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WO2025223536A1 - Composé bicyclique fusionné et son utilisation - Google Patents

Composé bicyclique fusionné et son utilisation

Info

Publication number
WO2025223536A1
WO2025223536A1 PCT/CN2025/091151 CN2025091151W WO2025223536A1 WO 2025223536 A1 WO2025223536 A1 WO 2025223536A1 CN 2025091151 W CN2025091151 W CN 2025091151W WO 2025223536 A1 WO2025223536 A1 WO 2025223536A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkylene
sub
alkyl
alkylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/091151
Other languages
English (en)
Chinese (zh)
Inventor
朱益忠
王斌
王路路
张钰
刘飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Publication of WO2025223536A1 publication Critical patent/WO2025223536A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This application belongs to the field of medicinal chemistry and relates to fused bicyclic compounds and their uses, specifically fused bicyclic compounds, their preparation methods, pharmaceutical compositions containing the compounds, and their uses in treating diseases.
  • WFS1 is a polymeric endoplasmic reticulum transmembrane protein that regulates endoplasmic reticulum stress by influencing intracellular Ca2 + homeostasis and the unfolded protein response (UPR).
  • URR unfolded protein response
  • this application relates to compounds of formula (I) or pharmaceutically acceptable salts thereof.
  • X1 , X2 , X5 , and X6 are each independently selected from N or CR1 ;
  • X3 and X4 are each independently selected from N, C or CR1 ;
  • Each R1 is independently selected from hydrogen, deuterium, oxo, halogen, -OH, -NH2 , -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, or halodiC1-6 alkylamino;
  • Ring A is selected from the following groups optionally substituted with one or more RA groups: 3-12-membered heterocyclic groups, 6-10-membered aryl groups, or 5-10-membered heteroaryl groups;
  • Each RA is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -C(O)NR a1Ra2 , -NR a1C(O)Ra2, -OC(O)Ra2, -C(O)OR a2 , -S ( O ) Ra2 , -S(O ) 2Ra2 , -NR a1S (O) 2Ra2 , -S(O) 2NR a1Ra2 , or optionally substituted with one or more Ra3 groups , including C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkylC1-6 alkylene, or 3-12 membered heterocycloalkylC1-6 alkylene;
  • Ra1 is independently selected from hydrogen, deuterium, or C1-6 alkyl groups optionally substituted with one or more Ra3 ;
  • Ra2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Ra3 groups of the following: C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkyl C1-6 alkylene, or 3-12 membered heterocycloalkyl C1-6 alkylene;
  • Each Ra3 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino;
  • the ring B is selected from the following groups optionally substituted with one or more R B : 3-12 membered cycloalkyl, 3-12 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • Each Rb is independently selected from oxo, deuterium, halogen, -CN, -ORb2 , -SRb2 , -NRb1Rb2 , -C(O) NRb1Rb2 , -C( O )NRb1ORb2, -NRb1C ( O)Rb2 , -NRb1C (O )NRb1Rb2 , -OC(O) Rb2 , -C( O ) ORb2 , -C(O) Rb2 , -S( O ) Rb2 , -S(O) 2Rb2 , -C( Rb1 ) 2S (O) 2Rb2 , -NRb1S (O) 2Rb2 , -S (O) 2NRb1Rb2 , or optionally substituted with one or more Rb3 groups , including the following groups : C 1-6 alkyl, 3-12 cycloalkyl, 3
  • Rb1 is independently selected from hydrogen, deuterium, or C1-6 alkyl groups optionally substituted with one or more Rb3 ;
  • Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more of the following groups: C1-6 alkyl, 3-12 cycloalkyl, 3-12 heterocycloalkyl, 3-12 heterocycloalkenyl, 5-10 heteroaryl, 3-12 cycloalkyl C1-6 alkylene, or 3-12 heterocycloalkyl C1-6 alkylene ;
  • Each Rb3 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, C1-4 alkylcarbonyl, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino;
  • Each R2 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, or halodiC1-6 alkylamino;
  • two R2 atoms located on the same ring atom together with the ring atom form a group optionally substituted by one or more R2a , namely a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl.
  • Each R 2a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, diC 1-4 alkylamino, haloC 1-4 alkyl, haloC 1-4 alkoxy , haloC 1-4 alkylthio , haloC 1-4 alkylamino, or halodiC 1-4 alkylamino;
  • n is selected from 0, 1, 2, 3, 4, 5, or 6.
  • the component is selected from single bonds. In some implementations, structural fragments... Selected from In some implementations, structural fragments Selected from
  • the component is selected from double bonds.
  • the structural segment optional Selected from In some implementations, structural fragments Selected from
  • structural fragments The ring C and structural fragments The N-connection. In some implementations, structural fragments Ring A and structural fragments N-connection.
  • structural fragments X1 , X2 , X5 , or X6 and structural fragments N-connection In some implementations, structural fragments X1 , X2 , X5 , or X6 and structural fragments N-connection.
  • structural fragments Selected from In some implementations, structural fragments Selected from
  • X1 , X2 , X5 , or X6 are not all selected from N.
  • X2 is N and X6 is N.
  • X2 is N and X6 is CR1 . In some implementations, X2 is N and X6 is CH.
  • X2 is CR1 and X6 is CR1 .
  • X2 is CR1 and X6 is N. In some implementations, X2 is CH and X6 is N.
  • X1 and X5 are selected from CR1 .
  • X3 and X4 are selected from C.
  • X3 and X4 are not both selected from N.
  • X3 is N, and X4 is C or CR1 . In some implementations, X3 is N, and X4 is C or CH.
  • X3 is C or CR1 , and X4 is N. In some implementations, X3 is C or CH, and X4 is N.
  • X3 is C or CR1
  • X4 is C or CR1
  • X3 is C or CH
  • X4 is C or CH.
  • structural fragments Selected from Wherein, the substitution position of R1 is on ring C; n is selected from 0, 1, 2, 3 or 4.
  • structural fragments Selected from Wherein, the substitution position of R1 is on ring C; n is selected from 0, 1, or 2.
  • each R1 is independently selected from hydrogen, deuterium, oxo, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino.
  • each R1 is independently selected from hydrogen, deuterium, oxo, halogen, -OH, -NH2 , -CN, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, diC1-3 alkylamino, haloC1-3 alkyl, haloC1-3 alkoxy, haloC1-3 alkylthio, haloC1-3 alkylamino, or halodiC1-3 alkylamino.
  • each R1 is independently selected from hydrogen, deuterium, oxo, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy.
  • each R1 is independently selected from hydrogen, deuterium, oxo, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, methoxy, methylamino, dimethylamino, -CF3 , or -OCF3 .
  • ring A is selected from the following groups optionally substituted with one or more RA groups: 3-10 membered heterocyclic groups, 6-10 membered aryl groups, or 5-10 membered heteroaryl groups.
