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WO2022111605A1 - Aryl or heteroaryl substituted 5-membered aromatic heterocyclic compound and use thereof - Google Patents

Aryl or heteroaryl substituted 5-membered aromatic heterocyclic compound and use thereof Download PDF

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Publication number
WO2022111605A1
WO2022111605A1 PCT/CN2021/133316 CN2021133316W WO2022111605A1 WO 2022111605 A1 WO2022111605 A1 WO 2022111605A1 CN 2021133316 W CN2021133316 W CN 2021133316W WO 2022111605 A1 WO2022111605 A1 WO 2022111605A1
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compound
alkyl
alkoxy
deuterium
pharmaceutically acceptable
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PCT/CN2021/133316
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French (fr)
Chinese (zh)
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王中利
郝欣
刘桑
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瑞石生物医药有限公司
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Priority to CN202180062290.0A priority Critical patent/CN116194451B/en
Publication of WO2022111605A1 publication Critical patent/WO2022111605A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure belongs to the field of medicine, and relates to an aryl or heteroaryl substituted five-membered aromatic heterocyclic compound and use thereof.
  • Phosphodiesterases are a class of phosphodiesters that cleave on second messenger molecules 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) key intracellular enzymes.
  • the cyclic nucleotides cAMP and cGMP act as second messengers in various cellular pathways.
  • PDE4 is highly specific for cAMP and has 4 isoforms: PDE4A, PDE4B, PDE4C and PDE4D.
  • PDE4 is involved in the promotion of monocyte and macrophage activation, neutrophil infiltration, proliferation of vascular smooth muscle, vasodilation and myocardial contraction and other related physiological and pathological processes. cell adhesion, etc. PDE4 plays a major regulatory role in the expression of pro- and anti-inflammatory mediators, and PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells.
  • PDE4 inhibitors have been discovered in recent years. For example, roflumilast is approved for severe chronic obstructive pulmonary disease (COPD) to reduce the number of flare-ups or prevent COPD symptoms from getting worse, and apremilast is approved to treat adults with active psoriatic arthritis.
  • COPD chronic chronic obstructive pulmonary disease
  • PDE4 inhibitors show good pharmacological activity, these PDE inhibitors suffer from side effects such as induced gastrointestinal symptoms such as vomiting and diarrhea, and there is still a need to develop selective PDE4 inhibitors, especially selective PDE4 inhibitors with affinity for PDE4B and PDE4D agent.
  • the disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof
  • R 1 is selected from aryl or heteroaryl, and said aryl or heteroaryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, nitro, cyano, amino, alkyl, alkoxy , alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy, and/or the aryl or heteroaryl is substituted with cycloalkane or heterocycloalkyl fused, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused rings are optionally substituted with one or more R A1 ;
  • R A1 is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkane oxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl, or 5- to 6-membered heteroaryl optionally supported by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, substituted by
  • R 2 is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, said aryl or heteroaryl optionally being surrounded by one or more selected from deuterium, halogen, hydroxyl, alkyl, cycloalkyl, Heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O) 2 R', -NR' ( R"), -COR', -COOR' or -CONR'(R"), the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkane Oxy, heterocycloalkoxy or cycloalkenyloxy optionally substituted by one or more R A2 ;
  • R A2 is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, C 6- 10 -aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 ring Alkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, C 6-10 aryl, or 5- to 6-membered heteroaryl are optionally substituted by one or more selected from halogen, deuterium, substituted by hydroxyl,
  • Ring A is selected from a 5-membered heteroaromatic ring optionally substituted by one or more R A3 , and R1 and ring B are in meta position on ring A;
  • R A3 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy Cycloalkoxy is optionally substituted with one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino;
  • Ring B is selected from a 3- to 6-membered carbocyclic or heterocyclic ring, optionally substituted by one or more R A4 ;
  • R A4 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy Cycloalkoxy is optionally substituted with one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino;
  • R' or R" is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, said alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano or amino.
  • R 1 is selected from C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or Multiple selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy group, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy, or C 3-6 cycloalkenyloxy, and/or the aryl or heteroaryl is fused to a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocycloalkyl group, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or
  • R 1 is selected from C 6-10 aryl, and the aryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl or C 3-6 cycloalkenyloxy , and/or the aryl group is fused with a 3- to 10-membered cycloalkyl group, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring is any Select is replaced by one or more R A1 as previously defined.
  • R 1 is selected from C 6-10 aryl, and the aryl is optionally surrounded by one or more selected from C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, and/or the aryl group is fused with a 3- to 10-membered heterocycloalkyl, the alkoxy, cycloalkoxy or the fused ring is optionally substituted with one or more R A1 as previously defined.
  • R 1 is selected from C 6-10 aryl, optionally with one or more selected from deuterium, halogen, hydroxyl or amino.
  • R 6 , R 7 , R 8 , R 9 or R 10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 Alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy, or C 3 -6 substituted by cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl Optionally substituted by one or more R A1 , or R 6 , R 7 and adjacent carbon atoms form a 5- to 10-membered carbocyclic ring or a 5- to 10-membered heterocyclic ring, and the carbo
  • R 8 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, the alkane The radical or alkoxy is optionally substituted with 1 to 3 R A1 as previously defined.
  • R 8 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 , and R A1 is as previously defined.
  • R 8 is selected from C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3- 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, the alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkene Oxy , cycloalkyl, heterocycloalkoxy or heterocycloalkyl are optionally substituted with 1 to 3 R A1 , as previously defined.
  • R 6 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, the Alkyl or alkoxy is optionally substituted with 1 to 3 R A1 as previously defined. In some embodiments, R 6 is selected from hydrogen or deuterium. In some embodiments, R 6 is selected from hydrogen.
  • R 10 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, the Alkyl or alkoxy is optionally substituted with 1 to 3 R A1 as previously defined.
  • R 10 is selected from hydrogen or deuterium.
  • R 10 is selected from hydrogen.
  • R 7 is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, so The alkyl or alkoxy group is optionally substituted with 1 to 3 R A1 , as previously defined.
  • R 7 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 , and R A1 is as previously defined.
  • R 7 is selected from C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3- 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, the alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkene Oxy , cycloalkyl, heterocycloalkoxy or heterocycloalkyl are optionally substituted with 1 to 3 R A1 , as previously defined.
  • R 7 is selected from 3 to 6 heterocycloalkoxy, preferably a heteroatom containing at least one heteroatom selected from N, O or S. Cycloalkoxy, said heterocycloalkoxy optionally substituted with 1 to 3 R A1 , R A1 as previously defined.
  • heterocycloalkoxy includes, but is not limited to
  • R 6 , R 9 or R 10 is selected from hydrogen or deuterium.
  • R 8 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 ;
  • R 7 is selected from From C 1-6 alkoxy, the alkoxy is optionally substituted with 1 to 3 R A1 .
  • R 8 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 ;
  • R 7 is selected from From C 1-6 alkoxy, the alkoxy is optionally substituted with 1 to 3 R A1 ;
  • R 6 , R 9 and R 10 are selected from hydrogen or deuterium.
  • R 7 in the compound of formula II or a pharmaceutically acceptable salt thereof is selected from a heterocycloalkoxy group containing at least one heteroatom selected from N, O or S, the heterocycloalkoxy group group is optionally substituted by 1 to 3 R A1 , R A1 is as defined above; R 8 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 ; R 6 , R 9 or R 10 is selected from hydrogen or deuterium.
  • the compound represented by formula II or a pharmaceutically acceptable salt thereof is provided in which R 6 and R 7 and adjacent carbon atoms form a 5- to 10-membered heterocyclic ring, and the heterocyclic ring is optionally surrounded by 1 to 3 R A1 Instead, R A1 is as previously defined.
  • R 6 , R 7 and adjacent carbon atoms form a 5- to 10-membered heterocycle, and the heterocycle is optionally surrounded by 1 to 3 R A1 substituted, R A1 is as defined in claim 1;
  • R 8 is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally Replaced by 1 to 3 R A1s as previously defined.
  • R 6 , R 7 and adjacent carbon atoms form a 5- to 10-membered heterocycle, and the heterocycle is optionally surrounded by 1 to 3 R A1 replaced;
  • R 8 is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by 1 to 3 R A1 ;
  • R 9 or R 10 is selected from hydrogen
  • R A1 is as previously defined.
  • R 1 is selected from a 5- to 10-membered heteroaryl group, and the heteroaryl group is optionally surrounded by one or more selected from the group consisting of deuterium, halogen, hydroxyl , amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl , 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, and/or the aryl group is substituted with a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkyl group A membered heterocycloalkyl fused, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cyclo
  • R 1 is selected from a 5- to 10-membered heteroaryl group, and the heteroaryl group is optionally surrounded by one or more selected from the group consisting of deuterium, halogen, hydroxyl, Amino, C 1-6 alkyl or C 1-6 alkoxy optionally substituted with one or more R A1 as previously defined.
  • R 11 , R 12 , R 13 , R 14 or R 15 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy is optionally substituted with one or more R A1 as previously defined.
  • Y 1 in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is selected from -S(O) n -, -S(O) m N(R 3 )- or -N(R 4 ) S(O) m- , n and m are each independently selected from an integer from 0 to 2, and R 3 or R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl.
  • R 2 is selected from C 6-10 aryl or 5- to 9-membered heteroaryl, and the aryl or heteroaryl is optionally by one or more selected from deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkane oxy, 3 to 6 heterocycloalkoxy, C 3-8 cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R"), the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy optionally substituted by one or more R Instead of A2 , R', R" and R A
  • R 2 is selected from C 6-10 aryl, and the aryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C 3-8 cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R") substituted, the Alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy optionally substituted with 1 to 3 R A2 , R', R" and R A2 as previously defined.
  • R 2 is selected from C 6-10 aryl, and the aryl is optionally substituted by 1 to 3 atoms selected from deuterium, halogen, hydroxyl , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy, the alkyl, alkoxy or cycloalkoxy is optional Replaced by 1 to 3 R A2s as previously defined.
  • R 2 is selected from C 6-10 aryl, and the aryl is optionally substituted by C 1-6 alkoxy, so The alkoxy group is optionally substituted with 1 to 3 R A2 , as previously defined.
  • R 2 is selected from C 6-10 aryl, and the aryl is optionally 1 to 3 selected from -SR', - S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R"), R' and R" as previously defined.
  • R 2 is selected from C 6-10 aryl, and the aryl is optionally 1 to 3 selected from C 2-6 alkene oxy, C 2-6 alkynyloxy, 3 to 6 heterocycloalkoxy or C 3-8 cycloalkenyloxy optionally substituted by 1 to 8 Substituted with 3 R A2s, R A2 is as previously defined.
  • R 2 is selected from phenyl, and the phenyl is surrounded by 1 to 3 selected from deuterium, halogen, hydroxyl, C 1-6 alkane substituted with 1 to 3 R A2 groups or C 1-6 alkoxy groups optionally substituted with 1 to 3 R A2 as previously defined.
  • R 2 is selected from phenyl, and the phenyl is substituted with 1 to 3 selected from C 1-6 alkoxy, such as Methoxy, ethoxy or propoxy.
  • R 2 is selected from a 5- to 9-membered heteroaryl group, and the heteroaryl group is optionally surrounded by 1 to 3 atoms selected from deuterium, halogen , hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy, the alkyl, cycloalkyl, alkoxy or Cycloalkoxy is optionally substituted with 1 to 3 R A2 as previously defined.
  • R 2 is selected from
  • R 2 is optionally selected from 1 to 3 groups selected from deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy base substituted.
  • R 2 is selected from:
  • R 2 is selected from C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, said cycloalkyl or heterocycle Alkyl is optionally substituted with 1 to 3 selected from deuterium, halogen, hydroxy, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy or C3-6 cycloalkoxy , the alkyl, cycloalkyl, alkoxy or cycloalkoxy is optionally substituted with 1 to 3 R A2 , where R A2 is as previously defined.
  • ring A in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is selected from
  • Ring A ring is optionally substituted with one or more R A3 as previously defined.
  • ring A in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from Further, the Ring A ring is optionally substituted with one or more R A3 as previously defined.
  • ring A in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from
  • ring A in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from
  • Ring B is selected from a 3- to 6-membered carbocyclic ring, and said Ring B is optionally substituted with one or more R A4 .
  • ring B in the compound of formula I or formula II is selected from Further said Ring B is optionally substituted with one or more R A4 .
  • P integer between 0-3.
  • p 0, 1 or 2 in the compound of formula VA or a pharmaceutically acceptable salt thereof.
  • p 0 in the compound of formula VA or a pharmaceutically acceptable salt thereof.
  • ring B in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is selected from a 4- to 6-membered nitrogen atom-containing heterocycle or an oxygen atom-containing heterocycle, and the ring B is optionally Replaced by one or more R A4 .
  • ring B in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from
  • Ring B is optionally substituted with one or more R A4 .
  • R A1 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
  • R A1 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
  • R A1 is selected from phenyl or 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is optionally Substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
  • R A2 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
  • R A2 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
  • R A3 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
  • R A3 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
  • R A4 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
  • R A4 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
  • R' or R" in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6Alkyl or C1-6alkoxy is optionally substituted with one or more selected from halogen or deuterium.
  • R 2 is selected from a 5- to 6-membered heteroaromatic ring.
  • R 2 is selected from thiazolyl, imidazolyl, pyridyl, oxazolyl, pyrimidinyl or pyrazolyl, further said R 2 is optionally surrounded by one or more selected from deuterium, halogen, hydroxyl , amino, C 1-6 alkyl or C 1-6 alkoxy optionally substituted with one or more R A2 as previously defined.
  • R 2 is selected from thiazolyl optionally by one or more selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, The alkyl or alkoxy group is optionally substituted with one or more R A2 as previously defined.
  • R 2 is selected from imidazolyl, optionally with one or more selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, The alkyl or alkoxy group is optionally substituted with one or more R A2 as previously defined.
  • R 16 or R 17 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally replaced by one or A plurality of R A1s are substituted, and R A1s are as previously defined.
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each of R 16 or R 17 in the compound of formula IIIC or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium or C 1-6 alkoxy.
  • each of R 16 or R 17 in the compound of formula IIIC or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, halogen, amino, hydroxyl or C 1-6 alkoxy.
  • each of R 16 or R 17 in the compound of formula IIIC or a pharmaceutically acceptable salt thereof is independently selected from C 1-6 alkyl or C 1-6 alkoxy.
  • R 2 is selected from pyridyl or oxazolyl, and the pyridyl or oxazolyl is optionally composed of one or more one is selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more R A2 , R A2 as previously described definition.
  • R 18 or R 19 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy
  • R 20 is selected from hydrogen, deuterium or C 1-6 alkoxy base
  • the alkyl or alkoxy is optionally substituted by one or more R A6
  • R A6 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3- 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy
  • the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, or 3- to 6-membered heterocycloalkoxy optionally by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, substituted with amino.
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 18 or R 19 are each independently selected from hydrogen, halogen, amino, hydroxyl or C 1-6 alkoxy, and R 20 is selected from hydrogen, Deuterium or C 1-6 alkyl.
  • R 18 or R 19 are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, and R 20 is selected from hydrogen , deuterium or C 1-6 alkyl.
  • the present disclosure also provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the following reaction scheme,
  • a method of preparing a compound of formula IIIA, or a pharmaceutically acceptable salt thereof comprises the step of reacting a compound of formula ZA with a compound of formula ZB to form a compound of formula IIIA,
  • Another aspect of the present disclosure also provides a compound of formula ZB or a pharmaceutically acceptable salt thereof.
  • a compound of formula ZB or a pharmaceutically acceptable salt thereof is used in the synthesis or preparation of a compound of formula IIIA or a pharmaceutically acceptable salt thereof.
  • the compound of formula ZB or a pharmaceutically acceptable salt thereof is
  • the present disclosure also provides a pharmaceutical composition, comprising at least one therapeutically effective amount of the compound represented by Formula I or Formula II or a pharmaceutically acceptable salt thereof, or a compound prepared by the foregoing method or a pharmaceutically acceptable salt thereof, and Pharmaceutically acceptable excipients.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains from 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.
  • the present disclosure also provides a method of preventing and/or treating a patient suffering from a disorder associated with PDE, by administering to the patient a therapeutically effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, or
  • the compounds or their pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions are prepared by the aforementioned methods.
  • the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.
  • the present disclosure also provides a method of preventing and/or treating a patient suffering from asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism, comprising: Administering to the patient a therapeutically effective amount of the compound represented by the aforementioned formula I or II or a pharmaceutically acceptable salt thereof, or administering to the patient a therapeutically effective amount of the compound prepared by the aforementioned method or a pharmaceutically acceptable salt thereof, or A therapeutically effective amount of the aforementioned pharmaceutical composition is administered to the patient.
  • the present disclosure also provides the use of the compound represented by the aforementioned formula I or formula II or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disorder related to PDE.
  • the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.
  • the present disclosure also provides the compound represented by the aforementioned formula I or formula II or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition prepared for the prevention and/or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, Use in the medicament of allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism.
  • the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts.
  • Compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton transfer such as keto-enol and imine-enamine, lactam-lactam isomerizations .
  • An example of a lactam-lactam equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 1000 times greater than the natural abundance of deuterium (which is 0.015%)) % of deuterium incorporated).
  • Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium.
  • the present disclosure also includes compounds of formula (I) in various deuterated forms.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to relevant literature to synthesize the compound of formula (I) in deuterated form.
  • Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative that has been approved by the US Food and Drug Administration as acceptable for use in humans or livestock animals , dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • an “effective amount” or “therapeutically effective amount” as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxygen substituted, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C The 3-8 cycloalkenyloxy, aryl or 5 to
  • Alkenyl includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups.
  • C 2-6 alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxygen substituted, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to
  • Alkynyl includes branched and straight chain alkynyl groups having from 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups, or if a specified number of carbon atoms is specified, that specific number is intended. Examples are ethynyl, propynyl (eg 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxygen substituted, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C The 3-8 cycloalkenyloxy, aryl or
  • cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro Ring, fused and bridged cycloalkyl groups.
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, Oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy , C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5
  • the cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzo rings Heptyl, etc.
  • Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano , amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy , C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy , aryl, or 5- to 6-membered
  • cycloalkenyl refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl.
  • Cycloalkenyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy , C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy , aryl, or 5- to 6-member
  • Heterocycloalkyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which are optional Heteroatoms from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 7 ring atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piper pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocycloalkyl groups include spiro, fused and bridged ring heterocycloalkyl groups.
  • Non-limiting examples of "heterocycloalkyl" include:
  • heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
  • Heterocycloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano base, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy base, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy aryl, aryl or 5 to
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 12 membered, such as benzene base and naphthyl.
  • the aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl , alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R"), R' or R" is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or Heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally containing one or more selected from halogen, deuterium, hydroxy, o
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6- to 12-membered, more preferably 5- or 6-membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, and many more.
  • the heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, alkyl, cycloalkyl, hetero Cycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R "), -COR', -COOR' or -CONR'(R"),R' or R" is independently selected from hydrogen, deuterium, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, Aryl or heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally being selected from one or more of halogen, deuterium, hydroxy,
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy , C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alky
  • heterocycloalkoxy refers to -O-(heterocycloalkyl), wherein heterocycloalkyl is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
  • Figure 1 Ear swelling inhibition rate of each group in the model.
  • Figure 2 The increase in ear thickness for each group in the model.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC used Agilent1100 high pressure liquid chromatograph, GAS15B DAD UV detector, Water Vbridge C18 150*4.6mm 5um chromatographic column.
  • the MS was measured using an Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, Waters Xbridge C18 4.6*50mm, 5um chromatographic column, scanning in positive/negative ion mode, and the mass scanning range was 80-1200.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 silica gel plate
  • the thin-layer chromatography (TLC) uses the silica gel plate with a specification of 0.2mm ⁇ 0.03mm
  • the thin-layer chromatography separation and purification product adopts a specification of 0.4mm-0.5mm.
  • the flash column purification system used Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
  • Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed pre-packed ultra-pure normal phase silica gel column (40-63 ⁇ m, 60g, 24g, 40g, 120g or other specifications).
  • the known starting materials in the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Bidder Pharmaceuticals and other companies.
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Company.
  • the nitrogen atmosphere or hydrogenation atmosphere is usually evacuated, filled with nitrogen or hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying the compound, and the volume of the solvent
  • TLC thin layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • compound 1b (12.0g, 52.2mmol) was added to a 250-ml single-necked flask, and ethyl acetate (80ml) was added and stirred until dissolved, then sulfamic acid (5.68g, 58.5mmol) and water (10ml) were added. .
  • the reaction temperature was controlled below 20° C., 25% aqueous sodium chlorite solution (21.2 g, 58.5 mmol) was added dropwise, and the reaction was completed by TLC detection.
  • compound 1f 5.8 g, 17.0 mmol was added to a 100 mL one-neck flask, and methanol (20 mL) and 25% aqueous sodium hydroxide solution (50 mL) were added. The reaction liquid was heated to 100°C and stirring was continued for 3-8 hours. The reaction solution was then cooled to room temperature and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether) to give compound 1 g (2.55 g). LCMS: m/z 300.0 (M+H) + .
  • Compound 2 was prepared according to the method described in Example 1 .
  • Compound 3 was prepared according to the method described in Example 1 .
  • Compound 4 was prepared according to the method described in Example 1 .
  • Compound 5 was prepared according to the method described in Example 1 .
  • Compound 6 was prepared according to the method described in Example 1 .
  • Compound 7 was prepared according to the method described in Example 1 .
  • Compound 8 was prepared according to the method described in Example 1 .
  • Compound 9 was prepared according to the method described in Example 1 .
  • Compound 10 was prepared according to the method described in Example 1 .
  • Compound 11 was prepared according to the method described in Example 1 .
  • Compound 12 was prepared according to the method described in Example 1 .
  • Compound 13 was prepared according to the method described in Example 1 .
  • Compound 14 was prepared according to the method described in Example 1 .
  • Compound 15 was prepared according to the method described in Example 1 .
  • Compound 16 was prepared according to the method described in Example 1 .
  • Compound 17 was prepared according to the method described in Example 1 .
  • the reaction solution was cooled to room temperature, water (100 mL) was added to the reaction solution to dilute, extracted with ethyl acetate (150 mL ⁇ 3), the organic phase was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give the target compound 18d (14.1 g).
  • reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate.
  • the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give 18i (499 mg).
  • Compound 19 was prepared according to the method described in Example 18.
  • Compound 20 was prepared according to the method described in Example 18.
  • reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate.
