WO2020156311A1 - Pyridazine derivative inhibitor, and preparation method and application thereof - Google Patents

Pyridazine derivative inhibitor, and preparation method and application thereof 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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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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Application filed by 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 filed Critical 江苏豪森药业集团有限公司
Priority to KR1020217025392A priority Critical patent/KR20210119426A/en
Priority to JP2021542491A priority patent/JP2022524279A/en
Priority to CN202211231199.XA priority patent/CN115448910B/en
Priority to CN202310827414.0A priority patent/CN117263918A/en
Priority to CN202080001485.XA priority patent/CN111757878B/en
Publication of WO2020156311A1 publication Critical patent/WO2020156311A1/en

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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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.

Abstract

The present invention relates to a pyridazine derivative inhibitor, and a preparation method and an application thereof. In particular, the present invention relates to a compound of formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and an application thereof in the preparation of TYK2 inhibitor drugs.

Description

一种哒嗪类衍生物抑制剂、其制备方法和应用Pyridazine derivative inhibitor, its preparation method and application 技术领域Technical field
本发明属于药物合成领域，具体涉及一种哒嗪类衍生物抑制剂及其制备方法和应用。The invention belongs to the field of drug synthesis, and specifically relates to a pyridazine derivative inhibitor and a preparation method and application thereof.
背景技术Background technique
Janus激酶(JAK)是一种胞内非受体酪氨酸激酶，介导各种细胞因子的信号传导和激活。JAK激酶家族分为JAK1、JAK2、JAK3和TYK2四个亚型，各亚型分别介导不同类型的细胞因子信号通路，JAK-1、JAK-2和TYK-2在人体各组织细胞中均有表达，JAK-3主要表达于各造血组织细胞中。细胞因子受体的共同特点是受体本身不具有激酶活性，但受体胞内段具有酪氨酸激酶JAK的结合位点。当细胞因子受体与其配体结合后，激活受体偶联的JAKs，进而使受体被磷酸化，磷酸化的酪氨酸位点可与含有SH2结构域的STAT蛋白结合，从而使STAT被募集到受体并通过JAKs磷酸化，随后磷酸酪氨酸介导STAT二聚化，激活的STAT二聚体转移到细胞核内并激活其靶点基因转录，进而调控多种细胞的生长、活化、分化等多种功能。Janus kinase (JAK) 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. 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是JAK家族最早发现的一个亚型，介导IFN-α、IL-6、IL-10、IL-12和IL-23等细胞因子的功能，研究表明TYK2缺失突变能有效抑制过敏、自身免疫和炎症等免疫性疾病的发生。IL-23在银屑病的发生发展过程中起着至关重要的作用，最新研究表明银屑病的发病机理是内源性未知抗原激活抗原递呈细胞APC分泌IL-23，IL-23激活Th17细胞而分泌IL-17等细胞因子，诱发角质细胞分化分裂和分泌IL-23，进一步刺激炎症和角质细胞增殖产生银屑病。TYK2和JAK2共同介导IL-23的下游信号通路，抑制JAK2会导致贫血和其它血液相关副作用，因此靶向TYK2是抑制IL-23信号通路是治疗银屑病的良好策略。TYK2 is the first subtype discovered in the JAK family. It mediates the functions of cytokines such as IFN-α, 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. Th17 cells secrete IL-17 and other cytokines, induce keratinocytes to divide and secrete IL-23, and further stimulate inflammation and keratinocyte proliferation to produce psoriasis. 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.
早期的TYK2抑制剂如Tofacitinib等都属于JAK非选择性抑制剂，是首个口服JAK抑制剂，对JAK1、2、3亚型均有显著的抑制活性。对其它亚型如JAK1、JAK2和JAK3的活性抑制增加了tofacitinib的疗效，但同时也带来了较为严重的副作用，不良反应包括感染、结核、肿瘤、贫血、肝损伤及胆固醇增加等。由于JAK2活性与红系细胞分化以及脂代谢过程相关，上述贫血等部分不良反应被认为可能与Tofacitinib对JAK-2选择性不足相关，是该药物的非选择性抑制引起的。目前还没有TYK2选择性抑制剂上市，早期JAK抑制剂主要是竞争激酶结构域与ATP的结合而发挥作用，因此普遍存在选择性不高的问题。Early TYK2 inhibitors, such as 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. As 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. At present, 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.
介于JAK非选择性抑制剂的良好疗效和多种靶点相关性严重副作用，开发一种安全性更高的TYK2选择性抑制剂药物用于银屑病等炎症性疾病的治疗具有巨大临床应用潜力。BMS国际申请WO2015069310A1和WO2018081488A1 报道了TYK2选择性抑制剂，其研发的BMS-986165目前临床二期取得良好疗效并进入三期临床研究，体现了TYK2选择性抑制剂的优势，具有重大的临床应用价值。Due to the good efficacy of JAK non-selective inhibitors and the serious side effects associated with multiple targets, the development of a safer 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. .
发明内容Summary of the invention
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I)所示的化合物结构如下：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:
Figure PCTCN2020073152-appb-000001
Figure PCTCN2020073152-appb-000001
其中：among them:
R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、氧代基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR aa、-SR aa、-C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb； 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 1选自环烷基、杂环基、芳基、杂芳基、-R aa、-(CH 2) n1OR bb、-(CH 2) n1NR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) m1R bb、-NR aaCR bb＝NR cc、-NR aaCR bb＝CR ccR dd、-(CH 2) n1S(O) m1NR aaR bb、-(CH 2) n1C(O)R aa、-NR aaC(O)OR bb、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaC(O)C(O)R aa或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、氘代烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R 1 is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -R aa , -(CH 2 ) n1 OR bb , -(CH 2 ) n1 NR aa R bb , -NR aa C(O) R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m1 R bb , -NR aa CR bb =NR cc , -NR aa CR bb =CR cc R dd , -(CH 2 ) n1 S(O) m1 NR aa R bb , -(CH 2 ) n1 C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa C(O)C(O)R aa or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkane Groups, heterocyclic groups, aryl groups and heteroaryl groups are optionally further selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano , Hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted One or more substituents in the substituted heteroaryl group;
R 2选自环烷基、杂环基、芳基、杂芳基、-R aa、-C(O)R aa、-(CH 2) n1OR bb、-(CH 2) n1NR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) m1R bb、-NR aaCR bb＝NR cc、-NR aaCR bb＝CR ccR dd、-(CH 2) n1S(O) m1NR aaR bb、-(CH 2) n1C(O)R aa、-NR aaC(O)OR bb、-(CH 2) n1S(O) m1R aa或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、氘代烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R 2 is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -R aa , -C(O)R aa , -(CH 2 ) n1 OR bb , -(CH 2 ) n1 NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m1 R bb , -NR aa CR bb = NR cc , -NR aa CR bb =CR cc R dd , -(CH 2 ) n1 S(O) m1 NR aa R bb , -(CH 2 ) n1 C(O)R aa , -NR aa C(O) OR bb , -(CH 2 ) n1 S(O) m1 R aa or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclic, aryl and heteroaromatic The group is optionally further selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy One or more of group, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl Substituted by a substituent;
R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基或炔基； 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和R 7存在或不存在，存在时选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、氧代基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-SR aa、-(CH 2) n1C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb； The presence or absence of 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) m1 R bb ;
或者，R 4和R 6或R 6和R 7链接形成一个环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, 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和R dd各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； 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 alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl , Substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group substituted by one or more substituents;
或者，任意两个相邻或者不相邻的R aa、R bb、R cc和R dd链接形成一个环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Or, 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为0、1、2或3的整数；x is an integer of 0, 1, 2 or 3;
m1为0、1或2的整数；且m1 is an integer of 0, 1 or 2; and
n1为0、1、2、3、4或5的整数。n1 is an integer of 0, 1, 2, 3, 4, or 5.
优选的方案为：R选自氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、卤素、氨基、巯基、-OR aa、-SR aa、-S(O) m1R aa或-NR aaR bb，优选氢、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、氟、氯、溴、-OR aa、-SR aa、-S(O) m1R aa或-NR aaR bb，更优选氢、甲基、乙基、丙基、FCH 2-、F 2CH-、F 3C-、ClCH 2-、Cl 2CH-、Cl 3C-、CH 3O-、CH 3CH 2O-、CH 3CH 2CH 2O-、FCH 2O-、F 2CHO-、F 3CO-、氟、氯、-OR aa、-SR aa、-S(O) m1R aa或-NR aaR bb，进一步优选CH 3O-、(CH 3) 2N-、CH 3S-、F 3CO-、F 2HCO-、F-或CH 3S(O) 2-； The preferred scheme is: 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 3 CH 2 CH 2 O-, FCH 2 O-, F 2 CHO-, F 3 CO-, fluorine, chlorine, -OR aa , -SR aa , -S(O) m1 R aa or -NR aa R bb , more preferably CH 3 O-, (CH 3 ) 2 N-, CH 3 S-, F 3 CO-, F 2 HCO-, F- or CH 3 S(O) 2 -;
其中，R aa或R bb各自独立地选自氢、氘、羟基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、氰基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-7元杂 环基，优选氢、羟基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、氰基、C 2-5烯基、C 2-5炔基、C 3-6环烷基或含1-3个N、O或S原子的3-6元杂环基，更优选氢、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、环丙基、环丁基、环己基、环氧乙基、环氧丙基、环氧丁基、环氧戊基、四氢吡咯基或哌啶基；进一步优选氢、甲基、乙基、丙基、环丙基或环丁基； Wherein, 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, Ethynyl, propynyl, FCH 2 -, F 2 CH-, F 3 C-, cyano, cyclopropyl, cyclobutyl, cyclohexyl, epoxyethyl, epoxypropyl, epoxybutyl, Epoxypentyl, tetrahydropyrrolyl or piperidinyl; more preferably hydrogen, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
R 1选自C 3-7环烷基、3-7元杂环基、C 6-12芳基、3-7元杂芳基、-NR cC(O)R d、-NR cC(O)NR dR e、-NR cS(O) m1R d、-NR cCR d＝NR e、-NR cCR d＝CR eR f、-NR cC(O)OR d、-(CH 2) n1S(O) m1R c、-(CH 2) n1NR cC(O)C(O)R g或-(CH 2) n1NR cS(O) m1R d、-NR cCR dR eR f、-NR cC(S)R d、-OC＝ONR cR d或-CR eR fC＝ONR cR d，优选C 3-6环烷基、3-6元杂环基、C 6-10芳基、3-6元杂芳基、-NR cC(O)R d、-NR cC(O)NR dR e、-NR cS(O) m1R d、-NR cCR d＝NR e、-NR cCR d＝CR eR f、-NR cC(O)OR d、-(CH 2) n1S(O) m1R c、-(CH 2) n1NR cC(O)C(O)R g或-(CH 2) n1NR cS(O) m1R d、-NR cCR dR eR f、-NR cC(S)R d、-OC＝ONR cR d或-CR eR fC＝ONR cR d，更优选C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、苯基、萘基、含1-3个N、O或S原子的3-6元杂芳基、-NR cC(O)R d、-NR cC(O)NR dR e、-NR cS(O) m1R d、-NR cCR d＝NR e、-NR cCR d＝CR eR f、-NR cC(O)OR d、-(CH 2) n1S(O) m1R c、-(CH 2) n1NR cC(O)C(O)R g或-(CH 2) n1NR cS(O) m1R d、-NR cCR dR eR f、-NR cC(S)R d、-OC＝ONR cR d或–CR eR fC＝ONR cR d，进一步优选 R 1 is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl, 3-7 membered heteroaryl, -NR c C(O)R d , -NR c C( O)NR d R e , -NR c S(O) m1 R d , -NR c CR d =NR e , -NR c CR d =CR e R f , -NR c C(O)OR d , -( CH 2 ) n1 S(O) m1 R c , -(CH 2 ) n1 NR c C(O)C(O)R g or -(CH 2 ) n1 NR c S(O) m1 R d , -NR c CR d R e R f , -NR c C(S)R d , -OC=ONR c R d or -CR e R f C=ONR c R d , preferably C 3-6 cycloalkyl, 3-6 member Heterocyclic group, C 6-10 aryl, 3-6 membered heteroaryl, -NR c C(O)R d , -NR c C(O)NR d R e , -NR c S(O) m1 R d , -NR c CR d =NR e , -NR c CR d =CR e R f , -NR c C(O)OR d , -(CH 2 ) n1 S(O) m1 R c , -(CH 2 ) n1 NR c C(O)C(O)R g or -(CH 2 ) n1 NR c S(O) m1 R d , -NR c CR d R e R f , -NR c C(S)R d , -OC=ONR c R d or -CR e R f C=ONR c R d , more preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms , Phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3 N, O or S atoms, -NR c C(O)R d , -NR c C(O)NR d R e ,- NR c S(O) m1 R d , -NR c CR d ＝NR e , -NR c CR d ＝CR e R f , -NR c C(O)OR d , -(CH 2 ) n1 S(O) m1 R c , -(CH 2 ) n1 NR c C(O)C(O)R g or -(CH 2 ) n1 NR c S(O) m1 R d , -NR c CR d R e R f ,- NR c C(S)R d , -OC=ONR c R d or -CR e R f C=ONR c R d , more preferably
Figure PCTCN2020073152-appb-000002
Figure PCTCN2020073152-appb-000002
Figure PCTCN2020073152-appb-000003
Figure PCTCN2020073152-appb-000003
R c、R d、R e、R f或R g各自独立地选自氢、氘、羟基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、C 6-12芳基和3-7元杂芳基，优选氢、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氰基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基和含1-3个N、O或S原子的3-6元杂芳基，更优选氢、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、氟、氯、CH 3O-、CH 3CH 2O-、环丙基、环丁基、环戊基、环己基、
Figure PCTCN2020073152-appb-000004
Figure PCTCN2020073152-appb-000005
Figure PCTCN2020073152-appb-000006
进一步优选氢、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、氟、氯、CH 3O-、CH 3CH 2O-、环丙基、环丁基、环戊基、环己基、
Figure PCTCN2020073152-appb-000007
Figure PCTCN2020073152-appb-000008
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, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 aryl groups and 3-6 membered heteroaryl groups containing 1-3 N, O or S atoms, More preferably hydrogen, methyl, ethyl, -CD 3 , -CD 2 CD 3 , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH 2 -, F 2 CH-, F 3 C-, cyano, fluorine, chlorine, CH 3 O-, CH 3 CH 2 O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020073152-appb-000004
Figure PCTCN2020073152-appb-000005
Figure PCTCN2020073152-appb-000006
More preferably hydrogen, methyl, ethyl, -CD 3 , -CD 2 CD 3 , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH 2 -, F 2 CH-, F 3 C-, cyano, fluorine, chlorine, CH 3 O-, CH 3 CH 2 O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020073152-appb-000007
Figure PCTCN2020073152-appb-000008
或者，任意两个相邻或者不相邻的R c、R d、R e或R f链接形成一个C 3-7环烷基、3-7元杂环基、芳基和3-7元杂芳基，优选C 3-6环烷基、3-6元杂环基、C 6-12芳基和3-6元杂芳基，更优选C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基和含1-2个N、O或S原子的3-6元杂芳基，进一步优选环丙基、环丁基、环戊基、环己基、
Figure PCTCN2020073152-appb-000009
Figure PCTCN2020073152-appb-000010
Figure PCTCN2020073152-appb-000011
更进一步优选环丙基、环丁基、环戊基、环己基、
Figure PCTCN2020073152-appb-000012
Alternatively, 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,
Figure PCTCN2020073152-appb-000009
Figure PCTCN2020073152-appb-000010
Figure PCTCN2020073152-appb-000011
More preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020073152-appb-000012
R 2选自C 3-7环烷基、3-7元杂环基、C 6-12芳基、3-7元杂芳基、C 1-6羟烷基、 -C(O)R hh、-(CH 2) n1OR ii、-(CH 2) n1NR hhR ii、-NR hhC(O)R ii、-NR hhC(O)NR iiR jj、-C(O)NR hhR ii、-NR hhS(O) m1R ii、-NR hhCR ii＝NR jj、-NR hhCR ii＝CR jjR kk、-(CH 2) n1S(O) m1NR hhR ii、-(CH 2) n1C(O)R hh、-NR hhC(O)OR ii、-(CH 2) n1S(O) m1R hh或-(CH 2) n1NR hhS(O) m1R ii，其中所述的C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，任选被氢、氘、卤素、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基中的一个或多个取代基取代；优选C 3-6环烷基、取代或未取代的3-6元杂环基、C 6-10芳基、取代或未取代的3-6元杂芳基、C 1-3羟烷基、-C(O)R hh、-(CH 2) n1OR ii、-(CH 2) n1NR hhR ii、-NR hhC(O)R ii、-NR hhC(O)NR iiR jj、-C(O)NR hhR ii、-NR hhS(O) m1R ii、-NR hhCR ii＝NR jj、-NR hhCR ii＝CR jjR kk、-(CH 2) n1S(O) m1NR hhR ii、-(CH 2) n1C(O)R hh、-NR hhC(O)OR ii、-(CH 2) n1S(O) m1R hh或-(CH 2) n1NR hhS(O) m1R ii，其中所述的C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，任选被氢、氘、氟、氯、溴、C 1-3烷基或C 3-5环烷基中的一个或多个取代基取代；更优选C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、苯基、萘基、含1-3个N、O或S原子的3-6元杂芳基、C 1-3羟烷基、-C(O)R hh、-(CH 2) n1OR ii、-(CH 2) n1NR hhR ii、-C(O)NR hhR ii、-(CH 2) n1S(O) m1NR hhR ii、-(CH 2) n1C(O)R hh、-(CH 2) n1S(O) m1R hh或-(CH 2) n1NR hhS(O) m1R ii，其中所述的C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，任选被氢、氘、氟、氯、溴、甲基、乙基、丙基、环丙基、环戊基或环己基中的一个或多个取代基取代；进一步优选HOCH 2-、HOCH 2CH 2-、HOCH 2C(O)-、CH 3NHC(O)-、D 3CNHC(O)-、CH 3NHS(O) 2-、D 3CNHS(O) 2-、
Figure PCTCN2020073152-appb-000013
