WO2024104398A1 - 吡啶氮氧化物类衍生物及其药物组合物、制备方法和用途 - Google Patents

吡啶氮氧化物类衍生物及其药物组合物、制备方法和用途 Download PDF

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WO2024104398A1
WO2024104398A1 PCT/CN2023/131862 CN2023131862W WO2024104398A1 WO 2024104398 A1 WO2024104398 A1 WO 2024104398A1 CN 2023131862 W CN2023131862 W CN 2023131862W WO 2024104398 A1 WO2024104398 A1 WO 2024104398A1
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compound
formula
pharmaceutically acceptable
halogen
acceptable salt
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French (fr)
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栾林波
黄年峰
姚元山
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上海美悦生物科技发展有限公司
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a pyridine nitrogen oxide derivative and a pharmaceutical composition, a preparation method and use thereof.
  • Mitogen-activated protein kinase is a group of serine-threonine protein kinases that can be activated by different intracellular and external stresses. It is an important transmitter of signals from the cell surface to the nucleus. Stress factors include cytokines, neurotransmitters, hormones, cell stress and cell adhesion.
  • p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152),924], so selectively inhibiting the activation of p38 MAPK downstream effectors is the main strategy to avoid side effects/lack of efficacy caused by overall inhibition of p38 MAPK.
  • MAPK-activated protein kinase 2 (MK2) is a direct substrate downstream of p38 MAPK and can be activated by p38 ⁇ and p38 ⁇ .
  • MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thus playing an important role in the regulation of multiple inflammatory diseases.
  • MK2 can increase the expression of inflammatory factors such as TNF- ⁇ , IL-6, IL-8 and COX-2 by stabilizing the AU-rich elements of mRNA.
  • MK2 inhibitors can reduce the expression of inflammatory factors such as MIP-1 ⁇ , TNF- ⁇ , IL-6 and IL-1 ⁇ , and also found a decrease in the infiltration of polymorphonuclear leukocytes, mast cells, and mononuclear macrophages and an improvement in the contractile properties of intestinal smooth muscle.
  • Z is selected from O, S and NH
  • R 1a and R 1b are the same or different and are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • R 1a and R 1b together with the carbon to which they are attached form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or the 3- to 8-membered heterocyclic group is optionally substituted with one or more substituents selected from halogen or C 1-6 alkyl;
  • R 1c and R 1d are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • R 1c and R 1d together with the carbon to which they are attached form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered cycloalkyl or the 3- to 8-membered heterocyclic group is optionally substituted with one or more substituents selected from halogen or C 1-6 alkyl;
  • Each R 2 is the same or different and is independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • Each R 3 is the same or different and is independently selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, oxo and 3 to 8 membered cycloalkyl;
  • R4 is selected from H, halogen, C1-6 alkyl and C1-6 haloalkyl
  • Each R 8 is the same or different and is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, hydroxy, amino, nitro and 3 to 8 membered cycloalkyl;
  • n is selected from 0, 1, 2, 3 and 4;
  • n is selected from 0, 1, 2, 3 and 4;
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl and 1,2,4-thiadiazole.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from
  • R 1 , R 2 and n are as defined for the compound of formula (I).
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyridazinyl and pyridonyl.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from The a terminal is connected to the ring A; R 3 and m are as defined in the compound of formula (I).
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
  • G 1 is N or CR 3c ;
  • G 2 is N or CR 2a ;
  • G 3 is N or CR 2b ;
  • R 3a is selected from halogen, cyano, hydroxy, amino, C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • R 3b and R 3c are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • R 2a and R 2b are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • q is selected from 0, 1 and 2;
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and t are as defined for the compound of formula (I).
  • the present disclosure provides a compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof,
  • G 1 is N or CR 3c ;
  • G 2 is N or CR 2a ;
  • G 3 is N or CR 2b ;
  • R 3a is selected from halogen, cyano, hydroxy, amino, C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • R 3b and R 3c are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • R 2a and R 2b are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • q is selected from 0, 1 and 2;
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and t are as defined for the compound of formula (I).
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a compound of formula (III) or a pharmaceutically acceptable salt thereof,
  • G 1 is N or CR 3c ;
  • R 3a is selected from halogen, cyano, hydroxy, amino, C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • R 3b and R 3c are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • U 1 is N or C
  • U2 is selected from N, S and CR U2 ;
  • U3 is selected from N, S and CR U3 ;
  • U4 is selected from N, S and CR U4 ;
  • R U2 , R U3 and R U4 are the same or different and are each independently selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3- to 8-membered cycloalkyl;
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 and t are as defined for the compound of formula (I).
  • the present disclosure provides a compound represented by formula (I) or formula (III) or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof,
  • G 1 is N or CR 3c ;
  • R 3a is selected from halogen, cyano, hydroxy, amino, C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • R 3b and R 3c are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl;
  • U 1 is N or C
  • U2 is selected from N, S and CR U2 ;
  • U3 is selected from N, S and CR U3 ;
  • U4 is selected from N, S and CR U4 ;
  • R U2 , R U3 and R U4 are the same or different and are each independently selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and 3- to 8-membered cycloalkyl;
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 and t are as defined for the compound of formula (I).
  • the present disclosure provides compounds represented by formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) and formula (III-2) or pharmaceutically acceptable salts thereof, wherein R 3a is selected from halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl.
  • the present disclosure provides compounds represented by formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) and formula (III-2) or pharmaceutically acceptable salts thereof, wherein R 3a is selected from F, Cl, methyl, ethyl, cyano, difluoromethyl, trifluoromethyl.
  • the present disclosure provides compounds represented by formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) and formula (III-2) or pharmaceutically acceptable salts thereof, wherein R 3b and R 3c are the same or different and are each independently selected from H or halogen.
  • the present disclosure provides compounds represented by formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) and formula (III-2) or pharmaceutically acceptable salts thereof, wherein R 3b and R 3c are the same or different and are each independently selected from H or F.
  • the present disclosure provides a compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are the same or different and are each independently selected from H, halogen, C 1-6 alkyl and cyano.
  • the present disclosure provides a compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are the same or different and are each independently selected from H, F, and cyano.
  • the present disclosure provides compounds represented by formula (III), formula (III-1) and formula (III-2) or pharmaceutically acceptable salts thereof, wherein R U2 , R U3 and R U4 are the same or different and are each independently selected from H, halogen and C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from: R 1 , R 2 , R 3 , n and m are as defined for the compound of formula (I).
  • the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, wherein Selected from R 1 , R 2 , R 3a , R 3b and n are as defined for the compound of formula (I).
  • the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein Selected from
  • R 1 , RU3 , RU4 , R 3a and R 3b are as defined for the compound of formula (I).
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from Y1 is selected from O, NR y1 or CR y2 R y3 ;
  • R y1 is H or C 1-6 alkyl
  • R y2 and R y3 are the same or different and are each independently selected from H, halogen and C 1-6 alkyl;
  • v 0, 1, 2, and 3;
  • w is 0, 1, 2 and 3; the condition is that v and w are not 0 at the same time.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from H, halogen, C 1-6 alkyl and cyano.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from H, F and cyano.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from H, halogen, cyano, oxo, C 1-6 alkyl and C 1-6 haloalkyl.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R4 is Cl, Br, methyl, or trifluoromethyl.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 4 is a halogen.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 4 is Cl.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 5 is a C 1-6 alkyl group.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are the same or different and are each independently H or D.
  • the present disclosure provides a compound of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), or formula (III-2):
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 8 is F.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein for R 8a and R 8b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein for R 8a and R 8b are the same or different and are each independently halogen.
  • the present disclosure provides a compound represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein for R 8a and R 8b are both F.
  • the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, wherein for R 1 is selected from R 2 is each independently selected from H, halogen, C 1-6 alkyl and cyano; R 3a is selected from halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl; R 3b is H or halogen; R 4 is Cl; R 5 is methyl; R 6 and R 7 are the same or different and are each independently H or D; for R 8a and R 8b are the same or different and are each independently halogen; n is 0, 1 or 2.
  • R 1 is selected from R 2 is each independently selected from H, halogen, C 1-6 alkyl and cyano
  • R 3a is selected from halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl
  • R 3b is H or halogen
  • R 4 is Cl
  • R 5 is methyl
  • R 6 and R 7 are the same or different and are each
  • the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, wherein for R1 is R2 is H or halogen; R3a is halogen or C1-6 alkyl; R3b is H; R4 is Cl; R5 is methyl; R6 and R7 are the same or different and are each independently H or D; for R 8a and R 8b are both F; n is 0, 1 or 2.
  • exemplary specific compounds of the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1) or formula (III-2) include, but are not limited to, the structures in Table A below:
  • exemplary specific compounds of the compound represented by formula (I) also include, but are not limited to, the structures in Table B below:
  • the present disclosure provides a compound of formula (IA) or a salt thereof,
  • X is halogen; preferably Br;
  • exemplary specific compounds of the compound represented by formula (IA) also include, but are not limited to, the following compounds:
  • the present disclosure provides a compound of formula (IIC) or a salt thereof,
  • G 1 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8 and t are as defined in formula (II).
  • the present disclosure provides a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of formula (IA) undergoes a coupling reaction with the compound of formula (IB) in the presence of a catalyst to obtain a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • X is a halogen; preferably Br;
  • Rw is -B(OH) 2 or
  • the present disclosure provides a method for preparing a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • Z is O
  • X is halogen; preferably Br;
  • Rw is -B(OH) 2 or
  • G1 , G2 , G3 , R1 , R2, R3a , R3b , R4 , R5 , R6 , R7 , R8 , q and t are as defined in formula (II).
  • the present disclosure provides a method for preparing a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of formula (IA) undergoes a coupling reaction with the compound of formula (IIIB) in the presence of a catalyst to obtain a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • Z is O
  • X is halogen; preferably Br;
  • Rw is -B(OH) 2 or
  • G1 , U1 , U2 , U3, U4 , R1 , R3a , R3b , R4 , R5 , R6 , R7 , R8 and t are as defined in formula (III).
  • the present disclosure provides a method for preparing a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of formula (IIC) undergoes a ring-closing reaction with the compound of formula (IID) to obtain a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • G1 , R1 , R2 , R3a , R3b , R4 , R5 , R6 , R7 , R8 , q and t are as defined in formula (II).
  • a pharmaceutical composition which comprises at least one therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the present disclosure also provides the use of the compounds shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B or their pharmaceutically acceptable salts or pharmaceutical compositions containing the same for preparing drugs for p38 kinase inhibitors.
  • the present disclosure also provides compounds shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, and their use in the preparation of drugs for preventing and/or treating p38 kinase-mediated diseases or conditions; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK/MK2 pathway.
