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WO2024125668A1 - Dérivé hétéroaryle pentagonal à six chaînons substitué hétérocyclique, composition pharmaceutique de celui-ci, procédé d'utilisation et de préparation associé - Google Patents

Dérivé hétéroaryle pentagonal à six chaînons substitué hétérocyclique, composition pharmaceutique de celui-ci, procédé d'utilisation et de préparation associé Download PDF

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Publication number
WO2024125668A1
WO2024125668A1 PCT/CN2024/074970 CN2024074970W WO2024125668A1 WO 2024125668 A1 WO2024125668 A1 WO 2024125668A1 CN 2024074970 W CN2024074970 W CN 2024074970W WO 2024125668 A1 WO2024125668 A1 WO 2024125668A1
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alkyl
halogenated
ring
alkoxy
group
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PCT/CN2024/074970
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English (en)
Chinese (zh)
Inventor
吴春艳
谢婧
杨文�
周宾山
朱卫星
Original Assignee
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 WO2024125668A1 publication Critical patent/WO2024125668A1/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
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of medical technology, and in particular to a heterocyclic substituted pentahedral and hexacyclic heteroaryl derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition, and an application and preparation method thereof.
  • the 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 (AP-2 associated kinase 1) was originally discovered as a phosphorylation-regulated kinase of AP-2, and both are involved in the formation of clathrin-coated vesicles.
  • AAK1 AP-2 associated kinase 1
  • 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 ⁇ -aminobutyric acid type A receptor
  • reducing the cell surface level of ⁇ 2 containing GABA A receptors and thus reducing endocytosis is related to the analgesic effect of AAK1 inhibitors.
  • Lexicon Through phenotypic screening of gene knockout mice, Lexicon found that 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.
  • AAK1 adapter-associated kinase 1
  • 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.
  • the present application provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • Z is C or N
  • Ra is hydrogen, deuterium , -NRa0Rb0 , halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), halogen (preferably fluorine, chlorine or bromine), 5- or 6-membered heteroaryl, cyano, hydroxyl, carboxyl, C3-6 cycloalkyl, halogenated 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), halogenated-C(O) C1-8 alkyl (preferably hal
  • Ra and Rb are linked to form a 5- or 6-membered heteroaryl ring, a benzene ring or a 5- or 6-membered heterocycloalkyl ring; wherein the 5- or 6-membered heteroaryl ring or the benzene 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, -NRa1Rb1 , -SO2C1-3 alkyl, -S(O) C1-3 alkyl , -C(O) NRa1Rb1 , -C(O) OC1-3 alkyl, -OC(O) C1-3 alkyl and C2-4 alkynyl ; the 5- or
  • R b does not exist
  • Ra and Rb are linked to 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 and C2-4 alkynyl; the 5- or 6-membered
  • 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 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, oxo, C 1-3 alkyl, C 1-3 alkoxy
  • 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), -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 1-8 alkyl (preferably -OC
  • heteroatoms on the heteroaryl or heteroaryl ring, heterocycloalkyl or heterocycloalkyl ring, and saturated monocyclic heterocycle are independently selected from N, O, and S.
  • the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is:
  • R b does not exist
  • Ra is -NRa0Rb0 , halosubstituted C3-6 cycloalkyl, halosubstituted-C(O) C1-8 alkyl (preferably halosubstituted-C(O) C1-6 alkyl, more preferably halosubstituted-C(O) C1-3 alkyl), C2-6 alkenyl, C2-6 alkynyl, halosubstituted C2-6 alkenyl or halosubstituted C2-6 alkynyl;
  • 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
  • U 1 and U 2 are N or C; and U 1 and U 2 are not N or C at the same time;
  • 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;
  • Ra is tetrahydropyrrolyl, oxazolidin-2-onyl, pyrrolidin-2-onyl, difluorocyclopropyl, difluoroacetyl, vinyl, monofluorovinyl, or difluorovinyl.
  • Ra is tetrahydropyrrolyl, oxazolidin-2-onyl, pyrrolidin-2-onyl, fluorocyclopropyl, fluoroacetyl, vinyl, ethynyl, fluorovinyl, or fluoroethynyl.
  • Ra is tetrahydropyrrolyl, oxazolidin-2-onyl, pyrrolidin-2-onyl, difluorocyclopropyl, difluoroacetyl, vinyl, monofluorovinyl, or difluorovinyl.
  • the compound of formula (I) is a compound of formula (II):
  • the structure A structure selected from one of the following groups:
  • the structure A structure selected from one of the following groups:
  • Z is C;
  • Ra is hydrogen, deuterium , -NRa0Rb0 , halogenated C1-8 alkyl (preferably halogenated C1-6 alkyl, more preferably halogenated C1-3 alkyl), halogenated C1-8 alkoxy (preferably halogenated C1-6 alkoxy, more preferably halogenated C1-3 alkoxy), C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), halogen (preferably fluorine or chlorine), C3-6 cycloalkyl, halogenated C3-6 cycloalkyl, -C(O) NRa1Rb1 , halogenated-C(O) C1-8 alkyl (preferably halogenated-C(O) C1-6 alkyl, more preferably halogenated-C(O)C 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
  • 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 5- or 6-membered heteroaryl; wherein each occurrence of the 5- or 6-membered heteroaryl is independently unsubstituted or substituted with 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 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C
  • R b is hydrogen or halogen (preferably fluorine or chlorine).
  • Z is C;
  • Ra is hydrogen, deuterium , -NRa0Rb0 , halo- C1-8 alkyl (preferably halo- C1-6 alkyl, more preferably halo- C1-3 alkyl), C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), halo- C1-8 alkoxy (preferably halo- C1-6 alkoxy, more preferably halo- C1-3 alkoxy), halogen (preferably fluorine or chlorine), -C(O )NRa1Rb1 , C3-6 cycloalkyl, halo- C3-6 cycloalkyl, halo-C(O) C1-8 alkyl (preferably halo-C(O) C1-6 alkyl, more preferably halo-C(O) C1-3 alkyl), pyrazolyl or thiazolyl; wherein the pyrazolyl and thiazolyl are each independently unsubstituted or substituted with
  • 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, pyrazolyl, thiazolyl, -C(O)C 3-6 cycloalkyl, -C(O)NR a1 R b1 or -C(O)R, R is pyrazolyl or thiazolyl; wherein each occurrence of the pyrazolyl and thiazolyl is each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, C 1-3 alkyl and halogenated C 1-3 alkyl;
  • R b is hydrogen or halogen (preferably fluorine or chlorine).
  • Z is C;
  • Ra is hydrogen, deuterium , -NRa0Rb0 , halo- C1-8 alkyl (preferably halo- C1-6 alkyl, more preferably halo- C1-3 alkyl), C1-8 alkyl (preferably C1-6 alkyl, more preferably C1-3 alkyl), halo- C1-8 alkoxy (preferably halo- C1-6 alkoxy, more preferably halo- C1-3 alkoxy), halogen (preferably fluorine or chlorine), -C(O) NRa1Rb1 , cyclopropyl , fluorocyclopropyl, fluoroacetyl, pyrazolyl or thiazolyl; wherein the pyrazolyl and 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 halo- C1-3 alkyl;
  • 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, pyrazolyl, thiazolyl, -C(O)C 3-6 cycloalkyl, -C(O)NR a1 R b1 or -C(O)R, R is pyrazolyl or thiazolyl; wherein each occurrence of the pyrazolyl and thiazolyl is each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, C 1-3 alkyl and halogenated C 1-3 alkyl;
  • R b is hydrogen or halogen (preferably fluorine or chlorine).
  • Z is 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, -NHCOCH3, -NHCOOCH3, -NHCO-cyclopropyl, -NHCO-thiazole, -NHCO-tetrahydropyrrole, -NHCONHCH2CH3 , pyrazolyl , methylpyrazolyl, -NH-methylpyrazole, -NH-thiazole, -NH-methylthiazole,
  • R b is hydrogen, fluorine or chlorine.
  • Z is C; Ra and Rb are linked to form a 5- or 6-membered heteroaryl ring, a benzene ring, or a 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring, the benzene 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, halo-substituted C1-3 alkyl, halo-substituted 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,
  • Z is C; Ra and Rb are linked to form:
  • a benzene ring or a 5- or 6-membered heteroaryl ring selected from the group consisting of a thiophene ring, a furan ring, a thiazole ring, an isothiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring (including a 1,2,3-triazole ring, a 1,2,4-triazole ring, a 1,2,5-triazole ring, and a 1,3,4-triazole ring), a tetrazole ring, an isoxazole ring, an oxadiazole ring (including a 1,2,3-oxadiazole ring, a 1,2,4-oxadiazole ring, a 1,2,5-oxadiazole ring, and a 1,3,4-oxadiazole ring), a thiadiazole
  • a 5- or 6-membered heterocycloalkyl ring selected from the group consisting of a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrroline ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide and a tetrahydropyran ring; the 5- or 6-membered heterocycloalkyl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, an oxo group, a halogen group, a cyano group, a hydroxyl group, a carboxyl group,
  • Z is N; Ra and Rb are linked to form a 5-membered heteroaryl ring, the 5-membered heteroaryl ring being selected from: thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring (including 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring), isoxazole ring, oxadiazole ring (including 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring) and thiadiazole ring; the 5-membered heteroaryl ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen,
  • Z is N;
  • Ra is hydrogen, deuterium , -NRa0Rb0 , haloC1-3 alkyl, halogen, cyano, hydroxy, carboxyl, C1-3 alkyl, C1-3 alkoxy, -C(O) C1-3 alkyl, -C(O)OC1-3 alkyl , C3-6 cycloalkyl, C2-4 alkenyl, or -OC(O) C1-3 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)NR a1 R b1 .
  • Z is N;
  • Ra is hydrogen, deuterium , halogen, fluoroC1-3 alkyl, chloroC1-3 alkyl, C1-3 alkyl , amino, hydroxy, -NHC(O) C1-3 alkyl, -NHC(O) OC1-3 alkyl, cyclopropyl, vinyl, or -NHC(O) NRa1Rb1 .
  • Z is N;
  • Ra is hydrogen, deuterium, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl , dichloroethyl, trichloroethyl, methyl, ethyl, fluorine, chlorine, -NH2 , -NHCOOCH3 , -NHCOOCH2CH3 , -NHCOCH3 , -NHCOCH2CH3 , -NHC (O) NH2 , cyclopropyl, vinyl, or
  • the structure Select one of the following structures:
  • R s1 , R s2 , R s3 , R s4 , R s5 , R s6 , R s7 , R s8 , R s9 , R s10 , R s11 , R s12 , R s13 , R s14 , R s15 and R s16 are each independently hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -SC 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C
  • n1, m3, m6, m10 are each independently 0, 1 or 2; m2 is 0, 1, 2, 3 or 4; m4, m7, m8, m9, m11, m12, m13, m14 are each independently 0 or 1; m5 is 0, 1, 2 or 3.
  • the structure A structure selected from one of the following groups:
  • Rs1, Rs2, Rs3, Rs4, Rs5, Rs6, Rs7, Rs8, Rs9, Rs10, Rs11 and Rs12 are each independently hydrogen , 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, -NH2 , -NHC1-3 alkyl, -N( C1-3 alkyl) 2 , -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 cycl
  • n1, m3, m6, m10 are each independently 0, 1 or 2; m2 is 0, 1, 2, 3 or 4; m4, m7, m8, m9 are each independently 0 or 1; m5 is 0, 1, 2 or 3.
  • Rs1 , Rs2 , Rs3 , Rs4 , Rs5 , Rs6 , Rs7, Rs8, Rs9, Rs10 , Rs11, and Rs12 are each independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl , ethynyl, propynyl, butynyl, vinyl, 1-fluorovinyl, 1-trifluoromethylvinyl, 2,2-difluorovinyl, -SCH3 , -SC2H5 , -SC3H7 , -SCH( CH3 ) 2 , methoxy, ethoxy, n-propoxy, isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobrom
  • 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.
  • the compound of formula (I) is a compound of formula (XII):
  • the compound of formula (I) is a compound of formula (III):
  • each occurrence of R s5 is independently hydrogen, 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 , -SO2C1-3alkyl , -S(O) C1-3alkyl , -SC1-3alkyl , -C(O) NH2, -C(O)NH(C1-3alkyl), -C(O)N(C1-3alkyl)2 , -C ( O ) OC1-3alkyl , -OC(O) C1-3alkyl , -C(O) C1-3alkyl or C3-6cycloalkyl ; the C2-4alkenyl is substituted with 0, 1, 2 or 3 substituent
  • n3 0, 1 or 2;
  • R c and R d are each independently hydrogen, fluorine, chlorine, halogenated C 1-3 alkyl, cyano, hydroxy, carboxyl, C 3-6 cycloalkyl, C 1-3 alkyl, -NR a1 R b1 or C 1-3 alkoxy;
  • R 1 n represents that the hydrogen on ring A is replaced by n R 1s , n is 0, 1 or 2; 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 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated 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)NR a1 R b1 ;
  • R 0 is hydrogen or 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 atom to which they are connected together form a C 3-6 cycloalkyl ring.
  • R 2 and R 3 are each independently methyl; or R 2 , R 3 and the carbon atom to which they are attached together form a cyclopropyl ring.
  • 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 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- 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 is independently selected from the group consisting of 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 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 compound of formula (I) is any one of the following compounds:
  • the second aspect of the present application provides a pharmaceutical composition, which includes the compound described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the third aspect of the present application provides use of the compound described in the first aspect of the present application, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition described in the second aspect of the present application 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.
  • the fourth aspect of the present application 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 present application provides a compound represented by formula (IV), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • the compound of formula (IV) is any one of the following compounds:
  • the sixth aspect of the present application provides a method for preparing the compound represented by formula (IV) according to the fifth aspect, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the following steps:
  • R G1 and R G2 are a pair of groups that can undergo coupling reaction.
  • R4 is a hydroxyl protecting group
  • R4 is a hydroxyl protecting group.
  • 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.
  • the hydroxyl protecting group is a common hydroxyl protecting group commonly used by those skilled in the art, including but not limited to C 1-6 alkyl (preferably C 1-3 alkyl), benzyl, -Cbz, -Boc, and the like.
  • 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 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 .
  • step S100 includes the following steps:
  • 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 in step S110 or step S120, is a mixed solvent consisting of 1,4-dioxane and water; further, the volume ratio of 1,4-dioxane to water is about (2-12):1.
  • the catalyst in step S110 or step S120, 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,
  • 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 about 60°C to about 180°C; further, the reaction temperature is about 80°C to about 150°C.
  • step S110 or step S120 is reacted under microwave conditions.
  • step S200 includes the following steps:
  • the acid in step S210 is an aqueous solution of hydrobromic acid.
  • the reaction temperature is about 60°C to about 150°C; further, the reaction temperature is about 80°C to about 130°C.
  • step S200 is to react the compound of formula (III-1) to obtain the compound of formula (IV-1):
  • step S200 includes the following steps:
  • step S220 when R 4 is benzyl, the compound represented by formula (III) is reacted under a hydrogen atmosphere and palladium-carbon catalysis to obtain the compound represented by formula (IV-1).
  • the present application provides a compound represented by formula (X), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • R 6 is an amino protecting group
  • the compound of formula (X) is selected from the following structures:
  • Z, U 1 , U 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, U 1 , U 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.
  • R6 is an amino protecting group.
  • the compound of formula (V) obtained in step S310 or the compound of formula (XI) obtained in step S320 can be modified by methods well known in the art (such as modifying the amino group by acylation reaction (such as modifying -NH2 to C2H5NHC (O)NH-, or modifying -NH2 to CH3OC (O)NH-, or modifying -NH2 to Or the carboxyl group is modified to an amide through an acylation reaction, or the halogen is converted into an amino group, or the amino group is alkylated, 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.
  • acylation reaction such as modifying -NH2 to C2H5NHC (O)NH-, or modifying -NH2 to CH3OC (O)NH-, or modifying -NH2 to Or the carboxyl group is modified to an amide through an acylation
  • 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 S310 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 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 20-150°C, further 30-150°C, and further 50-100°C.
  • R s5 is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, monofluoromethyl, monofluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, acetyl, -CO 2 CH 2 CH 3 , -CO 2 CH 3 or -C(O)NH 2 ; m3 is 0, 1 or 2.
  • step S320 the compound of formula (A) is selected from the following structures:
  • step S320 the reaction is carried out in acetic acid.
  • the reaction temperature is 50-150°C, preferably 60-120°C.
  • the reaction in step S410 or step S420 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 ninth aspect of the present application provides a compound of formula (I) prepared according to the method for preparing the compound of formula (I) described in the eighth aspect of the present application.
  • this type of heterocyclic substituted pentahedral hexaaryl derivatives have significant AAK1 kinase inhibitory 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 this application.