R 2 is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl, 3-7 membered heteroaryl, C 1-6 hydroxyalkyl, -C(O)R hh , -(CH 2 ) n1 OR ii , -(CH 2 ) n1 NR hh R ii , -NR hh C(O)R ii , -NR hh C(O)NR ii R jj , -C(O)NR hh R ii , -NR hh S(O) m1 R ii , -NR hh CR ii =NR jj , -NR hh CR ii =CR jj R kk , -(CH 2 ) n1 S(O) m1 NR hh R ii , -(CH 2 ) n1 C(O)R hh , -NR hh C(O)OR ii , -(CH 2 ) n1 S(O) m1 R hh or -(CH 2 ) n1 NR hh S(O) m1 R ii , wherein said C 3-7 cycloalkyl group, 3-7 membered heterocyclic group, C 6-12 aryl group or 3-7 membered heteroaryl group is optionally substituted by hydrogen, deuterium, halogen, C 1- One or more substituents in 6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; preferably C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group , C 6-10 aryl, substituted or unsubstituted 3-6 membered heteroaryl, C 1-3 hydroxyalkyl, -C(O)R hh , -(CH 2 ) n1 OR ii , -(CH 2 ) n1 NR hh R ii , -NR hh C(O)R ii , -NR hh C(O)NR ii R jj , -C(O)NR hh R ii , -NR hh S(O) m1 R ii , -NR hh CR ii =NR jj , -NR hh CR ii =CR jj R kk , -(CH 2 ) n1 S(O) m1 NR hh R ii , -(CH 2 ) n1 C(O)R hh ,- NR hh C(O)OR ii , -(CH 2 ) n1 S(O) m1 R hh or -(CH 2 ) n1 NR hh S(O) m1 R ii , wherein the C 3-7 cycloalkyl , 3-7 membered heterocyclic group, C 6-12 aryl group or 3-7 membered heteroaryl group, optionally by hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 alkyl or C 3-5 cycloalkane One or more substituents in the group; more preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, phenyl, naphthyl, 1- 3-6 membered heteroaryl with 3 N, O or S atoms, C 1-3 hydroxyalkyl, -C(O)R hh , -(CH 2 ) n1 OR ii , -(CH 2 ) n1 NR hh R ii , -C(O)NR hh R ii , -(CH 2 ) n1 S(O) m1 NR hh R ii , -(CH 2 ) n1 C(O)R hh , -(CH 2 ) n1 S(O) m1 R hh or -(CH 2 ) n1 NR hh S(O) m1 R ii , wherein the C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aromatic Group or 3-7 membered heteroaryl group, optionally substituted by one or more of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl or cyclohexyl Substitution; More preferably HOCH 2 -, HOCH 2 CH 2 -, HOCH 2 C(O)-, CH 3 NHC(O)-, D 3 CNHC(O)-, CH 3 NHS(O) 2 -, D 3 CNHS (O) 2 -、
Figure PCTCN2020073152-appb-000013
R hh、R ii、R jj或R kk各自独立地选自氢、氘、羟基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氰基、C 2-5烯基、C 2-5炔基、C 3-6环烷基或含1-3个N、O或S原子的3-6元杂环基，更优选氢、氘、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、氟、氯、CH 3O-、CH 3CH 2O-、环丙基、环丁基、环戊基、环己基、环氧丙基、环氧丁基、环氧戊基、环氧己基、四氢吡咯基或哌啶基； 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 heterocyclic group, more preferably hydrogen, deuterium, methyl, ethyl, -CD 3 , -CD 2 CD 3 , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propyl Alkynyl, FCH 2 -, F 2 CH-, F 3 C-, cyano, fluorine, chlorine, CH 3 O-, CH 3 CH 2 O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrolyl or piperidinyl;
R 3选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6 卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基或氰基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基或氰基，更优选氢、氘、甲基、乙基、丙基、甲氧基、乙氧基、氟、氯、羟基或氰基； 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和R 7存在或不存在，存在时选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基、氰基、氧代基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-7元杂环基、芳基、3-7元杂芳基、-(CH 2) n1R ll、-(CH 2) n1OR ll、-SR ll、-(CH 2) n1C(O)R ll、-C(O)OR ll、-S(O) m1R ll、-NR llR mm、-C(O)NR llR mm、-NR llC(O)R mm或-NR llS(O) m1R mm，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基、氰基、氧代基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-12芳基、含1-3个N、O或S原子的3-6元杂芳基、-(CH 2) n1R ll、-(CH 2) n1OR ll、-SR ll、-(CH 2) n1C(O)R ll、-C(O)OR ll、-S(O) m1R ll、-NR llR mm、-C(O)NR llR mm、-NR llC(O)R mm或-NR llS(O) m1R mm，更优选氢、氘、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基、氰基、氧代基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基、含1-3个N、O或S原子的3-6元杂芳基、-(CH 2) n1R ll、-(CH 2) n1OR ll或-NR llR mm，进一步优选氢、甲基、乙基、丙基、异丙基、丁基、(CH 3) 3C-、CF 3CH 2-、氟、氯、环丙基、环丁基、环戊基、环丁基、乙烯基、CH 2＝CHCH 2-、乙炔基、
Figure PCTCN2020073152-appb-000014
氰基、CNCH 2-、CNCH 2CH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CF 3C(CH 3) 2-、
Figure PCTCN2020073152-appb-000015
Figure PCTCN2020073152-appb-000016
The presence or absence of 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 mm , -NR ll C(O ) R mm or -NR ll S(O) m1 R mm , 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, cyano, oxo, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 ring Alkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 aryl groups, 3-6 membered heteroaryl groups containing 1-3 N, O or S atoms, -(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 mm , -NR ll C(O)R mm or -NR ll S(O) m1 R mm , more preferably hydrogen, deuterium, C 1-3 alkane Group, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl, cyano, oxo, 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, containing 1-3 A 3-6 membered heteroaryl group containing N, O or S atoms, -(CH 2 ) n1 R ll , -(CH 2 ) n1 OR ll or -NR ll R mm , more preferably hydrogen, methyl, ethyl, Propyl, isopropyl, butyl, (CH 3 ) 3 C-, CF 3 CH 2 -, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, vinyl, CH 2 = CHCH 2 -, ethynyl,
Figure PCTCN2020073152-appb-000014
Cyano, CNCH 2 -, CNCH 2 CH 2 -, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, CF 3 C(CH 3 ) 2 -,
Figure PCTCN2020073152-appb-000015
Figure PCTCN2020073152-appb-000016
R ll或R mm各自独立地选自氢、氘、羟基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氰基、C 2-5烯基、C 2-5炔基、C 3-6环烷基或含1-3个N、O或S原子的3-6元杂环基，更优选氢、氘、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、氟、氯、环丙基、环丁基、环戊基、环己基、环氧丙基、环氧丁基、环氧戊基、环氧己基、四氢吡咯基或哌啶基； 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, methyl, ethyl, -CD 3 , -CD 2 CD 3 , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH 2- , F 2 CH-, F 3 C-, cyano, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxy Hexyl, tetrahydropyrrolyl or piperidinyl;
或者，R 4和R 6或R 6和R 7链接形成一个杂环基或杂芳基，其中所述的杂环基或杂芳基，任选被氢、氘、卤素、C 1-6烷基或C 3-6环烷基中的一个或多个取代 基取代；优选3-6元杂环基或3-7元杂芳基，其中所述的杂环基或杂芳基，任选被氢、氘、氟、氯、溴、C 1-3烷基或C 3-5环烷基中的一个或多个取代基取代；更优选含1-3个N、O或S原子的3-6元杂环基或含1-3个N、O或S原子的3-7元杂芳基，其中所述的杂环基或杂芳基，任选被氢、氘、氟、氯、溴、甲基、乙基、丙基、环丙基、环戊基或环己基中的一个或多个取代基取代；进一步优选
Figure PCTCN2020073152-appb-000017
Alternatively, 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. Group or one or more substituents in 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
Figure PCTCN2020073152-appb-000017
任选的条件是，式I化合物不是
Figure PCTCN2020073152-appb-000018
Optional condition is that the compound of formula I is not
Figure PCTCN2020073152-appb-000018
Figure PCTCN2020073152-appb-000019
Figure PCTCN2020073152-appb-000019
Figure PCTCN2020073152-appb-000020
Figure PCTCN2020073152-appb-000020
本发明还提供了一种优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(II)所示：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:
Figure PCTCN2020073152-appb-000021
Figure PCTCN2020073152-appb-000021
其中：among them:
R～R 6和x如通式(I)所述。 R to R 6 and x are as described in the general formula (I).
本发明还提供了一种优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(III)所示：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:
Figure PCTCN2020073152-appb-000022
Figure PCTCN2020073152-appb-000022
其中：among them:
R、R 1、R 3～R 6和x如通式(I)所述。 R, R 1 , R 3 to R 6 and x are as described in the general formula (I).
本发明还提供了一种优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(IV)所示：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:
Figure PCTCN2020073152-appb-000023
Figure PCTCN2020073152-appb-000023
其中：among them:
环A选自环烷基、杂环基、芳基或杂芳基；优选杂芳基；Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably heteroaryl;
R 8选自氢、氘、烷基、氘代烷基、卤素、氰基、硝基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；优选氢、卤素、氨基、氰基、烷基、卤代烷基或环烷基； 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为0、1、2或3；y is 0, 1, 2 or 3;
R、R 1、R 3～R 6和x如通式(I)所述。优选的方案为：环A选自C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，优选C 3-6环烷基、3-6元杂环基、C 6-10芳基或3-6元杂芳基，更优选C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、苯基、萘基或含1-3个N、O或S原子的3-6元杂芳基，进一步优选
Figure PCTCN2020073152-appb-000024
Figure PCTCN2020073152-appb-000025
Figure PCTCN2020073152-appb-000026
更进一步优选
Figure PCTCN2020073152-appb-000027
Figure PCTCN2020073152-appb-000028
R, R 1 , R 3 to R 6 and x are as described in the general formula (I). The preferred scheme is: 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
Figure PCTCN2020073152-appb-000024
Figure PCTCN2020073152-appb-000025
Figure PCTCN2020073152-appb-000026
Further preferred
Figure PCTCN2020073152-appb-000027
Figure PCTCN2020073152-appb-000028
R 8选自氢、氘、C 1-6烷基、C 1-6氘代烷基、氟、氯、溴、氰基、硝基、C 1-6卤代烷基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-7元杂环基、C 6-12芳基和3-7元杂芳基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、氟、氯、溴、氰基、硝基、C 1-3卤代烷基、羟基、氨基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基和含1-3个N、O或S原子的3-6元杂芳基，更优选氢、氘、甲基、乙基、丙基、氯取代甲基、氯取代乙基、氟取代甲基、氟取代乙基、氟、氯、溴、氰基、硝基、、羟基、氨基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、环己基、
Figure PCTCN2020073152-appb-000029
Figure PCTCN2020073152-appb-000030
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, deuterium, methyl, ethyl, propyl, chlorine-substituted methyl, chlorine-substituted ethyl, fluorine-substituted methyl, fluorine-substituted ethyl, fluorine, chlorine, bromine, cyano, nitro Group, hydroxy, amino, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Figure PCTCN2020073152-appb-000029
Figure PCTCN2020073152-appb-000030
本发明还提供了一种优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(V)所示：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:
Figure PCTCN2020073152-appb-000031
Figure PCTCN2020073152-appb-000031
其中：among them:
R 9选自氢、氘、烷基、氘代烷基、卤素、氰基、硝基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-SR aa、-(CH 2) n1C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb，其中所述的烷基、卤代烷基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤代烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； 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, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, hydroxyl, amino, oxo, nitro Substituted by one or more substituents in the group, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R、R 3～R 6、R aa、R bb和x如通式(I)所述。 R, R 3 to R 6 , R aa , R bb and x are as described in the general formula (I).
优选的方案为：R 9选自氢、氘、C 1-6烷基、C 1-6氘代烷基、氟、氯、溴、氰基、硝基、C 1-6卤代烷基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-SR aa、-(CH 2) n1C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、氟、氯、溴、氰基、硝基、C 1-3卤代烷基、羟基、氨基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、3-6元杂环基、C 6-10芳基或3-6元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-SR aa、-(CH 2) n1C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb，更优选氢、氘、羟基取代的C 1-3烷基、C 1-3环烷基取代的C 1-3烷基、羟基取代的C 1-3氘代烷基、氟、氯、溴、氰基、硝基、C 1-3卤代烷基、羟基、C 3-6环烷基取代的氨基、卤素取代的C 2-5烯基、卤素取代的C 2-5炔基、卤素取代的C 3-6环烷基、C 1-3烷基取代的C 3-6环烷基、氰基取代的C 3-6环烷基、C 1-3烷氧基取代的C 3-6环烷基、C 1-3卤代烷基取代的C 3-6环烷基、含1-3个N、O或S原子的3-7元杂环基、苯基、萘基或含1-3个N、O或S原子的3-7元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1C(O)R aa或-NR aaR bb，更进一步优选
Figure PCTCN2020073152-appb-000032
Figure PCTCN2020073152-appb-000033
The preferred scheme is: 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 aa S(O) m1 R bb , 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 cycloalkane Group, 3-6 membered heterocyclic group, C 6-10 aryl group or 3-6 membered heteroaryl group, -(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 , more preferably hydrogen, deuterium, hydroxy substituted C 1-3 alkyl, C 1-3 cycloalkyl substituted C 1-3 alkyl, hydroxy substituted C 1-3 deuterated alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 haloalkyl, hydroxyl, C 3-6 cycloalkyl substituted amino, halogen substituted C 2-5 alkenyl, Halogen substituted C 2-5 alkynyl, halogen substituted C 3-6 cycloalkyl, C 1-3 alkyl substituted C 3-6 cycloalkyl, cyano substituted C 3-6 cycloalkyl, C 1-3 alkoxy substituted C 3-6 cycloalkyl, C 1-3 haloalkyl-substituted C 3-6 cycloalkyl, containing 1-3 N, O or S atoms and 3-7 membered heterocycle Group, phenyl, naphthyl or 3-7 membered heteroaryl containing 1-3 N, O or S atoms, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 C(O)R aa or -NR aa R bb , more preferably
Figure PCTCN2020073152-appb-000032
Figure PCTCN2020073152-appb-000033
R aa或R bb独立地选自氢、氘、C 1-6烷基、C 1-6氘代烷基、卤素、氰基、硝基、C 1-6卤代烷基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、氟、氯、溴、氰基、硝基、C 1-3卤代烷基、羟基、氨基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基或含1-3个N、O或S原子的3-7元杂芳基，更优选氢、甲基、乙基、丙基、氟、氯、环丙基、环丁基、环戊基、环己基、苯基、萘基或联苯基； 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, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or biphenyl;
m1为0、1、2或3；m1 is 0, 1, 2 or 3;
n1为0、1、2或3。n1 is 0, 1, 2 or 3.
本发明还提供了一种优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(VI)所示：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:
Figure PCTCN2020073152-appb-000034
Figure PCTCN2020073152-appb-000034
其中：among them:
环B选自环烷基、杂环基、芳基或杂芳基；优选杂芳基；Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably heteroaryl;
R 10选自氢、氘、烷基、氘代烷基、卤素、氰基、硝基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢、氘、烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；优选氢、卤素、氨基、氰基、烷基、卤代烷基或环烷基； 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为0、1、2或3；z is 0, 1, 2 or 3;
R、R 3～R 6和x如通式(I)所述。优选的方案为：环B选自C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，优选C 3-6环烷基、3-6元杂环基、C 6-10芳基或3-6元杂芳基，更优选C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、苯基、萘基或含1-3个N、O或S原子的3-6元杂芳基，进一步优选
Figure PCTCN2020073152-appb-000035
Figure PCTCN2020073152-appb-000036
Figure PCTCN2020073152-appb-000037
更进一步优选
Figure PCTCN2020073152-appb-000038
Figure PCTCN2020073152-appb-000039
R, R 3 to R 6 and x are as described in the general formula (I). The preferred scheme is: 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
Figure PCTCN2020073152-appb-000035
Figure PCTCN2020073152-appb-000036
Figure PCTCN2020073152-appb-000037
Further preferred
Figure PCTCN2020073152-appb-000038
Figure PCTCN2020073152-appb-000039
R 10选自氢、氘、C 1-6烷基、C 1-6氘代烷基、氟、氯、溴、氰基、硝基、C 1-6卤代烷基、羟基、氨基、烯基、炔基、C 3-7环烷基、3-7元杂环基、C 6-12芳基和3-7元杂芳基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、氟、氯、溴、氰基、硝基、 C 1-3卤代烷基、羟基、氨基、烯基、炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基或含1-3个N、O或S原子的3-6元杂芳基，更优选氢、甲基、乙基、丙基、氟、氯、羟基、氨基、环丙基、环丁基、环戊基或环己基。 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, Propyl, fluorine, chlorine, hydroxy, amino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
本发明还提供了一种优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(VII)所示：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:
Figure PCTCN2020073152-appb-000040
Figure PCTCN2020073152-appb-000040
其中：among them:
M为S、NR cc或CR ccR dd； M is S, NR cc or CR cc R dd ;
R 11选自氢、氘、烷基、氘代烷基、卤素、氰基、硝基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘代烷基、氘、烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；优选氢、卤素、氨基、氰基、烷基、卤代烷基或环烷基； 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和R dd各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基； 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;
或者R cc和R dd链接形成一个环烷基或杂环基，其中所述的环烷基或杂环基任选进一步被选自氘代烷基、氘、烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Or 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～R 6和x如通式(I)所述。 R, R 3 to R 6 and x are as described in the general formula (I).
