WO2023125707A1 - Régulateur de la voie p38 mapk/mk2, composition de celui-ci, son procédé de préparation et son utilisation - Google Patents

Régulateur de la voie p38 mapk/mk2, composition de celui-ci, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2023125707A1
WO2023125707A1 PCT/CN2022/142965 CN2022142965W WO2023125707A1 WO 2023125707 A1 WO2023125707 A1 WO 2023125707A1 CN 2022142965 W CN2022142965 W CN 2022142965W WO 2023125707 A1 WO2023125707 A1 WO 2023125707A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
halogen
independently selected
formula
Prior art date
Application number
PCT/CN2022/142965
Other languages
English (en)
Chinese (zh)
Inventor
栾林波
姚元山
陈永凯
王朝东
Original Assignee
上海美悦生物科技发展有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海美悦生物科技发展有限公司 filed Critical 上海美悦生物科技发展有限公司
Publication of WO2023125707A1 publication Critical patent/WO2023125707A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the disclosure belongs to the field of medicine, and in particular relates to a p38 MAPK/MK2 pathway regulator and its composition, preparation method and application.
  • Mitogen-activated protein kinase MAPK mitogen-activated protein kinase
  • MAPK mitogen-activated protein kinase
  • Stress factors include cytokines, neurotransmitters, hormones, cell stress, and cell adhesion.
  • p38 MAPK responds to external signals and inflammatory cytokines in cells. After p38 MAPK is activated, it phosphorylates and activates a variety of downstream protein kinases and transcription factors, thereby playing complex biological roles .
  • p38 MAPK includes four members, namely p38 ⁇ , p38 ⁇ , p38 ⁇ and p38 ⁇ . Among them, p38 ⁇ is considered to play an important role in the signaling pathway of the inflammatory process, while the biological functions of other isoforms have not been fully discovered, but they have pleiotropic effects.
  • MAP Kinase Kinase 3 mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates p38 ⁇ to play a role in the proliferation and survival of advanced colorectal cancer (CRC) cells.
  • MAP Kinase Kinase 3 mitogen-activated protein kinase MKK3
  • CRC colorectal cancer
  • the main reasons for clinical failure include dose limitation to avoid toxicity, resulting in insufficient exposure of drug molecules at the target site, downregulation of anti-inflammatory pathways, redundant signaling networks, or involvement of other MAPKs Key proteins of pathway feedback regulation are inhibited, etc., and inhibition of feedback mechanisms may upregulate other pro-inflammatory pathways, leading to increased inflammation. Therefore, developing a safe and effective p38 MAPK inhibitor is the main challenge facing drug development in this field.
  • p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152), 924], so selectively inhibiting the activation of downstream effectors of p38 MAPK is to avoid the side effects caused by the overall inhibition of p38 MAPK /Primary strategy for underpowered drugs.
  • MAPK-activated protein kinase 2 (MAPK-activated protein kinase 2, MK2) is the direct downstream substrate of p38 MAPK, which 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 element of mRNA.
  • MK2 inhibitors can reduce the expression of inflammatory factors MIP-1 ⁇ , TNF- ⁇ , IL-6 and IL-1 ⁇ , etc., It was also found that the infiltration of polymorphonuclear leukocytes, mast cells, and mononuclear macrophages was reduced and the contractility of intestinal smooth muscle was improved.
  • diseases are associated with the p38 MAPK/MK2 pathway, these diseases include (but are not limited to) autoimmune diseases and inflammatory diseases (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), skeletal diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases, etc.
  • autoimmune diseases such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.
  • inflammatory diseases such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic
  • the present disclosure provides a compound as shown in formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable Salts or prodrugs thereof:
  • W is CH or N; m is an integer of 0-5; n is an integer of 0-3;
  • Ring A is a nitrogen-containing heterocyclic group of 3-20 members, except for the parent nucleus In addition to the attached N atom, it optionally contains 1, 2 or more heteroatoms selected from O, N or S;
  • R 1 is selected from H, halogen, CN and C 1-6 alkyl
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is selected from H, C 1-10 alkyl and C 3-20 cycloalkyl
  • R 4 is selected from H, halogen and C 1-10 alkyl
  • R is selected from H, halogen and methyl
  • R 7 are independently selected from H, halogen, unsubstituted or substituted C 1-10 alkyl and C 3-20 cycloalkyl; Ra is selected from halogen and C 3-20 cycloalkyl;
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-10 unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 Rb Alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; each Rb is the same or different, independently selected from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl and C 1-10 alkoxy;
  • R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-6 alkyl, and C 3-20 cycloalkyl.
  • W is CH or N; m is an integer of 0-5; n is an integer of 0-3;
  • Ring A is a 3-20 membered nitrogen-containing heterocyclic group, which optionally contains 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the parent nucleus ;
  • R 1 is selected from H, halogen, CN and C 1-6 alkyl
