WO2020156311A1 - 一种哒嗪类衍生物抑制剂、其制备方法和应用 - Google Patents

一种哒嗪类衍生物抑制剂、其制备方法和应用 Download PDF

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WO2020156311A1
WO2020156311A1 PCT/CN2020/073152 CN2020073152W WO2020156311A1 WO 2020156311 A1 WO2020156311 A1 WO 2020156311A1 CN 2020073152 W CN2020073152 W CN 2020073152W WO 2020156311 A1 WO2020156311 A1 WO 2020156311A1
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alkyl
cycloalkyl
group
amino
cyano
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PCT/CN2020/073152
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English (en)
French (fr)
Chinese (zh)
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高鹏
曾蜜
谭松良
孙广俊
王少宝
修文华
包如迪
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to JP2021542491A priority Critical patent/JP2022524279A/ja
Priority to KR1020217025392A priority patent/KR20210119426A/ko
Priority to CN202211231199.XA priority patent/CN115448910B/zh
Priority to CN202080001485.XA priority patent/CN111757878B/zh
Priority to CN202310827414.0A priority patent/CN117263918A/zh
Publication of WO2020156311A1 publication Critical patent/WO2020156311A1/zh

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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a pyridazine derivative inhibitor and a preparation method and application thereof.
  • Janus kinase is an intracellular non-receptor tyrosine kinase that mediates the signal transduction and activation of various cytokines.
  • the JAK kinase family is divided into four subtypes: JAK1, JAK2, JAK3 and TYK2. Each subtype mediates different types of cytokine signaling pathways.
  • JAK-1, JAK-2 and TYK-2 are found in all tissues and cells of the human body.
  • Expression, JAK-3 is mainly expressed in hematopoietic tissue cells.
  • the common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK.
  • the receptor-coupled JAKs When the cytokine receptor binds to its ligand, the receptor-coupled JAKs are activated, and the receptor is phosphorylated.
  • the phosphorylated tyrosine site can bind to the STAT protein containing the SH2 domain, so that STAT is recruited to the receptor and phosphorylated by JAKs, and then phosphotyrosine mediates STAT dimerization.
  • the activated STAT dimer transfers to the nucleus and activates its target gene transcription, thereby regulating the growth, activation, and Differentiation and other functions.
  • TYK2 is the first subtype discovered in the JAK family. It mediates the functions of cytokines such as IFN- ⁇ , IL-6, IL-10, IL-12 and IL-23. Studies have shown that TYK2 deletion mutations can effectively inhibit allergies and autoimmunity. And inflammation and other immune diseases. IL-23 plays a vital role in the occurrence and development of psoriasis. The latest research shows that the pathogenesis of psoriasis is that the endogenous unknown antigen activates antigen-presenting cells APC to secrete IL-23 and IL-23 activates.
  • TYK2 and JAK2 jointly mediate the downstream signaling pathway of IL-23. Inhibition of JAK2 can cause anemia and other blood-related side effects. Therefore, targeting TYK2 is a good strategy for the treatment of psoriasis by inhibiting the IL-23 signaling pathway.
  • TYK2 inhibitors such as Tofacitinib
  • Tofacitinib are all non-selective JAK inhibitors. They are the first oral JAK inhibitors and have significant inhibitory activity against JAK1, 2, and 3 subtypes. Inhibition of the activity of other subtypes such as JAK1, JAK2 and JAK3 increases the efficacy of tofacitinib, but it also brings more serious side effects. Adverse reactions include infection, tuberculosis, tumor, anemia, liver damage and increased cholesterol.
  • JAK2 activity is related to erythroid cell differentiation and lipid metabolism
  • some of the above-mentioned anemia and other adverse reactions are believed to be related to the insufficient selectivity of Tofacitinib to JAK-2, which is caused by the non-selective inhibition of the drug.
  • TYK2 there is no selective inhibitor of TYK2 on the market.
  • Early JAK inhibitors mainly competed for the binding of the kinase domain and ATP. Therefore, there is a general problem of low selectivity.
