WO2023001282A1 - Dérivé de pyrimidine substitué par un hétérocycle - Google Patents

Dérivé de pyrimidine substitué par un hétérocycle Download PDF

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WO2023001282A1
WO2023001282A1 PCT/CN2022/107361 CN2022107361W WO2023001282A1 WO 2023001282 A1 WO2023001282 A1 WO 2023001282A1 CN 2022107361 W CN2022107361 W CN 2022107361W WO 2023001282 A1 WO2023001282 A1 WO 2023001282A1
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compound
membered heterocycloalkyl
group
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/107361
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English (en)
Chinese (zh)
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陈新海
王晶晶
姜奋
付志飞
张杨
罗妙荣
张丽
胡伯羽
夏尚华
周凯
陈兆国
张浩宇
归厚泽
胡国平
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2023001282A1 publication Critical patent/WO2023001282A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of heterocyclic substituted pyrimidine derivatives, in particular to compounds represented by formula (I) and pharmaceutically acceptable salts thereof.
  • Mitogen-activated protein kinases mitogen-activated protein kinases
  • MAPK mitogen-activated protein kinases
  • the MAPKs family includes four subfamilies of ERK, p38, JNK and ERK5. There are differences in the function of each MAPK subfamily. ERKs are the main regulators of growth-related stimuli, JNK is activated under stimuli such as hyperosmotic pressure and strong oxidative conditions, ERK5/BMK1 regulates the early expression of certain genes, and p38 can participate in inflammation, cell growth, and cell differentiation , cell cycle and cell death and many other physiological processes.
  • the biochemical characteristic of MAPKs is that after receiving certain stimuli, the two sites of threonine and tyrosine will be phosphorylated and activated.
  • MAPKs Downstream substrates of MAPKs include mitogen-activated protein kinase-activated protein (MAPKAP) kinases and transcription factors, whose phosphorylation directly or indirectly regulates gene expression at several points, including transcription, nuclear export, and mRNA stability and translation .
  • MAPK activation include inflammation, apoptosis, differentiation and proliferation.
  • Different genes encode the four p38MAPK kinases in humans: p38 ⁇ , p38 ⁇ , p38 ⁇ and p38 ⁇ . Significant amino acid sequence homology was observed between the 4 isoforms with 60%-75% overall sequence identity and >90% identity within the kinase domain.
  • P38 ⁇ is a key isoform in the MAPK signaling pathway that regulates cytokine production.
  • MK2 (MAPKAK2) is one of the main downstream proteins of P38. Activated MK2 can phosphorylate the AU-rich element binding protein TTP, regulate the stability of TNF- ⁇ , IL-1 ⁇ , IL-6 and other cytokine mRNAs, and regulate the factor biosynthesis.
  • Rheumatoid arthritis is a systemic, autoimmune, chronic inflammatory disorder characterized by inflammation of the synovial membrane of joints, leading to destruction of cartilage and bone.
  • Current treatments for RA include oral disease-modifying antirheumatic drugs (DMARDs) (methotrexate, leflunomide, sulfasalazine) and parenteral administration of biologic agents, particularly targeting IL-1 ⁇ or TNF- ⁇ , which Two key pro-inflammatory cytokines involved in RA pathogenesis.
  • DMARDs oral disease-modifying antirheumatic drugs
  • DMARDs metalhotrexate, leflunomide, sulfasalazine
  • parenteral administration of biologic agents particularly targeting IL-1 ⁇ or TNF- ⁇ , which Two key pro-inflammatory cytokines involved in RA pathogenesis.