  • ring A is selected from the following groups optionally substituted with one or more RA groups: 3-8 membered heterocyclic groups, 6-8 membered aryl groups, or 5-8 membered heteroaryl groups.
  • ring A is selected from the following groups optionally substituted with one or more RA groups: 5-6 membered heterocyclic group, phenyl group, or 5-6 membered heteroaryl group.
  • ring A is selected from the following groups optionally substituted with one or more RA groups: phenyl, pyrrolyl, dihydropyrrolyl, pyrrolyl, pyrazolyl, dihydropyrazolyl, pyrazolyl, tetrahydrofuranyl, dihydrofuranyl, furanyl, imidazoalkyl, dihydroimidazoyl, imidazoyl, thiophenyl, dihydrothiophenyl, thiophenyl, tetrahydropyranyl, dihydropyranyl, pyranyl, piperidinyl, tetrahydropyridinyl, dihydropyridinyl, pyridinyl, tetrahydropyrimidinyl, dihydropyrimidinyl
  • the group is pyrimidinyl, piperazinyl, tetrahydropyrazinyl, dihydropyrazinyl, pyrazinyl,
  • ring A is selected from the following groups optionally substituted with one or more RA groups: phenyl, dihydropyrrolyl, pyrrolyl, pyrazolyl, dihydrofuranyl, furanyl, imidazolyl, dihydrothiophenyl, thiophenyl, tetrahydropyridyl, pyridyl, thiazolyl, 1,2,3-triazolyl, or 1,2,4-triazolyl.
  • ring A is selected from the following groups optionally substituted with one or more RNA groups:
  • atoms marked with "*” represent X 3
  • atoms marked with "#” represent X 4 .
  • ring A is selected from the following groups optionally substituted with one or more RNA groups:
  • atoms marked with "*” represent X 3
  • atoms marked with "#” represent X 4 .
  • each RA is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -C(O)NR a1Ra2 , -NR a1C (O) Ra2 , -OC(O)Ra2 , -C ( O)OR a2 , -S(O) Ra2 , -S(O) 2Ra2 , -NR a1S (O )2Ra2 , -S(O) 2NR a1Ra2 , or optionally substituted with one or more Ra3 groups , including C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, 3-10 membered cycloalkylC1-4 alkylene, or 4-10 membered heterocycloalkylC1-4 alky
  • each RA is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -C(O)NR a1 Ra2 , -NR a1 C(O) Ra2 , -OC(O) Ra2 , -C(O)OR a2 , -S(O) Ra2 , -S (O) 2Ra2 , -NR a1 S(O)2Ra2 , -S (O) 2NR a1 Ra2 , or optionally substituted with one or more Ra3 groups, including C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, diC1-3 alkylamino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl C1-3 alkylene, or 4-6 membered heterocycloalkyl C1-3 alkylene.
  • each RA is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, -C(O)NR a1 Ra2 , -C(O)OR a2 , -S(O) Ra2 , -S(O) 2Ra2 , or optionally substituted with one or more Ra3 groups, namely: C1-3 alkyl, C1-3 alkoxy, C1-3 alkylamino, diC1-3 alkylamino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl C1-3 alkylene, or 4-6 membered heterocycloalkyl C1-3 alkylene.
  • each Ra is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, -C(O)NR a1 Ra2 , -C(O)OR a2 , -S(O) Ra2 , -S(O) 2Ra2 , or optionally substituted with one or more Ra3 groups, including: methyl, ethyl, n -propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, methylethylamino, cyclopropane, cyclobutane, cyclopentane, cyclohexane , aziridine, tetrahydrofuranyl, pyrrolyl, thiazolyl, piperidinyl, piperazine, morpholinyl , cyclo
  • each RA is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, Methyl, methoxy, -CF3 .
  • Ra1 is independently selected from hydrogen, deuterium, or C1-4 alkyl groups optionally substituted with one or more Ra3 .
  • Ra1 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Ra3 groups, such as methyl, ethyl, n-propyl, and isopropyl.
  • Ra1 is independently selected from hydrogen.
  • Ra2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Ra3 groups, namely: C1-4 alkyl, 3-10 cycloalkyl, 3-10 heterocycloalkyl, 3-10 cycloalkyl C1-4 alkylene, or 3-10 heterocycloalkyl C1-4 alkylene.
  • Ra2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Ra3 groups, namely: C1-3 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkyl C1-3 alkylene, or 4-6 membered heterocycloalkyl C1-3 alkylene.
  • Ra2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Ra3 groups, including: methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane , aziridine, pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, cyclopropane C1-3 alkylene, cyclobutane C1-3 alkylene, aziridine C1-3 alkylene, pyrrolidine C1-3 alkylene, tetrahydrofuranyl C1-3 alkylene, piperidinyl C1-3 alkylene, piperazinyl C1-3 alkylene, and morpholinyl C1-3 alkylene.
  • Ra3 groups including: methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane , aziridine, pyrrolidine, tetrahydrofurany
  • Ra2 is independently selected from groups optionally substituted with one or more Ra3 , namely methyl, ethyl, n-propyl, or isopropyl.
  • Ra2 is independently selected from ethyl groups.
  • each Ra3 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, diC1-3 alkylamino, haloC1-3 alkyl, haloC1-3 alkoxy, haloC1-3 alkylthio, haloC1-3 alkylamino , or halodiC1-3 alkylamino.
  • each Ra3 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy.
  • each Ra3 is independently selected from -F or -Cl.
  • ring A is selected from...
  • atoms marked with "*" represent X 3
  • atoms marked with "#” represent X 4 .
  • ring B is selected from the following groups optionally substituted with one or more RBs : 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl.
  • ring B is selected from the following groups optionally substituted with one or more RBs : 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, or 5-9 membered heteroaryl.
  • ring B is selected from the following groups optionally substituted with one or more RBs : 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 6-8 membered aryl, or 5-8 membered heteroaryl.
  • ring B is selected from the following groups optionally substituted with one or more RBs : 3-6 membered cycloalkyl, 4-6 membered heterocyclic, phenyl, naphthyl, or 5-6 membered heteroaryl.
  • ring B is selected from the following groups optionally substituted with one or more RBs : 6-10 aryl or 5-10 heteroaryl.
  • cycloB is selected from the following groups optionally substituted with one or more R B groups: cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, thiophenyl, thiazoyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazine, morpholinyl, dihydropyrrolyl, dihydropyrazolyl, dihydrofuranyl, dihydroimidazoyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyrazineyl Tetrahydropyrazin
  • ring B is selected from phenyl, naphthyl, pyridine, or pyridinium imidazolyl groups optionally substituted with one or more RBs . In some embodiments, ring B is selected from phenyl groups optionally substituted with one or more RBs . In some embodiments, ring B is selected from naphthyl groups optionally substituted with one or more RBs . In some embodiments, ring B is selected from pyridine groups optionally substituted with one or more RBs . In some embodiments, ring B is selected from pyridinium imidazolyl groups optionally substituted with one or more RBs .