优选的方案为：M为S、NR cc或CR ccR dd，优选S、NCH 3、NOCH 3、NCN、CH 2、CHCH 3或
Figure PCTCN2020073152-appb-000041
The preferred scheme is: M is S, NR cc or CR cc R dd , preferably S, NCH 3 , NOCH 3 , NCN, CH 2 , CHCH 3 or
Figure PCTCN2020073152-appb-000041
R 11选自氢、氘、C 1-6烷基、C 1-6氘代烷基、卤素、氰基、硝基、C 1-6卤代烷基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、C 6-12芳基和3-8元杂芳基，优选氢、C 1-3烷基、C 1-3氘代烷基、卤素、氨基、氰基、烷基、C 1-3卤代烷基或C 3-5环烷基，更优选甲基、乙基、丙基、环丙基、环丁基、环戊基、环己基、氟、氯、溴、二氟甲基、二氟乙基、三氟甲基或三氟乙基； 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和R dd各自独立地选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 1-6卤代烷氧基、氟、氯、溴、氰基、硝基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、C 6-12芳基或3-6元杂芳基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3羟烷基、C 1-3卤代烷氧基、氟、氯、溴、氰基、硝基、羟基、氨基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S的3-6元杂环基、C 6-10芳基或含1-3个N、O或S的3-6元杂芳基，更优选氢、甲基、乙基、丙基、氟、氯、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氨基、羟基或氰基； 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 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S, C 6-10 aryl group or containing 1-3 N, O or S 3 -6 membered heteroaryl, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, hydroxyl Or cyano;
或者R cc和R dd链接形成一个C 3-6环烷基或3-6元杂环基，优选C 3-6环烷基或含1-3个N、O或S的3-6元杂环基，更优选环丙基、环丁基、环戊基、环己基、
Figure PCTCN2020073152-appb-000042
Or 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,
Figure PCTCN2020073152-appb-000042
本发明还提供了一种优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，进一步如通式(VIII)所示：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):
Figure PCTCN2020073152-appb-000043
Figure PCTCN2020073152-appb-000043
其中：among them:
R 3～R 6和x如通式(I)所述。 R 3 to R 6 and x are as described in the general formula (I).
优选的方案为，所述The preferred solution is that the
R 3选自氢、氘、氟、氯或溴，优选氢、氘或氟，更优选氢或氟； R 3 is selected from hydrogen, deuterium, fluorine, chlorine or bromine, preferably hydrogen, deuterium or fluorine, more preferably hydrogen or fluorine;
R 4选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基，其中所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基，任选进一步选自甲基、乙基、氟或氯中的一个或多个取代基所取代；优选C 1-3烷基、C 2-5烯基、C 2-5炔基、C 3-5环烷基、3-5元杂环基，更优选C 1-3烷基、C 2-5烯基、C 2-5炔基、C 3-5环烷基、含1-3个N、O或S原子的3-5元杂环基，进一步优选甲基、乙基、丙基、环丙基、环丁基、环戊基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、
Figure PCTCN2020073152-appb-000044
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, cyclobutyl, cyclopentyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl,
Figure PCTCN2020073152-appb-000044
R 5或R 6各自独立地为氢或氘； R 5 or R 6 are each independently hydrogen or deuterium;
x为0、1、2或3。x is 0, 1, 2 or 3.
本发明还提供了一种优选方案，任一项所述的各通式所示的化合物、其立体异构体或其药学上可接受盐，其中，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:
环A和环B选自如下基团：Ring A and Ring B are selected from the following groups:
Figure PCTCN2020073152-appb-000045
Figure PCTCN2020073152-appb-000045
本发明还提供了一种优选方案，任一项所述的各通式、其立体异构体或其药学上可接受的盐，其中，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选自氢、C 1-6烷氧基、C 1-6卤代烷氧基、-OR aa、-SR aa或-NR aaR bb； R is selected from hydrogen, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR aa , -SR aa or -NR aa R bb ;
R 1选自3-8元杂环基、5-8元杂芳基、-(CH 2) n1NR aaR bb、-NR aaC(O)R bb、-NR aaC(＝S)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaC(O)OR bb、-NR aaS(O) m1R bb、-(CH 2) n1NR aaC(O)C(O)R aa、-NR aaCR bb＝NR cc或-NR aaCR bb＝CR ccR dd，其中所述的3-8元杂环基和5-8元杂芳基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氰基、氧代基和C 3-8环烷基中的一个或多个取代基所取代； R 1 is selected from 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, -(CH 2 ) n1 NR aa R bb , -NR aa C(O)R bb , -NR aa C(=S)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa C(O)OR bb , -NR aa S(O) m1 R bb , -(CH 2 ) n1 NR aa C(O)C(O)R aa , -NR aa CR bb =NR cc or -NR aa CR bb =CR cc R dd , wherein the 3-8 membered heterocyclic group and 5-8 membered Heteroaryl is optionally further selected from one of hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxyl, amino, cyano, oxo and C 3-8 cycloalkyl Or more substituents;
R 2选自3-8元杂环基、5-8元杂芳基、-C(O)R aa、-(CH 2) n1OR aa、-C(O)NR aaR bb或-S(O) m1NR aaR bb，其中所述的3-8元杂环基和5-8元杂芳基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氰基和C 3-8环烷基中的一个或多个取代基所取代； 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选自氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 3 is selected from hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
R 5选自氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
R 4和R 6各自独立的选自氢、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或-(CH 2) n1R aa；优选氢、环丙基或
Figure PCTCN2020073152-appb-000046
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
Figure PCTCN2020073152-appb-000046
或者R 4和R 6链接形成一个C 3-8环烷基；优选环戊烷基； Or R 4 and R 6 are linked to form a C 3-8 cycloalkyl group; preferably a cyclopentyl group;
R 7选自不存在、氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 7 is selected from absent, hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
或者R 6和R 7链接形成一个C 3-8环烷基；优选环戊烷基； Or R 6 and R 7 are linked to form a C 3-8 cycloalkyl; preferably cyclopentyl;
R 8和R 10各自独立的选自氢、卤素、氰基、C 1-6烷基、C 1-6卤代烷基或C 3-8环烷基； 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选自氢、C 1-6烷基、C 3-8环烷基、3-8元杂环基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1C(O)R aa、-C(O)OR aa、-NR aaR bb或-C(O)NR aaR bb，其中所述的C 1-6烷基、C 3-8环烷基和3-8元杂环基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氧代基、硝基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-8元杂芳基中的一个或多个取代基所取代； 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 heterocyclic group, C 6-10 One or more substituents in the aryl group and 5-8 membered heteroaryl group;
R 11选自氢、氘、C 1-6烷基、C 1-6氘代烷基、卤素、氰基、C 1-6卤代烷基、C 3-8 环烷基、3-8元杂环基、C 6-10芳基或5-8元杂芳基； 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和R dd各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基或5-8元杂芳基，其中所述的C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基和5-8元杂芳基任选进一步被选自氢、氘、C 1-6烷基、卤素、羟基、氨基、氧代基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-8元杂芳基中的一个或多个取代基所取代； 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 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-8 membered heteroaryl Substituted by a substituent;
或者，R cc和R dd链接形成一个C 3-8环烷基，其中所述的C 3-8环烷基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、氨基、氧代基、氰基、羟基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6羟烷基中的一个或多个取代基所取代。 Alternatively, 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.
本发明还涉及一种技术方案，提供一种通式(IX)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a technical solution, providing a compound represented by general formula (IX), its stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2020073152-appb-000047
Figure PCTCN2020073152-appb-000047
其中：among them:
环C选自如下基团：Ring C is selected from the following groups:
Figure PCTCN2020073152-appb-000048
Figure PCTCN2020073152-appb-000048
R 12独立地选自-OR ee、-C(O)NR eeR ff、-(CH 2) n1NR eeR ff或-S(O) m2NR eeR ff； 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选自氢、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或-(CH 2) n1R aa； 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和R ff各自独立地选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或5-8元杂芳基，其中所述的C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基和5-8元杂芳基任选进一步被选自氢、氘、C 1-6烷基、卤素、羟基、氨基、氧代基、氰基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-8元杂芳基中的一个或多个取代基所取代； 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为0、1或2；n1 is 0, 1 or 2;
m2为0、1或2，且m2 is 0, 1, or 2, and
q为0、1、2或3。q is 0, 1, 2 or 3.
优选的方案为：The preferred solution is:
R 12选自CD 3NHC(O)-、CH 3NHC(O)-、CH 3NHS(O) 2-、CH 3O-、D 3CNHS(O) 2-、
Figure PCTCN2020073152-appb-000049
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 -,
Figure PCTCN2020073152-appb-000049
R 17选自氢、卤素、氰基、C 1-3烷基、C 2-5烯基、C 2-5炔基、C 1-3卤代烷基、C 3-6环烷基、3-6元杂环基或-(CH 2) n1R aa，优选氢、卤素、氰基、C 1-3烷基、C 2-5烯基、C 2-5炔基、含1-3个氟、氯或溴原子取代的C 1-3烷基、C 3-6环烷基、3-6元含1-3个N、O或S原子的杂环基或-(CH 2) n1R aa，更优选氢、甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、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、氮杂环戊基、氮杂环己基、硫杂环丁基、硫杂环戊基、硫杂环己基、烯丙基、炔丙基、CF 3CH 2-、(CH 3) 2CF 3C-、CN-、CNCH 2-、CNCH 2CH 2-、
Figure PCTCN2020073152-appb-000050
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, cyclobutyl, cyclopentyl, cyclohexyl, oxa Cyclobutyl, oxalanyl, oxanyl, azetidinyl, azetidinyl, azetidinyl, thietanyl, thiolanyl, thiolanyl, alkene Propyl, propargyl, CF 3 CH 2 -, (CH 3 ) 2 CF 3 C-, CN-, CNCH 2 -, CNCH 2 CH 2 -,
Figure PCTCN2020073152-appb-000050
R aa选自烷氧基、羟烷基、卤代烷氧基、硝基、羟基、氰基、氨基、芳基或杂芳基，优选C 1-6烷氧基、C 1-6羟烷基、C 1-6卤代烷氧基、硝基、羟基、氰基、氨基、C 6-12芳基或3-12元杂芳基，更优选C 1-3烷氧基、C 1-3羟烷基、C 1-3卤代烷氧基、硝基、羟基、氰基、氨基、C 6-10芳基或5-8元杂芳基，进一步优选甲氧基、乙氧基、丙氧基、羟甲基、羟乙基、羟丙基、含1-3个氟、氯或溴原子取代的C 1-3烷氧基、硝基、羟基、氰基、氨基、芳基和含1-3个N、O或S原子的3-6元杂芳基； 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为1或2。n1 is 1 or 2.
本发明还涉及一种技术方案，提供一种通式(X)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a technical solution, providing a compound represented by general formula (X), its stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2020073152-appb-000051
Figure PCTCN2020073152-appb-000051
其中：among them:
R 13和R 14各自独立地选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或5-8元杂芳基； 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 15选自3-8元杂环基、5-8元杂芳基、-(CH 2) n1NR aaR bb、-NR aaC(O)R bb、-NR aaC(＝S)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaC(O)OR bb、-NR aaS(O) m1R bb、-(CH 2) n1NR aaC(O)C(O)R aa、-NR aaCR bb＝NR cc或-NR aaCR bb＝CR ccR dd，其中所述的3-8元杂环基和5-8元杂芳基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氰基和C 3-8环烷基中的一个或多个取代基所取代； R 15 is selected from 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, -(CH 2 ) n1 NR aa R bb , -NR aa C(O)R bb , -NR aa C(=S)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa C(O)OR bb , -NR aa S(O) m1 R bb , -(CH 2 ) n1 NR aa C(O)C(O)R aa , -NR aa CR bb =NR cc or -NR aa CR bb =CR cc R dd , wherein the 3-8 membered heterocyclic group and 5-8 membered Heteroaryl is optionally further substituted with one or more selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxy, amino, cyano and C 3-8 cycloalkyl Substituted by
R 16选自氢、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或-(CH 2) n1R aa； 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和R dd各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基或5-8元杂芳基，其中所述的C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基和5-8元杂芳基，任选进一步被选自氢、氘、C 1-6烷基、卤素、羟基、氨基、氧代基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-8元杂芳基中的一个或多个取代基所取代； 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 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-8 membered heteroaryl Substituted by a substituent;
n1为0、1或2；且n1 is 0, 1 or 2; and
m1为0、1或2。m1 is 0, 1, or 2.
本发明还涉及一种技术方案，提供一种通式(XI)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a technical solution, providing a compound represented by general formula (XI), its stereoisomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2020073152-appb-000052
Figure PCTCN2020073152-appb-000052
其中：among them:
R 18选自氢、氘、卤素、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-8环烷基、3-8元杂环基或-(CH 2) n1R aa，优选氢、氘、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、羟基、氰基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、3-6元杂环基或-(CH 2) n1R aa，更优选氢、甲基、环丙基、
Figure PCTCN2020073152-appb-000053
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,
Figure PCTCN2020073152-appb-000053
R 19选自氢、氘、卤素、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、氨基、羟基或氰基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氨基、羟基或氰基，更优选氢、氘、甲基、乙基、丙基、甲氧基、乙氧基、氟、氯、羟基或氰基； 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选自氢、氘、氰基、羟基、卤素、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、氟、氯、溴、氰基、C 2-5烯基、C 2-5炔基或C 3-6环烷基，更优选氢、甲基、乙炔基或环丙基； 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为0、1或2；n1 is 0, 1 or 2;
r为0、1、2或3。r is 0, 1, 2 or 3.
本发明还涉及一种技术方案，一种制备通式(V)所示的化合物或其立体异构体及其药学上可接受盐的方法，包含以下步骤，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:
Figure PCTCN2020073152-appb-000054
Figure PCTCN2020073152-appb-000054
通式(V-1)与通式(V-2)反应，得到通式(V-3)，通式(V-3)进一步反应得到与通式(V)所示化合物或其立体异构体及其药学上可接受盐；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;
其中：among them:
X选自卤素；X is selected from halogen;
R 3～R 6、R 9和x如通式(V)所述。 R 3 to R 6 , R 9 and x are as described in the general formula (V).
本发明还涉及一种技术方案，一种制备所述的通式(V)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，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:
Figure PCTCN2020073152-appb-000055
Figure PCTCN2020073152-appb-000055
通式(V-4)与通式(V-5)反应，得到通式(V-6)，通式(V-6)进一步与通式(V-2)反应，得到与通式(V)所示化合物或其立体异构体及其药学上可接受盐；General formula (V-4) reacts with general formula (V-5) to obtain general formula (V-6), and general formula (V-6) further reacts with general formula (V-2) to obtain general formula (V ) The compound or its stereoisomers and pharmaceutically acceptable salts thereof;
其中：among them:
X选自卤素；X is selected from halogen;
R 3～R 6、R 9和x如通式(V)所述。 R 3 to R 6 , R 9 and x are as described in the general formula (V).
本发明还涉及一种技术方案，一种药用组合物，其包括治疗有效剂量的权任一项所示的通式(I)化合物、任一项所示的通式(IX)化合物和任一项所示的通式(X)化合物、及其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。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.
本发明还涉及一种技术方案，任一项所述的通式(I)化合物、任一项所示的通式(IX)化合物和任一项所示的通式(X)化合物及其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备TYK2抑制剂药物中的应用。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.
本发明还涉及一种技术方案，任一项所述的通式(I)化合物、任一项所示的通式(IX)化合物和任一项所示的通式(X)化合物及其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备治疗炎性疾病和自身免疫疾病中的应用；其中所述炎性疾病和自身免疫疾病选自类风湿性关节炎、皮炎、银屑病、炎症性肠病(溃疡性结肠炎及克罗恩病)。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).
本发明进一步涉及通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗炎性疾病的方法。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.
本发明还涉及一种治疗预防和/或治疗预制备治疗自身免疫疾病的方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。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的盐, or a pharmaceutical composition thereof.
本发明还提供了使用本发明的化合物或药物组合物治疗疾病状况的方法，该 疾病状况包括但不限于与TYK2激酶功能障碍有关的状况。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.
本发明还涉及治疗哺乳动物中的过度增生病症的方法，其包括向所述哺乳动物施用治疗有效量的本发明的化合物或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。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.
在一些实施方案中，本方法涉及诸如癌症、骨病、炎性疾病、免疫疾病、神经系统疾病、代谢性疾病、呼吸性疾病和心脏病等病症的治疗。In some embodiments, 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.
在一些实施方案中，本方法涉及所述炎性疾病和自身免疫疾病选自类风湿性关节炎、皮炎、银屑病、炎症性肠病(溃疡性结肠炎及克罗恩病)。In some embodiments, the method involves the inflammatory disease and autoimmune disease selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease).
本文提供的治疗方法包括向受试者施用治疗有效量的本发明的化合物。在一个实施方案中，本发明提供了治疗哺乳动物中包括自身免疫病在内的炎症病症的方法。该方法包括向所述哺乳动物施用治疗有效量的本发明的化合物，或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。The treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, 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.