  • the organic phase was concentrated and the residue was subjected to column chromatography (petroleum ether/ethyl acetate) to give 21a (483 mg).
  • Compound 22 was prepared according to the method described in Example 21.
  • Compound 23 was prepared according to the method described in Example 21.
  • Compound 24 was prepared according to the method described in Example 21.
  • Compound 25 was prepared according to the method described in Example 21.
  • Compound 26 was prepared according to the method described in Example 21.
  • Compound 27 was prepared according to the method described in Example 21.
  • Compound 28 was prepared according to the method described in Example 1 .
  • Compound A was prepared by the method disclosed in the patent application "Example 1 on page 25 of the specification in CN104603116A”.
  • compound stock solutions at a concentration of 10 mM in 90% DMSO (10% in water) were prepared in test tubes and used to prepare serial dilutions with a dilution gradient of 1:5, starting at 100uM final concentrations, low to 0.05nM.
  • 0.2 ul of compound solutions were transferred into 384-well reaction plates, and both negative and positive controls were transferred into 0.2 ul of 100% DMSO.
  • 10ul of 2x concentration PDE4B1 enzyme solution (final concentration 0.04nM) was added to the wells, and 10ul of 1x reaction buffer was used to replace the enzyme solution for control wells with no enzyme activity. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 15 min.
  • Compound 1 29 Compound 2 139 Compound 3 67 Compound 4 NA Compound 5 NA Compound 6 138 Compound 7 NA Compound 8 NA Compound 9 194 Compound 10 NA Compound 11 NA Compound 12 NA Compound 13 NA Compound 14 NA Compound 15 19.5 Compound 16 16.5 Compound 17 43 Compound 18 17 Compound 19 115.3 Compound 20 40 Compound 21 twenty one Compound 22 153 Compound 23 103 Compound 24 30 Compound 25 60.36 Compound 26 71 Compound 27 64 Compound 28 96 Compound A 31.78
  • Test Example 2 Inhibitory effect of compounds on the release of proinflammatory cytokines from peripheral blood mononuclear cells (PBMCs)
  • compound 21 was formulated into an ointment with the following components: 1% compound 21, 10% triacetin, 62.5% white petrolatum, 20% liquid paraffin, 3% paraffin, 3.5% white beeswax, mechanical Stir until ointment
  • CD-1 male mice were selected.
  • the ear thickness was measured at a fixed position in the left ear of the experimental mouse (MDC-1"SB, Mitutoyo Corporation), and 20 ⁇ L of (12-) phorbol myristate (-13) was applied to the left ear.
  • -) 2 hours before and 15 minutes after ear swelling caused by acetate (PMA, P1585, Sigma) acetone solution (2ug/ear), apply 10mg of the test substance or positive drug or blank preparation to the inner and outer sides of the left ear respectively, namely 20mg/ear.
  • the ear thickness was measured 6 hours after PMA was applied.
  • This experiment set up a normal control group, a model control group, low, medium and high dose groups and a reference compound group.
  • Evaluation index Changes in ear thickness and swelling inhibition rate ([IC-IT]/IC X 100%) after PMA-induced ear swelling for 6 hours, IC and IT are the number of ear thickness increases (mm) in the control and treatment groups, respectively ) as an inflammatory index; the body weight change after 24 hours of PMA induction was used as an index of systemic toxicity.
  • Compound 21 can dose-dependently inhibit PMA-induced ear swelling in mice.
  • the inhibition rates of the low, middle and high dose groups were significantly higher than those of the model group.
  • the inhibition rates of ear swelling were 36.7 ⁇ 14.5%, 81.0% ⁇ 18.5% and 93.9 ⁇ 5.9% (mean ⁇ SD).
  • the low and high doses of reference compound A also inhibited the ear swelling of PMA-induced mice, and the inhibition rates of ear swelling in the low and high dose groups were 12.7% ⁇ 16.2% and 45.3% ⁇ 23.0% (mean ⁇ SD), respectively.

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Abstract

The present disclosure relates to an aryl or heteroaryl substituted 5-membered aromatic heterocyclic compound and the use thereof. In particular, provided is a compound as shown in formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, Y1, ring A and ring B are as defined herein.

Description

芳基或杂芳基取代五元芳杂环化合物及其用途Aryl or heteroaryl substituted five-membered aromatic heterocyclic compound and use thereof 技术领域technical field
本公开属于医药领域，涉及一种芳基或杂芳基取代五元芳杂环化合物及其用途。The present disclosure belongs to the field of medicine, and relates to an aryl or heteroaryl substituted five-membered aromatic heterocyclic compound and use thereof.
背景技术Background technique
磷酸二酯酶(PDEs)为一类裂解在第二信使分子3',5'-环腺苷单磷酸(cAMP)和3',5'-环鸟苷单磷酸(cGMP)上的磷酸二酯键的细胞内酶。环核苷酸cAMP和cGMP在各种细胞途径中充当第二信使。其中，PDE4对cAMP具有高度特异性，有4种亚型：PDE4A、PDE4B、PDE4C和PDE4D。PDE4参与了促进单核细胞与巨噬细胞活化、中性粒细胞浸润、血管平滑肌的增殖、血管扩张以及心肌收缩等相关生理病理过程，对中枢神经系统功能、心血管功能、炎症/免疫系统、细胞黏附等都有影响。PDE4在促炎介质和抗炎介质的表达中起主要调节作用，PDE4抑制剂能够抑制炎症细胞释放有害介质。Phosphodiesterases (PDEs) are a class of phosphodiesters that cleave on second messenger molecules 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) key intracellular enzymes. The cyclic nucleotides cAMP and cGMP act as second messengers in various cellular pathways. Among them, PDE4 is highly specific for cAMP and has 4 isoforms: PDE4A, PDE4B, PDE4C and PDE4D. PDE4 is involved in the promotion of monocyte and macrophage activation, neutrophil infiltration, proliferation of vascular smooth muscle, vasodilation and myocardial contraction and other related physiological and pathological processes. cell adhesion, etc. PDE4 plays a major regulatory role in the expression of pro- and anti-inflammatory mediators, and PDE4 inhibitors can inhibit the release of harmful mediators from inflammatory cells.
近年发现许多PDE4抑制剂。例如，罗氟司特获准用于严重慢性阻塞性肺病(COPD)以减少突然发作的次数或防止COPD症状恶化，阿普司特获批用于治疗患有活动性牛皮癣性关节炎的成人。虽然PDE4抑制剂显示良好药理活性，但这些PDE抑制剂会出现副作用，诸如诱发性胃肠症状如呕吐及腹泻，仍需要开发选择性PDE4抑制剂，尤其对PDE4B和PDE4D具有亲和力的选择性PDE4抑制剂。Many PDE4 inhibitors have been discovered in recent years. For example, roflumilast is approved for severe chronic obstructive pulmonary disease (COPD) to reduce the number of flare-ups or prevent COPD symptoms from getting worse, and apremilast is approved to treat adults with active psoriatic arthritis. Although PDE4 inhibitors show good pharmacological activity, these PDE inhibitors suffer from side effects such as induced gastrointestinal symptoms such as vomiting and diarrhea, and there is still a need to develop selective PDE4 inhibitors, especially selective PDE4 inhibitors with affinity for PDE4B and PDE4D agent.
另外，多种杂环结构如噁唑化合物已有报道，诸如WO03/072102、WO98/15274、WO2007058338等，然而，本公开的连环化合物并没有在任何文献中公开。In addition, various heterocyclic structures such as oxazole compounds have been reported, such as WO03/072102, WO98/15274, WO2007058338, etc. However, the concatenated compounds of the present disclosure are not disclosed in any literature.
发明内容SUMMARY OF THE INVENTION
本公开(The disclosure)提供了式I所示化合物或其可药用盐The disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof
Figure PCTCN2021133316-appb-000001
Figure PCTCN2021133316-appb-000001
其中，R 1选自芳基或杂芳基，所述芳基或杂芳基任选被一个或多个选自氘、卤素、羟基、硝基、氰基、氨基、烷基、烷氧基、烯氧基、炔氧基、环烷基、杂环烷基、环烷氧基、杂环烷氧基或环烯氧基所取代，和/或者所述芳基或杂芳基与环烷基或杂环烷基稠合，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基或稠合环任选被一个或多个R A1所取代； Wherein, R 1 is selected from aryl or heteroaryl, and said aryl or heteroaryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, nitro, cyano, amino, alkyl, alkoxy , alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy, and/or the aryl or heteroaryl is substituted with cycloalkane or heterocycloalkyl fused, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused rings are optionally substituted with one or more R A1 ;
R A1选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6 元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代； R A1 is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkane oxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl, or 5- to 6-membered heteroaryl optionally supported by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, substituted by cyano and amino groups;
R 2选自环烷基、杂环烷基、芳基或杂芳基，所述芳基或杂芳基任选被一个或多个选自氘、卤素、羟基、烷基、环烷基、杂环烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基、环烯氧基、-SR'、-S(O) 2R'、-NR'(R”)、-COR'、-COOR'或-CONR'(R”)所取代，所述烷基、环烷基、杂环烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基或环烯氧基任选被一个或多个R A2所取代； R 2 is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, said aryl or heteroaryl optionally being surrounded by one or more selected from deuterium, halogen, hydroxyl, alkyl, cycloalkyl, Heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O) 2 R', -NR' ( R"), -COR', -COOR' or -CONR'(R"), the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkane Oxy, heterocycloalkoxy or cycloalkenyloxy optionally substituted by one or more R A2 ;
R A2选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、C 6-10芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、C 6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代； R A2 is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, C 6- 10 -aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 ring Alkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, C 6-10 aryl, or 5- to 6-membered heteroaryl are optionally substituted by one or more selected from halogen, deuterium, substituted by hydroxyl, oxo, nitro, cyano, amino;
环A选自5元杂芳环，所述杂芳环任选被一个或多个R A3所取代，且R 1与环B在环A上处于间位； Ring A is selected from a 5-membered heteroaromatic ring optionally substituted by one or more R A3 , and R1 and ring B are in meta position on ring A;
R A3选自卤素、氘、羟基、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代； R A3 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy Cycloalkoxy is optionally substituted with one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino;
环B选自3至6元碳环或杂环，所述环B任选被一个或多个R A4所取代； Ring B is selected from a 3- to 6-membered carbocyclic or heterocyclic ring, optionally substituted by one or more R A4 ;
R A4选自卤素、氘、羟基、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代； R A4 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy Cycloalkoxy is optionally substituted with one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino;
Y 1选自键、-C(＝O)-、-C(＝O)N(R 3)-、-N(R 4)C(＝O)-、-S(O) n-、-S(O) mN(R 3)-或-N(R 4)S(O) m-，R 3或R 4独立地选自氢、氘或C 1-6烷基，n和m各自独立地选自0至2的整数； Y 1 is selected from bond, -C(=O)-, -C(=O)N( R3 ) - , -N(R4)C(=O)-, -S(O) n- , -S (O) m N(R 3 )- or -N(R 4 )S(O) m -, R 3 or R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl, and n and m are each independently an integer from 0 to 2;
R'或R”独立地选自氢、氘、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基，所述烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基或氨基所取代。R' or R" is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, said alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano or amino.
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自C 6-10芳基或5至10元杂芳基，所述芳基或杂芳基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基所取代，和/或者所述芳基 或杂芳基与3至10元环烷基或3至10元杂环烷基稠合，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基或稠合环任选被一个或多个R A1所取代，R A1如前所定义。 In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or Multiple selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy group, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy, or C 3-6 cycloalkenyloxy, and/or the aryl or heteroaryl is fused to a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocycloalkyl group, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused The ring is optionally substituted with one or more R A1 as previously defined.
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自C 6-10芳基，所述芳基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基或C 3-6环烯氧基所取代，和/或者所述芳基与3至10元环烷基稠合，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基或稠合环任选被一个或多个R A1所取代，R A1如前所定义。 In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from C 6-10 aryl, and the aryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl or C 3-6 cycloalkenyloxy , and/or the aryl group is fused with a 3- to 10-membered cycloalkyl group, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring is any Select is replaced by one or more R A1 as previously defined.
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自C 6-10芳基，所述芳基任选被一个或多个选自C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基所取代，和/或者所述芳基与3至10元杂环烷基稠合，所述烷氧基、环烷氧基或稠合环任选被一个或多个R A1所取代，R A1如前所定义。 In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from C 6-10 aryl, and the aryl is optionally surrounded by one or more selected from C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, and/or the aryl group is fused with a 3- to 10-membered heterocycloalkyl, the alkoxy, cycloalkoxy or the fused ring is optionally substituted with one or more R A1 as previously defined.
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自C 6-10芳基，所述芳基任选被一个或多个选自氘、卤素、羟基或氨基。 In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from C 6-10 aryl, optionally with one or more selected from deuterium, halogen, hydroxyl or amino.
另一方面，一些实施方案提供式I所示化合物为On the other hand, some embodiments provide that the compound of formula I is
Figure PCTCN2021133316-appb-000002
Figure PCTCN2021133316-appb-000002
其中，R 6、R 7、R 8、R 9或R 10各自独立地选自氢、氘、卤素、氨基、羟基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基所取代，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基、环烷基、杂环烷氧基或杂环烷基任选被一个或多个R A1所取代，或者R 6、R 7与相邻的碳原子形成5至10元碳环或5至10元杂环，所述碳环或杂环任选被一个或多个R A1所取代，R A1如前所定义。 wherein, R 6 , R 7 , R 8 , R 9 or R 10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 Alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy, or C 3 -6 substituted by cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl Optionally substituted by one or more R A1 , or R 6 , R 7 and adjacent carbon atoms form a 5- to 10-membered carbocyclic ring or a 5- to 10-membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally replaced by a is substituted by one or more R A1s , R A1 is as previously defined.
在一些实施方案中，式IIA所示化合物或其可药用盐中R 8选自氢、氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1所取代，R A1如前所定义。 In some embodiments, in the compound of formula IIA or a pharmaceutically acceptable salt thereof, R 8 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, the alkane The radical or alkoxy is optionally substituted with 1 to 3 R A1 as previously defined.
在一些实施方案中，式IIA所示化合物或其可药用盐中R 8选自C 1-6烷氧基，所述烷氧基任选被1至3个R A1所取代，R A1如前所定义。 In some embodiments, in the compound represented by formula IIA or a pharmaceutically acceptable salt thereof, R 8 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 , and R A1 is as previously defined.
在一些实施方案中，式IIA所示化合物或其可药用盐中R 8选自C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基，所述烯氧基、炔氧基、环烷氧基、环烯氧基、环烷基、杂环烷氧基或杂环烷基任选被1至3个R A1所取代，R A1如前所定义。 In some embodiments, in the compound of formula IIA or a pharmaceutically acceptable salt thereof, R 8 is selected from C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3- 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, the alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkene Oxy , cycloalkyl, heterocycloalkoxy or heterocycloalkyl are optionally substituted with 1 to 3 R A1 , as previously defined.
在另一些实施方案中，式IIA所示化合物或其可药用盐中R 6选自氢、氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1 所取代，R A1如前所定义。在一些实施方案中，R 6选自氢或氘。在一些实施方案中，R 6选自氢。 In other embodiments, in the compound represented by formula IIA or a pharmaceutically acceptable salt thereof, R 6 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, the Alkyl or alkoxy is optionally substituted with 1 to 3 R A1 as previously defined. In some embodiments, R 6 is selected from hydrogen or deuterium. In some embodiments, R 6 is selected from hydrogen.
在另一些实施方案中，式IIA所示化合物或其可药用盐中R 10选自氢、氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1所取代，R A1如前所定义。在一些实施方案中，R 10选自氢或氘。在一些实施方案中，R 10选自氢。 In other embodiments, in the compound represented by formula IIA or a pharmaceutically acceptable salt thereof, R 10 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, the Alkyl or alkoxy is optionally substituted with 1 to 3 R A1 as previously defined. In some embodiments, R 10 is selected from hydrogen or deuterium. In some embodiments, R 10 is selected from hydrogen.
另一方面，在一些实施方案中，式II所示化合物或其可药用盐中R 7选自氢、氘、卤素、羟基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1所取代，R A1如前所定义。 On the other hand, in some embodiments, in the compound represented by formula II or a pharmaceutically acceptable salt thereof, R 7 is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, so The alkyl or alkoxy group is optionally substituted with 1 to 3 R A1 , as previously defined.
在一些实施方案中，式II所示化合物或其可药用盐中R 7选自C 1-6烷氧基，所述烷氧基任选被1至3个R A1所取代，R A1如前所定义。 In some embodiments, in the compound represented by formula II or a pharmaceutically acceptable salt thereof, R 7 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 , and R A1 is as previously defined.
在一些实施方案中，式II所示化合物或其可药用盐中R 7选自C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基，所述烯氧基、炔氧基、环烷氧基、环烯氧基、环烷基、杂环烷氧基或杂环烷基任选被1至3个R A1所取代，R A1如前所定义。 In some embodiments, in the compound of formula II or a pharmaceutically acceptable salt thereof, R 7 is selected from C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3- 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, the alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkene Oxy , cycloalkyl, heterocycloalkoxy or heterocycloalkyl are optionally substituted with 1 to 3 R A1 , as previously defined.
在另一些实施方案中，式II所示化合物或其可药用盐中R 7选自3至6杂环烷氧基，优选含有至少一种选自N，O或S中的杂原子的杂环烷氧基，所述杂环烷氧基任选被1至3个R A1所取代，R A1如前所定义。在一些实施方案中，杂环烷氧基包括但不限于
Figure PCTCN2021133316-appb-000003
Figure PCTCN2021133316-appb-000004
In other embodiments, in the compound represented by formula II or a pharmaceutically acceptable salt thereof, R 7 is selected from 3 to 6 heterocycloalkoxy, preferably a heteroatom containing at least one heteroatom selected from N, O or S. Cycloalkoxy, said heterocycloalkoxy optionally substituted with 1 to 3 R A1 , R A1 as previously defined. In some embodiments, heterocycloalkoxy includes, but is not limited to
Figure PCTCN2021133316-appb-000003
Figure PCTCN2021133316-appb-000004
在另一些实施方案中，式II所示化合物或其可药用盐中R 6、R 9或R 10选自氢或氘。在一些实施方案中，式II所示化合物或其可药用盐中R 8选自C 1-6烷氧基，所述烷氧基任选被1至3个R A1所取代；R 7选自C 1-6烷氧基，所述烷氧基任选被1至3个R A1所取代。 In other embodiments, in the compound of formula II or a pharmaceutically acceptable salt thereof, R 6 , R 9 or R 10 is selected from hydrogen or deuterium. In some embodiments, in the compound represented by formula II or a pharmaceutically acceptable salt thereof, R 8 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 ; R 7 is selected from From C 1-6 alkoxy, the alkoxy is optionally substituted with 1 to 3 R A1 .
在一些实施方案中，式II所示化合物或其可药用盐中R 8选自C 1-6烷氧基，所述烷氧基任选被1至3个R A1所取代；R 7选自C 1-6烷氧基，所述烷氧基任选被1至3个R A1所取代；R 6、R 9和R 10选自氢或氘。 In some embodiments, in the compound represented by formula II or a pharmaceutically acceptable salt thereof, R 8 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 ; R 7 is selected from From C 1-6 alkoxy, the alkoxy is optionally substituted with 1 to 3 R A1 ; R 6 , R 9 and R 10 are selected from hydrogen or deuterium.
在一些实施方案中，式II所示化合物或其可药用盐中R 7选自含有至少一种选自N，O或S中的杂原子的杂环烷氧基，所述杂环烷氧基任选被1至3个R A1所取代，R A1如前所定义；R 8选自C 1-6烷氧基，所述烷氧基任选被1至3个R A1所取代；R 6、R 9或R 10选自氢或氘。 In some embodiments, R 7 in the compound of formula II or a pharmaceutically acceptable salt thereof is selected from a heterocycloalkoxy group containing at least one heteroatom selected from N, O or S, the heterocycloalkoxy group group is optionally substituted by 1 to 3 R A1 , R A1 is as defined above; R 8 is selected from C 1-6 alkoxy, and the alkoxy is optionally substituted by 1 to 3 R A1 ; R 6 , R 9 or R 10 is selected from hydrogen or deuterium.
另一些实施方案中提供式II所示化合物或其可药用盐中R 6、R 7与相邻的碳原子形成5至10元杂环，所述杂环任选被1至3个R A1所取代，R A1如前所定义。 In other embodiments, the compound represented by formula II or a pharmaceutically acceptable salt thereof is provided in which R 6 and R 7 and adjacent carbon atoms form a 5- to 10-membered heterocyclic ring, and the heterocyclic ring is optionally surrounded by 1 to 3 R A1 Instead, R A1 is as previously defined.
在一些实施方案中，式II所示化合物或其可药用盐中R 6、R 7与相邻的碳原子形成5至10元杂环，所述杂环任选被1至3个R A1所取代，R A1如权利要求1中所定义；R 8选自氢、氘、卤素、羟基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1所取代，R A1如前所定义。 In some embodiments, in the compound represented by formula II or a pharmaceutically acceptable salt thereof, R 6 , R 7 and adjacent carbon atoms form a 5- to 10-membered heterocycle, and the heterocycle is optionally surrounded by 1 to 3 R A1 substituted, R A1 is as defined in claim 1; R 8 is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally Replaced by 1 to 3 R A1s as previously defined.
在一些实施方案中，式II所示化合物或其可药用盐中R 6、R 7与相邻的碳原子形成5至10元杂环，所述杂环任选被1至3个R A1所取代； In some embodiments, in the compound represented by formula II or a pharmaceutically acceptable salt thereof, R 6 , R 7 and adjacent carbon atoms form a 5- to 10-membered heterocycle, and the heterocycle is optionally surrounded by 1 to 3 R A1 replaced;
R 8选自氢、氘、卤素、羟基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1所取代； R 8 is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally substituted by 1 to 3 R A1 ;
R 9或R 10选自氢； R 9 or R 10 is selected from hydrogen;
R A1如前所定义。 R A1 is as previously defined.
在另一些实施方案中，式I所示化合物或其可药用盐中R 1选自5至10元杂芳基，所述杂芳基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基所取代，和/或者所述芳基与3至10元环烷基或3至10元杂环烷基稠合，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基或稠合环任选被一个或多个R A1所取代，R A1如前所定义。 In other embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from a 5- to 10-membered heteroaryl group, and the heteroaryl group is optionally surrounded by one or more selected from the group consisting of deuterium, halogen, hydroxyl , amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl , 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, and/or the aryl group is substituted with a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkyl group A membered heterocycloalkyl fused, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring is optionally substituted with one or more R A1 , R A1 is as previously defined.