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is selected from H, C 1-10 alkyl and C 3-20 cycloalkyl
  • R 4 is selected from H, halogen and C 1-10 alkyl
  • R is selected from H, halogen and methyl
  • R 7 are independently selected from H, halogen, C 1-10 alkyl and C 3-20 cycloalkyl;
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-10 alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein C 6-14 aryl or 5-14 membered heteroaryl are each unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from each other Substituted from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl and C 1-6 alkoxy;
  • R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-6 alkyl, and C 3-20 cycloalkyl.
  • W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3;
  • Ring A is a 3-12 membered nitrogen-containing heterocyclic group, which optionally contains 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the parent nucleus ;
  • R 1 is selected from H, halogen, CN and C 1-6 alkyl
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is selected from H, C 1-6 alkyl and C 3-12 cycloalkyl
  • R 4 is selected from H, halogen and C 1-6 alkyl
  • R is selected from H, halogen and methyl
  • R 7 are independently selected from H, halogen, C 1-6 alkyl and C 3-12 cycloalkyl;
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-14 aryl-C 1-6 alkyl, 5-14 membered heteroaryl-C 1-6 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein each aryl or heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C 1- 6 alkyl, C 1-6 alkyl and C 1-3 alkoxy are substituted;
  • R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-6 alkyl, and C 3-10 cycloalkyl.
  • W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3;
  • Ring A is a 3-9 membered nitrogen-containing heterocyclic group, which optionally contains 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom connected to the parent nucleus ;
  • R 1 is selected from halogen
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is selected from C 1-3 alkyl and C 3-6 cycloalkyl
  • R 4 is C 1-3 alkyl or halogen
  • R is selected from H, halogen and methyl
  • R 7 are independently selected from H, halogen and C 1-3 alkyl
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from C 6-8 aryl-C 1-3 alkyl, 5-6 membered heteroaryl-C 1-3 alkyl, C 6-8 aryl, 5-6 membered heteroaryl; wherein each aryl or heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C 1- 3 alkyl, C 1-3 alkyl and C 1-3 alkoxy are substituted;
  • R 91a , R 91b , R 92 , R 93a , and R 93b are the same or different, and are independently selected from H, C 1-3 alkyl, and C 3-7 cycloalkyl.
  • W is CH or N; m is 0, 1, 2 or 3; n is 0 or 1;
  • Ring A is selected from the following structures:
  • R 1 is Cl or Br
  • R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;
  • R 3 is methyl or cyclopropyl
  • R 4 is methyl
  • R is selected from H, F and Cl
  • R7 is H
  • R 81 , R 82 , R 83 , and R 84 are the same or different, and are independently selected from phenylmethyl, pyridylmethyl, pyridylethyl, unsubstituted or optionally substituted by 1, 2 or 3 Rb, Phenyl and pyridyl; each Rb is the same or different, independently selected from F, Cl and CF3 .
  • the structure formed by R and ring A may be selected from:
  • the compound of formula I has the structure shown in formula Ia or Ib:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, W, m and n have the above-mentioned definitions, and the chemical bonds in bold indicate the existence of axial chirality in the compound.
  • the compound of formula I has the structure shown in formula II:
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, W and ring A independently of each other have the definitions stated above;
  • R 10 is selected from H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH 2 from the following groups: C 1-10 alkyl, C 1-10 alkoxy, Halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkenyloxy, C 2-10 alkynyl and C 2-10 alkynyloxy ;
  • Each R 11 is the same or different, independently selected from H, halogen, C 1-6 alkyl and halogenated C 1-10 alkyl;
  • p is an integer of 0-4.
  • R 10 is selected from the following groups H, halogen, unsubstituted or optionally substituted by 1, 2 or more halogens, OH, NH 2 : C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkenyloxy, C 2-6 alkynyl and C 2-6 alkynyloxy;
  • Each R 11 is the same or different, independently selected from H, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • p 0, 1, 2, 3 or 4.
  • R 10 is selected from H, halogen, C 1-3 alkyl and halogenated C 1-3 alkyl; p is 0, 1 or 2;
  • Each R 11 is the same or different and is independently selected from H, halogen, C 1-3 alkyl and halogenated C 1-3 alkyl.
  • R 10 is H or methyl; p is 0, 1 or 2;
  • Each R 11 is the same or different and is independently selected from F, Cl and CF 3 .
  • the compound of formula II has the structure shown in formula IIa or formula IIb:
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , A, W, m, n and p have the above definitions, and the chemical bonds in bold indicate the presence of axes Chirality.
  • the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug wherein R 2 is -OR 81 or -NHR 83 ; R 81 and R 83 are the same or different, independently of each other C 6-8 aryl-C 1-3 alkyl- or 5-6 membered heteroaryl -C 1 - 3 alkyl-; wherein C 6-8 aryl, 5-6 membered heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy are substituted , and the C 1-3 alkyl part is connected with O or NH.