发明的详细说明Detailed description of the invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨 基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。The term "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-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl 2-methylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. 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. Group, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. 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.
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。 The term "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. The term "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. When substituted, 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.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个碳原子，最优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。The term "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.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "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 Π electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, 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. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2020073152-appb-000056
Figure PCTCN2020073152-appb-000056
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：It also contains a spirocycloalkyl group in which a single spirocycloalkyl and a heterocycloalkyl share a spiro atom, non-limiting examples include:
Figure PCTCN2020073152-appb-000057
Figure PCTCN2020073152-appb-000057
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "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 π-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. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2020073152-appb-000058
Figure PCTCN2020073152-appb-000058
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "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 π 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. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2020073152-appb-000059
Figure PCTCN2020073152-appb-000059
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。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. When substituted, 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.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子。单环杂环基的非限制性实例包括氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯烷酮基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选氧杂环丁烷基、吡咯烷酮基、四氢呋喃基、吡唑烷基、吗啉基、哌嗪基和吡喃基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。 The term "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.
术语“螺杂环基”指3至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共 轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "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 π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the ring and the ring, 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:
Figure PCTCN2020073152-appb-000060
Figure PCTCN2020073152-appb-000060
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/5元、4元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "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 π-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. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 3 member/5 member, 4 member/5 member or 5 member/6 member Bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2020073152-appb-000061
Figure PCTCN2020073152-appb-000061
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多 环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括： The term "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 π-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. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure PCTCN2020073152-appb-000062
Figure PCTCN2020073152-appb-000062
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：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:
Figure PCTCN2020073152-appb-000063
等。
Figure PCTCN2020073152-appb-000063
Wait.
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclic group may be optionally substituted or unsubstituted. When substituted, 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.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "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 π-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:
Figure PCTCN2020073152-appb-000064
Figure PCTCN2020073152-appb-000064
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The aryl group may be substituted or unsubstituted. When substituted, 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.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为三唑基、噻吩基、咪唑基、吡唑基、吡啶基、嘧啶基和噻唑基；更有选三唑基、吡咯基、噻吩基、噻唑基、吡啶基和嘧啶基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "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, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2020073152-appb-000065
Figure PCTCN2020073152-appb-000065
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl group may be optionally substituted or unsubstituted. When substituted, 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.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, 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.
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"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.
“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"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.
“羟基”指-OH基团。"Hydroxy" refers to the -OH group.
“卤素”指氟、氯、溴或碘。"Halogen" refers to fluorine, chlorine, bromine or iodine.
“氨基”指-NH 2。 "Amino" refers to -NH 2 .
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO 2。 "Nitro" refers to -NO 2 .
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“THF”指四氢呋喃。"THF" means tetrahydrofuran.
“EtOAc”指乙酸乙酯。"EtOAc" refers to ethyl acetate.
“MeOH”指甲醇。"MeOH" means methanol.
“DMF”指N、N-二甲基甲酰胺。"DMF" means N, N-dimethylformamide.
“DIPEA”指二异丙基乙胺。"DIPEA" means diisopropylethylamine.
“TFA”指三氟乙酸。"TFA" refers to trifluoroacetic acid.
“MeCN”指乙晴。"MeCN" means Otoharu.
“DMA”指N,N-二甲基乙酰胺。"DMA" refers to N,N-dimethylacetamide.
“Et 2O”指乙醚。 "Et 2 O" means diethyl ether.
“DCE”指1,2二氯乙烷。"DCE" refers to 1,2 dichloroethane.
“DIPEA”指N，N-二异丙基乙胺。"DIPEA" refers to N,N-diisopropylethylamine.
“NBS”指N-溴代琥珀酰亚胺。"NBS" refers to N-bromosuccinimide.
“NIS”指N-碘代丁二酰亚胺。"NIS" refers to N-iodosuccinimide.
“Cbz-Cl”指氯甲酸苄酯。"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。 "Pd 2 (dba) 3 "refers to tris(dibenzylideneacetone) dipalladium.
“Dppf”指1,1’-双二苯基膦二茂铁。"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
“KHMDS”指六甲基二硅基胺基钾。"KHMDS" refers to potassium hexamethyldisilazide.
“LiHMDS”指双三甲基硅基胺基锂。"LiHMDS" refers to lithium bistrimethylsilylamide.
“MeLi”指甲基锂。"MeLi" refers to methyl lithium.
“n-BuLi”指正丁基锂。"N-BuLi" means n-butyl lithium.
“NaBH(OAc) 3”指三乙酰氧基硼氢化钠。 "NaBH(OAc) 3 "means sodium triacetoxyborohydride.
“DMAP”指4-二甲氨基吡啶。"DMAP" refers to 4-dimethylaminopyridine.
“SEM-Cl”指氯甲基三甲基硅乙基醚。"SEM-Cl" refers to chloromethyl trimethylsilyl ethyl ether.
“Xantphos”指4,5-双(二苯基膦)-9,9-二甲基氧杂蒽。"Xantphos" refers to 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.
“DCM”指二氯甲烷。"DCM" means dichloromethane.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。"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" and other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。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.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "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. .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"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.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"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.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"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.
附图说明Description of the drawings
图1为不同化合物在咪喹莫特诱导的小鼠银屑病模型中PASI评分结果。Figure 1 shows the PASI scores of different compounds in a mouse psoriasis model induced by imiquimod.
具体实施方式detailed description
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The present invention is further described below in conjunction with examples, but these examples do not limit the scope of the present invention.
实施例Example
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid-mass spectrometry (LC-MS). The NMR chemical shift (δ) 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).
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。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).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。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.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。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.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.
实施例1Example 1
6-(二环[1.1.1]戊烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-(Bicyclo[1.1.1]pentane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3 -Yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000066
Figure PCTCN2020073152-appb-000066
第一步：2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯胺的制备The first step: preparation of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Figure PCTCN2020073152-appb-000067
Figure PCTCN2020073152-appb-000067
3-溴-2-甲氧基苯胺(2.02g,10mmol)，双联频哪醇基二硼烷(3.05g,12mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(816.6mg,1mmol)，醋酸钾(2.45g,25mmol)，混合于二氧六环(20mL)中，反应体系氮气置换三次，100℃反应过夜，冷却至室温，减压浓缩反应液，残留物用水和CH 2Cl 2分液，分离有机相并用饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩后柱层析得到标题化合物2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯胺(2.0g,80％)。 3-Bromo-2-methoxyaniline (2.02g, 10mmol), double pinacol diborane (3.05g, 12mmol), [1,1'-bis(diphenylphosphine)ferrocene] Palladium dichloride dichloromethane complex (816.6mg, 1mmol), potassium acetate (2.45g, 25mmol), mixed in dioxane (20mL), the reaction system was replaced with nitrogen three times, reacted at 100℃ overnight, and cooled to The reaction solution was concentrated under reduced pressure at room temperature. The residue was separated into water and CH 2 Cl 2. The organic phase was separated and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and column chromatography to obtain the title compound 2. -Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 80%).
1H NMR(400MHz,CDCl 3)δ1.36(s,12H),3.83(s,3H),6.92-6.99(m,2H),7.16-7.20(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ 1.36 (s, 12H), 3.83 (s, 3H), 6.92-6.99 (m, 2H), 7.16-7.20 (m, 2H);
MS m/z(ESI):250.1[M+H] +. MS m/z(ESI): 250.1[M+H] + .
第二步：2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯胺的制备Step 2: Preparation of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline
Figure PCTCN2020073152-appb-000068
Figure PCTCN2020073152-appb-000068
2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯胺(2.0g,8mmol)，3-溴-1-甲基-1H-1,2,4-三唑(1.61g,10mmol)，Cs 2CO 3(7.6g,20mmol)，四(三苯基 膦)钯(924.5mg,0.8mmol)，混合于1,4-二氧六环(40mL)和水(5mL)中，反应体系氮气置换三次，100℃反应过夜，冷却至室温，减压浓缩反应液，残留物用水和CH 2Cl 2分液，分离有机相并用饱和氯化钠水溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩后柱层析得到标题化合物2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯胺(1.14g,70％)。 2-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0g, 8mmol), 3-bromo-1 -Methyl-1H-1,2,4-triazole (1.61g, 10mmol), Cs 2 CO 3 (7.6g, 20mmol), tetrakis (triphenylphosphine) palladium (924.5mg, 0.8mmol), mixed in In 1,4-dioxane (40mL) and water (5mL), the reaction system was replaced with nitrogen three times, reacted at 100°C overnight, cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was separated into water and CH 2 Cl 2 . The organic phase was separated and washed with a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and column chromatography to obtain the title compound 2-methoxy-3-(1-methyl-1H-1,2, 4-triazol-3-yl)aniline (1.14 g, 70%).
1H NMR(400MHz,CDCl 3)δ3.77(s,3H),3.99(s,3H),6.81-6.86(m,1H),6.96-7.02(m,1H),7.32-7.37(m,1H),8.1(s,1H)； 1 H NMR(400MHz, CDCl 3 )δ3.77(s,3H),3.99(s,3H),6.81-6.86(m,1H),6.96-7.02(m,1H),7.32-7.37(m,1H) ),8.1(s,1H);
MS m/z(ESI):205.1[M+H] +. MS m/z(ESI): 205.1[M+H] + .
第三步：4,6-二氯哒嗪-3-羧酸锂的制备The third step: Preparation of lithium 4,6-dichloropyridazine-3-carboxylate
Figure PCTCN2020073152-appb-000069
Figure PCTCN2020073152-appb-000069
甲基4,6-二氯哒嗪-3-羧酸酯(2.07g,10mmol)，溴化锂(2.6g,30mmol)溶于乙腈(20mL)和水(2mL)中，冷却至0℃，滴加DIPEA(5.2mL,30mmol)，自然升至室温反应1小时，反应液过滤，滤饼用乙腈(2mL×4)洗涤，收集滤饼，干燥得到标题化合物4,6-二氯哒嗪-3-羧酸锂(1.73g,87％)。Methyl 4,6-dichloropyridazine-3-carboxylate (2.07g, 10mmol), lithium bromide (2.6g, 30mmol) were dissolved in acetonitrile (20mL) and water (2mL), cooled to 0℃, and added dropwise DIPEA (5.2mL, 30mmol), naturally warmed to room temperature and reacted for 1 hour, the reaction solution was filtered, the filter cake was washed with acetonitrile (2mL×4), the filter cake was collected and dried to obtain the title compound 4,6-dichloropyridazine-3- Lithium carboxylate (1.73 g, 87%).
MS m/z(ESI):193.1[M+H] +. MS m/z(ESI): 193.1[M+H] + .
第四步：((6-氯-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧代)锌的制备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
Figure PCTCN2020073152-appb-000070
Figure PCTCN2020073152-appb-000070
2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯胺(1.02g,5.0mmol)，4,6-二氯哒嗪-3-羧酸锂(1.19g,6.0mmol)和醋酸锌(1.1g,6.0mmol)，混合于异丙醇(1mL)和水(7mL)中，65℃反应过夜。反应冷却至室温，加入水(6mL)，搅拌1h，反应液过滤，滤饼用水(6mL×2)和THF(6mL)洗涤，收集滤饼，干燥得到标题化合物((6-氯-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧代)锌(1.44g,73％)。2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.02g, 5.0mmol), 4,6-dichloropyridazine-3-carboxy Lithium oxide (1.19 g, 6.0 mmol) and zinc acetate (1.1 g, 6.0 mmol) were mixed in isopropanol (1 mL) and water (7 mL), and reacted at 65°C overnight. The reaction was cooled to room temperature, water (6mL) was added, stirred for 1h, the reaction solution was filtered, the filter cake was washed with water (6mL×2) and THF (6mL), the filter cake was collected and dried to obtain the title compound ((6-chloro-4-( (2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc (1.44g, 73%).
MS m/z(ESI):361.1[M+H] +. MS m/z(ESI): 361.1[M+H] + .
第五步：((6-(二环[1.1.1]戊烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧代)锌的制备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
Figure PCTCN2020073152-appb-000071
Figure PCTCN2020073152-appb-000071
((6-氯-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧代)锌(157mg,0.4mmol)，二环[1.1.1]戊烷-1-甲酰胺(111mg,1.0mmol)，DBU(61mg,0.4mmol)，碳酸钾(110mg,0.8mmol)，混合于甲苯(1.2mL)和乙腈(0.6mL)中，加入醋酸钯(4.5mg,0.02mmol)和(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(22mg,0.04mmol)，反应体系氮气置换三次，75℃反应过夜。反应冷却至室温，加入水(4mL)和乙酸(2mL)，用石油醚(6mL×2)洗涤，然后分离水相，向水相加水(2mL)，CH 2Cl 2(5mL×3)萃取，合并有机相，用饱和NaCl水溶液洗涤，分离有机相用无水硫酸钠干燥，减压浓缩有机溶剂得到标题化合物((6-(二环[1.1.1]戊烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧代)锌(122mg,65.2％)。 ((6-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl ) Oxo) zinc (157mg, 0.4mmol), bicyclo[1.1.1]pentane-1-carboxamide (111mg, 1.0mmol), DBU (61mg, 0.4mmol), potassium carbonate (110mg, 0.8mmol), Mix in toluene (1.2mL) and acetonitrile (0.6mL), add palladium acetate (4.5mg, 0.02mmol) and (R)-(-)-1-[(S)-2-(dicyclohexylphosphine) two Ferrocene] ethyl di-tert-butyl phosphine (22 mg, 0.04 mmol), the reaction system was replaced with nitrogen three times and reacted at 75°C overnight. The reaction was cooled to room temperature, water (4mL) and acetic acid (2mL) were added, washed with petroleum ether (6mL×2), then the aqueous phase was separated, water (2mL) was added to the aqueous phase, and CH 2 Cl 2 (5mL×3) was added for extraction Combine the organic phases, wash with saturated aqueous NaCl, separate the organic phase and dry with anhydrous sodium sulfate, and concentrate the organic solvent under reduced pressure to obtain the title compound ((6-(Bicyclo[1.1.1]pentane-1-carboxamido) -4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc (122mg, 65.2%).
MS m/z(ESI):436.2[M+H] +. MS m/z(ESI): 436.2[M+H] + .
第六步：6-(二环[1.1.1]戊烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 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
Figure PCTCN2020073152-appb-000072
Figure PCTCN2020073152-appb-000072
((6-(二环[1.1.1]戊烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-羰基)氧代)锌(94mg,0.2mmol)，氘代甲胺盐酸盐(71mg,1.0mmol)，DIPEA(258mg,2.0mmol)，混合于DMF(1mL)中，加入HATU(380mg,1.0mmol)，40℃反应过夜。反应冷却至室温，用饱和碳酸氢钠水溶液与CH 2Cl 2分液，有机相用饱和NaCl水溶液洗涤，用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析得到标题化合物6-(二环[1.1.1]戊烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺(41mg,45％)。 ((6-(Bicyclo[1.1.1]pentane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole -3-yl)phenyl)amino)pyridazine-3-carbonyl)oxo)zinc (94mg, 0.2mmol), deuterated methylamine hydrochloride (71mg, 1.0mmol), DIPEA (258mg, 2.0mmol), Mix in DMF (1 mL), add HATU (380 mg, 1.0 mmol), and react overnight at 40°C. The reaction was cooled to room temperature and separated with saturated aqueous sodium bicarbonate solution and CH 2 Cl 2. The organic phase was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and column chromatography was used to obtain the title compound 6-(two). Cyclo[1.1.1]pentane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzene (Yl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide (41 mg, 45%).
1H NMR(400MHz,CDCl 3)δ2.17(s,6H),2.53(s,1H),3.80(s,3H),4.00(s,3H),7.23-7.29(m,1H),7.51(dd,J＝7.9,1.3Hz,1H),7.81(dd,J＝7.9,1.4Hz,1H),8.09-8.14(m,2H),8.21(s,1H),8.39(s,1H),11.03(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 2.17 (s, 6H), 2.53 (s, 1H), 3.80 (s, 3H), 4.00 (s, 3H), 7.23-7.29 (m, 1H), 7.51 ( dd,J=7.9,1.3Hz,1H),7.81(dd,J=7.9,1.4Hz,1H),8.09-8.14(m,2H),8.21(s,1H),8.39(s,1H),11.03 (s,1H);
MS m/z(ESI):452.2[M+H] +. MS m/z(ESI): 452.2[M+H] + .
实施例2Example 2
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(噁丁环-3-甲酰胺基)哒嗪-3-甲酰胺的制备 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -(Obutacyclo-3-carboxamido)pyridazine-3-carboxamide preparation
Figure PCTCN2020073152-appb-000073
Figure PCTCN2020073152-appb-000073
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(噁丁环-3-甲酰胺基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -(Obutacyclo-3-carboxamido)pyridazine-3-carboxamide is prepared according to Example 1.
MS m/z(ESI):442.2[M+H] +. MS m/z(ESI): 442.2[M+H] + .
实施例3Example 3
6-(环丁甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-(Cyclobutanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -(Methyl-d 3 )pyridazine-3-carboxamide preparation
Figure PCTCN2020073152-appb-000074
Figure PCTCN2020073152-appb-000074
6-(环丁甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclobutanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N Refer to Example 1 for the preparation method of (methyl-d 3 )pyridazine-3-carboxamide.
