic heteroaryl having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms.
  • 5- to 6-membered heteroaryl refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tria
  • 8- to 10-membered heteroaryl refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, purinyl, Pyrido[3,2-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-na
  • Heteroatom refers to nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.
  • Alkoxy refers to -O-alkyl, wherein alkyl is as defined above. Preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, most preferably C 1-3 alkoxy. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.
  • Cycloalkyloxy refers to -O-cycloalkyl, wherein cycloalkyl is as defined above. Preferably C 3-8 cycloalkyloxy, more preferably C 3-6 cycloalkyloxy. Non-limiting examples of cycloalkyloxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • a bond means that the two groups connected thereto are connected via one covalent bond.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Halo means that one or more (eg, 1, 2, 3, 4 or 5) hydrogen atoms in a group are replaced by halogen.
  • haloalkyl refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein the definition of alkyl is as described above.
  • it is a halogenated C 1-8 alkyl group, more preferably a halogenated C 1-6 alkyl group, and more preferably a halogenated C 1-3 alkyl group.
  • halogenated alkyl groups include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
  • haloalkoxy refers to an alkoxy group substituted by one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein the definition of alkoxy is as described above.
  • it is a halogenated C 1-8 alkoxy group, more preferably a halogenated C 1-6 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group.
  • Halogenated alkoxy groups include (but are not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • halogenated cycloalkyl refers to a cycloalkyl group substituted by one or more (e.g., 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above. Preferably, it is a halogenated C 3-8 cycloalkyl group, and more preferably, it is a halogenated C 3-6 cycloalkyl group.
  • Halogenated cycloalkyl groups include (but are not limited to) trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
  • Amino refers to -NH 2
  • cyano refers to -CN
  • nitro refers to -NO 2
  • benzyl refers to -CH 2 -phenyl
  • oxo O
  • carboxyl refers to -C(O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • hydroxy refers to -OH
  • thiol refers to -SH
  • the structure of "cyclopropylene” is:
  • Ms refers to methylsulfonyl
  • Ts refers to p-toluenesulfonyl
  • “Saturated or partially unsaturated monocyclic heterocycle” means that 1, 2 or 3 ring carbon atoms in the saturated or partially unsaturated monocyclic ring are replaced by heteroatoms selected from nitrogen, oxygen or S(O) t (wherein t is an integer of 0, 1 or 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • “3- to 7-membered saturated or partially unsaturated monocyclic heterocycle” has 3 to 7 ring atoms, wherein 1, 2 or 3 ring atoms are the above-mentioned heteroatoms.
  • it is a 3- to 6-membered saturated or partially unsaturated monocyclic heterocycle having 3 to 6 ring atoms, wherein 1 or 2 ring atoms are the above-mentioned heteroatoms, more preferably a 5- to 6-membered saturated or partially unsaturated monocyclic heterocycle having 5 to 6 ring atoms, wherein 1 or 2 ring atoms are the above-mentioned heteroatoms, and most preferably a 5- or 6-membered saturated monocyclic heterocycle.
  • Non-limiting examples of saturated monocyclic heterocycles include oxetane ring, azetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, pyrroline ring, oxazolidine ring, piperazine ring, dioxolane ring, dioxane, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, azetidine-2-one ring, oxetane-2-one ring, pyrrolidine-2-one ring, pyrrolidine-2,5-dione ring, piperidine-2-one ring, dihydrofuran-2(3H)-one ring, dihydrofuran-2,5-dione ring, tetrahydro
  • Substituted means that one or more hydrogen atoms, preferably 1 to 5 hydrogen atoms, are independently replaced by a corresponding number of substituents in a group, and more preferably 1 to 3 hydrogen atoms are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (such as olefinic) bonds.
  • substituted independently selected from
  • substituents independently selected from means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be the same or different in type, and the substituents selected are independently of each other.
  • the term "... are the same or different and are each independently " used in the present invention means that when there is more than one identical substituent group in the general formula, the groups may be the same or different and are each independent species.
  • L is (CR L1 RL2 ) s
  • s is 2, that is, L is (CR L1 RL2 )-(CR L1 RL2 ), wherein the two RL1s may be the same or different, and the two RL2s may be the same or different and are each independent species.
  • L may be C( CH3 )(CN)-C( CH2CH3 ) (OH), C( CH3 )(CN)-C( CH3 )( OH ) or C(CN)( CH2CH3 )-C(OH)( CH2CH3 ) .
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 groups or less, independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, halogenated C 1-8 alkyl substituted amino, acetyl, hydroxyl, hydroxymethyl, hydroxyethyl, carboxyl,
  • any two “preferably” may be independent of each other.
  • any two substituents may be the same or different.
  • they may be substituted by two halogens that are the same or different, or by one halogen and one hydroxyl.
  • the term "about” is defined as close to as understood by those of ordinary skill in the art. In a non-limiting embodiment, the term is defined as within 10%, preferably within 5%, more preferably within 1%, and further preferably within 0.5%.
  • the compounds of the present invention or their pharmaceutically acceptable salts, or solvates, or stereoisomers, or prodrugs can be administered in a suitable dosage form with one or more pharmaceutical carriers.
  • dosage forms are suitable for oral, rectal, topical, oral, and other parenteral administrations (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
  • the compounds of the present invention contained in these preparations can be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, etc.
  • the above dosage forms can be made from active compounds and one or more carriers or excipients through common pharmaceutical methods.
  • the above carriers need to be compatible with active compounds or other excipients.
  • “Pharmaceutically acceptable carriers” refer to non-toxic, inert, solid, semi-solid substances or liquid filling machines, diluents, packaging materials or auxiliary preparations or any type of excipients, which are compatible with patients, preferably mammals, more preferably humans, and are suitable for delivering active agents to target targets without terminating the activity of the agents.
  • the active substance of the present invention or “the active compound of the present invention” refers to the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, which has higher AAK1 selective inhibitory activity.
  • compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • “Therapeutically effective amount” refers to the amount of the compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.