在一些实施方案中，式I所示化合物或其可药用盐中R 1选自5至10元杂芳基，所述杂芳基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A1所取代，R A1如前所定义。 In some embodiments, in the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 is selected from a 5- to 10-membered heteroaryl group, and the heteroaryl group is optionally surrounded by one or more selected from the group consisting of deuterium, halogen, hydroxyl, Amino, C 1-6 alkyl or C 1-6 alkoxy optionally substituted with one or more R A1 as previously defined.
另一方面，本公开提供式I所示化合物为On the other hand, the present disclosure provides that the compound represented by formula I is
Figure PCTCN2021133316-appb-000005
Figure PCTCN2021133316-appb-000005
其中，R 11、R 12、R 13、R 14或R 15各自独立地选自氢、氘、卤素、氨基、羟基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A1所取代，R A1如前所定义。 wherein, R 11 , R 12 , R 13 , R 14 or R 15 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkoxy is optionally substituted with one or more R A1 as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中Y 1选自-C(＝O)N(R 3)-或-N(R 4)C(＝O)-，R 3或R 4独立地选自氢、氘或C 1-6烷基。 In some embodiments, Y 1 in the compound represented by Formula I or Formula II or a pharmaceutically acceptable salt thereof is selected from -C(=O)N(R 3 )- or -N(R 4 )C(=O)- , R 3 or R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2-Y 1-为：R 2-C(＝O)N(R 3)-，R 3独立地选自氢、氘或C 1-6烷基。 In some embodiments, R 2 -Y 1 - in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is: R 2 -C(=O)N(R 3 )-, and R 3 is independently selected from hydrogen, deuterium or C 1-6 alkyl.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2-Y 1-为：R 2-C(＝O)N(R 3)-，R 3独立地选自氢。 In some embodiments, R 2 -Y 1 - in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is: R 2 -C(=O)N(R 3 )-, and R 3 is independently selected from hydrogen.
一些实施方案提供式I所示化合物为Some embodiments provide that the compound of formula I is
Figure PCTCN2021133316-appb-000006
Figure PCTCN2021133316-appb-000006
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2-Y 1-为：R 2-N(R 4)C(＝O)-，R 4独立地选自氢、氘或C 1-6烷基。 In some embodiments, R 2 -Y 1 - in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is: R 2 -N(R 4 )C(=O)-, and R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2-Y 1-为：R 2-N(R 4)C(＝O)-，R 4独立地选自氢。 In some embodiments, R 2 -Y 1 - in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is: R 2 -N(R 4 )C(=O)-, and R 4 is independently selected from hydrogen.
在一些实施方案中，式I或式II所示化合物或其可药用盐中Y 1选自键、-C(＝O)-。 In some embodiments, Y 1 in the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof is selected from a bond, -C(=O)-.
在一些实施方案中，式I或式II所示化合物或其可药用盐中Y 1选自-S(O) n-、-S(O) mN(R 3)-或-N(R 4)S(O) m-，n和m各自独立地选自0至2的整数，R 3或R 4独立地选自氢、氘或C 1-6烷基。 In some embodiments, Y 1 in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is selected from -S(O) n -, -S(O) m N(R 3 )- or -N(R 4 ) S(O) m- , n and m are each independently selected from an integer from 0 to 2, and R 3 or R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自C 6-10芳基或5至9元杂芳基，所述芳基或杂芳基任选被一个或多个选自氘、卤素、羟基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6杂环烷氧基、C 3-8环烯氧基、-SR'、-S(O) 2R'、-NR'(R”)、-COR'、-COOR'或-CONR'(R”)所取代，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基或环烯氧基任选被一个或多个R A2所取代，R'、R”和R A2如前所定义。 In some embodiments, in the compound represented by Formula I or Formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 6-10 aryl or 5- to 9-membered heteroaryl, and the aryl or heteroaryl is optionally by one or more selected from deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkane oxy, 3 to 6 heterocycloalkoxy, C 3-8 cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R"), the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy optionally substituted by one or more R Instead of A2 , R', R" and R A2 are as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自C 6-10芳基，所述芳基任选被一个或多个选自氘、卤素、羟基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6杂环烷氧基、C 3-8环烯氧基、-SR'、-S(O) 2R'、-NR'(R”)、-COR'、-COOR'或-CONR'(R”)所取代，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基或环烯氧基任选被1至3个R A2所取代，R'、R”和R A2如前所定义。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 6-10 aryl, and the aryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C 3-8 cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R") substituted, the Alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy optionally substituted with 1 to 3 R A2 , R', R" and R A2 as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自C 6-10芳基，所述芳基任选被1至3个选自氘、卤素、羟基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基或C 3-6环烷氧基所取代，所述烷基、烷氧基或环烷氧基任选被1至3个R A2所取代，R A2如前所定义。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 6-10 aryl, and the aryl is optionally substituted by 1 to 3 atoms selected from deuterium, halogen, hydroxyl , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy, the alkyl, alkoxy or cycloalkoxy is optional Replaced by 1 to 3 R A2s as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自C 6-10芳基，所述芳基任选被C 1-6烷氧基所取代，所述烷氧基任选被1至3个R A2所取代，R A2如前所定义。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 6-10 aryl, and the aryl is optionally substituted by C 1-6 alkoxy, so The alkoxy group is optionally substituted with 1 to 3 R A2 , as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自C 6-10芳基，所述芳基任选被1至3个选自-SR'、-S(O) 2R'、-NR'(R”)、-COR'、-COOR'或-CONR'(R”)所取代，R'和R”如前所定义。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 6-10 aryl, and the aryl is optionally 1 to 3 selected from -SR', - S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R"), R' and R" as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自C 6-10芳基， 所述芳基任选被1至3个选自C 2-6烯氧基、C 2-6炔氧基、3至6杂环烷氧基或C 3-8环烯氧基所取代，所述烯氧基、炔氧基或环烯氧基任选被1至3个R A2所取代，R A2如前所定义。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 6-10 aryl, and the aryl is optionally 1 to 3 selected from C 2-6 alkene oxy, C 2-6 alkynyloxy, 3 to 6 heterocycloalkoxy or C 3-8 cycloalkenyloxy optionally substituted by 1 to 8 Substituted with 3 R A2s, R A2 is as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自苯基，所述苯基被1至3个选自氘、卤素、羟基、C 1-6烷基或C 1-6烷氧基所取代，所述烷基或烷氧基任选被1至3个R A2所取代，R A2如前所定义。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from phenyl, and the phenyl is surrounded by 1 to 3 selected from deuterium, halogen, hydroxyl, C 1-6 alkane substituted with 1 to 3 R A2 groups or C 1-6 alkoxy groups optionally substituted with 1 to 3 R A2 as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自苯基，所述苯基被1至3个选自C 1-6烷氧基所取代，例如甲氧基、乙氧基或丙氧基。 In some embodiments, in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from phenyl, and the phenyl is substituted with 1 to 3 selected from C 1-6 alkoxy, such as Methoxy, ethoxy or propoxy.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自5至9元杂芳基，所述杂芳基任选被1至3个选自氘、卤素、羟基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基或C 3-6环烷氧基所取代，所述烷基、环烷基、烷氧基或环烷氧基任选被1至3个R A2所取代，R A2如前所定义。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from a 5- to 9-membered heteroaryl group, and the heteroaryl group is optionally surrounded by 1 to 3 atoms selected from deuterium, halogen , hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy, the alkyl, cycloalkyl, alkoxy or Cycloalkoxy is optionally substituted with 1 to 3 R A2 as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from
Figure PCTCN2021133316-appb-000007
进一步所述R 2任选被1至3个选自氘、卤素、羟基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基或C 3-6环烷氧基所取代。
Figure PCTCN2021133316-appb-000007
Further said R 2 is optionally selected from 1 to 3 groups selected from deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy base substituted.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自： In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from:
Figure PCTCN2021133316-appb-000008
Figure PCTCN2021133316-appb-000008
在一些实施方案中，式I或式II所示化合物或其可药用盐中R 2选自C 3-6环烷基或3至6元杂环烷基，所述环烷基或杂环烷基任选被1至3个选自氘、卤素、羟基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基或C 3-6环烷氧基所取代，所述烷基、环烷基、烷氧基或环烷氧基任选被1至3个R A2所取代，R A2如前所定义。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R 2 is selected from C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, said cycloalkyl or heterocycle Alkyl is optionally substituted with 1 to 3 selected from deuterium, halogen, hydroxy, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy or C3-6 cycloalkoxy , the alkyl, cycloalkyl, alkoxy or cycloalkoxy is optionally substituted with 1 to 3 R A2 , where R A2 is as previously defined.
另一方面，本公开中式I或式II所示化合物或其可药用盐中环A选自On the other hand, in the present disclosure, ring A in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2021133316-appb-000009
Figure PCTCN2021133316-appb-000010
进一步地，所述环A环任选被一个或多个R A3所取代，R A3如前所定义。
Figure PCTCN2021133316-appb-000009
Figure PCTCN2021133316-appb-000010
Further, the Ring A ring is optionally substituted with one or more R A3 as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中环A选自
Figure PCTCN2021133316-appb-000011
Figure PCTCN2021133316-appb-000012
进一步地，所述环A环任选被一个或多个R A3所取代，R A3如前所定义。 In some embodiments, ring A in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2021133316-appb-000011
Figure PCTCN2021133316-appb-000012
Further, the Ring A ring is optionally substituted with one or more R A3 as previously defined.
在一些实施方案中，式I或式II所示化合物或其可药用盐中环A选自
Figure PCTCN2021133316-appb-000013
In some embodiments, ring A in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2021133316-appb-000013
在一些实施方案中，式I或式II所示化合物或其可药用盐中环A选自
Figure PCTCN2021133316-appb-000014
Figure PCTCN2021133316-appb-000015
In some embodiments, ring A in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2021133316-appb-000014
Figure PCTCN2021133316-appb-000015
在一些实施方案中，式I所示化合物中
Figure PCTCN2021133316-appb-000016
为： In some embodiments, in the compound of formula I
Figure PCTCN2021133316-appb-000016
for:
Figure PCTCN2021133316-appb-000017
Figure PCTCN2021133316-appb-000017
在一些实施方案中，式I所示化合物中
Figure PCTCN2021133316-appb-000018
为： In some embodiments, in the compound of formula I
Figure PCTCN2021133316-appb-000018
for:
Figure PCTCN2021133316-appb-000019
Figure PCTCN2021133316-appb-000019
一些实施方案提供的式I或式II所示化合物为The compound shown in formula I or formula II provided by some embodiments is
Figure PCTCN2021133316-appb-000020
Figure PCTCN2021133316-appb-000020
另一方面，在一些实施方案中，式I或式II所示化合物中环B选自3至6元 碳环，所述环B任选被一个或多个R A4所取代。 On the other hand, in some embodiments, in the compound of Formula I or Formula II, Ring B is selected from a 3- to 6-membered carbocyclic ring, and said Ring B is optionally substituted with one or more R A4 .
在一些实施方案中，式I或式II所示化合物中环B选自
Figure PCTCN2021133316-appb-000021
进一步所述环B任选被一个或多个R A4所取代。 In some embodiments, ring B in the compound of formula I or formula II is selected from
Figure PCTCN2021133316-appb-000021
Further said Ring B is optionally substituted with one or more R A4 .
本公开提供的式I或式II所示化合物为The compound represented by formula I or formula II provided by the present disclosure is
Figure PCTCN2021133316-appb-000022
其中P＝0-3之间整数。在一些实施方案中，式VA所示化合物或其可药用盐中p＝0、1或2。在一些实施方案中，式VA所示化合物或其可药用盐中p＝0。
Figure PCTCN2021133316-appb-000022
Wherein P = integer between 0-3. In some embodiments, p=0, 1 or 2 in the compound of formula VA or a pharmaceutically acceptable salt thereof. In some embodiments, p=0 in the compound of formula VA or a pharmaceutically acceptable salt thereof.
在另一些实施方案中，式I或式II所示化合物或其可药用盐中环B选自4至6元含氮原子的杂环或含氧原子的杂环，所述环B任选被一个或多个R A4所取代。 In other embodiments, ring B in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is selected from a 4- to 6-membered nitrogen atom-containing heterocycle or an oxygen atom-containing heterocycle, and the ring B is optionally Replaced by one or more R A4 .
在一些实施方案中，式I或式II所示化合物或其可药用盐中环B选自In some embodiments, ring B in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2021133316-appb-000023
进一步所述环B任选被一个或多个R A4所取代。
Figure PCTCN2021133316-appb-000023
Further said Ring B is optionally substituted with one or more R A4 .
另一方面，在一些实施方案中，式I或式II所示化合物或其可药用盐中R A1选自卤素、氘、硝基或氰基，优选卤素，例如氟。 On the other hand, in some embodiments, in the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, R A1 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R A1选自羟基、C 1-6烷基、C 3-6环烷基或3至6元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R A1 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R A1选自苯基或5至6元杂芳基，所述苯基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R A1 is selected from phenyl or 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is optionally Substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R A2选自卤素、氘、硝基或氰基，优选卤素，例如氟。 In some embodiments, in the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, R A2 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R A2选自羟基、C 1-6烷基、C 3-6环烷基或3至6元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R A2 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R A3选自卤素、氘、硝基或氰基，优选卤素，例如氟。 In some embodiments, in the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, R A3 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R A3选自羟基、C 1-6烷基、C 3-6环烷基或3至6元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R A3 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R A4选自卤素、氘、硝基或氰基，优选卤素，例如氟。 In some embodiments, in the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, R A4 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R A4选自羟基、C 1-6烷基、C 3-6环烷基或3至6元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 In some embodiments, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof, R A4 is selected from hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
在一些实施方案中，式I或式II所示化合物或其可药用盐中R'或R”独立地选自氢、C 1-6烷基或C 1-6烷氧基，所述C 1-6烷基或C 1-6烷氧基任选被一个或多个选自卤素或氘所取代。 In some embodiments, R' or R" in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6Alkyl or C1-6alkoxy is optionally substituted with one or more selected from halogen or deuterium.
进一步地，本公开提供的式I或式II所示化合物或其可药用盐中R 2选自5至6元杂芳环。在一些实施方案中，R 2选自噻唑基、咪唑基、吡啶基、噁唑基、嘧啶基或吡唑基，进一步地所述R 2任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A2所取代，R A2如前述所定义。 Further, in the compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof provided by the present disclosure, R 2 is selected from a 5- to 6-membered heteroaromatic ring. In some embodiments, R 2 is selected from thiazolyl, imidazolyl, pyridyl, oxazolyl, pyrimidinyl or pyrazolyl, further said R 2 is optionally surrounded by one or more selected from deuterium, halogen, hydroxyl , amino, C 1-6 alkyl or C 1-6 alkoxy optionally substituted with one or more R A2 as previously defined.
在另一些实施方案中，R 2选自噻唑基，所述噻唑基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A2所取代，R A2如前述所定义。 In other embodiments, R 2 is selected from thiazolyl optionally by one or more selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, The alkyl or alkoxy group is optionally substituted with one or more R A2 as previously defined.
在另一些实施方案中，R 2选自咪唑基，所述咪唑基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A2所取代，R A2如前述所定义。 In other embodiments, R 2 is selected from imidazolyl, optionally with one or more selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, The alkyl or alkoxy group is optionally substituted with one or more R A2 as previously defined.
另一些实施方案提供式I所示化合物为Other embodiments provide that the compound of formula I is
Figure PCTCN2021133316-appb-000024
其中，R 16或R 17各自独立地选自氢、氘、卤素、氨基、羟基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A1所取代，R A1如前所定义。
Figure PCTCN2021133316-appb-000024
Wherein, R 16 or R 17 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally replaced by one or A plurality of R A1s are substituted, and R A1s are as previously defined.
在一些实施方案中，式I所示化合物为In some embodiments, the compound of formula I is
Figure PCTCN2021133316-appb-000025
Figure PCTCN2021133316-appb-000025
在一些实施方案中，式IIIC所示化合物或其可药用盐中R 16或R 17各自独立地选自氢、氘或C 1-6烷氧基。 In some embodiments, each of R 16 or R 17 in the compound of formula IIIC or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, deuterium or C 1-6 alkoxy.
在一些实施方案中，式IIIC所示化合物或其可药用盐中R 16或R 17各自独立地选自氢、卤素、氨基、羟基或C 1-6烷氧基。 In some embodiments, each of R 16 or R 17 in the compound of formula IIIC or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, halogen, amino, hydroxyl or C 1-6 alkoxy.
在一些实施方案中，式IIIC所示化合物或其可药用盐中R 16或R 17各自独立地选自C 1-6烷基或C 1-6烷氧基。 In some embodiments, each of R 16 or R 17 in the compound of formula IIIC or a pharmaceutically acceptable salt thereof is independently selected from C 1-6 alkyl or C 1-6 alkoxy.
另一方面，另一些实施方案提供的式I或式II所示化合物或其可药用盐中R 2选自吡啶基或噁唑基，所述吡啶基或噁唑基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A2所取代，R A2如前述定义。 On the other hand, in the compound shown in formula I or formula II or a pharmaceutically acceptable salt thereof provided by other embodiments, R 2 is selected from pyridyl or oxazolyl, and the pyridyl or oxazolyl is optionally composed of one or more one is selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more R A2 , R A2 as previously described definition.
另一些实施方案提供式I所示化合物为Other embodiments provide that the compound of formula I is
Figure PCTCN2021133316-appb-000026
其中，R 18或R 19各自独立地选自氢、氘、卤素、氨基、羟基、C 1-6烷基或C 1-6烷氧基，R 20选自氢、氘或C 1-6烷基，所述烷基或烷氧基任选被一个或多个R A6所取代，R A6选自卤素、氘、羟基、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。
Figure PCTCN2021133316-appb-000026
Wherein, R 18 or R 19 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, and R 20 is selected from hydrogen, deuterium or C 1-6 alkoxy base, the alkyl or alkoxy is optionally substituted by one or more R A6 , R A6 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3- 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, or 3- to 6-membered heterocycloalkoxy optionally by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, substituted with amino.
在一些实施方案中，式I所示化合物为In some embodiments, the compound of formula I is
Figure PCTCN2021133316-appb-000027
Figure PCTCN2021133316-appb-000027
在一些实施方案中，式III所示化合物或其可药用盐中R 18或R 19各自独立地选自氢、卤素、氨基、羟基或C 1-6烷氧基，R 20选自氢、氘或C 1-6烷基。 In some embodiments, in the compound represented by formula III or a pharmaceutically acceptable salt thereof, R 18 or R 19 are each independently selected from hydrogen, halogen, amino, hydroxyl or C 1-6 alkoxy, and R 20 is selected from hydrogen, Deuterium or C 1-6 alkyl.
在一些实施方案中，式III所示化合物或其可药用盐中R 18或R 19各自独立地选自氢、C 1-6烷基或C 1-6烷氧基，R 20选自氢、氘或C 1-6烷基。 In some embodiments, in the compound represented by formula III or a pharmaceutically acceptable salt thereof, R 18 or R 19 are each independently selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy, and R 20 is selected from hydrogen , deuterium or C 1-6 alkyl.
另一些实施方案提供式I所示化合物为Other embodiments provide that the compound of formula I is
Figure PCTCN2021133316-appb-000028
Figure PCTCN2021133316-appb-000028
另一些实施方案提供式I所示化合物为Other embodiments provide that the compound of formula I is
Figure PCTCN2021133316-appb-000029
Figure PCTCN2021133316-appb-000029
另一些实施方案提供式I所示化合物为Other embodiments provide that the compound of formula I is
Figure PCTCN2021133316-appb-000030
Figure PCTCN2021133316-appb-000030
另一些实施方案提供式I所示化合物为Other embodiments provide that the compound of formula I is
Figure PCTCN2021133316-appb-000031
Figure PCTCN2021133316-appb-000031
式I所示典型化合物或其可药用盐，包括但不限于：Typical compounds shown in formula I or their pharmaceutically acceptable salts, including but not limited to:
Figure PCTCN2021133316-appb-000032
Figure PCTCN2021133316-appb-000032
Figure PCTCN2021133316-appb-000033
Figure PCTCN2021133316-appb-000033
Figure PCTCN2021133316-appb-000034
Figure PCTCN2021133316-appb-000034
另一方面，本公开还提供一种制备式I化合物或其可药用盐的方法，包括以下反应流程，On the other hand, the present disclosure also provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the following reaction scheme,
Figure PCTCN2021133316-appb-000035
Figure PCTCN2021133316-appb-000035
在一些实施方案中，制备式IIIA化合物或其可药用盐方法，包括式ZA化合物与式ZB化合物反应以形成式IIIA化合物的步骤，In some embodiments, a method of preparing a compound of formula IIIA, or a pharmaceutically acceptable salt thereof, comprises the step of reacting a compound of formula ZA with a compound of formula ZB to form a compound of formula IIIA,
Figure PCTCN2021133316-appb-000036
Figure PCTCN2021133316-appb-000036
本公开另一方面还提供了式ZB化合物或其可药用盐。在一些实施方案中，式 ZB化合物或其可药用盐用于合成或制备式IIIA化合物或其可药用盐。Another aspect of the present disclosure also provides a compound of formula ZB or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of formula ZB or a pharmaceutically acceptable salt thereof is used in the synthesis or preparation of a compound of formula IIIA or a pharmaceutically acceptable salt thereof.
在一些实施方案中，式ZB化合物或其可药用盐为In some embodiments, the compound of formula ZB or a pharmaceutically acceptable salt thereof is
Figure PCTCN2021133316-appb-000037
Figure PCTCN2021133316-appb-000037
本公开中还提供了一种药物组合物，包括至少一种治疗有效量的前述式I或式II所示化合物或其可药用盐、或由前述方法制备获得化合物或其可药用盐以及药学上可接受的赋形剂。The present disclosure also provides a pharmaceutical composition, comprising at least one therapeutically effective amount of the compound represented by Formula I or Formula II or a pharmaceutically acceptable salt thereof, or a compound prepared by the foregoing method or a pharmaceutically acceptable salt thereof, and Pharmaceutically acceptable excipients.
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用盐。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用盐。In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains from 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.
本公开还提供一种预防和/或治疗患有与PDE相关病症患者的方法，其通过向所述患者施用治疗有效量的如前述式I或式II所示化合物或其可药用盐、或由前述方法制备获得化合物或其可药用盐或前述药物组合物。The present disclosure also provides a method of preventing and/or treating a patient suffering from a disorder associated with PDE, by administering to the patient a therapeutically effective amount of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, or The compounds or their pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions are prepared by the aforementioned methods.