  • ring B is selected from... In some implementation schemes, ring B is selected from...
  • ring B is selected from...
  • ring B is selected from... In some implementation schemes, ring B is selected from...
  • each Rb is independently selected from oxo, deuterium, halogen , -CN , -ORb2 , -SRb2 , -NRb1Rb2 , -C(O) NRb1Rb2 , -C(O)NRb1ORb2, -NRb1C (O) Rb2 , -NRb1C (O) NRb1Rb2 , -OC (O) Rb2 , -C (O) ORb2 , -C(O) Rb2 , -S(O) Rb2 , -S (O) 2Rb2 , -C( Rb1 ) 2S ( O ) 2Rb2 , -NRb1S ( O) 2Rb2 , -S(O) 2NRb1Rb2 , or optionally substituted with one or more Rb3 groups , including the following groups: C 1-4 alkyl, 3-10 cycloalkyl, -
  • each Rb is independently selected from oxo, deuterium, halogen, -CN , -ORb2 , -NRb1Rb2 , -C (O) NRb1Rb2 , -C(O) NRb1ORb2 , -NRb1C(O) Rb2 , -NRb1C (O )NRb1Rb2 , -OC(O ) Rb2 , -C( O ) ORb2 , -C(O) Rb2 , -S(O) Rb2 , -S( O )2Rb2 , -C( Rb1 ) 2S (O) 2Rb2 , -NRb1S (O) 2Rb2 , -S(O) 2NRb1Rb2 , or optionally substituted with one or more Rb3 groups , including the following groups: C 1-3 alkyl, 3-6 cycloalkyl, 4
  • each RB is independently selected from oxo, deuterium, -F, -Cl, -Br, -CN, -OR b2 , -NR b1 R b2 , -C(O)NR b1 R b2 , -C(O)NR b1 OR b2 , -C(O)OR b2 , -NR b1 C(O)R b2 , -NR b1 C(O)NR b1 R b2 , -C(O)R b2 , -S(O)R b2 , -S(O) 2 R b2 , -C(R b1 ) 2 S(O) 2 R b2 , -NR b1 S(O) 2 R b2 , or optionally by one or more R
  • the following groups are substituted with b3 : methyl, ethyl, n-propyl, isopropy
  • each Rb is independently selected from deuterium, halogen, -CN , -ORb2 , -NRb1Rb2 , -C(O) NRb1Rb2 , -C(O) NRb1ORb2 , -NRb1C( O)Rb2 , -NRb1C ( O ) NRb1Rb2 , -C(O) Rb2 , -S(O) Rb2 , -S (O) 2Rb2 , -C ( Rb1 ) 2S ( O ) 2Rb2 , -NRb1S (O) 2Rb2 , -S(O) 2NRb1Rb2 , or optionally substituted with one or more Rb3 groups, including 4-9-membered heterocyclic alkyl , 4-9-membered heterocyclic alkenyl, or 5-6-membered heteroaryl.
  • each Rb is independently selected from deuterium, -F, -Cl, -Br , -CN, -ORb2 , -NRb1Rb2 , -C(O) NRb1Rb2 , -C(O) NRb1ORb2 , -NRb1C (O ) Rb2 , -NRb1C (O) NRb1Rb2 , -C(O) Rb2 , -S(O)Rb2, -S(O)2Rb2, -C(Rb1)2S(O)2Rb2 , -NRb1S ( O ) 2Rb2 , or optionally substituted with one or more Rb3 groups, including pyrrolidinyl, isothiazolyl, piperidinyl, piperazinyl , morpholinyl, etc. Dihydropyrrole, tetrahydropyridyl, or pyrazolyl
  • Rb1 is independently selected from hydrogen, deuterium, or C1-4 alkyl groups optionally substituted with one or more Rb3 .
  • Rb1 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Rb3 groups, namely methyl, ethyl, n-propyl, and isopropyl.
  • Rb1 is independently selected from hydrogen or methyl.
  • Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Rb3 groups of the following: C1-4 alkyl, 3-10 cycloalkyl, 3-10 heterocycloalkyl, 3-10 heterocycloalkenyl, 5-10 heteroaryl, 3-10 cycloalkyl C1-4 alkylene, or 3-10 heterocycloalkyl C1-4 alkylene.
  • Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Rb3 groups, namely: C1-3 alkyl, 3-6 cycloalkyl, 4-6 heterocycloalkyl, 4-6 heterocycloalkenyl, 5-6 heteroaryl, 3-6 cycloalkyl C1-3 alkylene, or 4-6 heterocycloalkyl C1-3 alkylene.
  • Rb2 is independently selected from hydrogen, deuterium, or optionally substituted with one or more Rb3 groups, including: methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane, aziridine, oxacyclobutane, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, thiophenyl, thiazoalkyl, isothiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazine, morpholinyl, dihydropyrrolyl, dihydropyrazolyl, dihydrofuranyl, dihydroimidazoyl, and dihydrothiophenyl.
  • Rb3 groups including: methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane, aziridine, oxacyclobutane,
  • Rb2 is independently selected from hydrogen or optionally substituted with one or more Rb3 groups, namely: methyl, ethyl, n-propyl, isopropyl, cyclopropane, cyclobutane, oxetane, pyrrolyl, pyrazinyl, cyclobutanemethylene, or oxetanemethylene.
  • Rb2 is independently selected from methyl groups.
  • each Rb3 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, diC1-3 alkylamino, C1-3 alkylcarbonyl, haloC1-3 alkyl, haloC1-3 alkoxy, haloC1-3 alkylthio, haloC1-3 alkylamino, or halodiC1-3 alkylamino.
  • each Rb3 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, diC1-3 alkylamino, C1-3 alkylcarbonyl, haloC1-3 alkyl, haloC1-3 alkoxy, haloC1-3 alkylthio, haloC1-3 alkylamino, or halodiC1-3 alkylamino .
  • each Rb3 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, methylcarbonyl, halomethyl, or halomethoxy.
  • each Rb3 is independently selected from oxo, deuterium, -F, -Cl, -OH, methyl, methoxy, methyl carbonyl, or -CF3 .
  • each RB is independently selected from -F, -Cl, -NH2 , -OH, -OCH3 , -OCF3 , -CN,
  • ring B is selected from...
  • each R2 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino; or, two R2s located on the same ring atom together with the ring atom form a group optionally substituted with one or more R2a, which is a 3-10 membered cycloalkyl or a 3-10 membered heterocycloalkyl.
  • each R2 is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C1-3 alkylamino, diC1-3 alkylamino, haloC1-3 alkyl, haloC1-3 alkoxy, haloC1-3 alkylthio, haloC1-3 alkylamino, or halodiC1-3 alkylamino; or, two R2s located on the same ring atom together with the ring atom form a group optionally substituted by one or more R2a, which is a 3-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl.