  • TYK2 selective inhibitor drug for the treatment of inflammatory diseases such as psoriasis has huge clinical applications potential.
  • BMS international applications WO2015069310A1 and WO2018081488A1 reported on TYK2 selective inhibitors.
  • the BMS-986165 developed by them has achieved good efficacy in Phase II clinical trials and entered Phase III clinical studies. It reflects the advantages of TYK2 selective inhibitors and has significant clinical application value. .
  • the object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:
  • R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR aa , -SR aa , -C(O)R aa , -C(O)OR aa , -S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb or -NR aa S(O) m1 R bb ;
  • R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, alkenyl or alkynyl;
  • R 4 , R 5 , R 6 and R 7 are selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro Group, hydroxyl, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -SR aa , -(CH 2 ) n1 C(O)R aa , -C(O)OR aa , -S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb or -NR aa S(O)
  • R 4 and R 6 or R 6 and R 7 are linked to form a cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are any Optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, ring Substituted by one or more substituents in the alkyl group, heterocyclic group, aryl group and heteroaryl group;
  • R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro , Hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkyl Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted alken
  • any two adjacent or non-adjacent Raa , Rbb , Rcc, and Rdd are linked to form a cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein the cycloalkyl, hetero Cyclic, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy , Halogenated alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • x is an integer of 0, 1, 2 or 3;
  • n1 is an integer of 0, 1 or 2;
  • n1 is an integer of 0, 1, 2, 3, 4, or 5.
  • R is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, halogen, amino, mercapto, -OR aa , -SR aa , -S(O) m1 R aa or -NR aa R bb , preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, fluorine, chlorine, bromine, -OR aa , -SR aa , -S(O) m1 R aa or -NR aa R bb , more preferably hydrogen, methyl, ethyl, propyl, FCH 2 -, F 2 CH-, F 3 C-, ClCH 2 -, Cl 2 CH-, Cl 3 C-, CH 3 O-, CH 3 CH 2 O-, CH
  • R aa or R bb are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyanide Group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl or 3-7 membered heterocyclic group, preferably hydrogen, hydroxyl, C 1-3 alkyl, C 1-3 deuterated Alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, cyano, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl or containing 1-3 N, O or S atom 3-6 membered heterocyclic group, more preferably hydrogen, methyl, ethyl, -CD 3 , -CD 2 CD 3 , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, Ethyn
  • R c , R d , R e , R f or R g are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1 -6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, C 6-12 aryl group and 3-7 membered heteroaryl group, preferably hydrogen, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1 -3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, fluorine, chlorine, bromine, cyano, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 ring Alkyl groups,
  • any two adjacent or non-adjacent R c, R d, R e or R f form a linked group a C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 3-7 membered heteroaryl, and aryl, Aryl, preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-12 aryl and 3-6 membered heteroaryl, more preferably C 3-6 cycloalkyl, containing 1-3 3-6 membered heterocyclic groups with N, O or S atoms, C 6-10 aryl groups and 3-6 membered heteroaryl groups with 1-2 N, O or S atoms, more preferably cyclopropyl, cyclobutyl Group, cyclopentyl, cyclohexyl, More preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, More preferably cyclopropyl, cyclobutyl,
  • R hh , R ii , R jj or R kk are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 3-6 member Heterocyclic group, preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1 -3 halogenated alkoxy, fluorine, chlorine, bromine, cyano, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl or 3 containing 1-3 N, O or S atoms -6 membered
  • R 3 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, fluorine, chlorine , Bromine, amino, mercapto, nitro, hydroxyl or cyano, preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl or cyano, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, Fluorine, chlorine, hydroxyl or cyano;
  • R 4 , R 5 , R 6 and R 7 are selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1- 6 Alkoxy, C 1-6 haloalkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl, cyano, oxo, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, aryl, 3-7 membered heteroaryl, -(CH 2 ) n1 R ll , -(CH 2 ) n1 OR ll , -SR ll , -( CH 2 ) n1 C(O)R ll , -C(O)OR ll , -S(O) m1 R ll , -NR ll R mm , -C(O)NR ll R
  • R 11 or R mm are each independently selected from hydrogen, deuterium, hydroxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- 6 alkoxy, C 1-6 haloalkoxy, halogen, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, preferably hydrogen , Deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, Fluorine, chlorine, bromine, cyano, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group containing 1-3 N, O or S atoms , More preferably hydrogen, deuterium,
  • R 4 and R 6 or R 6 and R 7 are linked to form a heterocyclic group or heteroaryl group, wherein the heterocyclic group or heteroaryl group is optionally substituted by hydrogen, deuterium, halogen, or C 1-6 alkane.
