WO2023025298A1 - Dérivé de quinolinofurane et son utilisation - Google Patents

Dérivé de quinolinofurane et son utilisation Download PDF

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WO2023025298A1
WO2023025298A1 PCT/CN2022/115213 CN2022115213W WO2023025298A1 WO 2023025298 A1 WO2023025298 A1 WO 2023025298A1 CN 2022115213 W CN2022115213 W CN 2022115213W WO 2023025298 A1 WO2023025298 A1 WO 2023025298A1
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alkyl
compound
membered
alkoxy
halogen
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PCT/CN2022/115213
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Chinese (zh)
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王中利
郝欣
罗志阳
匡亮
柳梦林
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瑞石生物医药有限公司
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Priority to CN202280057194.1A priority Critical patent/CN117940433A/zh
Publication of WO2023025298A1 publication Critical patent/WO2023025298A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems

Definitions

  • the disclosure belongs to the field of medicine, and relates to a quinolinofuran derivative and its application.
  • MK2 Mitogen-activated protein kinase-activated protein kinase 2
  • TNF- ⁇ tumor necrosis factor alpha
  • IL-6 interleukin 6
  • IFN ⁇ interferon gamma
  • quinothiophene structure molecules developed based on the benzothiophene structure have shown MK2 inhibitory efficacy at the micromolar level, while showing high selectivity for other kinases, including but not limited to CDK2.
  • Bioorg.Med.Chem.Lett.19 (2009) 4882-4884 discloses:
  • WO2016044463 discloses another class of MK2 inhibitors, the representative molecules are as follows,
  • MK2 inhibitors are currently on the market, and the compounds of the present disclosure have not been disclosed in any literature, and such compounds exhibit specific MK2 inhibitory effects and selectivity to other kinases (including, for example, CDK2).
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from C 6-10 aryl or 5 to 10 membered heteroaryl containing 1-3 heteroatoms;
  • Each R is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said Alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 1A , each R 1A is independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;
  • any adjacent R1 and adjacent carbon atoms form a 3 to 6 membered cycloalkyl group or a 3 to 6 membered heterocycloalkyl group, which is optionally represented by one or more R1B Substitution, R 1B each independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkyloxy is optionally replaced by One or more groups selected from halogen, hydroxyl, oxo, nitro, cyano or amino are substituted;
  • R 2 and R 3 are each independently selected from hydrogen or C 1-6 alkyl, which is optionally substituted by one or more groups selected from halogen, hydroxyl, cyano or amino;
  • any adjacent two R 4 form a 3 to 6-membered cycloalkyl group or a 3 to 6-membered heterocycloalkyl group with adjacent atoms, and the cycloalkyl group or heterocycloalkyl group is optionally replaced by one or more R 5A Substituted, each R 5A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;
  • Each R is independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 2A , each R 2A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;
  • R 6 are each independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 3A , each R 3A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;
  • T is selected from a bond or -L-X-;
  • L is selected from a bond or a C 1-3 alkylene group optionally substituted by one or more R 6A , each R 6A independently selected from halogen, hydroxyl, oxo, nitro, cyano, Amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;
  • X is selected from -O-, -S-, -S(O)-, -SO 2 -, -C(O)-, -OC(O)-, -C(O)O-, -N(R 9 )-, -C(O)N(R 7 )- or -N(R 8 )C(O)-;
  • Z is -CH- or N, and when Z is -CH-, Z is optionally substituted by R 5 ;
  • R 7 , R 8 , R 9 are each independently selected from hydrogen or C 1-6 alkyl, and the alkyl is optionally replaced by one or more groups selected from halogen, hydroxyl, oxo, nitro, cyano or amino group replaced;
  • R 1a or R 1b are each independently selected from hydrogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkane Base, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R 7A , each R 7A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1 -6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;
  • R 1a , R 1b and adjacent atoms form a 3- to 6-membered heterocycloalkyl group
  • the heterocycloalkyl group is optionally substituted by one or more R 8A , each R 8A independently selected from halogen, hydroxyl, Oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;
  • n is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4;
  • n is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4;
  • s is selected from an integer between 0 and 3, such as 0, 1, 2, 3;
  • o and p are each selected from integers between 0 and 2, such as 0, 1, and 2.