  • the present disclosure also provides compounds shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, and their use in preparing drugs for preventing and/or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer; preferably, their use in preparing drugs for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis and Alzheimer's disease.
  • the present disclosure also provides a method for inhibiting p38 kinase, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.
  • the present disclosure also provides a method for preventing and/or treating a disease or condition mediated by p38 kinase, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope labelled substance, or the aforementioned pharmaceutical composition comprising the same; preferably, the p38 kinase mediated disease is a disease related to the p38 MAPK/MK2 pathway.
  • the present disclosure also provides a method for preventing and/or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.
  • the present disclosure also provides a method for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis and Alzheimer's disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used as a medicine.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used as a p38 kinase inhibitor.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, which is used as a drug for preventing and/or treating p38 kinase-mediated diseases or conditions; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK/MK2 pathway.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for preventing and/or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis and Alzheimer's disease.
  • the p38 kinase-mediated disease of the present disclosure is selected from the group consisting of autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer.
  • the p38 kinase-mediated disease of the present disclosure is selected from arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, Atherosclerosis and Alzheimer's disease.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt or its isotope label, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt or its isotope label.
  • the pharmaceutical composition contains 0.5%-99.5% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt or its isotope label. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound shown in the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Table A or Table B, or a pharmaceutically acceptable salt or an isotope-labeled substance thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of one or more pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of one or more pharmaceutically acceptable excipients.
  • the disclosed compounds can be administered in the form of a pharmaceutical composition.
  • These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. It can be administered topically (e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), oral or parenteral.
  • topically e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal
  • oral or parenteral e.g., by inhalation or insuff
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. It can be administered parenterally in a single bolus form, or it can be administered, for example, by a continuous infusion pump.
  • the active ingredient is typically mixed with excipients and the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • excipient refers to ingredients other than active ingredients, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • the pharmaceutically acceptable salts of the compounds described in the present disclosure may be inorganic salts or organic salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.
  • these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • cis and trans isomers for example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, as well as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure.
  • the bond Indicates that the configuration is not specified. Indicates the absolute configuration, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations, Indicates the presence of axial chirality.
  • Tautomer refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also referred to as prototransfer tautomers
  • proton migration such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds in the present disclosure are within the scope of the present disclosure.
  • the name of the compound named in a single manner does not exclude any tautomer.
  • the present disclosure also includes some structures that are the same as those described herein, but one or more atoms are replaced by an atomic mass or mass number different from that found in nature.
  • the present invention discloses isotopically labeled compounds of the present invention with atoms replaced with atomic weights or mass numbers commonly found in the present invention.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have deuterium (i.e., at least 10% deuterium incorporation) at least 1000 times greater than the natural abundance of deuterium (which is 0.015%).
  • the natural abundance of the compound in the example may be at least 1000 times greater than deuterium, at least 2000 times greater than deuterium, at least 3000 times greater than deuterium, at least 4000 times greater than deuterium, at least 5000 times greater than deuterium, at least 6000 times greater than deuterium, or more.
  • Each available hydrogen atom connected to a carbon atom may be independently replaced by a deuterium atom.
  • deuterated starting materials may be used, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.
  • the "therapeutically effective amount” of the present disclosure refers to the amount of active compound or drug that causes a biological or medical response in a tissue, system, animal, individual or human that is sought by researchers, veterinarians, physicians or other clinicians, and includes one or more of the following: (1) Prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the disease pathology or symptoms. (2) Suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms).
  • Relief of disease for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and/or symptoms).
  • a "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms that are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit/risk ratio, and are effective for the intended use.
  • the "patient” of the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
  • the present disclosure provides a small molecule compound having a pyridine nitrogen oxide structure, which can be used as a p38 MAPK/MK2 pathway inhibitor, such as a compound having a pyridine nitrogen oxide structure of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Table A or Table B, and such compounds or pharmaceutical compositions can be used to effectively treat or prevent diseases mediated by the p38 MAPK/MK2 pathway.
  • Such pyridine nitrogen oxide structure compounds inhibit p38 MAPK-dependent MK2 activity while maintaining selectivity for ATF2 and MK5; in addition, such compounds also have good in vivo pharmacokinetic properties.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms ( C1-6 alkyl).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof, etc.
  • the alkyl group can be substituted or unsubstituted.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined herein.
  • the alkoxy group contains 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (C 1-12 alkoxy), and more preferably, the alkoxy group contains 1 to 6 carbon atoms (C 1-6 alkoxy).
  • Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed, and bridged rings.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between each monocycle in the system, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl.
  • spirocycloalkyl include:
  • condensed cycloalkyl refers to 5 to 20 yuan, and each ring in the system shares a pair of carbon atoms adjacent to the full carbon polycyclic group with other rings in the system, wherein one or more rings can contain one or more double bonds.
  • 6 to 14 yuan more preferably 7 to 10 yuan (for example 7,8,9 or 10 yuan).
  • dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/6 yuan, 5
  • bridged cycloalkyl refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl group (including monocyclic, spirocyclic, fused and bridged rings) as described herein fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred The cycloalkyl group may be substituted or unsubstituted.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -O-O-, -O-S- or -S-S-, and the remaining ring atoms being carbon.
  • it contains 3 to 12 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g.
  • 1, 2, 3 and 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), of which 1-3 (e.g. 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms.
  • monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiro heterocyclic group refers to a polycyclic heterocyclic group of 5 to 20 yuan, in which one atom (called spiral atom) is shared between each monocyclic ring in the system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan).
  • the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. It is more preferably a 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral heterocyclic group.
  • spiral heterocyclic groups include:
  • fused heterocyclic radical refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system.
  • the polycyclic heterocyclic group, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, and more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan).
  • the composition ring it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a bicyclic or tricyclic, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan and 6 yuan/6 yuan bicyclic fused heterocyclic radical.
  • fused heterocyclic radicals include:
  • bridged heterocyclic group refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members).
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes a heterocyclyl as described herein (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated ⁇ electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • Aryl groups can be substituted or unsubstituted.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • yuan e.g., 5, 6, 7, 8, 9, or 10 yuan
  • 5 yuan or 6 yuan such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • a heteroaryl group can be substituted or unsubstituted.
  • alkyl alkoxy
  • cycloalkyl heterocyclyl
  • aryl and “heteroaryl” and the like herein may be substituted or unsubstituted; when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more identical or different substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", “divalent heterocyclic", "arylene” and "heteroarylene".
  • cycloalkyloxy refers to a cycloalkyl-O- group wherein cycloalkyl is as defined herein.
  • heterocyclyloxy refers to heterocyclyl-O- wherein heterocyclyl is as defined herein.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined herein.
  • halogen refers to F, Cl, Br or I.
  • hydroxy refers to -OH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined herein.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocycloalkyl group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Mass spectrometry was measured by Waters 2767 HPLC/Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC/Waters liquid chromatography-mass spectrometry.
  • the thin layer chromatography silica gel plate used is GF254 silica gel plate produced by Chenghua (Shanghai) Co., Ltd.
  • the specification of silica gel plate used in thin layer chromatography (TLC) is 0.2-0.25 mm, and the specification of thin layer chromatography separation and purification product is 0.4-0.5 mm.
  • Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1 liter.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.
  • reaction temperature is room temperature, ranging from 20°C to 30°C.
  • the separated chiral compounds can be distinguished by the order of retention time in the chiral chromatographic column. Therefore, the chiral compounds separated according to the order of retention time are distinguished by the corresponding number suffixes P1 and P2. That is, suffix P1 corresponds to the chiral structure separated first, and suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of the compound is listed in the structural formula, it does not mean that it corresponds one-to-one with the compounds with number suffixes P1 and P2, but only indicates two forms of existence of the absolute configuration. The absolute configuration of the compounds with number suffixes P1 and P2 shall be based on the absolute configuration objectively corresponding to the specific retention time.
  • N,N-dimethylformamide dimethyl acetal (3.58 g, 30 mmol) was added to N,N-dimethylformamide (20 mL) of compound 45c (1.70 g, 10 mmol), and the reaction mixture was stirred at 100°C for 3 hours. After the reaction, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain compound 45d (2.20 g, yield: 87.92%). MS m/z (ESI): 225.1 [M+1] + .
  • 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex 35 mg, 0.04 mmol was added to a solution of compound 45e (120 mg, 0.44 mmol), biboronic acid pinacol ester (166 mg, 0.65 mmol) and potassium acetate (85 mg, 0.87 mmol) in 1,4-dioxane (3 mL), and the reaction mixture was stirred at 120°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 45f (150 mg, crude product). MS m/z (ESI): 286.2 [M+1] + .
  • 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (16 mg, 0.014 mmol) was added to a mixed solution of compound A3 (50 mg, 0.14 mmol), compound 45f (39 mg, 0.14 mmol) and potassium carbonate (37 mg, 0.28 mmol) in 1,4-dioxane and water (2 mL/0.4 mL), and the reaction mixture was stirred at 90°C for 16 hours.
  • 1,1'-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex 138 mg, 0.17 mmol was added to a solution of compound 1a (470 mg, 1.7 mmol), pinacol borate (864 mg, 3.4 mmol) and potassium acetate (333 mg, 3.4 mmol) in 1,4-dioxane (8 mL), and the reaction mixture was stirred at 120°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 1b (400 mg, crude product). MS m/z(ESI):274.05[M+1] + .
  • Tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) was added to a mixed solution of compound 1b (400 mg, 1.47 mmol), compound A3 (195 mg, 0.73 mmol) and potassium carbonate (405 mg, 2.94 mmol) in 1,4-dioxane and water (2 mL/0.4 mL), and the reaction mixture was stirred at 90°C for 2 hours.
  • Methylmagnesium chloride (4.3 mL, 3M) was added dropwise to a solution of 19a (1.0 g, 4.29 mmol) in tetrahydrofuran (10.0 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, a saturated ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was washed with a saturated sodium chloride solution (10 mL ⁇ 2), dried over anhydrous sodium sulfate and filtered.
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (186 mg, 0.257 mmol) was added to a solution of compound 19b (600 mg, 2.57 mmol), pinacol borate (1.31 g, 5.15 mmol) and potassium acetate (505 mg, 5.15 mmol) in 1,4-dioxane (10 mL), and the reaction mixture was stirred at 90°C for 2 hours.
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (202 mg, 0.25 mmol) was added to a solution of compound 19d (700 mg, 2.5 mmol), pinacol borate (1.27 g, 5.0 mmol) and potassium acetate (490 mg, 5.0 mmol) in 1,4-dioxane (15 mL), and the reaction mixture was stirred at 120°C for 16 hours.