  • each R2 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy; or, two R2s located on the same ring atom together with the ring atom form a group optionally substituted with one or more R2a, namely: cyclopropane, cyclobutane, aziridine, pyrrolidinyl, thiazolyl, isothiazolyl, piperidinyl, piperazine, or morpholinyl.
  • each R2 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, methoxy, methylamino, dimethylamino, -CF3 , or -OCF3 ; or, two R2s located on the same ring atom together with the ring atom form a cyclopropane that is optionally substituted with one or more R2a .
  • each R2 is independently selected from -F; or, two R2s located on the same ring atom together with the ring atom form a cyclopropane group.
  • each R 2a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, diC 1-3 alkyl , haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylthio, haloC 1-3 alkylamino, or halodiC 1-3 alkylamino.
  • each R 2a is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino , diC 1-3 alkylamino, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylthio, haloC 1-3 alkylamino, or halodiC 1-3 alkylamino.
  • each R 2a is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, halomethyl, or halomethoxy.
  • each R 2a is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, methoxy, methylamino, dimethylamino, -CF 3 , or -OCF 3 .
  • n is selected from 0, 1, 2, or 3.
  • n is selected from 0, 1, or 2.
  • m is selected from 0, 1, 2, 3, or 4.
  • n is selected from 0, 1, 2, or 3.
  • m is selected from 0, 1, or 2.
  • p is selected from 0, 1, 2, or 3.
  • p is selected from 0, 1, or 2.
  • this application relates to compounds of formula (I-1), formula (II), formula (III), formula (II-1), formula (II-1-a'), formula (II-1-a”), formula (II-2), formula (II-2-a'), and formula (II-2-a”), their stereoisomers, or pharmaceutically acceptable salts thereof.
  • the C1-6 alkyl group is selected from C1-4 alkyl, C1-3 alkyl, or C1-2 alkyl.
  • the C1-6 alkylene is selected from C1-4 alkylene, C1-3 alkylene, or C1-2 alkylene.
  • the halogen is selected from -F, -Cl, -Br, or -I.
  • the halogenation is selected from fluorination, chlorination, or bromination. In some embodiments, the halogenation is selected from fluorination or chlorination. In some embodiments, the halogenation is selected from fluorination.
  • the one or more is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the one or more is selected from 1, 2, 3, 4, or 5. In some embodiments, the one or more is selected from 1, 2, 3, or 4. In some embodiments, the one or more is selected from 1, 2, or 3.
  • the 3-12 yuan is selected from 3 yuan, 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan, or 12 yuan, or a range thereof.
  • the 5-10 yuan is selected from 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, or 10 yuan, or a range thereof.
  • the 6-10 yuan is selected from 6 yuan, 7 yuan, 8 yuan, 9 yuan, or 10 yuan, or a range thereof.
  • the 6-10 yuan is selected from 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, or 6-7 yuan.
  • the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic or heteroaryl group contains one, two or three heteroatoms selected from N, O or S.
  • heterocyclic alkyl, heterocyclic alkenyl, heterocyclic or heteroaryl groups contain one, two or three nitrogen atoms.
  • the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic or heteroaryl groups contain one N atom and one O atom.
  • the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic or heteroaryl groups contain one N atom and one S atom.
  • the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic group, or heteroaryl group contains one oxygen atom. In some embodiments, the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic group, or heteroaryl group contains one sulfur atom. In some embodiments, the heterocyclic alkyl, heterocyclic alkenyl, heterocyclic group, or heteroaryl group contains one nitrogen atom.
  • the heterocyclic group, heterocyclic alkenyl group, or heterocyclic alkyl group includes a monocyclic, spirocyclic, fused, or bridged ring.
  • this application provides pharmaceutical compositions comprising the above-described compounds of this application, their stereoisomers, or pharmaceutically acceptable salts thereof.
  • the pharmaceutical compositions of this application further include pharmaceutically acceptable excipients.
  • this application provides a method for treating mammalian diseases, comprising administering to a mammal, preferably a human, a therapeutically effective amount of the above-described compound of this application, its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of this application.
  • this application provides the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for treating diseases.
  • this application provides the use of the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the treatment of diseases.
  • this application provides the above-mentioned compounds of this application, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of this application for the treatment of diseases.
  • the disease is selected from WFS1-related diseases.
  • the disease or WFS1-related disease is selected from solid tumors.
  • the disease or WFS1-related disease is selected from multiple myeloma and lung cancer (e.g., non-small cell lung cancer).
  • substituted refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable.
  • the terms “optional” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of said event or condition.
  • the ethyl group being “optionally” substituted with a halogen means that the ethyl group may be unsubstituted ( CH2CH3 ), monosubstituted (e.g. , CH2CH2F ), polysubstituted (e.g., CHFCH2F , CH2CHF2 , etc.), or fully substituted ( CF2CF3 ) .
  • CH2CH3 unsubstituted
  • monosubstituted e.g., CH2CH2F
  • polysubstituted e.g., CHFCH2F , CH2CHF2 , etc.
  • CF2CF3 fully substituted
  • substituted as used herein includes, but is not limited to, the terms "alkyl,”"alkoxy,””alkathioyl,””cycloalkoxy,”"heteroalkyl,””alkenyl,”"alkynyl,””cycloalkenyl,”"cycloalkyl,””cycloalkynyl,””heterocycloalkyl,””heterocycloalkenyl,”"heterocycloalkyl,””aryl,””heteroaryl,””alkylene,” etc., and their corresponding non-limiting or exemplary groups.
  • C ⁇ sub>mn ⁇ /sub> means that the part has an integer number of carbon atoms within a given range.
  • C ⁇ sub>1-6 ⁇ /sub> means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms.
  • any variable e.g., R
  • its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it indicates that the linking group is a covalent bond.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • alkylene refers to a saturated straight-chain or branched divalent hydrocarbon group of the general formula CnH2n , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • C1-6 alkylene refers to an alkylene containing 1 to 6 carbon atoms.
  • C0-6 alkylene refers to a single bond or a C1-6 alkylene.
  • Non-limiting examples of alkylene include, but are not limited to, methylene ( -CH2- ) , ethylene ( -CH2CH2- ), propylene ( -CH2CH2CH2- or -CH2CH ( CH3 )-), butylene ( -CH2CH2CH2CH2- , -CH2CH( CH3 ) CH2- or -CH2CH2CH ( CH3 )- ) , etc.
  • the alkylene group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocycl
  • alkyl refers to a hydrocarbon group with the general formula C ⁇ sub>n ⁇ /sub>H ⁇ sub>2n+1 ⁇ /sub>, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • the alkyl group can be straight-chain or branched.
  • C ⁇ sub>1-6 ⁇ /sub>alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • 1 to 6 carbon atoms e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.