  • Ring A is selected from C 6-10 aryl or 5 to 10 membered heteroaryl containing 1-3 heteroatoms;
  • Each R is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said Alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 1A , each R 1A is independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;
  • R 2 and R 3 are each independently selected from hydrogen or C 1-6 alkyl, which is optionally substituted by one or more groups selected from halogen, hydroxyl, cyano or amino;
  • any adjacent two R 4 form a 3 to 6-membered cycloalkyl group or a 3 to 6-membered heterocycloalkyl group with adjacent atoms, and the cycloalkyl group or heterocycloalkyl group is optionally replaced by one or more R 5A Substituted, each R 5A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;
  • Each R is independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 2A , each R 2A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;
  • R 6 are each independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 3A , each R 3A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;
  • T is selected from a bond or -L-X-;
  • L is selected from a bond or a C 1-3 alkylene group optionally substituted by one or more R 6A , each R 6A independently selected from halogen, hydroxyl, oxo, nitro, cyano, Amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;
  • X is selected from -O-, -S-, -S(O)-, -SO 2 -, -C(O)-, -OC(O)-, -C(O)O-, -C(O) N(R 7 )- or -N(R 8 )C(O)-;
  • R 7 and R 8 are each independently selected from hydrogen or C 1-6 alkyl, and the alkyl is optionally replaced by one or more groups selected from halogen, hydroxyl, oxo, nitro, cyano or amino replace;
  • R 1a or R 1b are each independently selected from hydrogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkane Base, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R 7A , each R 7A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1 -6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;
  • R 1a , R 1b and adjacent atoms form a 3- to 6-membered heterocycloalkyl group
  • the heterocycloalkyl group is optionally substituted by one or more R 8A , each R 8A independently selected from halogen, hydroxyl, Oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;
  • n is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4;
  • n is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4;
  • s is selected from an integer between 0 and 3, such as 0, 1, 2, 3, 4;
  • o and p are each selected from integers between 0 and 2, such as 0, 1, and 2.
  • each R is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-6 membered Cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted by one or more R 1A , each R 1A independently selected from alkyl Oxygen.
  • each R is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 Membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R 1A , each R 1A is independently selected from C 1-6 alkylamino.
  • R in the compound shown in formula I or formula IA is each independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, C 1-6 alkoxy, 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy, the C 1-6 alkyl , cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy or heterocycloalkoxy are optionally replaced by one or more halogen, hydroxyl, cyano, amino or C 1-6 alkyl.
  • T is selected from a bond or -LX-
  • L is selected from a bond or C 1-3 alkylene
  • the alkylene is optionally Substituted by 1-3 R 6A
  • X is selected from -O-, -OC(O)- or -C(O)O-
  • R 6A is as defined above.
  • T is selected from a bond.
  • ring A in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof is selected from 5-membered heterocycles containing 1-2 heteroatoms.
  • the example structure of ring A is as follows (not limited to):
  • R 4 and m are as defined above.
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • ring A in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof is selected from phenyl or a 6-membered heteroaromatic ring containing 1-2 heteroatoms.
  • the example structure of ring A is as follows (not limited to):
  • R 4 and m are as defined above.
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from
  • ring A in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof is selected from phenyl or a 9-10 membered heteroaromatic ring containing 1-2 heteroatoms.
  • R in the compound shown in formula I or formula IA or a pharmaceutically acceptable salt thereof is independently selected from halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, The alkyl or alkoxy group is optionally substituted by 1-3 R 2A , and R 2A is as defined above.
  • R in the compound shown in formula I or formula IA or a pharmaceutically acceptable salt thereof is independently selected from 3 to 6 membered cycloalkyl groups, and the cycloalkyl groups are optionally replaced by 1-3 R 2A , R 2A is as defined above.
  • some embodiments provide a compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof, wherein o is selected from 0 or 1.
  • R in the compound shown in formula I or formula IA or a pharmaceutically acceptable salt thereof is independently selected from halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, so The alkyl or alkoxy group is optionally substituted by 1-3 R 3A , and R 3A is as defined above.
  • R in the compound shown in formula I or formula IA or a pharmaceutically acceptable salt thereof is independently selected from 3 to 6 membered cycloalkyl groups, and the cycloalkyl groups are optionally replaced by 1-3 R 3A , R 3A is as defined above.
  • p is selected from 0 or 1 in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof.
  • R 3 is selected from hydrogen.
  • R in the compound shown in formula I or formula IA or its pharmaceutically acceptable salt, is selected from C 1-6 alkyl, and the alkyl is optionally replaced by 1-3 selected from halogen, hydroxyl or amino group replaced. Further, in some other embodiments, R in the compound shown in formula I or formula IA or its pharmaceutically acceptable salt is selected from methyl, ethyl, hydroxymethyl, hydroxyethyl, difluoromethyl or trifluoro methyl.
  • R 2 is selected from hydrogen
  • R 1 is selected from halogen, hydroxyl, amino or cyano.
  • R in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally Replaced by 1-3 R 1A .
  • R in the compound shown in formula I or formula IA or its pharmaceutically acceptable salt is selected from methyl, ethyl, hydroxymethyl, hydroxyethyl, difluoromethyl or trifluoro methyl.
  • R in the compound shown in formula I or formula IA or its pharmaceutically acceptable salts are each independently selected from 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl or alkoxy The group is optionally substituted by 1-3 R 1A , R 1A is as defined above.
  • R 1 , R 2 , R 4 , ring A, m, and T are as defined in formula I or formula IA.
  • R 1A in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, hydroxyl or amino. In some embodiments, R 1A in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from fluorine or chlorine.
  • R 2A in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, hydroxyl or amino. In some embodiments, R 2A in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from fluorine or chlorine.
  • R 1 , R 2 , R 4 , ring A, and m are as defined in formula I or formula IA.