  • lithium diisopropylamide (2.0M, 3.9mL, 7.8mmol) was added to a solution of compound 20a (1.0g, 5.22mmol) in anhydrous tetrahydrofuran (6mL). After the mixture was stirred for 0.5 hours, acetone (0.39g, 6.8mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred for 1 hour.
  • reaction solution was quenched with saturated ammonium chloride solution (10mL), diluted with water (15mL), extracted with ethyl acetate (20mL ⁇ 3), and the combined organic phase was washed with saturated brine (40mL ⁇ 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (325mg, 0.4mmol) was added to a solution of compound 20b (1.0g, 4.0mmol), pinacol borate (1.5g, 5.9mmol) and potassium acetate (784mg, 8.0mmol) in 1,4-dioxane (10mL), and the reaction mixture was stirred at 90°C for 2 hours.
  • Step 5 Synthesis of compounds 20, 20-P1 and 20-P2
  • Tetrakis(triphenylphosphine)palladium (81 mg, 0.07 mmol) was added to a mixed solution of compound 20e (200 mg, 0.65 mmol), compound A3 (237 mg, 0.65 mmol) and potassium carbonate (179 mg, 1.30 mmol) in 1,4-dioxane and water (4 mL/0.5 mL), and the reaction mixture was stirred at 90°C for 2 hours.
  • 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (135 mg, 0.17 mmol) was added to a solution of compound 118c (490 mg, 1.65 mmol), pinacol borate (631 mg, 2.48 mmol) and potassium acetate (487 mg, 4.96 mmol) in 1,4-dioxane (10 mL), and the reaction mixture was stirred at 90°C for 4 hours.
  • Step 4 Synthesis of compounds 118, 118-P1, 118-P2
  • Tetrakis(triphenylphosphine)palladium (95 mg, 0.08 mmol) was added to a solution of compound A3 (300 mg, 0.82 mmol), compound 118d (430 mg, 1.65 mmol) and sodium carbonate (175 mg, 1.65 mmol) in 1,4-dioxane and water (5 mL/0.5 mL), and the reaction mixture was stirred at 90°C for 3 hours.
  • Test Example 1 Determination of p38 MAPK/MK2 activity in vitro
  • the inhibitory effect of the compounds on p38 MAPK/MK2 was detected using the Z-LYTE kinase assay kit (Thermo, PV3177).
  • the test compounds were dissolved in DMSO to a 10 mM stock solution and stored at -20°C until use.
  • the starting concentration of the compound was 10 ⁇ M, 1% DMSO, 5-fold serial dilution, 8 concentrations, and duplicate wells; 50 mM HEPES pH 7.5, 10 mM MgCl 2 , 0.01% Brij-35, 1 mM EGTA were used as reaction buffer to prepare 2x active p38a/inactive MK2/Ser/Thr 4 mixture.
  • the final 10 ⁇ L reaction system was carried out in a 384-well plate (Corning, 4514), containing 500 ng/mL inactive MK2 (abcam, 79910), 8 ng/mL active p38a (Carna, 04-152), and 2 ⁇ M Ser/Thr 4; after reacting at 20°C for 1 hour, Development Reagent A diluted 2048 times was added to each well, and after incubation at room temperature for 1 hour, 5 ⁇ L stop buffer solution was added to terminate the reaction, and the microplate reader was used for detection (Ex. 400 nm, Em. 445 nm; Ex. 400 nm, Em. 520 nm). GraphPad Prism 8 software was used to fit the concentration-effect curve and calculate the compound concentration of 50% inhibition effect, ie, IC 50 . The results are shown in Table 1.
  • the compounds disclosed in the present invention have good inhibitory activity against p38 MAPK/MK2.
  • Test Example 2 In vitro activity determination of TNF- ⁇ in human PBMC cell supernatant
  • the experimental scheme for the inhibitory effect of the compound on TNF- ⁇ in the supernatant of human PBMC cells was detected using an Elisa detection kit (Biyuntian, PI518).
  • the test compound was dissolved in DMSO to a 10mM stock solution and stored at -20°C for later use.
  • the starting concentration of the compound was 2 ⁇ M, 5-fold dilution, 6 concentrations, cell plating double wells, Elisa detection was single well, and the final DMSO concentration was 0.4%.
  • the starting concentration of the compound, the dilution multiple, the number of gradient concentrations, and the number of duplicate wells can also be changed according to the actual situation of compound screening.
  • PBMC peripheral blood mononuclear cells
  • the cell culture supernatant was collected by centrifugation at 500rcf for 8min, and the concentration of TNF- ⁇ was detected according to the operation manual of the Elisaa kit.
  • concentration-effect curve was fitted using GraphPad Prism 8 software, and the compound concentration with 50% inhibitory effect, i.e., IC 50 , was calculated.

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Abstract

本公开涉及一种吡啶氮氧化物类衍生物及其用途，具体而言，提供了一类式(I)所示的吡啶氮氧化物类化合物或其药学上可接受的盐，其可用于制备药物，特别是制备预防和/或治疗.

Description

吡啶氮氧化物类衍生物及其药物组合物、制备方法和用途
本申请要求享有：
于2022年11月16日向中国国家知识产权局提交的，专利申请号为2022114366022，名称为“吡啶氮氧化物类衍生物及其药物组合物、制备方法和用途”的在先申请的优先权；
于2023年11月3日向中国国家知识产权局提交的，专利申请号为2023114599667，名称为“吡啶氮氧化物类衍生物及其药物组合物、制备方法和用途”的在先申请的优先权；
所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本公开属于医药领域，具体涉及一种吡啶氮氧化物类衍生物及其药物组合物、制备方法和用途。
背景技术
生物信号转导涉及特异性的蛋白-蛋白相互作用和翻译后修饰、调节遗传和表观遗传过程以应对内外环境的作用。丝裂原活化蛋白激酶MAPK(mitogen-activated protein kinase)是一组能被不同的细胞内外部应激激活的丝氨酸-苏氨酸蛋白激酶，是信号从细胞表面传导到细胞核内部的重要传递者。应激因素包括细胞因子、神经递质、激素、细胞应激和细胞黏附等。
作为MAPK家族的一个亚族，p38 MAPK在细胞对外界信号和炎性细胞因子的作用做出响应，p38MAPK被激活后磷酸化并激活下游多种蛋白激酶和转录因子，从而发挥复杂的生物学作用。p38 MAPK包括四个成员，即p38α、p38β、p38γ和p38δ。其中，p38α被认为在炎症过程的信号通路中起着重要作用，而其它异构体的生物学功能尚未完全被发现，但它们具有多效性。研究表明，p38β在细胞保护机制中起着重要的作用，而丝裂原活化蛋白激酶MKK3(MAP Kinase Kinase 3)介导p38δ对晚期结直肠癌(CRC)细胞的增殖和存活有作用。作为药物开发领域一个有吸引力的靶点，p38 MAPK有多个抑制剂药物进入临床研究，截至目前还没有药物被批准上市。根据公开信息，部分候选化合物在临床研究阶段失败。因此，开发一款安全有效的p38 MAPK抑制剂是目前该领域药物开发面临的主要挑战。
p38 MAPK可调控超过60种底物并行使不同的生理学功能[Cell 2013(152),924]，所以选择性地抑制p38 MAPK下游效应物的激活，是避免由于p38 MAPK的整体抑制而导致的副作用/药效不足的主要策略。MAPK激活蛋白激酶2(MAPK-activated protein kinase 2，MK2)是p38 MAPK下游的直接作用底物，可被p38α和p38β激活。作为第一个被发现的p38 MAPK底物，MK2可在转录和转录后水平调节炎症因子的表达，从而在多个炎症性疾病的调节中发挥重要作用。研究表明，MK2可通过稳定mRNA的AU-rich元件，从而使TNF-α、IL-6、IL-8和COX-2等炎症因子表达增加。在小鼠的术后肠梗阻模型中[The Journal of surgical research 2013(185),102]，MK2抑制剂可减少炎症因子MIP-1α、TNF-α、IL-6和IL-1β等的表达，同时发现多形核白细胞、肥大细胞、单核巨噬细胞浸润的减少和肠平滑肌收缩性能的改善。在小鼠的胶原诱发性关节炎(CIA)模型中[Journal of immunology 2006(177),1913]，敲除MK2基因可以减少胶原诱发性关节炎的发生，与野生型小鼠相比，MK2-/-和MK2+/-小鼠胶原诱发性关节炎的发病率减少、严重程度降低，且炎症因子TNF-α和IL-6表达也有不同程度的减少。在MK2敲除的高胆固醇血症小鼠模型中[Circ Res 2007(101),1104]，小鼠的大动脉的脂质沉积和巨噬细胞减少，而且VCAM-1和MCP-1等炎症因子表达减少。另外，有研究表明抑制MK2可以用于抗肿瘤药物的开发[Cancer cell 2007(11),175]。因此，需要寻找新的小分子抑制剂，通过选择性的调控p38 MAPK/MK2通路，在抑制p38 MAPK依赖性的MK2活性同时保持p38 MAPK其它底物的选择性(例如ATF2和MK5)，在保持治疗效果的同时提高药物的安全性。
发明内容
本公开提供了一种式(I)所示化合物或其药学上可接受的盐，
其中：
环A为苯基或5至6元杂芳基；
环B选自苯基、5至6元杂芳基和5至8元杂环基；
Z选自O、S和NH；
R1为
R1a和R1b相同或不同，且各自独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6羟烷基和3至8元环烷基；
或者R1a和R1b与其相连的碳一起形成3至8元环烷基或3至8元杂环基，所述的3至8元环烷基或3至8元杂环基任选被选自卤素或C1-6烷基中的一个或多个取代基取代；
