WO2023001282A1 - 杂环取代的嘧啶衍生物 - Google Patents

杂环取代的嘧啶衍生物 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)
French (fr)
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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/zh

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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.

Abstract

本发明公开了一系列杂环取代的嘧啶衍生物，具体公开了式(I)所示化合物及其药学上可接受的盐。

Description

杂环取代的嘧啶衍生物
本发明主张如下优先权：
CN202110837811.7，申请日2021年07月23日。
技术领域
本发明涉及一系列杂环取代的嘧啶衍生物，具体涉及式(I)所示化合物及其药学上可接受的盐。
背景技术
细胞对外界刺激的响应是由一系列胞内的激酶以及磷酸酶调控的。这一类酶催化的磷酸化或去磷酸化反应可以调控其下游各个成分的活性、与其他蛋白的相互作用、在细胞内的位置等。丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPK)是信号从细胞表面传导到细胞核内部的重要传递者，是一组能被不同的细胞外刺激，如细胞因子、神经递质、激素、细胞应激及细胞黏附等激活的丝氨酸-苏氨酸蛋白激酶。MAPKs家族包括ERK、p38、JNK和ERK5四个亚家族。每个MAPK的亚家族之间的功能存在着差异。ERKs是主要的生长相关刺激的调控者，JNK在受到高渗透压和强氧化条件等刺激下被激活，ERK5/BMK1调控某些基因的早期表达，p38则可以参与到炎症、细胞生长、细胞分化、细胞周期和细胞死亡等多个生理过程中。MAPKs的生化特点是在受到某些刺激后，其苏氨酸和酪氨酸两个位点会被磷酸化从而被激活。
MAPK的下游底物包括丝裂原活化蛋白激酶激活的蛋白(MAPKAP)激酶和转录因子，其磷酸化直接或间接地调节几个点的基因表达，包括转录、核输出及mRNA的稳定性和翻译。MAPK激活的细胞影响包括炎症、细胞凋亡、分化及增殖。不同的基因编码人体内的四种p38MAPK激酶：p38α、p38β、p38γ及p38δ。在4个亚型间观察到了显著的氨基酸序列同源性，所述亚型具有60％-75％的整体序列同一性，在激酶结构域内具有>90％的同一性。还观察到了组织选择性表达，其中p38γ主要存在于骨骼肌中，p38δ主要存在于睾丸、胰腺及小肠中。相比之下，p38α和p38β表达更加广泛。P38α是MAPK信号通路中调节细胞因子产生的关键亚型。
MK2(MAPKAK2)是P38的主要下游蛋白之一，激活的MK2可以磷酸化AU-rich元件结合蛋白TTP，调控TNF-α、IL-1β、IL-6等细胞因子mRNA的稳定性，调节这些细胞因子的生物合成。
类风湿性关节炎(RA)是***性的、自身免疫的慢性炎症性病症，其特征在于关节滑膜炎症，从而导致软骨和骨骼破坏。目前的RA的治疗包括口服调节病情抗风湿药物(DMARD)(甲氨蝶呤、来氟米特、柳氮磺吡啶)和肠胃外施用生物药剂，特别是针对IL-1β或TNF-α，这两种RA发病机制中涉及到的关键的促炎性细胞因子。后者这些药剂的优越功效被潜在的缺点稍微抵消，所述缺点包括需要肠胃外施用、难以调整剂量、由于较长的血浆半衰期导致的可逆性差、诱导宿主中和抗体反应及高的治疗费用。因此口服施用的具有改 善功效的DMARD就施用的便利性和依从性，没有注射部位/过敏反应，优越的剂量可调整性及有利的物品成本而言为患者和医师提供多种优势。因此，开发安全有效可口服的MK2抑制剂仍然具有广泛的临床需求。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022107361-appb-000001
其中，
T 1选自N和CH；
L 1选自O和S；
各R 1、各R 2和各R 3分别独立地选自H、F、Cl、Br、I、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；
或者，结构单元
Figure PCTCN2022107361-appb-000002
选自
Figure PCTCN2022107361-appb-000003
R 2和R 3分别独立地选自H、F、Cl、Br、I、CN、CH 3和OCH 3，环A选自5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R b取代；
R 4选自-NR 5R 6、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、4-6元杂环烷基和5-6元杂芳基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、4-6元杂环烷基和5-6元杂芳基分别独立地任选被1、2或3个R c取代；
R 5和R 6分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R d取代；
或者，R 5和R 6与它们共同连接的N原子一起形成4-6元杂环烷基或5-6元杂芳基，所述4-6元杂环烷基或5-6元杂芳基分别独立地任选被1、2或3个R e取代；
条件是，当L 1选自O，且T 1选自CH时，满足下列条件之一：
(1)R 1、R 2、R 3和R 4中至少有一个选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷 基分别独立地任选被1、2或3个R a取代；
(2)结构单元
Figure PCTCN2022107361-appb-000004
选自
Figure PCTCN2022107361-appb-000005
R 2和R 3分别独立地选自H、F、Cl、Br、I、CN、CH 3和OCH 3，环A选自5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R b取代；
(3)R 4选自-NR 5R 6、CN和C 1-3烷氧基，所述C 1-3烷氧基任选被1、2或3个R c取代；
n、m和p分别独立地选自0、1、2和3；
各R a、各R b、各R c、各R d和各R e分别独立地选自F、Cl、Br、I、OH、CH 3和OCH 3；
所述“4-6元杂环烷基”包含1或2个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团；
所述“5-10元杂环烷基”和“5-6元杂芳基”分别独立地包含1、2或3个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
在本发明的一些方案中，上述各R 1分别独立地选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，上述各R 2分别独立地选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，上述各R 3分别独立地选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，上述各R 1、R 2和R 3分别独立地选自H、F、Cl、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、环丙基和环丁基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、环丙基和环丁基任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，上述各R 1分别独立地选自H和F，其他变量如本发明所定义。
在本发明的一些方案中，上述各R 2分别独立地选自H、F、Cl、CH 3和
Figure PCTCN2022107361-appb-000006
其他变量如本发明所定义。
在本发明的一些方案中，上述各R 3分别独立地选自H和CH 3，其他变量如本发明所定义。
在本发明的一些方案中，上述R 2和R 3连接在一起使结构单元
Figure PCTCN2022107361-appb-000007
选自
Figure PCTCN2022107361-appb-000008
Figure PCTCN2022107361-appb-000009
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2022107361-appb-000010
选自
Figure PCTCN2022107361-appb-000011
其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自C 3-6环烷基、4-6元杂环烷基和5-6元杂芳基，所述C 3-6环烷基、4-6元杂环烷基和5-6元杂芳基分别独立地任选被1、2或3个R c取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R c取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自NH 2、-NHCH 3、-N(CH 3) 2、
Figure PCTCN2022107361-appb-000012
CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基、环丁基、吡咯基、吡唑基、咪唑基、***基、噻唑基、噁唑基和吡啶基，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基、环丁基、吡咯基、吡唑基、咪唑基、***基、噻唑基、噁唑基和吡啶基任选被1、2或3个R c取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自NH 2、-NHCH 3、-N(CH 3) 2、
Figure PCTCN2022107361-appb-000013
CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、吡咯烷基、哌啶基、***啉基、吡咯基、吡唑基、咪唑基、***基、噻唑基、噁唑基和吡啶基，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧 杂环戊基、氧杂环己基、氮杂环丁基、吡咯烷基、哌啶基、***啉基、吡咯基、吡唑基、咪唑基、***基、噻唑基、噁唑基和吡啶基任选被1、2或3个R c取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自NH 2、