  • Typical compounds shown in formula I or formula IA or pharmaceutically acceptable salts thereof include but are not limited to:
  • R 4 in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen or cyano.
  • each R in the compound shown in formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered Heterocycloalkyl, the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R 4A , R 4A is as defined above.
  • R 4 in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, C 1-6 alkyl, -(CH 2 ) s COR 1a , -(CH 2 ) s NR 1a R 1b , -(CH 2 ) s CONR 1a R 1b , -(CH 2 ) s OCONR 1a R 1b or -(CH 2 ) s NHCOR 1a , s, R 1a , R 1b such as as defined above.
  • R 4 in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, C 1-6 alkyl or -(CH 2 ) s CONR 1a R 1b , s, R 1a , R 1b are as defined above.
  • R 4 in the compound shown in formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, cyano, C 1-6 alkyl or -(CH 2 ) s CONR 1a R 1b , s, R 1a , R 1b are as defined above.
  • any adjacent two R in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt form a 3 to 6 membered cycloalkyl or a 3 to 6 membered hetero Cycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R 5A , R 5A is as defined above.
  • R 7 and R 8 in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof are each independently selected from hydrogen or C 1-6 alkyl, said alkyl The group is optionally substituted with 1-3 groups selected from halo, hydroxy, oxo, nitro, cyano or amino.
  • R 7 and R 8 are each independently selected from hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl.
  • R 1a or R 1b in the compound shown in formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, C 1-6 alkyl, 3 to 6 membered cycloalkyl Or a 3- to 6-membered heterocycloalkyl group, the alkyl group, cycloalkyl group or heterocycloalkyl group is optionally substituted by 1-3 R 7A , R 7A is as defined above.
  • R 1a , R 1b in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof form a 5 to 6 -membered heterocycloalkyl group with adjacent atoms, and the heterocycloalkyl group Optionally substituted by 1-3 R 8A , R 8A is as defined above.
  • R 7A is each independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl. In other embodiments, in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt, R 7A is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6-membered cycloalkyl. In other embodiments, in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof, R 7A is selected from halogen or cyano.
  • R 4A is each independently selected from halogen, hydroxyl, cyano, C 1-6 alkyl, 3 to 6 membered cycloalkyl , 3 to 6 membered heterocycloalkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6 membered heterocycloalkoxy.
  • R 4A is selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy , 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy.
  • R 4A is selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy Or 3 to 6 membered cycloalkoxy.
  • R 8A is each independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1 -6 alkoxy or 3 to 6 membered cycloalkyl. In other embodiments, in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt, R 8A is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6-membered cycloalkyl.
  • R 8A is selected from halogen, such as fluorine, chlorine, bromine or iodine. In other embodiments, in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof, R 8A is selected from C 1-6 alkyl.
  • the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 4A , R 4A is as defined in formula I.
  • the compound shown in 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-N-(2-aminoe-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
  • ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , T, o, p, m and n are as defined in formula I.
  • ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , Z, o, p, m and n are as defined in formula I.
  • R 1 , R 2 , R 3 , R 4 , R 9 , ring A and m are as defined in formula I.
  • Typical compounds represented by formula I or formula IC or pharmaceutically acceptable salts thereof include but are not limited to:
  • R 9 is each independently selected from hydrogen or C 1-6 alkyl, and the alkyl is optionally Substituted by 1-3 groups selected from halogen, hydroxy, oxo, nitro, cyano or amino.
  • R 9 is each independently selected from hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl.
  • ring A, R 2 , R 3 , R 4 , R 5 , R 6 , T, o, p and m are as defined in formula I,
  • R 10 , R 11 and adjacent carbon atoms form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group, the cycloalkyl group or heterocycloalkyl group is optionally substituted by one or more R 1c ,
  • Each R 1c is independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkyloxy is optionally replaced by one or Substituted by multiple groups selected from halogen, hydroxy, oxo, nitro, cyano or amino;
  • R is selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R 1d , each R 1d independently selected from halogen, hydroxy, oxo, nitro, cyano or amino.
  • R 12 is selected from C 1-6 alkyl, for example, methyl, ethyl or propyl.