  • C 3-6 cycloalkyl group preferably 3-6 membered heterocyclic group or 3-7 membered heteroaryl group, wherein the heterocyclic group or heteroaryl group, optionally Substituted by one or more substituents of hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 alkyl or C 3-5 cycloalkyl; more preferably 3 containing 1-3 N, O or S atoms -6 membered heterocyclic group or 3-7 membered heteroaryl group containing 1-3 N, O or S atoms, wherein the heterocyclic group or heteroaryl group is optionally substituted by hydrogen, deuterium, fluorine, chlorine, One or more substituents in bromo, methyl, ethyl, propyl, cyclopropyl, cyclopentyl or cyclohexyl are substituted; further preferred
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof, the general formula (I) is further as the general formula (II) Shown:
  • R to R 6 and x are as described in the general formula (I).
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and the general formula (I) is further as the general formula (III) Shown:
  • R, R 1 , R 3 to R 6 and x are as described in the general formula (I).
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and the general formula (I) is further as the general formula (IV) Shown:
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably heteroaryl;
  • R 8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Group, wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from hydrogen, deuterium, alkyl, halogen, hydroxy, amino , Oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents; Preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl;
  • y 0, 1, 2 or 3;
  • Ring A is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl or 3-7 membered heteroaryl, preferably C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, C 6-10 aryl group or 3-6 membered heteroaryl group, more preferably C 3-6 cycloalkyl group, 3-6 membered heterocyclic ring containing 1-3 N, O or S atoms Group, phenyl, naphthyl or 3-6 membered heteroaryl group containing 1-3 N, O or S atoms, more preferably Further preferred
  • R 8 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-6 haloalkyl, hydroxyl, amino, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl and 3-7 membered heteroaryl, preferably hydrogen, deuterium, C 1- 3 Alkyl, C 1-3 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 haloalkyl, hydroxyl, amino, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl group and 3-6 containing 1-3 N, O or S atoms Heteroaryl groups, more preferably hydrogen, de
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and the general formula (I) is further as the general formula (V) Shown:
  • R 9 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Base, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -SR aa , -(CH 2 ) n1 C(O)R aa , -C(O)OR aa , -S(O) m1 R aa , -NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb or -NR aa S(O) m1 R bb , wherein the alkyl group, halogenated alkyl group , Amino, alkenyl,
  • R, R 3 to R 6 , R aa , R bb and x are as described in the general formula (I).
  • R 9 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-6 haloalkyl, hydroxyl, Amino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl or 3-7 membered heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -SR aa , -(CH 2 ) n1 C(O)R aa , -C(O)OR aa , -S(O) m1 R aa ,- NR aa R bb , -C(O)NR aa R bb , -NR aa C(O)R bb or -NR a
  • R aa or R bb are independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, halogen, cyano, nitro, C 1-6 haloalkyl, hydroxyl, amino, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl or 3-7 membered heteroaryl, preferably hydrogen, deuterium, C 1 -3 alkyl, C 1-3 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 haloalkyl, hydroxyl, amino, C 2-5 alkenyl, C 2-5 alkynyl , C 3-6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl group or 3- containing 1-3 N, O or S atoms 7-membered heteroaryl
  • n1 0, 1, 2 or 3;
  • n1 0, 1, 2 or 3.