Figure PCTCN2022107361-appb-000014
Figure PCTCN2022107361-appb-000015
其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自
Figure PCTCN2022107361-appb-000016
Figure PCTCN2022107361-appb-000017
其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自NH 2、
Figure PCTCN2022107361-appb-000018
其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自
Figure PCTCN2022107361-appb-000019
其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自
Figure PCTCN2022107361-appb-000020
其他变量如本发明所定义。
在本发明的一些方案中，上述L 1选自S，其他变量如本发明所定义。
在本发明的一些方案中，上述L 1选自O，其他变量如本发明所定义。
在本发明的一些方案中，上述T 1选自CH，其他变量如本发明所定义。
在本发明的一些方案中，上述L 1选自O，T 1选自N，其他变量如本发明所定义。
在本发明的一些方案中，上述L 1选自O，T 1选自CH，且满足下列条件之一：
(1)R 1、R 2、R 3和R 4中至少有一个选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；
(2)R 2和R 3连接在一起形成5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R b取代；
(3)R 4选自-NR 5R 6、CN和C 1-3烷氧基，所述C 1-3烷氧基任选被1、2或3个R c取代；
其他变量如本发明所定义。
在本发明的一些方案中，上述L 1选自O，T 1选自CH，R 1、R 2、R 3和R 4中至少有一个选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，上述L 1选自O，T 1选自CH，结构单元
Figure PCTCN2022107361-appb-000021
选自
Figure PCTCN2022107361-appb-000022
R 2和R 3分别独立地选自H、F、Cl、Br、I、CN、CH 3和OCH 3，环A选自5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R b取代，其他变量如本发明所定义。
在本发明的一些方案中，上述L 1选自O，T 1选自CH，R 4选自-NR 5R 6、CN和C 1-3烷氧基，所述C 1-3烷氧基任选被1、2或3个R c取代，其他变量如本发明所定义。
在本发明的一些方案中，上述各R 1分别独立地选自H和F，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022107361-appb-000023
其中，
环B选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R c取代；
各R 2和各R 3分别独立地选自H、F、Cl、Br、I、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；
L 1、T 1、各R 1、各R a、各R c、n、m和p如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022107361-appb-000024
其中，环B、L 1、T 1、各R 1、各R 2和R 3如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022107361-appb-000025
其中，环B、L 1、T 1、各R 1、各R 2和R 3如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2022107361-appb-000026
具有立体轴手性，其对映异构体为
Figure PCTCN2022107361-appb-000027
R 3及其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其通过SFC分析为两个独立的色谱峰，所述SFC分析方法为：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)，流动相A为二氧化碳，流动相B选自体积比为3:1的甲醇:乙腈(0.05％二乙醇胺)或异丙醇:乙腈(0.05％二乙醇胺)，或者，流动相B为甲醇(0.05％二乙醇胺)。在本发明的一些方案中，上述SFC分析方法中流动相B的比例为40％、50％或60％，或者，流动相B的比例按5-40％或5-60％梯度设置。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其通过SFC分析的保留时间为两个独立的色谱峰中更早出峰的时间，所述SFC分析方法为：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)，流动相A为二氧化碳，流动相B选自体积比为3:1的甲醇:乙腈(0.05％二乙醇胺)或异丙醇:乙腈(0.05％二乙 醇胺)，或者，流动相B为甲醇(0.05％二乙醇胺)。在本发明的一些方案中，上述SFC分析方法中流动相B的比例为40％、50％或60％，或者，流动相B的比例按5-40％或5-60％梯度设置。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其通过SFC分析，柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)，流动相A为二氧化碳，流动相B选自体积比为3:1的甲醇:乙腈(0.05％二乙醇胺)，流动相B的比例为60％，保留时间为两个独立的色谱峰中更早出峰的时间。在本发明的实施例2中，上述化合物的保留时间为0.861分钟。在本发明的实施例4中，上述化合物的保留时间为0.907分钟。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其通过SFC分析，柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)，流动相A为二氧化碳，流动相B选自体积比为3:1的甲醇:乙腈(0.05％二乙醇胺)，流动相B的比例为40％，保留时间为两个独立的色谱峰中更早出峰的时间。在本发明的实施例3中，上述化合物的保留时间为0.935分钟。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其通过SFC分析，柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)，流动相A为二氧化碳，流动相B选自体积比为3:1的异丙醇:乙腈(0.05％二乙醇胺)，流动相B的比例为60％，保留时间为两个独立的色谱峰中更早出峰的时间。在本发明实施例5中，上述化合物的保留时间为0.591分钟。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其通过SFC分析，柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)，流动相A为二氧化碳，流动相B为甲醇(0.05％二乙醇胺)，流动相B的梯度比例为5％-40％，保留时间为两个独立的色谱峰中更早出峰的时间。在本发明的实施例6中，上述化合物的保留时间为1.822分钟。
在本发明的实施例7中，上述化合物通过SFC分析，柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)，流动相A为二氧化碳，流动相B为甲醇(0.05％二乙醇胺)，流动相B的比例为40％，保留时间为0.632分钟。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022107361-appb-000028
其中，
各R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；T 1、R 4、R a和n如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物选自，
Figure PCTCN2022107361-appb-000029
其中，
各R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；结构片段
Figure PCTCN2022107361-appb-000030
选自5-10元杂环烷基，5-10元杂环烷基分别独立地任选被1、2或3个R b取代；
L 1、T 1、R 4、R a、R b和n如本发明所定义。
本发明还提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022107361-appb-000031
其中，
T 1选自N和CH；
L 1选自O和S；
各R 1、R 2和R 3分别独立地选自H、F、Cl、Br、I、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环 烷基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；
或者，R 2和R 3连接在一起形成5-10元杂环烷基，所述5-10元杂环烷基分别独立地任选被1、2或3个R b取代；
R 4选自-NR 5R 6、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、4-6元杂环烷基和5-6元杂芳基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、4-6元杂环烷基和5-6元杂芳基分别独立地任选被1、2或3个R c取代；
R 5和R 6分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R d取代；