  • R 13 and R 14 are each independently selected from halogen (fluorine or chlorine), hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl , 3 to 6 membered heterocycloalkyl, C 1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 6 membered cycloalkylamino, 3 to 6 membered Heterocycloalkylamino, aryl or heteroaryl, -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -(CH 2 ) s COR 1a , -(CH 2 ) s NR 1a R 1b , -(CH 2 ) s CONR 1a R 1b , -(CH 2 )
  • R 13 is selected from halogen (fluorine or chlorine), C 1-6 alkyl, -S(O)R 1a and -S(O) 2 R 1a
  • R 14 is selected from halogen (fluorine or chlorine), hydroxyl, nitric acid Group, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 alkylthio, 3 to 6 6-membered cycloalkoxy, 3-6 membered heterocycloalkoxy, 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkylamino, aryl or heteroaryl, -SR 1a , -S(O) R 1a , -S(O) 2 R 1a , -(CH 2 ) s COR 1a , -(CH 2 )
  • R 14 is selected from halogen (fluorine or chlorine), hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 6-membered cycloalkylamino, 3 to 6-membered heterocycloalkylamino, aryl or heteroaryl, -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -(CH 2 ) s COR 1a , -(CH 2 ) s NR 1a R 1b , -(CH 2 ) s CONR
  • R 13 and R 14 are each independently selected from halogen (fluorine or chlorine), hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl , 3 to 6 membered heterocycloalkyl, C 1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 6 membered cycloalkylamino, 3 to 6 membered Heterocycloalkylamino, aryl or heteroaryl, -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -(CH 2 ) s COR 1a , -(CH 2 ) s NR 1a R 1b , -(CH 2 ) s CONR 1a R 1b , -(CH 2 )
  • R 13 and R 14 are each independently selected from halogen (fluorine or chlorine), hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl , 3 to 6 membered heterocycloalkyl, C 1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 6 membered cycloalkylamino, 3 to 6 membered Heterocycloalkylamino, aryl or heteroaryl, -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -(CH 2 ) s COR 1a , -(CH 2 ) s NR 1a R 1b , -(CH 2 ) s CONR 1a R 1b , -(CH 2 )
  • Typical compounds represented by formula I or pharmaceutically acceptable salts thereof include but are not limited to:
  • Typical compounds represented by formula I or pharmaceutically acceptable salts thereof include but are not limited to:
  • Another aspect of the present disclosure provides a method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof, the method comprising a step of a coupling reaction between a compound of formula A and a compound of formula B under metal catalysis,
  • X 1 is hydrogen or a leaving group, selected from but not limited to halogen such as chlorine, bromine; X 2 is hydrogen or a borate ester group.
  • the present disclosure also provides a method for preparing the compound represented by formula IA or a pharmaceutically acceptable salt thereof, the method comprising the step of coupling reaction between the compound of formula A and the compound of formula B-1 under metal catalysis,
  • X 1 is hydrogen or a leaving group, selected from but not limited to halogen such as chlorine, bromine; X 2 is hydrogen or a borate ester group.
  • the metal catalyst in the aforementioned reaction is selected from but not limited to metal palladium, such as divalent palladium catalyst (not limited to palladium acetate).
  • an appropriate base can also be added to the aforementioned coupling reaction to ensure that the reaction proceeds more smoothly.
  • the base is selected from, but not limited to, organic or inorganic bases, such as sodium tert-butoxide.
  • This aspect also provides a compound represented by formula B or a pharmaceutically acceptable salt thereof,
  • X is hydrogen or a leaving group, selected from but not limited to halogen such as chlorine, bromine;
  • R 1 , R 2 , R 3 , R 5 , R 6 , Z, o, p, n are as defined in formula I.
  • the present disclosure also provides a compound represented by formula B-1 or a pharmaceutically acceptable salt thereof,
  • X is hydrogen or a leaving group, selected from but not limited to halogen, such as chlorine, bromine;
  • R 1 , R 2 , R 3 , R 5 , R 6 , o, p, n are as defined in Formula IA.
  • the present disclosure also provides isotopic substitutions of the foregoing compounds or pharmaceutically acceptable salts thereof.
  • the isotopic substitution is deuterated.
  • the disclosed compound has good inhibitory effect on p38a-MK2 kinase.
  • compounds of the disclosure have an IC50 value for inhibition of p38a-MK2 kinase in the range of 0.01 to 500 nM.
  • compounds of the disclosure have an IC50 value for inhibition of p38a-MK2 kinase in the range of 0.01 to 100 nM.
  • compounds of the disclosure have an IC50 value for inhibition of p38a-MK2 kinase in the range of 0.01 to 20 nM.
  • compounds of the disclosure have an IC50 value for inhibition of p38a-MK2 kinase in the range of 0.1 to 20 nM. In some embodiments, compounds of the disclosure have an IC50 value for inhibition of p38a-MK2 kinase in the range of 0.1 to 30 nM. In some embodiments, compounds of the disclosure have an IC50 value of ⁇ 50 nM for inhibition of p38a-MK2 kinase.
  • the present disclosure also provides a pharmaceutical composition, comprising at least one therapeutically effective amount of the aforementioned compound represented by Formula I or Formula IA or Formula IIA or a pharmaceutically acceptable salt thereof, or an isotope substitution thereof and a pharmaceutically acceptable excipient.
  • 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 its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotope substitutions. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions.
  • the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
  • the present disclosure also provides a method for preventing and/or treating MK2-mediated diseases or disorders, which includes administering to patients a preventive or therapeutically effective amount of the compound shown in the aforementioned formula I or formula IA or formula IIA or its pharmaceutically acceptable Salt or its isotope substitution, or the aforementioned pharmaceutical composition.
  • the MK2-mediated disease or disorder is selected from an autoimmune disease, an inflammatory disease, cancer, a fibrotic disease, or a metabolic disease.