  • the therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer, or its prodrug contained in the pharmaceutical composition or the pharmaceutical composition of the present invention is preferably 0.1 mg/kg to 5 g/kg (body weight).
  • Patient refers to an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • Treatment means to lessen, slow the progression, attenuate, prevent, or maintain an existing disease or condition (eg, cancer, pain, etc.). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.
  • pharmaceutically acceptable salts include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • Pharmaceutically acceptable acid addition salts refer to salts formed with inorganic or organic acids that retain the biological effectiveness of free bases without other side effects. These salts can be prepared by methods known in the art.
  • the "pharmaceutically acceptable salts” can be freed by methods known in the art to obtain the corresponding free form of the compound.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts of inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts, etc., and include, but are not limited to, salts of organic bases such as ammonium salts, triethylamine salts, lysine salts, arginine salts, etc. These salts can be prepared by methods known in the art.
  • Asymmetric centers may be present in the compounds of the present invention. It should be understood that the present invention encompasses all stereochemical isomeric forms or mixtures thereof that have the ability to inhibit AAK1. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation (such as conversion into a mixture of diastereoisomers followed by separation or recrystallization, chromatography techniques, or direct separation of enantiomers on a chiral chromatographic column). Starting compounds of specific stereochemistry may be commercially available or may be prepared and resolved by techniques known in the art. Certain compounds of the present invention may also exist in different stable conformational forms that can be separated.
  • the present invention includes each conformer of these compounds and mixtures thereof.
  • the term "compound of the present invention” and equivalent expressions are intended to encompass compounds of formula (I) and pharmaceutically acceptable salts thereof, and enantiomers and diastereomers thereof.
  • references to intermediates are intended to encompass their salts where the context permits.
  • the present invention provides methods for preparing compounds of formula (I), which can be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein.
  • the solvents, temperatures and other reaction conditions provided herein can be varied according to the art.
  • the reactions can be used sequentially to provide compounds of the present invention, or they can be used to synthesize fragments, which are subsequently added by the methods described herein and/or methods known in the art.
  • the compounds described in the present invention can use the illustrative methods described in the methods or embodiments similar to the following, or the relevant open literature used by those skilled in the art, by using appropriate selectable starting raw materials to synthesize compounds.
  • the starting raw materials used to synthesize the compounds described in the present invention can be synthesized or can be obtained from commercial sources.
  • the compounds described in the present invention and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art.
  • the general method for preparing the compounds disclosed in the present invention can be from reactions known in the art, and the reaction can be modified by reagents and conditions considered appropriate by those skilled in the art to introduce various parts in the molecules provided by the present invention.
  • novel heterocyclic substituted nitrogen-containing heterocyclic derivatives which selectively inhibit AAK1 kinase activity and have excellent in vivo pharmacokinetic activity and weak hERG inhibition, with IC50 values of inhibitory activity on AAK1 kinase ranging from 0.1nM to 100nM, IC50 values of some compounds ranging from 0.1nM to 50nM, and IC50 values of some compounds ranging from 0.1nM to 0.1nM.
  • IC50 values of inhibitory activity on AAK1 kinase ranging from 0.1nM to 100nM
  • IC50 values of some compounds ranging from 0.1nM to 50nM IC50 values of some compounds ranging from 0.1nM to 0.1nM.
  • To 10 nM thus, they can be used as drugs for treating or controlling related diseases or conditions mediated by AAK1 activity. And these compounds have more excellent central nervous system penetration, thus having potential excellent therapeutic effects on central nervous system diseases mediated by AAK1 activity.
  • FA formic acid
  • THF tetrahydrofuran
  • DCM dichloromethane
  • DMSO dimethyl sulfoxide
  • PE petroleum ether
  • EA ethyl acetate
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • TFA trifluoroacetic acid
  • K 2 CO 3 potassium carbonate
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • PdCl 2 (dppf) [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • NH 4 HCO 3 ammonium bicarbonate
  • H 2 O water
  • LDA lithium diisopropylamide.
  • the percentage content involved in the present invention refers to mass percentage for solid-liquid mixing and solid-solid mixing, and refers to volume percentage for liquid-liquid mixing.
  • the solvent is water.
  • room temperature refers to about 20-30°C.
  • overnight means about 10 h to 16 h.
  • Step 1 Dissolve imidazole (25.90 g, 380.41 mmol) and triethylamine (21.17 g, 209.22 mmol, 29.18 mL) in dichloromethane (300 mL), then cool to -60°C under nitrogen protection, slowly add thionyl chloride (1M, 104.61 mL) at -60°C, and stir for 15 min at -60°C after the addition is complete.
  • Step 2 (4S)-tert-butyl-4-isobutyl-4-methyl-1,2,3-oxathiozolidine-3-carboxylate 2-oxide (26 g, 93.73 mmol) was dissolved in a mixed solvent of acetonitrile (270 mL) and water (108 mL), then ruthenium chloride trihydrate (100 mg, 382.45 ⁇ mol) was added, and finally sodium periodate (25 g, 115.79 mmol) was slowly added at room temperature, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was filtered and the filter cake was washed with ethyl acetate.
  • Step 1 Under ice bath, (S)-2-amino-2,4-dimethylpentane-1-ol (20 g, 152.42 mmol) and di-tert-butyl dicarbonate (49.90 g, 228.63 mmol) were added to dichloromethane (50 mL), and then triethylamine (46.27 g, 457.26 mmol, 63.78 mL) was added. The reaction solution was stirred at room temperature for 16 hours. LC-MS monitored the completion of the reaction and concentrated under reduced pressure.
  • Step 3 Z1-2 (550 mg, 2.94 mmol) was dissolved in THF (6 mL), and N-ethyl-N-(trifluorosulfanyl)ethylamine (711.15 mg, 4.41 mmol) was added. The reaction was stirred at 23 ° C for 12 hours. The reaction was monitored by LC-MS. Water was added to quench, and the organic phase was washed with sodium bicarbonate aqueous solution, washed with water, dried, and dried under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether containing 35% ethyl acetate) to obtain Z1-3 (400 mg, yield 65.07%).