1H NMR(400MHz,CDCl 3)δ1.85-2.05(m,2H),2.16-2.27(m,2H),2.45-2.33(m,2H),3.33-3.43(m,1H),3.82(s,3H),4.01(s,3H),7.26-7.33(m,1H),7.55(dd,J＝7.0Hz,1H),7.83(dd,J＝7.8,1.1Hz,1H),8.03-8.15(m,2H),8.29(s,1H),9.18(s,1H),11.06(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ1.85-2.05 (m, 2H), 2.16-2.27 (m, 2H), 2.45-2.33 (m, 2H), 3.33-3.43 (m, 1H), 3.82 (s ,3H),4.01(s,3H),7.26-7.33(m,1H),7.55(dd,J=7.0Hz,1H),7.83(dd,J=7.8,1.1Hz,1H),8.03-8.15( m,2H),8.29(s,1H),9.18(s,1H),11.06(s,1H);
MS m/z(ESI):440.2[M+H] +. MS m/z(ESI): 440.2[M+H] + .
实施例4Example 4
6-((1R,2R)-2-氟环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole -3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000075
Figure PCTCN2020073152-appb-000075
6-((1R,2R)-2-氟环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-((1R,2R)-2-fluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole The preparation method of -3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CDCl 3)δ1.18-1.28(m,1H),1.88-2.06(m,2H),3.81(s,3H),4.01(s,3H),4.65-4.95(m,1H),7.24-7.30(m,1H),7.53(dd,J＝7.9,1.3Hz,1H),7.81(dd,J＝7.9,1.4Hz,1H),8.02(s,1H),8.11(s,1H),8.27(s,1H),9.82(s,1H),11.07(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 1.18-1.28 (m, 1H), 1.88-2.06 (m, 2H), 3.81 (s, 3H), 4.01 (s, 3H), 4.65-4.95 (m, 1H) ), 7.24-7.30 (m, 1H), 7.53 (dd, J = 7.9, 1.3 Hz, 1H), 7.81 (dd, J = 7.9, 1.4 Hz, 1H), 8.02 (s, 1H), 8.11 (s, 1H), 8.27(s,1H), 9.82(s,1H), 11.07(s,1H);
MS m/z(ESI):444.2[M+H] +. MS m/z(ESI): 444.2[M+H] + .
实施例5Example 5
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1S,2R)-2-甲基环丙烷-1-甲酰胺基)哒嗪-3-甲酰胺的制备 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -((1S,2R)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000076
Figure PCTCN2020073152-appb-000076
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1S,2R)-2-甲基环丙烷-1-甲酰胺基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -((1S,2R)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide is prepared according to Example 1.
MS m/z(ESI):440.2[M+H] +. MS m/z(ESI): 440.2[M+H] + .
实施例6Example 6
6-((3-环丙基噁丁环-3-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-((3-Cyclopropyloxbutan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3 -Yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000077
Figure PCTCN2020073152-appb-000077
6-((3-环丙基噁丁环-3-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-((3-Cyclopropyloxbutan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3 The preparation method of -yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):454.2[M+H] +. MS m/z(ESI): 454.2[M+H] + .
实施例7Example 7
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((3-甲基噁丁环-3-基)氨基)哒嗪-3-甲酰胺的制备 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -((3-Methyloxbutacyclo-3-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000078
Figure PCTCN2020073152-appb-000078
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((3-甲基噁丁环-3-基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -((3-Methyloxbutacyclo-3-yl)amino)pyridazine-3-carboxamide is prepared according to Example 1.
MS m/z(ESI):428.2[M+H] +. MS m/z(ESI): 428.2[M+H] + .
实施例8Example 8
6-((1-环丙基-2,2,2-三氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-((1-Cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4- Preparation of triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000079
Figure PCTCN2020073152-appb-000079
6-((1-环丙基-2,2,2-三氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-((1-Cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4- The preparation method of triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):480.2[M+H] +. MS m/z(ESI): 480.2[M+H] + .
实施例9Example 9
(R)-6-((1-环丙基-2,2,2-三氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (R)-6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1, Preparation of 2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000080
Figure PCTCN2020073152-appb-000080
(R)-6-((1-环丙基-2,2,2-三氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (R)-6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1, Refer to Example 1 for the preparation method of 2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide.
MS m/z(ESI):480.2[M+H] +. MS m/z(ESI): 480.2[M+H] + .
实施例10Example 10
(S)-6-((1-环丙基-2,2,2-三氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (S)-6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1, Preparation of 2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000081
Figure PCTCN2020073152-appb-000081
(S)-6-((1-环丙基-2,2,2-三氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (S)-6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1, Refer to Example 1 for the preparation method of 2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide.
MS m/z(ESI):480.2[M+H] +. MS m/z(ESI): 480.2[M+H] + .
实施例11Example 11
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1,1,1-三氟丙烷-2-基)氨基)哒嗪-3-甲酰胺的制备 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -((1,1,1-Trifluoropropan-2-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000082
Figure PCTCN2020073152-appb-000082
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1,1,1-三氟丙烷-2-基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -((1,1,1-Trifluoropropan-2-yl)amino)pyridazine-3-carboxamide is prepared according to Example 1.
MS m/z(ESI):454.2[M+H] +. MS m/z(ESI): 454.2[M+H] + .
实施例12Example 12
(R)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1,1,1-三氟丙烷-2-基)氨基)哒嗪-3-甲酰胺的制备 (R)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) Preparation of -6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000083
Figure PCTCN2020073152-appb-000083
(R)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1,1,1-三氟丙烷-2-基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 (R)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) The preparation method of -6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):454.2[M+H] +. MS m/z(ESI): 454.2[M+H] + .
实施例13Example 13
(S)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1,1,1-三氟丙烷-2-基)氨基)哒嗪-3-甲酰胺的制备 (S)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) Preparation of -6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000084
Figure PCTCN2020073152-appb-000084
(S)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1,1,1-三氟丙烷-2-基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 (S)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) The preparation method of -6-((1,1,1-trifluoropropan-2-yl)amino)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):454.2[M+H] +. MS m/z(ESI): 454.2[M+H] + .
实施例14Example 14
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(1-甲基环丙烷-1-甲酰胺基)哒嗪-3-甲酰胺的制备 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -(1-Methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000085
Figure PCTCN2020073152-appb-000085
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(1-甲基环丙烷-1-甲酰胺基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 The preparation method of -(1-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CD 3OD)δ0.77-0.78(m,2H),1.23-1.25(m,2H),1.48(s,3H),3.73(s,3H),4.01(s,3H),7.32(t,J＝8.0Hz,1H),7.58(dd,J＝8.0,1.2Hz,1H),7.68(dd,J＝8.0,1.2Hz,1H),8.18(s,1H),8.47(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.77-0.78 (m, 2H), 1.23-1.25 (m, 2H), 1.48 (s, 3H), 3.73 (s, 3H), 4.01 (s, 3H) ,7.32(t,J=8.0Hz,1H),7.58(dd,J=8.0,1.2Hz,1H),7.68(dd,J=8.0,1.2Hz,1H),8.18(s,1H),8.47( s,1H);
MS m/z(ESI):440.2[M+H] +. MS m/z(ESI): 440.2[M+H] + .
实施例15Example 15
6-(1-氰基环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-(1-cyanocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) (Phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000086
Figure PCTCN2020073152-appb-000086
6-(1-氰基环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(1-cyanocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) Refer to Example 1 for the preparation method of phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide.
1H NMR(400MHz,CDCl 3)δ1.20-1.31(m,2H),1.63-1.67(m,2H),3.76(s,3H),4.01(s,3H),7.23-7.27(m,1H),7.45(dd,J＝8.0,1.2Hz,1H),7.80(dd,J＝8.0,1.2Hz,1H),7.96(s,1H),8.11(s,1H),8.16(br s,1H),9.00(br s,1H),10.99(br s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ1.20-1.31 (m, 2H), 1.63-1.67 (m, 2H), 3.76 (s, 3H), 4.01 (s, 3H), 7.23-7.27 (m, 1H) ),7.45(dd,J=8.0,1.2Hz,1H),7.80(dd,J=8.0,1.2Hz,1H),7.96(s,1H),8.11(s,1H),8.16(br s,1H ),9.00(br s,1H),10.99(br s,1H);
MS m/z(ESI):451.2[M+H] +. MS m/z(ESI): 451.2[M+H] + .
实施例16Example 16
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(1-(三氟甲基)环丙烷-1-甲酰胺基)哒嗪-3-甲酰胺的制备 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -(1-(Trifluoromethyl)cyclopropane-1-carboxamido)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000087
Figure PCTCN2020073152-appb-000087
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(1-(三氟甲基)环丙烷-1-甲酰胺基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 Refer to Example 1 for the preparation method of (1-(trifluoromethyl)cyclopropane-1-carboxamido)pyridazine-3-carboxamide.
1H NMR(400MHz,CD 3OD)δ1.28-1.38(m,2H),1.40-1.48(m,2H),3.73(s,3H),4.01(s,3H),7.29-7.33(m,1H),7.58(dd,J＝8.0,1.2Hz,1H),7.70(dd,J＝8.0,1.2Hz,1H),8.12(s,1H),8.48(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 1.28-1.38 (m, 2H), 1.40-1.48 (m, 2H), 3.73 (s, 3H), 4.01 (s, 3H), 7.29-7.33 (m, 1H), 7.58(dd,J=8.0,1.2Hz,1H), 7.70(dd,J=8.0,1.2Hz,1H), 8.12(s,1H), 8.48(s,1H)
MS m/z(ESI):494.2[M+H] +. MS m/z(ESI): 494.2[M+H] + .
实施例17Example 17
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(1-甲氧基环丙烷-1-甲酰胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1-methoxycyclopropane- Preparation of 1-carboxamido)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000088
Figure PCTCN2020073152-appb-000088
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(1-甲氧基环丙烷-1-甲酰胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1-methoxycyclopropane- The preparation method of 1-carboxamido)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):456.2[M+H] +. MS m/z(ESI): 456.2[M+H] + .
实施例18Example 18
(S)-6-(2,2-二甲基环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (S)-6-(2,2-Dimethylcyclopropane-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
Figure PCTCN2020073152-appb-000089
Figure PCTCN2020073152-appb-000089
(S)-6-(2,2-二甲基环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (S)-6-(2,2-Dimethylcyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4- The preparation method of triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):454.2[M+H] +. MS m/z(ESI): 454.2[M+H] + .
实施例19Example 19
(R)-6-(2,2-二甲基环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (R)-6-(2,2-Dimethylcyclopropane-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
Figure PCTCN2020073152-appb-000090
Figure PCTCN2020073152-appb-000090
(R)-6-(2,2-二甲基环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (R)-6-(2,2-Dimethylcyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4- The preparation method of triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):454.2[M+H] +. MS m/z(ESI): 454.2[M+H] + .
实施例20Example 20
(R)-6-(2,2-二氟环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (R)-6-(2,2-Difluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri (Azol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000091
Figure PCTCN2020073152-appb-000091
(R)-6-(2,2-二氟环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (R)-6-(2,2-Difluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri The preparation method of azol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):462.2[M+H] +. MS m/z(ESI): 462.2[M+H] + .
实施例21Example 21
(S)-6-(2,2-二氟环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (S)-6-(2,2-Difluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri (Azol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000092
Figure PCTCN2020073152-appb-000092
(S)-6-(2,2-二氟环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (S)-6-(2,2-Difluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri The preparation method of azol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):462.2[M+H] +. MS m/z(ESI): 462.2[M+H] + .
实施例22Example 22
6-(环丙磺酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-(Cyclopropanesulfonylamino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -(Methyl-d 3 )pyridazine-3-carboxamide preparation
Figure PCTCN2020073152-appb-000093
Figure PCTCN2020073152-appb-000093
6-(环丙磺酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropanesulfonylamino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N Refer to Example 1 for the preparation method of (methyl-d 3 )pyridazine-3-carboxamide.
1H NMR(400MHz,CD 3OD)δ0.80-0.87(m,2H),0.90-0.93(m,2H),2.51-2.55(m,1H),3.65(s,3H),3.92(s,3H),7.08(s,1H),7.21(t,J＝8.20Hz,1H),7.48(dd,J＝8.0,1.2Hz,1H),7.62(dd,J＝8.0,1.2Hz,1H),8.38(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.80-0.87 (m, 2H), 0.90-0.93 (m, 2H), 2.51-2.55 (m, 1H), 3.65 (s, 3H), 3.92 (s, 3H), 7.08 (s, 1H), 7.21 (t, J = 8.20 Hz, 1H), 7.48 (dd, J = 8.0, 1.2 Hz, 1H), 7.62 (dd, J = 8.0, 1.2 Hz, 1H), 8.38(s,1H);
MS m/z(ESI):462.2[M+H] +. MS m/z(ESI): 462.2[M+H] + .
实施例23Example 23
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-((甲基-d 3)氨基甲酰)哒嗪-3-基)吗啉-4-甲酰胺的制备 N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d 3 ) Preparation of carbamoyl)pyridazin-3-yl)morpholine-4-carboxamide
Figure PCTCN2020073152-appb-000094
Figure PCTCN2020073152-appb-000094
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-((甲基-d 3)氨基甲酰)哒嗪-3-基)吗啉-4-甲酰胺的制备方法参照实施例1。 N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl-d 3 ) The preparation method of carbamoyl)pyridazin-3-yl)morpholine-4-carboxamide refers to Example 1.
MS m/z(ESI):471.2[M+H] +. MS m/z(ESI): 471.2[M+H] + .
实施例24Example 24
6-(3-环丙基脲基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-(3-Cyclopropylureido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(methyl-d 3 )pyridazine-3-carboxamide preparation
Figure PCTCN2020073152-appb-000095
Figure PCTCN2020073152-appb-000095
6-(3-环丙基脲基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(3-Cyclopropylureido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) The preparation method of -N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CDCl 3)δ0.64-0.66(m,2H),0.82-0.87(m,2H),2.71-2.73(m,1H),3.79(s,3H),4.01(s,3H),7.23-7.27(m,1H),7.45(dd,J＝8.0,1.2Hz,1H),7.84(dd,J＝8.0,1.2Hz,1H),8.11(s,1H),11.01(br s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.64-0.66 (m, 2H), 0.82-0.87 (m, 2H), 2.71-2.73 (m, 1H), 3.79 (s, 3H), 4.01 (s, 3H) ),7.23-7.27(m,1H),7.45(dd,J=8.0,1.2Hz,1H),7.84(dd,J=8.0,1.2Hz,1H),8.11(s,1H),11.01(br s ,1H);
MS m/z(ESI):441.2[M+H] +. MS m/z(ESI): 441.2[M+H] + .
实施例25Example 25
环丙基(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-((甲基-d 3)氨基甲酰)哒嗪-3-基)氨基甲酸酯的制备 Cyclopropyl(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl- d 3 ) Preparation of carbamoyl)pyridazin-3-yl)carbamate
Figure PCTCN2020073152-appb-000096
Figure PCTCN2020073152-appb-000096
环丙基(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-((甲基-d 3)氨基甲酰)哒嗪-3-基)氨基甲酸酯的制备方法参照实施例1。 Cyclopropyl(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-((methyl- d 3 ) The preparation method of carbamoyl)pyridazin-3-yl)carbamate refers to Example 1.
MS m/z(ESI):442.2[M+H] +. MS m/z(ESI): 442.2[M+H] + .
实施例26Example 26
6-(2-环丙基乙酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-(2-Cyclopropylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(methyl-d 3 )pyridazine-3-carboxamide preparation
Figure PCTCN2020073152-appb-000097
Figure PCTCN2020073152-appb-000097
6-(2-环丙基乙酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(2-Cyclopropylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) The preparation method of -N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CD 3OD)δ0.24-0.28(m,2H),0.57-0.61(m,2H),1.12-1.15(m,1H),2.37(d,J＝8.0Hz,2H),3.76(s,3H),4.04(s,3H),7.32(t,J＝8.0Hz,1H),7.64(dd,J＝8.0,1.2Hz,1H),7.70(dd,J＝8.0,1.2Hz,1H),8.20(s,1H),8.50(s,1H)； 1 H NMR (400MHz, CD 3 OD) δ 0.24-0.28 (m, 2H), 0.57-0.61 (m, 2H), 1.12-1.15 (m, 1H), 2.37 (d, J = 8.0 Hz, 2H) ,3.76(s,3H),4.04(s,3H),7.32(t,J=8.0Hz,1H),7.64(dd,J=8.0,1.2Hz,1H),7.70(dd,J=8.0,1.2 Hz,1H),8.20(s,1H),8.50(s,1H);
MS m/z(ESI):440.2[M+H] +. MS m/z(ESI): 440.2[M+H] + .
实施例27Example 27
(E)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N'-甲氧基环丙甲酰亚胺酰氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (E)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl Preparation of oxycyclopropimidylamino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000098
Figure PCTCN2020073152-appb-000098
(E)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N'-甲氧基环丙甲酰亚胺酰氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (E)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl Refer to Example 1 for the preparation method of oxycyclopropimidylamino)-N-(methyl-d 3 )pyridazine-3-carboxamide.
MS m/z(ESI):455.2[M+H] +. MS m/z(ESI): 455.2[M+H] + .
实施例28Example 28
(E)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N'-甲氧基乙酰亚氨基酰氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (E)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl Preparation of oxyacetyliminoamido)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000099
Figure PCTCN2020073152-appb-000099
(E)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N'-甲氧基乙酰亚氨基酰氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (E)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl Refer to Example 1 for the preparation method of oxyacetyliminoamido)-N-(methyl-d 3 )pyridazine-3-carboxamide.
MS m/z(ESI):429.2[M+H] +. MS m/z(ESI): 429.2[M+H] + .