R1c和R1d相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
或者R1c和R1d与其相连的碳一起形成3至8元环烷基或3至8元杂环基，所述的3至8元环烷基或3至8元杂环基任选被选自卤素或C1-6烷基中的一个或多个取代基取代；
各个R2相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
各个R3相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氧代和3至8元环烷基；
R4选自H、卤素、C1-6烷基和C1-6卤代烷基；
R5选自H、卤素、C1-6烷基和C1-6卤代烷基；
R6和R7相同或不同，且各自独立地选自H、D、卤素和C1-6烷基；
各个R8相同或不同，且各自独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基、羟基、氨基、硝基和3至8元环烷基；
n选自0、1、2、3和4；
m选自0、1、2、3和4；
t选自0、1、2、3和4。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中Z为O。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中环A选自苯基、吡啶基、嘧啶基、吡唑基、咪唑基、噻唑基和1,2,4-噻二唑。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中选自
R1、R2和n如式(I)化合物所定义。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中环B选自苯基、吡啶基、嘧啶基、吡唑基、咪唑基、哒嗪基和吡啶酮基。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中选自 a端与环A相连；R3和m如式(I)化合物所定义。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其为式(II)所示的化合物或其药学上可接受的盐，
其中：
G1为N或CR3c；
G2为N或CR2a；
G3为N或CR2b；
R3a选自卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
R3b和R3c相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
R2a和R2b相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
q选自0、1和2；
R1、R2、R4、R5、R6、R7、R8和t如式(I)化合物所定义。
在一些实施方式中，本公开提供了式(I)或式(II)所示化合物或其药学上可接受的盐，其为式(II-1)或式(II-2)所示的化合物或其药学上可接受的盐，
其中：
G1为N或CR3c；
G2为N或CR2a；
G3为N或CR2b；
R3a选自卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
R3b和R3c相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
R2a和R2b相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
q选自0、1和2；
R1、R2、R4、R5、R6、R7、R8和t如式(I)化合物所定义。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其为式(III)所示的化合物或其药学上可接受的盐，
其中：
G1为N或CR3c；
R3a选自卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
R3b和R3c相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
为单健或双健；
U1为N或C；
U2选自N、S和CRU2；
U3选自N、S和CR U3；
U4选自N、S和CRU4；
RU2、R U3和RU4相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
R1、R4、R5、R6、R7、R8和t如式(I)化合物所定义。
在一些实施方式中，本公开提供了式(I)或式(III)所示化合物或其药学上可接受的盐，其为式(III-1)或式(III-2)所示的化合物或其药学上可接受的盐，
其中：
G1为N或CR3c；
R3a选自卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
R3b和R3c相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
为单健或双健；
U1为N或C；
U2选自N、S和CRU2；
U3选自N、S和CRU3；
U4选自N、S和CRU4；
RU2、RU3和RU4相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
R1、R4、R5、R6、R7、R8和t如式(I)化合物所定义。
在一些实施方式中，本公开提供了式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)和式(III-2)所示化合物或其药学上可接受的盐，其中R3a选自卤素、氰基、C1-6烷基和C1-6卤代烷基。
在一些实施方式中，本公开提供了式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)和式(III-2)所示化合物或其药学上可接受的盐，其中R3a选自F、Cl、甲基、乙基、氰基、二氟甲基、三氟甲基。
在一些实施方式中，本公开提供了式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)和式(III-2)所示化合物或其药学上可接受的盐，其中R3b和R3c相同或不同，且各自独立地选自H或卤素。
在一些实施方式中，本公开提供了式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)和式(III-2)所示化合物或其药学上可接受的盐，其中R3b和R3c相同或不同，且各自独立地选自H或F。
在一些实施方式中，本公开提供了式(II)、式(II-1)或式(II-2)所示化合物或其药学上可接受的盐，其中R2a和R2b相同或不同，且各自独立地选自H、卤素、C1-6烷基和氰基。
在一些实施方式中，本公开提供了式(II)、式(II-1)或式(II-2)所示化合物或其药学上可接受的盐，其中R2a和R2b相同或不同，且各自独立地选自H、F、氰基。
在一些实施方式中，本公开提供了式(III)、式(III-1)和式(III-2)所示化合物或其药学上可接受的盐，其中RU2、RU3和RU4相同或不同，且各自独立地选自H、卤素和C1-6烷基。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中选自： R1、R2、R3、n和m如式(I)化合物所定义。
在一些实施方式中，本公开提供了式(II)所示化合物或其药学上可接受的盐，其中选自 R1、R2、R3a、R3b和n如式(I)化合物所定义。
在一些实施方式中，本公开提供了式(III)所示化合物或其药学上可接受的盐，其中选自
R1、RU3、RU4、R3a和R3b如式(I)化合物所定义。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中R1选自 Y1选自O、NRy1或CRy2Ry3；
Ry1为H或C1-6烷基；
Ry2和Ry3相同或不同，且各自独立地选自H、卤素和C1-6烷基；
v为0、1、2和3；
w为0、1、2和3；条件是v和w不同时为0。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中R1选自
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中各个R2各自独立地选自H、卤素、C1-6烷基和氰基。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中各个R2各自独立地选自H、F和氰基。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中各个R3各自独立地选自H、卤素、氰基、氧代、C1-6烷基和C1-6卤代烷基。
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中各个R3各自独立地选自H、F、Cl、甲基、乙基、氰基、氧代(＝O)、二氟甲基、三氟甲基。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中R4为Cl、Br、甲基、三氟甲基。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中R4为卤素。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中R4为Cl。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中R5为C1-6烷基。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中R5为甲基。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中R6和R7相同或不同，且各自独立地为H或D。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2) 所示化合物或其药学上可接受的盐，其中各个R8相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中R8为F。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中为R8a和R8b相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中为R8a和R8b相同或不同，且各自独立地为卤素。
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中为R8a和R8b均为F。
在一些实施方式中，本公开提供了式(II)所示化合物或其药学上可接受的盐，其中为R1选自 R2各自独立地选自H、卤素、C1-6烷基和氰基；R3a选自卤素、氰基、C1-6烷基和C1-6卤代烷基；R3b为H或卤素；R4为Cl；R5为甲基；R6和R7相同或不同，且各自独立地为H或D；为R8a和R8b相同或不同，且各自独立地为卤素；n为0、1或2。
在一些实施方式中，本公开提供了式(II)所示化合物或其药学上可接受的盐，其中 为R1为R2为H或卤素；R3a为卤素或C1-6烷基；R3b为H；R4为Cl；R5为甲基；R6和R7相同或不同，且各自独立地为H或D；为R8a和R8b均为F；n为0、1或2。
在一些实施方式中，式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物的示例性的具体化合物包括，但不限于下表A中的结构：
表A







在一些实施方式中，式(I)所示化合物的示例性的具体化合物还包括，但不限于下表B中的结构：
表B


在本公开的另一方面中，提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)所示的、或表A或表B所示化合物的同位素标记物，所述的同位素标记优选为氘(D或2H)取代氢(1H)。
本公开另一方面，提供了一种式(IA)化合物或其盐，
其中：
X为卤素；优选为Br；
Z、R4、R5、R6、R7、R8和t如式(I)中所定义。
在一些实施方式中，式(IA)所示化合物的示例性的具体化合物还包括，但不限于下列化合物:
本公开另一方面，提供了一种式(IIC)化合物或其盐，
其中：G1、R3a、R3b、R4、R5、R6、R7、R8和t如式(II)中所定义。
本公开另一方面，提供了一种制备式(I)所示化合物或其药学上可接受的盐的方法，其包含如下步骤：
式(IA)的化合物与式(IB)化合物在催化剂的存在下发生偶联反应，得到式(I)所示的化合物或其药学上可接受的盐，
其中：X为卤素；优选为Br；
Rw为-B(OH)2或
Z、R1、R2、R3、R4、R5、R6、R7、R8、n、m和t如式(I)中所定义。
本公开另一方面，提供了一种制备式(II)所示化合物或其药学上可接受的盐的方法，其包含如下步骤：
式(IA)的化合物与式(IIB)化合物在催化剂的存在下发生偶联反应，得到式(II)所示的化合物或其药学 上可接受的盐，
其中：Z为O；
X为卤素；优选为Br；
Rw为-B(OH)2或
G1、G2、G3、R1、R2、R3a、R3b、R4、R5、R6、R7、R8、q和t如式(II)中所定义。
本公开另一方面，提供了一种制备式(III)所示化合物或其药学上可接受的盐的方法，其包含如下步骤：
式(IA)的化合物与式(IIIB)化合物在催化剂的存在下发生偶联反应，得到式(III)所示的化合物或其药学上可接受的盐，
其中：Z为O；
X为卤素；优选为Br；
Rw为-B(OH)2或
G1、U1、U2、U3、U4、R1、R3a、R3b、R4、R5、R6、R7、R8和t如式(III)中所定义。
本公开另一方面，提供了一种制备式(II)所示化合物或其药学上可接受的盐的方法，其包含如下步骤：
式(IIC)的化合物与式(IID)的化合物发生关环反应，得到式(II)所示的化合物或其药学上可接受的盐，
其中：
G2为N；G3为N；
G1、R1、R2、R3a、R3b、R4、R5、R6、R7、R8、q和t如式(II)中所定义。
本公开另一方面，提供了一种药物组合物，其包括至少一种治疗有效量的前述的化合物或其药学上可接受的盐，以及一种或多种药学上可接受的赋形剂。
本公开另一方面，还提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或包含其的药物组合物的用途，用于制备p38激酶抑制剂的药物。
本公开还提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或包含其的药物组合物，其在制备用于预防和/或治疗p38激酶介导的疾病或病症的药物中的用途；优选地，p38激酶介导的疾病为与p38 MAPK/MK2通路相关的疾病。