  • Step 4 Under argon protection, 7-bromo-4-methoxy-1H-indazole (100 mg, 440.42 ⁇ mol) and bis-pinacol boronate (167.76 mg, 660.63 ⁇ mol) were dissolved in dioxane (5 mL), and then Pd(dppf)Cl 2 (31.96 mg, 44.04 ⁇ mol) and potassium acetate (86.44 mg, 880.83 ⁇ mol) were added. The reaction was stirred at 100 °C for 12 hours. The reaction was monitored by LC-MS. Filtered, the filtrate was directly used in the next step. The obtained Z1-A (120 mg, yield 99.40%). MS m/z (ESI): 275.0 [M+H] + .
  • Step 5 Under argon protection, Z1-3 (90 mg, 430.64 ⁇ mol) and Z1-A (118.05 mg, 430.64 ⁇ mol) were dissolved in water (1 mL) and dioxane (8 mL), and then Pd(dppf)Cl 2 (31.25 mg, 43.06 ⁇ mol) and K 2 CO 3 (118.86 mg, 861.28 ⁇ mol) were added. The reaction was stirred at 100°C for 12 hours. The reaction was monitored by LC-MS. The reaction was complete. The mixture was dried under reduced pressure. The crude product was purified by column chromatography (petroleum ether containing 35% ethyl acetate) to give Z1-4 (85 mg, yield 71.45%). MS m/z (ESI): 276.7 [M+H] + .
  • Step 6 Dissolve Z1-4 (85 mg, 307.70 ⁇ mol) in aqueous hydrobromic acid (5 mL, 48%). The reaction was stirred at 100 °C for 12 hours. The reaction was monitored by LC-MS. The solvent was dried under reduced pressure. The crude product was purified by column chromatography (dichloromethane containing 15% methanol) to obtain intermediate Z1 (50 mg, yield 61.97%). MS m/z (ESI): 263.0 [M+H] + .
  • Step 1 Dissolve 2-difluoromethyl-4-bromopyridine (100 mg, 0.45 mmol) in dioxane (5 mL), add bis(pyridine)-1-(171 mg, 0.67 mmol), potassium acetate (110 mg, 1.12 mmol), Pd(dppf)Cl 2 (32.6 mg, 0.045 mmol) in turn, replace with argon three times, stir in an oil bath at 100°C for 5 hours. Cool to room temperature, filter the reaction solution, dilute with water (5 mL), and extract with dichloromethane (10 mL ⁇ 3).
  • Step 3 Z2-1 (5.4 g, 21.8 mmol) was placed in a 250 mL clean three-necked flask, 80 mL of dichloromethane was added, the temperature was lowered to -78 °C, diisobutylaluminum hydride (44 mL, 43.7 mmol) was added dropwise, and the mixture was stirred at -78 °C for 1.5 hours.
  • Step 4 Dissolve Z2-2 (100 mg, 0.46 mmol) in dichloromethane (3 mL), place in an ice-water bath, add diethylaminosulfur trifluoride (222 mg, 1.38 mmol), protect with argon, and continue to react for 2 hours.
  • the reaction solution was quenched with saturated sodium bicarbonate solution (3 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 5 Dissolve Z2-3 (300 mg, 1.25 mmol) and 2-difluoromethylpyridine-4-boronic acid (285 mg, 1.51 mmol) in dioxygen Pd(dppf)Cl 2 (90.6 mg, 0.125 mmol) and sodium carbonate (265 mg, 2.5 mmol) were added to hexacyclic ring (6 mL) and water (1.5 mL), and the argon gas was replaced three times. The oil bath was 100°C and the reaction was carried out for 5 hours. After cooling to room temperature, the reaction solution was filtered, diluted with water (20 mL), and extracted with dichloromethane (25 mL ⁇ 3).
  • Step 7 Dissolve Z2-5 (50 mg, 0.2 mmol) in phosphorus oxychloride (3 ml), protect with argon, stir in an oil bath at 100°C for 1 hour.
  • the reaction solution was cooled to room temperature, and the excess phosphorus oxychloride was concentrated under reduced pressure.
  • the pH was adjusted to about 8 with an ice-cold saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (10 mL ⁇ 3).
  • Step 3 Z3-2 (230 mg, 761.17 ⁇ mol), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (291.23 mg, 1.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (61.70 mg, 76.12 ⁇ mol), K 2 CO 3 (210.40 mg, 1.52 mmol) were added to water (1.5 mL) and 1,4-dioxane (15 mL). Under argon protection, the reaction solution was stirred at 110° C. for 18 hours. It was concentrated under reduced pressure.
  • Step 4 Dissolve Z3-3 (50 mg, 142.71 ⁇ mol) in ethanol (10 mL) and add palladium carbon (30 mg, 10% purity). Stir the reaction solution at room temperature for 3 hours under a hydrogen atmosphere. Filter and concentrate under reduced pressure to obtain intermediate Z3 (35 mg, yellow oil, yield 94.24%). MS m/z (ESI): 261.1 [M+H] + .
  • Step 1 2-Chloropyridine-4-boronic acid pinacol ester (150.31 mg, 627.57 ⁇ mol), 5-bromo-3-(difluoromethyl)-2-methoxypyrazine (150 mg, 627.57 ⁇ mol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (50.87 mg, 62.76 ⁇ mol) and K 2 CO 3 (173.47 mg, 1.26 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL). The reaction solution was heated to 100° C. and stirred for 16 hours under argon protection. It was concentrated under reduced pressure.
  • Step 2 Add Z4-1 (162 mg, 596.36 ⁇ mol) to aqueous hydrogen bromide solution (8 mL, 48%), and stir the reaction solution at 80°C for 1 hour. Concentrate under reduced pressure to obtain Z4-2 (150 mg, orange solid, yield 97.63%). The crude product is used directly in the next step. MS m/z (ESI): 258.1 [M+H] + .