  • the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug wherein R 2 is -OR 81 ; R 81 is C 6-8 aryl-C 1-3 alkyl or 5-6 membered heteroaryl-C 1-3 alkyl; wherein C 6-8 aryl And the 5-6 membered heteroaryl is unsubstituted or optionally 1, 2, 3, 4 or 5 independently selected from halogen, halogenated C 1 - 3 alkyl, C 1 - 3 alkyl and C 1- 3 alkoxy substitutions; C 1 - 3 alkyl moieties are connected to O.
  • the compound represented by Formula I, Formula Ia or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or Prodrug wherein R 2 is -OR 81 ; R 81 is -CH 2 -pyridyl; wherein, pyridyl is unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, halogen C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy are substituted .
  • compounds of formula I include but are not limited to the following structures:
  • compounds represented by formula I include but are not limited to the following structures:
  • the present disclosure also provides a preparation method of the compound of formula I, comprising:
  • Y is Cl or Br
  • W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n and ring A are independently defined above;
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , m, n, p and ring A independently of one another have the definitions stated above;
  • the reaction is carried out in the presence of an inorganic base;
  • the inorganic base is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.
  • the OH in compound b2 can be protected by a silicon protecting group, and the silicon protecting group can be tert-butyldiphenylsilyl; the silicon protecting group is in the It will be removed during the reaction to obtain the deprotected OH.
  • the present disclosure also provides at least one of the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound Use in the preparation of medicines.
  • the drug may be a drug for treating and/or preventing diseases related to p38 kinase inhibitors, for example, it may be an MK2 inhibitor or a p38 MAPK/MK2 pathway modulator.
  • the present disclosure also provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable At least one of the salts or prodrug compounds thereof.
  • the pharmaceutical composition further includes at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • the carrier includes a disintegrant, such as methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, carboxypropylcellulose, starch etc.; lubricants, including calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, etc.; binders, including gelatin, polyethylene glycol, sugar, gum, starch, hydroxyl Propyl cellulose, etc.; diluents, including mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch; surfactants, including polysorbate 80, sodium lauryl sulfate, talc and silica.
  • Compositions of the present disclosure can be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art.
  • the present disclosure also provides the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or its prodrug compound, in the treatment and/or Or the use in preventing diseases mediated by p38 kinase inhibitors.
  • the present disclosure also provides a method for treating and/or preventing diseases mediated by p38 kinase inhibitors, comprising administering to a patient an effective dose of a compound represented by formula I, its racemate, stereoisomer, tautomer At least one of isomers, isotope labels, solvates, pharmaceutically acceptable salts or prodrug compounds thereof.
  • the disease may be a disease related to the p38 MAPK/MK2 pathway, such as an autoimmune disease and an inflammatory disease (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, Inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), bone disease, metabolic disease, neurological and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease and hormone-related disease.
  • an autoimmune disease and an inflammatory disease such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, Inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.
  • an inflammatory disease such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, Inflammatory bowel disease
  • the disclosed compound has a good regulating effect on the p38 MAPK/MK2 pathway and has good selectivity.
  • the compounds of the present disclosure have good properties such as pharmacokinetics.
  • the disclosed compounds are useful in the treatment of diseases associated with the mediation of p38 kinase inhibitors, and in the preparation of medicaments for such conditions or diseases.
  • the numerical ranges described in the specification and claims are equivalent to at least recording each specific integer value therein.
  • the numerical range “1-20” is equivalent to recording every integer value in the numerical range “1-20", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20.
  • numbers it should be understood that both endpoints of the range, each integer within the range, and each decimal within the range are recited.
  • the number from 0 to 10 should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers respectively Sum with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • halogen denotes fluorine, chlorine, bromine and iodine.
  • C 1-10 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms.