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and the general formula (I) is further as the general formula (VI) Shown:
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably heteroaryl;
  • R 10 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Group, wherein said alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, alkyl, One or more of halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl Substituents are substituted; preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl;
  • z 0, 1, 2 or 3;
  • Ring B is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl or 3-7 membered heteroaryl, preferably C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, C 6-10 aryl group or 3-6 membered heteroaryl group, more preferably C 3-6 cycloalkyl group, 3-6 membered heterocyclic ring containing 1-3 N, O or S atoms Group, phenyl, naphthyl or 3-6 membered heteroaryl group containing 1-3 N, O or S atoms, more preferably Further preferred
  • R 1 0 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-6 haloalkyl, hydroxyl, amino, alkenyl , Alkynyl, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl and 3-7 membered heteroaryl, preferably hydrogen, deuterium, C 1-3 alkyl, C 1- 3 Deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 haloalkyl, hydroxyl, amino, alkenyl, alkynyl, C 3-6 cycloalkyl, containing 1-3 N, O or S atom 3-6 membered heterocyclic group, C 6-10 aryl group or 3-6 membered heteroaryl group containing 1-3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, Prop
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and the general formula (I) is further as the general formula (VII) Shown:
  • M is S, NR cc or CR cc R dd ;
  • R 11 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl Group, wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterated alkyl, deuterium, alkyl, halogen, One or more substituents of hydroxyl, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl Substituted; preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl;
  • R cc and R dd are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;
  • R cc and R dd are linked to form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally further selected from deuterated alkyl, deuterium, alkyl, halogen, hydroxyl, amino, Substituted by one or more substituents in oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R, R 3 to R 6 and x are as described in the general formula (I).
  • M is S, NR cc or CR cc R dd , preferably S, NCH 3 , NOCH 3 , NCN, CH 2 , CHCH 3 or
  • R 11 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, halogen, cyano, nitro, C 1-6 haloalkyl, hydroxyl, amino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-12 aryl and 3-8 membered heteroaryl, preferably hydrogen, C 1-3 alkyl, C 1 -3 Deuterated alkyl, halogen, amino, cyano, alkyl, C 1-3 haloalkyl or C 3-5 cycloalkyl, more preferably methyl, ethyl, propyl, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, difluoromethyl, difluoroethyl, trifluoromethyl or trifluoroethyl;
  • R cc and R dd are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxy Alkyl, C 1-6 haloalkoxy, fluorine, chlorine, bromine, cyano, nitro, hydroxyl, amino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, C 6-12 aryl group or 3-6 membered heteroaryl group, preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 haloalkoxy, fluorine, chlorine, bromine, cyano, nitro, hydroxyl, amino, C 2-5 alkenyl, C 2- 5 Alkynyl, C 3-6
  • R cc and R dd linked form a C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, C 3-6 cycloalkyl, or preferably containing 1-3 N, 3-6 membered O or S heteroatom Cyclic group, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the present invention also provides a preferred solution.
  • the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are further represented by general formula (VIII):
  • R 3 to R 6 and x are as described in the general formula (I).
  • R 3 is selected from hydrogen, deuterium, fluorine, chlorine or bromine, preferably hydrogen, deuterium or fluorine, more preferably hydrogen or fluorine;
  • R 4 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, wherein the C 1-6 alkane Group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, optionally further selected from one of methyl, ethyl, fluorine or chlorine or Multiple substituents are substituted; preferably C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, 3-5 membered heterocyclic group, more preferably C 1- 3- alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, 3-5 membered heterocyclic group containing 1-3 N, O or S atoms, more preferably methyl , Ethyl, propyl, cyclopropyl
  • R 5 or R 6 are each independently hydrogen or deuterium
  • x 0, 1, 2 or 3.