实施例29Example 29
(Z)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N'-甲氧基环丙甲酰亚胺酰氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (Z)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl Preparation of oxycyclopropimidylamino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000100
Figure PCTCN2020073152-appb-000100
(Z)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N'-甲氧基环丙甲酰亚胺酰氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (Z)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl Refer to Example 1 for the preparation method of oxycyclopropimidylamino)-N-(methyl-d 3 )pyridazine-3-carboxamide.
MS m/z(ESI):455.2[M+H] +. MS m/z(ESI): 455.2[M+H] + .
实施例30Example 30
(Z)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N'-甲氧基乙酰亚氨基酰氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (Z)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl Preparation of oxyacetyliminoamido)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000101
Figure PCTCN2020073152-appb-000101
(Z)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N'-甲氧基乙酰亚氨基酰氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (Z)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N'-methyl Refer to Example 1 for the preparation method of oxyacetyliminoamido)-N-(methyl-d 3 )pyridazine-3-carboxamide.
MS m/z(ESI):429.2[M+H] +. MS m/z(ESI): 429.2[M+H] + .
实施例31Example 31
(E)-6-(N'-氰基环丙甲酰亚胺酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (E)-6-(N'-cyanocyclopropylcarboximido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole -3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000102
Figure PCTCN2020073152-appb-000102
(E)-6-(N'-氰基环丙甲酰亚胺酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (E)-6-(N'-cyanocyclopropylcarboximido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole The preparation method of -3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):450.2[M+H] +. MS m/z(ESI): 450.2[M+H] + .
实施例32Example 32
(E)-6-(N'-氰基乙酰亚氨基酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (E)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3- (Yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000103
Figure PCTCN2020073152-appb-000103
(E)-6-(N'-氰基乙酰亚氨基酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (E)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3- The preparation method of phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):424.2[M+H] +. MS m/z(ESI): 424.2[M+H] + .
实施例33Example 33
(Z)-6-(N'-氰基环丙甲酰亚胺酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (Z)-6-(N'-cyanocyclopropylcarboximido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole -3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000104
Figure PCTCN2020073152-appb-000104
(Z)-6-(N'-氰基环丙甲酰亚胺酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (Z)-6-(N'-cyanocyclopropylcarboximido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole The preparation method of -3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):450.2[M+H] +. MS m/z(ESI): 450.2[M+H] + .
实施例34Example 34
(Z)-6-(N'-氰基乙酰亚氨基酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (Z)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3- (Yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000105
Figure PCTCN2020073152-appb-000105
(Z)-6-(N'-氰基乙酰亚氨基酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (Z)-6-(N'-cyanoacetimidamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3- The preparation method of phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):424.2[M+H] +. MS m/z(ESI): 424.2[M+H] + .
实施例35Example 35
6-((环亚丙基氟甲基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-((Cyclopropylenefluoromethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl )Amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000106
Figure PCTCN2020073152-appb-000106
6-((环亚丙基氟甲基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-((Cyclopropylenefluoromethyl)amino)-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.
MS m/z(ESI):428.2[M+H] +. MS m/z(ESI): 428.2[M+H] + .
实施例36Example 36
(Z)-6-((1-氟丙-1-烯-1-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (Z)-6-((1-fluoroprop-1-en-1-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4- Preparation of triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000107
Figure PCTCN2020073152-appb-000107
(Z)-6-((1-氟丙-1-烯-1-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (Z)-6-((1-fluoroprop-1-en-1-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4- The preparation method of triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):416.2[M+H] +. MS m/z(ESI): 416.2[M+H] + .
实施例37Example 37
6-((1-环亚丙基-2,2,2-三氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-((1-Cyclopropylene-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4 -Triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000108
Figure PCTCN2020073152-appb-000108
6-((1-环亚丙基-2,2,2-三氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-((1-Cyclopropylene-2,2,2-trifluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4 The preparation method of -triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):478.2[M+H] +. MS m/z(ESI): 478.2[M+H] + .
实施例38Example 38
(E)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1,1,1-三氟丁-2-烯-2-基)氨基)哒嗪-3-甲酰胺的制备 (E)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6-((1,1,1-trifluorobut-2-en-2-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000109
Figure PCTCN2020073152-appb-000109
(E)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1,1,1-三氟丁-2-烯-2-基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 (E)-4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) The preparation method of-6-((1,1,1-trifluorobut-2-en-2-yl)amino)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):466.2[M+H] +. MS m/z(ESI): 466.2[M+H] + .
实施例39Example 39
6-((1-环亚丙基-2,2-二氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 6-((1-Cyclopropylene-2,2-difluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri (Azol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000110
Figure PCTCN2020073152-appb-000110
6-((1-环亚丙基-2,2-二氟乙基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-((1-Cyclopropylene-2,2-difluoroethyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-tri The preparation method of azol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):460.2[M+H] +. MS m/z(ESI): 460.2[M+H] + .
实施例40Example 40
(E)-6-((1,1-二氟丁-2-烯-2-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备 (E)-6-((1,1-Difluorobut-2-en-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2 ,4-Triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000111
Figure PCTCN2020073152-appb-000111
(E)-6-((1,1-二氟丁-2-烯-2-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 (E)-6-((1,1-Difluorobut-2-en-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2 The preparation method of ,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):448.2[M+H] +. MS m/z(ESI): 448.2[M+H] + .
实施例41Example 41
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1-甲基环丙基)氨基)哒嗪-3-甲酰胺的制备 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -((1-Methylcyclopropyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000112
Figure PCTCN2020073152-appb-000112
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1-甲基环丙基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 Refer to Example 1 for the preparation method of ((1-methylcyclopropyl)amino)pyridazine-3-carboxamide.
MS m/z(ESI):412.2[M+H] +. MS m/z(ESI): 412.2[M+H] + .
实施例42Example 42
6-(5-环丙基-4H-1,2,4-三唑-3-基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4 -Triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000113
Figure PCTCN2020073152-appb-000113
6-(5-环丙基-4H-1,2,4-三唑-3-基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)-4-((2-methoxy-3-(1-methyl-1H-1,2,4 The preparation method of -triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):450.2[M+H] +. MS m/z(ESI): 450.2[M+H] + .
实施例43Example 43
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(5-甲基-4H-1,2,4-三唑-3-基)哒嗪-3-甲酰胺 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -(5-Methyl-4H-1,2,4-triazol-3-yl)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000114
Figure PCTCN2020073152-appb-000114
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(5-甲基-4H-1,2,4-三唑-3-基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 The preparation method of -(5-methyl-4H-1,2,4-triazol-3-yl)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):424.2[M+H] +. MS m/z(ESI): 424.2[M+H] + .
实施例44Example 44
6-(5-环丙基-1H-咪唑-2-基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 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
Figure PCTCN2020073152-appb-000115
Figure PCTCN2020073152-appb-000115
6-(5-环丙基-1H-咪唑-2-基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 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.
MS m/z(ESI):449.2[M+H] +. MS m/z(ESI): 449.2[M+H] + .
实施例45Example 45
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(5-甲基-1H-咪唑-2-基)哒嗪-3-甲酰胺 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -(5-Methyl-1H-imidazol-2-yl)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000116
Figure PCTCN2020073152-appb-000116
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(5-甲基-1H-咪唑-2-基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 The preparation method of -(5-methyl-1H-imidazol-2-yl)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):423.2[M+H] +. MS m/z(ESI): 423.2[M+H] + .
实施例46Example 46
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(吡啶-2-磺酰氨基)哒嗪-3-甲酰胺 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -(Pyridine-2-sulfonylamino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000117
Figure PCTCN2020073152-appb-000117
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-(吡啶-2-磺酰氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 The preparation method of -(pyridine-2-sulfonylamino)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):499.2[M+H] +. MS m/z(ESI): 499.2[M+H] + .
实施例47Example 47
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1-甲基-1H-吡唑)-3-磺酰氨基)哒嗪-3-甲酰胺 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 -((1-methyl-1H-pyrazole)-3-sulfonamido)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000118
Figure PCTCN2020073152-appb-000118
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-6-((1-甲基-1H-吡唑)-3-磺酰氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 )-6 Refer to Example 1 for the preparation method of ((1-methyl-1H-pyrazole)-3-sulfonamido)pyridazine-3-carboxamide.
MS m/z(ESI):502.2[M+H] +. MS m/z(ESI): 502.2[M+H] + .
实施例48Example 48
6-(环丙甲酰胺基)-4-((2-(二甲氨基)-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((2-(dimethylamino)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(Methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000119
Figure PCTCN2020073152-appb-000119
6-(环丙甲酰胺基)-4-((2-(二甲氨基)-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((2-(dimethylamino)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) The preparation method of -N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):439.2[M+H] +. MS m/z(ESI): 439.2[M+H] + .
实施例49Example 49
6-(环丙甲酰胺基)-N-(甲基-d 3)-4-((3-(1-甲基-1H-1,2,4-三唑-3-基)-2-(甲硫基)苯基)氨基)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-N-(methyl-d 3 )-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2- (Methylthio)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000120
Figure PCTCN2020073152-appb-000120
6-(环丙甲酰胺基)-N-(甲基-d 3)-4-((3-(1-甲基-1H-1,2,4-三唑-3-基)-2-(甲硫基)苯基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-N-(methyl-d 3 )-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2- The preparation method of (methylthio)phenyl)amino)pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CDCl 3)δ0.87-0.92(m,2H),1.09-1.12(m,2H),1.88-1.96(m,1H),2.27(s,3H),3.99(s,3H),7.41-7.49(m,2H),7.57-7.59(m,1H),8.04(s,1H),8.14(s,1H),8.30(s,1H),10.20(s,1H),11.30(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.87-0.92 (m, 2H), 1.09-1.12 (m, 2H), 1.88-1.96 (m, 1H), 2.27 (s, 3H), 3.99 (s, 3H) ), 7.41-7.49(m, 2H), 7.57-7.59(m, 1H), 8.04(s, 1H), 8.14(s, 1H), 8.30(s, 1H), 10.20(s, 1H), 11.30( s,1H);
MS m/z(ESI):442.2[M+H] +. MS m/z(ESI): 442.2[M+H] + .
实施例50Example 50
6-(环丙甲酰胺基)-N-(甲基-d 3)-4-((3-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-N-(methyl-d 3 )-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2- (Trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000121
Figure PCTCN2020073152-appb-000121
6-(环丙甲酰胺基)-N-(甲基-d 3)-4-((3-(1-甲基-1H-1,2,4-三唑-3-基)-2-(三氟甲氧基)苯基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-N-(methyl-d 3 )-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2- Refer to Example 1 for the preparation method of (trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide.
MS m/z(ESI):480.2[M+H] +. MS m/z(ESI): 480.2[M+H] + .
实施例51Example 51
6-(环丙甲酰胺基)-4-((2-(二氟甲氧基)-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((2-(Difluoromethoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) Amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000122
Figure PCTCN2020073152-appb-000122
6-(环丙甲酰胺基)-4-((2-(二氟甲氧基)-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((2-(Difluoromethoxy)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) The preparation method of amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CDCl 3)δ0.85-0.99(m,2H),1.03-1.12(m,2H),1.73-1.81(m,1H),4.00(s,3H),6.63-7.01(m,1H),7.43-7.48(m,1H),7.54-7.58(m,1H),7.92-7.99(m,2H),8.08-8.16(m,2H),9.83(s,1H),11.16(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.85-0.99 (m, 2H), 1.03-1.12 (m, 2H), 1.73-1.81 (m, 1H), 4.00 (s, 3H), 6.63-7.01 (m ,1H),7.43-7.48(m,1H),7.54-7.58(m,1H),7.92-7.99(m,2H),8.08-8.16(m,2H),9.83(s,1H),11.16(s ,1H);
MS m/z(ESI):462.2[M+H] +. MS m/z(ESI): 462.2[M+H] + .
实施例52Example 52
6-(环丙甲酰胺基)-4-((6-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) Amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000123
Figure PCTCN2020073152-appb-000123
6-(环丙甲酰胺基)-4-((6-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) The preparation method of amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CDCl 3)δ0.84-0.95(m,2H),1.02-1.11(m,2H),1.67-1.76(m,1H),3.78(s,3H),4.00(s,3H),7.06-7.13(m,1H),7.63-7.67(m,1H),7.91-7.97(m,1H),7.98-8.02(m,1H),8.08-8.12(m,1H),9.77(s,1H),10.80(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.84-0.95 (m, 2H), 1.02-1.11 (m, 2H), 1.67-1.76 (m, 1H), 3.78 (s, 3H), 4.00 (s, 3H) ), 7.06-7.13(m, 1H), 7.63-7.67(m, 1H), 7.91-7.97(m, 1H), 7.98-8.02(m, 1H), 8.08-8.12(m, 1H), 9.77(s ,1H),10.80(s,1H);
MS m/z(ESI):444.2[M+H] +. MS m/z(ESI): 444.2[M+H] + .
实施例53Example 53
6-(环丙甲酰胺基)-4-((6-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) Amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000124
Figure PCTCN2020073152-appb-000124
6-(环丙甲酰胺基)-4-((6-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((6-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) The preparation method of amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz，CDCl 3)δ0.89-0.94(m,2H),1.11-1.15(m,2H),1.78-1.84(m,1H),3.81(s,3H),4.01(s,3H),7.23-7.26(m,1H),7.53-7.56(m,1H),8.04(s,1H),8.11(s,1H),8.30(s,1H),9.73(s,1H),11.17(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.89-0.94 (m, 2H), 1.11-1.15 (m, 2H), 1.78-1.84 (m, 1H), 3.81 (s, 3H), 4.01 (s, 3H) ),7.23-7.26(m,1H),7.53-7.56(m,1H),8.04(s,1H),8.11(s,1H),8.30(s,1H),9.73(s,1H),11.17( s,1H);
MS m/z(ESI):444.2[M+H] +. MS m/z(ESI): 444.2[M+H] + .
实施例54Example 54
6-(环丙甲酰胺基)-4-((4-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((4-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) Amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000125
Figure PCTCN2020073152-appb-000125
6-(环丙甲酰胺基)-4-((4-氟-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((4-fluoro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) The preparation method of amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):444.2[M+H] +. MS m/z(ESI): 444.2[M+H] + .
实施例55Example 55
4-((6-氰基-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺 4-((6-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethyl Amido)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000126
Figure PCTCN2020073152-appb-000126
4-((6-氰基-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((6-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethyl The preparation method of amido)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):451.2[M+H] +. MS m/z(ESI): 451.2[M+H] + .
实施例56Example 56
4-((5-氰基-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺 4-((5-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethyl Amido)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000127
Figure PCTCN2020073152-appb-000127
4-((5-氰基-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((5-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethyl The preparation method of amido)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):451.2[M+H] +. MS m/z(ESI): 451.2[M+H] + .
实施例57Example 57
4-((4-氰基-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺 4-((4-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethyl Amido)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000128
Figure PCTCN2020073152-appb-000128
4-((4-氰基-2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(环丙甲酰 胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 4-((4-cyano-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(cyclopropylmethyl The preparation method of amido)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):451.2[M+H] +. MS m/z(ESI): 451.2[M+H] + .
实施例58Example 58
6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N -(Methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000129
Figure PCTCN2020073152-appb-000129
第一步2-甲氧基-3-硝基苯酰胺的的制备The first step is the preparation of 2-methoxy-3-nitrobenzamide
Figure PCTCN2020073152-appb-000130
Figure PCTCN2020073152-appb-000130
室温下，将甲基2-甲氧基-3-硝基苯酸酯(5g,23.7mmol)，溶于氨甲醇溶液中(100mL,7M)，加入氨水(28wt％,50mL)，混合液在室温下搅拌过夜，用乙酸乙酯(300mL)稀释，然后有机相用依次用饱和NaHCO 3水溶液(300mL×2)、饱和食盐水洗涤。分离有机相并用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得标题化合物2-甲氧基-3-硝基苯酰胺(4.3g,92％)。 At room temperature, dissolve methyl 2-methoxy-3-nitrobenzoate (5g, 23.7mmol) in ammonia methanol solution (100mL, 7M), add ammonia water (28wt%, 50mL), the mixture is in Stir overnight at room temperature, dilute with ethyl acetate (300 mL), and then wash the organic phase with saturated aqueous NaHCO 3 (300 mL×2) and saturated brine in turn. The organic phase was separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and column chromatography was used to separate the title compound 2-methoxy-3-nitrobenzamide (4.3 g, 92%).
MS m/z(ESI):197.1[M+H] +. MS m/z(ESI): 197.1[M+H] + .
第二步3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑的制备The second step is the preparation of 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
Figure PCTCN2020073152-appb-000131
Figure PCTCN2020073152-appb-000131
2-甲氧基-3-硝基苯酰胺(4.2g,21.4mmol)溶于DMF-DMA(28.6ml)中，加热至95℃反应1小时，减压浓缩后得到DMF-DMA加成产物粗品，溶于乙醇(20mL)中，以备使用。冰浴下，反应瓶中加入乙醇(70mL)，醋酸(21mL)，搅拌5分钟后，缓慢滴加水合肼(80wt.％,10.5mL)并继续搅拌15分钟后，然后滴加上述DMF-DMA加成产物粗品的乙醇溶液，缓慢升至室温，并在室温下继续搅拌4小时。反应液减压浓缩后，用乙酸乙酯(300mL)稀释，有机相依次 用饱和NaHCO 3水溶液(300mL×2)、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析分离得标题化合物3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(4.5g,95％)。 2-Methoxy-3-nitrobenzamide (4.2g, 21.4mmol) was dissolved in DMF-DMA (28.6ml), heated to 95°C for 1 hour, and concentrated under reduced pressure to obtain the crude DMF-DMA addition product , Dissolved in ethanol (20mL), ready for use. Under ice bath, add ethanol (70mL) and acetic acid (21mL) to the reaction flask. After stirring for 5 minutes, slowly add hydrazine hydrate (80wt.%, 10.5mL) and continue stirring for 15 minutes, then add the above DMF-DMA dropwise Add the ethanol solution of the crude product, slowly warm to room temperature, and continue to stir at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, it was diluted with ethyl acetate (300 mL), and the organic phase was washed with saturated NaHCO 3 aqueous solution (300 mL×2) and saturated brine successively, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography. The title compound 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (4.5 g, 95%).