在一些实施方案中，所述与PDE相关病症优选气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病。In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.
本公开还提供一种预防和/或治疗患有气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病患者的方法，其包括向所述患者施用治疗有效量的如前述式I或式II所示化合物或其可药用盐，或向所述患者施用治疗有效量的由前述方法制备获得化合物或其可药用盐，或向所述患者施用治疗有效量的前述药物组合物。The present disclosure also provides a method of preventing and/or treating a patient suffering from asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism, comprising: Administering to the patient a therapeutically effective amount of the compound represented by the aforementioned formula I or II or a pharmaceutically acceptable salt thereof, or administering to the patient a therapeutically effective amount of the compound prepared by the aforementioned method or a pharmaceutically acceptable salt thereof, or A therapeutically effective amount of the aforementioned pharmaceutical composition is administered to the patient.
本公开还提供了如前述式I或式II所示化合物或其可药用盐、或前述药物组合物在制备用于预防和/或治疗与PDE相关病症的药物中的用途。在一些实施方案中，所述与PDE相关病症优选气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病。The present disclosure also provides the use of the compound represented by the aforementioned formula I or formula II or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disorder related to PDE. In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.
本公开还提供了如前述式I或式II所示化合物或其可药用盐、或前述药物组合物在制备用于预防和/或治疗气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病的药物中的用途。The present disclosure also provides the compound represented by the aforementioned formula I or formula II or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition prepared for the prevention and/or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, Use in the medicament of allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism.
另一方面，本公开中所述化合物可药用盐选自无机盐或有机盐。In another aspect, the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts.
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。Compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
本公开所述化合物的化学结构中，键
Figure PCTCN2021133316-appb-000038
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021133316-appb-000039
可以为
Figure PCTCN2021133316-appb-000040
或者同时包含
Figure PCTCN2021133316-appb-000041
Figure PCTCN2021133316-appb-000042
两种构型。 In the chemical structure of the compound described in the present disclosure, the bond
Figure PCTCN2021133316-appb-000038
Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond
Figure PCTCN2021133316-appb-000039
can be
Figure PCTCN2021133316-appb-000040
or both
Figure PCTCN2021133316-appb-000041
Figure PCTCN2021133316-appb-000042
Two configurations.
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversion via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerizations . An example of a lactam-lactam equilibrium is between A and B as shown below.
Figure PCTCN2021133316-appb-000043
Figure PCTCN2021133316-appb-000043
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。All compounds in this disclosure can be drawn as either A or B type. All tautomeric forms are within the scope of this disclosure. The naming of compounds does not exclude any tautomers.
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。 The present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic weight or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 1000 times greater than the natural abundance of deuterium (which is 0.015%)) % of deuterium incorporated). Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium. The present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize the compound of formula (I) in deuterated form. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。 "Optionally" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "C 1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.
术语解释：Terminology Explanation:
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。"Pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative that has been approved by the US Food and Drug Administration as acceptable for use in humans or livestock animals , dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的 症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。An "effective amount" or "therapeutically effective amount" as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 "Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxygen substituted, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C The 3-8 cycloalkenyloxy, aryl or 5 to 6 membered heteroaryl is optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
“烯基”包括具有2至12个碳原子的支链和直链烯烃或含有脂族烃基团的烯烃。例如“C 2-6烯基”表示具有2、3、4、5或6个碳原子的烯基。烯基的实例包括但不限于，乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基及4-己烯基。烯基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代 "Alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. For example "C 2-6 alkenyl" means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxygen substituted, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino
“炔基”包括具有2至12个碳原子的支链和直链炔基或含有脂族烃基的烯烃，或若规定指定碳原子数，则意指该特定数目。例如乙炔基、丙炔基(例如1-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基及1-甲基戊-2-炔基。炔基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 "Alkynyl" includes branched and straight chain alkynyl groups having from 2 to 12 carbon atoms or alkenes containing aliphatic hydrocarbon groups, or if a specified number of carbon atoms is specified, that specific number is intended. Examples are ethynyl, propynyl (eg 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl. Alkynyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxyl, oxygen substituted, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C The 3-8 cycloalkenyloxy, aryl or 5 to 6 membered heteroaryl is optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
术语“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至7个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro Ring, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, Oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy , C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5 to 6 membered heteroaryl optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
所述环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzo rings Heptyl, etc. Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano , amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy , C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy , aryl, or 5- to 6-membered heteroaryl optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
术语“环烯基”指部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至8个碳原子。实例包括但不限于环戊烯基、环己烯基或环己二烯基。环烯基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. Cycloalkenyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy , C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy , aryl, or 5- to 6-membered heteroaryl optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
术语“杂环烷基(Heterocycloalkyl)”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至7个环原子。单环杂环烷基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环烷基包括螺环、 稠环和桥环的杂环烷基。“杂环烷基”非限制性实例包括： The term "Heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which are optional Heteroatoms from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piper pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl groups include spiro, fused and bridged ring heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:
Figure PCTCN2021133316-appb-000044
Figure PCTCN2021133316-appb-000045
等等。
Figure PCTCN2021133316-appb-000044
Figure PCTCN2021133316-appb-000045
and many more.
所述杂环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为杂环烷基，其非限制性实例包括：The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
Figure PCTCN2021133316-appb-000046
等。
Figure PCTCN2021133316-appb-000046
Wait.
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 Heterocycloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano base, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy base, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy aryl, aryl or 5 to 6 membered heteroaryl optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也 就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 12 membered, such as benzene base and naphthyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:
Figure PCTCN2021133316-appb-000047
Figure PCTCN2021133316-appb-000047
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氘、卤素、羟基、烷基、环烷基、杂环烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基、环烯氧基、-SR'、-S(O) 2R'、-NR'(R”)、-COR'、-COOR'或-CONR'(R”)，R'或R”独立地选自氢、氘、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基，所述烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基或氨基所取代。 Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl , alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R"), R' or R" is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or Heteroaryl, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally containing one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano group or amino group.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪，
Figure PCTCN2021133316-appb-000048
等等。 The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6- to 12-membered, more preferably 5- or 6-membered. E.g. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,
Figure PCTCN2021133316-appb-000048
and many more.
所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2021133316-appb-000049
Figure PCTCN2021133316-appb-000049
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氘、卤素、羟基、烷基、环烷基、杂环烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基、环烯氧基、-SR'、-S(O) 2R'、-NR'(R”)、-COR'、-COOR'或-CONR'(R”)，R'或R”独立地选自氢、氘、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基，所述烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基或氨基所取代。 Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, alkyl, cycloalkyl, hetero Cycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R "), -COR', -COOR' or -CONR'(R"),R' or R" is independently selected from hydrogen, deuterium, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, Aryl or heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally being selected from one or more of halogen, deuterium, hydroxy, oxo, nitro substituted with cyano, cyano or amino groups.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。同理，“炔氧基”、“烯氧基”、“环烷氧基”、“杂环烷氧基”、“环烯氧基”的定义如上述“烷氧基”定义。 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano , amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy , C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy , aryl or 5 to 6 membered heteroaryl optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino. Similarly, the definitions of "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy" and "cycloalkenyloxy" are as defined above for "alkoxy".
术语“杂环烷氧基”指-O-(杂环烷基)，其中杂环烷基如上述定义。The term "heterocycloalkoxy" refers to -O-(heterocycloalkyl), wherein heterocycloalkyl is as defined above.
术语“羟基”指-OH基团。The term "hydroxy" refers to the -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“氧代”指＝O取代基。The term "oxo" refers to the =O substituent.
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
说明书附图Instruction drawings
图1：模型中各组耳肿胀抑制率。Figure 1: Ear swelling inhibition rate of each group in the model.
图2：模型中各组耳厚增加量。Figure 2: The increase in ear thickness for each group in the model.
具体实施方式Detailed ways
以下结合实施例进一步描述本公开中，但这些实施例并非限制本公开中的范围。The present disclosure is further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。The experimental methods without specific conditions in the examples of the present disclosure generally follow conventional conditions or conditions suggested by raw material or commodity manufacturers. Reagents with no specific source indicated are conventional reagents purchased in the market.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(Methanol-d 4)，内标为四甲基硅烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (Methanol-d 4 ), and the internal standard was Tetramethylsilane (TMS).
HPLC的测定使用Agilent1100高压液相色谱仪，GAS15B DAD紫外检测器， Water Vbridge C18 150*4.6mm 5um色谱柱。The determination of HPLC used Agilent1100 high pressure liquid chromatograph, GAS15B DAD UV detector, Water Vbridge C18 150*4.6mm 5um chromatographic column.
MS的测定用Agilent6120三重四级杆质谱仪，G1315D DAD检测器，Waters Xbridge C18 4.6*50mm,5um色谱柱，以正/负离子模式扫描，质量扫描范围为80～1200。The MS was measured using an Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, Waters Xbridge C18 4.6*50mm, 5um chromatographic column, scanning in positive/negative ion mode, and the mass scanning range was 80-1200.
薄层层析硅胶板使用烟台黄海HSGF254硅胶板，薄层色谱法(TLC)使用硅胶板采用规格是0.2mm±0.03mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 silica gel plate, the thin-layer chromatography (TLC) uses the silica gel plate with a specification of 0.2mm±0.03mm, and the thin-layer chromatography separation and purification product adopts a specification of 0.4mm-0.5mm.
快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。The flash column purification system used Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
正向柱层析一般使用烟台黄海硅胶200～300目或300～400目硅胶为载体，或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm，60g，24g，40g，120g或其它规格)。Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed pre-packed ultra-pure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自上海泰坦科技，ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)，毕得医药等公司。The known starting materials in the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Bidder Pharmaceuticals and other companies.
实施例中无特殊说明，反应能够均在氮气氛下进行。There is no special description in the examples, and the reactions can all be carried out under nitrogen atmosphere.
氮气氛是指反应瓶连接一个约1L容积的氮气气球。Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
氢气是由上海全浦科学仪器公司QPH-1L型氢气发生仪制得。Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Company.
氮气氛或氢化氛通常抽真空，充入氮气或氢气，反复操作3次。The nitrogen atmosphere or hydrogenation atmosphere is usually evacuated, filled with nitrogen or hydrogen, and the operation is repeated 3 times.
实施例中无特殊说明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying the compound, and the volume of the solvent The ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
实施例1Example 1
Figure PCTCN2021133316-appb-000050
Figure PCTCN2021133316-appb-000050
Figure PCTCN2021133316-appb-000051
Figure PCTCN2021133316-appb-000051
步骤1：化合物1b的合成Step 1: Synthesis of Compound 1b
室温下，向250毫升单口瓶中加入化合物1a(10.0g，55.5mmol)，并加入N,N-二甲基甲酰胺(40ml)搅拌至溶解，加入异丙基溴(8.50g，69.1mmol)和碳酸钾(9.55g,69.2mmol)。反应液升温至80℃并继续搅拌2小时。反应液冷却至室温后，反应液用水(100ml)稀释，乙酸乙酯(200ml X 2)萃取，饱和食盐水(100ml)洗涤。有机相经无水硫酸钠干燥，浓缩，有机相得到化合物1b(12g粗品)。LCMS:m/z 231.1(M+H) +。 At room temperature, compound 1a (10.0g, 55.5mmol) was added to a 250ml single-necked flask, and N,N-dimethylformamide (40ml) was added and stirred until dissolved, and isopropyl bromide (8.50g, 69.1mmol) was added. and potassium carbonate (9.55 g, 69.2 mmol). The temperature of the reaction solution was raised to 80°C and stirring was continued for 2 hours. After the reaction solution was cooled to room temperature, the reaction solution was diluted with water (100ml), extracted with ethyl acetate (200ml×2), and washed with saturated brine (100ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 1b (12 g crude product) in the organic phase. LCMS: m/z 231.1 (M+H) + .
步骤2：化合物1c的合成Step 2: Synthesis of Compound 1c
冰水浴下，向250毫升单口瓶中加入化合物1b(12.0g，52.2mmol)，并加入乙酸乙酯(80ml)搅拌至溶解，随后加入氨基磺酸(5.68g，58.5mmol)和水(10ml)。控制反应温度在20℃以下，滴加25％的亚氯酸钠水溶液(21.2g，58.5mmol)，滴加完毕反应至TLC检测完全。随后依次加入25％的氢氧化钠水溶液(10ml)，10％的亚硫酸钠水溶液(80.4g，63.8mmol)，继续搅拌15分钟，向反应体系中加入浓盐酸(2ml)，分离有机相，减压浓缩。将甲醇(40ml)，水(80ml)和25％的氢氧化钠水溶液加入到浓缩的残余物中，搅拌溶解，滴加浓盐酸，搅拌1小时。过滤，所得滤饼经真空干燥，得化合物1c(6.4g)。Under the ice-water bath, compound 1b (12.0g, 52.2mmol) was added to a 250-ml single-necked flask, and ethyl acetate (80ml) was added and stirred until dissolved, then sulfamic acid (5.68g, 58.5mmol) and water (10ml) were added. . The reaction temperature was controlled below 20° C., 25% aqueous sodium chlorite solution (21.2 g, 58.5 mmol) was added dropwise, and the reaction was completed by TLC detection. Subsequently, 25% aqueous sodium hydroxide solution (10 ml) and 10% aqueous sodium sulfite solution (80.4 g, 63.8 mmol) were added successively, and stirring was continued for 15 minutes. Concentrated hydrochloric acid (2 ml) was added to the reaction system, the organic phase was separated, and concentrated under reduced pressure. . Methanol (40 ml), water (80 ml) and a 25% aqueous sodium hydroxide solution were added to the concentrated residue, dissolved with stirring, and concentrated hydrochloric acid was added dropwise, followed by stirring for 1 hour. After filtration, the obtained filter cake was dried under vacuum to obtain compound 1c (6.4 g).
LCMS:m/z 245.0(M-H) -。 LCMS: m/z 245.0 (MH) - .
步骤3：化合物1d的合成Step 3: Synthesis of Compound 1d
室温下，向250毫升单口瓶中加入化合物3c(6.4g，26mmol)，并加入乙腈(80ml)搅拌至溶解，随后加入羰基二咪唑(5.1g，31.2mmol)。反应液在室温下搅拌3小时，随后加入28％浓氨水，有大量白色沉淀生成。过滤，并洗涤滤饼，得化合物1d(6.2g)。LCMS:m/z 246.1(M+H) +。 At room temperature, compound 3c (6.4g, 26mmol) was added to a 250ml single-necked flask, and acetonitrile (80ml) was added and stirred until dissolved, followed by carbonyldiimidazole (5.1g, 31.2mmol). The reaction solution was stirred at room temperature for 3 hours, then 28% concentrated ammonia water was added, and a large amount of white precipitate was formed. Filtration and washing of the filter cake gave compound 1d (6.2 g). LCMS: m/z 246.1 (M+H) + .
步骤4：化合物1e的合成Step 4: Synthesis of Compound 1e
室温下，向100毫升单口瓶中加入化合物1d(5.5g,22.41mmol),1,3-二氯丙酮(5.46g,44.81mmol)和甲苯(55ml)。反应液升温至130℃并继续搅拌至TLC监测反应完成。冷却到室温后，浓缩反应液，残留物经柱层析纯化(乙酸乙酯/石油醚)得到化合物1e(4.5g)，LCMS:m/z 317.9(M+H) +。 At room temperature, compound 1d (5.5 g, 22.41 mmol), 1,3-dichloroacetone (5.46 g, 44.81 mmol) and toluene (55 ml) were added to a 100 ml one-necked flask. The temperature of the reaction solution was raised to 130°C and stirring was continued until the completion of the reaction was monitored by TLC. After cooling to room temperature, the reaction solution was concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to obtain compound 1e (4.5 g), LCMS: m/z 317.9 (M+H) + .
步骤5：化合物1f的合成Step 5: Synthesis of Compound 1f
室温下，向250毫升单口瓶中加入化合物1e(4.5g，14.19mmol)，乙酸钾(1.66g，17.03mmol)和N,N-二甲基甲酰胺(50mL)。反应液升温至100℃反应至TLC监测反应完成。反应液冷却至室温，随后用水(500ml)稀释，并用二氯甲烷萃取(200ml X 3)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥。浓缩有机相，浓缩得到粗品化合物1f(5.8g)。At room temperature, compound 1e (4.5 g, 14.19 mmol), potassium acetate (1.66 g, 17.03 mmol) and N,N-dimethylformamide (50 mL) were added to a 250 mL single-necked flask. The temperature of the reaction solution was raised to 100°C and the reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature, then diluted with water (500ml) and extracted with dichloromethane (200ml×3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to give crude compound 1f (5.8 g).
LCMS:m/z 342.0(M+H) +。 LCMS: m/z 342.0 (M+H) + .
步骤6：化合物1g的合成Step 6: Synthesis of Compound 1g
室温下，向100毫升单口瓶中加入化合物1f(5.8g，17.0mmol)，并加入甲醇(20ml)和25％氢氧化钠水溶液(50ml)。将反应体液加热至100℃，并继续搅拌3-8小时。随后反应液冷却至室温，过滤。浓缩滤液，所得的残留物经柱层析纯化(乙酸乙酯/石油醚)得到化合物1g(2.55g)。LCMS:m/z 300.0(M+H) +。 At room temperature, compound 1f (5.8 g, 17.0 mmol) was added to a 100 mL one-neck flask, and methanol (20 mL) and 25% aqueous sodium hydroxide solution (50 mL) were added. The reaction liquid was heated to 100°C and stirring was continued for 3-8 hours. The reaction solution was then cooled to room temperature and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether) to give compound 1 g (2.55 g). LCMS: m/z 300.0 (M+H) + .
步骤7：化合物1h的合成Step 7: Synthesis of Compound 1h
室温下，向250毫升单口瓶中加入化合物1g(1.5g，5.0mmol)，并加入四氢呋喃(15ml)搅拌至溶解，随后加入活性二氧化锰(4.3mg,50.0mmol)。反应液升温至70℃并继续搅拌至TLC监测反应完全。反应液冷却至室温，过滤。浓缩滤液，残留物经柱层析纯化(乙酸乙酯/石油醚)得到化合物1h(1.36g)，CMS:m/z 298.0(M+H) +。 At room temperature, compound 1 g (1.5 g, 5.0 mmol) was added to a 250-ml single-neck flask, and tetrahydrofuran (15 ml) was added and stirred until dissolved, and then active manganese dioxide (4.3 mg, 50.0 mmol) was added. The temperature of the reaction solution was raised to 70°C and stirring was continued until the completion of the reaction was monitored by TLC. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give compound 1h (1.36 g), CMS: m/z 298.0 (M+H) + .
步骤8：化合物1i的合成Step 8: Synthesis of Compound 1i
室温下，向100毫升单口瓶中加入化合物1h(1.55g，5.22mmol)，盐酸羟胺(368mg，5.22mmol)，乙酸钠(428mg，5.22mmol)并加入乙醇(35ml)搅拌至溶解。反应液升温至85℃并继续搅拌2-10小时。冷却至室温，浓缩反应液，所得的残留物经柱层析纯化(乙酸乙酯/石油醚)得到化合物1i(825mg)，LCMS:m/z 313.0(M+H) +。 At room temperature, compound 1h (1.55g, 5.22mmol), hydroxylamine hydrochloride (368mg, 5.22mmol), sodium acetate (428mg, 5.22mmol) were added to a 100ml single-neck flask, and ethanol (35ml) was added and stirred until dissolved. The reaction solution was warmed to 85°C and stirring was continued for 2-10 hours. After cooling to room temperature, the reaction solution was concentrated, and the obtained residue was purified by column chromatography (ethyl acetate/petroleum ether) to give compound 1i (825 mg), LCMS: m/z 313.0 (M+H) + .
步骤9：化合物1j的合成Step 9: Synthesis of Compound 1j
室温下，向100毫升单口瓶中加入化合物1i(825mg，2.64mmol)和乙酸酐(5ml)。反应液升温至120℃并搅拌至LCMS监测反应完全。反应液冷却至室温，加入饱和碳酸氢钠水溶液(10ml)，并用二氯甲烷萃取(10ml X 3)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥。浓缩有机相，所得的残留物经柱层析纯化(乙酸乙酯/石油醚)得到化合物1j(720mg)，LCMS:m/z 342.0(M+H) +。 Compound 1i (825 mg, 2.64 mmol) and acetic anhydride (5 ml) were added to a 100 ml one-neck flask at room temperature. The reaction solution was warmed to 120°C and stirred until the reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (10 ml) was added, and extracted with dichloromethane (10 ml X 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether) to give compound 1j (720 mg), LCMS: m/z 342.0 (M+H) + .
步骤10：化合物1k的合成Step 10: Synthesis of Compound 1k
室温下，向25毫升三口瓶中加入化合物1j(100mg，0.34mmol)，乙醚(3ml) 和甲苯(3ml)。反应液冷却至-78℃，依次加入钛酸四异丙酯(0.13ml，0.41mmol)和乙基溴化镁(0.27ml，0.82mmol)，并在-78℃反应10-40分钟。迅速升温至室温。随后加入三氟化硼乙醚(0.07ml，0.09mmol)，室温搅拌反应至LCMS监测反应完全。向反应液中加入1摩尔的稀盐酸，再加入1摩尔的氢氧化钠水溶液，乙酸乙酯萃取(10ml X 3)，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥。浓缩有机相，所得的残留物经柱层析纯化(甲醇/二氯甲烷)得到化合物1k(75mg)，LCMS:m/z 325.1(M+H) +。 At room temperature, compound 1j (100 mg, 0.34 mmol), diethyl ether (3 ml) and toluene (3 ml) were added to a 25 ml three-necked flask. The reaction solution was cooled to -78°C, tetraisopropyl titanate (0.13ml, 0.41mmol) and ethylmagnesium bromide (0.27ml, 0.82mmol) were added in sequence, and the reaction was carried out at -78°C for 10-40 minutes. Warm quickly to room temperature. Subsequently, boron trifluoride ether (0.07 ml, 0.09 mmol) was added, and the reaction was stirred at room temperature until the reaction was complete as monitored by LCMS. 1 mol of dilute hydrochloric acid was added to the reaction solution, followed by 1 mol of sodium hydroxide aqueous solution, extracted with ethyl acetate (10 ml × 3), the combined organic phases were washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and the resulting residue was purified by column chromatography (methanol/dichloromethane) to give compound 1k (75 mg), LCMS: m/z 325.1 (M+H) + .