  • C 1-6 alkyl means having 1, 2, 3 , straight-chain and branched-chain alkyl groups of 4, 5 or 6 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, etc. or their isomers.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined herein. Alkoxy groups containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (C 1-12 alkoxy) are preferred, more Alkoxy having 1 to 6 carbon atoms (C 1-6 alkoxy) is preferred. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups can be substituted or unsubstituted.
  • C 2-10 alkenyl is understood to preferably mean a straight or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably “C 2-8 alkenyl”.
  • C 2-10 alkenyl is understood to mean preferably a straight or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, For example, having 2, 3, 4, 5 or 6 carbon atoms (ie, C2-6 alkenyl), having 2 or 3 carbon atoms (ie, C2-3 alkenyl). It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl Base, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-eny
  • C 2-10 alkynyl is understood to preferably mean a straight or branched monovalent hydrocarbon radical comprising one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g., having 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e., "C alkynyl ”) having 2, 3, 4, 5 or 6 carbon atoms (ie, "C 2-6 alkynyl”), having 2 or 3 carbon atoms ("C 2-3 alkynyl").
  • the alkynyl group is for example ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , Pent-2-ynyl, Pent-3-ynyl, Pent-4-ynyl, Hex-1-ynyl, Hex-2-ynyl, Hex-3-ynyl, Hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-ynyl, 2-methylpent-3-ynyl, 1-methylp
  • C 3-20 cycloalkyl should be understood as meaning a saturated monovalent monocyclic, bicyclic (such as double ring, spiro ring, bridged ring) hydrocarbon ring or tricycloalkane, which has 3 to 20 carbon atoms, Preferable is “C 3-12 cycloalkyl", more preferably “C 3-8 cycloalkyl”.
  • C 3-12 cycloalkyl should be understood as meaning a saturated monovalent monocyclic, bicyclic (such as bridged, spiro) hydrocarbon ring or tricycloalkane, which has 3, 4, 5, 6, 7, 8 , 9, 10, 11 or 12 carbon atoms.
  • the C 3-12 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic Hydrocarbon groups such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.
  • a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl
  • a bicyclic Hydrocarbon groups
  • 3-20 membered nitrogen-containing heterocyclic group refers to a saturated or unsaturated nitrogen-containing non-aromatic ring or ring system, for example, which is 4-, 5-, 6- or 7-membered Monocyclic, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered bicyclic rings (such as double rings, spiro rings, bridged rings) or tricyclic ring systems, and contain at least A N, which may also contain or contain, for example, 1, 2, 3, 4, 5 or more heteroatoms selected from O and S and wherein N and S may also optionally be oxidized to various oxidation states, To form nitrogen oxides, -S(O)- or -S(O) 2 -state.
  • the heterocyclic group may be selected from "3-12 membered nitrogen-containing heterocyclic groups".
  • the term "3-12 membered nitrogen-containing heterocyclic group” means a saturated or unsaturated nitrogen-containing non-aromatic ring or ring system, and contains at least one N atom, does not contain or contains a group selected from O and S and of heteroatoms.
  • the heterocyclyl is attached to the parent nucleus through an N atom and may be attached to the remainder of the molecule through any of the carbon atoms or other nitrogen atoms, if present.
  • the heterocyclyl may include fused or bridged rings as well as spirocyclic rings.
  • the heterocyclic group may include but not limited to: 4-membered rings, such as azetidinyl; 5-membered rings, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6 A membered ring such as piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl; or a 7-membered ring such as diazepanyl.
  • the heterocyclyl group may be benzo-fused.
  • the heterocyclic group can be bicyclic, such as but not limited to 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrole And[1,2-a]pyrazin-2(1H)-yl ring.
  • a heterocyclyl group may be partially unsaturated, i.e.
  • the 3-12 membered nitrogen-containing heterocyclic group may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl , 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, alternatively, it may be benzo-fused such as but not limited to dihydroisoquinolinyl.
  • the 3-12 membered nitrogen-containing heterocyclic group is connected with other groups to form the compound of the present disclosure, it can be that the N atom on the 3-12 membered nitrogen-containing heterocyclic group is connected with the mother nucleus, and the carbon atom is connected with other groups. Group connected.
  • the nitrogen atom on the piperazinyl may be connected to the parent nucleus.
  • the nitrogen atom on the piperidinyl ring may be connected to the parent nucleus.
  • spiro refers to a ring system in which two rings share 1 ring-forming atom.
  • merged ring refers to a ring system in which two rings share 2 ring-forming atoms.
  • bridged ring refers to a ring system in which two rings share more than 3 ring-forming atoms.
  • C 6-14 aryl-C 1-10 alkyl refers to a C 1-10 alkyl substituted by a C 6-14 aryl, and the connection point is at the C 1-10 alkyl.