  • 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, and more preferably a C1-3 alkyl group; non-limiting examples of alkyl groups 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, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl,
  • 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 both 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 an oxo group.
  • C 3-8 cycloalkyl refers to a monocyclic cycloalkyl group having 3 to 8 carbon atoms.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, and the like.
  • Preferred are C 3-6 cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 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 groups include
  • Cycloalkenyl and “cycloalkenyl ring” are used interchangeably, and both refer to monocyclic, bicyclic or polycyclic cyclic hydrocarbon groups containing one or more carbon-carbon double bonds in the ring, which groups may be fused with aryl or heteroaryl groups.
  • the cycloalkenyl ring may be optionally substituted.
  • the cycloalkenyl ring contains one or more carbonyl groups, such as oxo groups.
  • C 3-8 cycloalkenyl refers to a cycloalkenyl group having a monocyclic structure of 3 to 8 carbon atoms. Preferably, C 3-6 cycloalkenyl.
  • Non-limiting examples of cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, cyclopentyl-2-ene-1-one, cyclohexyl-2,5-diene-1-one, cyclohexyl-2-ene-1-one, cyclohex-2-ene-1,4-dione, etc.
  • 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 having 5 to 6 ring atoms, of which 1, 2, 3 or 4 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, triazolyl,
  • Benzo-heterocycloalkyl refers to a group in which a benzene ring is fused to a heterocycloalkyl ring to form a bicyclic, tricyclic or polycyclic system, wherein the heterocycloalkyl ring is as defined above.
  • “7 to 11-membered phenyl-heterocycloalkyl” refers to a bicyclic cyclic group having 7 to 11 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • it is an 8 to 10-membered phenyl-heterocycloalkyl group having 8 to 10 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples include indoline, benzo[d][1,3]dioxazole, 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-2H-benzo[b][1,4]oxazine, and the like.
  • Heteroarylheterocycloalkyl refers to a group in which a heteroaryl ring is fused to a heterocycloalkyl ring to form a bicyclic, tricyclic or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above.
  • “7- to 11-membered heteroarylheterocycloalkyl” refers to a bicyclic cyclic group having 7 to 11 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • it is an 8- to 10-membered heteroarylheterocycloalkyl group having 8 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples include 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, [1,3]dioxolane[4,5-b]pyridine, 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine, 2,3,4,6-tetrahydropyrrolo[3,4-b][1,4]oxazine, 2,4,5,6-tetrahydropyrano[2,3-c]pyrazole, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, and the like.
  • 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 by 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.
  • Deuterated alkyl refers to an alkyl group substituted by one or more (e.g., 1, 2, 3, 4 or 5) deuterium atoms, wherein the definition of alkyl is as described above. Preferably, it is a deuterated C 1-8 alkyl group, more preferably a deuterated C 1-6 alkyl group, and more preferably a deuterated C 1-3 alkyl group. Examples of deuterated alkyl groups include (but are not limited to) monodeuterated methyl, monodeuterated ethyl, dialdeuterated methyl, dialdeuterated ethyl, trideuterated methyl, trideuterated ethyl, 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
  • Me refers to methyl
  • Bu refers to butyl
  • the "cyclopropylene” structure is:
  • Ms refers to methylsulfonyl
  • “Saturated or partially unsaturated monocyclic ring” refers to a saturated or partially unsaturated all-carbon monocyclic ring system, wherein “partially unsaturated” refers to a ring portion including at least one double bond or triple bond, and “partially unsaturated” is intended to cover a ring with multiple unsaturated sites, but is not intended to include aryl or heteroaryl moieties as defined herein.
  • a saturated or partially unsaturated monocyclic ring contains one or more carbonyl groups, such as an oxo group.
  • 3 to 7 yuan saturated or partially unsaturated monocyclic ring has 3 to 7 ring carbon atoms, preferably a saturated or partially unsaturated monocyclic ring with 3 to 6 ring carbon atoms, and more preferably a saturated monocyclic ring with 3 to 6 ring carbon atoms.
  • Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl rings, cycloheptatrienyl rings, cyclopentanone rings, cyclopentane-1,3-dione rings, etc.
  • “Saturated or partially unsaturated monocyclic heterocycle” means that 1, 2 or 3 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 does not include 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, and more preferably, it has 5 to 6 ring atoms, wherein 1 Or 2 ring atoms are 5 to 6 membered saturated or partially unsaturated monocyclic heterocycles of the above heteroatoms, most preferably 5 or 6 membered saturated monocyclic heterocycles.
  • Non-limiting examples of saturated monocyclic heterocycles include oxetane rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings, oxazolidine rings, piperazine rings, dioxolane rings, dioxane rings, morpholine rings, thiomorpholine rings, thiomorpholine-1,1-dioxide, tetrahydropyran rings, azetidine-2-one rings, oxetane-2-one rings, pyrrolidine-2-one rings, pyrrolidine-2,5-dione rings, piperidine-2-one rings, dihydrofuran-2 (3H)-one rings, dihydrofuran-2,5-dione rings, tetrahydro-2H-pyran-2-one rings, piperazine-2-one rings, morpho
  • Non-limiting examples of partially unsaturated monocyclic heterocycles include 1,2-dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, -pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazolidine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine ring, 2,5,6,7-t
  • 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.
  • the phrase "... are the same or different, and are each independently " used herein 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 two same or different halogen substitutions, or they may be one halogen and one hydroxyl substitution.
  • the compounds of the present application or their pharmaceutically acceptable salts, or their solvates, or their stereoisomers, or prodrugs can be used in a suitable dosage form with one or more pharmaceutical carriers.
  • These 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 application contained in these preparations can be solid powders or particles; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or water-in-oil emulsions, etc.
  • the above dosage forms can be made from active compounds and one or more carriers or excipients via a common pharmaceutical method.
  • the above carriers need to be compatible with the active compounds or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc.
  • Carriers for liquid preparations include water, saline, aqueous glucose solution, ethylene glycol, and polyethylene glycol, etc.
  • the active compound can form a solution or suspension with the above carriers.
  • “Pharmaceutically acceptable carrier” refers to a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of excipient that is compatible with a patient, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to a target site without terminating the activity of the agent.
  • active substance of the present application or “active compound of the present application” refers to the compound of formula (I) of the present application, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, which has a higher AAK1 selective inhibitory activity.
  • compositions of the present application 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 induce a biological or medical response in an individual, 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 application 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 application 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). 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 application. It should be understood that the present application encompasses all stereochemical isomeric forms or mixtures thereof, which have the ability to inhibit AAK1. Individual stereoisomers of the compounds can 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 are commercially available or can be prepared and resolved by techniques known in the art. Certain compounds of the present application may also exist in different stable conformational forms that can be separated.
  • the present application includes each conformer of these compounds and mixtures thereof.
  • the term "compound of the present application” 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 application provides a method for preparing a compound of formula (I).
  • the compound of formula (I) can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described in the present application.
  • the solvents, temperatures and other reaction conditions given in the present application can be varied according to the art.
  • the reactions can be used in sequence to provide the compounds of the present application, or they can be used to synthesize fragments, which are synthesized by the methods described in the present application. The methods described above and/or methods known in the art are then added.
  • the compounds described in this application 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 for synthesizing the compounds described in this application can be synthesized or can be obtained from commercial sources.
  • the compounds described in this application 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 compounds disclosed in this application 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 application.
  • a series of novel heterocyclic substituted pentahedral and hexaheteroaryl derivatives which have high selective inhibitory activity against AAK1, excellent in vivo pharmacokinetic activity and weak hERG inhibitory effect, and the IC 50 value of the inhibitory activity against AAK1 kinase is 50nM to 100nM, the IC 50 value of some compounds is 10nM to 50nM, and the IC 50 value of some compounds is 0.1nM to 10nM, so they can be used as drugs for treating or controlling related diseases or disorders mediated by AAK1 activity.
  • These compounds have more excellent central nervous system permeability, higher AAK1 selective inhibitory effect, and weaker hERG inhibitory effect, so they have potential excellent therapeutic effects and lower toxicity for central nervous system diseases mediated by AAK1 activity.
  • DCM dichloromethane
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • NaHMDS sodium bis(trimethylsilyl)amide
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • DIEA N,N-diisopropylethylamine
  • EA ethyl acetate
  • EtOAc ethyl acetate
  • PE petroleum ether
  • MeOH methanol
  • IPA isopropanol
  • NMP N-methylpyrrolidone
  • DMAP 4-dimethylaminopyridine
  • TsCl 4-toluenesulfonyl chloride
  • HA TU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DMF-DMA N,N-dimethylformamide dimethyl acetal
  • the present invention is obtained by lyophilization after purification by prep.HPLC (preparative high performance liquid chromatography).
  • room temperature refers to about 20-30° C.; “overnight” refers to about 10 h to 16 h; 1 M/1 N is 1 mol/L, 1 mM is 1 mmol/L; eq: equivalent.
  • 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 Dissolve (4S)-tert-butyl-4-isobutyl-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (26 g, 93.73 mmol) in acetonitrile (270 mL) and water (108mL) in a mixed solvent, then add ruthenium chloride trihydrate (100mg, 382.45 ⁇ mol), and finally slowly add sodium periodate (25g, 115.79mmol) at room temperature, and stir the reaction at room temperature for 2h. After the reaction is completed, filter and wash the filter cake with ethyl acetate.
  • thiazole-2-carboxylic acid (258 mg, 2.00 mmol) was dissolved in tetrahydrofuran (6 mL), oxalyl chloride (507.17 mg, 4.00 mmol, 338.11 ⁇ L) was added, and then N, N-dimethylformamide (0.1 mL) was added dropwise. The reaction was stirred at 20 ° C for 1 hour, and the intermediate c (290 mg, 1.96 mmol) was obtained by vacuum drying with a yield of 98.35%. The crude product was directly used in the next step.
  • Step 1 Dissolve imidazole (25.7 g, 378 mmol) and triethylamine (21.0 g, 207 mmol) in anhydrous dichloromethane (350 mL), cool to -60°C under nitrogen protection, slowly add thionyl chloride (12.2 g, 102 mmol) at -60°C, and stir for 30 minutes at -60°C after the addition is complete. Then cool the reaction solution to -70°C and slowly add a dichloromethane solution (60 mL) of N-tert-butyloxycarbonyl-L-leucine alcohol (20.3 g, 93.6 mmol) dropwise. After the addition is complete, the reaction is heated to 20°C and stirred for 12 hours.
  • Step 2 (4S)-4-isobutyl-1,2,3-oxathiazolidine-3-carboxylic acid-2-oxo-tert-butyl ester (27.3 g, 103 mmol) was dissolved in a mixed solvent of acetonitrile (270 mL) and water (100 mL), then ruthenium trichloride (18 mg, 86.7 ⁇ mol ⁇ mol) was added, and finally sodium periodate (24.4 g, 114 mmol) was slowly added at 20°C, and the reaction was stirred at 20°C for 2 hours.
  • Step 1 Dissolve (S)-2-amino-3-cyclopropylpropionic acid (12.5 g, 96.78 mmol) in sodium hydroxide aqueous solution (1M, 325.00 mL), and slowly add benzyl chloroformate (19.81 g, 116.14 mmol). Stir and react at 20°C for 16 hours.
  • Step 2 (S)-2-(((Benzyloxy)carbonyl)amino)-3-cyclopropylpropionic acid (17 g, 64.57 mmol) was dissolved in tetrahydrofuran (300 mL), and borane tetrahydrofuran solution (1 M, 83.94 mL) was slowly added dropwise under nitrogen atmosphere at 0°C, and stirred at 20°C under nitrogen atmosphere for 4 hours. The reaction solution was quenched by adding hydrochloric acid aqueous solution (1 M, 300 mL) at 0°C until bubbles were generated, and then the system was stirred at 20°C for 10 hours. Then the system was extracted with ethyl acetate (200 mL ⁇ 3).
  • Step 3 Dissolve imidazole (16.38 g, 240.67 mmol) in dichloromethane (150 mL) solvent, slowly dropwise add the reaction solution of thionyl chloride (8.59 g, 72.20 mmol) in dichloromethane (30 mL) solvent to the above reaction system under a nitrogen atmosphere at -5°C, and stir at -5°C for 1 hour. Then, slowly dropwise add a mixture of (S)-benzyl (1-cyclopropyl-3-hydroxypropane-2-yl) aminomethyl ester (10.0 g, 40.11 mmol) in dichloromethane (60 mL) to the above system under a nitrogen atmosphere at -10°C.
  • Step 4 Dissolve (4S)-4-(cyclopropylmethyl)-1,2,3-oxathiazolidine-3-carboxylic acid benzyl ester 2-oxide (4.80 g, 16.25 mmol) in acetonitrile (50 mL) and water (50 mL), add trichloromethane (67.42 mg, 325.03 ⁇ mol) and sodium periodate (8.69 g, 40.63 mmol) respectively in an ice bath at 0°C, and stir at room temperature for 2 hours.
  • Step 1 Dissolve p-chlorobenzaldehyde (101 g, 716 mmol) and DL-alanine methyl ester hydrochloride (100 g, 716 mmol) in anhydrous dichloromethane (1000 mL), add anhydrous magnesium sulfate (345 g, 2.87 mol) and triethylamine (254 g, 2.51 mmol), and react at 40 ° C for 32 hours under nitrogen protection.
  • Step 2 Under nitrogen protection at 25°C, sodium hydride (9.75g, 244mmol, purity 60%) was added to a solution of (E)-2-((4-chlorobenzylidene)amino)propionic acid methyl ester (50.0g, 222mmol) dissolved in anhydrous tetrahydrofuran (500mL), and the mixture was reacted at 25°C for 30 minutes. Bromomethylcyclopropane (29.9g, 222mmol) was slowly added, and the temperature was naturally raised to 25°C and the reaction was continued for 16 hours.
  • Step 3 Dissolve (E)-2-((4-chlorobenzylidene)amino)-3-cyclopropyl-2-methylpropionic acid methyl ester (40.0 g, 143 mmol) in anhydrous tetrahydrofuran (200 mL), cool to 0°C, add 178 mL of aqueous hydrogen chloride solution (1 M), and stir the reaction at 0°C for 1.5 hours.
  • Step 4 Methyl 2-amino-3-cyclopropyl-2-methylpropanoate (6.00 g, 38.2 mmol) was dissolved in anhydrous dichloromethane (60 mL), N,N-diisopropylethylamine (5.43 g, 42.0 mmol) was added, and benzyl chloroformate (5.43 g, 42.0 mmol) was slowly added dropwise at 0°C, and the reaction mixture was stirred at 0°C for 2 hours.
  • Step 5 2-(((Benzyloxy)carbonyl)amino)-3-cyclopropyl-2-methylpropanoic acid methyl ester (6.10 g, 20.9 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran, and a tetrahydrofuran solution of lithium aluminum hydroxide (1 M, 25.1 mL) was added dropwise at 0°C under nitrogen protection, and the ice bath was removed, and the mixture was reacted at 25°C for 3 hours. Water (100 mL) was added at 0°C and stirred for 30 minutes, and the mixture was filtered through diatomaceous earth.
  • Step 6 Purify (1-cyclopropyl-3-hydroxy-2-methylpropane-2-yl)benzylcarbamate (2.80 g, 10.6 mmol) by chiral HPLC (preparative column: DAICEL CHIRALPAK AD (250 mm ⁇ 50 mm, 10 ⁇ m); mobile phase: [0.1% NH 3 H 2 O IPA]; B%: 20%-20%, min) to obtain (S)-benzyl(1-cyclopropyl-3-hydroxy-2-methylpropane-2-yl)carbamate (980 mg, colorless oily liquid), yield: 35.0%. MS m/z(ESI): 263.9[M+H] + .
  • Step 7 Add thionyl chloride (339 mg, 2.85 mmol) to acetonitrile (3 mL) under nitrogen protection, cool to -40 ° C, slowly drop a solution of (S)-(1-cyclopropyl-3-hydroxy-2-methylpropane-2-yl)carbamic acid benzyl ester (300 mg, 1.14 mmol) dissolved in 1.5 mL of acetonitrile, immediately add pyridine (451 mg, 5.70 mmol), slowly warm to 25 ° C and stir for 1 hour.
  • Step 8 (4S)-4-(cyclopropylmethyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid benzyl ester 2-oxide (100 mg, 323 ⁇ mol) was dissolved in a mixed solution of acetonitrile (1.2 mL) and water (0.6 mL), and ruthenium trichloride (670 ug, 3.23 ⁇ mol) and sodium periodate (76.0 mg, 356 ⁇ mol) were added, and stirred at 20°C for 2 hours.
  • Step 1 Dissolve 2,4,6-trimethylbenzenesulfonyl chloride (15 g, 68.59 mmol) and tert-butyl N-hydroxycarbamate (9.13 g, 68.59 mmol) in methyl tert-butyl ether (100 mL). The reaction solution was cooled to 0°C, and then triethylamine (8.33 g, 82.30 mmol, 11.48 mL) was added. The reaction solution was stirred at 0°C for 2 hours. The reaction was monitored by LC-MS.