  • Step 1 Add bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (50.87 mg, 62.76 ⁇ mol) to 1,4-dioxane (20 mL) with 2-(239.05 mg, 941.35 ⁇ mol), 5-bromo-3-(difluoromethyl)-2-methoxypyrazine (150 mg, 627.57 ⁇ mol), potassium acetate (153.97 mg, 1.57 mmol) and 1,4-dioxane (20 mL). Stir the reaction solution at 80 ° C for 16 hours under argon protection. Obtain intermediate Z5-1 (128 mg), and use the solution directly in the next step without post-treatment. MS m/z (ESI): 205.1 [M+H] + .
  • Step 2 4-chloro-2-(difluoromethyl)pyrimidine (102.95 mg, 625.69 ⁇ mol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (50.72 mg, 62.57 ⁇ mol), Z5-1 (128 mg, 625.69 ⁇ mol), K 2 CO 3 (172.95 mg, 1.25 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL). Under argon protection, the reaction solution was stirred at 105°C for 16 hours.
  • Step 3 Add Z5-2 (145 mg, 503.12 ⁇ mol) to aqueous hydrogen bromide solution (8 mL, 48%), and stir the reaction solution at 80°C for 1 hour. Concentrate under reduced pressure to obtain Z5-3 (137 mg, yellow solid), which is used directly in the next step without purification. MS m/z (ESI): 275.0 [M+H] + .
  • Step 1 Add 5-bromo-3-(difluoromethyl)-2-methoxypyrazine (500 mg, 2.09 mmol), tributyl (1-ethoxyvinyl) stannane (982.13 mg, 2.72 mmol), bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (169.57 mg, 209.19 ⁇ mol) to 1,4-dioxane (20 mL). The reaction solution was heated to 100 ° C and stirred for 16 hours under argon protection. After cooling to room temperature, hydrochloric acid solution (2 mol/L) was added and stirred for 1 hour. Concentrate under reduced pressure.
  • Step 2 Add Z6-1 (335 mg, 1.66 mmol) to DMF-DMA (8.97 g, 10 mL), and stir the reaction solution at 100 ° C for 16 hours. Concentrate under reduced pressure to obtain Z6-2 (410 mg, yellow solid) with a yield of 96.18%. The crude product is directly used in the next step. MS m/z (ESI): 258.2 [M + H] + .
  • Step 4 Add Z6-3 (350 mg, 1.01 mmol) to aqueous hydrogen bromide solution (10 mL, 48%), and stir the reaction solution at 80°C for 1 hour. Concentrate under reduced pressure to obtain Z6-4 (335 mg, yellow solid), which is used directly in the next step. MS m/z (ESI): 332.1 [M+H] + .
  • Step 2 Add 4-chloro-2-(difluoromethyl)pyrimidine (52.77 mg, 320.71 ⁇ mol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (26.00 mg, 32.07 ⁇ mol), Z7-1 (112 mg, 320.71 ⁇ mol), K 2 CO 3 (88.65 mg, 641.41 ⁇ mol) to water (1 mL) and 1,4-dioxane (10 mL). Under argon protection, the reaction solution was stirred at 105°C for 16 hours. Concentrated under reduced pressure.
  • Step 3 Dissolve Z7-2 (54 mg, 153.69 ⁇ mol) in ethanol (10 mL) and add palladium carbon (30 mg, 10% purity). Stir the reaction solution at room temperature for 3 hours under a hydrogen atmosphere. Filter and concentrate under reduced pressure to obtain Z7 (40 mg, yellow solid), yield 99.63%. MS m/z (ESI): 262.1 [M+H] + .
  • Step 1 Add 4-bromo-2-(fluoromethyl)pyridine (155 mg, 815.73 ⁇ mol), compound Z5-1 (230 mg, 803.97 ⁇ mol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (65.17 mg, 80.40 ⁇ mol) and K 2 CO 3 (222.22 mg, 1.61 mmol) to 1,4-dioxane (20 mL) and water (2 mL). The reaction solution was heated to 110°C and stirred for 16 hours under argon protection.
  • Step 2 Add Z8-1 (185 mg, 687.16 ⁇ mol) to aqueous hydrogen bromide solution (5 mL, 48%), and stir the reaction solution at 80°C for 1 hour. Concentrate under reduced pressure. Obtain Z8-2 (175 mg, light yellow solid) with a yield of 99.79%. The crude product is used directly in the next step. MS m/z (ESI): 256.1 [M+H] + .
  • Step 1 2-Fluoropyridine-4-boronic acid pinacol ester (403.14 mg, 1.81 mmol), 5-bromo-3-(difluoromethyl)-2-methoxypyrazine (288 mg, 1.20 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (97.67 mg, 120.49 ⁇ mol) and K 2 CO 3 (333.07 mg, 2.41 mmol) were added to 1,4-dioxane (30 mL) and water (3 mL). The reaction solution was heated to 110°C and stirred for 16 hours under argon protection.
  • Step 2 Add Z9-1 (292 mg, 1.14 mmol) to aqueous hydrogen bromide solution (10 mL, 48%), and stir the reaction solution at 60°C for 0.5 hours. Concentrate under reduced pressure. Obtain Z9-2 (270 mg, light yellow solid) with a yield of 97.84%. The crude product is used directly in the next step. MS m/z (ESI): 242.1 [M+H] + .
  • Step 1 6-bromo-3-chloropyrazine-2-carboxylic acid methyl ester (361 mg, 1.44 mmol), 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (351.90 mg, 1.44 mmol), PdCl 2 (dppf) (20.83 mg, 28.71 ⁇ mol) and K 2 CO 3 (297.62 mg, 2.15 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). Under nitrogen protection, the reaction solution was stirred at 50°C for 4 hours.
  • Step 2 Dissolve Z10-1 (310 mg, 1.07 mmol) in anhydrous DCM (10 mL), cool to -78 ° C under argon protection, slowly add diisobutylaluminum hydride (1M toluene solution, 1.28 mL), and continue to stir at -78 ° C for 1 hour after the addition is complete. After the reaction is complete, add saturated ammonium chloride aqueous solution, stir for a while, add diatomaceous earth, and filter.