MS m/z(ESI):221.1[M+H] +. MS m/z(ESI): 221.1[M+H] + .
第三步1-环丙基-3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑的制备The third step is the preparation of 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
Figure PCTCN2020073152-appb-000132
Figure PCTCN2020073152-appb-000132
3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(200mg,0.91mmol)，醋酸铜(198mg,1.1mmol)，2,2’-联吡啶(170mg,1.1mmol)，碳酸钠(192mg,1.8mmol)，混合于1,2-二氯乙烷(5mL)中，室温下加入环丙基硼酸(234mg,2.72mmol)，加热至85℃搅拌过夜。反应液冷却至室温后，加入大量乙酸乙酯稀释。有机相用饱和食盐水洗涤多次，然后分离有机相用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得到标题化合物1-环丙基-3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(125mg,53％)。3-(2-Methoxy-3-nitrophenyl)-1H-1,2,4-triazole (200mg, 0.91mmol), copper acetate (198mg, 1.1mmol), 2,2'-bipyridine (170mg, 1.1mmol), sodium carbonate (192mg, 1.8mmol), mixed in 1,2-dichloroethane (5mL), add cyclopropylboronic acid (234mg, 2.72mmol) at room temperature, heat to 85℃ and stir overnight. After the reaction solution was cooled to room temperature, it was diluted by adding a large amount of ethyl acetate. 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 1-cyclopropyl-3-(2-methoxy-3). -Nitrophenyl)-1H-1,2,4-triazole (125 mg, 53%).
1H NMR(400MHz,CDCl 3)δ1.15-1.21(m,2H),1.24-1.29(m,2H),3.70-3.79(m,1H),3.94(s,3H),7.23-7.31(m,1H),7.78-7.81(m,1H),8.20-8.23(m,1H),8.36(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ1.15-1.21 (m, 2H), 1.24-1.29 (m, 2H), 3.70-3.79 (m, 1H), 3.94 (s, 3H), 7.23-7.31 (m ,1H),7.78-7.81(m,1H),8.20-8.23(m,1H),8.36(s,1H);
MS m/z(ESI):261.1[M+H] +. MS m/z(ESI): 261.1[M+H] + .
第四步3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧基苯胺的制备The fourth step is the preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline
Figure PCTCN2020073152-appb-000133
Figure PCTCN2020073152-appb-000133
往1-环丙基-3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(120mg,0.46mmol)的甲醇(5mL)溶液中加入钯/碳(30mg)，在常温常压氢气氛下反应12小时后，用硅藻土滤除催化剂。滤液减压浓缩有机溶剂得标题化合物3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧基苯胺(102mg)，直接用于下一步反应。To 1-cyclopropyl-3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (120mg, 0.46mmol) in methanol (5mL) was added palladium/ Carbon (30 mg), after reacting for 12 hours in a hydrogen atmosphere at room temperature and pressure, the catalyst was filtered off with celite. The filtrate was concentrated under reduced pressure to obtain the title compound 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (102mg), which was directly used in the next reaction. .
MS m/z(ESI):231.1[M+H] +. MS m/z(ESI): 231.1[M+H] + .
第五步6-氯-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羧酸锌的制备The fifth step 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3- Preparation of zinc carboxylate
Figure PCTCN2020073152-appb-000134
Figure PCTCN2020073152-appb-000134
3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧基苯胺(100mg,0.4mmol)，4,6-二氯哒嗪-3-羧酸锂(103.7mg,0.5mmol)和醋酸锌(95.6mg,0.5mmol)，混合于异丙醇(0.5mL)和水(3.5mL)中，加热至80℃反应过夜。反应冷却至室温，加入水(3mL)，搅拌1h，反应液过滤，滤饼用水(3mL×2)和THF(2mL)洗涤，收集滤饼，干燥得到标题化合物6-氯-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羧酸锌(130mg,78％)。3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyaniline (100mg, 0.4mmol), 4,6-dichloropyridazine-3-carboxy Lithium acid (103.7 mg, 0.5 mmol) and zinc acetate (95.6 mg, 0.5 mmol) were mixed in isopropanol (0.5 mL) and water (3.5 mL), and heated to 80° C. to react overnight. The reaction was cooled to room temperature, water (3mL) was added, stirred for 1h, the reaction solution was filtered, the filter cake was washed with water (3mL×2) and THF (2mL), the filter cake was collected and dried to obtain the title compound 6-chloro-4-((3 -(1-Cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino) zinc pyridazine-3-carboxylate (130 mg, 78%).
MS m/z(ESI):387.1[M+H] +. MS m/z(ESI): 387.1[M+H] + .
第六步6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羧酸锌的制备The sixth step 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino ) Preparation of zinc pyridazine-3-carboxylate
Figure PCTCN2020073152-appb-000135
Figure PCTCN2020073152-appb-000135
6-氯-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羧酸锌(130mg,0.31mmol)，环丙酰胺(86mg,1.0mmol)，DBU(61mg,0.4mmol)，碳酸钾(110mg,0.8mmol)，混合于甲苯(1.2mL)和乙腈(0.6mL)中，加入醋酸钯(4.5mg,0.02mmol)和(R)-(-)-1-[(S)-2-(二环己基膦)二茂铁]乙基二叔丁基膦(22mg,0.04mmol)，反应体系氮气置换三次，加热至75℃反应过夜。反应冷却至室温，加入水(4mL)和乙酸(2mL)，用石油醚(6mL×2)洗涤，然后分离水相，向水相加水(2mL)，CH 2Cl 2(5mL×3)萃取，合并有机相，用饱和NaCl水溶液洗涤，分离有机相用无水硫酸钠干燥，减压浓缩有机溶剂得到标题化合物6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羧酸锌(109mg,75％)。 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylic acid zinc (130mg, 0.31mmol), cyclopropanamide (86mg, 1.0mmol), DBU (61mg, 0.4mmol), potassium carbonate (110mg, 0.8mmol), mixed in toluene (1.2mL) and acetonitrile (0.6mL), add Palladium acetate (4.5mg, 0.02mmol) and (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyldi-tert-butylphosphine (22mg, 0.04mmol) The reaction system was replaced with nitrogen three times, and heated to 75°C for overnight reaction. The reaction was cooled to room temperature, water (4mL) and acetic acid (2mL) were added, washed with petroleum ether (6mL×2), then the aqueous phase was separated, water (2mL) was added to the aqueous phase, and CH 2 Cl 2 (5mL×3) was added for extraction The organic phases were combined, washed with saturated aqueous NaCl solution, the organic phase was separated and dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure to obtain the title compound 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl) Zinc-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxylate (109 mg, 75%).
MS m/z(ESI):436.1[M+H] +. MS m/z(ESI): 436.1[M+H] + .
第七步6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The seventh step 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-N-(Methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000136
Figure PCTCN2020073152-appb-000136
6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)哒嗪-3-羧酸锌(90mg,0.19mmol)，氘代甲胺盐酸盐(71mg,1.0mmol)，DIPEA(258mg,2.0mmol)，混合于DMF(1mL)中，加入HATU(380mg,1.0mmol)，50℃反应过夜。反应冷却至室温，用饱和碳酸氢钠水溶液与CH 2Cl 2分液，有机相用饱和NaCl水溶液洗涤，用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析得到标题化合物6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(35mg,38％)。 6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)pyridazine Zinc-3-carboxylate (90mg, 0.19mmol), deuterated methylamine hydrochloride (71mg, 1.0mmol), DIPEA (258mg, 2.0mmol), mixed in DMF (1mL), add HATU (380mg, 1.0mmol) ), react at 50°C overnight. The reaction was cooled to room temperature and separated with saturated aqueous sodium bicarbonate solution and CH 2 Cl 2. The organic phase was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and column chromatography was used to obtain the title compound 6- Propanamide)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl -d3) Pyridazine-3-carboxamide (35 mg, 38%).
1H NMR(400MHz,CDCl 3)δ0.86-0.99(m,2H),1.07-1.18(m,4H),1.22-1.26(m,2H),1.73-1.82(m,1H),3.65-3.72(m,1H),3.81(s,3H),7.27-7.29(m,1H),7.48-7.52(m,1H),7.81-7.84(m,1H),7.96(s,1H),8.17-8.24(m,2H),9.87(s,1H),11.27(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.86-0.99 (m, 2H), 1.07-1.18 (m, 4H), 1.22-1.26 (m, 2H), 1.73-1.82 (m, 1H), 3.65-3.72 (m, 1H), 3.81 (s, 3H), 7.27-7.29 (m, 1H), 7.48-7.52 (m, 1H), 7.81-7.84 (m, 1H), 7.96 (s, 1H), 8.17-8.24 (m,2H),9.87(s,1H),11.27(s,1H);
MS m/z(ESI):452.2[M+H] +. MS m/z(ESI): 452.2[M+H] + .
实施例59Example 59
6-(环丙甲酰胺基)-4-((3-(1-异丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((3-(1-isopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N -(Methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000137
Figure PCTCN2020073152-appb-000137
6-(环丙甲酰胺基)-4-((3-(1-异丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例58。 6-(Cyclopropylcarboxamido)-4-((3-(1-isopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N Refer to Example 58 for the preparation method of (methyl-d 3 )pyridazine-3-carboxamide.
MS m/z(ESI):454.2[M+H] +. MS m/z(ESI): 454.2[M+H] + .
实施例60Example 60
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(噁丁环-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropanamide)-4-((2-Methoxy-3-(1-(oxbutacyclo-3-yl)-1H-1,2,4-triazol-3-yl) (Phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000138
Figure PCTCN2020073152-appb-000138
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(噁丁环-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例58。 6-(Cyclopropanamide)-4-((2-Methoxy-3-(1-(oxbutacyclo-3-yl)-1H-1,2,4-triazol-3-yl) Refer to Example 58 for the preparation method of phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide.
1H NMR(400MHz,CDCl 3)δ0.90-0.96(m,2H),1.08-1.13(m,2H),1.74-1.80(m,1H),3.87(s,3H),5.07-5.09(m,2H),5.17-5.21(m,2H),5.57-5.64(m,1H),7.27-7.32(m,1H),7.53-7.56(m,1H),7.84-7.87(m,1H),8.02(s,1H),8.23-8.27(m,2H),9.64(s,1H),11.21(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.90-0.96 (m, 2H), 1.08-1.13 (m, 2H), 1.74-1.80 (m, 1H), 3.87 (s, 3H), 5.07-5.09 (m ,2H),5.17-5.21(m,2H),5.57-5.64(m,1H),7.27-7.32(m,1H),7.53-7.56(m,1H),7.84-7.87(m,1H),8.02 (s,1H),8.23-8.27(m,2H),9.64(s,1H),11.21(s,1H);
MS m/z(ESI):468.2[M+H] +. MS m/z(ESI): 468.2[M+H] + .
实施例61Example 61
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamide)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl) (Phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000139
Figure PCTCN2020073152-appb-000139
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(2-甲氧基乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例58。 6-(Cyclopropylcarboxamide)-4-((2-methoxy-3-(1-(2-methoxyethyl)-1H-1,2,4-triazol-3-yl) Refer to Example 58 for the preparation method of phenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide.
1H NMR(400MHz,CDCl 3)δ0.80-0.95(m,2H),1.05-1.15(m,2H),1.85-1.93(m,1H),3.35(s,3H),3.77-3.86(m,5H),4.36-4.44(m,2H),7.23-7.30(m,1H),7.52(dd,J＝7.6Hz,1H),7.82(dd,J＝7.7Hz,1H),8.02(s,1H),8.17-8.30(m,2H),10.14 (s,1H),11.06(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.80-0.95 (m, 2H), 1.05-1.15 (m, 2H), 1.85-1.93 (m, 1H), 3.35 (s, 3H), 3.77-3.86 (m ,5H),4.36-4.44(m,2H),7.23-7.30(m,1H),7.52(dd,J=7.6Hz,1H),7.82(dd,J=7.7Hz,1H),8.02(s, 1H), 8.17-8.30 (m, 2H), 10.14 (s, 1H), 11.06 (s, 1H);
MS m/z(ESI):470.2[M+H] +. MS m/z(ESI): 470.2[M+H] + .
实施例62Example 62
4-((3-(1-(2-氰基乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺 4-((3-(1-(2-cyanoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylmethyl Amido)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000140
Figure PCTCN2020073152-appb-000140
4-((3-(1-(2-氰基乙基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例58。 4-((3-(1-(2-cyanoethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylmethyl Refer to Example 58 for the preparation method of amido)-N-(methyl-d 3 )pyridazine-3-carboxamide.
1H NMR(400MHz,CDCl 3)δ0.86-0.94(m,2H),1.07-1.12(m,2H),1.22-1.26(m,2H),1.74-1.80(m,1H),3.08(t,J＝8.0Hz,2H),3.81(s,3H),4.53(t,J＝8.0Hz,2H),7.27-7.31(m,1H),7.53-7.55(m,1H),7.81-7.83(m,1H),8.05(s,1H),8.23(s,1H),8.26(s,1H),9.57(br s,1H),11.11(br s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.86-0.94 (m, 2H), 1.07-1.12 (m, 2H), 1.22-1.26 (m, 2H), 1.74-1.80 (m, 1H), 3.08 (t ,J=8.0Hz,2H),3.81(s,3H),4.53(t,J=8.0Hz,2H),7.27-7.31(m,1H),7.53-7.55(m,1H),7.81-7.83( m,1H),8.05(s,1H),8.23(s,1H),8.26(s,1H),9.57(br s,1H),11.11(br s,1H);
MS m/z(ESI):465.2[M+H] +. MS m/z(ESI): 465.2[M+H] + .
实施例63Example 63
6-(环丙甲酰胺基)-4-((3-(6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)-2-甲氧苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- 2-Methoxyphenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000141
Figure PCTCN2020073152-appb-000141
6-(环丙甲酰胺基)-4-((3-(6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)-2-甲氧苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)- Refer to Example 1 for the preparation method of 2-methoxyphenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide.
1H NMR(400MHz,CDCl 3)δ0.90-0.95(m,2H),1.08-1.12(m,2H),1.68-1.75(m,1H),2.72-2.79(m,2H),2.98-3.05(m,2H),3.80(s,3H),4.21-4.27(m,2H), 7.23-7.28(m,1H),7.46-7.49(m,1H),7.81-7.84(m,1H),8.00(s,1H),8.19(s,1H),9.42(s,1H),11.12(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.90-0.95 (m, 2H), 1.08-1.12 (m, 2H), 1.68-1.75 (m, 1H), 2.72-2.79 (m, 2H), 2.98-3.05 (m,2H),3.80(s,3H),4.21-4.27(m,2H), 7.23-7.28(m,1H),7.46-7.49(m,1H),7.81-7.84(m,1H),8.00 (s,1H), 8.19(s,1H), 9.42(s,1H), 11.12(s,1H);
MS m/z(ESI):452.2[M+H] +. MS m/z(ESI): 452.2[M+H] + .
实施例64Example 64
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(4-甲基-4H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-N -(Methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000142
Figure PCTCN2020073152-appb-000142
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(4-甲基-4H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)amino)-N Refer to Example 1 for the preparation method of (methyl-d 3 )pyridazine-3-carboxamide.
1H NMR(400MHz,CDCl 3)δ0.94-1.02(m,2H),1.07-1.11(m,2H),1.76-1.84(m,1H),3.48(s,3H),3.83(s,3H),7.30-7.42(m,2H),7.57-7.61(m,1H),7.97-8.02(m,2H),8.19(s,1H),9.97(s,1H),11.28(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.94-1.02 (m, 2H), 1.07-1.11 (m, 2H), 1.76-1.84 (m, 1H), 3.48 (s, 3H), 3.83 (s, 3H) ), 7.30-7.42 (m, 2H), 7.57-7.61 (m, 1H), 7.97-8.02 (m, 2H), 8.19 (s, 1H), 9.97 (s, 1H), 11.28 (s, 1H);
MS m/z(ESI):426.2[M+H] +. MS m/z(ESI): 426.2[M+H] + .
实施例65Example 65
6-(环丙甲酰胺基)-4-((3-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)- 2-Methoxyphenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000143
Figure PCTCN2020073152-appb-000143
6-(环丙甲酰胺基)-4-((3-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)- Refer to Example 1 for the preparation method of 2-methoxyphenyl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide.
1H NMR(400MHz,CDCl 3)δ0.91-0.97(m,2H),1.08-1.12(m,2H),1.96-2.02(m,2H),1.71-1.76(m,1H),2.76-2.80(m,2H),3.13-3.16(m,2H),3.57(s,3H),4.16-4.19(m,2H),7.41-7.43(m,1H),7.50-7.52(m,1H),7.69-7.71(m,1H),7.79(s,1H),8.09(s,1H),11.84(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.91-0.97 (m, 2H), 1.08-1.12 (m, 2H), 1.96-2.02 (m, 2H), 1.71-1.76 (m, 1H), 2.76-2.80 (m,2H),3.13-3.16(m,2H),3.57(s,3H),4.16-4.19(m,2H),7.41-7.43(m,1H),7.50-7.52(m,1H),7.69 -7.71(m,1H),7.79(s,1H),8.09(s,1H),11.84(s,1H);
MS m/z(ESI):452.2[M+H] +. MS m/z(ESI): 452.2[M+H] + .