步骤11：化合物1的合成Step 11: Synthesis of Compound 1
室温下，向25毫升三口瓶中加入化合物1k(75mg，0.23mmol)，2-乙氧基苯甲酸(38mg，0.23mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(132mg，0.35mmol)，N,N-二异丙基乙胺(60mg，0.46mmol)和N,N-二甲基甲酰胺(3ml)。反应液室温下搅拌至LCMS监测反应完全。浓缩反应液，残留物经高效液相色谱制备(碳酸氢铵/乙腈/水体系)，得到化合物1(25mg)。At room temperature, compound 1k (75mg, 0.23mmol), 2-ethoxybenzoic acid (38mg, 0.23mmol), 2-(7-azabenzotriazole)-N,N were added to a 25 ml there-necked flask. , N',N'-tetramethylurea hexafluorophosphate (132mg, 0.35mmol), N,N-diisopropylethylamine (60mg, 0.46mmol) and N,N-dimethylformamide (3ml ). The reaction solution was stirred at room temperature until the reaction was completed as monitored by LCMS. The reaction solution was concentrated, and the residue was prepared by high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system) to obtain compound 1 (25 mg).
LCMS:m/z 473.5(M+H) + LCMS: m/z 473.5 (M+H) +
1H NMR(400MHz,CD 3OD)δ7.80-7.78(m,2H),7.67(d,J＝1.8Hz,1H),7.56(dd,J＝8.4,1.8Hz,1H),7.50–7.43(m,1H),7.23(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),7.03(t,J＝7.5Hz,1H),6.80(t,J＝74.9Hz,1H),4.77–4.66(m,1H),4.25-4.2(m,2H),1.55–1.46(m,5H),1.37(d,J＝6.0Hz,6H),1.30-1.27(m,4H). 1 H NMR (400MHz, CD 3 OD) δ 7.80-7.78 (m, 2H), 7.67 (d, J=1.8Hz, 1H), 7.56 (dd, J=8.4, 1.8Hz, 1H), 7.50-7.43 (m, 1H), 7.23 (d, J=8.4Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 7.03 (t, J=7.5Hz, 1H), 6.80 (t, J=74.9Hz) ,1H),4.77-4.66(m,1H),4.25-4.2(m,2H),1.55-1.46(m,5H),1.37(d,J＝6.0Hz,6H),1.30-1.27(m,4H) ).
Figure PCTCN2021133316-appb-000052
Figure PCTCN2021133316-appb-000052
按照实施例1中描述的方法制备化合物2。Compound 2 was prepared according to the method described in Example 1 .
LCMS:m/z 430.1(M+H) +。 LCMS: m/z 430.1 (M+H) + .
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.57(d,J＝4.1Hz,1H),8.21(d,J＝7.8Hz,1H),7.89-7.87(m,1H),7.59–7.50(m,3H),7.48-7.45(m,1H),7.18(d,J＝8.3Hz,1H),6.60(t,J＝75.2Hz,1H),473-4.65(m,1H),1.59–1.55(m,2H),1.39(d,J＝6.1Hz,6H),1.35-1.32(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (s, 1H), 8.57 (d, J=4.1 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 7.89-7.87 (m, 1H) ,7.59-7.50(m,3H),7.48-7.45(m,1H),7.18(d,J=8.3Hz,1H),6.60(t,J=75.2Hz,1H),473-4.65(m,1H) ),1.59-1.55(m,2H),1.39(d,J=6.1Hz,6H),1.35-1.32(m,2H).
Figure PCTCN2021133316-appb-000053
Figure PCTCN2021133316-appb-000053
按照实施例1中描述的方法制备化合物3。Compound 3 was prepared according to the method described in Example 1 .
LCMS:m/z 444.1(M+H) +。 LCMS: m/z 444.1 (M+H) + .
1H NMR(400MHz,CDCl 3)δ8.80(s,1H),8.40(d,J＝4.6Hz,1H),7.68–7.46(m,4H),7.34(dd,J＝7.8,4.6Hz,1H),7.18(d,J＝8.3Hz,1H),6.60(t,J＝75.3Hz,1H),4.71-4.65(m,1H),2.74(s,3H),1.57–1.52(m,2H),1.39(d,J＝6.1Hz,6H),1.33-1.29(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 8.80 (s, 1H), 8.40 (d, J=4.6Hz, 1H), 7.68-7.46 (m, 4H), 7.34 (dd, J=7.8, 4.6Hz, 1H), 7.18(d, J=8.3Hz, 1H), 6.60(t, J=75.3Hz, 1H), 4.71-4.65(m, 1H), 2.74(s, 3H), 1.57-1.52(m, 2H) ),1.39(d,J=6.1Hz,6H),1.33-1.29(m,2H).
Figure PCTCN2021133316-appb-000054
Figure PCTCN2021133316-appb-000054
按照实施例1中描述的方法制备化合物4。Compound 4 was prepared according to the method described in Example 1 .
LCMS:m/z 431.0(M+H) +。 LCMS: m/z 431.0 (M+H) + .
1H NMR(400MHz,CDCl 3)δ8.90(d,J＝4.9Hz,2H),8.66(s,1H),7.62(s,1H),7.58-7.53(m,2H),,7.48-7.46(m,1H),7.18(d,J＝8.3Hz,1H),6.60(t,J＝75.2Hz,1H),4.72-4.68(m,1H),1.61–1.58(m,2H),1.39(d,J＝6.1Hz,6H),1.37–1.33(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.90 (d, J=4.9 Hz, 2H), 8.66 (s, 1H), 7.62 (s, 1H), 7.58-7.53 (m, 2H), 7.48-7.46 (m,1H),7.18(d,J=8.3Hz,1H),6.60(t,J=75.2Hz,1H),4.72-4.68(m,1H),1.61-1.58(m,2H),1.39( d, J = 6.1Hz, 6H), 1.37–1.33 (m, 2H).
Figure PCTCN2021133316-appb-000055
Figure PCTCN2021133316-appb-000055
按照实施例1中描述的方法制备化合物5。Compound 5 was prepared according to the method described in Example 1 .
LCMS:m/z 474.1(M+H) +。 LCMS: m/z 474.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ8.37(s,1H),8.18(d,J＝8.0Hz,1H),7.93-7.89(m,2H),7.67(d,J＝2.0Hz,1H),7.57(dd,J＝8.0,2.0Hz,1H),7.24(d,J＝8.0Hz,1H),6.80(t,J＝76.0Hz,1H),4.75-4.69(m,1H),4.43(q,J＝8.0Hz,2H),1.58-1.54(m,4H),1.38(d,J＝2.0Hz,6H),1.32-1.29(m,3H). 1 H NMR (400MHz, deuterated methanol-d4)δ8.37(s,1H),8.18(d,J=8.0Hz,1H),7.93-7.89(m,2H),7.67(d,J=2.0Hz ,1H),7.57(dd,J＝8.0,2.0Hz,1H),7.24(d,J＝8.0Hz,1H),6.80(t,J＝76.0Hz,1H),4.75-4.69(m,1H) ,4.43(q,J=8.0Hz,2H),1.58-1.54(m,4H),1.38(d,J=2.0Hz,6H),1.32-1.29(m,3H).
Figure PCTCN2021133316-appb-000056
Figure PCTCN2021133316-appb-000056
按照实施例1中描述的方法制备化合物6。Compound 6 was prepared according to the method described in Example 1 .
LCMS:m/z 420.2(M+H) +。 LCMS: m/z 420.2 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ8.61-8.44(m,2H),7.74-7.64(m,2H),7.56(d,J＝8.2Hz,1H),7.22(d,J＝8.3Hz,1H),6.79(t,J＝74.9Hz,1H),4.73-4.68(m,1H),1.53-1.48(m,2H),1.33(d,J＝6.0Hz,6H),1.32-1.28(m,2H). 1 H NMR (400MHz, deuterated methanol-d4) δ8.61-8.44(m, 2H), 7.74-7.64(m, 2H), 7.56(d, J=8.2Hz, 1H), 7.22(d, J= 8.3Hz, 1H), 6.79(t, J＝74.9Hz, 1H), 4.73-4.68(m, 1H), 1.53-1.48(m, 2H), 1.33(d, J＝6.0Hz, 6H), 1.32- 1.28(m,2H).
Figure PCTCN2021133316-appb-000057
Figure PCTCN2021133316-appb-000057
按照实施例1中描述的方法制备化合物7。Compound 7 was prepared according to the method described in Example 1 .
LCMS:m/z 433.1(M+H) +。 LCMS: m/z 433.1 (M+H) + .
1H NMR(400MHz,DMSO-d 6)δ8.80(s,1H),8.14(s,1H),7.87-7.86(m,2H),7.55–7.50(m,2H),7.33–6.96(m,2H),4.75-4.69(m,1H),3.85(s,3H),1.34-1.30(m,8H),1.15-1.12(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.80(s,1H),8.14(s,1H),7.87-7.86(m,2H),7.55-7.50(m,2H),7.33-6.96(m ,2H),4.75-4.69(m,1H),3.85(s,3H),1.34-1.30(m,8H),1.15-1.12(m,2H).
Figure PCTCN2021133316-appb-000058
Figure PCTCN2021133316-appb-000058
按照实施例1中描述的方法制备化合物8。Compound 8 was prepared according to the method described in Example 1 .
LCMS:m/z 420.1(M+H) +。 LCMS: m/z 420.1 (M+H) + .
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.72(s,1H),7.59-7.52(m,3H),7.24(s,1H),7.19(d,J＝8.0Hz,1H),6.61(t,J＝76.0Hz,1H),4.72-4.65(m,1H),1.57–1.55(m,2H),1.40(d,J＝8.0Hz,6H),1.36-1.33(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 7.82(s, 1H), 7.72(s, 1H), 7.59-7.52(m, 3H), 7.24(s, 1H), 7.19(d, J=8.0Hz, 1H), 6.61(t, J＝76.0Hz, 1H), 4.72-4.65(m, 1H), 1.57-1.55(m, 2H), 1.40(d, J＝8.0Hz, 6H), 1.36-1.33(m , 2H).
Figure PCTCN2021133316-appb-000059
Figure PCTCN2021133316-appb-000059
按照实施例1中描述的方法制备化合物9。Compound 9 was prepared according to the method described in Example 1 .
LCMS:m/z 448.1(M+H) +。 LCMS: m/z 448.1 (M+H) + .
1H NMR(400MHz,CDCl 3)δ8.51(s,1H),8.39(d,J＝8.0Hz,1H),7.61(s,1H),7.59–7.43(m,4H),7.18(d,J＝8.0Hz,1H),6.60(t,J＝76.0Hz,1H),4.71-4.65(m,1H),1.56-1.53(m,2H),1.39(d,J＝8.0Hz,6H),1.35-1.32(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 8.51(s, 1H), 8.39(d, J=8.0Hz, 1H), 7.61(s, 1H), 7.59-7.43(m, 4H), 7.18(d, J=8.0Hz, 1H), 6.60(t, J=76.0Hz, 1H), 4.71-4.65(m, 1H), 1.56-1.53(m, 2H), 1.39(d, J=8.0Hz, 6H), 1.35-1.32(m,2H).
Figure PCTCN2021133316-appb-000060
Figure PCTCN2021133316-appb-000060
按照实施例1中描述的方法制备化合物10。Compound 10 was prepared according to the method described in Example 1 .
LCMS:m/z 477.1(M+H) +。 LCMS: m/z 477.1 (M+H) + .
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.58(d,J＝2.0Hz,1H),7.54(dd,J＝8.0,2.0Hz,1H),7.35-7.29(m,1H),7.19(d,J＝8.0Hz,1H),6.80-6.42(m,4H),4.70-4.67(m,1H),3.90(s,3H),1.62–1.58(m,2H),1.40(d,J＝6.1Hz,6H),1.35-1.32(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (s, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.54 (dd, J=8.0, 2.0 Hz, 1H), 7.35-7.29 (m, 1H), 7.19(d, J=8.0Hz, 1H), 6.80-6.42(m, 4H), 4.70-4.67(m, 1H), 3.90(s, 3H), 1.62-1.58(m, 2H), 1.40 (d,J=6.1Hz,6H),1.35-1.32(m,2H).
Figure PCTCN2021133316-appb-000061
Figure PCTCN2021133316-appb-000061
按照实施例1中描述的方法制备化合物11。Compound 11 was prepared according to the method described in Example 1 .
LCMS:m/z 460.1(M+H) +。 LCMS: m/z 460.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ8.37-8.18(m,1H),7.82(s,1H),7.70-7.68(m,4H),7.24(d,J＝8.0Hz,1H),6.80(t,J＝76.0Hz,1H),4.75-4.69(m,1H),3.98(s,3H),1.54-1.48(m,2H),1.38(d,J＝4.0Hz,6H),1.33-1.29(m,2H). 1 H NMR (400MHz, deuterated methanol-d4)δ8.37-8.18(m,1H),7.82(s,1H),7.70-7.68(m,4H),7.24(d,J=8.0Hz,1H) ,6.80(t,J＝76.0Hz,1H),4.75-4.69(m,1H),3.98(s,3H),1.54-1.48(m,2H),1.38(d,J＝4.0Hz,6H), 1.33-1.29(m,2H).
Figure PCTCN2021133316-appb-000062
Figure PCTCN2021133316-appb-000062
按照实施例1中描述的方法制备化合物12。Compound 12 was prepared according to the method described in Example 1 .
LCMS:m/z 477.1(M+H) +。 LCMS: m/z 477.1 (M+H) + .
1H NMR(400MHz,CDCl 3)δ8.29(s,1H),8.22(dd,J＝8.8,7.2Hz,1H),7.58–7.53(m,3H),7.18(d,J＝8.4Hz,1H),6.81–6.76(m,1H),6.73-6.69(m,1H),6.60(d,J＝75.2Hz,1H),4.71-4.65(m,1H),3.99(s,3H),1.55-1.53(m,2H),1.39(d,J＝6.4Hz,6H),1.29–1.26(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 8.22 (dd, J=8.8, 7.2 Hz, 1H), 7.58-7.53 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 6.81-6.76(m, 1H), 6.73-6.69(m, 1H), 6.60(d, J=75.2Hz, 1H), 4.71-4.65(m, 1H), 3.99(s, 3H), 1.55 -1.53(m, 2H), 1.39(d, J=6.4Hz, 6H), 1.29–1.26(m, 2H).
Figure PCTCN2021133316-appb-000063
Figure PCTCN2021133316-appb-000063
按照实施例1中描述的方法制备化合物13。Compound 13 was prepared according to the method described in Example 1 .
LCMS:m/z 464.1(M+H) +。 LCMS: m/z 464.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ8.58(s,1H),8.05(d,J＝8.4Hz,1H),7.90(s,1H),7.69(d,J＝2.0Hz,1H),7.58(dd,J＝8.4,2.0Hz,2H),7.24(d,J＝8.4Hz,1H),6.79(t,J＝74.8Hz,1H),4.76-4.70(m,1H),1.55–1.52(m,2H),1.38(d,J＝6.0Hz,6H),1.36-1.33(m,2H). 1 H NMR (400MHz, deuterated methanol-d4)δ8.58(s, 1H), 8.05(d, J=8.4Hz, 1H), 7.90(s, 1H), 7.69(d, J=2.0Hz, 1H ),7.58(dd,J＝8.4,2.0Hz,2H),7.24(d,J＝8.4Hz,1H),6.79(t,J＝74.8Hz,1H),4.76-4.70(m,1H),1.55 –1.52(m,2H),1.38(d,J=6.0Hz,6H),1.36-1.33(m,2H).
Figure PCTCN2021133316-appb-000064
Figure PCTCN2021133316-appb-000064
按照实施例1中描述的方法制备化合物14。Compound 14 was prepared according to the method described in Example 1 .
LCMS:m/z 466.1(M+H) +。 LCMS: m/z 466.1 (M+H) + .
1H NMR(400MHz,CDCl 3)δ8.34(s,1H),8.30(d,J＝2.0Hz,1H),7.60(s,1H),7.57(d,J＝1.6Hz,1H),7.53(d,J＝8.4,2.0Hz,1H),7.37–7.31(m,1H),7.19(d,J＝8.4Hz,1H),6.60(t,J＝75.2Hz,2H),4.71-4.65(m,1H),1.54-1.53(m,2H),1.43(d,J＝6.0Hz,6H),1.34–1.30(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 8.34 (s, 1H), 8.30 (d, J=2.0 Hz, 1H), 7.60 (s, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.53 (d, J=8.4, 2.0Hz, 1H), 7.37–7.31 (m, 1H), 7.19 (d, J=8.4Hz, 1H), 6.60 (t, J=75.2Hz, 2H), 4.71-4.65 ( m,1H),1.54-1.53(m,2H),1.43(d,J=6.0Hz,6H),1.34-1.30(m,2H).
Figure PCTCN2021133316-appb-000065
Figure PCTCN2021133316-appb-000065
按照实施例1中描述的方法制备化合物15。Compound 15 was prepared according to the method described in Example 1 .
LCMS:m/z 433.0(M+H) +。 LCMS: m/z 433.0 (M+H) + .
1H NMR(400MHz,DMSO-d 6)δ9.07(s,1H),7.92(s,1H),7.55(d,J＝1.8Hz,1H),7.51(dd,J＝8.4,1.8Hz,1H),7.36(s,1H),7.30(d,J＝8.0Hz,1H),7.14(t,J＝74.0Hz,1H),6.99(d,J＝1.2Hz,1H),4.76–4.70(m,1H),3.93(s,3H),1.34-1.28(m,8H),1.24–1.21(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ 9.07 (s, 1H), 7.92 (s, 1H), 7.55 (d, J=1.8Hz, 1H), 7.51 (dd, J=8.4, 1.8Hz, 1H), 7.36(s, 1H), 7.30(d, J=8.0Hz, 1H), 7.14(t, J=74.0Hz, 1H), 6.99(d, J=1.2Hz, 1H), 4.76–4.70( m,1H),3.93(s,3H),1.34-1.28(m,8H),1.24-1.21(m,2H).
Figure PCTCN2021133316-appb-000066
Figure PCTCN2021133316-appb-000066
按照实施例1中描述的方法制备化合物16。Compound 16 was prepared according to the method described in Example 1 .
LCMS:m/z 436.1(M+H) +。 LCMS: m/z 436.1 (M+H) + .
1H NMR(400MHz,DMSO-d 6)δ9.19(d,J＝2.0Hz,1H),9.16(s,1H),8.35(d,J＝2.0Hz,1H),7.90(s,1H),7.55(d,J＝2.0Hz,1H),7.51(dd,J＝8.4,2.0Hz,1H),7.30(d,J＝8.4Hz,1H),7.14(t,J＝74.0Hz,1H),4.76–4.70(m,1H),1.37-1.34(m,2H),1.31(d,J＝6.0Hz,6H),1.26-1.23(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ9.19(d,J=2.0Hz,1H),9.16(s,1H),8.35(d,J=2.0Hz,1H),7.90(s,1H) ,7.55(d,J＝2.0Hz,1H),7.51(dd,J＝8.4,2.0Hz,1H),7.30(d,J＝8.4Hz,1H),7.14(t,J＝74.0Hz,1H) ,4.76-4.70(m,1H),1.37-1.34(m,2H),1.31(d,J=6.0Hz,6H),1.26-1.23(m,2H).
Figure PCTCN2021133316-appb-000067
Figure PCTCN2021133316-appb-000067
按照实施例1中描述的方法制备化合物17。Compound 17 was prepared according to the method described in Example 1 .
LCMS:m/z 450.1(M+H) +。 LCMS: m/z 450.1 (M+H) + .
1H NMR(400MHz,DMSO-d 6)δ8.99(s,1H),8.92(s,1H),7.89(s,1H),7.58(s,1H),7.53–7.47(m,1H),7.35–6.88(m,2H),4.82–4.59(m,1H),2.74(s,3H),1.35-1.30(m,8H),1.23-1.21(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ8.99(s,1H), 8.92(s,1H), 7.89(s,1H), 7.58(s,1H), 7.53-7.47(m,1H), 7.35–6.88 (m, 2H), 4.82–4.59 (m, 1H), 2.74 (s, 3H), 1.35–1.30 (m, 8H), 1.23–1.21 (m, 2H).
Figure PCTCN2021133316-appb-000068
Figure PCTCN2021133316-appb-000068
Figure PCTCN2021133316-appb-000069
Figure PCTCN2021133316-appb-000069
步骤1：中间体18b的合成Step 1: Synthesis of Intermediate 18b
室温下，向500mL单口瓶中加入18a(20g,99.8mmol)和N,N-二甲基甲酰胺(300mL)搅拌至溶解。向反应液分批加入N-溴代琥珀酰亚胺(19.6g,110.1mmol)。反应液在室温下搅拌3小时。LCMS监测，反应完成。向反应液加水(100mL)稀释，乙酸乙酯(100mL X 3)萃取。合并的有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。减压浓缩有机相，剩余物经快速柱层析纯化(乙酸乙酯/石油醚)得到目标化合物18b(25.5g)。At room temperature, 18a (20 g, 99.8 mmol) and N,N-dimethylformamide (300 mL) were added to a 500 mL single-necked flask and stirred until dissolved. To the reaction was added N-bromosuccinimide (19.6 g, 110.1 mmol) in portions. The reaction solution was stirred at room temperature for 3 hours. As monitored by LCMS, the reaction was complete. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (ethyl acetate/petroleum ether) to give the target compound 18b (25.5 g).
1H NMR(400MHz,CDCl 3)δ7.42-7.38(m,6H),7.06(d,J＝2.2Hz,1H),7.01(dd,J＝8.4,2.2Hz,1H),6.82(d,J＝8.4Hz,1H),5.07(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ 7.42-7.38 (m, 6H), 7.06 (d, J=2.2Hz, 1H), 7.01 (dd, J=8.4, 2.2Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 5.07(s, 2H).
步骤2：中间体18c的合成Step 2: Synthesis of Intermediate 18c
室温下，向500mL单口瓶中依次加入18b(25.5g,91.3mmol)，溴二氟甲基膦酸二乙酯(48.8g,182.7mmol)和乙腈(300mL)搅拌至溶解。向反应液缓慢滴加氢氧化钾(25.7g,458.1mmol)的水(100mL)溶液。反应液在室温下搅拌18小时。TLC监测，反应完成。向反应液加水(100mL)稀释，乙酸乙酯(100mL X 3)萃取。合并的有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。减压浓缩有机相，所得的残留物经柱层析纯化(石油醚)得到18c(14.5g)。At room temperature, 18b (25.5 g, 91.3 mmol), diethyl bromodifluoromethylphosphonate (48.8 g, 182.7 mmol) and acetonitrile (300 mL) were sequentially added to a 500 mL single-necked flask and stirred until dissolved. A solution of potassium hydroxide (25.7 g, 458.1 mmol) in water (100 mL) was slowly added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 18 hours. As monitored by TLC, the reaction was complete. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the resulting residue was purified by column chromatography (petroleum ether) to give 18c (14.5 g).