本公开还提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或包含其的药物组合物，其在制备用于预防和/或治疗自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经系统疾病和癌症的药物中的用途；优选地，其在制备用于预防和/或治疗关节炎、银屑病、系统性红斑狼疮、糖尿病、白血病、淋巴瘤、动脉粥样硬化和阿尔兹海默症的药物中的用途。
本公开还提供了一种抑制p38激酶的方法，其包括给予所需患者治疗有效量的式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或前述同位素标记物或前述包含其的药物组合物。
本公开还提供了一种预防和/或治疗p38激酶介导的疾病或病症的方法，其包括给予所需患者治疗有效量的式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或前述同位素标记物或前述包含其的药物组合物；优选地，p38激酶介导的疾病为与p38 MAPK/MK2通路相关的疾病。
本公开还提供了一种预防和/或治疗自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经系统疾病和癌症的方法，其包括给予所需患者治疗有效量的式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物。
本公开还提供了一种预防和/或治疗关节炎、银屑病、系统性红斑狼疮、糖尿病、白血病、淋巴瘤、动脉粥样硬化和阿尔兹海默症的方法，其包括给予所需患者治疗有效量的式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物。
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或前述药物组合物，其用作药物。
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或前述药物组合物，其用作p38激酶抑制剂。
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物，其用作预防和/或治疗p38激酶介导的疾病或病症的药物；优选地，p38激酶介导的疾病为与p38 MAPK/MK2通路相关的疾病。
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物，其用作预防和/或治疗自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经系统疾病和癌症的药物。
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物，其用作预防和/或治疗关节炎、银屑病、系统性红斑狼疮、糖尿病、白血病、淋巴瘤、动脉粥样硬化和阿尔兹海默症的药物。
本公开所述的p38激酶介导的疾病选自自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经系统疾病和癌症。
本公开所述的p38激酶介导的疾病选自关节炎、银屑病、系统性红斑狼疮、糖尿病、白血病、淋巴瘤、 动脉粥样硬化和阿尔兹海默症。
在一些实施方式中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在一些实施方式中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或其同位素标记物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐其同位素标记物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或其同位素标记物。在某些实施方案中，所述的药物组合物含有1％-99％的前述式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示化合物或其药学上可接受的盐或其同位素标记物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的一种或多种赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的一种或多种赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的一种或多种赋形剂。
作为药物时，可按药物组合物的形式给予本公开化合物。可按药剂领域中熟知的方式制备这些组合物，可通过多种途径给予，这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如，透皮、皮肤、眼和粘膜包括鼻内、阴道和直肠递药)、肺(例如，通过吸入或吹入粉末或气雾剂，包括通过喷雾器；气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药，或可通过例如连续灌注泵给药。
在制备本公开的组合物时，通常将活性成分与赋形剂混合，组合物可以是以下形式：片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒)、含例如高达10％重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
本公开所述的“赋形剂”是指除活性成分以外的成分，例如包括稀释剂、填充剂、吸收剂、润湿剂、粘合剂、崩解剂和润滑剂等。
另一方面，本公开中所述化合物的药学上可接受的盐可为无机盐或有机盐，如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基)，则其还可以形成内盐。
另一方面，本公开化合物可以存在特定的几何或立体异构体形式。例如顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，外消旋混合物和其他混合物，以及对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。
本公开所述化合物的化学结构中，键表示未指定构型，表示绝对构型，即如果化学结构中存在手性异构体，键可以为或者同时包含两种构型，表示存在轴手性。
键表示未指定构型，包括顺式(E)或反式(Z)构型。
另外，本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。“互变异构体”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇异构化、亚胺-烯胺异构化和内酰胺-内酰亚胺异构化。本公开中的所有化合物的所有的互变异构形式均在本公开的范围内。用单一方式命名的化合物的名称不排除任何互变异构体。
本公开还包括一些与本文中记载的结构相同的，但一个或多个原子被原子量或质量数不同于自然中通 常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
本公开的“治疗有效量”是指研究人员、兽医、医师或其它临床医师等在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。针对药物或药理学活性剂而言，“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本公开“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本公开的“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。
有益效果
本公开提供了一种具有吡啶氮氧化物结构的小分子化合物，可作为p38 MAPK/MK2通路抑制剂，例如具有吡啶氮氧化物结构的式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、表A或表B所示的化合物，该类化合物或药物组合物可以用于有效治疗或预防p38 MAPK/MK2通路介导的疾病。这类吡啶氮氧化物类结构化合物在抑制p38 MAPK依赖性的MK2活性同时保持了对ATF2和MK5的选择性；此外，这类化合物也具有良好的体内药代动力学性质。
术语定义与说明
除非有相反陈述，否则在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选含有1至6个碳原子的烷基(C1-6烷基)。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基，及其各种支链异构体等。烷基可以是取代的或未取代的。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如本文中所述。优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷氧基(C1-12烷氧基)，更优选含有1至6个碳原子的烷氧基(C1-6烷氧基)。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是取代的或未取代的。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子或3至8个(例如3、4、5、6、7和8个)碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元，系统中的每个单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环烷基。稠环烷基的非限制性实例包括：
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
所述环烷基环包括如本文中所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括 等；优选所述环烷基可以是取代的或未取代的。
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3个(例如1、2和3个)是杂原子；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元，系统中的每个单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
所述杂环基环包括如本文中所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
等。所述杂环基可以是取代的或未取代的。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如本文中所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
芳基可以是取代的或未取代的。
术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如本文中所述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
杂芳基可以是取代的或未取代的。
本文中的术语“烷基”、“烷氧基”、“环烷基”、“杂环基”、“芳基”和“杂芳基”等可以是取代的或未取代的；当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基。
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同或两个不同的环原子上除去两个氢原子所衍生的残基，即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。
术语“环烷基氧基”指环烷基-O-，其中环烷基如本文中所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如本文中所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如本文中所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如本文中所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如本文中所定义。
术语“卤素”指F、Cl、Br或I。
术语“羟基”指-OH。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代基”或“氧代”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如本文中所定义。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环烷基团”意味着烷基可以但不必须存在，该说明包括杂环烷基团被烷基取代的情形和杂环烷基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
具体实施方式
下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术均涵盖在本公开旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker Avance III 400MHz核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
质谱(MS)是通过Waters 2767HPLC/Waters SQD，Waters H-class UPLC-SQD2，Agilent HPLC/Waters液相质谱联用仪测定的。
手性HPLC分析测定使用Shimadzu LC-20AD。
薄层层析硅胶板使用于成化工(上海)有限公司GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.2～0.25mm,薄层层析分离纯化产品采用的规格是0.4～0.5mm。
柱层析一般使用于成化工(上海)有限公司100～200目硅胶为载体。
高效液相制备使用Waters HPLC、Gilson HPLC和Biotage MPLC制备型色谱仪。
手性分离柱层析使用GilsonGX-281制备型HPLC。
实施例中如无特殊说明，反应均在氮气氛下进行。
氮气氛是指反应瓶连接一个约1升容积的氮气气球。
氢气氛是指反应瓶连接一个约1升容积的氢气气球。
实施例中如无特殊说明，反应温度均为室温，温度范围是20℃-30℃。
本领域技术人员应当理解，拆分的手性化合物可以通过在手性色谱柱中的保留时间的先后进行区分，因此，针对保留时间先后拆分出来的手性化合物以编号后缀P1、P2对应区分。即后缀P1对应先拆分出来的手性结构，后缀P2对应后拆分出来的手性结构。结构式中若有列出化合物的绝对构型，则其不意味着与编号后缀P1、P2的化合物一一对应，仅是示意绝对构型的两种存在形式。编号后缀P1、P2的化合物的绝对构型以特定保留时间客观对应的绝对构型为准。