  • the present invention also provides a preferred solution, the compound represented by any of the general formulae, its stereoisomers or pharmaceutically acceptable salts thereof, wherein:
  • Ring A and Ring B are selected from the following groups:
  • the present invention also provides a preferred solution, each of the general formulas, stereoisomers or pharmaceutically acceptable salts thereof according to any one of them, wherein:
  • R is selected from hydrogen, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR aa , -SR aa or -NR aa R bb ;
  • R 2 is selected from 3-8 membered heterocyclic groups, 5-8 membered heteroaryl groups, -C(O)R aa , -(CH 2 ) n1 OR aa , -C(O)NR aa R bb or -S( O) m1 NR aa R bb , wherein the 3-8 membered heterocyclic group and 5-8 membered heteroaryl group are optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl , Halogen, hydroxyl, amino, cyano and C 3-8 cycloalkyl substituted by one or more substituents;
  • R 3 is selected from hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 4 and R 6 are each independently selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic group or -(CH 2 ) n1 R aa ; preferably hydrogen, cyclopropyl or
  • R 4 and R 6 are linked to form a C 3-8 cycloalkyl group; preferably a cyclopentyl group;
  • R 7 is selected from absent, hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6 and R 7 are linked to form a C 3-8 cycloalkyl; preferably cyclopentyl;
  • R 8 and R 10 are each independently selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl;
  • R 9 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 C(O)R aa , -C(O)OR aa , -NR aa R bb or -C(O)NR aa R bb , wherein the C 1-6 alkyl group, C 3-8 ring Alkyl and 3-8 membered heterocyclic groups are optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxyl, amino, oxo, nitro, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered hetero
  • R 11 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, halogen, cyano, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycle Group, C 6-10 aryl group or 5-8 membered heteroaryl group;
  • R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group or 5-8 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and 5-8
  • the membered heteroaryl group is optionally further selected from hydrogen, deuterium, C 1-6 alkyl, halogen, hydroxyl, amino, oxo, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1 One or more of -6
  • R cc and R dd are linked to form a C 3-8 cycloalkyl group, wherein the C 3-8 cycloalkyl group is optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 One or more substituents among haloalkyl, halogen, amino, oxo, cyano, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl are substituted.
  • the present invention also relates to a technical solution, providing a compound represented by general formula (IX), its stereoisomers or pharmaceutically acceptable salts thereof:
  • Ring C is selected from the following groups:
  • R 12 is independently selected from -OR ee , -C(O)NR ee R ff , -(CH 2 ) n1 NR ee R ff or -S(O) m2 NR ee R ff ;
  • R 17 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 Membered heterocyclic group or -(CH 2 ) n1 R aa ;
  • R ee and R ff are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group or 5-8 membered heteroaryl group, wherein the C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group, C 3-8 cycloalkyl group, 3-8 membered Heterocyclyl and 5-8 membered heteroaryl are optionally further selected from hydrogen, deuterium, C 1-6 alkyl, halogen, hydroxy, amino, oxo, cyano, C 1-6 alkoxy, C Substituted by one or more substituents in 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-8 membered heteroaryl;
  • n1 0, 1 or 2;
  • n2 0, 1, or 2
  • q 0, 1, 2 or 3.
  • R 12 is selected from CD 3 NHC(O)-, CH 3 NHC(O)-, CH 3 NHS(O) 2 -, CH 3 O-, D 3 CNHS(O) 2 -,
  • R 17 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 3-6 Membered heterocyclic group or -(CH 2 ) n1 R aa , preferably hydrogen, halogen, cyano, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, containing 1-3 fluorine, Chlorine or bromine atom substituted C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms or -(CH 2 ) n1 R aa , More preferably hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cycl
  • R aa is selected from alkoxy, hydroxyalkyl, halogenated alkoxy, nitro, hydroxy, cyano, amino, aryl or heteroaryl, preferably C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, nitro, hydroxy, cyano, amino, C 6-12 aryl or 3-12 membered heteroaryl, more preferably C 1-3 alkoxy, C 1-3 hydroxyalkyl , C 1-3 haloalkoxy, nitro, hydroxy, cyano, amino, C 6-10 aryl or 5-8 membered heteroaryl, more preferably methoxy, ethoxy, propoxy, hydroxymethyl Group, hydroxyethyl, hydroxypropyl, C 1-3 alkoxy substituted with 1-3 fluorine, chlorine or bromine atoms, nitro, hydroxyl, cyano, amino, aryl and containing 1-3 N , 3-6 membered heteroaryl group with O or S atom
  • n1 is 1 or 2.