  • Step 2 Dissolve (tert-butyloxycarbonylamino) 2,4,6-trimethylbenzenesulfonate (12.6 g, 39.95 mmol) in trifluoroacetic acid (25 mL). The reaction solution was cooled to 0°C and stirred at 0°C for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, ice water was added and filtered to obtain amino 2,4,6-trimethylbenzenesulfonate (8.6 g, white solid). Yield 100%. MS m/z (ESI): 233.1 [M+18] + .
  • Step 3 Dissolve amino 2,4,6-trimethylbenzenesulfonate (8.59 g, 39.89 mmol) and 2-bromo-5-methoxypyridine (5 g, 26.59 mmol) in dichloromethane (50 mL). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the 2,4,6-trimethylbenzenesulfonate of 2-bromo-5-methoxypyridine-1-bromo-1-amine (5.43 g, yellow oil) was obtained by spin drying. The yield was 100%. MS m/z (ESI): 205.0 [M+H] + .
  • Step 5 Dissolve 7-bromo-4-methoxypyrazole [1,5-a] pyridine-3-carboxylic acid methyl ester (500 mg, 1.75 mmol) in hydrobromic acid (5 mL, 48%). Heat the reaction solution to 100 ° C and stir for 2 hours. After the reaction is completed, spin dry to obtain 7-bromo-4-methoxypyrazole [1,5-a] pyridine (330 mg, purple solid). Yield 82.87%. MS m/z (ESI): 229.0 [M + H] + .
  • Step 6 7-bromo-4-methoxypyrazolo[1,5-a]pyridine (80 mg, 352.33 ⁇ mol), 2-aminopyridine-4-boronic acid pinacol ester (116.31 mg, 528.50 ⁇ mol), tetrakis(triphenylphosphine)palladium (40.71 mg, 35.23 ⁇ mol) and cesium carbonate (137.76 mg, 422.80 ⁇ mol) were added to 1,4-dioxane (5 mL) and water (0.5 mL), and the reaction solution was stirred at 100°C for 4 hours.
  • Step 7 Dissolve 4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)pyridin-2-amine (80 mg, 332.97 ⁇ mol) in hydrobromic acid (5 mL, 48%), and stir the reaction solution at 120°C for 48 hours. After the reaction is completed, spin dry to obtain intermediate 1 (70 mg, yellow solid). Yield 92.93%. MS m/z (ESI): 227.1 [M+H] + .
  • Step 1 7-bromo-4-methoxypyrazolo[1,5-a]pyridine (110 mg, 484.46 ⁇ mol), 2-difluoromethyl-4-pyridineboronic acid pinacol ester (185.35 mg, 726.69 ⁇ mol), tetrakis(triphenylphosphine)palladium (55.98 mg, 48.45 ⁇ mol) and cesium carbonate (189.42 mg, 581.35 ⁇ mol) were added to 1,4-dioxane (5 mL) and water (0.5 mL), and the reaction solution was stirred at 100°C for 16 hours.
  • Step 2 Dissolve 7-[2-(difluoromethyl)-4-pyridyl]-4-methoxypyrazolo[1,5-a]pyridine (110 mg, 399.63 ⁇ mol) in hydrobromic acid (5 mL, 48%), and stir the reaction solution at 120°C for 48 hours. After the reaction is completed, the solvent is dried to obtain intermediate 2 (100 mg, yellow solid). Yield 95.79%. MS m/z (ESI): 262.1 [M+H] + .
  • Step 2 Dissolve amino 2,4,6-trimethylbenzenesulfonate (2.15 g, 10.00 mmol) and 5-benzyloxy-2-bromopyridine (1.32 g, 5.00 mmol) in dichloromethane (20 mL). Stir the reaction solution at room temperature for 2 hours. After the reaction, spin dry to obtain 2,4,6-trimethylbenzenesulfonate of 5-benzyloxy-2-bromopyridine-1-bromo-1-amine (1.40 g, white solid). Yield 100%. MS m/z (ESI): 281.0 [M+H] + .
  • Step 3 Dissolve 2,4,6-trimethylbenzenesulfonate (1.4 g, 5.00 mmol) of 5-benzyloxy-2-bromopyridin-1-bromo-1-amine and methyl propiolate (840.31 mg, 10.00 mmol) in N,N-dimethylformamide (20 mL). The reaction solution was cooled to 0°C, and then potassium carbonate (1.73 g, 12.49 mmol) was added. The reaction solution was stirred at room temperature for 16 hours.
  • Step 4 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (180 mg, 498.35 ⁇ mol), 7-azaindole-4-boronate (145.98 mg, 598.02 ⁇ mol), tetrakis(triphenylphosphine)palladium (28.79 mg, 24.92 ⁇ mol) and potassium carbonate (68.88 mg, 498.35 ⁇ mol) were added to 1,4-dioxane (5 mL) and water (0.5 mL), and the reaction solution was stirred at 100°C for 4 hours.
  • Step 5 Dissolve 4-benzyloxy-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (180 mg, 451.79 ⁇ mol) in The reaction solution was stirred at 100°C for 4 hours in hydrobromic acid (10 mL, 48%). After the reaction was completed, the intermediate 3 (100 mg, yellow solid) was obtained by spin drying. The yield was 88.45%. MS m/z (ESI): 251.1 [M+H] + .
  • Step 1 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (540 mg, 1.50 mmol), 2-(tert-butoxycarbonylamino)pyridine-4-boronic acid pinacol ester (478.70 mg, 1.50 mmol), tetrakis(triphenylphosphine)palladium (86.38 mg, 74.75 ⁇ mol) and potassium carbonate (206.63 mg, 1.50 mmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL), and the reaction solution was stirred at 100°C for 16 hours.
  • Step 2 Dissolve 4-benzyloxy-7-[2-(tert-butyloxycarbonylamino)-4-pyridyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (100 mg, 210.74 ⁇ mol), iodomethane (59.83 mg, 421.49 ⁇ mol) and potassium carbonate (43.69 mg, 316.12 ⁇ mol) in N,N-dimethylformamide (5 mL), and stir the reaction solution at room temperature for 16 hours.
  • Step 3 Dissolve 4-benzyloxy-7-[2-[tert-butyloxycarbonyl(methyl)amino]-4-pyridyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (95 mg, 194.46 ⁇ mol) in hydrobromic acid (5 mL, 48%), and stir the reaction solution at 100°C for 4 hours. After the reaction is completed, spin dry to obtain intermediate 4 (40 mg, yellow solid). Yield 85.61%. MS m/z (ESI): 241.1 [M+H] + .
  • Step 1 Dissolve 4-benzyloxy-7-[2-(tert-butoxycarbonylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (100 mg, 210.74 ⁇ mol), 1,1-difluoro-2-iodoethane (80.90 mg, 421.49 ⁇ mol) and potassium carbonate (58.25 mg, 421.49 ⁇ mol) in N,N-dimethylformamide (5 mL), and stir the reaction solution at 70°C for 16 hours.
  • Step 2 Dissolve 4-benzyloxy-7-[2-[tert-butyloxycarbonyl(2,2-difluoroethyl)amino]-4-pyridyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (90 mg, 167.12 ⁇ mol) in hydrobromic acid, and stir the reaction solution at 100°C for 4 hours. After the reaction is completed, spin dry to obtain intermediate 5 (40 mg, yellow solid). Yield 82.46%. MS m/z(ESI):291.1[M+H] + .
  • Step 1 Dissolve 8-iodo-5-methoxyimidazo[1,2-a]pyridine (1 g, 3.65 mmol) in tetrahydrofuran (20 mL), cool to -70 °C, add n-butyl lithium (2.5 M, 2.63 mL) dropwise under argon protection, stir at low temperature for 10 minutes, slowly add triisopropyl borate (1.37 g, 7.30 mmol) in tetrahydrofuran, and continue stirring for 1.5 hours.
  • Step 1 (5-methoxyimidazo[1,2-a]pyridin-8-yl)boric acid (191 mg, 1 mmol), 4-chloro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (168 mg, 1 mmol) and bis(triphenylphosphine)palladium chloride (36.40 mg, 0.05 mmol) were dissolved in 1,4-dioxane (15 mL), potassium carbonate (413 mg, 3 mmol) was added, and argon was replaced three times.
  • Step 1 Dissolve 7-bromo-4-methoxypyrazolo[1,5-a]pyridine (454 mg, 2 mmol) in tetrahydrofuran (25 mL), cool to -70 °C, add n-butyl lithium (2.5 M, 1.44 mL) dropwise under argon protection, stir at low temperature for 10 minutes, slowly add tributyltin chloride (1.13 g, 4 mmol) in tetrahydrofuran, and continue stirring for 1.5 hours.
  • Step 2 4-methoxy-7-(tributyltinyl)pyrazolo[1,5-a]pyridine (451 mg, 1 mmol), 5-fluoro-4-iodo-2-pyridinamine (238 mg, 1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) were dissolved in toluene (20 mL), replaced with argon three times, heated to 150° C.
  • Step 3 Dissolve 5-fluoro-4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)pyridin-2-amine (120 mg, 0.465 mmol) in 40% aqueous hydrobromic acid solution (15 mL), heat to 120°C, stir for 2 hours, cool, and concentrate to obtain a yellow solid intermediate 10 (95 mg, yield: 83.7%), which is used directly in the next step.
  • Step 1 4-methoxy-7-(tributyltinyl)pyrazolo[1,5-a]pyridine (226 mg, 0.5 mmol), 4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (106 mg, 0.5 mmol) and bis(triphenylphosphine)palladium chloride (17.6 mg, 0.025 mmol) were dissolved in 1,4-dioxane (10 mL), replaced with argon three times, heated to 150° C.
  • Step 2 Dissolve 4-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine (90 mg, 0.32 mmol) in 40% aqueous hydrobromic acid solution (10 mL), heat to 120°C, stir for 2 hours, cool, and concentrate to obtain the remaining yellow solid intermediate 11 (80 mg, yield: 93.6%), which was used directly in the next step. MS m/z (ESI): 265.1 [M+H] + .
  • Step 1 Add 4-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (500 mg, 1.38 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (980.81 mg, 2.77 mmol) to acetonitrile (20 mL) and stir at room temperature for 16 hours under argon protection. Add saturated sodium bicarbonate solution and extract with dichloromethane (30 mL ⁇ 3). The organic phase is dried, filtered, and concentrated under reduced pressure.
  • Step 2 4-(Benzyloxy)-7-bromo-2-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (200 mg, 527.45 ⁇ mol), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (201.81 mg, 791.18 ⁇ mol), tetrakis(triphenylphosphine)palladium (60.95 mg, 52.75 ⁇ mol) and potassium carbonate (87.48 mg, 632.94 ⁇ mol) were added to water (1 mL) and 1,4-dioxane (10 mL), and the reaction solution was stirred at 90°C for 6 hours.
  • Step 3 Dissolve 4-(benzyloxy)-7-(2-(difluoromethyl)pyridin-4-yl)-2-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (75 mg, 175.49 ⁇ mol) in ethanol (10 mL), add 10% palladium carbon (40 mg, 175.49 ⁇ mol), and stir the reaction solution at room temperature for 1 hour under the protection of hydrogen. Filter and concentrate under reduced pressure. Intermediate 13 (53 mg, yellow oil) was obtained, and the crude product was used directly in the next step. MS m/z (ESI): 338.0 [M+H] + .
  • Step 1 Add (4-methoxyphenyl)methylamine (1.20 g, 8.76 mmol), 2,6-dichloro-4-iodo-pyridine (1.2 g, 4.38 mmol) and N,N-diisopropylethylamine (1.70 g, 13.14 mmol, 2.29 mL) to N-methylpyrrolidone (10 mL). The reaction solution was stirred at 155°C for 6 hours.
  • Step 2 6-chloro-4-iodo-N-(4-methoxybenzyl)pyridin-2-amine (840 mg, 2.24 mmol), biboronic acid pinacol ester (626.36 mg, 2.47 mmol), potassium acetate (550.18 mg, 5.61 mmol) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (82.04 mg, 112.12 ⁇ mol) were added to 1,4-dioxane (20 mL). Under argon protection, the reaction solution was stirred at 80°C for 16 hours.
  • Step 3 Add 4-(methyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (639.17 mg, 2.24 mmol), (2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)boric acid (840 mg, 2.24 mmol), tetrakis(triphenylphosphine)palladium (129.54 mg, 112.10 ⁇ mol) and potassium carbonate (619.73 mg, 4.48 mmol) to water (1 mL) and 1,4-dioxane (10 mL), and stir the reaction solution at 100°C for 16 hours. Filter and spin dry the solvent.
  • Step 4 Add methyl 7-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (520 mg, 1.15 mmol) to a 48% aqueous solution of hydrogen bromide (12 mL), and stir the reaction solution at 130°C for 48 hours. Concentrate under reduced pressure to obtain the product intermediate 14 (210 mg, brown solid), which is used directly in the next step. MS m/z (ESI): 261.1 [M+H] + .
  • Step 1 Dissolve 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (1.1 g, 3.05 mmol) in 1,4-dioxane (30 mL), add (2,6-dichloro-4-pyridyl)boric acid (584.15 mg, 3.05 mmol), potassium carbonate (841.84 mg, 6.09 mmol), tetrakis(triphenylphosphine)palladium (351.92 mg, 304.55 ⁇ mol) and water (3 mL), stir at 100 ° C overnight, and the reaction is complete after LC-MS detection. Concentrate under reduced pressure to obtain a brown solid.
  • Step 2 Dissolve 4-benzyloxy-7-(2,6-dichloro-4-pyridinyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (600 mg, 1.40 mmol) in N-methylpyrrolidone (10 mL), add 4-methoxybenzylamine (192.19 mg, 1.40 mmol) and N,N-diisopropylethylamine (543.19 mg, 4.20 mmol), stir at 150 ° C for 2 hours, and the reaction is complete when LC-MS is detected. Concentrate under reduced pressure to obtain a brown solid.
  • Step 3 Dissolve 4-benzyloxy-7-[2-chloro-6-[(4-methoxyphenyl)methylamine]-4-pyridyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (700 mg, 1.32 mmol) in water (10 mL), add aqueous hydrogen bromide solution (428.28 mg, 40%), stir at 100°C for 4 hours, and the reaction is complete after LC-MS detection. Concentrate under reduced pressure to obtain intermediate 14 (300 mg, brown solid), yield: 86.97%. MS m/z (ESI): 261.1 [M+H] + .
  • Step 1 Dissolve 2-amino-6-chloropyridine (2.56 g, 19.91 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.06 g, 23.90 mmol) in tetrahydrofuran (20 mL).
  • Step 2 4-Benzyloxy-7-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (1 g, 2.77 mmol), 2-amino-6-chloro-pyridine-4-boronic acid pinacol ester (845.61 mg, 3.32 mmol), tetrakis(triphenylphosphine)palladium (159.97 mg, 138.43 ⁇ mol) and potassium carbonate (459.18 mg, 3.32 mmol) were added to 1,4-dioxane (50 mL) and water (5 mL), and the reaction solution was stirred at 100°C for 16 hours.
  • Step 1 Dissolve 2,3-difluoro-4-iodopyridine (2 g, 8.30 mmol) in aqueous ammonia (20 mL). The reaction was stirred at 135 °C for 12 hours. Cooled to room temperature, filtered, and the solid was dried under reduced pressure to obtain 3-fluoro-4-iodopyridin-2-amine (1.5 g, 6.30 mmol, white solid). Yield: 75.94%. MS m/z (ESI): 238.9 [M+H] + .
  • Step 2 Dissolve 3-fluoro-4-iodopyridin-2-amine (1 g, 4.20 mmol), tert-butyl tert-butyloxycarbonyl carbonate (1.83 g, 8.40 mmol), and triethylamine (848.74 mg, 424.37 mmol, 1.17 mL) in dichloromethane (10 mL). The reaction was stirred at 40 °C for 3 hours.
  • Step 3 Under argon protection, tert-butyl (3-fluoro-4-iodopyridin-2-yl)carbamate (200 mg, 591.51 ⁇ mol) and (5-methoxyimidazo[1,2-a]pyridin-8-yl)boronic acid (113.56 mg, 591.51 ⁇ mol) were dissolved in 1,4-dioxane (6 mL) and water (2 mL), and then tetrakis(triphenylphosphine)palladium (68.35 mg, 59.15 ⁇ mol) and potassium carbonate (163.26 mg, 1.18 mmol) were added. The reaction was stirred at 100 ° C for 5 hours.