  • the alkyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • the alkyl portion i.e., alkyl group
  • alkyl portion i.e., alkyl group of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.
  • alkoxy refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • the alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • alkylamino refers to -NH-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • the alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • dialkylamino refers to -N(alkyl) 2 , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • the alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • alkylsulfonyl refers to -SO2 -alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • the alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • alkylthio refers to -S-alkyl, which typically has 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • the alkyl moiety is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.
  • the alkenyl group may optionally be substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkoxy, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkoxy, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, hetero
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C- CH3 ), 2-propynyl (-CH2 - C ⁇ CH), 1,3-butyrynyl (-C ⁇ CC ⁇ CH), etc.
  • the alkynyl group may optionally be substituted by one or more substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • substituents selected from: oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyloxy
  • cycloalkyl refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, or 5- to 6-membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.
  • the cycloalkyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O ) 2NH2 , -S(O ) 2NH -alkyl, -S(O) 2NH -alkyl, -S(O
  • cycloalkenyl refers to an incompletely saturated non-aromatic carbon ring having at least one double bond and which may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, or 5- to 6-membered ring.
  • Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl.
  • the cycloalkenyl group is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O ) -alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2NH -alkyl, -S(O)
  • heterocyclic alkyl refers to a fully saturated cyclic group that may exist as a monocyclic, bridged, or spirocyclic ring.
  • the heterocycle is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and/or boron (preferably 1 or 2 heteroatoms).
  • 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene;
  • non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutylcycloyl;
  • examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl;
  • examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaox
  • the heterocyclic alkyl group is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 ⁇ , -C(O)NH2-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S ( O) 2 -alkyl, -S(O) 2NH2 , -S(O ) 2NH2-alkyl, -S(O) 2NH2-alkyl, -S(O) 2
  • heterocyclic group refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated) and can exist as a monocyclic, bridged, fused, or spirocyclic ring.
  • heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazine, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophene, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, etc.
  • the heterocyclic group is selected from monocyclic or fused-ring groups.
  • the heterocyclic group is fused-ring, such as benzo5-6-membered heterocyclic groups, 5-6-membered heteroaryl- C5-6 cycloalkyl groups, 5-6-membered heteroaryl-5-6-membered heterocyclic groups, etc., specifically as follows:
  • the ring connected to the parent structure by the heterocyclic group can be either an aromatic ring or a non-aromatic ring.
  • the heterocyclic group is optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O ) -alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2NH2 , -S(O) 2NH -
  • aryl refers to an aromatic cyclic group consisting of an all-carbon monocyclic or fused polycyclic ring with a conjugated ⁇ -electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene.
  • the aryl group is optionally substituted by one or more substituents selected from the following: hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl, -S(O)2NH2 , -S(O) 2NH -alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S
  • the heteroaryl can be a monocyclic, fused bicyclic, or fused tricyclic system, wherein each ring is aromatic.
  • the heteroaryl typically has 5 to 14 ring atoms, 5 to 12 ring atoms, 5 to 10 ring atoms, 5 to 8 ring atoms, 5 to 7 ring atoms, or 5 to 6 membered ring atoms.
  • Preferred heteroaryls are selected from a single 4 to 8-membered ring, especially a 5 to 6-membered ring, or multiple fused rings containing 5 to 14, especially 5 to 10, ring atoms.
  • the heteroaryl can be attached to the rest of the molecule via heteroatoms or carbon atoms.
  • Non-limiting examples of the heteroaryl group include, but are not limited to, pyrrole rings (including N-pyrrole, 2-pyrrole, and 3-pyrrole rings, etc.), pyrazole rings (including 2-pyrrole and 3-pyrrole rings, etc.), imidazole rings (including N-imidazolium, 2-imidazolium, 4-imidazolium, and 5-imidazolium rings, etc.), oxazole rings (including 2-oxazole, 4-oxazole, and 5-oxazole rings, etc.), triazole rings (1H-1,2,3-triazole rings, 2H-1,2,3-triazole rings, 1H-1,2,4-triazole rings, and 4H-1,2,4-triazole rings, etc.), tetrazolium rings, isoxazole rings (3-isooxazole rings, 4-isooxazole rings, and 5-isooxazole rings, etc.), and thiazole rings (including 2-thiazole rings
  • the rings include azole rings and 5-thiazole rings, furan rings (including 2-furan rings and 3-furan rings), thiophene rings (including 2-thiophene rings and 3-thiophene rings), pyridine rings (including 2-pyridine rings, 3-pyridine rings and 4-pyridine rings), pyrazine rings, pyrimidine rings (including 2-pyrimidine rings and 4-pyrimidine rings), benzothiazole rings (including 5-benzothiazole rings), purine rings, benzimidazole rings (including 2-benzimidazole rings), benzoxazole rings, indole rings (including 5-indole rings), isoquinoline rings (including 1-isoquinoline rings and 5-isoquinoline rings), quinoxaline rings (including 2-quinoxaline rings and 5-quinoxaline rings), and quinoline rings (including 3-quinoline rings and 6-quinoline rings).
  • the heteroaryl group is optionally substituted by one or more substituents selected from: hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O )2NH2 , -S(O) 2NH -alkyl, -S(O) 2NH -alkyl, -S(O) 2NH , -S(O
  • treatment means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:
  • prevention means administering the compounds or preparations described in this disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.
  • therapeutic effective amount means the amount of the compound of this application used to treat (i) the specific disease, condition, or disorder described herein, (ii) reduce, improve, or eliminate one or more symptoms of the specific disease, condition, or disorder described herein, or (iii) prevent or delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein.
  • the amount of the compound of this application constituting a “therapeutic effective amount” varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.
  • pharmaceutical acceptable refers to compounds, materials, compositions, and/or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit/risk ratio.
  • salts formed with organic bases salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.
  • composition refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.
  • pharmaceutically acceptable excipient refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • tautomer or tautomer form
  • proton tautomers also known as proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerization
  • a specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions via the recombination of some bonding electrons.
  • This application also includes compounds of this application that are identical to those described herein, but with one or more atoms labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature.
  • isotopes that can be incorporated into compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H , 3H , 11C , 13C , 14C , 13N, 15N , 15O , 17O , 18O , 31P , 32P , 35S , 18F , 123I , 125I , and 36Cl , respectively.
  • isotopically labeled compounds of this application can be used in the analysis of compound and/or substrate tissue distribution.
  • Tritium (i.e., 3H ) and carbon-14 (i.e., 14C ) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emission isotopes, such as 15O , 13N , 11C , and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of this application can generally be prepared by replacing unlabeled reagents with isotopically labeled reagents using a procedure similar to those disclosed in the schemes and/or examples below.
  • substitution with a heavier isotope can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen atom being replaced by at least one deuterium atom.
  • exemplary deuterated compounds are shown below, but are not limited thereto.