  • the superior efficacy of these latter agents is somewhat offset by potential disadvantages including the need for parenteral administration, difficulty in dose adjustment, poor reversibility due to long plasma half-life
  • Orally administered DMARDs with improved efficacy therefore offer multiple advantages to patients and physicians in terms of ease and compliance of administration, absence of injection site/allergic reactions, superior dose scalability, and favorable cost of goods. Therefore, the development of safe, effective and orally available MK2 inhibitors still has extensive clinical needs.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T1 is selected from N and CH ;
  • L is selected from O and S ;
  • Each R 1 , each R 2 and each R 3 are independently selected from H, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently optionally replaced by 1 , 2 or 3 R a substitutions;
  • the structural unit selected from R 2 and R 3 are independently selected from H, F, Cl, Br, I, CN, CH 3 and OCH 3 , ring A is selected from 5-10 membered heterocycloalkyl, and the 5-10 membered heterocycloalkane The group is optionally substituted by 1, 2 or 3 R b ;
  • R 4 is selected from -NR 5 R 6 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl
  • the C 1-3 alkyl group, C 1-3 alkoxy group, C 3-6 cycloalkyl group, 4-6 membered heterocycloalkyl group and 5-6 membered heteroaryl group are independently optionally replaced by 1 , 2 or 3 R c substitutions;
  • R 5 and R 6 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R d ;
  • R 5 and R 6 form a 4-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group together with the N atoms they are connected to, and the 4-6 membered heterocycloalkyl group or 5-6 membered heteroaryl group
  • the groups are independently optionally substituted by 1, 2 or 3 R e ;
  • the proviso is that when L is selected from O and T is selected from CH, one of the following conditions is met:
  • At least one of R 1 , R 2 , R 3 and R 4 is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 3-6 cycloalkyl and 4-6
  • the membered heterocycloalkyl groups are independently optionally substituted by 1, 2 or 3 R a ;
  • Structural unit selected from R 2 and R 3 are independently selected from H, F, Cl, Br, I, CN, CH 3 and OCH 3 , ring A is selected from 5-10 membered heterocycloalkyl, and the 5-10 membered heterocycloalkane The group is optionally substituted by 1, 2 or 3 R b ;
  • R 4 is selected from -NR 5 R 6 , CN and C 1-3 alkoxy, and the C 1-3 alkoxy is optionally substituted by 1, 2 or 3 R c ;
  • n, m and p are independently selected from 0, 1, 2 and 3;
  • each R a , each R b , each R c , each R d and each Re is independently selected from F, Cl, Br, I, OH, CH 3 and OCH 3 ;
  • the "4-6 membered heterocycloalkyl” contains 1 or 2 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N;
  • the "5-10 membered heterocycloalkyl” and “5-6 membered heteroaryl” each independently contain 1, 2 or 3 hetero atoms or heteroatom groups.
  • each of the above R 1s is independently selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, and the C 3-6 cycloalkyl and 4-6 membered heterocyclic
  • the alkyl groups are each independently optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
  • each of the above R 2 is independently selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, and the C 3-6 cycloalkyl and 4-6 membered heterocyclic
  • the alkyl groups are each independently optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
  • each of the above R 3 is independently selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, and the C 3-6 cycloalkyl and 4-6 membered heterocyclic
  • the alkyl groups are each independently optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
  • each of the above-mentioned R 1 , R 2 and R 3 is independently selected from H, F, Cl, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , cyclopropyl and cyclobutyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , ring Propyl and cyclobutyl are optionally substituted with 1, 2 or 3 R a , other variables are as defined herein.
  • each R 1 above is independently selected from H and F, and other variables are as defined in the present invention.
  • each of the above R 2 is independently selected from H, F, Cl, CH 3 and Other variables are as defined herein.
  • each R 3 above is independently selected from H and CH 3 , and other variables are as defined in the present invention.
  • R 2 and R 3 are connected together to make the structural unit selected from Other variables are as defined herein.
  • the above-mentioned R 4 is selected from C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl, the C 3-6 cycloalkyl, 4-
  • the 6-membered heterocycloalkyl group and the 5-6-membered heteroaryl group are independently optionally substituted by 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the above-mentioned R is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, and the C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently is optionally substituted with 1, 2 or 3 Rc , other variables are as defined herein.