1H NMR(400MHz,CDCl 3)δ7.46–7.30(m,6H),7.16(d,J＝1.8Hz,1H),7.08–7.01(m,1H),6.53(t,J＝74.8Hz,1H),5.10(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ 7.46-7.30 (m, 6H), 7.16 (d, J=1.8Hz, 1H), 7.08-7.01 (m, 1H), 6.53 (t, J=74.8Hz, 1H), 5.10(s, 2H).
步骤3：中间体18d的合成Step 3: Synthesis of Intermediate 18d
室温下，向500mL单口瓶中依次加入18c(14.5g,44.0mmol)，4,4,5,5-四甲基-2-(四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧杂硼烷(16.8g,66.1mmol)和二 氧六环(250mL)搅拌至溶解。向反应液加入醋酸钾(8.7g,88.6mmol)和双[5-(二苯基膦基)环戊-1,3-二烯-1-基]铁二氯化钯(1g,1.3mmol)。反应液在氮气保护下90℃搅拌18小时。LCMS监测，反应完成。反应液冷却至室温，向反应液加水(100mL)稀释，乙酸乙酯(150mL X 3)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。减压浓缩有机相，剩余物经柱层析纯化(乙酸乙酯/石油醚)得到目标化合物18d(14.1g)。At room temperature, 18c (14.5g, 44.0mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborane- 2-yl)-1,3,2-dioxaborane (16.8 g, 66.1 mmol) and dioxane (250 mL) were stirred until dissolved. To the reaction solution were added potassium acetate (8.7 g, 88.6 mmol) and bis[5-(diphenylphosphino)cyclopent-1,3-dien-1-yl]iron palladium dichloride (1 g, 1.3 mmol) . The reaction solution was stirred at 90°C for 18 hours under nitrogen protection. As monitored by LCMS, the reaction was complete. The reaction solution was cooled to room temperature, water (100 mL) was added to the reaction solution to dilute, extracted with ethyl acetate (150 mL×3), the organic phase was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give the target compound 18d (14.1 g).
LCMS:m/z 375.2(M-H) +。 LCMS: m/z 375.2 (MH) + .
步骤4：中间体18e的合成Step 4: Synthesis of Intermediate 18e
室温下，向50mL单口瓶中加入18d(13.5g,35.8mmol)和二氧六环(240mL)和水(80mL)搅拌至溶解。向反应液依次加入2-氯-1,3-恶唑-4-羧酸乙酯(6g,34.1mmol)，双[5-(二苯基膦基)环戊-1,3-二烯-1-基]铁二氯化钯(1.3g,1.7mmol)和磷酸钾(16.6g,72.086mmol)。反应液在氮气保护下70℃反应18小时。LCMS监测，反应完成。反应液冷却至室温，向反应液加水(80mL)稀释，乙酸乙酯(100mL X 3)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。减压浓缩有机相，剩余物经柱层析纯化(乙酸乙酯/石油醚)得到目标化合物18e(8.2g)。At room temperature, 18d (13.5 g, 35.8 mmol), dioxane (240 mL) and water (80 mL) were added to a 50 mL one-neck flask and stirred until dissolved. To the reaction solution were sequentially added 2-chloro-1,3-oxazole-4-carboxylic acid ethyl ester (6g, 34.1mmol), bis[5-(diphenylphosphino)cyclopent-1,3-diene- 1-yl]iron palladium dichloride (1.3 g, 1.7 mmol) and potassium phosphate (16.6 g, 72.086 mmol). The reaction solution was reacted at 70°C for 18 hours under nitrogen protection. As monitored by LCMS, the reaction was complete. The reaction solution was cooled to room temperature, water (80 mL) was added to the reaction solution to dilute, extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give the target compound 18e (8.2 g).
1H NMR(400MHz,CDCl 3)δ8.26(s,1H),7.84(d,J＝2.0Hz,1H),7.70-7.68(m,1H),7.47-7.33(m,5H),7.41(d,J＝7.6Hz,1H),6.64(t,J＝74.8Hz,1H),5.21(s,2H),4.43(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.26 (s, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.70-7.68 (m, 1H), 7.47-7.33 (m, 5H), 7.41 ( d, J=7.6Hz, 1H), 6.64 (t, J=74.8Hz, 1H), 5.21 (s, 2H), 4.43 (q, J=7.2Hz, 2H), 1.41 (t, J=7.2Hz, 3H).
步骤5：中间体18f的合成Step 5: Synthesis of Intermediate 18f
室温下，向50mL单口瓶中加入18e(8g,20.5mmol)和甲醇(80mL)搅拌至溶解。向反应液加入7M氨甲醇溶液(80mL,560mmol)。反应液在60℃下搅拌18小时。LCMS监测，反应完成。将反应液过滤并浓缩。得到目标化合物17q(6.9g)。At room temperature, 18e (8 g, 20.5 mmol) and methanol (80 mL) were added to a 50 mL one-neck flask and stirred until dissolved. To the reaction solution was added 7M ammonia methanol solution (80 mL, 560 mmol). The reaction solution was stirred at 60°C for 18 hours. As monitored by LCMS, the reaction was complete. The reaction solution was filtered and concentrated. The title compound 17q (6.9 g) was obtained.
LCMS:m/z 361.3(M+1) +。 LCMS: m/z 361.3 (M+1) + .
步骤6：中间体18g的合成Step 6: Synthesis of Intermediate 18g
室温下，向50mL单口瓶中加入18f(6.9g,19.1mmol)和二氯甲烷(50mL)搅拌至溶解。向反应液加入伯吉斯试剂(9.1g,38.2mmol)。反应液在室温下搅拌18小时。LCMS监测，反应完成。向反应液加水(10mL)稀释，乙酸乙酯(50mL X 3)萃取，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。有机相减压浓缩，剩余物经柱层析纯化(乙酸乙酯/石油醚)得到目标化合物18g(4.9g)。At room temperature, 18f (6.9 g, 19.1 mmol) and dichloromethane (50 mL) were added to a 50 mL single-neck flask and stirred until dissolved. To the reaction solution was added Burgess reagent (9.1 g, 38.2 mmol). The reaction solution was stirred at room temperature for 18 hours. As monitored by LCMS, the reaction was complete. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (50 mL×3), the organic phase was washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to obtain 18 g (4.9 g) of the target compound.
LCMS:m/z 343.2(M+H) +。 LCMS: m/z 343.2 (M+H) + .
步骤7：中间体18h的合成Step 7: Synthesis of Intermediate 18h
室温下，向50mL三口瓶中加入18g(500mg,1.4mmol)和甲苯(10mL)和乙醚(10mL)的混合溶剂搅拌至溶解。反应液冷却至-78℃，向反应液加入四异丙醇钛(0.5mL,1.7mmol)和3M乙基溴化镁(1.2mL，3.6mmoL)。反应液在-78℃继续搅拌30分钟后回升至室温，继续搅拌1小时。向反应液加入三氟化 硼乙醚络合物(0.01mL,0.07mmol)。反应液再搅拌2小时。LCMS监测，反应完成。向体系中加入1M盐酸(10mL)稀释，并用1M氢氧化钠溶液将pH调至10，混合液用乙酸乙酯萃取(30mL X 3)。合并的有机相用饱和食盐(30mL)洗涤，无水硫酸钠干燥。减压浓缩有机相，剩余物经柱层析纯化(甲醇/二氯甲烷)得到目标化合物18h(458mg)。At room temperature, 18 g (500 mg, 1.4 mmol) and a mixed solvent of toluene (10 mL) and diethyl ether (10 mL) were added to a 50 mL three-necked flask and stirred until dissolved. The reaction solution was cooled to -78°C, and titanium tetraisopropoxide (0.5 mL, 1.7 mmol) and 3M ethylmagnesium bromide (1.2 mL, 3.6 mmol) were added to the reaction solution. The reaction solution was stirred at -78°C for 30 minutes, then returned to room temperature, and the stirring was continued for 1 hour. To the reaction solution was added boron trifluoride diethyl ether complex (0.01 mL, 0.07 mmol). The reaction solution was stirred for an additional 2 hours. As monitored by LCMS, the reaction was complete. 1M hydrochloric acid (10 mL) was added to the system to dilute, and the pH was adjusted to 10 with 1M sodium hydroxide solution, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated common salt (30 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (methanol/dichloromethane) to give the target compound 18h (458 mg).
LCMS:m/z 373.1(M+H) +。 LCMS: m/z 373.1 (M+H) + .
步骤8：中间体18i的合成Step 8: Synthesis of Intermediate 18i
室温下，向50mL单口瓶中依次加入18h(600mg，1.61mmol)，1-甲基-1H-咪唑-2-羧酸(203mg，1.61mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.23g，3.23mmol)，N,N-二异丙基乙胺(416mg，3.23mmol)和N,N-二甲基甲酰胺(10mL)搅拌至溶解。反应液室温搅拌反应6小时。反应液用水(40mL)稀释，用乙酸乙酯(20mL X 3)萃取。合并的有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。减压浓缩有机相，剩余物经柱层析(乙酸乙酯/石油醚)纯化得到18i(499mg)。At room temperature, 18h (600mg, 1.61mmol), 1-methyl-1H-imidazole-2-carboxylic acid (203mg, 1.61mmol), 2-(7-azobenzotriazole) were successively added to the 50mL single-necked flask )-N,N,N',N'-tetramethylurea hexafluorophosphate (1.23 g, 3.23 mmol), N,N-diisopropylethylamine (416 mg, 3.23 mmol) and N,N-diisopropylethylamine (416 mg, 3.23 mmol) Methylformamide (10 mL) was stirred until dissolved. The reaction solution was stirred at room temperature for 6 hours. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give 18i (499 mg).
LCMS m/z 480.6(M+H) +。 LCMS m/z 480.6 (M+H) + .
步骤9：中间体18j的合成Step 9: Synthesis of Intermediate 18j
室温下，向25毫升三口瓶中加入18i(499mg,1.04mmol)和无水甲醇(10.0mL)搅拌至完全溶解。向反应液中加入10％钯碳(40mg)。反应液在氢气球下室温下搅拌反应16小时。LCMS监测，反应完成。反应液过滤，滤液浓缩得到目标化合物18j(368mg)。At room temperature, 18i (499 mg, 1.04 mmol) and anhydrous methanol (10.0 mL) were added to a 25 mL three-necked flask and stirred until completely dissolved. To the reaction solution was added 10% palladium on carbon (40 mg). The reaction solution was stirred under a hydrogen balloon at room temperature for 16 hours. As monitored by LCMS, the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to obtain the target compound 18j (368 mg).
LCMS:m/z 391.1(M+H) +。 LCMS: m/z 391.1 (M+H) + .
步骤10：化合物18的合成Step 10: Synthesis of Compound 18
室温下，向25毫升三口瓶中依次加入18j(100mg，0.26mmol)，(S)-四氢呋喃-3-醇(22.56mg，0.26mmol)，三苯基膦(100.79mg,0.38mmol)和四氢呋喃(5mL)搅拌至溶解。向反应液加入偶氮二甲酸二异丙酯(93.57mg,0.41mmol)。反应液在室温下搅拌反应16小时。LCMS监测，反应完成。减压浓缩反应液，剩余物用制备级液相色谱纯化得到目标化合物18(8.45mg)。At room temperature, 18j (100mg, 0.26mmol), (S)-tetrahydrofuran-3-ol (22.56mg, 0.26mmol), triphenylphosphine (100.79mg, 0.38mmol) and tetrahydrofuran ( 5 mL) and stir until dissolved. To the reaction solution was added diisopropyl azodicarboxylate (93.57 mg, 0.41 mmol). The reaction solution was stirred at room temperature for 16 hours. As monitored by LCMS, the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain the target compound 18 (8.45 mg).
LCMS:m/z 461.1(M+H) +。 LCMS: m/z 461.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ7.82(s,1H),7.59(d,J＝1.6Hz,1H),7.59(d,J＝8.4Hz,1H),7.40(s,1H),7.25(d,J＝8.4Hz,1H),7.24(s,1H),6.80(t,J＝74.8Hz,1H),5.17-5.15(m,1H),4.03(s,3H),4.02–3.96(m,3H),3.93-3.88(m,1H),2.35–2.25(m,1H),2.20-2.14(m,1H),1.52-1.48(m,2H),1.35-1.31(m,2H). 1 H NMR (400MHz, deuterated methanol-d4)δ7.82(s,1H),7.59(d,J=1.6Hz,1H),7.59(d,J=8.4Hz,1H),7.40(s,1H) ), 7.25(d, J=8.4Hz, 1H), 7.24(s, 1H), 6.80(t, J=74.8Hz, 1H), 5.17-5.15(m, 1H), 4.03(s, 3H), 4.02 –3.96(m,3H),3.93-3.88(m,1H),2.35-2.25(m,1H),2.20-2.14(m,1H),1.52-1.48(m,2H),1.35-1.31(m, 2H).
Figure PCTCN2021133316-appb-000070
Figure PCTCN2021133316-appb-000070
按照实施例18中描述的方法制备化合物19。Compound 19 was prepared according to the method described in Example 18.
LCMS:m/z 461.1(M+H) +。 LCMS: m/z 461.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ7.84(s,1H),7.65(s,1H),7.61(d,J＝8.4Hz,1H),7.44(s,1H),7.27(d,J＝8.4Hz,2H),6.80(t,J＝74.8Hz,1H),5.17-5.16(m,1H),4.05(s,3H),4.02-3.96(m,3H),3.93-3.88(m,1H),2.35-2.29(m,1H),2.20–2.14(m,1H),1.52–1.49(m,2H),1.35-1.32(m,2H). 1 H NMR (400MHz, deuterated methanol-d4)δ7.84(s,1H),7.65(s,1H),7.61(d,J=8.4Hz,1H),7.44(s,1H),7.27(d , J=8.4Hz, 2H), 6.80(t, J=74.8Hz, 1H), 5.17-5.16(m, 1H), 4.05(s, 3H), 4.02-3.96(m, 3H), 3.93-3.88( m,1H), 2.35-2.29(m,1H), 2.20-2.14(m,1H), 1.52-1.49(m,2H), 1.35-1.32(m,2H).
Figure PCTCN2021133316-appb-000071
Figure PCTCN2021133316-appb-000071
按照实施例18中描述的方法制备化合物20。 Compound 20 was prepared according to the method described in Example 18.
LCMS:m/z 447.1(M+H) +。 LCMS: m/z 447.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ7.78(s,1H),7.62(dd,J＝8.4,1.8Hz,1H),7.30-7.28(m,2H),7.24(s,1H),7.07-6.70(m,2H),5.48–5.36(m,1H),5.06(t,J＝6.8Hz,2H),4.77-4.74(m,2H),4.00(s,3H),1.50-1.47(m,2H),1.32-1.29(m,2H). 1 H NMR (400MHz, deuterated methanol-d4)δ7.78(s,1H),7.62(dd,J=8.4,1.8Hz,1H),7.30-7.28(m,2H),7.24(s,1H) ,7.07-6.70(m,2H),5.48-5.36(m,1H),5.06(t,J=6.8Hz,2H),4.77-4.74(m,2H),4.00(s,3H),1.50-1.47 (m,2H),1.32-1.29(m,2H).
Figure PCTCN2021133316-appb-000072
Figure PCTCN2021133316-appb-000072
步骤1：中间体21a的合成Step 1: Synthesis of Intermediate 21a
室温下，向25mL单口瓶中依次加入18h(620mg，1.67mmol)，噻唑-4-羧 酸(215mg，1.67mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(760mg，2.00mmol)，N,N-二异丙基乙胺(431mg，3.34mmol)和N,N-二甲基甲酰胺(10mL)。反应液在20℃搅拌6小时。LCMS监测，反应完成。反应液用水(40mL)稀释，乙酸乙酯(20mL X 3)萃取。合并的有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。浓缩有机相，剩余物经柱层析(石油醚/乙酸乙酯)得到21a(483mg)。At room temperature, 18h (620mg, 1.67mmol), thiazole-4-carboxylic acid (215mg, 1.67mmol), 2-(7-azobenzotriazole)-N,N,N were successively added to a 25mL single-necked flask. ',N'-Tetramethylurea hexafluorophosphate (760 mg, 2.00 mmol), N,N-diisopropylethylamine (431 mg, 3.34 mmol) and N,N-dimethylformamide (10 mL). The reaction solution was stirred at 20°C for 6 hours. As monitored by LCMS, the reaction was complete. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated and the residue was subjected to column chromatography (petroleum ether/ethyl acetate) to give 21a (483 mg).
LCMS:m/z:484.0(M+H) +。 LCMS: m/z: 484.0 (M+H) + .
步骤2：中间体21b的合成Step 2: Synthesis of Intermediate 21b
室温下，向25mL单口瓶中依次加入21b(200mg,0.41mmol)，三甲基碘硅烷(331mg,1.65mmol)和乙腈(4mL)搅拌至溶解。反应液在60℃搅拌6小时。减压浓缩反应液，剩余物用二氯甲烷(50mL)溶解，饱和食盐水(50mL)洗涤，无水硫酸钠干燥。浓缩有机相，剩余物经制备板层析纯化得到21c(86mg)。At room temperature, 21b (200 mg, 0.41 mmol), trimethylsilyl iodide (331 mg, 1.65 mmol) and acetonitrile (4 mL) were sequentially added to a 25 mL single-necked flask and stirred until dissolved. The reaction solution was stirred at 60°C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and the residue was purified by preparative plate chromatography to give 21c (86 mg).
LCMS:m/z 394.0(M+H) +。 LCMS: m/z 394.0 (M+H) + .
步骤3：化合物21的合成Step 3: Synthesis of Compound 21
室温下，向25毫升三口瓶中依次加入21c(40mg，0.11mmol)，(S)-四氢呋喃-3-醇(35.2mg，0.41mmol)，三苯基膦(107mg,0.41mmol)和四氢呋喃(5mL)搅拌至溶解。向反应液加入偶氮二甲酸二异丙酯(82.2mg,0.408mmol)。反应液在室温下搅拌反应16小时。LCMS监测，反应完成。减压浓缩反应液，剩余物经制备级液相色谱纯化得到目标化合物21(9.37mg)。At room temperature, 21c (40mg, 0.11mmol), (S)-tetrahydrofuran-3-ol (35.2mg, 0.41mmol), triphenylphosphine (107mg, 0.41mmol) and tetrahydrofuran (5mL) were successively added to a 25ml there-necked flask ) and stir until dissolved. To the reaction solution was added diisopropyl azodicarboxylate (82.2 mg, 0.408 mmol). The reaction solution was stirred at room temperature for 16 hours. As monitored by LCMS, the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain the target compound 21 (9.37 mg).
LCMS:m/z 464.2(M+H) +。 LCMS: m/z 464.2 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ9.02(d,J＝2.0Hz,1H),8.29(d,J＝2.0Hz,1H),7.74(s,1H),7.66(d,J＝2.0Hz,1H),7.60(dd,J＝8.4,2.0Hz,1H),7.26(d,J＝8.4Hz,1H),6.80(t,J＝74.4Hz,1H),5.18-5.16(m,1H),4.02-3.88(m,4H),2.32-2.26(m,1H),2.18-2.16(m,1H),1.53-1.50(m,2H),1.35-1.32(m,2H). 1 H NMR (400MHz, deuterated methanol-d4)δ9.02(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),7.74(s,1H),7.66(d,J ＝2.0Hz,1H),7.60(dd,J＝8.4,2.0Hz,1H),7.26(d,J＝8.4Hz,1H),6.80(t,J＝74.4Hz,1H),5.18-5.16(m ,1H),4.02-3.88(m,4H),2.32-2.26(m,1H),2.18-2.16(m,1H),1.53-1.50(m,2H),1.35-1.32(m,2H).
Figure PCTCN2021133316-appb-000073
Figure PCTCN2021133316-appb-000073
按照实施例21中描述的方法制备化合物22。Compound 22 was prepared according to the method described in Example 21.
LCMS:m/z 464.0(M+H) +。 LCMS: m/z 464.0 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ9.02(d,J＝2.0Hz,1H),8.29(d,J＝2.0Hz,1H),7.74(s,1H),7.66(d,J＝2.0Hz,1H),7.60(dd,J＝8.4,2.0Hz,1H),7.26(d,J＝8.4Hz,1H),6.80(t,J＝74.4Hz,1H),5.18-5.17(m,1H),4.03-3.88(m,4H),2.35-2.26(m,1H),2.19-2.14(m,1H),1.53-1.50(m,2H),1.34-1.32(m,2H). 1 H NMR (400MHz, deuterated methanol-d4)δ9.02(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),7.74(s,1H),7.66(d,J ＝2.0Hz,1H),7.60(dd,J＝8.4,2.0Hz,1H),7.26(d,J＝8.4Hz,1H),6.80(t,J＝74.4Hz,1H),5.18-5.17(m ,1H),4.03-3.88(m,4H),2.35-2.26(m,1H),2.19-2.14(m,1H),1.53-1.50(m,2H),1.34-1.32(m,2H).
Figure PCTCN2021133316-appb-000074
Figure PCTCN2021133316-appb-000074
按照实施例21中描述的方法制备化合物23。Compound 23 was prepared according to the method described in Example 21.
LCMS:m/z 450.0(M+H) +。 LCMS: m/z 450.0 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ9.02(d,J＝1.6Hz,1H),8.29(d,J＝2.0Hz,1H),7.73(s,1H),7.62(dd,J＝8.4,1.6Hz,1H),7.29-7.28(m,2H),6.88(t,J＝74.0Hz,1H),5.42-5.38(m,1H),5.05(t,J＝6.8Hz,2H),4.76-4.73(m,2H),1.51-1.49(m,2H),1.34-1.32(m,2H). 1 H NMR (400MHz, deuterated methanol-d4)δ9.02(d,J=1.6Hz,1H),8.29(d,J=2.0Hz,1H),7.73(s,1H),7.62(dd,J ＝8.4,1.6Hz,1H),7.29-7.28(m,2H),6.88(t,J＝74.0Hz,1H),5.42-5.38(m,1H),5.05(t,J＝6.8Hz,2H) ,4.76-4.73(m,2H),1.51-1.49(m,2H),1.34-1.32(m,2H).
Figure PCTCN2021133316-appb-000075
Figure PCTCN2021133316-appb-000075
按照实施例21中描述的方法制备化合物24。Compound 24 was prepared according to the method described in Example 21.