  • Step 1 Add 5-bromo-3-(difluoromethyl)-2-methoxypyrazine (500 mg, 2.09 mmol) and hydrobromic acid aqueous solution (10 mL, 48%) into a single-mouth bottle, and stir the reaction solution at 40°C for 3 hours. After the reaction is complete, concentrate under reduced pressure to obtain Z11-1 (450 mg, yellow solid) with a yield of 84.99%. The crude product is directly used for the next step. MS m/z (ESI): 221.0. (non-molecular ion peak)
  • Step 3 Dissolve Z11-2 (320 mg, 1.02 mmol), diboronic acid pinacol ester (386.81 mg, 1.52 mmol), PdCl 2 (dppf) (14.74 mg, 20.31 ⁇ mol) and potassium acetate (179.39 mg, 1.83 mmol) in 1,4-dioxane (15 mL). Stir the reaction solution at 100 °C for 16 hours under nitrogen protection. After the reaction is complete, filter and concentrate the filtrate to obtain Z11-3 (360 mg, black solid). The crude product is directly used for the next step. MS m/z (ESI): 363.3 [M+H] + .
  • Step 5 Add Z11-4 (110 mg, 310.43 ⁇ mol) and hydrobromic acid aqueous solution (5 mL, 48%) to a single-mouth bottle, and stir the reaction solution at 40°C for 0.5 hours. After the reaction is complete, concentrate under reduced pressure to obtain Z11-5 (75 mg, yellow solid) with a yield of 91.44%. The crude product is directly used for the next step. MS m/z (ESI): 265.1 [M+H] + .
  • Step 1 Dissolve 3-bromo-5-chloro-pyrazine-2-amine (1 g, 4.80 mmol) in water (2 mL), add K 2 CO 3 (1.33 g, 9.59 mmol), cyclopropylboronic acid (535.71 mg, 6.24 mmol), PdCl 2 (dppf) (351.03 mg, 479.75 ⁇ mol) and dioxane (20 mL), and stir at 100 ° C overnight under nitrogen protection. Concentrate under reduced pressure to obtain a crude product, which is purified by combiflash chromatography (0-60% EA/100-40% PE) to obtain Z13-1 (450 mg, yellow oil), with a yield of 55.30%. MSm/z (ESI): 170.1 [M+H] + .
  • Step 2 Dissolve Z13-1 (0.45 g, 2.65 mmol) in dioxane (18 mL), add [2-(difluoromethyl)-4-pyridyl]boronic acid (458.79 mg, 2.65 mmol), potassium carbonate (733.35 mg, 5.31 mmol), PdCl 2 (dppf) (194.13 mg, 265.31 ⁇ mol) and water (2 mL), and stir at 100 ° C overnight under nitrogen protection. Concentrate under reduced pressure to obtain a crude product, which is purified by combiflash (0-60% EA/PE) to obtain Z13-2 (200 mg, yellow oil), with a yield of 28.74%. MSm/z (ESI): 263.1 [M+H] + .
  • Step 3 Dissolve Z13-2 (200 mg, 762.61 ⁇ mol) in concentrated hydrochloric acid (10 mL), add sodium nitrite (263.08 mg, 3.81 mmol) at 0°C, stir at 0°C for 30 minutes, add potassium carbonate to adjust the pH to 8, extract with dichloromethane to remove organic phase impurities, and concentrate the aqueous phase under reduced pressure to obtain intermediate Z13 (60 mg, yellow solid) with a yield of 27.93%, which is directly used in the next step.
  • Step 1 Dissolve intermediate Z1 (50 mg, 190.68 ⁇ mol) and intermediate a (83.91 mg, 286.03 ⁇ mol) in DMF (6 mL), then add K 2 CO 3 (52.63 mg, 381.37 ⁇ mol). The reaction is stirred at 80°C for 12 hours. The reaction is monitored by LC-MS. The solvent is dried under reduced pressure. The crude product is purified by column chromatography (dichloromethane containing 25% methanol) to obtain H-1-a (21 mg, yield 22.06%). MS m/z (ESI): 476.1 [M+H] + .
  • Step 2 H-1-a (21 mg, 44.16 ⁇ mol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction was stirred at 23 ° C for 2 hours. The reaction was monitored by LC-MS. The crude product was dried under reduced pressure and prepared by Prep.HPLC to obtain H-1 (1.22 mg, purity: 100%, yield: 7.36%). MS m/z (ESI): 376.2 [M+H] + .
  • Step 1 Add intermediate b (8 mg, 0.034 mmol) to a 25 mL clean three-necked flask, add THF (1 mL) to dissolve, cool to 0 ° C, add sodium hydride (5 mg, 0.204 mmol), stir at 0 ° C for 30 min, add intermediate Z2 (10 mg, 0.034 mmol), stir at 0 ° C for 1 h. LC-MS monitoring shows that the raw material has reacted.
  • Step 2 Place H-2-a (30 mg, 0.062 mmol) in a 25 mL clean three-necked flask, dissolve it with dichloromethane (2 mL), add trifluoroacetic acid (0.5 mL, 0.183 mmol), stir at room temperature for 0.5 hours, and monitor by LC-MS sampling. After the reaction of the raw materials is complete, add saturated sodium bicarbonate to adjust the pH to 7, extract with ethyl acetate (5 mL ⁇ 3), combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by preparative liquid chromatography to obtain H-2 (8.9 mg, yield 37.43%).
  • Step 1 Dissolve intermediate Z3 (35 mg, 134.49 ⁇ mol) in DMF (10 mL), add K 2 CO 3 (37.18 mg, 268.98 ⁇ mol), and then add intermediate a (59.19 mg, 201.74 ⁇ mol). Stir the reaction mixture at 80°C for 3 hours. Filter and concentrate under reduced pressure to obtain H-3-a (60 mg, brown oil, yield: 94.21%). The crude product was used directly in the next step without purification. MS m/z (ESI): 474.3 [M+H] + .