  • the present disclosure also provides a method for preventing and/or treating autoimmune diseases, inflammatory diseases, cancer, fibrotic diseases or metabolic diseases, which comprises administering to patients a preventive or therapeutic effective amount of the aforementioned formula I or formula IA or formula The compound shown in IIA or its pharmaceutically acceptable salt or its isotope substitution, or the aforementioned pharmaceutical composition.
  • the present disclosure also provides the use of the compound shown in the aforementioned formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of medicines for preventing and/or treating MK2-mediated diseases or disorders .
  • the MK2-mediated disease or disorder is preferably an autoimmune disease, an inflammatory disease, cancer, a fibrotic disease, or a metabolic disease.
  • the present disclosure also provides a compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition as shown in the aforementioned formula I or formula IA or formula IIA for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, cancer, fibrosis Use in medicine for disease or metabolic disease.
  • the present disclosure also provides a compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt or its isotope substitution or the aforementioned pharmaceutical composition, which is used for preventing and/or treating MK2-mediated diseases or conditions.
  • the present disclosure also provides a compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt or its isotope substitution or the aforementioned pharmaceutical composition, which is used for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, Cancer, fibrotic disease, or metabolic disease.
  • compositions described in the present disclosure may be selected from inorganic or organic salts.
  • Compounds of the present disclosure may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. 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 reagents.
  • 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 chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
  • the bond If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • lactam-lactim isomerization
  • An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation).
  • exemplary compounds having a natural abundance greater than deuterium can 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 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • the present disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated starting materials can be used when preparing deuterated forms of compounds, or conventional techniques can be used to synthesize deuterated reagents, including but not limited to deuterated borane, trideuterioborane tetrahydrofuran solution, Deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvants, carriers, glidants, sweeteners, diluents, preservatives that have been approved by the U.S. Food and Drug Administration to be acceptable for human or livestock use , dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
  • Effective amount or “therapeutically effective amount” in the present disclosure includes an amount sufficient to ameliorate or prevent symptoms or conditions of a medical disease.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • Effective amounts 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 may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • alkyl refers to a saturated aliphatic hydrocarbon group, 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 its various branched 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, hydroxy, oxo, Nitro, cyano, amino, C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 To 6-membered heterocycloalkoxy, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally selected from one or more halogen, hydroxyl , Oxo, nitro, cyano or amino groups are substituted.
  • 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 6 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.
  • multicyclic cycloalkyls include spiro Cycloalkyl rings, fused rings and bridged rings.
  • 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, hydroxy, oxo , nitro, cyano, amino, C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally replaced by one or more selected from halogen, Hydroxy, oxo, nitro, cyano or amino groups are substituted.
  • heterocycloalkyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 ring atoms
  • heterocycloalkyl include: etc.
  • Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, Amino, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, 3-6 membered cycloalkoxy or 3-6 membered heterocycloalkane Oxygen, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally replaced by one or more selected from halogen, hydroxyl, oxo, nitro , cyano or amino groups are substituted.
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C1- 6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6 membered heterocycloalkoxy.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 3 heteroatoms, 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5- or 6-membered. For example, non-limiting examples thereof include: etc.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino , C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6 membered heterocycloalkoxy group, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally selected from one or more halogen, hydroxyl, oxo, nitro, cyano or amino substituted.
  • cycloalkoxy or -O-(cycloalkyl) and “heterocycloalkoxy or -O-(heterocycloalkyl)” are as defined for alkoxy.
  • alkylthio refers to -S-(alkyl), wherein alkyl is as defined above.
  • alkylthio include: methylthio, ethylthio, propylthio, butylthio.
  • Alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, Amino, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, 3-6 membered cycloalkoxy or 3-6 membered heterocycloalkane Oxygen, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally replaced by one or more selected from halogen, hydroxyl, oxo, nitro , cyano or amino.
  • cycloalkylamino wherein alkyl is as defined above.
  • Non-limiting examples of cycloalkylamino include: methylamino, ethylamino or dimethylamino.
  • Cycloalkylamino may be optionally substituted or unsubstituted, and when substituted, the substituents are as defined for "alkylthio".
  • cycloalkylamino or “cycloalkylamino” refers to -N-(cycloalkyl), wherein cycloalkyl is as defined above.
  • heterocycloalkylamino or “heterocycloalkylamino” refers to -N-(heterocycloalkyl), wherein heterocycloalkyl is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • amino refers to -NH2 .
  • 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 are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • HPLC HPLC-based analytical chromatography
  • GAS15B DAD ultraviolet detector Water Vbridge C18 150*4.6mm 5um chromatographic column.
  • MS was determined with 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 specification of the thin-layer chromatography (TLC) silica gel plate is 0.2mm ⁇ 0.03mm, and the specification of the thin-layer chromatography separation and purification product is 0.4mm-0.5mm.
  • the flash column purification system uses 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 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 this disclosure can be adopted or synthesized 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), Bear Pharmaceutical and other companies.
  • the reactions can all be carried out under a nitrogen atmosphere.