  • the above-mentioned R 4 is selected from NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl and pyridyl, the -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, pyrrolyl , pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl and pyridyl are optionally substituted with 1, 2 or 3 Rc , other variables are as defined herein.
  • the above-mentioned R 4 is selected from NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolyl, oxygen Heterocyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl and pyridyl, the -NHCH 3.
  • R 4 is selected from NH 2 ,
  • Other variables are as defined herein.
  • R 4 is selected from NH 2 ,
  • Other variables are as defined herein.
  • the above - mentioned L1 is selected from S, and other variables are as defined in the present invention.
  • L 1 is selected from O, and other variables are as defined in the present invention.
  • T 1 is selected from CH, and other variables are as defined in the present invention.
  • L 1 is selected from O
  • T 1 is selected from N
  • other variables are as defined in the present invention.
  • L 1 is selected from O
  • T 1 is selected from CH
  • one of the following conditions is met:
  • At least one of R 1 , R 2 , R 3 and R 4 is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 3-6 cycloalkyl and 4-6
  • the membered heterocycloalkyl groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 and R 3 are connected together to form a 5-10 membered heterocycloalkyl group, and the 5-10 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R b ;
  • R 4 is selected from -NR 5 R 6 , CN and C 1-3 alkoxy, and the C 1-3 alkoxy is optionally substituted by 1, 2 or 3 R c ;
  • the above-mentioned L 1 is selected from O
  • T 1 is selected from CH
  • at least one of R 1 , R 2 , R 3 and R 4 is selected from C 3-6 cycloalkyl and 4-6 membered Heterocycloalkyl
  • the C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R a
  • other variables are as defined in the present invention.
  • L 1 is selected from O
  • T 1 is selected from CH
  • the structural unit selected from R 2 and R 3 are independently selected from H, F, Cl, Br, I, CN, CH 3 and OCH 3
  • ring A is selected from 5-10 membered heterocycloalkyl
  • the 5-10 membered heterocycloalkane The group is optionally substituted with 1, 2 or 3 R b , other variables are as defined herein.
  • L 1 is selected from O
  • T 1 is selected from CH
  • R 4 is selected from -NR 5 R 6
  • CN and C 1-3 alkoxy
  • the C 1-3 alkoxy Optionally substituted with 1, 2 or 3 Rc , other variables are as defined herein.
  • each R 1 above is independently selected from H and F, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of,
  • Ring B is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently optionally replaced by 1, 2 or 3 R c replacement;
  • Each R 2 and each R 3 are independently selected from H, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently optionally replaced by 1, 2 or 3 R a replaces;
  • L 1 , T 1 , each R 1 , each R a , each R c , n, m and p are as defined herein.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of,
  • ring B, L 1 , T 1 , each R 1 , each R 2 and R 3 are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of,
  • ring B, L 1 , T 1 , each R 1 , each R 2 and R 3 are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof wherein, the structural unit With stereo axis chirality, its enantiomers are R3 and other variables are as defined herein.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is analyzed as two independent chromatographic peaks by SFC, and the SFC analysis method is: column model: Chiralpak IG-3 50 ⁇ 4.6mm I.D. , 3 ⁇ m), mobile phase A is carbon dioxide, and mobile phase B is selected from methanol with a volume ratio of 3:1: acetonitrile (0.05% diethanolamine) or isopropanol: acetonitrile (0.05% diethanolamine), or mobile phase B is Methanol (0.05% diethanolamine).
  • the proportion of mobile phase B in the above SFC analysis method is 40%, 50% or 60%, or the proportion of mobile phase B is set in a gradient of 5-40% or 5-60%.