或者，R 5和R 6与它们共同连接的N原子一起形成4-6元杂环烷基或5-6元杂芳基，所述4-6元杂环烷基或5-6元杂芳基分别独立地任选被1、2或3个R e取代；
条件是，当L 1选自O，且T 1选自CH时，满足下列条件之一：
(1)R 1、R 2、R 3和R 4中至少有一个选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；
(2)R 2和R 3连接在一起形成5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R b取代；
(3)R 4选自-NR 5R 6、CN和C 1-3烷氧基，所述C 1-3烷氧基任选被1、2或3个R c取代；
n、m和p分别独立地选自0、1、2和3；
各R a、R b、R c、R d和R e分别独立地选自F、Cl、Br、I、OH、CH 3和OCH 3；
所述“4-6元杂环烷基”包含1或2个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团；
所述“5-10元杂环烷基”和“5-6元杂芳基”分别独立地包含1、2或3个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明还有一些方案由上述变量任意组合而来。
本发明还提供了下列所示化合物或其药学上可接受的盐，
Figure PCTCN2022107361-appb-000032
Figure PCTCN2022107361-appb-000033
在本发明的一些方案中，上述化合物或其药学上可接受的盐选自，
Figure PCTCN2022107361-appb-000034
Figure PCTCN2022107361-appb-000035
本发明还提供了下列生物测试方法：
测试方法1：LPS刺激人源PBMC TNF-α表达的影响体外药效试验
实验目的：研究化合物对在人外周血单个核细胞(hPBMC)中脂多糖(LPS)诱导TNF-α表达的影响。
PBMC实验：PBMC细胞以100000个/100μL/孔的密度种入细胞培养级别的96孔板中，细胞培养基是加10％血清的RPMI-1640。在37℃，5％CO 2培养箱中培养2个小时。在细胞里加入16.8μL/孔的待测 化合物后在37℃，5％CO 2培养箱中培养60分钟，后在细胞里加入16.8μL/孔的LPS在37℃，5％CO 2培养箱中培养18小时，最终DMSO浓度为0.1％。
化合物剂量梯度稀释：第一步将化合物从储藏浓度用100％的DMSO稀释到1.5mM。第二步将稀释过的化合物作为第一个点用100％DMSO 3倍稀释9个点。第三步用不含有血清的培养基125倍稀释，此时DMSO的浓度是0.8％。然后转16.8μL已经用培养基稀释好的化合物到100μL的细胞板里。加好化合物后将细胞板放入37℃，5％CO 2培养箱中孵育1个小时。
LPS稀释：第一步将LPS用超纯水稀释到储藏浓度1mg/mL。第二步储藏浓度的LPS用不含血清的培养基稀释到1μg/mL。第三步用不含有血清的培养基1666.666倍稀释。然后转16.8μL已经用培养基稀释好的LPS到116.8μL的细胞板里，此时DMSO终浓度是0.1％，加好LPS后将细胞板放入37℃，5％CO2培养箱中孵育18个小时。
ELISA实验：
第一天：
1.将TNF-α抗体在包被液中稀释至1x，然后每孔100μL加到96孔高结合性能的板子中，板子用膜封住放到4℃18个小时。
2.配制2000mL清洗缓冲液至1x备用。
第二天：
3.包被的板子过夜后，将包被液倒掉，用清洗缓冲液每孔300μL/孔清洗3遍。
4.板子清洗过后加每孔200μL的封闭缓冲液，板子用膜封住。放到25℃孵育箱中孵育一个小时。
5.将孵育18个小时的细胞板子放到离心机中离心，温度：25℃，转速：2000转，时间：10分钟，升速：9，降速：1。离心后取每孔100μL细胞上清到3599细胞板中，后放到4℃冰箱备用。
6.将细胞上清用封闭缓冲液稀释40倍放到4℃冰箱待用，后配制标准品也放置4℃冰箱备用。
7.封闭完成后，将封闭液倒掉，用清洗缓冲液每孔300μL清洗3遍。
8.将稀释好的细胞上清样品以及标准品加到ELISA板子中，板子用膜封住。后放到25℃孵育箱中孵育两个小时。
9.将板中液体倒掉，用清洗缓冲液每孔300μL清洗5遍。
10.配制抗体，并每孔加入100μL，用封板膜封板。后放到25℃孵育箱中孵育一个小时。
11.将板中液体倒掉，用清洗缓冲液每孔300μL清洗7遍。
12.配制显色液，每孔加100μL。后避光放到25℃孵育箱中孵育半个小时。
13.每孔加50μL终止液，离心，温度：25℃，转速：1000转，时间：1分钟，升速：9，降速：9。
14.离心后30分钟内在Envision上读数，设置为吸收光450减去吸收光570的值为最终的原始数据 使用值。
数据处理：根据原始数据计算抑制率，抑制率计算公式为：
抑制率＝(1-(原始值-HPE平均值)/(ZPE平均值-HPE平均值))*100
其中ZPE为：0％抑制(75pg/mL LPS,0.1％DMSO)，HPE为：100％抑制(不含LPS，0.1％DMSO)。用XLfit统计软件进行数据分析。IC50的计算公式为:用4参数logistic剂量响应方程，绘制了被测化合物的浓度和抑制率(％)，并确定了50％抑制所需的化合物浓度(IC50)。
技术效果
本发明化合物可显著抑制p38/MK2的活性，对MK2/MK5有着优秀的选择性，可以显著抑制人外周血单个核细胞(hPBMC)中脂多糖(LPS)诱导TNF-α的表达，并且具有优异的药代动力学性质。
相关定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022107361-appb-000036
和楔形虚线键
Figure PCTCN2022107361-appb-000037
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022107361-appb-000038
和直形虚线键
Figure PCTCN2022107361-appb-000039
表示立体中心的相对构型，用波浪线
Figure PCTCN2022107361-appb-000040
表示楔形实线键
Figure PCTCN2022107361-appb-000041
或楔形虚线键
Figure PCTCN2022107361-appb-000042
或用波浪线
Figure PCTCN2022107361-appb-000043
表示直形实线键
Figure PCTCN2022107361-appb-000044
和直形虚线键
Figure PCTCN2022107361-appb-000045
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022107361-appb-000046
直形虚线键
Figure PCTCN2022107361-appb-000047
或波浪线
Figure PCTCN2022107361-appb-000048
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2022107361-appb-000049
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2022107361-appb-000050
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2022107361-appb-000051
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2022107361-appb-000052
Figure PCTCN2022107361-appb-000053
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022107361-appb-000054
仍包括
Figure PCTCN2022107361-appb-000055
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。
除非另有规定，术语“C 1-3烷基”本身或者与其他术语联合分别表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3烷氧基”本身或者与其他术语联合分别表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，“C 3-6环烷基”本身或者与其他术语联合分别表示由3至6个碳原子组成的饱和单环碳氢基团，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和或部分不饱和的单环环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。此外，就该“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基
Figure PCTCN2022107361-appb-000056
等。
除非另有规定，术语“5-10元杂环烷基”本身或者与其他术语联合分别表示由5至10个环原子组成的饱和或部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“5-10元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-10元杂环烷基包括5-8元、5-6元、6-10元、8-10元、6元、7元、8元、9元和10元杂环烷基等。5-10元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2- 噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基、二氧杂环庚烷基、
Figure PCTCN2022107361-appb-000057
等。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基和4H-1,2,4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯(OTf)；氯、溴、碘；磺酸酯基，如甲磺酸酯(OMs)、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯(OTs)等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基，如乙酰基(Ac)；芳基甲基，如苄基(Bn)、对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS) 等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022107361-appb-000058