  • Step 4 3-Fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (70 mg, 271.05 ⁇ mol) and tert-butyl tert-butyloxycarbonyl carbonate (118.31 mg, 542.11 ⁇ mol), N,N-dimethylpyridin-4-amine (3.31 mg, 27.11 ⁇ mol) were dissolved in dichloromethane (10.02 mL). The reaction was stirred at 40 ° C for 3 hours. The solvent was dried under reduced pressure.
  • Step 5 Dissolve tert-butyl N-tert-butoxycarbonyl-N-[3-fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)-2-pyridinyl]carbamate (80 mg, 174.49 ⁇ mol), lithium chloride (14.79 mg, 348.98 ⁇ mol), and 4-methylbenzenesulfonic acid (60.09 mg, 348.98 ⁇ mol) in N,N-dimethylformamide (6 mL). The reaction was stirred at 120°C for 0.5 hours. The solvent was evaporated under reduced pressure. The crude product was subjected to prep.HPLC to obtain intermediate 15 (10 mg, 40.95 ⁇ mol) with a yield of 23.47%. MS m/z (ESI): 245.1 [M+H] + .
  • Step 1 Under argon protection, 2,6-difluoropyridine-4-boronic acid (571.91 mg, 3.60 mmol) and 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (1 g, 2.77 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), and then potassium carbonate (764.14 mg, 5.54 mmol) and tetrakis(triphenylphosphine)palladium (159.97 mg, 138.43 ⁇ mol) were added. The reaction was stirred at 100°C for 12 hours, and the crude product was dried under reduced pressure to give a crude product.
  • Step 2 4-Benzyloxy-7-(2,6-difluoro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (440 mg, 1.11 mmol) and (4-methoxyphenyl)methylamine (198.47 mg, 1.45 mmol) were dissolved in N-methylpyrrolidone (8 mL), and then N,N-diisopropylethylamine (287.67 mg, 2.23 mmol, 387.70 ⁇ L) was added. The reaction was stirred at 120°C for 2 hours.
  • Step 3 Dissolve methyl 4-(benzyloxy)-7-(2-fluoro-6-((4-methoxybenzyl)amino)pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.35 g, 682.89 ⁇ mol) in hydrobromic acid (8 mL, 48%). The reaction was stirred at 100 °C for 12 hours. The intermediate 16 (160 mg, 655.14 ⁇ mol) was obtained by vacuum drying with a yield of 95.94%. The crude product was used directly in the next step. MS m/z (ESI): 245.1 [M+H] + .
  • Step 1 2-amino-6-fluoropyridine (1.12 g, 9.99 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.53 g, 11.99 mmol) were dissolved in tetrahydrofuran (20 mL).
  • Step 2 4-Benzyloxy-7-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (0.5 g, 1.38 mmol), 2-amino-6-fluoro-pyridine-4-boronic acid pinacol ester (395.47 mg, 1.66 mmol), tetrakis(triphenylphosphine)palladium (79.98 mg, 69.22 ⁇ mol) and potassium carbonate (229.59 mg, 1.66 mmol) were added to 1,4-dioxane (50 mL) and water (5 mL), and the reaction solution was stirred at 100 ° C for 16 hours.
  • Step 1 Dissolve 6-chloro-3-iodopyridin-2-amine (4 g, 15.72 mmol) in isopropanol (30 mL), add 2-bromo-1,1-diethoxyethane (3.72 g, 18.86 mmol) and hydrogen bromide solution (2.54 g, 31.44 mmol, 48%), stir at 90°C overnight and concentrate under reduced pressure to obtain a yellow solid, which is washed with ether and filtered to obtain a yellow solid 5-chloro-8-iodoimidazo[1,2-a]pyridine (4 g, 14.36 mmol, 91.37% yield). MS m/z (ESI): 279.1 [M+H] + .
  • Step 2 Dissolve 5-chloro-8-iodoimidazo[1,2-a]pyridine (5 g, 17.95 mmol) in methanol (100 mL), add sodium methoxide (2.91 g, 53.86 mmol), stir at 65°C for 6 hours, and concentrate under reduced pressure to obtain a white solid. The solid was passed through a combiflash (0-100% EA/PE) column to obtain a white solid 8-iodo-5- Methoxyimidazo[1,2-a]pyridine (4.9 g, 17.88 mmol, 99.58% yield). MS m/z (ESI): 275.1 [M+H] + .
  • Step 3 8-iodo-5-methoxyimidazo[1,2-a]pyridine (1 g, 3.65 mmol) was dissolved in water (2 mL), 1,4-dioxane (20 mL), potassium carbonate (1.01 g, 7.30 mmol), Pd(dppf) 2 Cl 2 (295.77 mg, 364.89 ⁇ mol) and 2-aminopyridine-4-boronic acid pinacol ester (803.03 mg, 3.65 mmol) were added, and the mixture was stirred for 1 hour at 120 °C in a microwave oven under nitrogen protection. The mixture was filtered and concentrated under reduced pressure to obtain a black solid.
  • Step 4 Dissolve 4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (400 mg, 1.66 mmol) in N,N-dimethylformamide (2 mL), add lithium chloride (141.16 mg, 3.33 mmol) and p-toluenesulfonic acid (573.38 mg, 3.33 mmol), and stir at 120°C for 30 minutes. Concentrate under reduced pressure to obtain a brown solid. The solid is passed through a combiflash (0-20% DCM/MeOH) column to obtain a yellow solid intermediate 17 (280 mg, 1.24 mmol, 74.34% yield). MS m/z (ESI): 227.1 [M+H] + .
  • Step 1 Dissolve 4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (180 mg, 749.19 ⁇ mol) in dichloromethane (8 mL), add acetyl chloride (117.62 mg, 1.50 mmol) and triethylamine (227.43 mg, 2.25 mmol, 313.48 ⁇ L) at 0°C, and stir at 0°C for 1 hour.
  • Step 2 Dissolve N-acetyl-N-[4-(5-methoxyimidazo[1,2-a]pyridin-8-yl)-2-pyridinyl]acetamide (120 mg, 369.99 ⁇ mol) in N,N-dimethylformamide (5 mL), add lithium chloride (15.69 mg, 369.99 ⁇ mol) and p-toluenesulfonic acid (63.71 mg, 369.99 ⁇ mol), and stir at 120°C for 30 minutes. Concentrate under reduced pressure to obtain a yellow solid. The solid was purified by pre-HPLC to obtain yellow solid intermediate 18 (50 mg, 186.38 ⁇ mol, 50.37% yield). MS m/z (ESI): 269.1 [M+H] + .
  • Step 1 5-chloro-8-(2-(difluoromethyl)pyridin-4-yl)imidazo[1,2-a]pyridine (0.2 g, 0.72 mmol) was dissolved in anhydrous methanol (6 mL), and potassium hydroxide (0.12 g, 2.15 mmol) was added. The reaction was stirred at 65°C for 16 h. After the reaction was completed, the solvent was removed under reduced pressure, and water (10 mL) was added to the reaction. Then, the mixture was extracted with ethyl acetate (20 mL ⁇ 2).
  • Step 2 8-(2-(Difluoromethyl)pyridin-4-yl)-5-methoxyimidazo[1,2-a]pyridine (0.14 g, 0.51 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and then p-toluenesulfonic acid (0.48 g, 2.54 mmol) and lithium chloride (0.11 g, 2.54 mmol) were added. The reaction was stirred at 120°C under nitrogen protection for 0.5 h. After the reaction was completed, water (20 mL) was added to quench the reaction, and then extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 1 Dissolve 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (720 mg, 1.99 mmol), (2-chloro-4-pyridyl)boric acid (313.69 mg, 1.99 mmol), potassium carbonate (275.51 mg, 1.99 mmol) and tetrakis(triphenylphosphine)palladium (2.30 g, 1.99 mmol) in 1,4-dioxane (10 mL) and water (2 mL), and stir the reaction solution at 100°C for 16 hours.
  • Step 2 4-benzyloxy-7-(2-chloro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (420 mg, 1.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (221.90 mg, 1.07 mmol), potassium carbonate (176.88 mg, 1.28 mmol) and tetrakis(triphenyl)benzene were added.
  • Step 3 Dissolve 4-benzyloxy-7-[2-(1-methylpyrazol-4-yl)-4-pyridinyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (100 mg, 227.55 ⁇ mol) in 40% hydrobromic acid aqueous solution (5 mL), and stir the reaction solution at 120°C for 2 hours. After the reaction is completed, spin dry to obtain intermediate 20 (66 mg, yellow solid). Yield 99.57%. MS m/z (ESI): 292.1 [M+H] + .
  • Step 1 Dissolve 2-bromo-4-chloropyridine (1.92 g, 10 mmol) and 1-methylpyrazol-4-amine (971 mg, 10 mmol) in 1,4-dioxane (60 mL), add tris(dibenzylideneacetone)dipalladium (275 mg, 0.3 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (347 mg, 0.6 mmol) and cesium carbonate (6.52 g, 20 mmol), replace with argon three times, heat to 100 ° C, and stir for 2 hours.
  • Step 2 Dissolve 4-chloro-N-(1-methylpyrazol-4-yl)pyridin-2-amine (1.5 g, 7.19 mmol) and biboronic acid pinacol ester (3.65 g, 14.38 mmol) in 1,4-dioxane (50 mL), add tris(dibenzylideneacetone)dipalladium (197.50 mg, 0.215 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (205 mg, 0.43 mmol) and potassium acetate (2.12 g, 21.6 mmol), replace with argon three times, heat to 100 ° C, stir for 2 hours, filter after cooling, and concentrate to obtain crude (2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)boric acid (black solid, 1.5 g, yield: 95.7%), which is directly used in the next step.
  • Step 3 Dissolve (2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)boronic acid (1.4 g, 6.42 mmol) and methyl 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylate (2.32 g, 6.42 mmol) in 1,4-dioxane (50 mL), add potassium acetate (1.89 g, 19.26 mmol) and 1,1-bis(diphenylphosphino)ferroxene.
  • Step 4 Dissolve the compound 4-(benzyloxy)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (0.2 g, 440.06 ⁇ mol) in 40% aqueous hydrobromic acid solution (10 mL), heat to 120°C, stir for 4 hours, cool, and concentrate to obtain the crude intermediate 21 (black solid, 0.13 g, yield: 96.4%), which is directly used in the next step. MS m/z (ESI): 307.0 [M+H] + .
  • Step 1 Dissolve 4-bromo-6-fluoroquinoline (2.26 g, 10.00 mmol) in DCM (30 mL), then add m-chloroperbenzoic acid (6.09 g, 29.99 mmol, purity 85%). The reaction solution was stirred at room temperature for 16 hours. Saturated sodium sulfite was added to the reaction solution, stirred for half an hour, then saturated sodium bicarbonate was added, stirred for half an hour, extracted with dichloromethane, dried over anhydrous sodium sulfate, and spin-dried to obtain 4-bromo-6-fluoroquinoline nitrogen oxide (2.3 g, yellow solid), with a yield of 95.05%. MS m/z (ESI): 244.0 [M+H] + .
  • Step 2 Dissolve 4-bromo-6-fluoroquinoline nitrogen oxide (2.3 g, 9.50 mmol) in chloroform (30 mL), add p-toluenesulfonic anhydride (9.30 g, 28.51 mmol) and tert-butylamine (3.47 g, 47.51 mmol) under ice bath, and stir the reaction solution at room temperature for 48 hours.
  • LC-MS monitoring shows about 75% product, and the raw material remains.
  • Step 3 4-Bromo-N-tert-butyl-6-fluoroquinolin-2-amine (920 mg, 3.10 mmol), pinacol boronate (943.40 mg, 3.72 mmol), Pd(dppf)Cl 2 (226.53 mg, 309.59 ⁇ mol) and potassium acetate (911.50 mg, 9.29 mmol) were added to 1,4-dioxane (10 mL), and the reaction solution was stirred at 80°C for 16 hours. Filter and spin dry to obtain 4-pinacol boronate-N-tert-butyl-6-fluoroquinolin-2-amine (1.05 g, yellow solid), with a yield of 98.53%. MS m/z (ESI): 345.2 [M+H] + .
  • Step 4 4-Benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (0.5 g, 1.38 mmol), 4-pinacol borate-N-tert-butyl-6-fluoroquinolin-2-amine (524.18 mg, 1.52 mmol), Pd(PPh 3 ) 4 (47.99 mg, 41.53 ⁇ mol) and potassium carbonate (229.59 mg, 1.66 mmol) were added to dioxane (10 mL) and water (1 mL), and the reaction solution was stirred at 100° C. for 16 hours.
  • Step 1 Dissolve 4-bromoquinoline (2.08 g, 10.00 mmol) in DCM (30 mL), then add m-chloroperbenzoic acid (6.09 g, 29.99 mmol, purity 85%), and stir the reaction solution at room temperature for 16 hours. Add saturated sodium sulfite to the reaction solution, stir for half an hour, then add saturated sodium bicarbonate, stir for half an hour, extract with dichloromethane, dry with anhydrous sodium sulfate, and spin dry to obtain 4-bromoquinoline nitrogen oxide (2.1 g, yellow solid), with a yield of 93.75%. MS m/z (ESI): 224.1 [M+H] + .
  • Step 2 Dissolve 4-bromoquinoline nitrogen oxide (1 g, 4.46 mmol) in chloroform (20 mL), add p-toluenesulfonic anhydride (4.37 g, 13.39 mmol) and tert-butylamine (1.63 g, 22.32 mmol) under ice bath, and stir the reaction solution at room temperature for 48 hours.
  • LC-MS monitoring shows about 75% product, and the raw material remains.
  • Step 3 4-Bromo-N-tert-butylquinolin-2-amine (430 mg, 1.54 mmol), pinacol boronate (469.35 mg, 1.85 mmol), Pd(dppf)Cl 2 (112.70 mg, 154.03 ⁇ mol) and potassium acetate (453.48 mg, 4.62 mmol) were added to 1,4-dioxane (10 mL), and the reaction solution was stirred at 80°C for 16 hours. Filter and spin dry to obtain 4-pinacol boronate-N-tert-butylquinolin-2-amine (500 mg, yellow solid), with a yield of 99.50%. MS m/z (ESI): 327.3 [M+H] + .
  • Step 4 4-Benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (0.5 g, 1.38 mmol), 4-pinacol borate-N-tert-butylquinolin-2-amine (496.78 mg, 1.52 mmol), Pd(PPh 3 ) 4 (47.99 mg, 41.53 ⁇ mol) and potassium carbonate (229.59 mg, 1.66 mmol) were added to dioxane (10 mL) and water (1 mL), and the reaction solution was stirred at 100° C. for 16 hours.
  • Step 2 Dissolve 4-bromo-2-(difluoromethyl)pyridine 1-oxide (0.7 g, 3.12 mmol) in chloroform (30 mL), add 4-toluenesulfonic anhydride (3.06 g, 9.37 mmol) and tert-butylamine (1.14 g, 15.62 mmol) under ice bath, and stir the reaction solution at room temperature for 48 hours.
  • Step 3 Dissolve 4-bromo-N-(tert-butyl)-6-(difluoromethyl)pyridin-2-amine (0.4 g, 1.43 mmol) and biboronic acid pinacol ester (727.81 mg, 2.87 mmol) in 1,4-dioxane (50 mL), add 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (52.43 mg, 71.65 ⁇ mol), heat to 100°C under argon atmosphere, and stir for 3 hours.
  • Step 4 (2-(tert-butylamino)-6-(difluoromethyl)pyridin-4-yl)boronic acid (0.25 g, 1.02 mmol), 4-(benzyloxy)-7-bromopyrazolo[1,5-a] Methyl pyridine-3-carboxylate (370.00 mg, 1.02 mmol) was dissolved in 1,4-dioxane (30 mL), potassium carbonate (283.16 mg, 2.05 mmol) was added, and the mixture was heated to 100°C under argon atmosphere and stirred overnight.
  • Step 5 Dissolve methyl 4-(benzyloxy)-7-(2-(tert-butylamino)-6-(difluoromethyl)pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.15 g, 312.17 ⁇ mol) in 40% aqueous hydrobromic acid (20 mL), heat to 120°C, and stir for 3 hours. Concentrate under reduced pressure to obtain the crude intermediate 24 (70 mg), which is used directly in the next step. MS m/z (ESI): 277.0 [M+H] + .
  • Step 1 4-bromopyrimidin-2-amine (174 mg, 1.00 mmol) and 4-methoxy-7-(tributyltriphenyltinyl)pyrazolo[1,5-a]pyridine (437.21 mg, 1.00 mmol) were placed in a single-mouth bottle, NMP (5 mL) was added, and then Pd(PPh 3 ) 4 (115.56 mg, 100.00 ⁇ mol) was added. The reaction was stirred at 100° C. for 12 hours.
  • Step 1 4-bromopicolinonitrile (1.5 g, 8.20 mmol), biboronic acid pinacol ester (4.16 g, 16.39 mmol), potassium acetate (2.01 g, 20.49 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (599.74 mg, 819.65 ⁇ mol) were added to 1,4-dioxane (30 mL). Under argon protection, the reaction solution was stirred at 100 ° C for 16 hours. Filter and concentrate under reduced pressure to obtain a crude product.