  • above-mentioned compound or its pharmaceutically acceptable salt its retention time by SFC analysis is the time of earlier peak in two independent chromatographic peaks, and described SFC analysis method is: column type: Chiralpak IG-3 50 ⁇ 4.6mm I.D., 3 ⁇ m), mobile phase A is carbon dioxide, and mobile phase B is selected from methanol:acetonitrile (0.05% diethanolamine) or isopropanol:acetonitrile (0.05% diethylamine) with a volume ratio of 3:1 ethanolamine), alternatively, mobile phase B was methanol (0.05% diethanolamine).
  • the proportion of mobile phase B in the above SFC analysis method is 40%, 50% or 60%, or the proportion of mobile phase B is set in a gradient of 5-40% or 5-60%.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is analyzed by SFC, column model: Chiralpak IG-3 50 ⁇ 4.6mm I.D., 3 ⁇ m), mobile phase A is carbon dioxide, and mobile phase B is selected From methanol:acetonitrile (0.05% diethanolamine) at a volume ratio of 3:1, the proportion of mobile phase B is 60%, and the retention time is the earlier eluting time of two independent chromatographic peaks.
  • the retention time of the above compound was 0.861 minutes.
  • Example 4 of the present invention the retention time of the above compound was 0.907 minutes.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is analyzed by SFC, column model: Chiralpak IG-3 50 ⁇ 4.6mm I.D., 3 ⁇ m), mobile phase A is carbon dioxide, and mobile phase B is selected From methanol:acetonitrile (0.05% diethanolamine) at a volume ratio of 3:1, the proportion of mobile phase B is 40%, and the retention time is the earlier eluting time of the two independent chromatographic peaks.
  • the retention time of the above compound was 0.935 minutes.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is analyzed by SFC, column model: Chiralpak IG-3 50 ⁇ 4.6mm I.D., 3 ⁇ m), mobile phase A is carbon dioxide, and mobile phase B is selected From isopropanol: acetonitrile (0.05% diethanolamine) with a volume ratio of 3:1, the proportion of mobile phase B is 60%, and the retention time is the earlier eluting time of two independent chromatographic peaks.
  • the retention time of the above compound was 0.591 minutes.
  • above-mentioned compound or its pharmaceutically acceptable salt it is analyzed by SFC, column model: Chiralpak IG-3 50 * 4.6mm I.D., 3 ⁇ m), mobile phase A is carbon dioxide, mobile phase B is Methanol (0.05% diethanolamine), the gradient ratio of the mobile phase B is 5%-40%, and the retention time is the earlier eluting time of the two independent chromatographic peaks.
  • the retention time of the above compound was 1.822 minutes.
  • Example 7 of the present invention the above-mentioned compound is analyzed by SFC, column model: Chiralpak IG-3 50 * 4.6mm I.D., 3 ⁇ m), mobile phase A is carbon dioxide, mobile phase B is methanol (0.05% diethanolamine), mobile phase The proportion of phase B was 40%, and the retention time was 0.632 minutes.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of,
  • Each R 1 , R 2 and R 3 are independently selected from H, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4 -6-membered heterocycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently optionally replaced by 1, 2 Or 3 R a substitutions; T 1 , R 4 , R a and n are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of,
  • Each R 1 , R 2 and R 3 are independently selected from H, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4 -6-membered heterocycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently optionally replaced by 1, 2 or 3 R a substitutions; structural fragments Selected from 5-10 membered heterocycloalkyl groups, 5-10 membered heterocycloalkyl groups are independently optionally substituted by 1, 2 or 3 R b ;
  • L 1 , T 1 , R 4 , R a , R b and n are as defined in the present invention.