  • the present invention also relates to a technical solution, providing a compound represented by general formula (X), its stereoisomers or pharmaceutically acceptable salts thereof:
  • R 13 and R 14 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic or 5-8 membered heteroaryl;
  • R 16 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 Membered heterocyclic group or -(CH 2 ) n1 R aa ;
  • R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group or 5-8 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group and 5-8 Member heteroaryl, optionally further selected from hydrogen, deuterium, C 1-6 alkyl, halogen, hydroxyl, amino, oxo, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C One or more of 1-6 alkoxy, C 1-6
  • n1 0, 1 or 2;
  • n1 0, 1, or 2.
  • the present invention also relates to a technical solution, providing a compound represented by general formula (XI), its stereoisomers or pharmaceutically acceptable salts thereof:
  • R 18 is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic group or -(CH 2 ) n1 R aa , preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, fluorine, chlorine, bromine, hydroxyl, cyano, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkane Group, 3-6 membered heterocyclic group or -(CH 2 ) n1 R aa , more preferably hydrogen, methyl, cyclopropyl,
  • R 19 is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino , Hydroxy or cyano, preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, Fluorine, chlorine, bromine, amino, hydroxy or cyano, more preferably hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine, hydroxyl or cyano;
  • R aa is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocyclic group, preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 Deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, fluorine, chlorine, bromine, cyano, C 2-5 alkenyl, C 2-5 alkynyl Or C 3-6 cycloalkyl, more preferably hydrogen, methyl, ethynyl or cyclopropyl;
  • n1 0, 1 or 2;
  • r 0, 1, 2 or 3.
  • the present invention also relates to a technical solution, a method for preparing a compound represented by general formula (V) or its stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:
  • the general formula (V-1) is reacted with the general formula (V-2) to obtain the general formula (V-3), and the general formula (V-3) is further reacted to obtain the compound represented by the general formula (V) or its stereoisomers Body and its pharmaceutically acceptable salt;
  • X is selected from halogen
  • R 3 to R 6 , R 9 and x are as described in the general formula (V).
  • the present invention also relates to a technical solution, a method for preparing the compound represented by the general formula (V) or its stereoisomers and pharmaceutically acceptable salts thereof, characterized by comprising the following steps:
  • X is selected from halogen
  • R 3 to R 6 , R 9 and x are as described in the general formula (V).
  • the present invention also relates to a technical solution, a pharmaceutical composition, which includes a therapeutically effective dose of the compound of general formula (I) shown in any one of the rights, the compound of general formula (IX) shown in any one, and any A compound of general formula (X) shown in one item, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a technical solution, the compound of general formula (I) described in any one, the compound of general formula (IX) shown in any one, the compound of general formula (X) shown in any one and its stereo Application of the isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of TYK2 inhibitor drugs.
  • the present invention also relates to a technical solution, the compound of general formula (I) described in any one, the compound of general formula (IX) shown in any one, the compound of general formula (X) shown in any one and its stereo Isomers or pharmaceutically acceptable salts thereof, or the use of said pharmaceutical composition in the preparation and treatment of inflammatory diseases and autoimmune diseases; wherein said inflammatory diseases and autoimmune diseases are selected from rheumatoid arthritis , Dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn’s disease).
  • the present invention further relates to a method for preparing the compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of inflammatory diseases.
  • the present invention also relates to a method of treatment, prevention and/or treatment of pre-preparation and treatment of autoimmune diseases, which comprises administering to a patient a therapeutically effective dose of a compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable ⁇ , or a pharmaceutical composition thereof.
  • the present invention also provides methods for using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions related to TYK2 kinase dysfunction.
  • the present invention also relates to a method for treating a hyperproliferative disorder in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, or hydrate thereof Or derivatives.
  • the method involves the treatment of conditions such as cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, and heart disease.
  • the method involves the inflammatory disease and autoimmune disease selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease).
  • the treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention.