中间体化合物A1的合成
第一步：化合物A1-2的合成
将氯化亚砜(22.43g,0.19mol)缓慢滴加到化合物A1-1(20g,0.13mol)的乙醇(60mL)溶液中，反应混合物加热至60℃并在该温度下搅拌3小时。反应结束后，反应液减压浓缩，得到化合物A1-2(20g,粗品)。产物不经纯化直接进行下一步反应。MS m/z(ESI):187.9[M+1]+。
第二步：化合物A1-3的合成
0℃下，将硼氢化钠(6.48g,0.17mol)分批加入化合物A1-2(16g,0.086mol)的乙醇(60mL)溶液中。反应混合物缓慢升至室温，并在室温下搅拌3小时。反应结束后，反应液减压浓缩，所得残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/5)纯化得化合物A1-3(16g,收率：73.5％)。MS m/z(ESI):146.1[M+1]+。
第三步：化合物A1的合成
将5滴N,N-二甲基甲酰胺加入化合物A1-3(1.80g,12.4mmol)的二氯甲烷(50mL)溶液中，反应混合物搅拌十分钟。室温下，将氯化亚砜(1.77g,14.88mmol)缓慢加入上述溶液中。所得混合物在室温下搅拌1小时。反应结束后，反应液中加入4M的氯化铵溶液至pH＝7，用二氯甲烷萃取(60mL×3)。合并有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～5/1)纯化得到化合物A1(1.80g,收率：84.7％)。1HNMR(400MHz,CDCl3)δ8.35(d,J＝2.4Hz,1H),7.26(ddd,J＝9.1,8.0,2.6Hz,1H),4.72(d,J＝2.1Hz,2H)。
中间体化合物A2的合成
第一步：化合物A2-2的合成
将硼氢化钠(598mg,15.8mmol)加入到化合物A2-1(2g,14.4mmol)的甲醇(20mL)溶液中，反应混合物室温搅拌16小时。反应结束后，反应液用2N盐酸调pH＝7，所得溶液减压浓缩除去甲醇，用乙酸乙酯萃取(10mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物A2-2(1.0g，收率：64％)。1H NMR(400MHz,CD3OD)δ3.57(s,2H),1.40–1.14(m,2H),1.04–0.80(m,2H)。
第二步：化合物A2-3的合成
将羟胺水溶液(3.4g,103mmol)加入到化合物A2-2(1.0g,10.3mmol)的乙醇(10mL)溶液中，反应混合物加热至75℃并在该温度下搅拌16小时。反应结束后，反应液减压浓缩得到化合物A2-3(1.2g，粗品)。MS m/z(ESI):131.2[M+1]+。
第三步：化合物A2的合成
将雷尼镍(1.32g,15.4mmol)加入到化合物A2-3(1g,7.68mmol)和乙酸(46mg,0.77mmol)的甲醇(10mL)溶液中，反应混合物在氢气气氛下室温搅拌12小时。反应结束，反应液过滤，过滤液减压浓 缩得到化合物A2(1.0g，粗品)。MS m/z(ESI):115.2[M+1]+。
中间体化合物A3的合成
第一步：化合物A3-2的合成
将NCS(10.6g,80mmol)加入到化合物A3-1(10g,53mmol)的DMF(200mL)溶液中，反应混合物在80℃下搅拌2小时。反应结束后，反应液加水(800mL)水稀释，用乙酸乙酯萃取(200mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～1:1)纯化得到化合物A3-2(10g，收率：75.94％)。MS m/z(ESI):221.7[M+1]+。
第二步：化合物A3-3的合成
0℃下，依次将NaH(2.16g,90mmol)和碘甲烷(12.8g,90mmol)加入到化合物A3-2(10g,45mmol)的DMF(100mL)溶液中，反应混合物缓慢升至室温搅拌16小时。反应结束后，反应液加水(300mL)淬灭，用乙酸乙酯萃取(200mL×2)，合并的有机相经饱和食盐水(100mL×1)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～5:1)纯化得到化合物A3-3(8g，收率：67.56％)。MS m/z(ESI):236.0[M+1]+。
第三步：化合物A3-4的合成
将化合物A3-3(8g,34mmol)加入到TFA和H2O2(40mL/40mL)的混合溶液中，反应混合物在100℃下搅拌16小时。反应结束后，反应液减压浓缩，残余物用饱和碳酸氢钠溶液调pH＝8，经乙酸乙酯萃取(100mL×2)，合并的有机相减压浓缩，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～1:1)纯化得到化合物A3-4(2g，收率：21.3％)。MS m/z(ESI):251.9[M+1]+。
第四步：化合物A3-5的合成
将三氯化铝(4.2g,32mmol)和乙硫醇(2g,32mmol)依次加入到化合物A3-4(1.6g,6.3mmol)的二氯甲烷(40mL)溶液中，反应混合物室温搅拌16小时。反应结束后，反应液减压浓缩，残余物加水(100mL)，析出白色固体，过滤，滤饼干燥后得到化合物A3-5(1g，收率：59.56％)。MS m/z(ESI):237.9[M+1]+。
第五步：化合物A3的合成
将碳酸钾(1.16g，8.4mmol)加入到化合物A3-5(1g，4.2mmol)和化合物A1(0.7g，4.2mmol)的N,N-二甲基甲酰胺(20mL)溶液中，反应混合物在65℃下搅拌3小时。反应结束后，反应液加水(100mL)稀释，经乙酸乙酯萃取(100mL×3)，合并的有机相经饱和食盐水洗(100mL×1)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～1:1)纯化得化合物A3(1g，收率：59.52％)。MS m/z(ESI):364.7[M+1]+。
实施例1(化合物45)
第一步：化合物45b的合成
在氮气气氛下，将双三苯基膦二氯化钯(974mg,1.388mmol)加入到化合物45a(4.5g,27.77mmol)和三丁基(1-乙氧基乙烯)锡(10.03g,27.77mmol)的1,4-二氧六环(75mL)溶液中，反应混合物在120℃下搅拌2小时。反应结束后，反应液加水(100mL)稀释，用乙酸乙酯萃取(30mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～20:1)纯化得到化合物45b(2.4g，收率：34.97％)。MS m/z(ESI):198.1[M+1]+。
第二步：化合物45c的合成
将浓盐酸(0.1mL)加入到化合物45b(2.4g,12.1mmol)的四氢呋喃(50mL)溶液中，反应混合物室温搅拌2小时。反应结束，反应液用饱和的碳酸氢钠溶液调节pH＝7并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～7:1)纯化得化合物45c(1.7g，收率：74.29％)。1HNMR(400MHz,)δ8.62(s,1H),7.86(s,1H),2.57(s,3H),2.36(s,3H)。
第三步：化合物45d的合成
将N,N-二甲基甲酰胺二甲基缩醛(3.58g,30mmol)加入到化合物45c(1.70g,10mmol)的N,N-二甲基甲酰胺(20mL)中，反应混合物在100℃下搅拌3小时。反应结束后，反应液过滤，过滤液减压浓缩，得到化合物45d(2.20g，收率：87.92％)。MS m/z(ESI):225.1[M+1]+。
第四步：化合物45e的合成
将碳酸钾(185mg,1.33mmol)加入到化合物45d(300mg,1.33mmol)和化合物A2(304mg,2.66mmol)的乙腈(10mL)溶液中，反应混合物在90℃下搅拌32小时。反应结束后，反应液过滤浓缩，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～1:1)纯化得到化合物45e(180mg，收率44％)。MS m/z(ESI):276.0[M+1]+。
第五步：化合物45f的合成
将1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(35mg,0.04mmol)加入到化合物45e(120mg,0.44mmol)、联硼酸频哪醇酯(166mg,0.65mmol)和乙酸钾(85mg,0.87mmol)的1,4-二氧六环(3mL)溶液中，反应混合物在120℃下搅拌16小时，反应结束后，反应液减压浓缩得到化合物45f(150mg,粗品)。MS m/z(ESI):286.2[M+1]+。
第六步：化合物45的合成
将1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(16mg,0.014mmol)加入到化合物A3(50mg,0.14mmol)、化合物45f(39mg,0.14mmol)和碳酸钾(37mg,0.28mmol)的1,4-二氧六环和水(2mL/0.4mL)混合溶液中，反应混合物在90℃下搅拌16小时。反应结束后，反应液减压浓缩，残余物经薄层层析硅胶板(二氯甲烷:甲醇＝20:1)纯化得到化合物45(7.1mg,收率9.36％)。MS m/z(ESI):526.1[M+1]+。1H NMR(400MHz,CD3OD)δ8.74(d,J＝5.2Hz,1H),8.71(s,1H),8.44(d,J＝2.4Hz,1H),8.31(s,1H),8.11(d,J＝5.2Hz,1H),7.75–7.69(m,1H),7.61(s,1H),5.49(d,J＝1.9Hz,2H),4.05–3.92(m,2H),2.16(s,3H),2.11 (s,3H),1.38(dd,J＝8.0,4.0Hz,2H),1.09–1.04(m,2H)。
实施例2(化合物117)
第一步：化合物117b的合成
将[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(70mg,0.1mmol)加入到化合物117a(2.13g,10mmol)、联硼酸频哪醇酯(2.79g,11mmol)和乙酸钾(1.9 6g,20mmol)的1,4-二氧六环(30mL)溶液中，反应混合物在110℃搅拌12小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～20:1)纯化得到化合物117b(2.2g，收率：80％)。MS m/z(ESI):261.1[M+1]+。
第二步：化合物117c的合成
将四三苯基膦钯(31mg,0.03mmol)加入到化合物117b(155mg,0.6mmol)、化合物A3(200mg,0.54mmol)和碳酸钾(150mg,0.6mmol)的1,4-二氧六环和水(10mL/2mL)混合溶液中，反应混合物在90℃下搅拌16小时，反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:0～1:1)纯化得到化合物117c(150mg，收率：52.4％)。MS m/z(ESI):419.0[M+1]+。
第三步：化合物117d的合成
将N,N-二甲基甲酰胺二甲基缩醛(300mg,2.5mmol)加入到化合物117c(350mg,0.83mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在100℃下搅拌3小时。反应结束，反应液加水(10mL)稀释，用乙酸乙酯(20mL×3)萃取，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～10:1)纯化得到化合物117d(370mg，收率：74％)。MS m/z(ESI):473.8[M+1]+。
第四步：化合物117的合成
将碳酸钾(215mg,1.6mmol)加入到化合物117d(370mg，0.77mmol)和化合物A2(445mg,4mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液过滤浓缩，残余物经硅胶柱层析(二氯甲烷:甲醇＝1:0～20:1)纯化得到粗品化合物117，粗品经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：30-40％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)纯化得到化合物117(26.9mg，收率6.4％)。MS m/z(ESI):525.1[M+1]+。1H NMR(400MHz,CDCl3)δ8.64(d,J＝5.5Hz,1H),8.44(d,J＝2.4Hz,1H),8.21(dd,J＝8.1,1.9Hz,1H),7.98(d,J＝1.9Hz,1H),7.76(d,J＝5.6Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),7.59(s,1H),7.53(d,J＝8.1Hz,1H),5.48(d,J＝2.0Hz,2H),3.99(d,J＝3.5Hz,2H),2.13(s,3H),2.09(s,3H),1.44(dd,J＝4.3,2.4Hz,2H),1.11(d,J＝2.8Hz,2H)。
实施例3(化合物1，1-P1，1-P2)
第一步：化合物1a的合成
将碳酸钾(491mg,3.56mmol)加入到化合物45d(400mg,1.78mmol)和2-羟基-2-甲基丙脒盐酸盐(491mg,3.56mmol)的乙腈(8mL)溶液中，反应混合物60℃搅拌2小时，反应完成后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/1)纯化得到化合物1a(470mg，收率94.6％)。MS m/z(ESI):264.05[M+1]+。
第二步：化合物1b的合成
将1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(138mg,0.17mmol)加入到化合物1a(470mg,1.7mmol)、频哪醇硼酸酯(864mg,3.4mmol)和乙酸钾(333mg,3.4mmol)的1,4-二氧六环(8mL)溶液中，反应混合物120℃搅拌16小时。反应结束后，反应液减压浓缩得到化合物1b(400mg，粗品)。MS m/z(ESI):274.05[M+1]+。
第三步：化合物1，1-P1和1-P2的合成