  • Step 2 Under argon protection, 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (700 mg, 1.94 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinecarbonitrile (700 mg, 3.04 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (335.93 mg, 290.71 ⁇ mol) and potassium carbonate (535.71 mg, 3.88 mmol) were added to 1,4-dioxane (50 mL) and water (5 mL), and the reaction solution was stirred at 110° C.
  • Step 1 Dissolve 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (2 g, 5.54 mmol) in water (3 mL), add (2-chloro-4-pyridyl)boronic acid (871.36 mg, 5.54 mmol), potassium carbonate (2.30 g, 16.61 mmol), Pd(dppf)Cl 2 (405.16 mg, 553.73 ⁇ mol) and dioxane (30 mL), and stir at 100 ° C overnight under nitrogen protection. Filter and concentrate to obtain a black solid.
  • Step 1 Dissolve 4-chloro-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (220 mg, 997.38 ⁇ mol) in dioxane (10 mL), add bis-pinacol borate (253.27 mg, 997.38 ⁇ mol), potassium acetate (97.88 mg, 997.38 ⁇ mol) and Pd(dppf)Cl 2 (72.98 mg, 99.74 ⁇ mol), and stir overnight at 100°C under nitrogen protection.
  • Step 2 Dissolve 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (200 mg, 640.83 ⁇ mol) in dioxane (8 mL), add 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (231.46 mg, 640.83 ⁇ mol), potassium carbonate (88.57 mg, 640.83 ⁇ mol), Pd(dppf)Cl 2 (46.89 mg, 64.08 ⁇ mol) and water (0.8 mL), stir at 100°C overnight under nitrogen protection.
  • Step 3 4-Benzyloxy-7-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (200 mg, 643.21 ⁇ mol) was added to a 48% aqueous solution of hydrobromic acid (15 mL), and the reaction solution was stirred at 120°C overnight. The reaction mixture was concentrated under reduced pressure to give intermediate 28 (100 mg, black solid, yield 48.85%). MS m/z (ESI): 319.1 [M+H] + .
  • Step 1 Methyl 4-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1 g, 2.77 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (1.14 g, 4.15 mmol), Pd(dppf) Cl2 (40.18 mg, 55.37 ⁇ mol) and potassium carbonate (765.30 mg, 5.54 mmol) were dissolved in dioxane (20 mL) and water (2 mL). Under nitrogen protection, the reaction solution was stirred at 110°C for 16 hours.
  • Step 1 Place 4-bromo-2-(difluoromethyl)pyrimidine (95 mg, 454.56 ⁇ mol) and tributyl-(4-methoxypyrazolo[1,5-a]pyridin-7-yl)stannane (258.36 mg, 590.93 ⁇ mol) in a microwave tube, add DMF (10 mL), and then add Pd(PPh 3 ) 4 (52.53 mg, 45.46 ⁇ mol). The reaction was stirred at 135° C. in a microwave reactor for 60 minutes. LC-MS monitored the completion of the reaction. The mixture was dried under reduced pressure.
  • Step 2 7-[2-(Difluoromethyl)pyrimidin-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine (85.00 mg, 307.70 ⁇ mol) was dissolved in 48% aqueous hydrobromic acid (5 mL). The reaction was stirred at 120 °C for 12 hours. The reaction was monitored by LC-MS. The crude product was purified by column chromatography (dichloromethane containing 15% methanol) to give intermediate 30 (50 mg, yield 61.97%), MS m/z (ESI): 263.0 [M+H] + .
  • Step 2 4-(Benzyloxy)-7-(2-chloropyridin-4-yl)pyrazolo[1,5-a]pyridine (400 mg, 1.19 mmol), tBuXPhos (25.29 mg, 59.56 ⁇ mol), Pd 2 (dba) 3 (21.82 mg, 23.82 ⁇ mol) and potassium hydroxide (133.68 mg, 2.38 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). Under nitrogen protection, the reaction solution was subjected to microwave reaction at 120°C for 2 hours.
  • Step 3 4-(4-(Benzyloxy)pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-ol (100 mg, 315.12 ⁇ mol) and sodium difluorochloroacetate (72.06 mg, 472.68 ⁇ mol) were dissolved in DMF (5 mL), and potassium carbonate (87.11 mg, 630.24 ⁇ mol) was added. The reaction solution was stirred at 60°C for 12 hours.
  • Step 4 Dissolve 4-(benzyloxy)-7-(2-(difluoromethoxy)pyridin-4-yl)pyrazolo[1,5-a]pyridine (80 mg, 217.78 ⁇ mol) in MeOH (10 mL), add 10% Pd/C (10 mg), and stir the reaction solution at room temperature for 12 hours under a hydrogen atmosphere. After the reaction, filter and concentrate under reduced pressure to obtain intermediate 31 (75 mg, yellow oil), which is used directly in the next step without purification. MS m/z (ESI): 278.1 [M+H] + .
  • Step 1 Dissolve 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (700 mg, 1.94 mmol) in water (1.5 mL), add (2-bromo-4-pyridyl)boronic acid (391.12 mg, 1.94 mmol), sodium carbonate (205.41 mg, 1.94 mmol), Pd(dppf)Cl 2 (1.42 g, 1.94 mmol) and dioxane (15 mL), and stir at 100°C overnight under nitrogen protection. Filter, check and concentrate to obtain a black solid.
  • Step 2 Add 4-benzyloxy-7-(2-bromo-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (80 mg, 182.53 ⁇ mol) to a 48% aqueous solution of hydrobromic acid (10 mL), and stir the reaction solution at 110°C for 3 hours. Concentrate under reduced pressure to obtain intermediate 32 (42 mg, yield 79.31%, brown solid). Used directly in the next step. MS m/z (ESI): 290.1 [M+H] + .
  • Step 1 (2-methyl-4-pyridyl)boronic acid (400 mg, 2.92 mmol), methyl 4-benzyloxy-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1.05 g, 2.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (213.72 mg, 292.09 mmol) and potassium carbonate (807.40 mg, 5.84 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL), argon was replaced 3 times, and the reaction was stirred at 100°C overnight.
  • Step 2 Dissolve 4-benzyloxy-7-(2-methyl-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (70 mg, 187.46 ⁇ mol) in 48% aqueous hydrogen bromide solution (2 mL) and react at 120°C for 2 hours. Cool the reaction solution to room temperature and add saturated sodium bicarbonate (15 mL) to adjust the pH to 8. The mixture was extracted with ethyl acetate (3 ⁇ 20 mL), and the organic phase was concentrated under reduced pressure to obtain intermediate 33 (50 mg, yellow solid, crude product). MS m/z (ESI): 226.1 [M+H] + . Preparation of intermediate 34
  • Step 1 Under argon protection, 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (555.79 mg, 2.49 mmol), 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (600 mg, 1.66 mmol) and XPhos Pd G2 (130.54 mg, 166.12 ⁇ mol) and potassium carbonate (459.18 mg, 3.32 mmol) were added to 1,4-dioxane (30 mL) and water (3 mL), and the reaction solution was stirred at 120°C for 20 hours. The solvent was dried under reduced pressure.
  • Step 2 Add 4-benzyloxy-7-(3-fluoro-4-pyridyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (550 mg, 1.46 mmol) to 48% aqueous hydrogen bromide solution (10 mL), and stir the reaction solution at 120°C for 2 hours. Concentrate under reduced pressure to obtain intermediate 34 (330 mg, brown solid, yield 98.78%). The crude product is used directly in the next step. MS m/z (ESI): 230.1 [M+H] + .
  • Step 1 Dissolve 4-pyridineboronic acid (100 mg, 813.55 ⁇ mol) and 4-benzyloxy-7-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (195.90 mg, 542.37 ⁇ mol) in 1,4-dioxane (3 mL) and water (0.3 mL) at room temperature, and add Pd(dppf)Cl 2 (39.69 mg, 54.24 ⁇ mol). React at 100°C for 12 hours under nitrogen protection. The solvent is evaporated under reduced pressure.
  • Step 1 4-bromo-2-chloro-pyrimidine (400 mg, 2.07 mmol), 4-methoxy-7-(tributyltinyl)pyrazolo[1,5-a]pyridine (904.11 mg, 2.07 mmol) and Pd(PPh 3 ) 4 (23.90 mg, 20.68 ⁇ mol) were added to DMF (10 mL), replaced with argon three times, and stirred at 120° C. for 5 h. The reaction was completed after LC-MS monitoring. The reaction solution was cooled to room temperature, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure.
  • Step 2 Dissolve 7-(2-chloropyrimidin-4-yl)-4-methoxy-pyrazolo[1,5-a]pyridine (100 mg, 383.61 ⁇ mol) in dioxane (4 mL), add 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (48.16 mg, 383.61 ⁇ mol), potassium carbonate (53.02 mg, 383.61 ⁇ mol), Pd(dppf)Cl 2 (28.07 mg, 38.36 ⁇ mol) and water (0.4 mL), and stir at 100 °C overnight under nitrogen protection. Filter and concentrate to obtain a black solid.
  • Step 3 Dissolve 4-methoxy-7-(2-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine (30 mg, 124.86 ⁇ mol) in 48% aqueous hydrogen bromide solution (30.31 mg, 374.59 ⁇ mol) and stir overnight at 140°C. Concentrate under reduced pressure to obtain intermediate 36 (25 mg, yield 88.50%, yellow solid). Used directly in the next step. MS m/z (ESI): 227.1 [M+H] + .
  • Step 1 Dissolve intermediate 26 (600 mg, 2.35 mmol) in methanol (5 mL), add thionyl chloride (839.04 mg, 7.05 mmol) dropwise under ice bath, stir for 30 minutes, raise the temperature to 60°C, and stir overnight.
  • the reaction solution was concentrated under reduced pressure and dried by spin drying.
  • Step 1 4-(Benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (210 mg, 581.41 ⁇ mol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (220.14 mg, 639.55 ⁇ mol), Pd(dppf)Cl 2 (8.44 mg, 11.63 ⁇ mol) and K 2 CO 3 (160.71 mg, 1.16 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL).
  • Step 1 Add 4-benzyloxy-7-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (150 mg, 415.29 ⁇ mol), 4-(tributyltinyl)pyrimidine (229.95 mg, 622.94 ⁇ mol) and tetrakis(triphenylphosphine)palladium (47.99 mg, 41.53 ⁇ mol) to N,N-dimethylformamide (15 mL). Under argon protection, the reaction solution was stirred at 120°C for 16 hours. Filter and concentrate under reduced pressure.
  • Step 2 Add 4-(benzyloxy)-7-(pyrimidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (137 mg, 380.17 ⁇ mol) to 48% aqueous solution of hydrogen bromide (10 mL), and stir the reaction solution at 110°C for 3 hours. Concentrate under reduced pressure to obtain intermediate 39 (75 mg, brown solid, yield 91.54%). The crude product is directly used for the next step. MS m/z (ESI): 213.1 [M+H] + .
  • Step 3 4-(Benzyloxy)-7-bromopyrazolo[1,5-a]pyridine (120 mg, 395.84 ⁇ mol), 2-fluoropyridine-4-boronic acid pinacol ester (105.95 mg, 475.01 ⁇ mol), Pd(dppf)Cl 2 (5.74 mg, 7.92 ⁇ mol) and K 2 CO 3 (109.42 mg, 791.68 ⁇ mol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen protection, the reaction solution was stirred at 100°C for 16 hours.
  • Step 2 Dissolve compound H-1-a (30 mg, 70.50 ⁇ mol) in 4M HCl 1,4-dioxane solution (5 mL). Stir the reaction solution at room temperature for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-1 (1.17 mg). Yield 5.10%. MS m/z (ESI): 326.2 [M+H] + .
  • Step 2 Dissolve compound H-2-a (50 mg, 113.75 ⁇ mol) in dichloromethane (5 mL), then add trifluoroacetic acid (2 mL). Stir the reaction solution at room temperature for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-2 (5 mg). Yield 12.10%. MS m/z (ESI): 340.2 [M+H] + .
  • Step 2 Compound H-3-a (45 mg, 97.72 ⁇ mol) was dissolved in 4M HCl/1,4-dioxane (5 mL). The reaction solution was stirred at room temperature for 2 hours. The solvent was dried and 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; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-3 (13 mg). Yield: 36.52%. MS m/z (ESI): 361.2 [M+H] + .
  • Step 1 Dissolve intermediate 2 (50 mg, 191.40 ⁇ mol) and intermediate a (84.23 mg, 287.11 ⁇ mol) in N,N-dimethylformamide (5 mL), and then add potassium carbonate (52.91 mg, 382.81 ⁇ mol). The reaction solution was stirred at 80 ° C for 16 hours. After the reaction was completed, the solvent was dried, water was added, and dichloromethane was extracted and dried over anhydrous sodium sulfate. Compound H-4-a (45 mg, yellow solid) was obtained by drying. The yield was 49.54%. MS m/z (ESI): 475.3 [M + H] + .
  • Step 2 Dissolve compound H-4-a (45 mg, 94.83 ⁇ mol) in 4M HCl/1,4-dioxane (5 mL). Stir the reaction solution at room temperature for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-4 (5 mg, white solid). Yield 13.64%. MS m/z (ESI): 375.2 [M+H] + .
  • Step 2 Dissolve compound H-5-a in dichloromethane (10 mL), then add trifluoroacetic acid (2 mL). Stir the reaction solution at room temperature for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-5 (20 mg). Yield 48.27%. MS m/z (ESI): 368.2 [M+H] + .
  • Step 2 Dissolve compound H-6-a (45 mg, 93.44 ⁇ mol) in dichloromethane (5 mL), then add trifluoroacetic acid (2 mL). Stir the reaction solution at room temperature for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-6 (5 mg). Yield 13.88%. MS m/z (ESI): 382.3 [M+H] + .
  • Step 2 Dissolve compound H-7-a (60 mg, 133.47 ⁇ mol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL). Stir the reaction solution at room temperature for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-7 (16 mg). Yield 34.17%. MS m/z (ESI): 350.2 [M+H] + .
  • Step 2 Dissolve compound H-8-a (50 mg, 107.86 ⁇ mol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL). Stir the reaction solution at room temperature for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-8 (15 mg, white solid). Yield 37.21%. MS m/z (ESI): 364.2 [M+H] + .
  • Step 2 Dissolve compound H-9-a (180 mg, 372.24 ⁇ mol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL). Stir the reaction solution at room temperature for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-9 (92 mg). Yield 63.51%. MS m/z (ESI): 384.2 [M+H] + .
  • Step 2 Dissolve compound H-10-a (170 mg, 341.65 ⁇ mol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL). Stir the reaction solution at room temperature for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-10 (73 mg). Yield 53.55%. MS m/z (ESI): 398.2 [M+H] + .
  • Step 2 Dissolve compound H-11-a (50 mg, 110.24 ⁇ mol) in trifluoroacetic acid (1 mL) and dichloromethane (4 mL). Stir the reaction solution at 22°C for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-11 (5 mg). Yield 12.71%. MS m/z (ESI): 354.2 [M+H] + .
  • Step 2 Dissolve compound H-12-a (40 mg, 79.43 ⁇ mol) in trifluoroacetic acid (1 mL) and dichloromethane (4 mL). Stir the reaction solution at 22°C for 2 hours. Spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product H-12 (2 mg). Yield 6.17%. MS m/z (ESI): 404.1 [M+H] + .
  • Step 2 Add trifluoroacetic acid (2 mL) to a solution of compound H-13-a (30 mg, 0.066 mmol) in dichloromethane (8 mL), stir at room temperature for 1 hour, concentrate, and purify the residue by preparative HPLC to obtain compound H-13 (9.67 mg, yield: 40.83%). MS m/z (ESI): 351.2 [M+H] + .
  • Step 2 Add trifluoroacetic acid (2 mL) to a solution of compound H-14-a (50 mg, 0.107 mmol) in dichloromethane (6 mL), stir at room temperature for 1 hour, concentrate, and purify the residue by preparative HPLC to obtain compound H-14 (6.01 mg, yield: 15.31%). MS m/z (ESI): 366.2 [M+H] + .
  • Step 2 Add trifluoroacetic acid (2 mL) to a solution of compound H-15-a (20 mg, 0.043 mmol) in dichloromethane (6 mL), stir at room temperature for 1 hour, concentrate, and purify the residue by preparative HPLC to obtain compound H-15 (3.84 mg, yield: 24.51%). MS m/z (ESI): 360.2 [M+H] + .
  • Step 2 Add trifluoroacetic acid (3 mL) to a solution of compound H-16-a (100 mg, 0.225 mmol) in dichloromethane (9 mL), stir at room temperature for 1 hour, concentrate, and purify the residue by preparative HPLC to obtain compound H-16 (55.5 mg, yield: 71.7%). MS m/z (ESI): 344.2 [M+H] + .