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明采用下述缩略词：DMSO代表二甲基亚砜；MeOH代表甲醇；ACN代表乙腈；DEA代表二乙胺；CO 2代表二氧化碳；psi代表磅力/平方英寸；Ph代表苯基；SFC代表超临界流体色谱法。
本发明所使用的溶剂可经市售获得。化合物依据本领域常规命名原则或者使用
Figure PCTCN2022107361-appb-000059
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2022107361-appb-000060
Figure PCTCN2022107361-appb-000061
步骤1
将化合物1-1(10.00g,70.13mmol)和2,2-二甲基-6-(2-氧代丙基)-1,3-二噁英-4-酮(21.96g,119.23mmol)溶于二氧六环(100mL)中，加热至100℃搅拌3.5小时，然后加入浓硫酸(8.25g,84.16mmol,4.49mL)，反应液在100℃继续搅拌1小时。反应液减压浓缩，然后加入水(100mL)，在25℃下搅拌20min，将反应液过滤，收集滤饼，真空中干燥得化合物1-2，直接用于下一步反应。MS(ESI)m/z:251.1[M+H] +。
步骤2
将化合物1-2(14.50g,57.84mmol)、4-甲氧基苄氯(9.51g,60.73mmol)和18-冠-6-醚(229.33mg,867.64μmol)溶于N,N-二甲基甲酰胺(150mL)中，加入碳酸钾(19.99g,144.61mmol)。反应液加热至60℃搅拌4小时。反应液中加入水(400mL)，用乙酸乙酯(200mL)萃取3次，合并有机相，用饱和食盐水(200mL)洗涤2次，无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品经硅胶柱(石油醚：乙酸乙酯＝5:1至1:1)纯化得化合物1-3。MS(ESI)m/z:371.1[M+H] +。
步骤3
将化合物1-3(2.5g,6.74mmol)、三丁基(1-乙氧基乙烯)锡(2.68g,7.42mmol)和二(三苯基膦)二氯化钯(229.33mg,867.64μmol)溶于二氧六环(15mL)中。反应液微波加热至120℃搅拌3小时。反应液中加入氟化钾水溶液(100mL)，在室温下搅拌20分钟，过滤，滤液用乙酸乙酯(150mL)萃取2次，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品1-4。MS(ESI)m/z:407.3[M+H] +。
步骤4
将化合物1-4(20g,49.20mmol)溶于四氢呋喃(30mL)中，加入盐酸(4M,24.60mL)。反应液20℃ 搅拌10小时。反应液减压浓缩，所得粗品经硅胶柱(石油醚：乙酸乙酯＝1:1至二氯甲烷：甲醇＝20：1)纯化得化合物1-5。MS(ESI)m/z:259.2[M+H] +。
步骤5
将化合物1-5(0.3g,1.16mmol)溶于二氯甲烷(5mL)中，加入吡啶((275.64mg,3.48mmol)和对甲苯磺酰氯(253.98mg,3.60mmol)。反应液室温搅拌16小时。反应液减压浓缩，所得粗品经制备型薄层层析板(石油醚：乙酸乙酯＝1:2)纯化得化合物1-6。MS(ESI)m/z:412.9[M+H] +。
步骤6
将硫氢化钠(190.29mg,3.39mmol)溶于乙醇(3mL)中，加入化合物1-6(280mg,678.86μmol)的乙醇(3mL)溶液中。反应液室温搅拌24小时。将反应液过滤，滤液减压浓缩得粗品化合物1-7，直接用于下一步反应。MS(ESI)m/z:274.9[M+H] +。
步骤7
将化合物1-7(150mg,546.77μmol)和2-氯甲基-3,5-二氟吡啶(89.43mg,546.77μmol)溶于乙醇(3mL)中，加入碳酸钾(151.13mg,1.09mmol)和18-冠-6-醚(14.45mg,54.68μmol)。反应液在室温下搅拌24小时。将反应液减压浓缩。所得粗品经薄层层析硅胶板(石油醚：乙酸乙酯＝1:3)纯化得化合物1-8。MS(ESI)m/z:402.0[M+H] +。
步骤8
将化合物1-8(100mg,249.11μmol)溶于异丙醇(3mL)中，加入二氯乙酸(32.12mg,249.11μmol)和N-氯代丁二酰亚胺(36.59mg,274.02μmol)。反应液在60℃搅拌3小时。将反应液减压浓缩。所得粗品经薄层层析硅胶板(石油醚：乙酸乙酯＝1:3)纯化得化合物1-9。MS(ESI)m/z:435.9[M+H] +。
步骤9
将化合物1-9(45mg,103.24μmol)溶于N,N-二甲基甲酰胺(1.6mL)中，加入N,N-二甲基缩二甲醛(22.14mg,185.83μmol)，反应液在55-60℃搅拌15小时。加入另一批次的N,N-二甲基缩二甲醛(30.76mg,258.10μmol)，反应液在60℃搅拌5小时。将反应液减压浓缩得粗品化合物1-10。MS(ESI)m/z:491.0[M+H] +。
步骤10
将化合物1-10(50mg,101.84μmol)和2-羟基-2-甲基-丙脒(28.23mg,203.69μmol)溶于N,N-二甲基甲酰胺(2mL)中，加入碳酸钾(49.26mg,356.45μmol)，反应液在80℃下搅拌16小时。将反应液过滤，滤液减压浓缩，所得粗品经制备型高效液相分离纯化(柱子型号:Waters Xbridge 150*25mm*5μm；流动相:[水+0.05％(25％氨水)-乙腈]；梯度：乙腈％:32％-62％,9分钟)得化合物1。 1H NMR(400MHz,氘代DMSO)δppm 8.97(d,J＝5.2Hz,1H),8.87(s,1H),8.72(s,1H),8.56(d,J＝2.4Hz,1H),8.24(d,J＝5.2Hz,1H),8.02-8.09(m,1H),6.83(s,1H),5.24(br s,1H),4.62(s,2H),2.11(s,3H),1.97(s,3H),1.54(s,3H),1.52(s,3H).MS(ESI)m/z:530.1 [M+H] +。
实施例2
Figure PCTCN2022107361-appb-000062
步骤1
将化合物1-5(1g,3.87mmol)和2-氯甲基-3,5-二氟吡啶(696.58mg,4.26mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入碳酸钾(1.61g,11.62mmol)和18-冠-6-醚(102.34mg,387.19μmol)。反应液在60℃搅拌4小时。将反应液倒入水(30mL)中，用二氯甲烷(30mL)萃取3次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品化合物2-1，直接用于下一步反应。MS(ESI)m/z:386.0[M+H] +。
步骤2
将化合物2-1(1.50g,3.89mmol)溶于异丙醇(20mL)中，加入二氯乙酸(501.90mg,3.89mmol)和N-氯代丁二酰亚胺(571.73mg,4.28mmol)。反应液在60℃搅拌3小时。将反应液减压浓缩。所得粗品用二氯甲烷(20mL)稀释，用饱和碳酸氢钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品化合物2-2，直接用于下一步反应。MS(ESI)m/z:420.1[M+H] +。
步骤3
将化合物2-2(0.25g,595.51μmol)溶于N,N-二甲基甲酰胺(2.5mL)中，加入N,N-二甲基缩二甲醛 (127.73mg,1.07mmol)，反应液在55℃搅拌15小时。将反应液减压浓缩得粗品化合物2-3。MS(ESI)m/z:475.1[M+H] +。
步骤4
将化合物2-3(0.19g,400.10μmol)和1-苄氧基环丙烷甲脒(544.21mg,2.40mmol)溶于N,N-二甲基甲酰胺(3mL)中，加入碳酸钾(276.48mg,2.00mmol)，反应液在100℃下搅拌24小时。将反应液过滤，滤液减压浓缩，所得粗品经制备型薄层层析板(展开剂：乙酸乙酯)纯化得化合物2-4。
步骤5
将化合物2-4(170mg,282.38μmol)溶于四氢呋喃(3.5mL)和水(3.5mL)中，加入浓盐酸(12M,4.5mL)，反应液在60℃下搅拌12小时，再次加入浓盐酸(12M,2.5mL)，反应液在60℃下搅拌8小时。将反应液减压浓缩，所得粗品经制备型高效液相分离纯化(柱子型号:Waters Xbridge 150*25mm*5μm；流动相:[水+0.05％(25％氨水)-乙腈]；梯度：乙腈％:24％-54％)得化合物2。 1H NMR(400MHz,氘代DMSO)δppm8.88(d,J＝5.2Hz,1H),8.86(s,1H),8.61(d,J＝2.4Hz,1H),8.57(s,1H),8.15(d,J＝4.8Hz,1H),8.07-8.14(m,1H),6.84(s,1H),6.05(br s,1H),5.50(d,J＝1.6Hz,2H),2.11(s,3H),1.98(s,3H),1.32-1.43(m,2H),1.14-1.23(m,2H)；MS(ESI)m/z:512.1[M+H] +。
步骤6
化合物2(90mg,175.81μmol)使用手性分离(柱子型号:Daicel ChiralPak IG(250*30mm,10μm)；流动相:[A：二氧化碳，B：体积比甲醇：0.1％氨水＝3:1]；梯度(流动相B)：65％-65％)分离得到化合物2a和化合物2b。
化合物2a：(保留时间0.861分钟，ee＝100％,分析方法：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：体积比甲醇:乙腈(0.05％二乙醇胺)＝3:1]；梯度(流动相B)：60％) 1H NMR(400MHz,氘代DMSO)δppm 8.86-8.90(m,2H),8.61(d,J＝2.4Hz,1H),8.57(s,1H),8.16(d,J＝4.8Hz,1H),8.09-8.13(m,1H),6.85(s,1H),6.06(br s,1H),5.51(d,J＝1.6Hz,2H),2.11(s,3H),1.98(s,3H),1.36-1.39(m,2H),1.18-1.19(m,2H)；MS(ESI)m/z:512.1[M+H] +。