  • 5-14 membered heteroaryl-C 1-10 alkyl refers to a C 1-10 alkyl group substituted by a 5-14 membered heteroaryl group, and the attachment point is at the C 1-10 alkyl group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ -electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl, or cycloalkyl ring as described herein, wherein the ring bonded to the parent structure is an aryl ring, which is not limiting Examples include:
  • Aryl groups can be substituted or unsubstituted.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 (eg 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 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkyl Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl rings include heteroaryl fused to aryl, heterocyclyl or cycloalkyl rings as described herein, where the ring attached to the parent structure is a heteroaryl ring, without limitation Sexual examples include:
  • Heteroaryl groups can be substituted or unsubstituted.
  • alkyl alkoxy
  • cycloalkyl heterocyclyl
  • aryl and “heteroaryl” etc. herein may be substituted or unsubstituted; when substituted , which may be substituted at any available point of attachment, said substituents are preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano One or more of the same or different substituents among , amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • the pharmaceutically acceptable salts of the compounds described in this disclosure may be inorganic salts or organic salts, and if these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form bases. Addition salts; these compounds can also form internal salts if they contain both an acidic center (eg carboxyl group) and a basic center (eg amino group).
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. For example cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers isomers, (L)-isomers, racemic and other mixtures, as well as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
  • the bond means unspecified configuration, or Indicates the absolute configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or or both and 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 known as prototropic tautomers
  • prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam imide isomerization. All tautomeric forms of all compounds in the disclosure are within the scope of the disclosure.
  • the names of compounds named in a single way do not exclude any tautomers.
  • the present disclosure also includes some isotopically labeled compounds of the disclosure having the same structure as described herein, but wherein one or more atoms are replaced by an atom with an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation).
  • exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound.
  • deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • the "therapeutically effective amount” in the present disclosure refers to the amount of active compound or drug that researchers, veterinarians, physicians or other clinicians look for in tissues, systems, animals, individuals or humans to cause biological or medical responses, including One or more of the following: (1) Preventing a disease: eg, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed disease pathology or symptoms. (2) Inhibiting a disease: For example, inhibiting a disease, disorder or condition (ie preventing further development of the pathology and/or symptoms) in an individual experiencing or developing pathology or symptoms of the disease, disorder or condition.
  • Alleviating disease For example, alleviating a disease, disorder or condition (ie reversing the pathology and/or symptoms) in an individual experiencing or developing the pathology or symptoms of the disease, disorder or condition.
  • a drug or a pharmacologically active agent 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, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • “Pharmaceutically acceptable” in the present disclosure means that these compounds, materials, compositions and/or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without undue toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit/risk ratio, and are effective for the intended use.
  • Principal in the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably people.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • Agilent 6110, Agilent 1100, Agilent 6120, Agilent G6125B liquid phase mass spectrometer were used for the determination of MS.
  • HPLC high performance liquid chromatography
  • the thin-layer chromatography silica gel plate uses Yantai Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm-0.5mm. .
  • High-performance liquid phase preparation uses Waters 2767, Waters 2545, and innovative Hengtong LC3000 preparative chromatography.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.
  • the microwave reaction uses a Biotage initiator+ type microwave reactor.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 liter.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.
  • reaction temperature is room temperature, and the temperature range is 20°C-30°C.
  • a tetrahydrofuran solution (141mL, 141mmol) of bis(trimethylsilyl)amide lithium was slowly added to a solution of compound A-1 (20g, 141mmol) in tetrahydrofuran (500mL), and the reaction solution was in- After stirring at 78°C for 1 hour, acetyl chloride (6.6 g, 844 mmol) was slowly added dropwise, and the resulting mixture was stirred at -78°C for 1 hour. After the reaction, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (500 mL), and extracted with ethyl acetate (300 mL ⁇ 3).