将四(三苯基膦)钯(173mg,0.15mmol)加入到化合物1b(400mg,1.47mmol)、化合物A3(195mg,0.73mmol)和碳酸钾(405mg,2.94mmol)的1,4-二氧六环和水(2mL/0.4mL)混合溶液中，反应混合物90℃搅拌2小时。反应完成后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/2)纯化得到粗品化合物1，粗品化合物1经高效液相制备色谱(制备柱：YMC Triart C18 12nm 10u，30*250mm,流速：40mL/min,流动相：A:水(0.1％氨水)B:制备乙腈)纯化得到化合物1(150mg,收率40.0％)。化合物1经手性制备色谱(制备柱：YMC CHIRALART Amylose-C NEO，30*250mm，流速：30mL/min，流动相：A:正己烷，B:乙醇：异丙醇＝1:1)拆分得到化合物1-P1(48.7mg，收率32.5％)和化合物1-P2(51.1mg，收率34.1％)。
化合物1-P1:
MS m/z(ESI):514.1[[M+1]+。手性HPLC：保留时间＝9.60min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝5.2Hz,1H),8.75(s,1H),8.59(d,J＝2.4Hz,1H),8.54(s,1H),8.21(d,J＝5.2Hz,1H),8.08(td,J＝9.6,2.4Hz,1H),7.56(s,1H),5.47(d,J＝1.6Hz,2H),5.18(s,1H),2.09(s,3H),2.02(s,3H),1.50(d,J＝4.8Hz,6H)。
化合物1-P2:
MS m/z(ESI):514.1[[M+1]+。手性HPLC：保留时间＝23.15min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝5.2Hz,1H),8.75(s,1H),8.59(d,J＝2.4Hz,1H),8.53(s,1H),8.21(d,J＝5.2Hz,1H),8.12–7.99(m,1H),7.56(s,1H),5.47(d,J＝1.6Hz,2H),5.18(s,1H),2.09(s,3H),2.02(s,3H),1.50(d,J＝4.8Hz,6H)。
实施例4(化合物19，19-P1，19-P2)
第一步：化合物19b的合成
0℃下，将甲基氯化镁(4.3mL,3M),滴加到19a(1.0g,4.29mmol)的四氢呋喃(10.0mL)溶液中，反应混合物室温搅拌2小时。反应完成后，反应液加入饱和氯化铵溶液(10mL)，用乙酸乙酯(20mL×3)萃取，合并的有机相经饱和氯化钠溶液洗涤(10mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～4/1)纯化得到化合物19b(0.7g，收率：70.0％)，MS m/z(ESI):214.95[M-18]+。
第二步：化合物19c的合成
将1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(186mg,0.257mmol)加入到化合物19b(600mg,2.57mmol)、频哪醇硼酸酯(1.31g,5.15mmol)和乙酸钾(505mg,5.15mmol)的1,4-二氧六环(10mL)溶液中中，反应混合物在90℃下搅拌2小时。反应完成后，反应液过滤除去不溶物，过滤液经减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/20～1/5)纯化得到化合物19c(450mg，收率：62.4％)。MS m/z(ESI):281.2[M+1]+。
第三步：化合物19d的合成
将四(三苯基膦)钯(289mg,0.25mmol)加入到化合物19c(700mg,2.5mmol)、化合物45a(402mg,2.5mmol)和碳酸钠(430mg,5.0mmol)的1,4-二氧六环和水(15mL/3mL)混合溶液中，反应混合物80℃搅拌2小时。反应完成后，反应液减压浓缩，残余物经硅胶柱层析(石油醚：乙酸乙酯＝1:1)纯化得到化合物19d(700mg，收率：100％)。MS m/z(ESI):280.00[M+1]+。
第四步：化合物19e的合成
将1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(202mg,0.25mmol)加入到化合物19d(700mg,2.5mmol)、频哪醇硼酸酯(1.27g,5.0mmol)和乙酸钾(490mg,5.0mmol)的1,4-二氧六环(15mL)溶液中，反应混合物120℃搅拌16小时。反应完成后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～2/1)纯化得到化合物19e(370mg，收率：51.2％)。MS m/z(ESI):290.1[M+1]+。
第五步：化合物19、19-P1和19-P2的合成
将四(三苯基膦)钯(138mg,0.12mmol)加入到化合物19e(370mg,1.28mmol)、化合物A3(373mg,1.02mmol)和碳酸钾(353mg,2.56mmol)的1,4-二氧六环和水(8mL/1mL)混合溶液中，反应混合物90℃搅拌2小时，反应完成后，反应液减压浓缩，残余物经硅胶柱柱层析(石油醚/乙酸乙酯＝1/2)纯化得到粗品化合物19，粗品经高效液相制备色谱(制备柱：YMC Triart C18 12nm 10u，30*250mm,流速：40mL/min,柱温：室温,流动相：A:水(0.1％氨水)B:制备乙腈)纯化得到化合物19(150mg,收率27.8％)。将化合物19经手性制备色谱(制备柱：YMC CHIRALART Amylose-C NEO，30*250mm，流速：30mL/min，柱温：室温，流动相：A:正己烷，B:异丙醇)拆分得到化合物19-P1(23.2mg，收率15.5％)和化合物19-P2 (23.3mg，收率15.5％)。化合物19-P1:
MS m/z(ESI):530.1[[M+1]+。手性HPLC：保留时间＝8.12min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.58(d,J＝2.4Hz,1H),8.12–8.01(m,1H),7.72–7.70(m,2H),7.59–7.49(m,2H),7.25(t,J＝7.6Hz,1H),5.45(d,J＝1.6Hz,2H),5.29(s,1H),2.04(s,3H),2.02(s,3H),1.50(s,6H)。
化合物19-P2:
MS m/z(ESI):530.1[[M+1]+。手性HPLC：保留时间＝12.05min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.58(d,J＝2.4Hz,1H),8.07(td,J＝9.6,2.4Hz,1H),7.75–7.62(m,2H),7.61–7.47(m,2H),7.25(t,J＝7.6Hz,1H),5.45(s,2H),5.29(s,1H),2.04(s,3H),2.02(s,3H),1.50(s,6H)。
实施例5(化合物20,20-P1,20-P2)
第一步：化合物20b的合成
-78℃下，将二异丙基氨基锂(2.0M,3.9mL,7.8mmol)加入到化合物20a(1.0g，5.22mmol)的无水四氢呋喃(6mL)溶液中，混合物搅拌0.5小时后，加入丙酮(0.39g,6.8mmol)，反应混合物缓慢升至室温并搅拌1小时。反应完成后，反应液用饱和氯化铵溶液(10mL)淬灭，加水(15mL)稀释，乙酸乙酯萃取(20mL×3)，合并的有机相用饱和食盐水洗涤(40mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝10/1～8/1)纯化得到化合物20b(1.0g，收率76.9％)。MS m/z(ESI):234.95[M-17]+。
第二步：化合物20c的合成
将1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(325mg,0.4mmol)加入化合物20b(1.0g,4.0mmol)、频哪醇硼酸酯(1.5g,5.9mmol)和乙酸钾(784mg,8.0mmol)的1,4-二氧六环(10mL)溶液中，反应混合物在90℃下搅拌2小时。反应完成后，反应液冷却至室温后经硅藻土过滤，过滤液加水(25mL)稀释，乙酸乙酯萃取(25mL×3)，合并的有机相用饱和食盐水洗涤(30mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝10/1～3/1)纯化得到化合物20c(500mg，收率41.9％)。MS m/z(ESI):281.10[M-17]+。
第三步：化合物20d的合成
将将四(三苯基膦)钯(265mg,0.23mmol)加入到化合物20c(700mg,2.3mmol)、化合物45a(370mg,2.3mmol)和碳酸钠(498mg,4.6mmol)的1,4-二氧六环和水(15mL/3mL)混合溶液中，反应混合物在80℃下搅拌2小时。反应完成后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/1)纯化得到化合物20d(500mg，收率：71.5％)。MS m/z(ESI):298.00[M+1]+。
第四步：化合物20e的合成
将1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(137mg,0.17mmol)加入到化合物20d(500mg,1.68mmol)、频哪醇硼酸酯(853mg,3.36mmol)和乙酸钾(329mg,3.36mmol)的1,4-二氧六环(10 mL)溶液中，反应混合物120℃下搅拌5小时。反应完成后，将反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/2)纯化得到化合物20e(360mg，收率：69.6％)。MS m/z(ESI):308.1[M+1]+。
第五步：化合物20，20-P1和20-P2的合成
将四(三苯基膦)钯(81mg,0.07mmol)加入到化合物20e(200mg,0.65mmol)、化合物A3(237mg,0.65mmol)和碳酸钾(179mg,1.30mmol)的1,4-二氧六环和水(4mL/0.5mL)混合溶液中，反应混合物90℃搅拌2小时。反应完成后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/2)纯化得到粗品化合物20，粗品化合物20经高效液相制备色谱纯化(制备柱：YMC Triart C18 12nm 10u，30*250mm,流速：40mL/min,柱温：室温,流动相：A:水(0.1％氨水)B:制备乙腈)得到化合物20(150mg,收率42.1％)。将化合物20(150mg)经手性制备色谱(制备柱：YMC CHIRALART Amylose-C NEO，30*250mm，流速：30mL/min，柱温：室温，流动相：A:正己烷，B:乙醇：异丙醇＝1:1)拆分得到化合物20-P1(35.4mg，收率23.6％)和化合物20-P2(35.3mg，收率23.5％)。
化合物20-P1:
MS m/z(ESI):547.9[[M+1]+。手性HPLC：保留时间＝12.37min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.57(d,J＝2.4Hz,1H),8.06(td,J＝9.6,2.4Hz,1H),7.75(td,J＝8.8,6.0Hz,1H),7.52(s,2H),7.10(dd,J＝11.2,9.6Hz,1H),5.45(d,J＝1.6Hz,2H),5.28(s,1H),2.03(s,3H),2.02(s,3H),1.59(s,6H)。
化合物20-P2:
MS m/z(ESI):548.0[[M+1]+。手性HPLC：保留时间＝19.04min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.57(d,J＝2.4Hz,1H),8.06(td,J＝9.6,2.4Hz,1H),7.75(td,J＝8.8,6.0Hz,1H),7.52(s,2H),7.10(dd,J＝11.2,9.6Hz,1H),5.45(d,J＝1.6Hz,2H),5.28(s,1H),2.04(s,3H),2.02(s,3H),1.59(s,6H)。
实施例6(化合物45-P1,45-P2)
将化合物45(60mg)经手性制备色谱(制备柱：YMC CHIRALART Amylose-C NEO，30*250mm；流速：30mL/min柱温：室温；流动相：A:正己烷B:乙醇)拆分得到化合物45-P1(17.7mg,收率29.5％)和化合物45-P2(17.0mg,收率28.3％)
化合物45-P1:
MS m/z(ESI):526.2[[M+1]+。手性HPLC：保留时间＝8.64min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.82(d,J＝5.2Hz,1H),8.76(s,1H),8.61(d,J＝2.4Hz,1H),8.26(s,1H),8.13–8.07(m,2H),7.58(s,1H),5.48(d,J＝1.6Hz,2H),4.53(s,1H),3.96(dd,J＝20.4,10.0Hz,2H),2.10(s,3H),2.03(s,3H),1.31(dd,J＝9.2,3.6Hz,1H),1.21(dd,J＝9.2,3.6Hz,1H),1.06(d,J＝3.6Hz,2H)。
化合物45-P2:
MS m/z(ESI):526.2[[M+1]+。手性HPLC：保留时间＝16.09min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.82(d,J＝5.2Hz,1H),8.76(s,1H),8.61(d,J＝2.4Hz,1H),8.26(s,1H),8.15–8.06(m,2H),7.58(s,1H),5.48(d,J＝1.6Hz,2H),4.55(s,1H),3.96(q,J＝11.2Hz,2H),2.10(s,3H),2.03(s,3H),1.31(dd,J＝9.2,3.6Hz,1H),1.21(dd,J＝9.2,3.6Hz,1H),1.06(d,J＝3.6Hz,2H)。
实施例7(化合物118，118-P1，118-P2)
第一步：化合物118b的合成
将化合物118a(500mg，3.97mmol)和4-溴-2-氟-5-甲基吡啶(750mg，3.97mmol)混合于反应瓶中，反应混合物升温至130℃熔融搅拌16小时。反应完成后，反应液冷却，粗品经硅胶柱层析(石油醚/乙酸乙酯＝5/1-3/1)纯化得到化合物118b(900mg，收率：95.2％)。MS m/z(ESI):295.90[M+H]+。
第二步：化合物118c的合成