化合物2b:(保留时间1.757分钟，ee＝97.7％,分析方法：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：体积比甲醇:乙腈(0.05％二乙醇胺)＝3:1]；梯度(流动相B)：60％) 1H NMR(400MHz,氘代DMSO)δppm 8.86-8.90(m,2H),8.61(d,J＝2.4Hz,1H),8.57(s,1H),8.16(d,J＝5.2Hz,1H),8.09-8.13(m,1H),6.85(s,1H),6.06(br s,1H),5.51(d,J＝1.6Hz,2H),2.11(s,3H),1.98(s,3H),1.37-1.39(m,2H),1.18-1.19(m,2H)；MS(ESI)m/z:512.1[M+H] +。
实施例3
Figure PCTCN2022107361-appb-000063
步骤1
将化合物3-1(9.8g,139.82mmol)溶于二氯甲烷(150mL)中，冰浴降温至0℃，加入三甲基氰硅烷(13.87g,139.82mmol)和二碘化锌(4.46g,13.98mmol)，反应液在0℃搅拌15分钟，随后升至25℃搅拌3小时。反应液中加入水(26mL)和饱和碳酸氢钠(100mL)，搅拌10分钟，静置分液，水相用二氯甲烷(40mL x 2)萃取，有机相合并，饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品化合物3-2，直接用于下一步。
步骤2
将化合物3-2(5g,51.49mmol)溶于甲醇(10mL)中，加入盐酸甲醇溶液(3M,20mL)，反应液在25℃搅拌12小时。反应液过滤，滤饼减压浓缩得粗品化合物3-3的盐酸盐，直接用于下一步。
步骤3
将化合物3-3的盐酸盐粗品(0.32g)加入甲醇(1mL)中，冰浴下降温至0℃，加入饱和氨气甲醇溶液(2mL)，反应液在0℃搅拌10分钟，随后缓慢升温至50℃搅拌1小时。将反应液过滤，滤饼减压干燥得粗品化合物3-4，直接用于下一步。MS(ESI)m/z:115.1[M+H] +。
步骤4
将化合物2-3(50mg,101.84μmol)和化合物3-4(60.09mg,398.99μmol)溶于N,N-二甲基甲酰胺(2mL)中，加入碳酸钾(43.66mg,315.86μmol)，反应液在20℃下搅拌10分钟，随后升温至90℃继续搅拌12小时。将反应液加入20毫升冰水稀释，搅拌10分钟，乙酸乙酯萃取两次，每次4毫升，经饱和食盐水洗涤三次，每次5毫升，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经制备型高效液相分离纯化(柱子型号:Phenomenex Synergi Polar-RP 100*25mm*4μm；流动相:[水(0.05％三氟乙酸)-乙腈]；梯度(乙腈％):46％-66％)得到化合物3。MS(ESI)m/z:526.2[M+H] +。
步骤5
化合物3(50mg,95.02μmol)经超临界流体色谱柱分离(柱子型号:DAICEL CHIRALCEL OD(250mm*30mm,10μm)；流动相:[A：二氧化碳，B：0.1％氨水：乙醇＝1:3]；梯度：B％:45％-45％)分离得到化合物3a和化合物3b。
化合物3a：(保留时间0.935分钟，ee＝100％，分析方法：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：体积比甲醇:乙腈(0.05％二乙醇胺)＝3:1]；梯度：流动相B 40％)， 1H NMR(400MHz,氘代DMSO)δppm 9.02(d,J＝5.2Hz,1H),8.87(s,1H),8.63(s,1H),8.61(d,J＝2.4Hz,1H),8.26(d,J＝5.2Hz,1H),8.15-8.06(m,1H),6.84(s,1H),5.67(s,1H),5.50(s,2H),2.67-2.60(m,2H),2.33-2.25(m,2H),2.11(s,3H),1.98(s,3H),1.95-1.79(m,2H)；MS(ESI)m/z:526.1[M+H] +。
化合物3b：(保留时间1.613分钟,ee＝100％，分析方法：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：体积比甲醇:乙腈(0.05％二乙醇胺)＝3:1]；梯度：流动相B 40％)， 1H NMR(400MHz,氘代DMSO)δppm 9.02(d,J＝5.2Hz,1H),8.87(s,1H),8.63(s,1H),8.61(d,J＝2.8Hz,1H),8.26(d,J＝5.2Hz,1H),8.14-8.07(m,1H),6.84(s,1H),5.67(s,1H),5.49(s,2H),2.67-2.60(m,2H),2.32-2.25(m,2H),2.11(s,3H),1.98(s,3H),1.95-1.79(m,2H)；MS(ESI)m/z:526.1[M+H] +。
实施例4
Figure PCTCN2022107361-appb-000064
步骤1
将化合物4-1(9.75g,115.91mmol)溶于二氯甲烷(100mL)中，冰浴降温至0℃，加入三甲基氰硅烷(13.80g,139.09mmol)和二碘化锌(3.70g,11.59mmol)，随后升至25℃搅拌18小时。反应液减压浓缩，剩余物中加入乙酸乙酯(10mL)和1N盐酸(10mL)，搅拌10分钟，静置分液，水相用乙酸乙酯(10mL)萃取，有机相合并，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经过柱层析分离纯化(石油醚：乙酸乙酯＝10:1到3:1)后得到化合物4-2。
步骤2
将化合物4-2(1g,9.00mmol,1eq)溶于甲醇(20mL)中，0℃下通入氯化氢气体20分钟，反应液在0℃搅拌10小时。反应液减压浓缩得粗品化合物4-3的盐酸盐，直接用于下一步。MS(ESI)m/z:144.2[M+H] +。
步骤3：
将化合物4-3的盐酸盐(0.5g)悬浮于甲醇(10mL)中，冰浴下降温至0℃，通入氨气20分钟，随后缓慢升温至20℃搅拌16小时。将反应液减压浓缩得粗品化合物4-4，直接用于下一步。MS(ESI)m/z:129.3[M+H] +。
步骤4：
将化合物2-3(100mg,210.58μmol,1eq)和化合物4-4(173.34mg,1.05mmol,5eq)溶于N,N-二甲基甲酰胺(2mL)中，加入碳酸钾(116.42mg,842.32μmol,4eq)，反应液在100℃下搅拌12小时。将反应液过滤后，滤液经制备型高效液相分离纯化(柱子型号:Waters Xbridge 150*25mm*5μm；流动相:[水+0.05％(25％氨水)-乙腈]；梯度(B％):31％-61％)得到化合物4。MS(ESI)m/z:540.1[M+H] +。
步骤5：
化合物4(50mg,92.60μmol)经超临界流体色谱柱分离(柱子型号:DAICEL CHIRALCEL OD(250mm*30mm,10μm)；流动相:[A：二氧化碳，B：0.1％氨水-甲醇]；梯度：B％:65％-65％)分离得到化合物4a()和化合物4b。
化合物4a：(保留时间0.907分钟，ee＝99.0％，分析方法：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：体积比：甲醇+乙腈(0.05％二乙醇胺)＝3:1]；梯度：流动相B 60％)； 1H NMR(400MHz,氘代DMSO)δppm 8.96(d,J＝4.8Hz,1H),8.86(s,1H),8.65(s,1H),8.61(d,J＝2.4Hz,1H),8.23(d,J＝4.8Hz,1H),8.07-8.14(m,1H),6.86(s,1H),5.49(s,2H),2.12(s,3H),1.98(s,3H),1.96-1.90(m,9H),MS(ESI)m/z:540.1[M+H] +。
化合物4b：(保留时间1.659分钟,ee＝96.4％，分析方法：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：体积比：甲醇：乙腈(0.05％二乙醇胺)＝3:1]；梯度：流动相B 60％)； 1H NMR(400MHz,氘代DMSO)δppm 8.98(d,J＝5.2Hz,1H),8.87(s,1H),8.66(s,1H),8.62(d,J＝2.4Hz,1H),8.23(d,J＝5.2Hz,1H),8.09-8.14(m,1H),6.85(s,1H),5.50(s,2H),2.11(s,3H),1.99(s,3H),1.93-1.89(m,9H)MS(ESI)m/z:540.1[M+H] +。
实施例5
Figure PCTCN2022107361-appb-000065
步骤1：
将化合物5-1(10g,101.89mmol)溶于二氯甲烷(150mL)中，冰浴降温至0℃，加入三甲基氰硅烷(13.88g,139.88mmol)和二碘化锌(3.25g,10.19mmol)，随后氮气保护下升至25℃搅拌18小时。反应液减压浓缩得粗品化合物5-2，直接用于下一步。
步骤2：
将化合物5-2(10g,50.67mmol,1eq)溶于甲醇(80mL)中，-30℃下通入氯化氢气体1小时，随后反应液在25℃下搅拌16小时。反应液减压浓缩得粗品化合物5-3的盐酸盐，直接用于下一步。MS(ESI)m/z: 158.2[M+H] +。
步骤3：
将化合物5-3的盐酸盐(8g)悬浮于甲醇(100mL)中，-30℃通入氨气30分钟，反应液缓慢升温至20℃并搅拌12小时。将反应液减压浓缩得粗品化合物5-4，直接用于下一步。MS(ESI)m/z:143.2[M+H] +
步骤4：
将化合物2-3(50mg,105.29μmolq)和化合物5-4(86mg,604.79μmol)溶于N,N-二甲基甲酰胺(1.5mL)中，20℃下加入碳酸钾(43.65mg,315.86μmol)，随后升温至100℃搅拌16小时。将反应液过滤，滤液减压浓缩，所得粗品经制备型高效液相分离纯化(柱子型号:Waters Xbridge 150*25mm*5μm；流动相:[水+0.05％(25％氨水)-乙腈]；梯度(乙腈％):43％-73％)得到化合物5。MS(ESI)m/z:554.2[M+H] +。
步骤5：