  • the present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T1 is selected from N and CH ;
  • L is selected from O and S ;
  • Each R 1 , R 2 and R 3 are independently selected from H, F, Cl, Br, I, CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4 -6-membered heterocycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are independently optionally replaced by 1, 2 or 3 R a substitutions;
  • R 2 and R 3 are connected together to form a 5-10 membered heterocycloalkyl group, and the 5-10 membered heterocycloalkyl groups are independently optionally substituted by 1, 2 or 3 R b ;
  • R 4 is selected from -NR 5 R 6 , CN, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl
  • the C 1-3 alkyl group, C 1-3 alkoxy group, C 3-6 cycloalkyl group, 4-6 membered heterocycloalkyl group and 5-6 membered heteroaryl group are independently optionally replaced by 1 , 2 or 3 R c substitutions;
  • R 5 and R 6 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R d ;
  • R 5 and R 6 form a 4-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group together with the N atoms they are connected to, and the 4-6 membered heterocycloalkyl group or 5-6 membered heteroaryl group
  • the groups are independently optionally substituted by 1, 2 or 3 R e ;
  • the proviso is that when L is selected from O and T is selected from CH, one of the following conditions is met:
  • At least one of R 1 , R 2 , R 3 and R 4 is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 3-6 cycloalkyl and 4-6
  • the membered heterocycloalkyl groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 and R 3 are connected together to form a 5-10 membered heterocycloalkyl group, and the 5-10 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R b ;
  • R 4 is selected from -NR 5 R 6 , CN and C 1-3 alkoxy, and the C 1-3 alkoxy is optionally substituted by 1, 2 or 3 R c ;
  • n, m and p are independently selected from 0, 1, 2 and 3;
  • R a , R b , R c , R d and Re are independently selected from F, Cl, Br, I, OH, CH 3 and OCH 3 ;
  • the "4-6 membered heterocycloalkyl” contains 1 or 2 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N;
  • the "5-10 membered heterocycloalkyl” and “5-6 membered heteroaryl” each independently contain 1, 2 or 3 hetero atoms or heteroatom groups.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the above compound or a pharmaceutically acceptable salt thereof is selected from,
  • the present invention also provides the following biological testing methods:
  • Test method 1 Effect of LPS on human PBMC TNF- ⁇ expression in vitro drug efficacy test
  • PBMC experiment PBMC cells were seeded into a 96-well plate of cell culture level at a density of 100,000 cells/100 ⁇ L/well, and the cell culture medium was RPMI-1640 with 10% serum. Incubate for 2 hours at 37 °C in a 5% CO2 incubator. Add 16.8 ⁇ L/well of the compound to be tested in the cells and incubate for 60 minutes at 37°C in a 5% CO 2 incubator, then add 16.8 ⁇ L/well of LPS in the cells and incubate at 37°C in a 5% CO 2 incubator Incubate for 18 hours with a final DMSO concentration of 0.1%.
  • Compound dose gradient dilution In the first step, the compound was diluted from stock concentration to 1.5 mM with 100% DMSO. In the second step, the diluted compound was used as the first point and diluted 9 points 3-fold with 100% DMSO. In the third step, it is diluted 125 times with a serum-free medium, and the concentration of DMSO at this time is 0.8%. Then transfer 16.8 ⁇ L of the compound diluted with culture medium to a 100 ⁇ L cell plate. After adding the compound, place the cell plate in a 37°C, 5% CO 2 incubator and incubate for 1 hour.
  • LPS dilution In the first step, dilute LPS with ultrapure water to a stock concentration of 1 mg/mL. In the second step, the stock concentration of LPS was diluted to 1 ⁇ g/mL with serum-free medium. In the third step, it is diluted 1666.666 times with serum-free medium. Then transfer 16.8 ⁇ L of LPS that has been diluted with culture medium to a 116.8 ⁇ L cell plate. At this time, the final concentration of DMSO is 0.1%. After adding LPS, place the cell plate in a 37°C, 5% CO2 incubator and incubate 18 Hour.
  • Inhibition rate (1-(original value-HPE average value)/(ZPE average value-HPE average value))*100
  • ZPE 0% inhibition (75pg/mL LPS, 0.1% DMSO)
  • HPE 100% inhibition (without LPS, 0.1% DMSO).
  • Data analysis was performed with XLfit statistical software.