LCMS:m/z:501.2(M+H) +。 LCMS: m/z: 501.2 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ7.80–7.78(m,2H),7.65(s,1H),7.61(dd,J＝8.4,2.0Hz,1H),7.48–7.45(m,1H),7.27(d,J＝8.0Hz,1H),7.12(d,J＝8.4Hz,1H),7.04(t,J＝7.6Hz,1H),6.80(t,J＝74.8Hz,1H),5.18-5.17(m,1H),4.23(q,J＝7.0Hz,2H),4.08-3.95(m,3H),3.91-3.88(m,1H),2.33-2.28(m,1H),2.19-2.15(m,1H),1.53-1.50(m,5H),1.30-1.28(m,2H). 1 H NMR (400MHz, deuterated methanol-d4) δ 7.80–7.78 (m, 2H), 7.65 (s, 1H), 7.61 (dd, J=8.4, 2.0Hz, 1H), 7.48–7.45 (m, 1H), 7.27(d, J＝8.0Hz, 1H), 7.12(d, J＝8.4Hz, 1H), 7.04(t, J＝7.6Hz, 1H), 6.80(t, J＝74.8Hz, 1H) ,5.18-5.17(m,1H),4.23(q,J＝7.0Hz,2H),4.08-3.95(m,3H),3.91-3.88(m,1H),2.33-2.28(m,1H),2.19 -2.15(m,1H),1.53-1.50(m,5H),1.30-1.28(m,2H).
Figure PCTCN2021133316-appb-000076
Figure PCTCN2021133316-appb-000076
按照实施例21中描述的方法制备化合物25。Compound 25 was prepared according to the method described in Example 21.
LCMS:m/z 472.1(M+H) +。 LCMS: m/z 472.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ9.06(s,1H),7.76(d,J＝7.6Hz,1H),7.66(s,1H),7.53(d,J＝8.4Hz,1H),7.47(t,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),7.07(s,1H),7.04(t,J＝7.6Hz,1H),6.79(t,J＝74.8Hz,1H),4.73-4.67(m,1H),4.21(q,J＝7.2Hz,2H),1.54-1.51(m,2H),1.48(t,J＝8.0Hz,3H), 1.42-1.39(m,2H),1.37(d,J＝6.0Hz,6H) 1 H NMR (400MHz, deuterated methanol-d4)δ9.06(s,1H),7.76(d,J=7.6Hz,1H),7.66(s,1H),7.53(d,J=8.4Hz,1H ),7.47(t,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),7.07(s,1H),7.04(t,J =7.6Hz,1H),6.79(t,J=74.8Hz,1H),4.73-4.67(m,1H),4.21(q,J=7.2Hz,2H),1.54-1.51(m,2H),1.48 (t, J＝8.0Hz, 3H), 1.42-1.39(m, 2H), 1.37(d, J＝6.0Hz, 6H)
Figure PCTCN2021133316-appb-000077
Figure PCTCN2021133316-appb-000077
按照实施例21中描述的方法制备化合物26。Compound 26 was prepared according to the method described in Example 21.
LCMS:m/z 432.1(M+H) +。 LCMS: m/z 432.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ7.66(d,J＝2.0Hz,1H),7.53(dd,J＝8.0,1.6Hz,1H),7.27(s,1H),7.23(d,J＝8.4Hz,1H),7.06-7.05(m,2H),6.80(t,J＝74.8Hz,1H),4.72-4.70(m,1H),4.00(s,3H),1.53-1.49(m,2H),1.43-1.39(m,2H),1.37(d,J＝6.4Hz,6H). 1 H NMR (400MHz, deuterated methanol-d4)δ7.66(d,J=2.0Hz,1H),7.53(dd,J=8.0,1.6Hz,1H),7.27(s,1H),7.23(d , J=8.4Hz, 1H), 7.06-7.05(m, 2H), 6.80(t, J=74.8Hz, 1H), 4.72-4.70(m, 1H), 4.00(s, 3H), 1.53-1.49( m, 2H), 1.43-1.39 (m, 2H), 1.37 (d, J=6.4Hz, 6H).
Figure PCTCN2021133316-appb-000078
Figure PCTCN2021133316-appb-000078
按照实施例21中描述的方法制备化合物27。Compound 27 was prepared according to the method described in Example 21.
LCMS:m/z 435.1(M+H) +。 LCMS: m/z 435.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ9.02(d,J＝2.0Hz,1H),8.31(d,J＝2.0Hz,1H),7.65(d,J＝2.0Hz,1H),7.52(dd,J＝8.4,2.0Hz,1H),7.23(d,J＝8.4Hz,1H),7.03(s,1H),6.79(t,J＝74.8Hz,1H),4.74-4.68(m,1H),1.54-1.51(m,2H),1.45-1.41(m,2H),1.37(d,J＝6.0Hz,6H). 1 H NMR (400MHz, deuterated methanol-d4)δ9.02(d,J=2.0Hz,1H),8.31(d,J=2.0Hz,1H),7.65(d,J=2.0Hz,1H), 7.52(dd,J=8.4,2.0Hz,1H),7.23(d,J=8.4Hz,1H),7.03(s,1H),6.79(t,J=74.8Hz,1H),4.74-4.68(m ,1H),1.54-1.51(m,2H),1.45-1.41(m,2H),1.37(d,J=6.0Hz,6H).
Figure PCTCN2021133316-appb-000079
Figure PCTCN2021133316-appb-000079
按照实施例1中描述的方法制备化合物28。Compound 28 was prepared according to the method described in Example 1 .
LCMS:m/z:459.1(M+H) +。 LCMS: m/z: 459.1 (M+H) + .
1H NMR(400MHz,氘代甲醇-d4)δ9.03(s,1H),7.79-7.78(m,2H),7.67(d,J＝2.0Hz,1H),7.57(dd,J＝8.0,2.0Hz,1H),7.49-7.45(m,1H),7.23(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),7.04(t,J＝8.0Hz,1H),6.82(t,J＝76.0Hz,1H),4.26-4.16(m,4H),1.53-1.44(m,8H),1.30-1.27(m,2H). 1 H NMR (400MHz, deuterated methanol-d4)δ9.03(s,1H),7.79-7.78(m,2H),7.67(d,J=2.0Hz,1H),7.57(dd,J=8.0, 2.0Hz,1H),7.49-7.45(m,1H),7.23(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),7.04(t,J=8.0Hz,1H) ,6.82(t,J＝76.0Hz,1H),4.26-4.16(m,4H),1.53-1.44(m,8H),1.30-1.27(m,2H).
生物学评价Biological evaluation
以下结合测试例进一步描述解释本公开中，但这些测试例并非意味着限制本公开中的范围。The following is further described in conjunction with test examples to explain the present disclosure, but these test examples are not meant to limit the scope of the present disclosure.
化合物A的结构为：The structure of compound A is:
Figure PCTCN2021133316-appb-000080
Figure PCTCN2021133316-appb-000080
化合物A是采用专利申请“CN104603116A中说明书第25页的实施例1”公开的方法制备而得的。Compound A was prepared by the method disclosed in the patent application "Example 1 on page 25 of the specification in CN104603116A".
测试例1：体外PDE4B酶活性检测实验Test Example 1: In vitro PDE4B Enzyme Activity Detection Experiment
1.实验材料1. Experimental materials
名称name 品牌brand 货号/型号Item/Model
PDE4B1PDE4B1 BPSBPS 6004160041
TrequinsinTrequinsin T℃RIST°CRIS 2337/102337/10
IMAP FP IPP Explorer KitIMAP FP IPP Explorer Kit Molecular DeviceMolecular Device R8124R8124
FAM-cAMPFAM-cAMP Molecular DeviceMolecular Device R7506R7506
OptiPlate TM-384 F black assay plate OptiPlate TM -384 F black assay plate PerkinElmerPerkinElmer 60072796007279
384 well Echo plate384 well Echo plate LabcyteLabcyte PP-0200PP-0200
2.实验步骤2. Experimental steps
为了进行化合物测试，先在试管中以90％的DMSO(10％的水)配置浓度为10mM的化合物储备溶液，并用其制备稀释梯度为1:5的系列稀释液，终浓度从100uM开始，低至0.05nM。为了进行酶测定，将0.2ul化合物溶液转入384孔反应板中，阴性对照和阳性对照均转入0.2ul的100％DMSO。然后向孔中加入10ul的2倍浓度PDE4B1酶溶液(终浓度为0.04nM)，对于无酶活对照孔，用10ul的1倍反应缓冲液替代酶溶液。1000rpm离心1min，室温下孵育15分钟。接着向384孔反应板每孔中加入10ul的2倍FAM-cAMP底物溶液(底物终浓度为0.1uM)，1000rpm离心1min，25℃反应30分钟。反应结束后向384孔反应板每孔中加入60ul的反应终止液终止反应，室温下摇床600rpm振荡避光孵育60分钟。孵育结束后读取RLU数据并计算抑制率，根据浓度和抑制率拟合曲线计算出IC 50值，其中最大值是指DMSO对照的读值，最小值是指无酶活对照的读值。 For compound testing, compound stock solutions at a concentration of 10 mM in 90% DMSO (10% in water) were prepared in test tubes and used to prepare serial dilutions with a dilution gradient of 1:5, starting at 100uM final concentrations, low to 0.05nM. For enzymatic assays, 0.2 ul of compound solutions were transferred into 384-well reaction plates, and both negative and positive controls were transferred into 0.2 ul of 100% DMSO. Then 10ul of 2x concentration PDE4B1 enzyme solution (final concentration 0.04nM) was added to the wells, and 10ul of 1x reaction buffer was used to replace the enzyme solution for control wells with no enzyme activity. Centrifuge at 1000 rpm for 1 min and incubate at room temperature for 15 min. Then, 10ul of 2-fold FAM-cAMP substrate solution (substrate final concentration of 0.1uM) was added to each well of the 384-well reaction plate, centrifuged at 1000 rpm for 1 min, and reacted at 25°C for 30 minutes. After the reaction, 60ul of reaction stop solution was added to each well of the 384-well reaction plate to terminate the reaction, and the reaction was incubated at room temperature with shaking at 600 rpm in the dark for 60 minutes. After the incubation, read the RLU data and calculate the inhibition rate, and calculate the IC 50 value according to the concentration and inhibition rate fitting curve, where the maximum value refers to the reading value of DMSO control, and the minimum value refers to the reading value of no enzyme activity control.
本公开的实施例在体外对PDE4B1酶活性抑制通过以上的试验进行测定，测得的IC 50值见表1。 In vitro inhibition of PDE4B1 enzymatic activity by the embodiments of the present disclosure was determined by the above test, and the measured IC 50 values are shown in Table 1.
编号Numbering PDE4B1/IC 50(nM) PDE4B1/ IC50 (nM) 编号Numbering PDE4B1/IC 50(nM) PDE4B1/ IC50 (nM)
化合物1Compound 1 2929 化合物2Compound 2 139139
化合物3Compound 3 6767 化合物4Compound 4 NANA
化合物5Compound 5 NANA 化合物6Compound 6 138138
化合物7Compound 7 NANA 化合物8Compound 8 NANA
化合物9Compound 9 194194 化合物10Compound 10 NANA
化合物11Compound 11 NANA 化合物12Compound 12 NANA
化合物13Compound 13 NANA 化合物14Compound 14 NANA
化合物15Compound 15 19.519.5 化合物16Compound 16 16.516.5
化合物17Compound 17 4343 化合物18Compound 18 1717
化合物19Compound 19 115.3115.3 化合物20 Compound 20 4040
化合物21Compound 21 21twenty one 化合物22Compound 22 153153
化合物23Compound 23 103103 化合物24Compound 24 3030
化合物25Compound 25 60.3660.36 化合物26Compound 26 7171
化合物27Compound 27 6464 化合物28Compound 28 9696
化合物ACompound A 31.7831.78      
注：N/A未检测Note: N/A not detected
测试例2：化合物对外周血单核细胞(PBMC)促炎细胞因子的释放的抑制作用Test Example 2: Inhibitory effect of compounds on the release of proinflammatory cytokines from peripheral blood mononuclear cells (PBMCs)
解冻冻存的PBMC，台盼蓝染色检测细胞活率和数目。用RPMI1640完全培养基(RPMI1640+10％FBS+1％PS)清洗解冻后的PBMC，离心后弃去上清。用RPMI1640完全培养基重悬PBMC，将细胞密度调至2×10 6cells/mL。铺2×10 5PBMC细胞于96孔细胞培养板中，加入不同浓度的待测化合物，从化合物最大浓度100μM开始，按照1:5的比例做9个浓度的梯度稀释，双复孔检测。加入终浓度为0.1ng/mL的LPS，总体积为200μL。设置阴性和阳性对照，阴性对照孔内只加LPS和终浓度为DMSO，阳性对照孔内除细胞和LPS之外，还加入1μg/mL的地塞米松作为阳性对照。将细胞于37度培养箱孵育24小时。孵育完成后，收集100μL细胞培养上清，用ELISA检测TNF-α的水平。向每孔剩余的细胞中加入100μL CellTiter-Glo，检测细胞活力水平。计算化合物抑制TNF-α释放的IC 50值。 Thaw the cryopreserved PBMC, and trypan blue staining to detect the cell viability and number. The thawed PBMCs were washed with RPMI1640 complete medium (RPMI1640+10%FBS+1%PS), and the supernatant was discarded after centrifugation. The PBMCs were resuspended in RPMI1640 complete medium, and the cell density was adjusted to 2×10 6 cells/mL. Spread 2×10 5 PBMC cells in a 96-well cell culture plate, add different concentrations of the compounds to be tested, starting from the maximum compound concentration of 100 μM, make 9 concentration gradient dilutions at a ratio of 1:5, and double-well detection. Add LPS at a final concentration of 0.1 ng/mL to a total volume of 200 μL. Negative and positive controls were set. Only LPS and final concentration of DMSO were added to the negative control wells. In addition to cells and LPS, 1 μg/mL dexamethasone was also added to the positive control wells as a positive control. Cells were incubated in a 37°C incubator for 24 hours. After incubation, 100 μL of cell culture supernatant was collected, and the level of TNF-α was detected by ELISA. Add 100 μL of CellTiter-Glo to the remaining cells in each well and measure the level of cell viability. IC50 values of compounds for inhibition of TNF-α release were calculated.
本公开的实施例在体外对PBMC促炎细胞因子释放的抑制通过以上的试验进行测定，测得的IC 50值见表2。 The inhibition of the release of pro-inflammatory cytokines from PBMC in vitro by the embodiments of the present disclosure was determined by the above experiments, and the measured IC 50 values are shown in Table 2.
表2Table 2
编号Numbering PBMC/IC 50(nM) PBMC/ IC50 (nM) 编号Numbering PBMC/IC 50(nM) PBMC/ IC50 (nM)
化合物1Compound 1 164164 化合物15Compound 15 173.48173.48
化合物16Compound 16 161.66161.66 化合物18Compound 18 98.8798.87
化合物21Compound 21 12.0112.01 化合物24Compound 24 76.4776.47
化合物ACompound A 213213      
测试例3过敏性皮炎抑制实验 Test Example 3 Allergic Dermatitis Inhibition Experiment
取适量化合物21配制成下述成分的软膏：1％的化合物21，10％的三乙酸甘油酯，62.5％的白凡士林，20％的液状石蜡，3％的石蜡，3.5％的白蜂蜡，机械搅拌至软膏An appropriate amount of compound 21 was formulated into an ointment with the following components: 1% compound 21, 10% triacetin, 62.5% white petrolatum, 20% liquid paraffin, 3% paraffin, 3.5% white beeswax, mechanical Stir until ointment
造模和给药：Modeling and drug delivery:
选用CD-1雄性小鼠，实验当天在实验鼠左耳固定位置量耳厚(MDC-1“SB，Mitutoyo Corporation)后，在左耳涂20μL(12-)十四酸佛波酯(-13-)乙酸盐(PMA，P1585，Sigma)丙酮溶液(2ug/耳)致耳肿胀的前2小时以及后15分钟，在左耳内外两面分别涂抹10mg受试物或阳性药或空白制剂，即20mg/耳。在PMA涂抹6小时后测量耳厚。本实验设正常对照组，模型对照组，低、中、高剂量组以及参比化合物组。CD-1 male mice were selected. On the day of the experiment, the ear thickness was measured at a fixed position in the left ear of the experimental mouse (MDC-1"SB, Mitutoyo Corporation), and 20 μL of (12-) phorbol myristate (-13) was applied to the left ear. -) 2 hours before and 15 minutes after ear swelling caused by acetate (PMA, P1585, Sigma) acetone solution (2ug/ear), apply 10mg of the test substance or positive drug or blank preparation to the inner and outer sides of the left ear respectively, namely 20mg/ear. The ear thickness was measured 6 hours after PMA was applied. This experiment set up a normal control group, a model control group, low, medium and high dose groups and a reference compound group.
评价指标：PMA诱导耳肿胀6小时后耳厚的改变以及肿胀抑制率([IC-IT]/IC X 100％，IC和IT分别为对照组与治疗组小鼠的耳厚增加数(mm))作为炎症指标；PMA诱导24小时后体重改变作为系统毒副作用指标。Evaluation index: Changes in ear thickness and swelling inhibition rate ([IC-IT]/IC X 100%) after PMA-induced ear swelling for 6 hours, IC and IT are the number of ear thickness increases (mm) in the control and treatment groups, respectively ) as an inflammatory index; the body weight change after 24 hours of PMA induction was used as an index of systemic toxicity.
实验结果：化合物21可以剂量依赖性的抑制PMA诱导的小鼠耳肿胀，低中高三个剂量组抑制率显著高于模型组，耳肿胀抑制率分别为36.7±14.5％，81.0％±18.5％和93.9±5.9％(均值±SD)。参比化合物A的低高剂量也对PMA诱导小鼠的耳肿胀有抑制作用，低高剂量组耳肿胀抑制率分别为12.7％±16.2％和45.3％±23.0％(均值±SD)。Experimental results: Compound 21 can dose-dependently inhibit PMA-induced ear swelling in mice. The inhibition rates of the low, middle and high dose groups were significantly higher than those of the model group. The inhibition rates of ear swelling were 36.7±14.5%, 81.0%±18.5% and 93.9±5.9% (mean±SD). The low and high doses of reference compound A also inhibited the ear swelling of PMA-induced mice, and the inhibition rates of ear swelling in the low and high dose groups were 12.7%±16.2% and 45.3%±23.0% (mean±SD), respectively.
以上结果说明，化合物21在PMA诱导的皮肤炎症模型上的治疗效果优于参比化合物A。The above results indicated that the therapeutic effect of compound 21 on the PMA-induced skin inflammation model was better than that of the reference compound A.

Claims (52)

  1. 式I所示化合物或其可药用盐A compound represented by formula I or a pharmaceutically acceptable salt thereof
    Figure PCTCN2021133316-appb-100001
    Figure PCTCN2021133316-appb-100001
    其中，R 1选自芳基或杂芳基，所述芳基或杂芳基任选被一个或多个选自氘、卤素、羟基、硝基、氰基、氨基、烷基、烷氧基、烯氧基、炔氧基、环烷基、杂环烷基、环烷氧基、杂环烷氧基或环烯氧基所取代，和/或者所述芳基或杂芳基与环烷基或杂环烷基稠合，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基或稠合环任选被一个或多个R A1所取代； Wherein, R 1 is selected from aryl or heteroaryl, and the aryl or heteroaryl is optionally replaced by one or more selected from deuterium, halogen, hydroxyl, nitro, cyano, amino, alkyl, alkoxy , alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy, and/or the aryl or heteroaryl is substituted with cycloalkane or heterocycloalkyl fused, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused rings are optionally substituted with one or more R A1 ;
    R A1选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代； R A1 is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkane oxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, aryl, or 5- to 6-membered heteroaryl optionally supported by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, substituted by cyano and amino groups;
    R 2选自环烷基、杂环烷基、芳基或杂芳基，所述芳基或杂芳基任选被一个或多个选自氘、卤素、羟基、烷基、环烷基、杂环烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基、环烯氧基、-SR'、-S(O) 2R'、-NR'(R”)、-COR'、-COOR'或-CONR'(R”)所取代，所述烷基、环烷基、杂环烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基或环烯氧基任选被一个或多个R A2所取代； R 2 is selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, said aryl or heteroaryl optionally being surrounded by one or more selected from deuterium, halogen, hydroxyl, alkyl, cycloalkyl, Heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S(O) 2 R', -NR' ( R"), -COR', -COOR' or -CONR'(R"), the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkane Oxy, heterocycloalkoxy or cycloalkenyloxy optionally substituted by one or more R A2 ;
    R A2选自卤素、氘、羟基、氧代、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、C 6-10芳基或5至6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、C 6-10芳基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代； R A2 is selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkane Oxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, C 6- 10 -aryl or 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 ring Alkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 cycloalkenyloxy, C 6-10 aryl, or 5- to 6-membered heteroaryl are optionally substituted by one or more selected from halogen, deuterium, substituted by hydroxyl, oxo, nitro, cyano, amino;
    环A选自5元杂芳环，所述杂芳环任选被一个或多个R A3所取代，且R 1与环B在环A上处于间位； Ring A is selected from a 5-membered heteroaromatic ring optionally substituted by one or more R A3 , and R1 and ring B are in meta position on ring A;
    R A3选自卤素、氘、羟基、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代； R A3 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy Cycloalkoxy is optionally substituted with one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino;
    环B选自3至6元碳环或杂环，所述环B任选被一个或多个R A4所取代； Ring B is selected from a 3- to 6-membered carbocyclic or heterocyclic ring, optionally substituted by one or more R A4 ;
    R A4选自卤素、氘、羟基、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代； R A4 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy Cycloalkoxy is optionally substituted with one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, amino;
    Y 1选自键、-C(＝O)-、-C(＝O)N(R 3)-、-N(R 4)C(＝O)-、-S(O) n-、-S(O) mN(R 3)-或-N(R 4)S(O) m-，R 3或R 4独立地选自氢、氘或C 1-6烷基，n和m各自独立地选自0至2的整数； Y 1 is selected from bond, -C(=O)-, -C(=O)N( R3 ) - , -N(R4)C(=O)-, -S(O) n- , -S (O) m N(R 3 )- or -N(R 4 )S(O) m -, R 3 or R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl, and n and m are each independently an integer from 0 to 2;
    R'或R”独立地选自氢、氘、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基，所述烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基或氨基所取代。R' or R" is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, said alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano or amino.