  • N,N-Dimethylformamide dimethyl acetal (0.85g, 7.2mmol) was added to a solution of compound A-9 (1.30g, 3.1mmol) in N,N-dimethylformamide (15mL) , and the reaction mixture was stirred at 100° C. for 3 hours. After the reaction, the reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (30 mL ⁇ 3).
  • Diphenylphosphoryl azide (23.5 g, 0.085 mol) was added to a mixture of compound B-1 (10 g, 0.057 mol) and triethylamine (17.3 g, 0.17 mol) in tert-butanol/toluene (50 mL/50 mL) In solution, the reaction mixture was carried out at 110°C for 16 hours. After the reaction, the reaction solution was poured into water and extracted with dichloromethane (200 mL ⁇ 3).
  • methylboronic acid 530mg, 8.8mmol
  • cesium carbonate 8.96g, 27.5mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 450mg , 0.55mmol
  • N-chlorosuccinimide (330mg, 2.48mmol) and glacial acetic acid (0.20mL) were successively added to a solution of compound B-10 (910mg, 2.25mmol) in isopropanol (12mL) and reacted at 60°C Stir for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain Compound B-11 (1.13 g).
  • N,N-dimethylformamide dimethyl acetal 600mg, 5.0mmol was added to a solution of compound B-11 (1.08g, 2.5mmol) in N,N-dimethylformamide (15mL), The reaction was stirred at 100°C for 3 hours. After the reaction, the reaction solution was naturally cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3).
  • the second step the synthesis of compounds 12-P1 and 12-P2
  • the amplified batch of compound 33 (30 mg) was subjected to supercritical fluid chiral chromatography ((equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5 ⁇ m, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) to obtain compound 33-P1 (12.6mg) and compound 33-P2 (10.4mg).
  • supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5 ⁇ m, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) to obtain compound 33-P1 (12.6mg) and compound 33-P2 (10.4mg).
  • the amplified batch of compound 41 was subjected to supercritical fluid chiral chromatography ((equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5 ⁇ m, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2% ), total flow rate: 40g/min) to obtain compound 41-P1 (33.3mg, yield 10.5%) and compound 41-P2 (29.8mg, yield 9.3%).
  • supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5 ⁇ m, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2% ), total flow rate: 40g/min) to obtain compound 41-P1 (33.3mg, yield 10.5%) and compound 41-P2 (29.8mg, yield 9.3%).
  • the inhibitory effect of compounds on p38 MAPK/MK2 was detected by Z-LYTE Kinase Assay Kit (Thermo, PV3177).
  • the test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use.
  • the initial concentration of the compound is 10 ⁇ M, 1% DMSO, 5-fold dilution, 8 concentrations, duplicate holes; 50mM HEPES pH 7.5, 10mM MgCl 2 , 0.01% Brij-35, 1mM EGTA as the reaction buffer to configure 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 500ng/mL inactive MK2 (abcam, 79910), 8ng/mL active p38a (Carna, 04-152), 2 ⁇ M Ser/Thr 4; after 1 hour of reaction at 20°C, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 ⁇ L of stop buffer solution to terminate the reaction, and detect with a microplate reader (Ex.
  • the inhibitory effect of compounds on p38 MAPK/MK5 was detected by Z-LYTE Kinase Assay Kit (Thermo, PV3177).
  • the test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use.
  • the initial concentration of the compound is 10 ⁇ M, 1% DMSO, 5-fold dilution, 8 concentrations, duplicate holes; 50mM HEPES pH 7.5, 10mM MgCl 2 , 0.01% Brij-35, 1mM EGTA as the reaction buffer to configure 2x active p38a/inactive MK5/Ser/Thr 4 mixture, the final 10 ⁇ L reaction system was carried out in a 384-well plate (Corning, 4514), containing 10 ⁇ g/mL inactive MK5 (abcam, 217826), 1ng/mL active p38a (Carna, 04-152), 2 ⁇ M Ser/Thr 4; after 4 hours of reaction at 20°C, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 ⁇ L of stop buffer solution to stop the reaction, and detect with a microplate reader (Ex.
  • the inhibitory effect of compounds on p38a-catalyzed ATF2 was detected by HTRF method.
  • the test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use.
  • the initial concentration of the compound is 10 ⁇ M, 0.25% DMSO, 5-fold dilution, 8 concentrations, double-well; 40mM Tris pH 7.5, 20mM MgCl2, 0.1mg/mL BSA, 50 ⁇ M DTT are used as the reaction buffer to configure 3.5 x p38a (MAPK14, Carna Biosciences, 04-152) protein working solution, 3.5x Human ATF2 Protein (Sino Biological, 11599-H20B) working solution and 3.5 x ATP working solution, 10mM EDTA was used to stop the reaction, and the final 14 ⁇ L reaction system Carried out in 96-well plate (cisbio, 66PL96025), containing 0.29ng/ ⁇ L p38a, 0.29 ⁇ M Human
  • the inhibitory effect of compounds on human PBMC cell supernatant TNF- ⁇ was detected by Elisa detection kit (Beiyuntian, PI518).
  • the test compound was dissolved in DMSO to 10 mM stock solution and stored at -20°C until use.
  • the initial concentration of the compound is 2 ⁇ M, 5-fold dilution, 6 concentrations, the cells are plated in double wells, the Elisa is detected as a single well, and the final concentration of DMSO is 0.4%.
  • the initial concentration of the compound can also be changed according to the actual situation of compound screening , ratio dilution factor, gradient concentration quantity and duplicate hole number.
  • PBMC peripheral blood mononuclear cells