  • the nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Company.
  • Nitrogen atmosphere or hydrogenation atmosphere is usually evacuated and 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 embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of 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 50.0 g, 223 mmol
  • N,N-dimethylformamide 500 mL
  • Sodium hydrogen 60%, 22.3g, 557mmol
  • ethyl bromoacetate 67.1g, 401mmol
  • the crude product was used directly in the next step without purification.
  • compound 1d (15.1 g, 58.9 mmol) and tetrahydrofuran (200 mL) were added into a 1 L three-neck flask.
  • Potassium tert-butoxide (6.61 g, 58.9 mmol) was added at 0° C. and stirred at room temperature for 1 hour.
  • Step 5 Preparation of (R)-1-((2-((tert-butoxycarbonyl)amino)propyl)amino)furo[3,2-f]quinoline-2-carboxylic acid ethyl ester (1f)
  • compound 1e (1.50 g, 5.85 mmol), sodium hydrogen (60%, 0.28 g, 7.024 mmol) and N-methylpyrrolidone (60 mL) were sequentially added into a 100 mL three-neck flask. After stirring at 0°C for 1 hour, (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide (1.42 g, 5.97 mmol) was added.
  • Step 6 Preparation of ethyl (R)-1-((2-aminopropyl)amino)furo[3,2-f]quinoline-2-carboxylate (1 g)
  • Step 8 (R)-10-Methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepine[5',6':4,5]furo[3 ,2-f] Preparation of di-tert-butyl quinoline-9,12-dicarboxylate (1i)
  • compound 1i (2.15 g, 4.60 mmol) and dichloromethane (100 mL) were sequentially added into a 250 mL three-neck flask. After stirring and dissolving, m-chloroperoxybenzoic acid (85%, 1.40 g, 6.90 mmol) was added and reacted at 35° C. for 8 hours. Add water (30mL), extract with dichloromethane (50mL X 2), wash with saturated sodium bicarbonate (30mL X 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and beat with diethyl ether (30mL) to obtain compound 1j.
  • compound 1j (2.08 g, 4.30 mmol) and N,N-dimethylformamide (80 mL) were sequentially added into a 250 mL three-neck flask. After stirring to dissolve, oxalyl chloride (5.0 mL, 59.1 mmol) was added dropwise. Stir at room temperature for 8 hours. Add water (50mL), extract with dichloromethane (100mL X 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 1k.
  • Step 13 (R)-3-((2-Chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- Preparation of 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (1)
  • Step 2 (R)-3-((6-Chloro-2-(morpholinylmethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H Preparation of -[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (15)
  • Step 1 Preparation of tert-butyl 4-((4,6-dichloropyrimidin-2-yl)methyl)-2,6-dimethylpiperazine-1-carboxylate (23b)
  • 2,6-Dimethylpiperazine-1-carboxylate tert-butyl ester 23a (250 mg, 1.17 mmol) was dissolved in dichloromethane (5 mL), and 4,6-dichloropyrimidine-2 was added to the mixture -Formaldehyde (206mg, 1.17mmol), sodium triacetoxyborohydride (492mg, 2.33mmol), the mixture was reacted at 15°C for 8 hours. Concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 23b.
  • Step 2 4-((4-chloro-6-(((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine And[5',6':4,5]furo[3,2-f]quinolin-3-yl)oxy)pyrimidin-2-yl)methyl)-2,6-dimethylpiperazine -
  • tert-butyl 1-carboxylate 23c
  • Step 3 (10R)-3-((6-Chloro-2-((3,5-dimethylpiperazin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl -9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one ( 23) Preparation
  • Step 2 (R)-3-((6-Chloro-2-isopropoxypyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[ Preparation of 1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (24)
  • Step 2 (R)-3-((6-Chloro-2-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9 ,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (25)
  • Step 2 (R)-3-((6-Chloro-2-(2-hydroxy-2-methylpropoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 , Preparation of 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (26)
  • compound 1m 80mg, 0.28mmol
  • potassium carbonate 390mg, 2.82mmol
  • N,N-dimethylformamide 5mL
  • compound 26a 134mg, 0.57mmol
  • the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 26.
  • Step 2 (R)-3-((2-Chloro-6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- Preparation of tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (30)
  • Step 2 (R)-3-((2-Chloro-6-(2-hydroxy-2-methylpropoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 , Preparation of 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (32)
  • Step 2 (R)-3-((6-Chloro-2-(isopropoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro Preparation of -8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (33)
  • compound 1m 100mg, 0.35mmol
  • compound 33a 100mg, 0.45mmol
  • potassium carbonate 488mg, 3.53mmol
  • N,N-dimethylformamide 2mL
  • Nitrogen was replaced three times, and stirred at 90°C for 3 hours.
  • the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 33.
  • the preparation method was the same as in Example 33, except that sodium ethoxide was used instead of isopropanol to obtain compound 34.
