WO2022111605A1 - Composé hétérocyclique aromatique à 5 chaînons substitué par aryle ou hétéroaryle et son utilisation - Google Patents

Composé hétérocyclique aromatique à 5 chaînons substitué par aryle ou hétéroaryle et son utilisation Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
alkoxy
deuterium
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2021/133316
Other languages
English (en)
Chinese (zh)
Inventor
王中利
郝欣
刘桑
Original Assignee
瑞石生物医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 瑞石生物医药有限公司 filed Critical 瑞石生物医药有限公司
Priority to CN202180062290.0A priority Critical patent/CN116194451A/zh
Publication of WO2022111605A1 publication Critical patent/WO2022111605A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic 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
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—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
    • C—CHEMISTRY; METALLURGY
    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un composé hétérocyclique aromatique à 5 chaînons substitué par aryle ou hétéroaryle et son utilisation. En particulier, l'invention concerne un composé tel que représenté dans la formule I ou un sel pharmaceutiquement acceptable de celui-ci, formule dans laquelle R1, R2, Y1, le cycle A et le cycle B sont tels que définis dans la description.
PCT/CN2021/133316 2020-11-27 2021-11-26 Composé hétérocyclique aromatique à 5 chaînons substitué par aryle ou hétéroaryle et son utilisation WO2022111605A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180062290.0A CN116194451A (zh) 2020-11-27 2021-11-26 芳基或杂芳基取代五元芳杂环化合物及其用途

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202011355943 2020-11-27
CN202011355943.8 2020-11-27
CN202110017886.0 2021-01-07
CN202110017886 2021-01-07
CN202110281972.2 2021-03-16
CN202110281972 2021-03-16

Publications (1)

Publication Number Publication Date
WO2022111605A1 true WO2022111605A1 (fr) 2022-06-02

Family

ID=81753722

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/133316 WO2022111605A1 (fr) 2020-11-27 2021-11-26 Composé hétérocyclique aromatique à 5 chaînons substitué par aryle ou hétéroaryle et son utilisation

Country Status (3)

Country Link
CN (1) CN116194451A (fr)
TW (1) TW202227424A (fr)
WO (1) WO2022111605A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115974824A (zh) * 2022-12-27 2023-04-18 瑞石生物医药有限公司 一种组织蛋白酶c小分子抑制剂

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101014578A (zh) * 2004-09-16 2007-08-08 安斯泰来制药有限公司 三唑衍生物或其盐
CN101309912A (zh) * 2005-11-15 2008-11-19 大塚制药株式会社 噁唑化合物和药物组合物
CN106715417A (zh) * 2014-04-04 2017-05-24 爱欧梅特制药公司 药物中使用的吲哚衍生物
US20180072708A1 (en) * 2015-03-25 2018-03-15 National Center For Geriatrics And Gerontology Novel oxadiazole derivative and pharmaceutical containing same
CN108348503A (zh) * 2015-09-16 2018-07-31 爱欧梅特制药公司 药物化合物
WO2020227101A1 (fr) * 2019-05-03 2020-11-12 Praxis Precision Medicines, Inc. Inhibiteurs de kcnt1 et procédés d'utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101014578A (zh) * 2004-09-16 2007-08-08 安斯泰来制药有限公司 三唑衍生物或其盐
CN101309912A (zh) * 2005-11-15 2008-11-19 大塚制药株式会社 噁唑化合物和药物组合物
CN106715417A (zh) * 2014-04-04 2017-05-24 爱欧梅特制药公司 药物中使用的吲哚衍生物
US20180072708A1 (en) * 2015-03-25 2018-03-15 National Center For Geriatrics And Gerontology Novel oxadiazole derivative and pharmaceutical containing same
CN108348503A (zh) * 2015-09-16 2018-07-31 爱欧梅特制药公司 药物化合物
WO2020227101A1 (fr) * 2019-05-03 2020-11-12 Praxis Precision Medicines, Inc. Inhibiteurs de kcnt1 et procédés d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 1 September 2020 (2020-09-01), ANONYMOUS : "Cyclopropanecarboxamide, N-[1-[4-(2-fluorophenyl)-5-methyl-2- thiazolyl]cyclobutyl]-1-hydroxy- (CA INDEX NAME)", XP055932366, retrieved from STN Database accession no. 2468487-09-2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115974824A (zh) * 2022-12-27 2023-04-18 瑞石生物医药有限公司 一种组织蛋白酶c小分子抑制剂

Also Published As

Publication number Publication date
CN116194451A (zh) 2023-05-30
TW202227424A (zh) 2022-07-16

Similar Documents

Publication Publication Date Title
JP2009506127A (ja) 糖尿病の処置に有用なアニリノピラゾール誘導体
KR20180088627A (ko) 1,2 나프토퀴논 유도체 및 이의 제조방법
WO2014169817A1 (fr) Composé de phénylalanine ayant un groupe de liaison hétérocyclique azoté, composition pharmaceutique associée, son procédé de préparation et son utilisation
CN106892878B (zh) 噻唑类衍生物及其在抑制二氢乳清酸脱氢酶中的应用
WO2022111605A1 (fr) Composé hétérocyclique aromatique à 5 chaînons substitué par aryle ou hétéroaryle et son utilisation
TW202214576A (zh) 作為ｊａｋ激酶抑制劑的小分子化合物及其用途
WO2022135550A1 (fr) Dérivé de borate et ses utilisations
WO2022228544A1 (fr) Composé d'isoquinolone et son utilisation
TWI746551B (zh) 吡啶基衍生物、醫藥組合物及其用途
JP6612882B2 (ja) プテリジンジオンモノカルボン酸トランスポータ阻害薬
TW202322793A (zh) 用於治療冠狀病毒感染之sars-cov-2抑制劑
CN117580836A (zh) 一种嘧啶并环结构衍生物及其用途
CN114057769A (zh) 大环哒嗪类化合物及其用途
WO2019233366A1 (fr) Antagoniste sélectif du récepteur a2a
CN115785014A (zh) 四唑衍生物及其用途
CN114853812A (zh) 含氧化膦基团的化合物、其制备方法及其在医药上的应用
CN115887463A (zh) 一种含环酰胺化合物的药物组合物
JP2022516922A (ja) フッ素含有置換ベンゾチオフェン化合物ならびにその医薬組成物および応用
WO2023246858A1 (fr) Sel pharmaceutique de dérivé de borate, et forme de cristallisation de celui-ci et utilisation associée
TW202411226A (zh) 一種芳基取代五員芳雜環化合物的結晶及其製備方法
CN114621190B (zh) 一种烯丙基胺类衍生物及其用途
CN114621189B (zh) 一种内酰胺类衍生物及其用途
TWI828783B (zh) 聯芳基衍生物及其用途
JP2024518569A (ja) アルキルフェノール系化合物およびその製造方法
TW202411227A (zh) 一種芳基取代五員芳雜環化合物的可藥用鹽及晶型形式

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21897105

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21897105

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 21897105

Country of ref document: EP

Kind code of ref document: A1