化合物5(50mg,90.22μmol)经超临界流体色谱柱分离(柱子型号:DAICEL CHIRALPAK IC(250mm*30mm,10μm)；流动相:[A：二氧化碳，B：体积比乙腈：异丙醇(0.1％氨水)＝3:1]；梯度：B％:70％-70％)分离得到化合物5a和化合物5b。
化合物5a：(保留时间0.591分钟，ee＝100％,分析方法：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：体积比：异丙醇：乙腈(0.05％二乙醇胺)＝3:1]；梯度(流动相B)：60％) 1H NMR(400MHz,氘代DMSO)δppm 8.98(d,J＝5.2Hz,1H),8.86(s,1H),8.66(s,1H),8.62(s,1H),8.24(d,J＝4.8Hz,1H),8.15-8.08(m,1H),6.85(s,1H),5.50(s,2H),5.02(s,1H),2.11(s,3H),2.05-2.00(m,1H),1.98(s,3H),1.77-1.65(m,5H),1.58-1.51(m,3H),1.31-1.23(m,1H).MS(ESI)m/z:554.2[M+H] +。
化合物5b：(保留时间1.589分钟，ee＝98.6％,分析方法：柱子型号:Chiralpak IG-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：体积比：异丙醇：乙腈(0.05％二乙醇胺)＝3：1]；梯度(流动相B)：60％) 1H NMR(400MHz,氘代DMSO)δppm 8.98(d,J＝5.2Hz,1H),8.86(s,1H),8.66(s,1H),8.62(s,1H),8.24(d,J＝5.2Hz,1H),8.16-8.06(m,1H),6.85(s,1H),5.50(s,2H),5.02(s,1H),2.11(s,3H),2.05-2.00(m,1H),1.98(s,3H),1.79-1.49(m,8H),1.34-1.22(m,1H).MS(ESI)m/z:554.2[M+H] +。
实施例6
Figure PCTCN2022107361-appb-000066
Figure PCTCN2022107361-appb-000067
步骤1：
将化合物6-1(10g,99.88mmol)溶于二氯甲烷(100mL)中，冰浴降温至0℃，加入三甲基氰硅烷(11.89g,119.86mmol)和二碘化锌(3.19g,9.99mmol)，反应液缓慢升至25℃并搅拌12小时。反应液旋干后，加入乙酸乙酯(10mL)和1N盐酸(10mL)，静置分液，水相用乙酸乙酯(10mL)萃取，有机相合并，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后，剩余物经过柱层析分离纯化(石油醚：乙酸乙酯＝10:1到3:1)后得到化合物6-2。
步骤2：
将化合物6-2(5g,25.09mmol,1eq)溶于甲醇(50mL)中，0℃下持续通入氯化氢气体30分钟，反应液在10℃下搅拌12小时。反应液减压浓缩得粗品化合物6-3的盐酸盐，直接用于下一步。MS(ESI)m/z:160.1[M+H] +。
步骤3：
将化合物6-3的盐酸盐(5g)悬浮于甲醇(50mL)中，0℃下持续通入氨气气体30分钟，反应液缓慢升至20℃并搅拌12小时。反应液减压浓缩后经制备型高效液相分离纯化(柱子型号:Waters Atlantis T3 150*30mm*5μm；流动相:[水(0.05％甲酸)-乙腈]；梯度(乙腈％):1％-20％)得到化合物6-4。MS(ESI)m/z:145.2[M+H] +。
步骤4：
将化合物2-3(0.21g,442.21μmol)和化合物6-4(382.52mg,2.65mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入碳酸钾(305.59mg,2.21mmol)，反应液在100℃下搅拌4小时。将反应液过滤后，滤液减压浓缩，所得粗品经制备型高效液相分离纯化(柱子型号:3_Phenomenex Luna C18 75*30mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；梯度(乙腈％):27％-47％)得到化合物6。MS(ESI)m/z:556.0[M+H] +。
步骤5：
化合物6(50mg,89.93μmol)经超临界流体色谱柱分离(柱子型号:DAICEL CHIRALCEL OD(250mm*30mm,10μm)；流动相:[A：二氧化碳，B：0.1％氨水-乙醇]；梯度：B％:60％-60％)分离得到手性异构体化合物6a和化合物6b。
化合物6a：(保留时间1.822分钟，ee＝100％,分析方法：柱子型号:Chiralpak OD-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：甲醇(0.05％二乙醇胺)]；梯度(流动相B)：5％-40％) 1H NMR(400MHz,氘代DMSO)δppm 9.01(d,J＝5.2Hz,1H),8.86(s,1H),8.63(s,1H),8.61(d,J＝2.4Hz,1H),8.25(d,J＝5.2Hz,1H),8.06-8.14(m,1H),6.84(s,1H),5.49(s,2H),5.33(s,1H),3.73-3.86(m,4H),2.19-2.31(m,2H),2.11(s,3H),1.98(s,3H),1.66-1.69(m,2H)；MS(ESI)m/z:556.0[M+H] +。
化合物6b：(保留时间2.469分钟，ee＝100％,分析方法：柱子型号:Chiralpak OD-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：甲醇(0.05％二乙醇胺)]；梯度(流动相B)：5％-40％) 1H NMR(400MHz,氘代DMSO)δppm 9.01(d,J＝5.2Hz,1H),8.87(s,1H),8.64(s,1H),8.62(d,J＝2.0Hz,1H),8.27(d,J＝5.2Hz,1H),8.06-8.17(m,1H),6.85(s,1H),5.50(s,2H),5.33(s,1H),3.69-3.86(m,4H),2.17-2.32(m,2H),2.11(s,3H),1.98(s,3H),1.67-1.70(m,2H)；MS(ESI)m/z:556.0[M+H] +。
实施例7
Figure PCTCN2022107361-appb-000068
Figure PCTCN2022107361-appb-000069
步骤1：
将化合物7-1(10g,116.16mmol)溶于二氯甲烷(100mL)中，冰浴降温至0℃，加入三甲基氰硅烷(13.83g,139.39mmol)和二碘化锌(3.71g,11.62mmol)，反应液在25℃下搅拌12小时。反应液浓缩后，加入乙酸乙酯(10mL)和1N盐酸(10mL)，静置分液，水相用乙酸乙酯(10mL)萃取，有机相合并，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，过滤，滤液减压浓缩后，剩余物经过柱层析分离纯化(石油醚：乙酸乙酯＝10:1到3:1)后得到化合物7-2。
步骤2：
将化合物7-2(5g,26.98mmol,1eq)溶于甲醇(50mL)中，0℃下持续通入氯化氢气体30分钟，反应液在10℃下搅拌12小时。反应液减压浓缩得粗品化合物7-3的盐酸盐，直接用于下一步。MS(ESI)m/z:146.1[M+H] +
步骤3：
将化合物7-3的盐酸盐(8.2g)加入甲醇(50mL)中，0℃下持续通入氨气气体30分钟，反应液缓慢升至20℃并搅拌2小时。反应液减压浓缩后经制备型高效液相分离纯化(柱子型号:Waters Atlantis T3 150*30mm*5μm；流动相:[水(0.05％甲酸)-乙腈]；梯度(乙腈％):1％-20％)得到化合物7-4。
步骤4：
将化合物2-3(0.3g,631.73μmol)和化合物7-4(246.65mg,1.90mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入碳酸钾(218.28mg,1.58mmol)，反应液在100℃下搅拌4小时。将反应液过滤，滤液减压浓缩，所得粗品经制备型高效液相分离纯化(柱子型号:3_Phenomenex Luna C18 75*30mm*3μm；流动相:[水 (0.05％三氟乙酸)-乙腈]；梯度(乙腈％):33％-53％)得到化合物7。MS(ESI)m/z:542.0[M+H] +。
步骤5：
将化合物7(50mg)经超临界流体色谱柱分离(柱子型号:DAICEL CHIRALCEL OD(250mm*30mm,10μm)；流动相:[A：二氧化碳，B：体积比：0.1％氨水:甲醇＝1：3]；梯度：B％:70％-70％)分离得到化合物7a和7b的混合物，化合物7c和化合物7d。随后化合物7a和7b的混合物经超临界流体色谱柱分离(柱子型号:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[A：二氧化碳，B：异丙醇:乙腈(0.1％氨水)＝3:1]；梯度：B％:70％-70％)分离得到化合物7a和化合物7b。
化合物7a:(保留时间0.632分钟,ee＝100％,分析方法：柱子型号:Chiralcel OD-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：甲醇(0.05％二乙醇胺)]；梯度：流动相B为40％)； 1H NMR(400MHz,氘代DMSO)δppm 9.01(d,J＝4.8Hz,1H),8.88(s,1H),8.62(d,J＝2.0Hz,1H),8.28(d,J＝5.2Hz,1H),8.08-8.19(m,1H),6.86(s,1H),5.71(s,1H),5.50(s,2H),4.08-4.11(m,1H),3.99-4.05(m,2H),3.88(d,J＝8.0Hz,1H),2.12-2.19(m,2H),2.11(s,3H),1.98(s,3H)MS(ESI)m/z:542.0[M+H] +。
化合物7b:(保留时间0.706分钟,ee＝75％,分析方法：柱子型号:Chiralcel OD-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：甲醇(0.05％二乙醇胺)]；梯度：流动相B 40％) 1H NMR(400MHz,氘代DMSO)δppm 9.01(d,J＝5.2Hz,1H),8.88(s,1H),8.62(d,J＝5.2Hz,2H),8.28(d,J＝5.2Hz,1H),8.08-8.19(m,1H),6.89(s,1H),5.77(s,1H),5.50(s,2H),4.14(d,J＝8.8Hz,1H),3.97-4.05(m,2H),3.87(d,J＝8.0Hz,1H),2.12-2.22(m,2H),2.11(s,3H),1.98(s,3H)MS(ESI)m/z:542.0[M+H] +。