  • Step 2 Add H-3-a (60 mg, 126.70 ⁇ mol) to dichloromethane (10 mL), and then add trifluoroacetic acid (3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated, dissolved in dichloromethane, and then neutralized by adding 7 mol/L methanol solution of ammonia, and concentrated under reduced pressure.
  • Step 2 H-4-a (361.81 mg, 2.62 mmol) was dissolved in anhydrous THF (15 mL), cooled to -78 °C under nitrogen protection, and LDA (2.0 M THF solution, 3.46 mL) was added dropwise.
  • the reaction system was stirred at -78 °C for 2 hours, and DMF (8.66 mmol, 670.25 ⁇ L) was added, and the reaction was continued at low temperature for 1 hour. After the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL ⁇ 2), the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
  • Step 5 H-4-d (60 mg, 126.44 ⁇ mol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure, dissolved in dichloromethane, and neutralized by adding 7 mol/L ammonia methanol solution, and concentrated under reduced pressure again.
  • Step 2 H-5-a (65 mg, 131.71 ⁇ mol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure, dissolved in dichloromethane, and neutralized by adding 7 mol/L methanol solution of ammonia, and concentrated under reduced pressure again.
  • Step 2 H-6-a (40 mg, 87.15 ⁇ mol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure, dissolved in dichloromethane, and neutralized by adding 7 mol/L methanol solution of ammonia, and concentrated under reduced pressure again.
  • Step 3 H-7-b (90 mg, 169.00 ⁇ mol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure, dissolved in dichloromethane, and neutralized by adding 7 mol/L methanol solution of ammonia, and concentrated under reduced pressure again.
  • Step 2 Add H-8-a (140 mg, 257.11 ⁇ mol) to DCM (10 mL), then add TFA (5 mL), and stir the reaction solution at room temperature for 1 hour. Concentrate under reduced pressure. Dissolve in dichloromethane and add 7 mol/L ammonia methanol solution to neutralize and concentrate. Purify by preparative liquid chromatography to obtain H-8 (35 mg, yield 27.74%). MS m/z (ESI): 445.2 [M+H] + .
  • Step 1 Dissolve intermediate Z7 (40 mg, 153.12 ⁇ mol) in DMF (10 mL), add K 2 CO 3 (42.33 mg, 306.25 ⁇ mol), and then add intermediate a (67.38 mg, 229.69 ⁇ mol). The reaction solution was stirred at 80°C for 3 hours. Filter and concentrate the filtrate to obtain H-9-a (72 mg, brown oil). The crude product was used directly in the next step without purification. MS m/z (ESI): 475.3 [M+H] + .
  • Step 2 Add H-9-a (72 mg, 151.73 ⁇ mol) to DCM (6 mL), then add TFA (3 mL), and stir the reaction solution at room temperature for 1 hour. Concentrate under reduced pressure. Dissolve in dichloromethane and add 7 mol/L methanol solution of ammonia to neutralize and concentrate. Purify by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%-30% acetonitrile change) to obtain H-9 (46.32 mg, yield 79.06%).
  • Step 2 Add H-10-a (61 mg, 125.13 ⁇ mol) to DCM (6 mL), and then add TFA (3 mL). The reaction solution was stirred at room temperature for 1 hour. Concentrate under reduced pressure. After dissolving in dichloromethane, 7 mol/L ammonia in methanol solution was added for neutralization and concentrated. Purification by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%-30% acetonitrile change) gave H-10 (29.60 mg, yield: 60.69%).
  • Step 2 H-11-a (22 mg, 40.48 ⁇ mol) was dissolved in DCM (3 mL) and TFA (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure, dissolved in dichloromethane, and neutralized by adding 7 mol/L ammonia methanol solution, and concentrated under reduced pressure again. Purification was performed by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain H-11 (6.40 mg, yield 35.10%).
  • Step 1 Dissolve intermediate b (50 mg, 216.14 ⁇ mol) in DMF (10 mL), cool to 0 ° C, add sodium hydride (10.41 mg, 271.67 ⁇ mol, 60% purity), stir for 30 minutes, and then add intermediate Z4 (50 mg, 181.11 ⁇ mol). The color turns black, and the reaction solution is stirred at 0 ° C for 1.5 hours. The reaction solution is concentrated to obtain H-12-a (85 mg, brown oil), and the crude product is used directly in the next step without purification. MS m/z (ESI): 471.2 [M + H] + .
  • Step 2 Add H-12-a (85 mg, 180.49 ⁇ mol) to DCM (6 mL), then add TFA (3 mL), and stir the reaction solution at room temperature for 1 hour. Concentrate under reduced pressure. Dissolve in dichloromethane and add 7 mol/L ammonia methanol solution to neutralize, and concentrate under reduced pressure. Purify by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%--30% acetonitrile change) to obtain H-12 (45.19 mg, yield 66.80%).
  • Step 2 Dissolve H-13-a (50 mg, 113.75 ⁇ mol) in dichloromethane (3 mL) and add trifluoroacetic acid (1 mL). Stir the reaction solution at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure, dissolve in dichloromethane, and add 7 mol/L ammonia methanol solution. The residue was purified by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 5%-95% acetonitrile change) to obtain H-13 (15.02 mg, yield 38.90%).
  • Step 2 H-16-a (80 mg, 170.75 ⁇ mol) was added to DCM (5 mL), and then trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 1 hour. Concentrated under reduced pressure. After dissolving in dichloromethane, 7N ammonia methanol solution was added to neutralize and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%--30% acetonitrile change) to obtain H-16 (18 mg, colorless oil) with a yield of 28.38%.
  • Example 14-Example 15 Example 17-Example 28
  • Step 2 H-29-a (271 mg, 596.28 ⁇ mol) was added to DCM (10 mL), and then trifluoroacetic acid (5 mL) was added. The reaction solution was stirred at room temperature for 1 hour. Concentrated under reduced pressure. After dissolving in dichloromethane, 7N ammonia methanol solution was added to neutralize and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%--30% acetonitrile change) to obtain H-29 (96.08 mg) with a yield of 45.47%.