  • Step 2 Add trifluoroacetic acid (2 mL) to a solution of compound H-17-a (50 mg, 0.112 mmol) in dichloromethane (8 mL), stir at room temperature for 1 hour, concentrate, and purify the residue by preparative HPLC to obtain compound H-17 (7.13 mg, yield: 18.2%). MS m/z (ESI): 344.2 [M+H] + .
  • Step 2 Add trifluoroacetic acid (1.5 mL) to a solution of compound H-18-a (20 mg, 0.042 mmol) in dichloromethane (6 mL), stir at room temperature for 1 hour, concentrate, and purify the residue by preparative-HPLC to obtain compound H-18 (6.5 mg, yield: 40.5%). MS m/z (ESI): 378.2 [M+H] + .
  • Step 2 Add trifluoroacetic acid (1.5 mL) to a solution of compound H-19-a (30 mg, 0.065 mmol) in dichloromethane (6 mL), stir at room temperature for 1 hour, concentrate, and purify the residue by preparative HPLC to obtain compound H-19 (6.58 mg, yield: 27.98%). MS m/z (ESI): 364.2 [M+H] + .
  • Step 1 Add intermediate b (545.92 mg, 2.36 mmol), intermediate 12 (330 mg, 1.18 mmol), allylpalladium (II) chloride dimer (20 mg, 54.66 ⁇ mol), 2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2'4'6'-triisopropyl-biphenyl (30 mg, 64.01 ⁇ mol) and cesium carbonate (576.68 mg, 1.77 mmol) to toluene (10 mL). The reaction solution was heated to 90°C under argon protection and stirred for 2 hours.
  • Step 2 Compound H-20-a (180 mg, 379.31 ⁇ mol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The reaction solution was stirred at room temperature for 1 hour. The solvent was dried under reduced pressure, and ammonia methanol solution was added to neutralize it, and then concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography with a chromatography system (dichloromethane/methanol: 10/1) to obtain a light yellow oil.
  • Step 1 Dissolve intermediate 1 (390 mg, 1.72 mmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (476.52 mg, 3.45 mmol), and then add (S)-4-isobutyl-1,2,3-oxothiazolidine-3-carboxylic acid tert-butyl ester-2,2-dioxide (481.57 mg, 1.72 mmol). The reaction solution was stirred at 50°C for 4 hours.
  • Step 2 Add compound H-21-a (100 mg, 197.79 ⁇ mol) to dichloromethane (15 mL), add triethylamine (60.04 mg, 593.37 ⁇ mol, 82.76 ⁇ L), and then dropwise add cyclopropanecarbonyl chloride (62.03 mg, 593.37 ⁇ mol). The reaction solution was stirred at room temperature for 1 hour. After concentration under reduced pressure, methanol (10 mL) and water (1 mL) were added, and then sodium hydroxide (10 mg) was added, and the reaction solution was stirred at room temperature for 30 minutes.
  • Step 3 Compound H-21-b (110 mg, 191.75 ⁇ mol) was added to trifluoroacetic acid (5 mL) and dichloromethane (5 mL), and the reaction solution was stirred at room temperature for 1 hour. After concentration under reduced pressure, ammonia methanol solution was added for neutralization, and the mixture was further concentrated under reduced pressure. 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; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain compound H-21 (45.07 mg) with a yield of 59.73%.
  • Step 1 Add compound H-2-a (100 mg, 227.51 ⁇ mol) to dichloromethane (15 mL), add triethylamine (69.06 mg, 682.52 ⁇ mol, 95.19 ⁇ L), and then dropwise add cyclopropanecarbonyl chloride (71.35 mg, 682.52 ⁇ mol). The reaction solution was stirred at room temperature for 1 hour. After concentration under reduced pressure, methanol (10 mL) and water (1 mL) were added, and then sodium hydroxide (10 mg) was added, and the reaction solution was stirred at room temperature for 30 minutes. The pH was adjusted to 7 with 1M hydrochloric acid solution, and the crude product compound H-22-a (100 mg, yellow oil) was obtained by concentration under reduced pressure. The crude product was directly used in the next step. MS m/z (ESI): 508.3 [M+H] + .
  • Step 2 Compound H-22-a (100 mg, 197 ⁇ mol) was added to trifluoroacetic acid (5 mL) and dichloromethane (5 mL), and the reaction solution was stirred at room temperature for 1 hour. After concentration under reduced pressure, ammonia methanol solution was added for neutralization, and the mixture was further concentrated under reduced pressure. 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; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain compound H-22 (61.02 mg) with a yield of 75.25%.
  • Step 1 Dissolve intermediate 13 (53 mg, 157.15 ⁇ mol) in ethyl acetate (5 mL) and N,N-dimethylformamide (1 mL), add potassium carbonate (43.44 mg, 314.30 ⁇ mol), and then add (S)-4-isobutyl-1,2,3-oxothiazolidine-3-carboxylic acid tert-butyl ester-2,2-dioxide (52.68 mg, 188.58 ⁇ mol). The reaction solution was stirred at room temperature for 16 hours. Concentrate under reduced pressure to obtain compound H-23-a (84 mg, yellow oil), and the crude product was used directly in the next step. MS m/z (ESI): 481.2 [M-56+H] + .
  • Step 2 Compound H-23-a (84 mg, 156.56 ⁇ mol) was dissolved in tetrahydrofuran (5 mL), and lithium hydroxide monohydrate (9.85 mg, 234.84 ⁇ mol) and water (0.5 mL) were added. The reaction solution was stirred at room temperature for 1 hour. After adjusting the acid with trifluoroacetic acid, it was concentrated under reduced pressure. Trifluoroacetic acid (2 mL) and dichloromethane (2 mL) were added to the residual solution. The reaction solution was stirred at room temperature for 1 hour. After concentration under reduced pressure, it was neutralized with 7N ammonia methanol solution and concentrated under reduced pressure again.
  • Step 1 Dissolve intermediate 15 (10 mg, 40.95 ⁇ mol) and intermediate d (11.44 mg, 40.95 ⁇ mol) in ethyl acetate (6 mL) and N,N-dimethylformamide (1 mL), and then add potassium carbonate (11.30 mg, 81.89 ⁇ mol). The reaction was stirred at 50 ° C for 12 hours. The solvent was dried under reduced pressure. The crude product was subjected to Prep.HPLC to obtain compound H-25-a (10 mg, 22.55 ⁇ mol) with a yield of 55.07%. MS m/z (ESI): 388.2 [M-56+H] + .
  • Step 2 Compound H-25-a (10 mg, 22.55 ⁇ mol) was dissolved in 4M hydrochloric acid/1,4-dioxane solution. The reaction was stirred at 23°C for 1 hour. The crude product was dried under reduced pressure and subjected to Prep.HPLC to obtain compound H-25 (1.1 mg, 3.20 ⁇ mol, 100% purity) with a yield of 14.21%. MS m/z (ESI): 344.2 [M+H] + .
  • Step 1 Dissolve intermediate c (29.19 mg, 197.79 ⁇ mol) and compound H-2-a (50 mg, 98.90 ⁇ mol) in dichloromethane (10 mL), and then add triethylamine (29.97 mg, 296.69 ⁇ mol). The reaction is stirred at 20 ° C for 1 hour. Dilute hydrochloric acid is used to adjust the pH to about 7. Reduce the pressure and spin dry to obtain compound H-26-a (60 mg, 97.29 ⁇ mol), and the crude product is used directly in the next step. Yield: 98.38%. MS m/z (ESI): 551.24 [M+H] + .
  • Step 2 Compound H-26-a (45 mg, 85.95 ⁇ mol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction was stirred at 23 ° C for 1 hour, and the mixture was dried under reduced pressure. The pH of the ammonia methanol solution was adjusted to about 8, and the crude product was dried under reduced pressure. The crude product was prepared by prep.HPLC to obtain compound H-26 (17.83 mg, 39.49 ⁇ mol), with a yield of 62.26% and a purity of 99.78%. MS m/z (ESI): 451.2 [M+H] + .
  • Step 2 Compound H-27-a (45 mg, 85.95 ⁇ mol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction was stirred at 23 ° C for 1 hour. The mixture was dried under reduced pressure, and the pH of the ammonia methanol solution was adjusted to about 8, and the crude product was dried under reduced pressure. The crude product was prepared by prep.HPLC to obtain compound H-27 (5.13 mg, 14.20 ⁇ mol), with a yield of 16.52% and a purity of 95.07%. MS m/z (ESI): 344.2 [M+H] + .
  • Step 1 Dissolve intermediate 17 (180 mg, 795.64 ⁇ mol) and (S)-4-isobutyl-1,2,3-oxathiozolidine-3-carboxylic acid tert-butyl ester-2,2-dioxide (222.26 mg, 795.64 ⁇ mol) in N,N-dimethylformamide (10 mL), add potassium carbonate (329.88 mg, 2.39 mmol), and stir at 100°C for 4 hours. Concentrate under reduced pressure to obtain a yellow solid. The solid is passed through a combiflash (0-30% DCM/MeOH) column to obtain a brown solid compound H-28-a (100 mg, 235.01 ⁇ mol, 29.54% yield). MS m/z (ESI): 426.1 [M+H] + .
  • Step 2 Compound H-28-a (100 mg, 235.01 ⁇ mol) was dissolved in dichloromethane (5 mL), cyclopropane chloride (29.48 mg, 282.01 ⁇ mol) and triethylamine (71.34 mg, 705.02 ⁇ mol, 98.33 ⁇ L) were added at 0°C, and stirred at 0°C for 30 minutes. The mixture was concentrated under reduced pressure to obtain yellow solid compound H-28-b (100 mg, 202.59 ⁇ mol, 86.21% yield). MS m/z (ESI): 494.1 [M+H] + .
  • Step 3 Compound H-28-b (100 mg, 235.01 ⁇ mol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (2 mL, 4 N) and stirred at room temperature for 2 hours. Concentrated under reduced pressure to obtain a yellow solid. The solid was purified by pre-HPLC (preparation conditions: preparation column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%--60% acetonitrile change) to obtain compound H-28 (11.07 mg, 27.74 ⁇ mol, 13.69% yield). MS m/z (ESI): 394.1 [M+H] + .
  • Step 1 Dissolve compound H-28-a (100 mg, 235.01 ⁇ mol) in dichloromethane (5 mL), add thiazole-2-carbonyl chloride (34.68 mg, 235.01 ⁇ mol) and triethylamine (71.34 mg, 705.02 ⁇ mol, 98.33 ⁇ L) at 0°C, and stir at 0°C for 1 hour. Concentrate under reduced pressure to obtain yellow solid compound H-29-a (80 mg, 149.07 ⁇ mol, 63.43% yield). MS m/z (ESI): 537.1 [M+H] + .
  • Step 2 Compound H-29-a (80 mg, 149.07 ⁇ mol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (50.99 mg, 447.22 ⁇ mol) was added, and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a yellow solid. The solid was purified by pre-HPLC (preparation conditions: preparation column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%-60% acetonitrile change) to obtain compound H-29 (10.23 mg, 23.43 ⁇ mol, 15.72% yield, 100% purity).
  • Step 1 Dissolve compound H-28-a (1 g, 2.35 mmol) in dichloromethane (20 mL), add methyl chloroformate (382.55 mg, 3.53 mmol) and triethylamine (713.40 mg, 7.05 mmol, 983.33 ⁇ L) at 0°C, and stir at 0°C for 1 hour. Concentrate under reduced pressure to obtain yellow solid compound H-30-a (0.8 g, 1.65 mmol, 70.40% yield). MS m/z (ESI): 484.1 [M+H] + .
  • Step 2 Dissolve compound H-30-a (0.8 g, 1.65 mmol) in dichloromethane (30 mL), add trifluoroacetic acid (565.90 mg, 4.96 mmol), and stir at room temperature for 2 hours. Concentrate under reduced pressure to obtain a yellow solid.
  • the solid is purified by pre-HPLC (preparation conditions: preparation column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%--60% acetonitrile change) to obtain compound H-30 (33 mg, 85.78 ⁇ mol, 5.18% yield, 99.67% purity).
  • Step 1 Dissolve intermediate 18 (300 mg, 1.33 mmol) and intermediate d (370.44 mg, 1.33 mmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (549.81 mg, 3.98 mmol), and stir at 100°C for 4 hours. Concentrate under reduced pressure to obtain a yellow solid. The solid is passed through a combiflash (0-30% DCM/MeOH) column to obtain a brown solid compound H-31-a (300 mg, 705.02 ⁇ mol, 53.17% yield). MS m/z (ESI): 468.1 [M+H] + .
  • Step 2 Compound H-31-a (20 mg, 42.78 ⁇ mol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (3 mL, 4 M) and stirred at room temperature for 2 hours. Concentrated under reduced pressure to obtain a yellow solid. Compound H-31 (2.57 mg, 6.99 ⁇ mol, 16.35% yield, 100% purity) was obtained by pre-HPLC preparation (preparation conditions: preparation column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%--60% acetonitrile change). MS m/z (ESI): 368.1 [M+H] + .
  • Step 3 Compound H-31 (20 mg, 42.78 ⁇ mol) was dissolved in H 2 O (1 mL), potassium hydroxide (7.20 mg, 128.33 ⁇ mol) and ethanol (2 mL) were added, stirred at 85°C for 4 hours, and concentrated under reduced pressure to obtain a yellow solid.
  • the solid was purified by pre-HPLC (preparation conditions: preparation column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%--60% acetonitrile change) to obtain compound H-32 (1.10 mg, 3.37 ⁇ mol, 7.88% yield).
  • Step 2 Compound H-33-a (80 mg, 0.17 mmol) was dissolved in anhydrous dichloromethane (3 mL), and then trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at room temperature for 2 h. After the reaction was completed, a saturated sodium bicarbonate aqueous solution was added to adjust the pH of the solution to weak alkalinity, and then extracted with dichloromethane (10 mL ⁇ 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound H-33 (30 mg), yield: 49%. MS m/z (ESI): 361.1 [M+H] + .
  • Step 1 Dissolve methyl 3-hydroxypyridine-2-carboxylate (4.15 g, 27.1 mmol) in water (240 mL), slowly add liquid bromine (4.33 g, 27.1 mmol) at 20°C, and stir the reaction at 20°C for 3 hours.
  • the reaction solution was extracted with dichloromethane (150 mL ⁇ 2), washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 6-bromo-3-hydroxypyridine-2-carboxylate (5.18 g, purity 83.1%, light yellow solid), yield: 68.5%.
  • Step 2 Dissolve methyl 6-bromo-3-hydroxypyridine-2-carboxylate (3.00 g, 12.9 mmol) in a mixed solvent of ethyl acetate (75 mL) and N,N-dimethylformamide (7.5 mL), then add potassium carbonate (7.15 g, 51.7 mmol) and intermediate d (4.88 g, 17.4 mmol), and stir the reaction at 50 °C for 2 hours.
  • Step 3 Compound H-34-a (3.94 g, 9.13 mmol) was dissolved in tetrahydrofuran (80 mL), the reaction solution was cooled to ⁇ 0°C, 1M lithium triethylborohydride tetrahydrofuran solution (45 mL) was added dropwise, and the reaction was stirred at 15°C for 3 hours. The reaction solution was cooled to about 0°C, water (150 mL) was added and stirred for 30 minutes, then extracted with ethyl acetate (120 mL), washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 4 Dissolve compound H-34-b (2.15 g, 5.33 mmol) in dichloromethane (80 mL), add manganese dioxide (9.27 g, 106 mmol), and stir the reaction at 15°C for 36 hours. Filter through a layer of diatomaceous earth, and concentrate the filtrate under reduced pressure to obtain compound H-34-c (1.50 g, white solid), yield: 70.1%. MS m/z (ESI): 401.0/403.0 [M+H] + .
  • Step 5 Compound H-34-c (1.50 g, 3.74 mmol) was dissolved in 15 mL N,N-dimethylformamide, glycine (309 mg, 4.12 mmol) was added, nitrogen was replaced three times, and then iodine (948 mg, 3.74 mmol) and sodium carbonate (792 mg, 7.48 mmol) were added, and the reaction was stirred at 60 ° C for 9 hours. 240 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (150 mL ⁇ 2). The organic phases were combined and washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 6 1H-pyrrolo[2,3-b]pyridine-4-boronic acid (50 mg, 308 ⁇ mol) and compound H-34-d (138 mg, 91.9% purity, 308 ⁇ mol) were dissolved in a mixed solvent of dioxane (10 mL) and water (2 mL), potassium carbonate (107 mg, 774 ⁇ mol) was added, nitrogen was replaced three times, Xphos-Pd-G2 (12.5 mg, 15.89 ⁇ mol) was added, and nitrogen was replaced three times. Stir and react at 85°C for 2 hours.