化合物7c:(保留时间1.383分钟,ee＝97.9％,分析方法：柱子型号:Chiralcel OD-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：甲醇(0.05％二乙醇胺)]；梯度：流动相B 40％) 1H NMR(400MHz,氘代DMSO)δppm 9.00(d,J＝5.2Hz,1H),8.87(s,1H),8.62(d,J＝4.0Hz,2H),8.28(d,J＝5.2Hz,1H),8.08-8.12(m,1H),6.84(s,1H),5.68(s,1H),5.49(s,2H),4.14(d,J＝8.8Hz,1H),3.97-4.05(m,2H),3.87(d,J＝8.10Hz,1H),2.12-2.22(m,2H),2.11(s,3H),1.97(s,3H)MS(ESI)m/z:542.0[M+H] +。
化合物7d:(保留时间2.733分钟,ee＝99.4％,分析方法：柱子型号:Chiralcel OD-3 50×4.6mm I.D.,3μm)；流动相:[A：二氧化碳，B：甲醇(0.05％二乙醇胺)]；梯度：流动相B 40％) 1H NMR(400MHz,氘代DMSO)δppm 9.01(d,J＝5.2Hz,1H),8.87(s,1H),8.62(br s,2H),8.28d,J＝5.2Hz,1H),8.09–8.11(m,1H),6.84(s,1H),5.68(s,1H),5.50(s,2H),4.07-4.13(m,1H),3.98-4.04(m,2H),3.86(J＝8.0Hz,1H),2.12-2.18(m,2H),2.11(s,3H),1.98(s,3H)MS(ESI)m/z:542.0[M+H] +。
生物测试数据
实验例1：LPS刺激人源PBMC TNF-α表达的影响体外药效试验
实验目的：研究本发明化合物对在人外周血单个核细胞(hPBMC)中脂多糖(LPS)诱导TNF-α表达的影响。
实验方案：
PBMC实验：PBMC细胞以100000个/100μL/孔的密度种入细胞培养级别的96孔板中，细胞培养基是加10％血清的RPMI-1640。在37℃，5％CO 2培养箱中培养2个小时。在细胞里加入16.8μL/孔的待测化合物后在37℃，5％CO 2培养箱中培养60分钟，后在细胞里加入16.8μL/孔的LPS在37℃，5％CO 2培养箱中培养18小时，最终DMSO浓度为0.1％。
化合物剂量梯度稀释：第一步将化合物从储藏浓度用100％的DMSO稀释到1.5mM。第二步将稀释过的化合物作为第一个点用100％DMSO 3倍稀释9个点。第三步用不含有血清的培养基125倍稀释，此时DMSO的浓度是0.8％。然后转16.8μL已经用培养基稀释好的化合物到100μL的细胞板里。加好化合物后将细胞板放入37℃，5％CO 2培养箱中孵育1个小时。
LPS稀释：第一步将LPS用超纯水稀释到储藏浓度1mg/mL。第二步储藏浓度的LPS用不含血清的培养基稀释到1μg/mL。第三步用不含有血清的培养基1666.666倍稀释。然后转16.8μL已经用培养基稀释好的LPS到116.8μL的细胞板里，此时DMSO终浓度是0.1％，加好LPS后将细胞板放入37℃，5％CO2培养箱中孵育18个小时。
ELISA实验：
第一天：
1.将TNF-α抗体在包被液中稀释至1x，然后每孔100μL加到96孔高结合性能的板子中，板子用膜封住放到4℃18个小时。
2.配制2000mL清洗缓冲液至1x备用。
第二天：
3.包被的板子过夜后，将包被液倒掉，用清洗缓冲液每孔300μL/孔清洗3遍。
4.板子清洗过后加每孔200μL的封闭缓冲液，板子用膜封住。放到25℃孵育箱中孵育一个小时。
5.将孵育18个小时的细胞板子放到离心机中离心，温度：25℃，转速：2000转，时间：10分钟，升速：9，降速：1。离心后取每孔100μL细胞上清到3599细胞板中，后放到4℃冰箱备用。
6.将细胞上清用封闭缓冲液稀释40倍放到4℃冰箱待用，后配制标准品也放置4℃冰箱备用。
7.封闭完成后，将封闭液倒掉，用清洗缓冲液每孔300μL清洗3遍。
8.将稀释好的细胞上清样品以及标准品加到ELISA板子中，板子用膜封住。后放到25℃孵育箱中孵育两个小时。
9.将板中液体倒掉，用清洗缓冲液每孔300μL清洗5遍。
10.配制抗体，并每孔加入100μL，用封板膜封板。后放到25℃孵育箱中孵育一个小时。
11.将板中液体倒掉，用清洗缓冲液每孔300μL清洗7遍。
12.配制显色液，每孔加100μL。后避光放到25℃孵育箱中孵育半个小时。
13.每孔加50μL终止液，离心，温度：25℃，转速：1000转，时间：1分钟，升速：9，降速：9。
14.离心后30分钟内在Envision上读数，设置为吸收光450减去吸收光570的值为最终的原始数据使用值。
数据处理：根据原始数据计算抑制率，抑制率计算公式为：
抑制率＝(1-(原始值-HPE平均值)/(ZPE平均值-HPE平均值))*100
其中ZPE为：0％抑制(75pg/mL LPS,0.1％DMSO)，HPE为：100％抑制(不含LPS，0.1％DMSO)。
用XLfit统计软件进行数据分析。IC 50的计算公式为:用4参数logistic剂量响应方程，绘制了被测化合物的浓度和抑制率(％)，并确定了50％抑制所需的化合物浓度(IC 50)。
实验结果：实验结果见表1。
表1本发明化合物抑制LPS刺激人源PBMC TNF-α表达的测试结果
化合物 IC 50(nM)
2a 10
3a 13
4a 10
5a 38
6a 12
7a 44
结论：本发明化合物可以显著抑制人外周血单个核细胞(hPBMC)中脂多糖(LPS)诱导的炎症因子TNF-α的分泌。
实验例2：MK2/MK5选择性试验
试验方案：
1.向试验孔中加入5μL/孔2X MAPK14(p38α)。
2.使用声学技术(Echo550)将化合物溶于100％DMSO中，并在室温下孵育20分钟。
3.将含有非活性MAPKAPK2或MAPKAPK5、FITC-KKKALSRQLSVAA(热休克蛋白27肽)和ATP与2X MAPKAPK2或MAPKAPK5底物混合。
4.向测定孔中加入5μL/孔2X MAPKAPK2或MAPKAPK5底物混合物(非活性MAPKAPK2或MAPKAPK5，FITC-KKKALSRQLSVAA，ATP)。
5.室温下孵育2小时。
6.向测定孔中加入30μL/孔1X IMAP结合溶液。
7.室温下孵育1小时。
8.EnVision中的FP信号测量(Ex＝485nm；Em＝S-pol和P-pol 535nm)。
p38α滴定：
试验条件：MAPK14(p38α)：10个浓度，从5nM开始，以2倍稀释；
MAPKAPK2，非活性：1nM或MAPKAPK5，非活性：10nM；
FITC-KKKALSRQLSVAA：1μM；
ATP：10μM；
缓冲液：20mM HEPES pH 7.5，10mM MgCl 2，0.05％Brij-35，0.01％BSA(牛血清白蛋白)，1mM DTT(二硫苏糖醇)，1％DMSO；
检测：1X IMAP结合溶液，75％渐进结合缓冲液A，25％渐进结合缓冲液B，1/300渐进结合试剂；
反应时间：2小时；
MAPKAPK2和MAPKAPK5化合物IC 50测定：
试验条件：MAPK14(p38α)：0.3nM和0.5nM；
MAPKAPK2，非活性：1nM或MAPKAPK5，非活性：10nM；
FITC-KKKALSRQLSVAA：1μM；
ATP：10μM；
缓冲液：20mM HEPES pH 7.5，10mM MgCl 2，0.05％Brij-35，0.01％BSA，1mM DTT；
试验中的DMSO：1％；
检测：1X IMAP结合溶液，75％渐进结合缓冲液A，25％渐进结合缓冲液B，1/300渐进结合试剂；
反应时间：1或2小时
化合物配置：
用DMSO将化合物溶解至10mM储备液中；
从10μM开始进行4倍连续稀释，在10个浓度IC 50下测试，复孔。
实验结果：实验结果见表2。
表2本发明化合物对MK2/MK5的抑制结果
化合物 MK2IC 50(nM) MK5IC 50(nM) MK2/MK5选择性
2a 0.99 2530 2555倍
结论：本发明化合物可以有效抑制p38/MK2的活性，并且对MK2/MK5有着优秀的选择性。
实验例3：小鼠药代动力学评价
采用CD-1(ICR)小鼠(雄性，25-35g，5～11周龄，维通利华北京)测试化合物的体内药代动力学性质，实验方法如下：
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶 液给予小鼠单次静脉注射(IV)及单次口服(PO)给药。溶媒为20％SBE-β-CD水溶液。分别于给药后24小时内(口服：0.25、0.5、1、2、4、8、24h，静注：0.25、0.5、1、2、4、6、8、24h)的全血样品，每次血液采集(每个时间点0.025mL)将从每只动物的隐静脉或其他合适部位进行到预冷的商用EDTA-K2管中，并置于湿冰上直至离心。血液样品将在4℃、3200克条件下离心10分钟后得到血浆。将收集的血浆转移至预先标记的的96孔板或聚丙烯管中，在干冰上快速冷却并保持在-60℃或更低直至LC-MS/MS定量分析血药浓度，并计算药代参数，如达峰浓度(C max)，分布体积(Vd ss)清除率(Cl)，半衰期(T 1/2)，药时曲线下面积(AUC 0-last)，生物利用度(F)等。测试结果见表3。
表3本发明化合物药代动力学数据
Figure PCTCN2022107361-appb-000070
结论：本发明化合物具有优异的小鼠药代动力学性质。
实验例4：大鼠药代动力学评价
采用SD大鼠(雄性,250-350g,5～11周龄，维通利华平湖)测试化合物的体内药代动力学性质，实验方法如下：
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液给予小鼠单次静脉注射(IV)及单次口服(PO)给药。溶媒为20％SBE-β-CD水溶液。分别于给药后24小时内(口服：0.25、0.5、1、2、4、8、24h，静注：0.25、0.5、1、2、4、6、8、24h)的全血样品，每次血液采集(每个时间点0.2mL)将从每只动物的隐静脉或其他合适部位进行到预冷的商用EDTA-K2管中，并置于湿冰上直至离心。血液样品将在4℃、3200克条件下离心10分钟后得到血浆。将收集的血浆转移至预先标记的的96孔板或聚丙烯管中，在干冰上快速冷却并保持在-60℃或更低直至LC-MS/MS定量分析血药浓度，并计算药代参数，如达峰浓度，达峰时间，清除率，半衰期，药时曲线下面积，生物利用度等。