  • Step 2 H-30-a (60 mg, 135.59 ⁇ mol) was dissolved in DCM (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure, dissolved in dichloromethane, and neutralized by adding 7N ammonia methanol solution, and concentrated under reduced pressure again.
  • Step 2 Dissolve H-31-a (120 mg, 251.81 ⁇ mol) in DCM (3 mL) and add trifluoroacetic acid (1 mL). Stir the reaction solution at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure, dissolve in dichloromethane, and add 7N ammonia methanol solution to neutralize. The residue was purified by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 /H 2 O-acetonitrile; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile) to obtain H-31 (30 mg, yellow oil) with a yield of 31.65%.
  • Step 2 H-32-a (30 mg, 62.82 ⁇ mol) was dissolved in DCM (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure, dissolved in dichloromethane, and neutralized by adding 7N ammonia methanol solution, and concentrated under reduced pressure again.
  • Step 2 H-33-a (35 mg, 77.69 ⁇ mol) was dissolved in DCM (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated under reduced pressure, dissolved in dichloromethane, and neutralized by adding 7N ammonia methanol solution, and concentrated under reduced pressure again.
  • Step 1 Dissolve intermediate Z13 (60 mg, 227.93 ⁇ mol) in DMF (10 mL), add intermediate a (66.87 mg, 227.93 ⁇ mol) and K 2 CO 3 (94.51 mg, 683.78 ⁇ mol), and stir at 80°C overnight. After the reaction is complete, concentrate under reduced pressure to obtain a crude product, which is purified by combiflash chromatography (0-20% MeOH/100-80% DCM) to obtain H-34-a (60 mg, yellow solid), yield: 55.24%, MSm/z (ESI): 477.1 [M+H] + .
  • Step 2 H-34-a (60 mg, 125.90 ⁇ mol) was dissolved in DCM (3 mL), trifluoroacetic acid (43.07 mg, 377.71 ⁇ mol) was added, and the mixture was stirred at room temperature for 2 hours.
  • step (3) Add 2 ⁇ L of the compound solution prepared in step (2) to the compound wells and centrifuge at 1000 rpm for 1 min.
  • the control wells were all added with 5% DMSO prepared in 1x buffer;
  • Inhibition% inhibition percentage of the compound on AAK1 kinase
  • Max positive control well, i.e., maximum value well
  • Min negative control well, i.e., minimum value well
  • Compound compound well
  • Signal is the fluorescence signal value of each well.
  • XLFIT 5.0 software (IDBS, UK) was used for fitting, with the logarithm of the compound concentration as the X-axis and the inhibition rate as the Y-axis, and the half maximal inhibition concentration IC 50 of the compound was calculated using a four-parameter model. The results are shown in Table 1.
  • the compounds of the present invention have a high inhibitory activity against AAK1 enzyme.
  • step (3) Add 2 ⁇ L of the compound solution prepared in step (2) to the compound wells, centrifuge at 1000 rpm for 1 min, and add 5% DMSO prepared in 1x buffer to both the positive and negative control wells;
  • Inhibition% the inhibition percentage of the compound on BMP2K enzyme
  • Max positive control well, i.e. the maximum value well
  • Min negative control well, i.e. the minimum value well
  • Compound compound well
  • Signal is the fluorescence signal value of each well.
  • XLFIT 5.0 software (IDBS, UK) was used for fitting, with the logarithm of the compound concentration as the X-axis and the inhibition rate as the Y-axis, and the half maximal inhibition concentration IC 50 of the compound was calculated using a four-parameter model. The results are shown in Table 2.
  • Test Example 3 Manual patch clamp test of hERG potassium channel function
  • Solvent Name: DMSO (dimethyl sulfoxide). Source: purchased from Sigma, item number: 276855-100mL. Molecular weight: 78.13. Storage conditions: Store in sealed container at room temperature and away from light.
  • Cell information Species & strain: CHO-hERG cell line (Chinese Hamster Ovary) (Chinese hamster ovary cells stably expressing hERG channel)
  • Source Internal construction. Culture conditions: 5% CO 2 (volume fraction, the rest is air), 37°C incubator. Cryopreservation conditions: liquid nitrogen.
  • HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid).
  • EGTA ethylene glycol bis(2-aminoethyl ether)tetraacetic acid.
  • CHO cells stably expressing hERG were cultured in a 35 mm diameter cell culture dish, placed in an incubator at 37°C and 5% CO2 , and subcultured every 48 hours at a ratio of 1:5.
  • the culture medium formula was: 90% F12 culture medium (Invitrogen), 10% fetal bovine serum (Gibco), 100 ⁇ g/mL G418 antibiotics (Invitrogen) and 100 ⁇ g/mL Hygromycin B antibiotics (Invitrogen).
  • the cell culture medium was aspirated, and after rinsing with extracellular fluid, 0.25% trypsin-EDTA (Trypsin-EDTA, Invitrogen) solution was added and digested at room temperature for 3-5 minutes. The digestion solution was aspirated, and the cells were resuspended with extracellular fluid and transferred to a laboratory dish for electrophysiological recording for later use.
  • the compound was prepared with DMSO to the stock concentration, and then serially diluted 3-fold with DMSO, that is, 10 ⁇ L was added to 20 ⁇ L of DMSO, and then 10 ⁇ L of the serially diluted compound DMSO solution was added to 4990 ⁇ L of extracellular fluid, and the final concentration to be tested was obtained by 500-fold dilution.
  • Preparation of positive control compound cisapride Take 10 ⁇ L of 150 ⁇ M cisapride DMSO stock solution, add it to 4990 ⁇ L extracellular fluid, and dilute it 500 times to get the final concentration of 300nM to be tested.
  • the DMSO content in the final test concentration does not exceed 0.2%, and this concentration of DMSO has no effect on hERG potassium channels.
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature.
  • the glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after perfusion of the electrode liquid was about 2-5M ⁇ .
  • the glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier.