  • the calculation formula of IC50 is: using 4 parameters logistic dose-response equation, the concentration of the tested compound and the inhibition rate (%) are plotted, and the compound concentration (IC50) required for 50% inhibition is determined.
  • the compound of the present invention can significantly inhibit the activity of p38/MK2, has excellent selectivity to MK2/MK5, can significantly inhibit the expression of TNF- ⁇ induced by lipopolysaccharide (LPS) in human peripheral blood mononuclear cells (hPBMC), and has excellent pharmacokinetic properties.
  • LPS lipopolysaccharide
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • 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 the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key and straight dashed keys
  • tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-3 alkyl by itself or in combination with other terms means a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms, respectively.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy by itself or in combination with other terms respectively means those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-6 cycloalkyl by itself or in combination with other terms represents a saturated monocyclic hydrocarbon group composed of 3 to 6 carbon atoms, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms represents a saturated or partially unsaturated monocyclic ring group composed of 4 to 6 ring atoms, of which 1, 2 , 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e. NO and S(O) p , p is 1 or 2).
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 4-6-membered heterocycloalkyl group includes 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like.
  • 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.),
  • the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms represents a saturated or partially unsaturated cyclic group consisting of 5 to 10 ring atoms, whose 1, 2, 3 Or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S( O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings.
  • the 5-10 membered heterocycloalkyl group includes 5-8-membered, 5-6-membered, 6-10-membered, 8-10-membered, 6-membered, 7-membered, 8-membered, 9-membered and 10-membered heterocycloalkyl groups etc. .
  • Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl,
  • the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.
  • C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1- 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • representative leaving groups include triflate (OTf); chlorine, bromine, iodine; sulfonate groups such as mesylate (OMs), tosylate, brosylate Esters, p-toluenesulfonates (OTs), etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxyl protecting group” or “mercapto protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxy group.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl, such as acetyl (Ac); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert Butyldimethylsilyl (TBS) etc.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • DMSO dimethylsulfoxide
  • MeOH stands for methanol
  • ACN stands for acetonitrile
  • DEA diethylamine
  • CO2 stands for carbon dioxide
  • psi pounds force per square inch
  • Ph stands for phenyl
  • SFC Stands for supercritical fluid chromatography.
  • the solvent used in the present invention is commercially available.
  • Compounds are named according to the conventional naming principles in this field or using The software is named, and the commercially available compounds adopt the supplier catalog name.
  • reaction solution was diluted with 20 ml of ice water, stirred for 10 minutes, extracted twice with ethyl acetate, 4 ml each time, washed three times with saturated brine, 5 ml each time, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure, and the resulting crude product was separated and purified by preparative high performance liquid phase (column model: Phenomenex Synergi Polar-RP 100*25mm*4 ⁇ m; mobile phase: [water (0.05% trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile% ): 46%-66%) to obtain compound 3.
  • step 1
  • step 1
  • step 1
  • the hydrochloride of compound 7-3 (8.2 g) was added into methanol (50 mL), and ammonia gas was continuously flowed in at 0° C. for 30 minutes, and the reaction solution was slowly raised to 20° C. and stirred for 2 hours. After the reaction solution was concentrated under reduced pressure, it was separated and purified by preparative high performance liquid phase (column model: Waters Atlantis T3 150*30mm*5 ⁇ m; mobile phase: [water (0.05% formic acid)-acetonitrile]; gradient (acetonitrile%): 1%- 20%) to obtain compound 7-4.
  • PBMC experiment PBMC cells were seeded into a 96-well plate of cell culture level at a density of 100,000 cells/100 ⁇ L/well, and the cell culture medium was RPMI-1640 with 10% serum. Incubate for 2 hours at 37 °C in a 5% CO2 incubator. Add 16.8 ⁇ L/well of the compound to be tested in the cells and incubate for 60 minutes at 37°C in a 5% CO 2 incubator, then add 16.8 ⁇ L/well of LPS in the cells and incubate at 37°C in a 5% CO 2 incubator Incubate for 18 hours with a final DMSO concentration of 0.1%.