冰浴下，将甲基溴化镁的四氢呋喃溶液(23.65mL，1M)加入到化合物118b(700mg，2.36mmol)的四氢呋喃(15mL)溶液中，反应混合物自然升至室温并搅拌16小时。反应完成后，反应液滴加饱和氯化铵溶液(50mL)淬灭，用乙酸乙酯萃取(50mL×3)，合并的有机相经饱和盐水(50mL)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝5/1-3/1)纯化得到化合物118c(590mg，收率：84.3％)。MS m/z(ESI):295.95[M+H]+。
第三步：化合物118d的合成
将1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(135mg,0.17mmol)加入到化合物118c(490mg,1.65mmol)、频哪醇硼酸酯(631mg,2.48mmol)和乙酸钾(487mg,4.96mmol)的1,4-二氧六环(10mL)溶液中，反应混合物在90℃下搅拌4小时。反应完成后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝5/1-7/3)得到化合物118d(560mg，粗品)。MS m/z(ESI):262.10[M+H]+。
第四步：化合物118，118-P1，118-P2的合成
将四(三苯基膦)钯(95mg，0.08mmol)加入到化合物A3(300mg，0.82mmol)、化合物118d(430mg，1.65mmol)和碳酸钠(175mg，1.65mmol)的1,4-二氧六环和水(5mL/0.5mL)溶液中，反应混合物在90℃下搅拌3小时。反应完成后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝3/1-1/4)纯化得到粗品化合物118，粗品化合物118经高效液相制备色谱(制备柱：YMC Triart C18 12nm 10u，30*250mm；流速：40mL/min；柱温：室温；流动相：A:水(0.1％氨水)B:制备乙腈)纯化得到化合物118(220mg，收率53.5％)。将化合物118(220mg，0.44mmol)经手性制备色谱(制备柱：YMC CHIRALART Amylose-C NEO，30*250mm；流速：30mL/min柱温：室温；流动相：A:正己烷B:异丙醇)拆分得到化合物118-P1(81.6mg，收率37.1％)和化合物118-P2(86.4mg，收率39.3％)。
化合物118-P1:
MS m/z(ESI):502.2[[M+1]+。手性HPLC：保留时间＝10.89min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.60(d,J＝2.3Hz,1H),8.50(d,J＝2.6Hz,1H),8.45(s,1H),8.15–8.03(m,1H),7.68(s,1H),7.55(s,1H),6.54(d,J＝2.6Hz,1H),5.47(d,J＝1.5Hz,2H),5.07(s,1H),2.04(s,3H),2.02(s,3H),1.46(s,6H)。
化合物118-P2:
MS m/z(ESI):502.2[[M+1]+。手性HPLC：保留时间＝16.19min，UV＝220nm。1H NMR(400MHz,DMSO-d6)δ8.60(d,J＝2.4Hz,1H),8.50(d,J＝2.6Hz,1H),8.45(s,1H),8.14–8.05(m,1H),7.68(s,1H),7.55(s,1H),6.54(d,J＝2.6Hz,1H),5.47(d,J＝1.5Hz,2H),5.07(s,1H),2.04(s,3H),2.02(s,3H),1.46(s,6H)。
生物学评价
测试例1.p38 MAPK/MK2体外活性的测定
化合物对p38 MAPK/MK2的抑制作用采用Z-LYTE激酶检测试剂盒(Thermo,PV3177)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为10μM，1％DMSO,5倍倍比稀释，8个浓度，双复孔；50mM HEPES pH 7.5,10mM MgCl2,0.01％Brij-35,1mM EGTA作为反应缓冲液用来配置2x active p38a/inactive MK2/Ser/Thr 4混合液，最终10μL的反应体系在384孔板(Corning,4514)中进行，含有500ng/mL inactive MK2(abcam,79910),8ng/mL active p38a(Carna,04-152),2μM Ser/Thr 4；20℃反应1小时后，每孔加入稀释2048倍后的Development Reagent A，室温孵育1小时后加入5μL终止缓冲溶液终止反应，酶标仪检测(Ex.400nm,Em.445nm；Ex.400nm,Em.520nm)。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC50。结果如表1所示。
表1
从表1可知，本公开的化合物对p38 MAPK/MK2具有良好的抑制活性。
测试例2.对人PBMC细胞上清TNF-α体外活性测定
化合物对人PBMC细胞上清TNF-α的抑制作用实验方案用Elisa检测试剂盒(碧云天，PI518)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为2μM，5倍倍比稀释，6个浓度，细胞铺板双复孔，Elisa检测为单孔，DMSO终浓度为0.4％，也可根据化合物筛选的实际情况，变更化合物起始浓度、倍比稀释倍数、梯度浓度数量和复孔数。
新鲜人外周血单个核细胞(PBMC)(赛笠生物)以2*10^5的数量铺在96孔板(Corning,3599)中，每孔含有100μL的RPMI-1640(Gibco#A1049101)+10％FBS(Gibco,10099141C),37℃，5％CO2过夜培养；待测化合物已25μL/孔的体积加入96孔培养板中，1h后，加入5μL的LPS，使其终浓度为100ng/mL，阴性对照孔不加LPS及化合物，阳性对照孔中不加化合物，37℃，5％CO2继续培养24h后，500rcf离心8min收集细胞培养上清，按照Elisaa试剂盒中操作手册进行操作，检测TNF-α的浓度。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC50。
以上对本公开技术方案的实施方式进行了示例性的说明。应当理解，本公开的保护范围不拘囿于上述实施方式。凡在本公开的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。

Claims (23)

  1. 一种如式(I)所示的化合物或其药学上可接受的盐，
    其中：
    环A为苯基或5至6元杂芳基；
    环B选自苯基、5至6元杂芳基和5至8元杂环基；
    Z选自O、S和NH；
    R1为
    R1a和R1b相同或不同，且各自独立地选自H、C1-6烷基、C1-6卤代烷基、C1-6羟烷基和3至8元环烷基；
    或者R1a和R1b与其相连的碳一起形成3至8元环烷基或3至8元杂环基，所述的3至8元环烷基或3至8元杂环基任选被选自卤素或C1-6烷基中的一个或多个取代基取代；
    R1c和R1d相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
    或者R1c和R1d与其相连的碳一起形成3至8元环烷基或3至8元杂环基，所述的3至8元环烷基或3至8元杂环基任选被选自卤素或C1-6烷基中的一个或多个取代基取代；
    各个R2相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；
    各个R3相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氧代和3至8元环烷基；
    R4选自H、卤素、C1-6烷基和C1-6卤代烷基；
    R5选自H、卤素、C1-6烷基和C1-6卤代烷基；
    R6和R7相同或不同，且各自独立地选自H、D、卤素和C1-6烷基；
    各个R8相同或不同，且各自独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基、羟基、氨基、硝基和3至8元环烷基；
    n选自0、1、2、3和4；
    m选自0、1、2、3和4；
    t选自0、1、2、3和4。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中Z为O。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中选自 R1、R2和n如权利要求1中所定义。
  4. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其中选自 a端与环A相连；R3和m如权利要求1中所定义。
  5. 根据权利要求1或2所述中所述的化合物或其药学上可接受的盐，其为式(II)、式(II-1)或式(II-2)所示的化合物或其药学上可接受的盐，
    其中：
    G1为N或CR3c；
    G2为N或CR2a；
    G3为N或CR2b；
    R3a选自卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；优先地，R3a选自卤素、氰基、C1-6烷基和C1-6卤代烷基；
    R3b和R3c相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；优先地，R3b和R3c相同或不同，且各自独立 地选自H或卤素；
    R2a和R2b相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；优先地，R2a和R2b相同或不同，且各自独立地选自H、卤素、C1-6烷基和氰基；
    q选自0、1和2；
    R1、R2、R4、R5、R6、R7、R8和t如权利要求1中所定义。
  6. 根据权利要求1或2中所述的化合物或其药学上可接受的盐，其为式(III)、式(III-1)或式(III-2)所示的化合物或其药学上可接受的盐，
    其中：
    G1为N或CR3c；
    R3a选自卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；优先地，R3a选自卤素、氰基、C1-6烷基和C1-6卤代烷基；
    R3b和R3c相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；优先地，R3b和R3c相同或不同，且各自独立地选自H或卤素；
    为单健或双健；
    U1为N或C；
    U2选自N、S和CRU2；
    U3选自N、S和CRU3；
    U4选自N、S和CRU4；
    RU2、RU3和RU4相同或不同，且各自独立地选自H、卤素、氰基、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基和3至8元环烷基；优先地，RU2、RU3和RU4相同或不同，且各自独立地选自H、卤素和C1-6烷基；
    R1、R4、R5、R6、R7、R8和t如权利要求1中所定义。
  7. 根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐，其中
    选自： R1、R2、R3、n和m如权利要求1中所定义。
  8. 根据权利要求5所述的化合物或其药学上可接受的盐，其中选自 R1、R2、R3a、R3b和n如权利要求5中所定义。
  9. 根据权利要求6所述的化合物或其药学上可接受的盐，其中选自
    R1、RU3、RU4、R3a和R3b如权利要求6中所定义。
  10. 根据权利要求1至9中任一项所述的化合物或其药学上可接受的盐，其中R1选自 Y1选自O、NRy1或CRy2Ry3；
    Ry1为H或C1-6烷基；
    Ry2和Ry3相同或不同，且各自独立地选自H、卤素和C1-6烷基；
    v为0、1、2和3；
    w为0、1、2和3；条件是v和w不同时为0。
  11. 根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐，其中R4为卤素；优选地，R4为Cl。
  12. 根据权利要求1至11中任一项所述的化合物或其药学上可接受的盐，其中R5为C1-6烷基；优选地，R5为甲基。
  13. 根据权利要求1至12中任一项所述的化合物或其药学上可接受的盐，其中R6和R7相同或不同，且各自独立地为H或D。
  14. 根据权利要求1至13中任一项所述的化合物或其药学上可接受的盐，其中各个R8相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基。
  15. 根据权利要求1至14中任一项所述的化合物或其药学上可接受的盐，其中所述的化合物选自以下任一化合物，






  16. 根据权利要求1至15中任一项所述的化合物或其药学上可接受的盐，其中所述的化合物选自以下任一化合物，


  17. 一种式(IA)化合物或其盐，
    其中：
    X为卤素；优选为Br；
    Z、R4、R5、R6、R7、R8和t如权利要求1-14中所定义。
  18. 根据权利要求17所述的化合物或其盐，其中所述的化合物选自以下任一化合物，
  19. 权利要求1-16任一项所述化合物或其药学上可接受的盐的制备方法，其包含如下步骤：
    式(IA)的化合物与式(IB)化合物在催化剂的存在下发生偶联反应，得到式(I)所示的化合物或其药学 上可接受的盐，
    其中：X为卤素；优选为Br；
    Rw为-B(OH)2或
    Z、R1、R2、R3、R4、R5、R6、R7、R8、n、m和t如权利要求1-14中所定义。
  20. 一种药物组合物，其包括至少一种治疗有效量的根据权利要求1-16任一项所述的化合物或其药学上可接受的盐，以及一种或多种药学上可接受的赋形剂。
  21. 根据权利要求1-16任一项所述的化合物或其药学上可接受的盐、或权利要求20所述的药物组合物，其在制备用作p38激酶抑制剂的药物中的用途。
  22. 根据权利要求1-16任一项所述的化合物或其药学上可接受的盐、或权利要求20所述的药物组合物，其在制备用于预防和/或治疗p38激酶介导的疾病的药物中的用途；优选地，p38激酶介导的疾病为与p38 MAPK/MK2通路相关的疾病。
  23. 根据权利要求1-16任一项所述的化合物或其药学上可接受的盐、或权利要求20所述的药物组合物，其在制备用于预防和/或治疗自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经系统疾病和癌症的药物中的用途；优选地，其在制备用于预防和/或治疗关节炎、银屑病、系统性红斑狼疮、糖尿病、白血病、淋巴瘤、动脉粥样硬化和阿尔兹海默症的药物中的用途。
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