  • the clamping voltage and data recording were controlled and recorded by pClamp software through a computer, with a sampling frequency of 10kHz and a filter frequency of 2kHz.
  • the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I hERG) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s.
  • This voltage stimulation was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (1 minute).
  • Compounds were administered for at least 1 min to steady state of action or for a maximum of 3 min at each tested concentration, and at least 2 cells (n ⁇ 2) were tested at each concentration.
  • Inhibition% [1-(I/Io)] ⁇ 100%, where Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
  • Compound IC50 was calculated using GraphPad Prism 8 software by fitting the following equation:
  • Y Bottom + (Top-Bottom) / (1 + 10 ⁇ ((LogIC 50 -X)*HillSlope)), where X is the Log value of the compound concentration, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum inhibition percentage and maximum inhibition percentage measured at each compound concentration during the test; HillSlope is the slope factor.
  • Table 3 Show.
  • Test Example 4 In vivo pharmacokinetic study in rats after single administration
  • the pharmacokinetic characteristics of rodents after intravenous and oral administration of the test compound were tested using a standard protocol.
  • the test compound was prepared into a clear solution or a uniform suspension with a solvent according to the dosage and concentration, and a single intravenous injection and oral administration were given to SD rats.
  • SD rats source: Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., male, 200-300g, 7-9 weeks old
  • 3 rats/group were randomly divided into groups.
  • the intravenous injection group was free to eat and drink before administration; the oral gavage group was fasted overnight before administration, and food was resumed four hours after administration (except for special circumstances), and free drinking water was given.
  • the solvents of the intravenous injection group and the oral gavage group were a certain ratio (volume ratio of 5:10:85) of dimethyl sulfoxide, polyethylene glycol-15 hydroxystearate and 20 mol/L citric acid buffer, vortexed and stirred, and the compound was dissolved after ultrasound to prepare a solution with a compound concentration of 5 mg/mL or 1 mg/mL or other concentrations (such as 0.5 mg/mL, according to the solubility properties of the compound itself).
  • the intravenous injection group required the solution to be clear, and the oral group required the solution to be a uniform suspension or a clear solution for use.
  • a certain amount of whole blood samples, brain homogenate samples, and cerebrospinal fluid samples were collected.
  • the whole blood sample was centrifuged at 3700 rpm for 15 minutes, and the supernatant was separated to obtain a plasma sample.
  • a certain volume of acetonitrile solution containing internal standard was added to plasma, brain homogenate and cerebrospinal fluid samples to precipitate protein.
  • the supernatant was centrifuged and added with a certain volume of diluent (such as pure water, methanol/water solution, etc., which can be adjusted according to the situation).
  • the plasma drug concentration C plasma and the brain drug concentration C brain were quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters such as peak concentration Cmax, peak time Tmax, clearance CL, half-life T1/2, area under the drug-time curve AUC, bioavailability F, etc. were calculated using Data Analysie System software (Shanghai Bojia Pharmaceutical Technology Co., Ltd., version number 3.0).
  • the structure of the positive compound D1 in Test Example 1 is: (D1, CAS No.: 2092891-50-2), the structure of the positive compound D2 in Test Example 1-4 is: (D2, CAS No.: 1815613-42-3), D1 and D2 can be prepared by referring to the existing technology, or can be obtained through commercial channels.

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Abstract

L'invention concerne un dérivé hétéroaryle à cinq et six chaînons substitué par un hétérocycle, dont la structure est représentée dans la formule (I). De plus, l'invention concerne également un sel pharmaceutiquement acceptable du dérivé, un stéréoisomère de celui-ci, une composition pharmaceutique et une utilisation de celui-ci. Le composé de la présente invention a une inhibition sélective significative sur l'activité de la kinase AAK1, un effet inhibiteur de hERG plus faible et une meilleure pénétration du système nerveux central, et a une grande valeur pratique.
PCT/CN2024/072518 2023-01-16 2024-01-16 Dérivé hétérocyclique contenant de l'azote substitué par un hétérocycle, composition pharmaceutique, utilisation et procédé de préparation associé WO2024153067A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106458994A (zh) * 2014-04-02 2017-02-22 百时美施贵宝公司 联芳激酶抑制剂
CN108290843A (zh) * 2015-10-01 2018-07-17 百时美施贵宝公司 联芳基激酶抑制剂
CN108368084A (zh) * 2015-10-01 2018-08-03 百时美施贵宝公司 联芳基激酶抑制剂
CN113429410A (zh) * 2020-03-23 2021-09-24 上海海雁医药科技有限公司 多杂环取代的嘧啶或吡啶胺衍生物、其组合物及医药上的用途
CN115484951A (zh) * 2020-04-21 2022-12-16 莱西肯医药有限公司 用于治疗病毒感染的aak1抑制剂
WO2023284838A1 (fr) * 2021-07-15 2023-01-19 四川海思科制药有限公司 Inhibiteur d'aak1 et son utilisation
CN115872927A (zh) * 2021-09-30 2023-03-31 武汉人福创新药物研发中心有限公司 Aak1抑制剂及其用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106458994A (zh) * 2014-04-02 2017-02-22 百时美施贵宝公司 联芳激酶抑制剂
CN108290843A (zh) * 2015-10-01 2018-07-17 百时美施贵宝公司 联芳基激酶抑制剂
CN108368084A (zh) * 2015-10-01 2018-08-03 百时美施贵宝公司 联芳基激酶抑制剂
CN113429410A (zh) * 2020-03-23 2021-09-24 上海海雁医药科技有限公司 多杂环取代的嘧啶或吡啶胺衍生物、其组合物及医药上的用途
CN115484951A (zh) * 2020-04-21 2022-12-16 莱西肯医药有限公司 用于治疗病毒感染的aak1抑制剂
WO2023284838A1 (fr) * 2021-07-15 2023-01-19 四川海思科制药有限公司 Inhibiteur d'aak1 et son utilisation
CN115872927A (zh) * 2021-09-30 2023-03-31 武汉人福创新药物研发中心有限公司 Aak1抑制剂及其用途

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