  2. 如权利要求1所述的化合物或其可药用盐，其中R 1选自C 6-10芳基或5至10元杂芳基，所述芳基或杂芳基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基所取代，和/或者所述芳基或杂芳基与3至10元环烷基或3至10元杂环烷基稠合，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基或稠合环任选被一个或多个R A1所取代，R A1如权利要求1中所定义。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, optionally substituted by one or more selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, and/or the aryl or heteroaryl is substituted with 3- to 10-membered cycloalkyl or 3- to 10-membered heterocycloalkyl fused, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring is any is replaced by one or more R A1 as defined in claim 1 .
  3. 如权利要求1或2所述的化合物或其可药用盐，其中R 1选自C 6-10芳基，所述芳基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基所取代，和/或者所述芳基与3至10元环烷基或3至10元杂环烷基稠合，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基或稠合环任选被一个或多个R A1所取代，R A1如权利要求1中所定义。 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 6-10 aryl, optionally by one or more selected from deuterium, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 -membered cycloalkenyloxy, and/or the aryl group is substituted with a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocycle Alkyl condensed, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or condensed ring is optionally substituted by one or more R A1 , R A1 such as as defined in claim 1.
  4. 如权利要求1-3任一项所述的化合物或其可药用盐，其中R 1选自C 6-10芳基，所述芳基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷基、3至6元杂环烷基或C 3-6环烯氧基所取代，和/或者所述芳基与3至10元环烷基稠合，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基或稠合环任选被一个或多个R A1所取代，R A1如权利要求1中所定义。 The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 6-10 aryl, optionally by one or more selected from deuterium, halogen, hydroxyl , amino, C 1-6 alkyl, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl or C 3-6 cycloalkenyloxy and/or the aryl group is substituted with a 3- to 10-membered cycloalkyl group, the alkyl group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkoxy group, cycloalkenyloxy group or fused The closed ring is optionally substituted with one or more R A1 as defined in claim 1 .
  5. 如权利要求1-3任一项所述的化合物或其可药用盐，其中R 1选自C 6-10芳基，所述芳基任选被一个或多个选自C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基所取代，和/或者所述芳基与3至10元杂环烷基稠合，所述烷氧基、环烷氧基或稠合环任选被一个或多个R A1所取代，R A1如权利要求1中所定义。 The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 6-10 aryl, optionally by one or more selected from C 1-6 alkane oxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, and/or the aryl group is fused with a 3- to 10-membered heterocycloalkyl, the alkoxy, ring The alkoxy or fused ring is optionally substituted with one or more R A1 as defined in claim 1 .
  6. 如权利要求1-3任一项所述的化合物或其可药用盐，其中R 1选自C 6-10芳基，所述芳基任选被一个或多个选自氘、卤素、羟基或氨基。 The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 6-10 aryl, optionally by one or more selected from deuterium, halogen, hydroxyl or amino.
  7. 如权利要求1-3任一项所述的化合物或其可药用盐，其中所述式I化合物选自The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
    Figure PCTCN2021133316-appb-100002
    Figure PCTCN2021133316-appb-100002
    其中，R 6、R 7、R 8、R 9或R 10各自独立地选自氢、氘、卤素、氨基、羟基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基所取代，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基、环烷基、杂环烷氧基或杂环烷基任选被一个或多个R A1所取代，或者R 6、R 7与相邻的碳原子形成5至10元碳环或5至10元杂环，所述碳环或杂环任选被一个或多个R A1所取代，R A1如权利要求1中所定义。 wherein, R 6 , R 7 , R 8 , R 9 or R 10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 Alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy, or C 3 -6 substituted by cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl Optionally substituted by one or more R A1 , or R 6 , R 7 and adjacent carbon atoms form a 5- to 10-membered carbocyclic ring or a 5- to 10-membered heterocyclic ring, and the carbocyclic or heterocyclic ring is optionally replaced by a is substituted with one or more R A1s as defined in claim 1 .
  8. 如权利要求7所述的化合物或其可药用盐，其中R 8选自氢、氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1所取代，R A1如权利要求1中所定义。 The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or The alkoxy group is optionally substituted with 1 to 3 R A1 as defined in claim 1 .
  9. 如权利要求7或8所述的化合物或其可药用盐，其中R 8选自C 1-6烷氧基，所述烷氧基任选被1至3个R A1所取代，R A1如权利要求1中所定义。 The compound as claimed in claim 7 or 8 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from C 1-6 alkoxy, said alkoxy is optionally substituted by 1 to 3 R A1 , R A1 is as as defined in claim 1.
  10. 如权利要求7所述的化合物或其可药用盐，其中R 8选自C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基，所述烯氧基、炔氧基、环烷氧基、环烯氧基、环烷基、杂环烷氧基或杂环烷基任选被1至3个R A1所取代，R A1如权利要求1中所定义。 The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 ring Alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, said alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy , cycloalkyl, heterocycloalkoxy or heterocycloalkyl optionally substituted with 1 to 3 R A1 as defined in claim 1 .
  11. 如权利要求7-10任一项所述的化合物或其可药用盐，其中R 6选自氢、氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1所取代，R A1如权利要求1中所定义，R 6优选氢或氘。 The compound of any one of claims 7-10, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, Said alkyl or alkoxy is optionally substituted with 1 to 3 R A1 , R A1 as defined in claim 1 , R6 preferably hydrogen or deuterium.
  12. 如权利要求7-11任一项所述的化合物或其可药用盐，其中R 10选自氢、氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1所取代，R A1如权利要求1中所定义，R 10优选氢或氘。 The compound of any one of claims 7-11, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, Said alkyl or alkoxy is optionally substituted with 1 to 3 R A1 , R A1 as defined in claim 1 , R10 preferably hydrogen or deuterium.
  13. 如权利要求7-12任一项所述的化合物或其可药用盐，其中R 7选自氢、氘、卤素、羟基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被1至3个R A1所取代，R A1如权利要求1中所定义。 The compound of any one of claims 7-12 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, the Alkyl or alkoxy is optionally substituted with 1 to 3 R A1 as defined in claim 1 .
  14. 如权利要求7-13任一项所述的化合物或其可药用盐，其中R 7选自C 1-6烷氧基，所述烷氧基任选被1至3个R A1所取代，R A1如权利要求1中所定义。 The compound of any one of claims 7-13 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from C 1-6 alkoxy optionally substituted with 1 to 3 R A1 , R A1 is as defined in claim 1 .
  15. 如权利要求7-12任一项所述的化合物或其可药用盐，其中R 7选自C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基，所述烯氧基、炔氧基、环烷氧基、环烯氧基、环烷基、杂环烷氧基或杂环烷基任选被1至3个R A1所取代，R A1如权利要求1中所定义。 The compound of any one of claims 7-12 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, the alkenyloxy, alkynyloxy, cycloalkoxy , cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl are optionally substituted with 1 to 3 R A1 as defined in claim 1 .
  16. 如权利要求7-12任一项所述的化合物或其可药用盐，其中R 7选自3至6杂环烷氧基，优选含有至少一种选自N，O或S中的杂原子的杂环烷氧基，所述杂环烷氧基任选被1至3个R A1所取代，R A1如权利要求1中所定义。 The compound of any one of claims 7-12 or a pharmaceutically acceptable salt thereof, wherein R is selected from 3 to 6 heterocycloalkoxy, preferably containing at least one heteroatom selected from N, O or S The heterocycloalkoxy group is optionally substituted with 1 to 3 R A1 , where R A1 is as defined in claim 1 .
  17. 如权利要求7-16任一项所述的化合物或其可药用盐，其中R 6、R 9或R 10选自氢或氘。 The compound of any one of claims 7-16, or a pharmaceutically acceptable salt thereof, wherein R6 , R9 or R10 is selected from hydrogen or deuterium.
  18. 如权利要求7-17任一项所述的化合物或其可药用盐，其中R 6、R 7与相邻的碳原子形成5至10元杂环，所述杂环任选被1至3个R A1所取代，R A1如权利要求1中所定义。 The compound of any one of claims 7-17 or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 and adjacent carbon atoms form a 5- to 10-membered heterocyclic ring, the heterocyclic ring is optionally substituted by 1 to 3 substituted with R A1 as defined in claim 1 .
  19. 如权利要求1或2所述的化合物或其可药用盐，其中R 1选自5至10元杂芳基，所述杂芳基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、C 3-6环烷基、3至6元杂环烷基、3至6元杂环烷氧基或C 3-6环烯氧基所取代，和/或者所述芳基与3至10元环烷基或3至10元杂环烷基稠合，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、环烯氧基或稠合环任选被一个或多个R A1所取代，R A1如权利要求1中所定义。 The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a 5- to 10-membered heteroaryl group optionally surrounded by one or more selected from the group consisting of deuterium, halogen, hydroxyl, Amino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkoxy or C 3-6 cycloalkenyloxy, and/or the aryl group is substituted with 3- to 10-membered cycloalkyl or 3- to 10-membered Heterocycloalkyl fused, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring is optionally substituted by one or more R A1 , R A1 is as defined in claim 1 .
  20. 如权利要求1-19任一项所述的化合物或其可药用盐，其中Y 1选自-C(＝O)N(R 3)-或-N(R 4)C(＝O)-，R 3或R 4独立地选自氢、氘或C 1-6烷基。 The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein Y 1 is selected from -C(=O)N(R 3 )- or -N(R 4 )C(=O)- , R 3 or R 4 is independently selected from hydrogen, deuterium or C 1-6 alkyl.
  21. 如权利要求1或20所述的化合物或其可药用盐，其中所述式I化合物选自The compound of claim 1 or 20, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
    Figure PCTCN2021133316-appb-100003
    Figure PCTCN2021133316-appb-100003
  22. 如权利要求1-21任一项所述的化合物或其可药用盐，其中R 2选自C 6-10芳基或5至9元杂芳基，所述芳基或杂芳基任选被一个或多个选自氘、卤素、羟基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6杂环烷氧基、C 3-8环烯氧基、-SR'、-S(O) 2R'、-NR'(R”)、-COR'、-COOR'或-CONR'(R”)所取代，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基或环烯氧基任选被一个或多个R A2所取代，R'、R”和R A2如权利要求1中所定义。 The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 6-10 aryl or 5- to 9-membered heteroaryl, optionally by one or more selected from deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkane oxy, 3 to 6 heterocycloalkoxy, C 3-8 cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R"), the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy optionally substituted by one or more R Instead of A2 , R', R" and R A2 are as defined in claim 1.
  23. 如权利要求1-22任一项所述的化合物或其可药用盐，其中R 2选自C 6-10芳基，所述芳基任选被一个或多个选自氘、卤素、羟基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、C 3-6环烷氧基、3至6杂环烷氧基、C 3-8环烯氧基、-SR'、-S(O) 2R'、-NR'(R”)、-COR'、-COOR'或-CONR'(R”)所取代，所述烷基、烷氧基、烯氧基、炔氧基、环烷氧基、杂环烷氧基或环烯氧基任选被1至3个R A2所取代，R'、R”和R A2如权利要求1中所定义。 The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 6-10 aryl, optionally with one or more selected from deuterium, halogen, hydroxy , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 3-6 cycloalkoxy, 3 to 6 heterocycloalkoxy, C 3-8 cycloalkenyloxy, -SR', -S(O) 2 R', -NR'(R"), -COR', -COOR' or -CONR'(R") substituted, the Alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy optionally substituted with 1 to 3 R A2 , R', R" and R A2 As defined in claim 1 .
  24. 如权利要求1-23任一项所述的化合物或其可药用盐，其中R 2选自C 6-10芳基，所述芳基任选被1至3个选自氘、卤素、羟基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基或C 3-6环烷氧基所取代，所述烷基、烷氧基或环烷氧基任选被1至3个R A2所取代，R A2如权利要求1中所定义；进一步地，R 2优选自苯基，所述苯基被1至3个选自氘、卤素、羟基、C 1-6烷基或C 1-6烷氧基所取代，所述烷基或烷氧基任选被1至3个R A2所取代，R A2如权利要求1中所定义。 The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 6-10 aryl, optionally with 1 to 3 selected from deuterium, halogen, hydroxy , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy, the alkyl, alkoxy or cycloalkoxy is optional is substituted by 1 to 3 R A2 , R A2 is as defined in claim 1; further, R 2 is preferably selected from phenyl, said phenyl is replaced by 1 to 3 selected from deuterium, halogen, hydroxyl, C 1- 6 alkyl or C 1-6 alkoxy optionally substituted with 1 to 3 R A2 as defined in claim 1 .
  25. 如权利要求1-23任一项所述的化合物或其可药用盐，其中R 2选自5至9元杂芳基，所述杂芳基任选被1至3个选自氘、卤素、羟基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基或C 3-6环烷氧基所取代，所述烷基、环烷基、烷氧基或环烷氧基任选被1至3个R A2所取代，R A2如权利要求1中所定义。 The compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a 5- to 9-membered heteroaryl group optionally surrounded by 1 to 3 atoms selected from deuterium, halogen , hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy, the alkyl, cycloalkyl, alkoxy or Cycloalkoxy is optionally substituted with 1 to 3 R A2 as defined in claim 1 .
  26. 如权利要求25所述的化合物或其可药用盐，其中R 2选自： The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein R is selected from:
    Figure PCTCN2021133316-appb-100004
    进一步所述R 2任选被1至3个选自氘、卤素、羟基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基或C 3-6环烷氧基所取代。
    Figure PCTCN2021133316-appb-100004
    Further said R 2 is optionally selected from 1 to 3 groups selected from deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or C 3-6 cycloalkoxy base substituted.
  27. 如权利要求1-26任一项所述的化合物或其可药用盐，其中环A选自The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from
    Figure PCTCN2021133316-appb-100005
    Figure PCTCN2021133316-appb-100006
    优选
    Figure PCTCN2021133316-appb-100007
    进一步地，所述环A环任选被一个或多个R A3所取代，R A3如权利要求1中所定义。
    Figure PCTCN2021133316-appb-100005
    Figure PCTCN2021133316-appb-100006
    preferred
    Figure PCTCN2021133316-appb-100007
    Further, the Ring A ring is optionally substituted with one or more R A3 as defined in claim 1 .
  28. 如权利要求1-27任一项所述的化合物或其可药用盐，其中式I化合物选自The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
    Figure PCTCN2021133316-appb-100008
    Figure PCTCN2021133316-appb-100008
  29. 如权利要求1-28任一项所述的化合物或其可药用盐，其中环B选自3至6元碳环，优选
    Figure PCTCN2021133316-appb-100009
    所述环B任选被一个或多个R A4所取代。     The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 3 to 6 membered carbocyclic rings, preferably
    Figure PCTCN2021133316-appb-100009
    The ring B is optionally substituted with one or more R A4 .
  30. 如权利要求1-29任一项所述的化合物或其可药用盐，其中式I化合物选自The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
    Figure PCTCN2021133316-appb-100010
    其中p＝0-3之间整数，优选p＝0、1或2，更优选p＝0。
    Figure PCTCN2021133316-appb-100010
    wherein p=an integer between 0-3, preferably p=0, 1 or 2, more preferably p=0.
  31. 如权利要求1-30任一项所述的化合物或其可药用盐，其中R A1选自卤素、氘、硝基或氰基，优选卤素，例如氟。 The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R A1 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
  32. 如权利要求1-30任一项所述的化合物或其可药用盐，其中R A1选自羟基、C 1-6烷基、C 3-6环烷基或3至6元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 The compound of any one of claims 1-30 or a pharmaceutically acceptable salt thereof, wherein R A1 is selected from hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
  33. 如权利要求1-30任一项所述的化合物或其可药用盐，其中R A1选自苯基 或5至6元杂芳基，所述苯基或5至6元杂芳基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 The compound of any one of claims 1-30 or a pharmaceutically acceptable salt thereof, wherein R A1 is selected from phenyl or 5- to 6-membered heteroaryl, said phenyl or 5- to 6-membered heteroaryl optionally Substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
  34. 如权利要求1-33任一项所述的化合物或其可药用盐，其中R A2选自卤素、氘、硝基或氰基，优选卤素，例如氟。 The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R A2 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
  35. 如权利要求1-33任一项所述的化合物或其可药用盐，其中R A2选自羟基、C 1-6烷基、C 3-6环烷基或3至6元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R A2 is selected from hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
  36. 如权利要求1-35任一项所述的化合物或其可药用盐，其中R A3选自卤素、氘、硝基或氰基，优选卤素，例如氟。 The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R A3 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
  37. 如权利要求1-35任一项所述的化合物或其可药用盐，其中R A3选自羟基、C 1-6烷基、C 3-6环烷基或3至6元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R A3 is selected from hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
  38. 如权利要求1-37任一项所述的化合物或其可药用盐，其中R A4选自卤素、氘、硝基或氰基，优选卤素，例如氟。 The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein R A4 is selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
  39. 如权利要求1-38任一项所述的化合物或其可药用盐，其中R A4选自羟基、C 1-6烷基、C 3-6环烷基或3至6元杂环烷基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein R A4 is selected from hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl , the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkoxy group or 3- to 6-membered heterocycloalkoxy group are optionally substituted by one or more selected from halogen, deuterium, hydroxyl , oxo, nitro, cyano, amino substituted.
  40. 如权利要求25所述的化合物或其可药用盐，其中R 2选自5至6元杂芳环，优选自噻唑基、咪唑基、吡啶基、噁唑基、嘧啶基或吡唑基，进一步地所述R 2任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A2所取代，R A2如权利要求1中所定义。 A compound as claimed in claim 25 or a pharmaceutically acceptable salt thereof, wherein R is selected from a 5- to 6 -membered heteroaromatic ring, preferably from thiazolyl, imidazolyl, pyridyl, oxazolyl, pyrimidinyl or pyrazolyl, Further, the R 2 is optionally selected from one or more deuterium, halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally selected by a is substituted with one or more R A2 , R A2 as defined in claim 1.
  41. 如权利要求40所述的化合物或其可药用盐，其中R 2选自噻唑基，所述噻唑基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A2所取代，R A2如权利要求1中所定义。 The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from thiazolyl optionally surrounded by one or more selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally substituted with one or more R A2 as defined in claim 1 .
  42. 如权利要求40所述的化合物或其可药用盐，其中R 2选自咪唑基，所述咪 唑基任选被一个或多个选自氘、卤素、羟基、氨基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A2所取代，R A2如权利要求1中所定义。 The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from imidazolyl optionally surrounded by one or more selected from deuterium, halogen, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy, said alkyl or alkoxy optionally substituted with one or more R A2 as defined in claim 1 .
  43. 如权利要求41所述的化合物或其可药用盐，其中式I化合物选自The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
    Figure PCTCN2021133316-appb-100011
    Figure PCTCN2021133316-appb-100011
    其中，R 16或R 17各自独立地选自氢、氘、卤素、氨基、羟基、C 1-6烷基或C 1-6烷氧基，所述烷基或烷氧基任选被一个或多个R A5所取代，R A5选自卤素、氘、羟基、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 Wherein, R 16 or R 17 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally replaced by one or Replaced by multiple R A5 , R A5 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3 to 6 membered heterocycloalkoxy optionally substituted with one or more selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
  44. 如权利要求43所述的化合物或其可药盐，其中式I化合物选自The compound of claim 43, or a pharmaceutically salt thereof, wherein the compound of formula I is selected from
    Figure PCTCN2021133316-appb-100012
    Figure PCTCN2021133316-appb-100012
  45. 如权利要求42所述的化合物或其可药用盐，其中式I化合物选自The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
    Figure PCTCN2021133316-appb-100013
    Figure PCTCN2021133316-appb-100013
    其中，R 18或R 19各自独立地选自氢、氘、卤素、氨基、羟基、C 1-6烷基或C 1-6烷氧基，R 20选自氢、氘或C 1-6烷基，所述烷基或烷氧基任选被一个或多个R A6所取代，R A6选自卤素、氘、羟基、硝基、氰基、氨基、C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基，所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷氧基或3至6元杂环烷氧基任选被一个或多个选自卤素、氘、羟基、氧代、硝基、氰基、氨基所取代。 Wherein, R 18 or R 19 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy, and R 20 is selected from hydrogen, deuterium or C 1-6 alkane base, the alkyl or alkoxy is optionally substituted by one or more R A6 , R A6 is selected from halogen, deuterium, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 3- 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy or 3- to 6-membered heterocycloalkoxy, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, or 3- to 6-membered heterocycloalkoxy optionally by one or more selected from halogen, deuterium, hydroxyl, oxo, nitro, cyano, substituted with amino.
  46. 如权利要求45所述的化合物或其可药用盐，其中式I化合物选自The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
    Figure PCTCN2021133316-appb-100014
    Figure PCTCN2021133316-appb-100014
  47. 式I所示化合物或其可药用盐A compound represented by formula I or a pharmaceutically acceptable salt thereof
    Figure PCTCN2021133316-appb-100015
    Figure PCTCN2021133316-appb-100015
    Figure PCTCN2021133316-appb-100016
    Figure PCTCN2021133316-appb-100016
    Figure PCTCN2021133316-appb-100017
    Figure PCTCN2021133316-appb-100018
    优选：
    Figure PCTCN2021133316-appb-100019
    Figure PCTCN2021133316-appb-100017
    Figure PCTCN2021133316-appb-100018
    Preferred:
    Figure PCTCN2021133316-appb-100019
  48. 一种药物组合物，包括至少一种治疗有效量的如权利要求1-47任一项所述的化合物或其可药用盐以及药学上可接受的赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  49. 一种预防和/或治疗与PDE相关病症患者的方法，其通过向所述患者施用治疗有效量的如权利要求1-47任一项所述的化合物或其可药用的盐或权利要求48所述的药物组合物。A method of preventing and/or treating a patient with a PDE-related disorder by administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-47 or a pharmaceutically acceptable salt thereof or claim 48 the pharmaceutical composition.
  50. 一种预防和/或治疗气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病患者的方法，其通过向所述患者施用治疗有效量的如权利要求1-47任一项所述的化合物或其可药用盐、或权利要求48所述的药物组合物。A method of preventing and/or treating patients with asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism, by administering treatment to said patient An effective amount of the compound of any one of claims 1-47 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 48.
  51. 权利要求1-47任一项所述的化合物或其可药用的盐、或权利要求48所述的药物组合物在制备用于预防和/或治疗与PDE相关病症的药物中的用途。Use of the compound of any one of claims 1-47 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 48 in the manufacture of a medicament for preventing and/or treating a disorder associated with PDE.
  52. 权利要求1-47任一项所述的化合物或其可药用的盐、或权利要求48所述的药物组合物在制备用于预防和/或治疗气喘、阻塞性肺病、败血病、肾炎、糖尿病、变应性鼻炎、变应性结膜炎、溃疡性肠炎或风湿病的药物中的用途。The compound of any one of claims 1-47 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 48 is prepared for the prevention and/or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis , diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis or rheumatism in medicine.
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