  • the compounds of this invention can exist in specific geometric or stereoisomeric forms.
  • This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.
  • wedge-shaped solid line keys and wedge-shaped dashed key
  • the absolute configuration of the center of a solid is represented by a straight solid line key.
  • straight dashed key Represents the relative configuration of the center of a solid.
  • the compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents.
  • stereoisomers include, but are not limited to:
  • the compounds disclosed herein may have one or more blocked isomers, unless otherwise stated, which are photoactive isomers resulting from the restriction of free rotation between single bonds.
  • the chiral axis compounds of this disclosure can be isolated in racemic form. When the energy barrier for free rotation of the single bonds in the chiral axis compounds of this disclosure is sufficiently high, their blocked isomers can be isolated in photoactive pure form.
  • compositions disclosed herein can be prepared by combining the compounds disclosed herein with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.
  • Typical routes of administration of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
  • compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, gels, pastes, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation.
  • suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.
  • the daily dose is from 0.01 to 200 mg/kg body weight.
  • the compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.
  • the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis by referring to the following route, wherein X1 , X2 , X3, X4 , X5 , X6 , R1 , R2 , n, m , ring A, and ring B are defined as described in this application; LG1 and LG2 are each independently selected from suitable leaving groups, which may be selected from halogens (e.g., -Cl).
  • the compounds of this application can be prepared by those skilled in the art of organic synthesis with reference to the routes or methods of the following embodiments.
  • the resulting compounds can be characterized by known instruments or methods, including but not limited to mass spectrometry, nuclear magnetic resonance, etc.
  • Step b
  • Copper(II) trifluoromethanesulfonate 14.15 g was dispersed in dichloromethane (500 mL) and hexafluoroisopropanol (130 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (4.2 g) was slowly added dropwise, and the reaction was allowed to proceed for 1 h at room temperature. Compound 1a was dispersed in dichloromethane (60 mL) and slowly added to the above reaction system, and the reaction was allowed to proceed overnight at room temperature.
  • reaction solution was poured into a saturated sodium bicarbonate solution (300 mL) and 10% ammonia solution (200 mL), stirred for 30 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), and the organic phases were combined.
  • the organic phases were washed successively with a saturated sodium bicarbonate solution (200 mL) and a saturated sodium chloride solution (200 mL), collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure.
  • Compound 1 was prepared by SFC (YMC AD-H 10 ⁇ m 30*250 column; 0.2% diethylamine methanol-CO2 (50%-50%/0-15min isocratic elution)) to obtain compound 1-A (Rt 2.7min) and compound 1-B (Rt 5.2min).
  • Compound 1-A has a shorter retention time in a chiral column than 1-B, while compound 1-B has a longer retention time in a chiral column than 1-A.
  • Compound 2-A has a shorter retention time in chiral columns than 2-B, while compound 2-B has a longer retention time in chiral columns than 2-A.
  • Copper(II) trifluoromethanesulfonate (1.5 g) was dispersed in dichloromethane (20 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.46 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 46a was dispersed in dichloromethane (60 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into a saturated sodium bicarbonate solution (100 mL) and 10% ammonia solution (50 mL), stirred for 30 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL), collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure.
  • Copper(II) trifluoromethanesulfonate (0.78 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (10 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.23 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 47a was dispersed in dichloromethane (15 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • LC-MS: m/z 306.12(M+H) + .
  • Copper(II) trifluoromethanesulfonate (4.4 g) was dispersed in dichloromethane (90 mL) and hexafluoroisopropanol (30 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (1.3 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 48a was dispersed in dichloromethane (30 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • compound 50 was prepared by replacing 2-chloro-4,6-difluorobenzaldehyde with 2-chloro-3,4-difluorobenzaldehyde.
  • LC-MS: m/z 452.13 (M+H) + .
  • compound 54 was prepared by replacing 6-bromo-2,4-dichlorothieno[3,2-D]pyrimidine with 7-bromo-2,4-dichlorothieno[3,2-D]pyrimidine.
  • LC-MS: m/z 440.19 (M+H) + .
  • compound 56 was prepared by replacing 2,4,6-trichloro-pyridano[3,2-D]pyrimidine with 2,4,7-trichloro-pyridano[3,2-D]pyrimidine.
  • LC-MS: m/z 435.23 (M+H) + .
  • Copper(II) trifluoromethanesulfonate (25.0 g) was dispersed in dichloromethane (600 mL) and hexafluoroisopropanol (260 mL) under nitrogen protection and stirred at room temperature.
  • 2,6-Dimethylpyridine (7.4 g) was slowly added dropwise, and the reaction was allowed to proceed for 1 h at room temperature.
  • Compound 57a was dispersed in dichloromethane (400 mL) and slowly added to the above reaction system, and the reaction was allowed to proceed overnight at room temperature.
  • Compound 60-R was separated into compound 60-R-A (Rt 12.09 min) and compound 60-R-B (Rt 17.03 min) by preparative liquid chromatography (YMC SA 10 ⁇ m 20*250 column; 0.1% diethylamine ethanol-n-hexane (5%-50%/0-40 min) gradient elution).
  • Compound 60-R-A has a shorter retention time in chiral columns than 60-R-B, while compound 60-R-B has a longer retention time in chiral columns than 60-R-A.
  • Compound 60-S was separated into compound 60-S-A (Rt 12.45 min) and compound 60-S-B (Rt 15.30 min) by preparative liquid chromatography (YMC SA 10 ⁇ m 20*250 column; 0.1% diethylamine ethanol-n-hexane (5%-50%/0-40 min) gradient elution).
  • Compound 60-S-A has a shorter retention time in chiral columns than 60-S-B, while compound 60-S-B has a longer retention time in chiral columns than 60-S-A.
  • Compound 61 was separated by preparative liquid chromatography (YMC Amylose-SA, 30*150mm, 10 ⁇ m, mobile phase: A: n-hexane, B: 0.2% diethylamine ethanol; gradient: 5%-65% B/0-60min; gradient elution) to obtain compound 61-A (Rt 20min) and compound 61-B (Rt 23min).
  • Compound 61-A has a shorter retention time in chiral columns than 61-B, while compound 61-B has a longer retention time in chiral columns than 61-A.
  • reaction solution was filtered, the filtrate was collected and concentrated under reduced pressure, and compound 84 was obtained by preparative liquid chromatography (YMC TA C18, specification 30*250 mm, 10 ⁇ m, mobile phase: A: 0.1% ammonia, B: acetonitrile; gradient: 10%-50% B 0-60 min gradient elution).
  • Compound 85-R was separated into compound 85-R-A (Rt 13.28 min) and compound 85-R-B (Rt 19.34 min) by preparative liquid chromatography (YMC SA 10 ⁇ m 30*250 column; 0.1% diethylamine ethanol-n-hexane (10%-70%/0-45 min) gradient elution).