  • Step 7 Compound H-34-e (22.4 mg, 49.8 ⁇ mol) was dissolved in 0.2 mL of dioxane, and 0.47 mL of 4M hydrogen chloride/dioxane was added dropwise under an ice bath. The reaction was stirred at 15°C for 1 hour. The dioxane was removed by vortexing the reaction solution under reduced pressure, and acetonitrile was added to remove the residual dioxane. After freeze-drying with water, 26 mg of yellow solid was obtained.
  • Step 1 Dissolve 2-amino-4-bromopyridine (5.00 g, 28.9 mmol, 1 eq) in 50 mL of dichloromethane, and slowly add acetic anhydride (4.43 g, 43.35 mmol, 4.06 mL, 1.50 eq) and 4-dimethylaminopyridine (353.07 mg, 2.89 mmol, 0.1 eq) in sequence. The system was stirred at room temperature under nitrogen atmosphere for 16 hours.
  • Step 2 Dissolve N-(4-bromopyridin-2-yl)acetamide (2.00 g, 9.30 mmol, 1.00 eq) in 20 mL of dioxane, add bis-naphthalene borate (2.41 g, 9.49 mmol, 1.02 eq), potassium acetate (2.74 g, 27.90 mmol, 3.00 eq), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (379.75 mg, 465.01 ⁇ mol, 0.05 eq) in sequence, degas with nitrogen, stir at 100 ° C under nitrogen atmosphere for 16 hours.
  • Step 3 Compound H-34-d (100 mg, 242.53 ⁇ mol, 1.00 eq) was dissolved in 2 mL of dioxane and 0.2 mL of water, and 2-acetylaminopyridine-4-boric acid (76.28 mg, 291.04 ⁇ mol, 1.20 eq), potassium carbonate (83.80 mg, 606.32 ⁇ mol, 2.50 eq), (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) [2-(2-amino-1,1-biphenyl)] palladium (II) chloride (9.54 mg, 12.13 ⁇ mol, 0.05 eq) were added in sequence and degassed with nitrogen, and stirred at 85 ° C under nitrogen atmosphere for 2 hours.
  • Step 4 Dissolve compound H-35-a (95.0 mg, 203.18 ⁇ mol, 1 eq) in 0.5 mL of dioxane, and slowly add 4 M hydrochloric acid ethyl acetate solution (0.5 mL) at 0°C. The system is stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure to remove the solvent to obtain the product compound H-35 (50 mg), with a yield of 64.4%. MS m/z (ESI): 368.0 [M+H] + .
  • Step 1 Dissolve 6-bromo-3-[(2S)-2-(tert-butylcarbonylamino)-4-methylpentyloxy]pyridine-2-carboxylic acid methyl ester (1.70 g, 3.94 mmol) and 2-(difluoromethyl)pyridine-4-boronic acid pinacol ester (1.11 g, 4.34 mmol) in a mixed solvent of dioxane (20 mL) and water (4 mL), add potassium carbonate (1.36 g, 9.85 mmol), tetrakis(triphenylphosphine)palladium (228 mg, 197 ⁇ mol), replace with nitrogen three times, and react at 80°C with stirring for 3 hours.
  • Step 2 Compound H-36-a (1.52 g, 3.17 mmol) was dissolved in tetrahydrofuran (30 mL), the reaction solution was cooled to 0°C, 1M lithium triethylborohydride tetrahydrofuran solution (15.9 mL) was added dropwise, and the reaction was stirred at 25°C for 3 hours.
  • Step 3 Dissolve compound H-36-b (750 mg, 1.66 mmol) in dichloromethane (30 mL), add manganese dioxide (2.89 g, 33.2 mmol), and stir the reaction at 25°C for 5 hours. Filter through celite, and concentrate the filtrate under reduced pressure to obtain compound H-36-c (480 mg, purity 95.8%, light yellow jelly), yield: 61.6%. MS m/z (ESI): 450.2 [M+23] + .
  • Step 4 Compound H-36-c (480 mg, 1.07 mmol) was dissolved in 5 mL N,N-dimethylformamide, glycine (88.2 mg, 1.17 mmol), iodine (271 mg, 1.07 mmol) and sodium carbonate (226 mg, 2.14 mmol) were added, and the reaction was stirred at 60°C for 6 hours. 30 mL of water and 10 mL of saturated sodium sulfite were added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL ⁇ 3). The organic phases were combined and washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 5 Compound H-36-d (400 mg, 868 ⁇ mol) was dissolved in 5 mL of ethyl acetate, and 10 mL of 4 M hydrogen chloride/dioxane was added dropwise under ice bath. The reaction was stirred at 25°C for 3 hours.
  • Step 2 Dissolve compound H-37-a (50 mg, 101.92 ⁇ mol) in dichloromethane (8 mL), then add trifluoroacetic acid (2 mL). Stir the reaction solution at room temperature for 2 hours. After the reaction is complete, spin dry the solvent and purify the residue by preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain the target product compound H-37 (5.73 mg). Yield 13.97%. MS m/z (ESI): 391.1 [M+H] + .
  • Step 2 Dissolve compound H-38-a (70 mg, 134.71 ⁇ mol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 1 hour. Concentrate, and purify the residue by preparative HPLC to obtain compound H-38 (13.7 mg, yield: 24.1%). MS m/z (ESI): 420.3 [M+H] + .
  • Step 1 Dissolve intermediate 1 (115 mg, 508.32 ⁇ mol) and intermediate e (189.92 mg, 609.99 ⁇ mol) in anhydrous DMF (5 mL), add cesium carbonate (662.49 mg, 2.03 mmol) at room temperature. Stir the reaction at 50 ° C for 5 hours. After cooling, filter, wash the filter cake with tetrahydrofuran (3 mL ⁇ 2), and concentrate the filtrate under reduced pressure to obtain H-71-a (220 mg, brown oil), yield: 94.6%. MS m/z (ESI): 458.0 [M + H] + .
  • Step 2 H-71-a (100 mg, 218.57 ⁇ mol) and triethylamine (66.35 mg, 655.70 ⁇ mol) were dissolved in anhydrous dichloromethane (2 mL), and methyl chloroformate (24.78 mg, 262.28 ⁇ mol) was added dropwise in batches under an ice-water bath. After the addition, the mixture was stirred at room temperature for 3 hours. Water (2 mL) was added to quench the mixture, and dichloromethane was extracted (2 mL ⁇ 3).
  • Step 3 H-71-b (80.0 mg, 139.47 ⁇ mol) was dissolved in 2 mL of methanol solution, and sodium hydroxide (11.16 mg, 278.94 ⁇ mol) was added at room temperature. Stir at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain H-71-c (40.0 mg, yellow solid), with a yield of 55.6%. MS m/z (ESI): 516.0 [M+H] + .
  • Step 4 H-71-c (40.0 mg, 77.59 ⁇ mol) was dissolved in 1 mL of methanol solution, palladium carbon (4.00 mg, 10% purity) was added, and stirred at room temperature for 5 hours under a hydrogen atmosphere. Filter, concentrate the filtrate under reduced pressure, and purify it by preparative separation (preparative column: Xtimate C18 150 ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: [water(HCl)-ACN]; B%: 12%-42%, 10min) to obtain HY-71 (20.0 mg, light yellow powder), yield: 67.5%. MS m/z (ESI): 382.0 [M+H] + .
  • Step 1 Dissolve compound H-71-a (100 mg, 218.57 ⁇ mol) and triethylamine (66.35 mg, 655.70 ⁇ mol) in anhydrous dichloromethane (3 mL), and add cyclopropanecarbonyl chloride (27.42 mg, 262.28 ⁇ mol) in batches under an ice-water bath. Stir at room temperature for 16 hours after addition. Add water (2 mL) to quench, extract with dichloromethane (2 mL ⁇ 3), combine the organic phases, wash with saturated brine (2 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain H-72-a (100 mg, yellow solid), yield: 77.0%. MS m/z (ESI): 594.0 [M+H] + .
  • Step 2 Dissolve H-72-a (100 mg, 168.44 ⁇ mol) in 2 mL of methanol solution, add sodium hydroxide (13.47 mg, 336.89 ⁇ mol) at room temperature. Stir at room temperature for 16 hours. Filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain crude H-72-b (40.0 mg, yellow solid), yield: 45.1%. MS m/z (ESI): 526.0 [M+H] + .
  • Step 3 H-72-b (40.0 mg, 76.10 ⁇ mol) was dissolved in 2 mL of methanol solution, palladium carbon (4 mg, 10% purity) was added, and stirred at room temperature for 3 hours under a hydrogen atmosphere. Filter, concentrate the filtrate under reduced pressure, and purify it by preparative separation (preparative column: Xtimate C18 150 ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: [water(HCl)-ACN]; B%: 10%-40%, 10 min) to obtain HY-72 (10.0 mg, light yellow powder), yield: 29.8%. MS m/z (ESI): 392.0 [M+H] + .
  • Step 1 Dissolve intermediate 1 (160 mg, 708 ⁇ mol) in anhydrous N,N-dimethylformamide (2.5 mL), add intermediate f (278 mg, 854 ⁇ mol) and cesium carbonate (921 mg, 2.83 mmol), and stir at 50°C for 2 hours.
  • the reaction solution was filtered, and the filter cake was rinsed with dichloromethane (5 mL ⁇ 3).
  • Step 2 H-73-a (25.0 mg, 53.0 ⁇ mol) was dissolved in anhydrous dichloromethane (2 mL), triethylamine (16.1 mg, 159 ⁇ mol) and cyclopropanecarbonyl chloride (11.0 mg, 106.0 ⁇ mol) were added under nitrogen protection, and the reaction was stirred at 25 ° C for 2 hours. 2 mL of water was added, and the mixture was extracted with dichloromethane (2 mL ⁇ 3) in turn. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product H-73-b (32.0 mg, light yellow jelly), with a yield of 99.0%. The crude product was used directly in the next step. MS m/z (ESI): 608.1 [M + H] + .
  • Step 3 Dissolve H-73-b (32.0 mg, 52.7 ⁇ mol) in anhydrous methanol (2 mL), add sodium hydroxide (4.20 mg, 52.7 ⁇ mol), react at 60°C for 3 hours, then add sodium hydroxide (4.20 mg, 52.7 ⁇ mol), react at 60°C for 6 hours. Filter and spin dry to obtain crude H-73-c (35.0 mg, light yellow oil), which is used directly in the next step. MS m/z (ESI): 540.1 [M+H] + .
  • Step 4 H-73-c (35.0 mg, 64.9 ⁇ mol) was dissolved in anhydrous methanol (5 mL), Pd/C (30 mg, purity 10%) was added, hydrogen was replaced three times, and the mixture was reacted at 20°C in a hydrogen (15 psi) atmosphere for 0.5 hours. A layer of diatomaceous earth was applied for filtration, and the filtrate was concentrated and prepared by HPLC (preparative column: Phenomenex C18 150 ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: [water(HCl)-ACN]; B%: 5%-35%, 10 min), and lyophilized to obtain HY-73 (3.5 mg, light yellow solid), yield: 13.3%.
  • Step 2 H-74-a (60 mg, 117.50 ⁇ mol) was dissolved in DCM (4 mL), trifluoroacetic acid (40.19 mg, 352.51 ⁇ mol) was added, and stirred at room temperature for 2 hours. After concentration under reduced pressure, it was purified by pre-HPLC (preparative column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%-60% acetonitrile change) to obtain H-74 (9.98 mg, purity 98.9%), with a yield of 20.46%. MSm/z (ESI): 411.3 [M+H] + .
  • Step 1 In a 250mL three-necked flask, add 50mL of anhydrous DMF, methyl 4-(benzyloxy)-7-bromopyrazolo[1,5-a]pyridine-3-carboxylate (5.75g, 13.84mmol), replace the system with nitrogen three times, slowly inject tributyl(1-ethoxyethylene)tin (6.50g, 18.00mmol) into the system with a syringe, and after the addition is completed, heat the system to 120°C and react for 1 hour.
  • tributyl(1-ethoxyethylene)tin (6.50g, 18.00mmol)
  • Step 3 In a 100 mL three-necked flask, add aqueous hydrogen bromide solution (50 mL, 48%), add H-75-b (1.00 g, 3.08 mmol), and react at 110°C for 48 hours. After the reaction, cool the reaction solution to room temperature, concentrate the reaction solution to remove most of the HBr, extract the concentrate with ethyl acetate (20 mL ⁇ 4), combine the organic phases, wash with 50 mL of saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain H-75-c (500 mg, yellow solid), yield: 92.1%. MS m/z (ESI): 176.8 [M + H] + .
  • Step 4 In an 8mL AK bottle, add anhydrous DMF (3mL), add H-75-c (250mg, 1.42mmol) and intermediate e (530.20mg, 1.70mmol), and add cesium carbonate (3.70g, 11.35mmol) to the system. The reaction solution was heated to 50°C and reacted for 2 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product H-75-d (300mg, yellow solid), which was directly used for the next step. MS m/z (ESI): 407.9 [M+H] + .
  • Step 6 Add 2 mL of acetic acid to a 5 mL thumb bottle, add H-75-e (170 mg, 367.54 ⁇ mol) and 1H-pyrazole-5-amine (30.54 mg, 367.54 ⁇ mol). Heat the reaction solution to 110 ° C for 2 hours. After the reaction is completed, cool the reaction solution to room temperature, pour it into 10 mL of ice water, stir for two minutes and filter, wash the filter cake with water (2 mL ⁇ 1), collect the filter cake and concentrate it to obtain H-75-f (80.0 mg, yellow solid), yield: 45.1%. MS m/z (ESI): 483.0 [M + H] + .
  • Step 7 In a 5 mL thumb bottle, add anhydrous tetrahydrofuran (2 mL), H-75-f (50 mg, 103.62 ⁇ mol), palladium hydroxide (50.0 mg, 356.04 ⁇ mol), replace the gas three times with a hydrogen balloon (15 psi), and react the reaction solution at 25 ° C in a hydrogen atmosphere for 1.5 hours. After the reaction is completed, filter, and the filtrate is separated by HPLC (preparative column: Xtimate C18 150 ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: [water(HCl)-ACN]; B%: 1%-30%, 10min), and HY-75 (11.0 mg, yellow solid) is purified with a yield of 27.6%.
  • Step 2 H-76-a (280 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (8.57 g, 72.0 mmol). The reaction solution was stirred at 110°C for 16 hours. H-76-b (280 mg, yellow solid) was obtained by spin drying with a yield of 87.59%. MS m/z (ESI): 445.3 [M+H] + .
  • Step 3 H-76-b (280 mg, 629.83 ⁇ mol) and 3-trifluoromethyl-1H-pyrazole-5-amine (95.16 mg, 629.83 ⁇ mol) were dissolved in acetic acid (5 mL), and the reaction solution was stirred at 80 ° C for 4 hours. The solvent was dried, the product was dissolved in dichloromethane (8 mL), and then trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at room temperature for 2 hours.
  • Step 1 H-76-b (280 mg, 629.83 ⁇ mol) and 3-chloro-1H-pyrazole-5-amine (74.03 mg, 629.83 ⁇ mol) were dissolved in acetic acid (5 mL). The reaction solution was stirred at 80 ° C for 4 hours. The solvent was dried and the residue was dissolved in dichloromethane (8 mL), and then trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 2 hours.
  • Step 1 H-76-b (0.25 g, 562.35 ⁇ mol) and 3-amino-5-bromopyrazole (91.09 mg, 562.35 ⁇ mol) were dissolved in acetic acid (10 mL). The reaction solution was stirred at 80 ° C for 2 hours. The solvent was dried, and then DCM (8 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. H-78-a (150 mg, yellow solid) was prepared by drying, and the yield was 49.08%. MS m/z (ESI): 445.1 [M-100 + H] + .
  • Step 2 H-78-a (50 mg, 92.00 ⁇ mol) was dissolved in DCM (5 mL), trifluoroacetic acid (31.47 mg, 276.01 ⁇ mol) was added, and stirred at room temperature for 2 hours. After concentration under reduced pressure, it was purified by pre-HPLC (preparative column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%-60% acetonitrile change) to obtain H-78 (7.83 mg, purity 100%), yield: 19.20%. MSm/z (ESI): 443.1 [M+H] + .
  • Step 1 H-76-b (50 mg, 112.47 ⁇ mol) was dissolved in acetic acid (4 mL) and 3-methyl-1H-pyrazol-5-amine (10.92 mg, 112.47 ⁇ mol) was added, and stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a yellow solid, which was purified by combiflash (0-50% EA/PE) to obtain H-79-a (40 mg, yellow solid), yield: 74.31%. MSm/z (ESI): 479.1 [M+H] + .