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Dermatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Transplantation (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé tel que représenté dans la formule I, un racémate, un stéréoisomère, un tautomère, un marqueur isotopique, un solvate, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci, et une composition de celui-ci, son procédé de préparation et son utilisation. Le composé a un bon effet de régulation sur la voie p38 MAPK/MK2, une bonne sélectivité et de bonnes propriétés pharmacocinétiques. En outre, le composé peut être utilisé pour traiter des maladies médiées par un inhibiteur de la kinase p38, et pour préparer un médicament pour de telles affections ou maladies.
PCT/CN2022/142965 2021-12-29 2022-12-28 Régulateur de la voie p38 mapk/mk2, composition de celui-ci, son procédé de préparation et son utilisation WO2023125707A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111642855.0 2021-12-29
CN202111642855 2021-12-29

Publications (1)

Publication Number Publication Date
WO2023125707A1 true WO2023125707A1 (fr) 2023-07-06

Family

ID=86998070

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/142965 WO2023125707A1 (fr) 2021-12-29 2022-12-28 Régulateur de la voie p38 mapk/mk2, composition de celui-ci, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN116444492A (fr)
WO (1) WO2023125707A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046327A1 (fr) * 2022-08-30 2024-03-07 长春金赛药业有限责任公司 Composés inhibiteurs de p38α-mk2, compositions pharmaceutiques et leur utilisation
US11987574B2 (en) 2021-03-31 2024-05-21 Xinthera, Inc. MK2 inhibitors and uses thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101277962A (zh) * 2005-10-04 2008-10-01 诺瓦提斯公司 用作促分裂原活化蛋白激酶活化蛋白激酶-2抑制剂的双环芳香化合物
CN103391718A (zh) * 2010-12-06 2013-11-13 汇合生命科学股份有限公司 取代的吡啶酮-吡啶基化合物
CN105163738A (zh) * 2013-03-15 2015-12-16 西建阿维拉米斯研究公司 Mk2抑制剂和其用途
CN105263326A (zh) * 2013-06-07 2016-01-20 汇合生命科学股份有限公司 甲基/氟-吡啶基-甲氧基取代的吡啶酮-吡啶基化合物及氟-嘧啶基-甲氧基取代的吡啶酮-吡啶基化合物
WO2021022186A1 (fr) * 2019-07-31 2021-02-04 Aclaris Therapeutics, Inc. Inhibiteurs deutérés de la voie de signalisation mk2 et méthodes d'utilisation de ceux-ci
WO2022212489A1 (fr) * 2021-03-31 2022-10-06 Xinthera, Inc. Inhibiteurs de mk2 et leurs utilisations
CN115636814A (zh) * 2022-02-28 2023-01-24 瑞石生物医药有限公司 一种嘧啶衍生物及其用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101277962A (zh) * 2005-10-04 2008-10-01 诺瓦提斯公司 用作促分裂原活化蛋白激酶活化蛋白激酶-2抑制剂的双环芳香化合物
CN103391718A (zh) * 2010-12-06 2013-11-13 汇合生命科学股份有限公司 取代的吡啶酮-吡啶基化合物
CN105163738A (zh) * 2013-03-15 2015-12-16 西建阿维拉米斯研究公司 Mk2抑制剂和其用途
CN105263326A (zh) * 2013-06-07 2016-01-20 汇合生命科学股份有限公司 甲基/氟-吡啶基-甲氧基取代的吡啶酮-吡啶基化合物及氟-嘧啶基-甲氧基取代的吡啶酮-吡啶基化合物
WO2021022186A1 (fr) * 2019-07-31 2021-02-04 Aclaris Therapeutics, Inc. Inhibiteurs deutérés de la voie de signalisation mk2 et méthodes d'utilisation de ceux-ci
WO2022212489A1 (fr) * 2021-03-31 2022-10-06 Xinthera, Inc. Inhibiteurs de mk2 et leurs utilisations
CN115636814A (zh) * 2022-02-28 2023-01-24 瑞石生物医药有限公司 一种嘧啶衍生物及其用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11987574B2 (en) 2021-03-31 2024-05-21 Xinthera, Inc. MK2 inhibitors and uses thereof
WO2024046327A1 (fr) * 2022-08-30 2024-03-07 长春金赛药业有限责任公司 Composés inhibiteurs de p38α-mk2, compositions pharmaceutiques et leur utilisation