  • Compound 85-R-A has a shorter retention time in chiral columns than 85-R-B, while compound 85-R-B has a longer retention time in chiral columns than 85-R-A.
  • Compound 85-S-A has a shorter retention time in chiral columns than 85-S-B, while compound 85-S-B has a longer retention time in chiral columns than 85-S-A.
  • Compound 103 was separated by preparative liquid chromatography (YMC Amylose-C Neo(AD) coated type, size 20*200mm, 10 ⁇ m, mobile phase: A: n-hexane, B: 0.2% diethylamine-ethanol; gradient: 20%-70% B 0-30min; gradient elution) to obtain compound 103-A (Rt 17min) and compound 103-B (Rt 19min).
  • Compound 103-A has a shorter retention time in chiral columns than 103-B, while compound 103-B has a longer retention time in chiral columns than 103-A.
  • Compound 104 was separated by preparative liquid chromatography (YMC-SJ, specification 20*250, 10 ⁇ m; mobile phase: 0.2% diethylamine ethanol-n-hexane (10%-80%/0-70min gradient elution)) to obtain compound 104-A (Rt 39min) and compound 104-B (Rt 44min).
  • Compound 104-A has a shorter retention time in chiral columns than 104-B, while compound 104-B has a longer retention time in chiral columns than 104-A.
  • Compound 105-R was separated by preparative liquid chromatography (CHIRALPAK IG 5 ⁇ m 20*250 column; 0.1% diethylamine ethanol-n-hexane (10%-70%/0-45min gradient elution)) to obtain compound 105-R-A (Rt 31.41min) and compound 105-R-B (Rt 34.16min).
  • Compound 105-R-A has a shorter retention time in chiral columns than 105-R-B, while compound 105-R-B has a longer retention time in chiral columns than 105-R-A.
  • Compound 105-S was separated into compound 105-S-A (Rt 25.05 min) and compound 105-S-B (Rt 31.29 min) by preparative liquid chromatography (CHIRALPAK IG, 5 ⁇ m, 20*250 column; 0.1% diethylamine ethanol-n-hexane (15%-70%/0-45 min gradient elution)).
  • CHIRALPAK IG 5 ⁇ m, 20*250 column; 0.1% diethylamine ethanol-n-hexane (15%-70%/0-45 min gradient elution
  • Compound 105-S-A has a shorter retention time in chiral columns than 105-S-B, while compound 105-S-B has a longer retention time in chiral columns than 105-S-A.
  • Compound 110 was separated by preparative liquid chromatography (SA, size 30*150mm, 10 ⁇ m, mobile phase: A: n-hexane, B: ethanol; gradient: 10%-70% B0-60min, gradient elution) to obtain compound 110-A (Rt 32min) and compound 110-B (Rt 36min).
  • SA preparative liquid chromatography
  • Compound 110-A has a shorter retention time in chiral columns than 110-B, while compound 110-B has a longer retention time in chiral columns than 110-A.
  • Compound 111 was separated by preparative liquid chromatography (SA, size 30*150mm, 10 ⁇ m, mobile phase: A: n-hexane, B: ethanol; gradient: 10%-70% B0-60min, gradient elution) to obtain compound 111-A (Rt 17min) and compound 111-B (Rt 23min).
  • SA preparative liquid chromatography
  • Compound 111-A has a shorter retention time in chiral columns than 111-B, while compound 111-B has a longer retention time in chiral columns than 111-A.
  • Copper(II) trifluoromethanesulfonate (2.2 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.64 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 112a was dispersed in dichloromethane (25 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • LC-MS: m/z 237.11(M+H) + .
  • Copper(II) trifluoromethanesulfonate (2.5 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.75 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 114a was dispersed in dichloromethane (25 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • LC-MS: m/z 242.10(M+H) + .
  • Copper(II) trifluoromethanesulfonate (2.5 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.75 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 115a was dispersed in dichloromethane (25 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • LC-MS: m/z 286.13(M+H) + .
  • Copper(II) trifluoromethanesulfonate (2.2 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (20 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.64 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 116a was dispersed in dichloromethane (25 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • LC-MS: m/z 229.95(M+H) + .
  • step 1 4-bromo-1-naphthoaldehyde was replaced with 4-methanesulfonylnaphthoaldehyde to prepare compound 118a.
  • compound 120 was prepared by replacing compound 119a with 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,5-dihydro-1H-pyrrole.
  • LC-MS: m/z 442.03 (M+H) + .
  • compound 121a was prepared by replacing compound 119a with 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine.
  • LC-MS: m/z 542.07 (M+H) + .
  • Copper(II) trifluoromethanesulfonate (2.1 g) was dispersed in hexafluoroisopropanol (14 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.67 g) was slowly added dropwise, and the reaction was carried out at room temperature for 0.5 h.
  • Compound 122a was dispersed in dichloromethane (56 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into 10% ammonia water (28 mL) and saturated sodium bicarbonate solution (14 mL), stirred for 15 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Compound 122 was separated by preparative liquid chromatography (Daicel IG 5 ⁇ m 10*250 column; 0.1% diethylamine ethanol-n-hexane (15%-60%/0-45min gradient elution)) to obtain compound 122-A (Rt 24.23min) and compound 122-B (Rt 27.58min).
  • Compound 122-A has a shorter retention time in chiral columns than 122-B, while compound 122-B has a longer retention time in chiral columns than 122-A.
  • Compound 123 was separated by preparative liquid chromatography (YMC TA C18 10 ⁇ m 30*250 column; acetonitrile-0.1% ammonia-water (30%-70%/0-60min gradient elution)) to obtain compound 123-A (Rt 23.2min) and compound 123-B (Rt 30.3min).
  • Compound 123-A has a shorter retention time in chiral columns than 123-B, while compound 123-B has a longer retention time in chiral columns than 123-A.
  • Copper(II) trifluoromethanesulfonate (1.8 g) was dispersed in hexafluoroisopropanol (10 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.57 g) was slowly added dropwise, and the reaction was carried out at room temperature for 0.5 h. Compound 125a was dispersed in dichloromethane (40 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into 10% ammonia water (20 mL) and saturated sodium bicarbonate solution (10 mL), stirred for 15 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Copper(II) trifluoromethanesulfonate (1.54 g) was dispersed in dichloromethane (30 mL) and hexafluoroisopropanol (19 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (0.46 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. Compound 130a was dispersed in dichloromethane (46 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into 10% ammonia water (50 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (50 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • LC-MS: m/z 304.09(M+H) + .
  • LC-MS: m/z 252.09 (M+H) + .
  • Copper(II) trifluoromethanesulfonate (6.1 g) was dispersed in dichloromethane (300 mL) and hexafluoroisopropanol (85 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (1.8 g) was slowly added dropwise, and the reaction was allowed to proceed overnight at room temperature.