  • 6-(chloromethyl)pyrimidine-2,4-diol 35a (1.00 g, 6.15 mmol) and methanol solution of sodium methoxide (10 mL, 30%) were sequentially added to a 50 ml single-necked bottle, and replaced with nitrogen three times, Stir at 70°C for 3 hours.
  • Concentrate under reduced pressure dissolve the residue in water (50 mL), adjust the pH of the solution to ⁇ 7 with 2N hydrochloric acid, and extract with ethyl acetate (50 mL X 3).
  • the organic phase was dried, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 35b.
  • Step 3 (R)-3-((2-Chloro-6-(methoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- Preparation of 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (35)
  • Step 1 Preparation of 2,4-dichloro-6-(oxetan-3-yloxy)pyrimidine (36a)
  • Step 2 (R)-3-((2-Chloro-6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 , Preparation of 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (36)
  • Example 1 According to the preparation method of Example 1, replace 2,4-dichloro-5-(ethoxymethyl) in step 13 with 3-cyano-2,6-dichloro-4-(trifluoromethyl)pyridine ) pyrimidine to obtain compound 37 and compound 38.
  • Step 1 (R)-2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5' ,6':4,5]furo[3,2-f]quinolin-3-yl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- Preparation of tert-butyl carboxylate (42b)
  • Step 2 (R)-3-((2-Chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-10-methyl-9 ,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (42)
  • 5-(hydroxymethyl)pyrimidine-2,4-diol 44a (10.00g, 70.37mmol) was dissolved in toluene (25mL), and phosphorus oxychloride (13.08mL, 140.74mmol) and N , N-diisopropylethylamine (34.89mL, 211.10mmol), replaced with nitrogen three times, heated to 120°C and stirred for 16 hours.
  • Step 4 (R)-3-((5-((tert-butylamino)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- Preparation of Tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (44)
  • (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester 48a (1.00 g, 4.36 mmol), benzylamine (0.47 g, 4.36mmol) and methanol (10mL), stirred at 60°C for 16 hours under nitrogen atmosphere. Cool to room temperature, add sodium borohydride (0.25 g, 6.54 mmol), and react at room temperature for 4 hours.
  • compound 48c (1.34g, 5.81mmol), cesium carbonate (2.52g, 7.75mmol), 1,1-binaphthalene-2, 2'-bisdiphenylphosphine (241mg, 0.39mmol) and tris(dibenzylideneacetone)dipalladium (355mg, 0.39mmol) were replaced with nitrogen three times, and reacted overnight at 110°C.
  • Cool to room temperature add water (20mL), extract with dichloromethane (30mL ⁇ 3), dry the organic phase, filter, concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 48e .
  • Step 5 Preparation of (S)-1-((2-amino-3-hydroxypropyl)amino)furo[3,2-f]quinoline-2-carboxylic acid ethyl ester (48f)
  • Step 7 (S)-10-(((tert-butoxycarbonyl)oxy)methyl)-8-oxo-10,11-dihydro-8H-[1,4]diazepine[5' Preparation of ,6':4,5]furo[3,2-f]quinoline-9,12-dicarboxylic acid di-tert-butyl ester (48h)
  • Step 8 (S)-9,12-Bis(tert-butoxycarbonyl)-10-(((tert-butoxycarbonyl)oxy)methyl)-8-oxo-9,10,11,12-tetra Preparation of Hydrogen-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinoline 4-oxide (48i)
  • Step 9 (S)-10-(((tert-butoxycarbonyl)oxy)methyl)-3-chloro-8-oxo-10,11-dihydro-8H-[1,4]diazepine
  • Step 11 (S)-3-((6-Chloropyrimidin-4-yl)amino)-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]di Preparation of azepine[5',6':4,5]furo[3,2-f]quinolin-8-one (48)
  • compound 48k (20mg, 0.063mmol), 4-amino-6-chloropyrimidine (16.32mg, 0.13mmol), cesium carbonate (677mg, 2.08mmol) were added to dioxane (5mL), nitrogen replacement 5 times, stirred for 10 minutes, then added 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (3.65mg, 0.006mmol) and tris(dibenzylideneacetone)dipalladium (5.77mg , 0.006mmol), and replaced with nitrogen 5 times, and reacted overnight at 100°C. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 48.
  • Step 2 (S)-3-((6-chloropyrimidin-4-yl)oxy)-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4] Preparation of diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (49)
  • Step 1 Preparation of 1-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-2-ol (51a)
  • Step 2 (R)-3-((2-Chloro-6-((2-hydroxy-2-methylpropyl)amino)pyrimidin-4-yl)oxy)-10-methyl-9,10 , Preparation of 11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (51)
  • compound 1m 100mg, 0.35mmol
  • compound 51a 83mg, 0.35mmol
  • N,N-dimethylformamide 3mL
  • potassium carbonate 147mg, 1.06mmol
  • nitrogen replacement was performed three times , 130°C for 6 hours.
  • the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 51.
  • oxetan-3-ol 300 mg, 4.05 mmol was dissolved in tetrahydrofuran (3 mL) and potassium tert-butoxide (454 mg, 4.05 mmol), replaced with nitrogen three times, and stirred at -78°C for 20 minutes.