  • Compound dose gradient dilution In the first step, the compound was diluted from stock concentration to 1.5 mM with 100% DMSO. In the second step, the diluted compound was used as the first point and diluted 9 points 3-fold with 100% DMSO. In the third step, it is diluted 125 times with a serum-free medium, and the concentration of DMSO at this time is 0.8%. Then transfer 16.8 ⁇ L of the compound diluted with culture medium to a 100 ⁇ L cell plate. After adding the compound, place the cell plate in a 37°C, 5% CO 2 incubator and incubate for 1 hour.
  • LPS dilution In the first step, dilute LPS with ultrapure water to a stock concentration of 1 mg/mL. In the second step, the stock concentration of LPS was diluted to 1 ⁇ g/mL with serum-free medium. In the third step, it is diluted 1666.666 times with serum-free medium. Then transfer 16.8 ⁇ L of LPS that has been diluted with culture medium to a 116.8 ⁇ L cell plate. At this time, the final concentration of DMSO is 0.1%. After adding LPS, place the cell plate in a 37°C, 5% CO2 incubator and incubate 18 Hour.
  • Inhibition rate (1-(original value-HPE average value)/(ZPE average value-HPE average value))*100
  • ZPE is: 0% inhibition (75pg/mL LPS, 0.1% DMSO)
  • HPE is: 100% inhibition (without LPS, 0.1% DMSO).
  • IC 50 concentration of the tested compound and the inhibition rate (%) are plotted, and the concentration of the compound required for 50% inhibition (IC 50 ) is determined.
  • Table 1 The compound of the present invention inhibits the test result that LPS stimulates human source PBMC TNF- ⁇ expression
  • the compound of the present invention can significantly inhibit the secretion of inflammatory factor TNF- ⁇ induced by lipopolysaccharide (LPS) in human peripheral blood mononuclear cells (hPBMC).
  • LPS lipopolysaccharide
  • MAPKAPK2 or MAPKAPK5 substrate mix (inactive MAPKAPK2 or MAPKAPK5, FITC-KKKALSRQLSVAA, ATP) to the assay wells.
  • MAPKAPK2 inactive: 1 nM or MAPKAPK5, inactive: 10 nM;
  • Buffer 20mM HEPES pH 7.5, 10mM MgCl 2 , 0.05% Brij-35, 0.01% BSA (bovine serum albumin), 1mM DTT (dithiothreitol), 1% DMSO;
  • MAPKAPK2 inactive: 1 nM or MAPKAPK5, inactive: 10 nM;
  • Buffer 20mM HEPES pH 7.5, 10mM MgCl 2 , 0.05% Brij-35, 0.01% BSA, 1mM DTT;
  • the compound of the present invention can effectively inhibit the activity of p38/MK2, and has excellent selectivity to MK2/MK5.
  • Adopt CD-1 (ICR) mouse male, 25-35g, 5 ⁇ 11 weeks old, Weitong Lihua Beijing
  • experimental method is as follows:
  • the pharmacokinetic characteristics of the compounds in rodents after intravenous injection and oral administration were tested according to the standard protocol.
  • the candidate compounds were formulated into clear solutions and given to mice for single intravenous injection (IV) and single oral administration (PO).
  • the vehicle is 20% SBE- ⁇ -CD aqueous solution.
  • Whole blood samples within 24 hours after administration oral: 0.25, 0.5, 1, 2, 4, 8, 24h, intravenous injection: 0.25, 0.5, 1, 2, 4, 6, 8, 24h), each Secondary blood collections (0.025 mL per time point) will be performed from the saphenous vein or other suitable site from each animal into pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifuged.