  • Compound 137a was dispersed in dichloromethane (40 mL) and slowly added to the above reaction system, and the reaction was allowed to proceed overnight at room temperature.
  • reaction solution was poured into 10% ammonia water (150 mL), stirred for 30 min, allowed to stand for phase separation, extracted with dichloromethane (150 mL * 3), the organic phases were combined, washed with saturated sodium chloride solution (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • LC-MS: m/z 334.16 (M + H) + .
  • Compound 139 was separated by preparative liquid chromatography (YMC-Amylose-SA, 10 ⁇ m, 30*250 column; hexane-0.2% diethylamine in ethanol solution (10%-90%/0-40 min gradient elution)) to obtain compound 139-A (Rt 17 min) and compound 139-B (Rt 25 min).
  • Compound 139-A has a shorter retention time in chiral columns than 139-B, while compound 139-B has a longer retention time in chiral columns than 139-A.
  • Copper(II) trifluoromethanesulfonate (5.0 g) was dispersed in dichloromethane (25 mL) and hexafluoroisopropanol (60 mL) under nitrogen protection and stirred at room temperature. 2,6-Dimethylpyridine (1.5 g) was slowly added dropwise, and the reaction was allowed to proceed for 0.5 h at room temperature.
  • Compound 142a was dispersed in dichloromethane (90 mL) and slowly added to the above reaction system. The reaction was allowed to proceed overnight at room temperature.
  • LC-MS: m/z 290.83 (M + H) + .
  • Compound 142 was subjected to preparative liquid chromatography (Daicel IC, 10 ⁇ m, 30*250 column; hexane-0.2% diethylamine in ethanol solution (20%-80%/0-40 min gradient elution)) to obtain compound 142-A (Rt 18 min) and compound 142-B (Rt 25 min).
  • Compound 142-A has a shorter retention time in chiral columns than 142-B, while compound 142-B has a longer retention time in chiral columns than 142-A.
  • Copper(II) trifluoromethanesulfonate (2.57 g) was dispersed in dichloromethane (150 mL) and hexafluoroisopropanol (39 mL) under nitrogen protection and stirred at room temperature.
  • 2,6-Dimethylpyridine (0.76 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h.
  • Compound 143a was dispersed in dichloromethane (60 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into a saturated sodium bicarbonate solution (300 mL) and 10% ammonia solution (200 mL), stirred for 30 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL), collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure.
  • Copper(II) trifluoromethanesulfonate (4.91 g) was dispersed in dichloromethane (150 mL) and hexafluoroisopropanol (39 mL) under nitrogen protection and stirred at room temperature.
  • 2,6-Dimethylpyridine (1.45 g) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h.
  • Compound 145a was dispersed in dichloromethane (60 mL) and slowly added to the above reaction system, and the reaction was carried out overnight at room temperature.
  • reaction solution was poured into a saturated sodium bicarbonate solution (300 mL) and 10% ammonia solution (200 mL), stirred for 30 min, allowed to stand for separation, extracted with dichloromethane (50 mL * 3), and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL), collected, dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was concentrated under reduced pressure.
  • Compound 145 was subjected to preparative liquid chromatography (Daicel ID 10 ⁇ m 20*250 column; 0.1% diethylamine ethanol-n-hexane (20%-80%/0-40min gradient elution)) to obtain compound 145-A (Rt 15.0min) and compound 145-B (Rt 22.5min).
  • Compound 145-A has a shorter retention time in chiral columns than 145-B, while compound 145-B has a longer retention time in chiral columns than 145-A.
  • compound 149 was prepared by replacing compound 148a with 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester.
  • LC-MS: m/z 484.02 (M+H) + .
  • compound 153 was prepared by replacing compound 148a with 1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester.
  • LC-MS: m/z 442.21 (M+H) + .
  • Compound 153 was subjected to preparative liquid chromatography (YMC-Amylose-SA, 10 ⁇ m, 30*250 column; 0.2% diethylamine ethanol-n-hexane (20%-80%/0-60 min gradient elution)) to obtain compound 153-A (Rt 22 min) and compound 153-B (Rt 25 min).
  • Liver microsomal incubation samples (species: human and mouse) were prepared as follows: mixed PBS buffer (pH 7.4), liver microsomal solution (0.5 mg/mL), test compound, and NADPH + MgCl2 solution were incubated at 37°C and 300 rpm for 1 hour. Samples at 0 hours were prepared as follows: mixed PBS buffer (pH 7.4), liver microsomal solution (0.5 mg/mL), and test compound. After adding acetonitrile solution containing internal standard, protein precipitation was performed to prepare the supernatant, which was then diluted for LC/MS/MS analysis. The results are shown in Table 2.
  • Huh7 cells in good growth condition were collected into centrifuge tubes, and the cell density was adjusted to 2.5 ⁇ 105 cells/mL. The cells were then seeded into 6-well plates (2 mL/well) and cultured overnight in a cell culture incubator. The compound was manually diluted and added to a final concentration of 1 ⁇ M. A control was also set up. After further culturing for 2 h, 6 h, and 24 h, cells were collected, lysed, and proteins were extracted and quantified. Subsequent protein sample preparation and primary antibody preparation (XBP1s (manufacturer: Abcam); GAPDH (manufacturer: CST)) were performed according to the Protein Simple experimental instructions. The secondary antibody was directly used from the kit.
  • the sample plate was taken from the rabbit secondary antibody detection kit (manufacturer: Protein Simple) of the protein quantification analyzer, and the prepared sample and reagents were added sequentially to the plate.
  • the protein quantification analyzer was run according to the instrument's operating procedures, and the protein content was analyzed based on the grayscale scanning of the bands.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine de la chimie pharmaceutique, et concerne un composé bicyclique fusionné et son utilisation, et en particulier un composé bicyclique fusionné, un procédé de préparation du composé, une composition pharmaceutique contenant le composé, et une utilisation du composé dans le traitement de maladies. La structure du composé bicyclique fusionné est représentée par la formule (I).
PCT/CN2025/091151 2024-04-26 2025-04-25 Composé bicyclique fusionné et son utilisation Pending WO2025223536A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120095216A1 (en) * 2009-04-02 2012-04-19 Sanofi 3-[1,4]oxazepane-4-pyrimidone derivatives
CN112236428A (zh) * 2018-04-24 2021-01-15 默克专利股份有限公司 抗增殖化合物及其用途
CN115429796A (zh) * 2021-06-03 2022-12-06 同济大学 利鲁唑靶向治疗Wolfram综合征

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120095216A1 (en) * 2009-04-02 2012-04-19 Sanofi 3-[1,4]oxazepane-4-pyrimidone derivatives
CN112236428A (zh) * 2018-04-24 2021-01-15 默克专利股份有限公司 抗增殖化合物及其用途
CN115429796A (zh) * 2021-06-03 2022-12-06 同济大学 利鲁唑靶向治疗Wolfram综合征

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