  • the invention provides a method of treating inflammatory conditions including autoimmune diseases in a mammal.
  • the method includes administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • Alkyl groups may be substituted or unsubstituted.
  • the substituents When substituted, the substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate group, preferred in the present invention is methyl, ethyl, isopropyl, tert-butyl, haloalkyl , Deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
  • alkylene means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "Butylene” refers to -(CH 2 ) 4 -, etc.
  • alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 Carbon atoms, most preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • spirocycloalkyl group in which a single spirocycloalkyl and a heterocycloalkyl share a spiro atom
  • non-limiting examples include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietane, pyrrolidinyl, pyrrolidone, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydro Hydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl , Pyrrolidone, tetrahydrofuryl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between 3 to 20 membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • Non-limiting examples of spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and thiazolyl; more preferably triazolyl, pyrrolyl , Thienyl, thiazolyl, pyridyl and pyrimidinyl.
  • the heteroaryl ring may be fused on an aryl
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxy or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent group is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxy or carboxylate.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • alkenyl refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), where the alkynyl group may be further substituted by other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate group.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH 2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc refers to ethyl acetate
  • MeOH means methanol
  • DMF N, N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN means Otoharu.
  • DMA refers to N,N-dimethylacetamide.
  • Et 2 O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi refers to methyl lithium
  • N-BuLi means n-butyl lithium
  • DMAP refers to 4-dimethylaminopyridine.
  • SEM-Cl refers to chloromethyl trimethylsilyl ethyl ether.
  • Xantphos refers to 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.
  • DCM dichloromethane
  • X is selected from A, B, or C
  • X is selected from A, B and C
  • X is A, B or C
  • X is A, B and C
  • other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
  • the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present.
  • the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms independently of each other substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.
  • Figure 1 shows the PASI scores of different compounds in a mouse psoriasis model induced by imiquimod.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in units of parts per million (ppm).
  • the NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • the liquid mass spectrometry LC-MS measurement uses an Agilent 1200 Infinity Series mass spectrometer.
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and can be bought on the market, or can be synthesized by using or following methods known in the art.
  • the first step preparation of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
  • the third step Preparation of lithium 4,6-dichloropyridazine-3-carboxylate
  • the fourth step ((6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine -3-carbonyl)oxo)zinc preparation
  • the fifth step ((6-(Bicyclo[1.1.1]pentane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2, Preparation of 4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc
  • Step Six 6-(Bicyclo[1.1.1]pentane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4- Preparation of triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
  • 6-(5-Cyclopropyl-1H-imidazol-2-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl )Phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide is prepared according to Example 1.
  • the first step is the preparation of 2-methoxy-3-nitrobenzamide
  • the second step is the preparation of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
  • the third step is the preparation of 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
  • the fourth step is the preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline
  • the first step is the preparation of 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole
  • the second step is the preparation of 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
  • reaction solution was poured into ice water, ammonia water was slowly added dropwise, the pH value was adjusted to about 9, ethyl acetate extracted, the organic phase was separated and dried, and the organic solvent was concentrated under reduced pressure to obtain the title compound 3-(5-fluoro-2-methyl)
  • the crude oxy-3-nitrophenyl)-1H-1,2,4-triazole (1.26g) was directly used in the next reaction.
  • the third step is the preparation of 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
  • the fourth step is the preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline
  • reaction solution was diluted with dichloromethane, the organic phase was washed with saturated brine several times, and then the organic phase was separated and dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure and the column chromatography was separated to obtain the title compound 6-chloro-4-((3 -(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3 -Formamide (290 mg, 74%).
  • 6-(Cyclopropylcarboxamido)-4-((2-methoxy-5-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl )Amino)-N-(methyl-d3)pyridazine-3-carboxamide is prepared according to Example 1.
  • the sixth step 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanamide )-N-(Methyl-d3)pyridazine-3-carboxamide
  • Step 6 6-(Cyclopropanamide)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole -3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
  • 6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole-3 -Yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1 for the preparation method.
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