Also Published As

Publication number Publication date
TW202334119A (zh) 2023-09-01
CN116444492A (zh) 2023-07-18

Similar Documents

Publication Publication Date Title
CA2996318C (fr) Composes heteroaryle servant d'inhibiteurs d'irak, et leurs utilisations
EP3237418B1 (fr) Composés triazolopyrimidine et leurs utilisations
JP5769199B2 (ja) ピラゾロピリミジンｊａｋ阻害剤化合物と方法
JP4954200B2 (ja) ヒストン脱アセチル化酵素阻害剤
TW202144345A (zh) Ｋｒａｓ突變蛋白抑制劑
WO2023125707A1 (fr) Régulateur de la voie p38 mapk/mk2, composition de celui-ci, son procédé de préparation et son utilisation
WO2018177403A1 (fr) Composé 1h-imidazo[4,5-h]quinazoline utilisé en tant qu'inhibiteur de protéine kinase
CN108349964A (zh) N-（吡啶-2-基）-4-（噻唑-5-基）嘧啶-2-胺类化合物作为治疗性化合物
TW201002683A (en) Novel substituted pyridin-2-ones and pyridazin-3-ones
CN104478875A (zh) 聚(adp-核糖)聚合酶(parp)的二氢吡啶并酞嗪酮抑制剂
CA3092625A1 (fr) Composes heteroaryle en tant qu'inhibiteurs d'irak de type ii et leurs utilisations
EP1921077A1 (fr) Agent de traitement et/ou de prevention des troubles du sommeil
WO2018019222A1 (fr) Composé hétérocyclique en tant qu'inhibiteur de jak, ses sels et leur utilisation thérapeutique
WO2019206069A1 (fr) Composé macrocyclique diaryle, composition pharmaceutique et utilisation associée
CN104066431A (zh) 吡嗪激酶抑制剂
WO2023125708A1 (fr) Modulateur de la voie p38 mapk/mk2, composition de celui-ci, son procédé de préparation et son utilisation
WO2020038387A1 (fr) Agoniste de protéine sting à haute activité
WO2015058661A1 (fr) Inhibiteur de bcr-abl kinase et application correspondante
WO2020156283A1 (fr) Composé alkynylpyrimidine ou alkynylpyridine, et composition et application de celui-ci
WO2023134266A1 (fr) Composé pyrimidine substitué par 2-pipéridyle ou 2-pyrazolyle servant d'inhibiteur d'egfr
US10793575B2 (en) Oxoisoquinoline derivatives
WO2020108538A1 (fr) INHIBITEUR DE RORγ À STRUCTURE SULFONYLE
WO2022017494A1 (fr) Forme cristalline d'un dérivé pyridazinique sous forme de base libre, son procédé de préparation et son utilisation
CN108947974B (zh) 一种氨基嘧啶类化合物及包含该化合物的组合物及其用途
WO2022089389A1 (fr) Composé hétérocyclique, procédé de préparation s'y rapportant, composition pharmaceutique associée et application associée

Legal Events

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

Ref document number: 22914958

Country of ref document: EP

Kind code of ref document: A1