  • Step 2 H-79-a (40 mg, 83.58 ⁇ mol) was dissolved in DCM (5 mL), trifluoroacetic acid (50.03 mg, 438.79 ⁇ mol) was added, and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%-60% acetonitrile change) to obtain H-79 (6.90 mg, purity 95.91%), yield: 11.95%. MSm/z(ESI):379.2[M+H] + .
  • Step 1 H-76-b (100 mg, 224.94 ⁇ mol) was dissolved in acetic acid (5 mL), 3-(difluoromethyl)-1H-pyrazol-5-amine (29.94 mg, 224.94 ⁇ mol) was added, and stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a yellow solid, which was purified by combiflash (0-50% EA/PE) to obtain H-80-a (80 mg, yellow solid), yield: 69.12%. MSm/z(ESI):515.1[M+H] + .
  • Step 2 H-80-a (80 mg, 155.47 ⁇ mol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (53.18 mg, 466.41 ⁇ mol) was added, and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%-60% acetonitrile change) to obtain H-80 (21.55 mg, purity 100%), yield: 33.44%. MSm/z(ESI):415.2[M+H] + .
  • Step 1 Add phthalic anhydride (15 g, 101.27 mmol) and 5-amino-1H-pyrazole-3-ol (10 g, 100.92 mmol) to acetic acid (400 mL), and stir the reaction solution at 130°C for 2 hours. Cool to room temperature, precipitate solid, filter, and wash the solid with ether. Dry to obtain 2-(3-hydroxy-1H-pyrazole-5-yl)isoindoline-1,3-dione (12 g, yellow solid), with a yield of 51.88%. MS m/z (ESI): 230.1 [M+H] + .
  • Step 2 Add 2-(3-hydroxy-1H-pyrazol-5-yl)isoindoline-1,3-dione (4g, 17.45mmol) to water (10mL) and DMF (40mL), then add cesium carbonate (11.37g, 34.91mmol) and sodium difluorochloroacetate (6.39g, 41.89mmol). The reaction solution was stirred at 110°C for 22 hours. Carefully add saturated sodium bicarbonate solution (100mL) to quench, and extract with dichloromethane (100mL ⁇ 3). The organic phase was washed with saturated brine, dried, filtered, and concentrated under reduced pressure.
  • Step 4 H-81-a (85 mg, 160.21 ⁇ mol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (4 mL) was added. The reaction solution was stirred at room temperature for 1 hour. It was concentrated under reduced pressure. After being dissolved in dichloromethane, 7N ammonia methanol solution was added for neutralization, and it was concentrated under reduced pressure.
  • Step 1 2-(3-Hydroxy-1H-pyrazol-5-yl)isoindoline-1,3-dione (1.16 g, 5.06 mmol) and 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzoiodooxolane (2 g, 6.06 mmol) were added to DMF (10 mL), and the reaction solution was stirred at 60°C for 6 hours. Saturated sodium bicarbonate solution (50 mL) was added and extracted with ethyl acetate (50 mL ⁇ 3). The organic phase was dried, filtered, and concentrated under reduced pressure.
  • Step 1 Dissolve potassium tert-butoxide (6.09 g, 54.30 mmol) in tetrahydrofuran (50 mL), cool to 0°C, add ethyl 2,2-difluoropropionate (5 g, 36.20 mmol) and acetonitrile (2.23 g, 54.30 mmol). Allow the reaction mixture to warm to room temperature and stir for 16 hours. Add water (100 mL) and adjust with dilute hydrochloric acid. The pH value was less than 2.
  • Step 4 H-83-a (98 mg, 185.40 ⁇ mol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (4 mL) was added. The reaction solution was stirred at room temperature for 1 hour. It was concentrated under reduced pressure. After being dissolved in dichloromethane, 7N ammonia methanol solution was added for neutralization, and it was concentrated under reduced pressure again.
  • Step 2 Add H-84-a (30 mg, 61.28 ⁇ mol) to trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and stir the reaction solution at room temperature for 2 hours. Concentrate under reduced pressure. Add 7N methanol solution of ammonia to neutralize, and then concentrate under reduced pressure again. Purify the residue by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%--30% acetonitrile change) to obtain HY-84 (5.15 mg, yellow solid), with a yield of 21.58%.
  • Step 1 H-84-a (30 mg, 61.28 ⁇ mol) was dissolved in DMSO (3 mL), and potassium carbonate (8.47 mg, 61.28 ⁇ mol) and H 2 O 2 aqueous solution (4.17 mg, 30%) were added. The reaction solution was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution, and the ethyl acetate layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. H-85-a (20 mg, yellow solid) was obtained by spin drying, with a yield of 64.30%. MS m/z (ESI): 452.2 [M-56+H] + .
  • Step 2 Add H-85-a (20 mg, 39.45 ⁇ mol) to trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and stir the reaction solution at room temperature for 2 hours. Concentrate under reduced pressure. Add 7N methanol solution of ammonia to neutralize, and then concentrate under reduced pressure again. Purify the residue by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%-30% acetonitrile change) to obtain HY-85 (1.15 mg, yellow solid) with a yield of 4.38%.
  • Step 2 Add H-86-a (35 mg, 69.36 ⁇ mol) to trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and stir the reaction solution at room temperature for 2 hours. Concentrate under reduced pressure. Add 7N methanol solution of ammonia to neutralize, and then concentrate under reduced pressure again. Purify the residue by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%-30% acetonitrile change) to obtain H-86 (12.09 mg, yellow solid), with a yield of 42.57%.
  • Step 3 Add H-87-b (50 mg, 102.34 ⁇ mol) to trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and stir the reaction solution at room temperature for 1 hour. Concentrate under reduced pressure. Add 7N methanol solution of ammonia to neutralize, and then concentrate under reduced pressure again. Purify the residue by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% ammonium bicarbonate, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%-60% acetonitrile change) to obtain H-87 (15.60 mg, yellow solid) with a yield of 24.47%.
  • Step 1 H-78-a (50 mg, 92.00 ⁇ mol) was dissolved in DMF (4 mL), tetrakis(triphenylphosphine)palladium (10.63 mg, 9.20 ⁇ mol) and tributyl(1-ethoxyvinyl)tin (33 mg, 92.00 ⁇ mol) were added, and the mixture was reacted at 100 °C overnight under nitrogen protection. A saturated solution of potassium fluoride was added and stirred for 1 hour, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow solid.
  • Step 2 Dissolve H-88-a (40 mg, 78.96 ⁇ mol) in DCM (4 mL), add trifluoroacetic acid (27.01 mg, 236.88 ⁇ mol), and stir at room temperature for 1 hour. . Concentrate under reduced pressure to obtain a yellow solid. The solid was purified by pre-HPLC (preparative column: 21.2 ⁇ 250 mm C18 column, system: 10 mM NH 4 HCO 3 H 2 O, wavelength: 254/214 nm, gradient: 30%-60% acetonitrile change) to obtain H-88 (7.90 mg, purity 100%), yield: 24.61%. MSm/z(ESI):407.2[M+H] + .
  • Step 2 H-89-a (40 mg, 73.04 ⁇ mol) was added to trifluoroacetic acid (2 mL) and dichloromethane (8 mL), and the reaction solution was stirred at room temperature for 2 hours. Concentrated under reduced pressure. After neutralization by adding 7N ammonia methanol solution, it was concentrated under reduced pressure again. The residue was purified by preparative liquid chromatography (preparative column: water-sunfire; system: A: water + 0.045% formic acid, B: acetonitrile; wavelength: 254/214 nm; gradient: 5%-30% acetonitrile change) to obtain H-89 (11.92 mg, yellow solid) with a yield of 36.20%.
  • Step 2 H-92-a (650 mg, 1.42 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. Concentrated under reduced pressure. After dissolving in dichloromethane, 7 mol/L methanol solution of ammonia (5 mL) was added for neutralization, and concentrated under reduced pressure.
  • Step 2 H-93-a (200 mg, 405.25 ⁇ mol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (4 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.
  • reaction solution was purified by preparative liquid chromatography (preparative The residue was purified by HPLC (column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain H-93 (46 mg, yield 28.85%). MS m/z (ESI): 394.2 [M+H] + .
  • Step 2 Add H-95-a (1.5 g, 3.20 mmol), tributyl (prop-1-ynyl) stannane (1.05 g, 3.20 mmol), tetrakis (triphenylphosphine) palladium (250.00 mg, 216.35 ⁇ mol) and cuprous iodide (72.22 mg, 379.22 ⁇ mol) to toluene (25 mL). Under argon protection, the reaction solution was stirred at 60 ° C for 1.5 hours. Filter and concentrate under reduced pressure.
  • Step 4 H-95-c (120 mg, 315.04 ⁇ mol), 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (160.71 mg, 630.07 ⁇ mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25.54 mg, 31.50 ⁇ mol), potassium carbonate (87.08 mg, 630.07 ⁇ mol) was added to 1,4-dioxane (20 mL) and water (2 mL). Under argon protection, the reaction solution was stirred at 115°C for 18 hours. It was concentrated under reduced pressure.
  • Step 5 H-95-d (50 mg, 91.15 ⁇ mol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at room temperature for 1 hour. It was concentrated under reduced pressure. After being dissolved in dichloromethane, 7 mol/L ammonia methanol solution was added for neutralization, and it was concentrated under reduced pressure again.
  • Step 4 H-96-c (20 mg, 43.81 ⁇ mol) was dissolved in DCM (2 mL), trifluoroacetic acid (0.2 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. After being dissolved in dichloromethane, 7 mol/L ammonia in methanol solution was added for neutralization, and the mixture was concentrated under reduced pressure. 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; wavelength: 254/214 nm; gradient: 30%-60% acetonitrile change) to obtain H-96 (1 mg, yellow oil, yield 6.15%). MS m/z (ESI): 357.2 [M+H] + .
  • Step 1 Dissolve H-76-b (470 mg, 1.06 mmol) in ethanol (5 mL), add urea (126.98 mg, 2.11 mmol) and sodium ethoxide (215.83 mg, 3.17 mmol), and stir at 100°C for 2 hours. Filter and concentrate under reduced pressure to obtain a yellow solid. The solid is combiflashed (0-60% EA/PE) to obtain H-97-a (250 mg, yield 53.56%, yellow solid). MS m/z (ESI): 442.1 [M+H] + .
  • Step 2 H-97-a (200 mg, 452.98 ⁇ mol) was dissolved in POCl 3 (5 mL) and stirred at 105°C overnight. The mixture was concentrated under reduced pressure to obtain a yellow solid. The solid was added with ice water, extracted with DCM/MeOH (10/1), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • Step 1 Compound 40 (60 mg, 261.77 ⁇ mol) and (S)-4-isobutyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide (92.16 mg, 314.12 ⁇ mol) were dissolved in DMF (5 mL), K 2 CO 3 (90.45 mg, 654.42 ⁇ mol) was added, and the reaction solution was stirred at 80°C for 12 hours.
  • Step 2 Compound H-112-a (60 mg, 135.59 ⁇ 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 7N ammonia methanol solution, and concentrated under reduced pressure again.
  • Step 1 H-76-b (200 mg, 449.88 ⁇ mol) was dissolved in EtOH (10 mL), cyclopropanecarboxamide (75.69 mg, 899.75 ⁇ mol) and sodium ethoxide (91.84 mg, 1.35 mmol) were added, and stirred at 100 ° C for 2 hours. Filter and concentrate under reduced pressure to obtain a yellow solid. The solid was purified by combiflash (0-60% EA/PE) to obtain H-113-a (150 mg, yield 71.61%, yellow solid). MSm/z (ESI): 466.1 [M+H] + .
  • Step 2 H-113-a (150 mg, 322.17 ⁇ mol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (110.20 mg, 966.52 ⁇ mol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a yellow solid.
  • Step 1 H-97 (70 mg, 194.52 ⁇ mol) was dissolved in water (0.5 mL), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (59.92 mg, 389.05 ⁇ mol), potassium carbonate (53.77 mg, 389.05 ⁇ mol), Pd(dppf)Cl 2 (14.23 mg, 19.45 ⁇ mol) and 1,4-dioxane (5 mL) were added, and the mixture was stirred at 100 °C overnight under nitrogen protection.
  • Max positive control well, i.e., the maximum value well (blank control well with enzyme activity);
  • Min negative control well, i.e., the minimum value well (blank control well without enzyme activity);
  • Compound compound 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 examples of the present application have a high inhibitory activity against the AAK1 enzyme.
  • the structure of the positive compound D1 is: (D1, CAS No.: 2092891-50-2), which can be prepared by referring to the prior art, or obtained through commercial channels.
  • Max positive control well (blank control well with enzyme activity), i.e., the maximum value well
  • Min negative control well (blank control well without enzyme activity), i.e., the minimum value well
  • Compound compound 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.
  • the compounds of the present application have relatively low inhibitory activity against BMP2K enzyme.
  • the structure of the positive compound D2 is: (D2, CAS No.: 1815613-42-3), which can be prepared by referring to the prior art, or obtained through commercial channels.
  • 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 a 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 , 37°C incubator.
  • Cryopreservation conditions liquid nitrogen.
  • CHO cells stably expressing hERG were cultured in a cell culture dish with a diameter of 35 mm, 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 (Invitrogen) and 100 ⁇ g/mL Hygromycin B (Invitrogen).
  • the cell culture medium was aspirated, and the cells were rinsed with extracellular fluid and then added with 0.25% Trypsin-EDTA (Invitrogen) solution, 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 the experimental dish for electrophysiological recording for use.
  • the compound was prepared with DMSO to the stock concentration, and then serially diluted 3 times with DMSO, that is, 10 ⁇ L was added to 20 ⁇ L of DMSO, and then take 10 ⁇ L of the serially diluted compound DMSO solution and add it to 4990 ⁇ L of extracellular fluid, and dilute 500 times to obtain the final concentration to be tested.
  • 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 confirmed to be stable (1 minute).
  • Compounds were administered for at least 1 min to steady state of action or for a maximum of 3 aliquots at each tested concentration, and at least 2 cells (n ⁇ 2) were tested at each concentration.
  • 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 group was free to eat and drink before administration; the 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 for the intravenous injection group and the oral group were (volume ratio of 5:10:85) dimethyl sulfoxide, polyethylene glycol-15 hydroxystearate and 20 mol/L citric acid buffer, vortexed and dissolved after ultrasound to prepare 5 mg/mL or 1 mg/mL or other concentration solutions.
  • the intravenous injection group required the solution to be clear, and the oral group required the solution to be uniformly suspended or clear for use.
  • intravenous administration of 1 mg/kg (mpk) or oral administration of 5 mg/kg (mpk) or other doses (such as 10 mg/kg (mpk)) to rats a certain amount of whole blood samples, brain homogenate samples, and cerebrospinal fluid samples were collected.
  • the whole blood samples were centrifuged at 3700 rpm for 15 minutes, and the supernatant was separated to obtain plasma samples.
  • 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 blood 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 C max , peak time T max , clearance rate CL, half-life T 1/2 , 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 area under the plasma drug-time curve AUC plasma and AUC plasma dose norminized and the area under the brain homogenate drug-time curve AUC brain and AUC brain dose norminized obtained by software fitting can be used to calculate the ratio of drug in brain to plasma Kp .
  • the formula is as follows:
  • Kp area under the brain homogenate drug-time curve/area under the plasma drug-time curve
  • test results are shown in Tables 4 and 5.
  • the test results of the plasma and brain drug concentrations 4 hours after a single oral administration of compound H-112 and compound D2 are shown in Table 6:
  • the structure of the positive compound D2 is: (D2, CAS No.: 1815613-42-3), which can be prepared by referring to the prior art, or obtained through commercial channels.

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Abstract

Est divulgué dans la présente demande un dérivé hétéroaryle pentagonal à six chaînons substitué hétérocyclique, sa structure étant telle que représentée par la formule (I). De plus, la présente demande concerne en outre un sel pharmaceutiquement acceptable du dérivé et un stéréoisomère et une composition pharmaceutique de celui-ci, ainsi qu'une utilisation associée. Le composé selon la présente demande a une activité inhibitrice sélective significative de AAK1, un effet inhibiteur de hERG inférieur, une pénétration du système nerveux central plus avantageuse, et a une grande valeur pratique.
PCT/CN2024/074970 2022-12-13 2024-01-31 Dérivé hétéroaryle pentagonal à six chaînons substitué hétérocyclique, composition pharmaceutique de celui-ci, procédé d'utilisation et de préparation associé WO2024125668A1 (fr)

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Citations (4)

* 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
CN114380835A (zh) * 2022-01-06 2022-04-22 南京桦冠生物技术有限公司 一种7-(3,4-二甲氧苯基)-2-吡唑[1,5-a]嘧啶羧酸的制备方法
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 (4)

* 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
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
CN114380835A (zh) * 2022-01-06 2022-04-22 南京桦冠生物技术有限公司 一种7-(3,4-二甲氧苯基)-2-吡唑[1,5-a]嘧啶羧酸的制备方法

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