  • Compound 24a (1.01 g, 4.45 mmol) was added and reacted at -78°C for 3 hours.
  • Step 2 (R)-3-((6-Chloro-2-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 , Preparation of 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (52)
  • Step 1 Preparation of 1-((4,6-dichloropyrimidin-2-yl)amino)-2-methylpropan-2-ol (53a)
  • Step 2 (R)-3-((6-Chloro-2-((2-hydroxy-2-methylpropyl)amino)pyrimidin-4-yl)oxy)-10-methyl-9,10 , Preparation of 11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (53)
  • compound 42 (8.3mg, 0.018mmol), paraformaldehyde (3.64mg, 0.040mmol), sodium cyanoborohydride (3.47mg, 0.055mmol) and methanol (1.5ml) were added sequentially, and stirred at room temperature for 40 minutes. After filtration, the filtrate was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 62.
  • Step 1 (R)-3-Bromo-10-methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepine[5',6':4,5] Preparation of di-tert-butyl furo[3,2-f]quinoline-9,12-dicarboxylate (63a)
  • compound 1j (1.70g, 3.52mmol) was dissolved in N,N-dimethylformamide (20mL), replaced with nitrogen three times, cooled to 0°C, and phosphorus oxybromide (0.89g, 3.10mmol) was added dropwise ), stirred at room temperature for 2 hours. It was quenched by adding methanol (5 mL), extracted with dichloromethane (50 mL), washed with water (50 mL X 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and washed with ether to obtain compound 63a.
  • Step 4 (R)-3-((2-Chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H- Preparation of [1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (63)
  • compound 63c (61.14 mg, 0.34 mmol) was dissolved in 1,4-dioxane (1.5 mL), compound 63b (60 mg, 0.17 mmol), cesium carbonate (337.02 mg, 1.03 mmol), three (Dibenzylideneacetone)dipalladium (31.80mg, 0.035mmol), 1,1-binaphthyl-2,2'-bisdiphenylphosphine (43.26mg, 0.069mmol), nitrogen replacement three times, react at 100°C for 0.5 hours . After filtration and concentration under reduced pressure, the residue was purified by column chromatography (dichloromethane/methanol) and preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 63.
  • test examples are not meant to limit the scope of the present disclosure.
  • Compound A was prepared by the method disclosed in the patent application "Example 11 on page 99 of the specification in WO2018170203".
  • Test Example 1 In vitro MK2 Enzyme Activity Detection Test
  • the IC50 values of the compounds were fitted with XLFit excel add-in version 5.4.0.8.
  • Y is the conversion signal value
  • X is the concentration of the test compound
  • Top is the highest position of the dose-response curve
  • Bottom is the baseline position of the dose-response curve
  • HillSlope is the slope coefficient
  • the MK2 kinase biochemical inhibitory activity of the disclosed compounds was determined by the above tests, and the measured IC 50 values are shown in Table 1.
  • the disclosed compound has strong inhibitory activity on MK2 kinase.
  • the in vitro PBMC cell cytokine assay was tested by the method of LPS-induced cell production of cytokine TNF- ⁇ .
  • the initial test concentration of the test compound was 10000 nM, diluted 3 times, and a total of 9 concentrations were tested in duplicate wells.
  • PBMC cells were collected for cell counting and viability calculation. Seed 2 ⁇ 10 cells/0.1 mL/well into a 96-well plate. Compounds (initial stock solution 40 ⁇ M dissolved in DMSO, used 1:4) and LPS dilutions (0.4 ng/mL dissolved in PBS, used 1:4) were prepared. Add 50 ⁇ l compound diluent and 50 ⁇ l LPS diluent (final concentration 0.1 ng/ml) to each well, and incubate at 37° C. 5% CO 2 for 24 hours. The normal control group used DMSO instead of the compound dilution, and the test control group used medium instead of the LPS dilution.
  • the compounds of the present disclosure can inhibit the release of PBMC pro-inflammatory cytokines in vitro through the above tests, and the measured IC 50 values are shown in Table 2.
  • the disclosed compound has strong inhibitory effect on the release of PBMC pro-inflammatory cytokines.
  • Plasma samples were collected within 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, and the plasma drug concentrations were determined using LC-MS/MS, and non-atrial Compartmental analysis was used to estimate pharmacokinetic parameters.
  • the disclosed compound has good pharmacokinetic absorption activity in SD rats, and has pharmacokinetic advantages.

Abstract

Sont divulgués un dérivé de quinolinofurane représenté par la formule I ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le contenant, et son utilisation dans la préparation d'un médicament pour la prévention et/ou le traitement de maladies médiées par MK2. La définition des groupes dans la formule générale est la même que celle dans la description.
PCT/CN2022/115213 2021-08-27 2022-08-26 Dérivé de quinolinofurane et son utilisation WO2023025298A1 (fr)

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US20200102325A1 (en) * 2017-03-16 2020-04-02 Celgene Car Llc Heteroaryl compounds useful as mk2 inhibitors
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