  • Plasma samples will be centrifuged at 3200 g for 10 minutes at 4°C to obtain plasma. Transfer the collected plasma to a pre-labeled 96-well plate or polypropylene tube, quickly cool it on dry ice and keep it at -60°C or lower until LC-MS/MS quantifies the plasma concentration and calculates the pharmacokinetic parameters , such as peak concentration (C max ), volume of distribution (Vd ss ), clearance rate (Cl), half-life (T 1/2 ), area under the drug-time curve (AUC 0-last ), bioavailability (F), etc.
  • C max peak concentration
  • Vd ss volume of distribution
  • Cl clearance rate
  • T 1/2 half-life
  • AUC 0-last area under the drug-time curve
  • bioavailability F
  • the compounds of the present invention have excellent pharmacokinetic properties in mice.
  • Adopt SD rats male, 250-350g, 5-11 weeks old, Weitong Li Huaping Lake
  • the experimental method is as follows:
  • the pharmacokinetic characteristics of the compounds in rodents after intravenous injection and oral administration were tested according to the standard protocol.
  • the candidate compounds were formulated into clear solutions and given to mice for single intravenous injection (IV) and single oral administration (PO).
  • the vehicle is 20% SBE- ⁇ -CD aqueous solution.
  • Whole blood samples within 24 hours after administration oral: 0.25, 0.5, 1, 2, 4, 8, 24h, intravenous injection: 0.25, 0.5, 1, 2, 4, 6, 8, 24h), each Secondary blood collections (0.2 mL per time point) will be performed from the saphenous vein or other suitable site from each animal into pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifuged.
  • Blood samples will be centrifuged at 3200 g for 10 minutes at 4°C to obtain plasma. Transfer the collected plasma to a pre-labeled 96-well plate or polypropylene tube, quickly cool it on dry ice and keep it at -60°C or lower until LC-MS/MS quantifies the plasma concentration and calculates the pharmacokinetic parameters , such as peak concentration, peak time, clearance rate, half-life, area under the drug-time curve, bioavailability, etc.
  • pharmacokinetic parameters such as peak concentration, peak time, clearance rate, half-life, area under the drug-time curve, bioavailability, etc.
  • the compounds of the present invention have excellent pharmacokinetic properties in rats.
  • the pharmacokinetic characteristics of the compounds in rodents after intravenous injection and oral administration were tested according to the standard protocol.
  • the candidate compounds were formulated into clear solutions and given to mice for single intravenous injection (IV) and single oral administration (PO).
  • the vehicle is 20% SBE- ⁇ -CD aqueous solution.
  • Whole blood samples within 24 hours after administration oral: 0.25, 0.5, 1, 2, 4, 8, 24h, intravenous injection: 0.25, 0.5, 1, 2, 4, 6, 8, 24h), each Secondary blood collections (0.5 mL per time point) will be performed from the saphenous vein or other suitable site from each animal into pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifuged.
  • Plasma samples will be collected within 1 hour and then centrifuged at 2-8°C and 3200g for 10 minutes to obtain plasma. Aliquot approximately 0.2 mL of plasma sample into approximately 0.1 mL (one for BA and one for spare) into labeled polypropylene microcentrifuge tubes and store frozen in a freezer at -60°C or below , until bioanalysis. Quantitative analysis of blood drug concentration by LC-MS/MS, and calculation of pharmacokinetic parameters, such as peak concentration, time to peak, clearance rate, half-life, area under the drug-time curve, bioavailability, etc.
  • the compound of the present invention has excellent canine pharmacokinetic properties.

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Abstract

La présente invention concerne une série de dérivés de pyrimidine substitués par un hétérocycle, et spécifiquement un composé tel que représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2022/107361 2021-07-23 2022-07-22 Dérivé de pyrimidine substitué par un hétérocycle WO2023001282A1 (fr)

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* 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

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Publication number Priority date Publication date Assignee Title
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
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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

Cited By (1)

* 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

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