结论：本发明化合物具有优异的大鼠药代动力学性质。
实验例5：犬药代动力学评价
采用比格犬(雄性,8-12kg,5～11周龄，Marshell)测试化合物的体内药代动力学性质，实验方法如下：
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液给予小鼠单次静脉注射(IV)及单次口服(PO)给药。溶媒为20％SBE-β-CD水溶液。分别于给药后24小时内(口服：0.25、0.5、1、2、4、8、24h，静注：0.25、0.5、1、2、4、6、8、24h)的全血样品，每次血液采集(每个时间点0.5mL)将从每只动物的隐静脉或其他合适部位进行到预冷的商用EDTA-K2管中，并置于湿冰上直至离心。血液样品将收集1小时内2-8℃、3200克条件下离心10分钟后得到血浆。将约0.2mL血浆样品等分成0.1mL左右(一份用于BA，另一份备用)转移到标记的聚丙烯微量离心管中，并冷冻储存在冷冻箱中，保持在-60℃或更低，直至生物分析。通过LC-MS/MS定量分析血药浓度，并计算药代参数，如达峰浓度，达峰时间，清除率，半衰期，药时曲线下面积，生物利用度等。
结论：本发明化合物具有优异的犬药代动力学性质。

Claims (16)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022107361-appb-100001
    其中，
    T 1选自N和CH；
    L 1选自O和S；
    各R 1、各R 2和各R 3分别独立地选自H、F、Cl、Br、I、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；
    或者，结构单元
    Figure PCTCN2022107361-appb-100002
    选自
    Figure PCTCN2022107361-appb-100003
    R 2和R 3分别独立地选自H、F、Cl、Br、I、CN、CH 3和OCH 3，环A选自5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R b取代；
    R 4选自-NR 5R 6、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、4-6元杂环烷基和5-6元杂芳基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、4-6元杂环烷基和5-6元杂芳基分别独立地任选被1、2或3个R c取代；
    R 5和R 6分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R d取代；
    或者，R 5和R 6与它们共同连接的N原子一起形成4-6元杂环烷基或5-6元杂芳基，所述4-6元杂环烷基或5-6元杂芳基分别独立地任选被1、2或3个R e取代；
    条件是，当L 1选自O，且T 1选自CH时，满足下列条件之一：
    (1)R 1、R 2、R 3和R 4中至少有一个选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；
    (2)结构单元
    Figure PCTCN2022107361-appb-100004
    选自
    Figure PCTCN2022107361-appb-100005
    R 2和R 3分别独立地选自H、F、Cl、Br、I、CN、CH 3和OCH 3，环A选自5-10元杂环烷基，所述5-10元杂环烷基任选被1、2或3个R b取代；
    (3)R 4选自-NR 5R 6、CN和C 1-3烷氧基，所述C 1-3烷氧基任选被1、2或3个R c取代；
    n、m和p分别独立地选自0、1、2和3；
    各R a、各R b、各R c、各R d和各R e分别独立地选自F、Cl、Br、I、OH、CH 3和OCH 3；
    所述“4-6元杂环烷基”包含1或2个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团；
    所述“5-10元杂环烷基”和“5-6元杂芳基”分别独立地包含1、2或3个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，各R 1、各R 2和各R 3分别独立地选自H、F、Cl、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、环丙基和环丁基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、OCH 3、OCH 2CH 3、环丙基和环丁基分别独立地任选被1、2或3个R a取代。
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，各R 1分别独立地选自H和F。
  4. 根据权利要求2所述化合物或其药学上可接受的盐，其中，各R 2分别独立地选自H、F、Cl、CH 3和
    Figure PCTCN2022107361-appb-100006
  5. 根据权利要求2所述化合物或其药学上可接受的盐，其中，各R 3分别独立地选自H和CH 3。
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022107361-appb-100007
    选自
    Figure PCTCN2022107361-appb-100008
  7. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4选自NH 2、-NHCH 3、-N(CH 3) 2、
    Figure PCTCN2022107361-appb-100009
    CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、吡咯烷基、哌啶基、***啉基、吡咯基、吡唑基、咪唑基、***基、噻唑基、噁唑基和吡啶基，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、吡咯烷基、哌啶基、***啉基、吡咯基、吡唑基、咪唑基、***基、噻唑基、噁唑基和吡啶基任选被1、2或3个R c取代。
  8. 根据权利要求7所述化合物或其药学上可接受的盐，其中，R 4选自NH 2、
    Figure PCTCN2022107361-appb-100010
    Figure PCTCN2022107361-appb-100011
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，R 4选自
    Figure PCTCN2022107361-appb-100012
    Figure PCTCN2022107361-appb-100013
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，L 1选自O。
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中，T 1选自CH。
  12. 根据权利要求1所述化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022107361-appb-100014
    其中，
    环B选自C 3-6环烷基和4-6元杂环烷基，所述C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R c取代；
    各R 2和各R 3分别独立地选自H、F、Cl、Br、I、CN、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R a取代；
    L 1、T 1、各R 1、各R a、各R c、n、m和p如权利要求1所定义。
  13. 根据权利要求12所述化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022107361-appb-100015
    其中，环B、L 1、T 1、各R 1、各R 2和R 3如权利要求12所定义。
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022107361-appb-100016
    其中，环B、L 1、T 1、各R 1、各R 2和R 3如权利要求12所定义。
  15. 下列所示化合物或其药学上可接受的盐，
    Figure PCTCN2022107361-appb-100017
    Figure PCTCN2022107361-appb-100018
  16. 根据权利要求15所述化合物或其药学上可接受的盐，其化合物选自，
    Figure PCTCN2022107361-appb-100019
    Figure PCTCN2022107361-appb-100020
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Citations (3)

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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 (en) * 2019-07-31 2021-02-04 Aclaris Therapeutics, Inc. Deuterated mk2 pathway inhibitors and methods of using the same

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 (en) * 2019-07-31 2021-02-04 Aclaris Therapeutics, Inc. Deuterated mk2 pathway inhibitors and methods of using the same

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