实施例66Example 66
6-(环丙甲酰胺基)-4-((3-(5-氟-1-甲基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((3-(5-fluoro-1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-N-(Methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000144
Figure PCTCN2020073152-appb-000144
6-(环丙甲酰胺基)-4-((3-(5-氟-1-甲基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((3-(5-fluoro-1-methyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-N-(methyl-d 3 )pyridazine-3-carboxamide is prepared according to Example 1.
MS m/z(ESI):444.2[M+H] +. MS m/z(ESI): 444.2[M+H] + .
实施例67Example 67
6-(环丙甲酰胺基)-5-氟-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) Amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000145
Figure PCTCN2020073152-appb-000145
6-(环丙甲酰胺基)-5-氟-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-5-fluoro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) The preparation method of amino)-N-(methyl-d 3 )pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):444.2[M+H] +. MS m/z(ESI): 444.2[M+H] + .
实施例68Example 68
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-5-甲基-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5 -Methyl-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000146
Figure PCTCN2020073152-appb-000146
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-5-甲基-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5 -Methyl-N-(methyl-d 3 )pyridazine-3-carboxamide is prepared according to Example 1.
MS m/z(ESI):440.2[M+H] +. MS m/z(ESI): 440.2[M+H] + .
实施例69Example 69
5-氰基-6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 5-cyano-6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl )Amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000147
Figure PCTCN2020073152-appb-000147
5-氰基-6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 5-cyano-6-(cyclopropylcarboxamido)-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.
MS m/z(ESI):451.2[M+H] +. MS m/z(ESI): 451.2[M+H] + .
实施例70Example 70
N-(6-(1H-咪唑-2-基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺N-(6-(1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl )Amino)pyridazin-3-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000148
Figure PCTCN2020073152-appb-000148
N-(6-(1H-咪唑-2-基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。N-(6-(1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl The preparation method of )amino)pyridazin-3-yl)cyclopropanamide refers to Example 1.
MS m/z(ESI):432.2[M+H] +. MS m/z(ESI): 432.2[M+H] + .
实施例71Example 71
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(4H-1,2,4-三唑-3-基)哒嗪-3-基)环丙甲酰胺N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(4H-1,2 ,4-Triazol-3-yl)pyridazin-3-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000149
Figure PCTCN2020073152-appb-000149
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(4H-1,2,4-三唑-3-基)哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(4H-1,2 Refer to Example 1 for the preparation method of 4-triazol-3-yl)pyridazin-3-yl)cyclopropanamide.
MS m/z(ESI):433.2[M+H] +. MS m/z(ESI): 433.2[M+H] + .
实施例72Example 72
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(1H-四唑-5-基)哒嗪-3-基)环丙甲酰胺N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1H-tetrazole- 5-yl)pyridazin-3-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000150
Figure PCTCN2020073152-appb-000150
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(1H-四唑-5-基)哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(1H-tetrazole- Refer to Example 1 for the preparation method of 5-yl)pyridazin-3-yl)cyclopropanamide.
MS m/z(ESI):434.2[M+H] +. MS m/z(ESI): 434.2[M+H] + .
实施例73Example 73
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(5-甲基-1H-咪唑-2-基)哒嗪-3-基)环丙甲酰胺N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl- 1H-imidazol-2-yl)pyridazin-3-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000151
Figure PCTCN2020073152-appb-000151
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(5-甲基-1H-咪唑-2-基)哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl- Refer to Example 1 for the preparation method of 1H-imidazol-2-yl)pyridazin-3-yl)cyclopropanamide.
MS m/z(ESI):446.2[M+H] +. MS m/z(ESI): 446.2[M+H] + .
实施例74Example 74
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(5-甲基-4H-1,2,4-三唑-3-基)哒嗪-3-基)环丙甲酰胺N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl- 4H-1,2,4-triazol-3-yl)pyridazin-3-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000152
Figure PCTCN2020073152-appb-000152
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(5-甲基-4H-1,2,4-三唑-3-基)哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。N-(5-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(5-methyl- Refer to Example 1 for the preparation method of 4H-1,2,4-triazol-3-yl)pyridazin-3-yl)cyclopropanamide.
MS m/z(ESI):447.2[M+H] +. MS m/z(ESI): 447.2[M+H] + .
实施例75Example 75
N-(6-(5-环丙基-1H-咪唑-2-基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺N-(6-(5-Cyclopropyl-1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole- 3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000153
Figure PCTCN2020073152-appb-000153
N-(6-(5-环丙基-1H-咪唑-2-基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。N-(6-(5-Cyclopropyl-1H-imidazol-2-yl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole- Refer to Example 1 for the preparation method of 3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide.
MS m/z(ESI):472.2[M+H] +. MS m/z(ESI): 472.2[M+H] + .
实施例76Example 76
N-(6-(5-环丙基-4H-1,2,4-三唑-3-基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺N-(6-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-5-((2-methoxy-3-(1-methyl-1H-1, 2,4-Triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000154
Figure PCTCN2020073152-appb-000154
N-(6-(5-环丙基-4H-1,2,4-三唑-3-基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。N-(6-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-5-((2-methoxy-3-(1-methyl-1H-1, Refer to Example 1 for the preparation method of 2,4-triazol-3-yl)phenyl)amino)pyridazin-3-yl)cyclopropanamide.
MS m/z(ESI):473.2[M+H] +. MS m/z(ESI): 473.2[M+H] + .
实施例77Example 77
N 6-环丙基-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N 3-(甲基-d 3)哒嗪-3,6-二甲酰胺 N 6 -cyclopropyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N 3 -( Methyl-d 3 )pyridazine-3,6-dimethylamide
Figure PCTCN2020073152-appb-000155
Figure PCTCN2020073152-appb-000155
N 6-环丙基-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N 3-(甲基-d 3)哒嗪-3,6-二甲酰胺的制备方法参照实施例1。 N 6 -cyclopropyl-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N 3 -( Refer to Example 1 for the preparation method of methyl-d 3 )pyridazine-3,6-dimethylamide.
1H NMR(400MHz,CDCl 3)δ0.67-0.72(m,2H).0.86-0.90(m,2H),2.92-2.99(m,1H),3.79(s,3H),4.02(s,3H),7.23-7.27(m,1H),7.43-7.45(m,1H),7.88-7.90(m,2H),8.16(s,1H),8.22(s,1H),8.29(s,1H),11.15(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.67-0.72 (m, 2H).0.86-0.90 (m, 2H), 2.92-2.99 (m, 1H), 3.79 (s, 3H), 4.02 (s, 3H) ), 7.23-7.27(m,1H),7.43-7.45(m,1H),7.88-7.90(m,2H), 8.16(s,1H), 8.22(s,1H), 8.29(s,1H), 11.15(s,1H);
MS m/z(ESI):426.2[M+H] +. MS m/z(ESI): 426.2[M+H] + .
实施例78Example 78
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N-(甲基-d 3)氨磺酰)哒嗪-3-基)环丙甲酰胺 N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N-(methyl -d 3 )sulfamoyl)pyridazin-3-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000156
Figure PCTCN2020073152-appb-000156
N-(5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-6-(N-(甲基-d 3)氨磺酰)哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。 N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-(N-(methyl -d 3 )sulfamoyl)pyridazin-3-yl)cyclopropanamide The preparation method refers to Example 1.
MS m/z(ESI):462.2[M+H] +. MS m/z(ESI): 462.2[M+H] + .
实施例79Example 79
N-(6-(羟甲基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺N-(6-(hydroxymethyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) (Azin-3-yl) cyclopropanamide
Figure PCTCN2020073152-appb-000157
Figure PCTCN2020073152-appb-000157
N-(6-(羟甲基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。N-(6-(hydroxymethyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) Refer to Example 1 for the preparation method of azin-3-yl)cyclopropanamide.
MS m/z(ESI):396.2[M+H] +. MS m/z(ESI): 396.2[M+H] + .
实施例80Example 80
N-(6-(2-羟基乙酰基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-基)环丙甲酰胺N-(6-(2-hydroxyacetyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino )Pyridazin-3-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000158
Figure PCTCN2020073152-appb-000158
N-(6-(2-羟基乙酰基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基) 哒嗪-3-基)环丙甲酰胺的制备方法参照实施例1。N-(6-(2-hydroxyacetyl)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino ) The preparation method of pyridazin-3-yl)cyclopropanamide refers to Example 1.
MS m/z(ESI):424.2[M+H] +. MS m/z(ESI): 424.2[M+H] + .
实施例81Example 81
2-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)嘧啶-5-甲酰胺 2-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -(Methyl-d 3 )pyrimidine-5-carboxamide
Figure PCTCN2020073152-appb-000159
Figure PCTCN2020073152-appb-000159
2-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)嘧啶-5-甲酰胺的制备方法参照实施例1。 2-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N Refer to Example 1 for the preparation method of (methyl-d 3 )pyrimidine-5-carboxamide.
MS m/z(ESI):426.2[M+H] +. MS m/z(ESI): 426.2[M+H] + .
实施例82Example 82
3-(环丙甲酰胺基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-1,2,4-三嗪-6-甲酰胺 3-(Cyclopropylcarboxamido)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -(Methyl-d 3 )-1,2,4-triazine-6-carboxamide
Figure PCTCN2020073152-appb-000160
Figure PCTCN2020073152-appb-000160
3-(环丙甲酰胺基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)-1,2,4-三嗪-6-甲酰胺的制备方法参照实施例1。 3-(Cyclopropylcarboxamido)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N Refer to Example 1 for the preparation method of -(methyl-d 3 )-1,2,4-triazine-6-carboxamide.
MS m/z(ESI):427.2[M+H] +. MS m/z(ESI): 427.2[M+H] + .
实施例83Example 83
6-甲氧基-N 2-(2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)-N 4-(5-甲基-1H-吡唑-3-基)嘧啶-2,4-二胺 6-Methoxy-N 2 -(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-N 4 -(5-methyl -1H-pyrazol-3-yl)pyrimidine-2,4-diamine
Figure PCTCN2020073152-appb-000161
Figure PCTCN2020073152-appb-000161
6-甲氧基-N 2-(2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)-N 4-(5-甲基-1H-吡唑-3-基)嘧啶-2,4-二胺的制备方法参照实施例1。 6-Methoxy-N 2 -(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-N 4 -(5-methyl The preparation method of -1-H-pyrazol-3-yl)pyrimidine-2,4-diamine refers to Example 1.
MS m/z(ESI):408.2[M+H] +. MS m/z(ESI): 408.2[M+H] + .
实施例84Example 84
2-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基嘧啶-5-甲酰胺2-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -Methylpyrimidine-5-carboxamide
Figure PCTCN2020073152-appb-000162
Figure PCTCN2020073152-appb-000162
2-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基嘧啶-5-甲酰胺的制备方法参照实施例1。2-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -Methylpyrimidine-5-carboxamide is prepared according to Example 1.
1H NMR(400MHz,DMSO-d 6)δ0.76-0.95(m,4H),2.09-2.21(m,1H),2.82(d,J＝4.4Hz,3H),3.80(s,3H),3.95(s,3H),7.15(t,J＝8.1Hz,1H),7.49(dd,J＝7.8,1.6Hz,1H),8.55(s,1H),8.67(d,J＝4.7Hz,1H),8.75(s,1H),10.92(s,1H),11.90(s,1H)； 1 H NMR(400MHz,DMSO-d 6 )δ0.76-0.95(m,4H), 2.09-2.21(m,1H), 2.82(d,J=4.4Hz,3H), 3.80(s,3H), 3.95 (s, 3H), 7.15 (t, J = 8.1 Hz, 1H), 7.49 (dd, J = 7.8, 1.6 Hz, 1H), 8.55 (s, 1H), 8.67 (d, J = 4.7 Hz, 1H) ),8.75(s,1H),10.92(s,1H),11.90(s,1H);
MS m/z(ESI):423.2[M+H] +. MS m/z(ESI): 423.2[M+H] + .
实施例85Example 85
N-(4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-5-(N-甲基氨磺酰)吡啶-2-基)环丙甲酰胺N-(4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(N-methylamino Sulfonyl)pyridin-2-yl)cyclopropanamide
Figure PCTCN2020073152-appb-000163
Figure PCTCN2020073152-appb-000163
N-(4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-5-(N-甲基氨磺酰)吡啶-2-基)环丙甲酰胺的制备方法参照实施例1。N-(4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(N-methylamino Refer to Example 1 for the preparation method of sulfonyl)pyridin-2-yl)cyclopropanamide.
MS m/z(ESI):458.2[M+H] +. MS m/z(ESI): 458.2[M+H] + .
实施例86Example 86
3-(环丙甲酰胺基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基-1,2,4-三嗪-6-甲酰胺3-(Cyclopropylcarboxamido)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -Methyl-1,2,4-triazine-6-carboxamide
Figure PCTCN2020073152-appb-000164
Figure PCTCN2020073152-appb-000164
3-(环丙甲酰胺基)-5-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-甲基-1,2,4-三嗪-6-甲酰胺的制备方法参照实施例1。3-(Cyclopropylcarboxamido)-5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -Methyl-1,2,4-triazine-6-carboxamide is prepared according to Example 1.
MS m/z(ESI):424.2[M+H] +. MS m/z(ESI): 424.2[M+H] + .
实施例87Example 87
6-(2-环丙基-2-羰基乙酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺 6-(2-Cyclopropyl-2-carbonylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzene (Yl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000165
Figure PCTCN2020073152-appb-000165
6-(2-环丙基-2-羰基乙酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯 基)氨基)-N-(甲基-d 3)哒嗪-3-甲酰胺的制备方法参照实施例1。 6-(2-Cyclopropyl-2-carbonylacetamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzene For the preparation method of (yl)amino)-N-(methyl-d 3 )pyridazine-3-carboxamide, refer to Example 1.
MS m/z(ESI):454.2[M+H] +. MS m/z(ESI): 454.2[M+H] + .
实施例88Example 88
6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl) Amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000166
Figure PCTCN2020073152-appb-000166
第一步3-(5-氟-2-甲氧苯基)-1H-1,2,4-三唑的的制备The first step is the preparation of 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole
Figure PCTCN2020073152-appb-000167
Figure PCTCN2020073152-appb-000167
5-氟-2-甲氧基苯酰胺(3.5g,20.7mmol)溶于DMF-DMA(25ml)中，加热至95℃反应1小时，减压浓缩后得到DMF-DMA加成产物粗品，溶于乙醇(20mL)中，以备使用。冰浴下，反应瓶中加入乙醇(56mL)，醋酸(17mL)，搅拌5分钟后，滴加水合肼(80wt.％,8.4mL)并继续搅拌15分钟后，然后滴加上述DMF-DMA加成产物粗品的乙醇溶液，缓慢升至室温，并在室温下继续搅拌4小时。反应液减压浓缩后，用乙酸乙酯(300mL)稀释，饱和NaHCO 3水溶液(300mL×2)洗涤，分离有机相用饱和食盐水洗涤，有机相用无水硫酸钠干燥，减压浓缩后柱层析分离得标题化合物3-(5-氟-2-甲氧苯基)-1H-1,2,4-三唑(3.1g,77％)。 5-Fluoro-2-methoxybenzamide (3.5g, 20.7mmol) was dissolved in DMF-DMA (25ml), heated to 95°C for 1 hour, and concentrated under reduced pressure to obtain the crude DMF-DMA addition product. In ethanol (20mL), ready for use. Under ice bath, add ethanol (56mL) and acetic acid (17mL) to the reaction flask. After stirring for 5 minutes, add hydrazine hydrate (80wt.%, 8.4mL) dropwise and continue stirring for 15 minutes, then add the above DMF-DMA dropwise. The ethanol solution of the crude product was slowly raised to room temperature, and stirring was continued for 4 hours at room temperature. After the reaction solution was concentrated under reduced pressure, it was diluted with ethyl acetate (300 mL), washed with saturated NaHCO 3 aqueous solution (300 mL×2), the separated organic phase was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Chromatographic separation yielded the title compound 3-(5-fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (3.1 g, 77%).
MS m/z(ESI):194.2[M+H] +. MS m/z(ESI): 194.2[M+H] + .
第二步3-(5-氟-2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑的的制备The second step is the preparation of 3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
Figure PCTCN2020073152-appb-000168
Figure PCTCN2020073152-appb-000168
3-(5-氟-2-甲氧苯基)-1H-1,2,4-三唑(1.1g,5.69mmol)溶于浓硫酸(10mL)中，冰浴下，滴加硝酸(68wt.％,1.05g,11.39mmol),滴加完毕后，冰浴下继续搅拌2小时。反应液倒入冰水中，缓慢滴加氨水，将pH值调至9左右，乙酸乙 酯萃取，分离并干燥有机相，减压浓缩有机溶剂后得到标题化合物3-(5-氟-2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑粗品(1.26g)直接用于下一步反应。3-(5-Fluoro-2-methoxyphenyl)-1H-1,2,4-triazole (1.1g, 5.69mmol) was dissolved in concentrated sulfuric acid (10mL), and nitric acid (68wt .%, 1.05g, 11.39mmol), after the addition is complete, continue to stir under ice bath for 2 hours. The 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.
MS m/z(ESI):239.2[M+H] +. MS m/z(ESI): 239.2[M+H] + .
第三步1-环丙基-3-(5-氟-2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑的的制备The third step is the preparation of 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole
Figure PCTCN2020073152-appb-000169
Figure PCTCN2020073152-appb-000169
3-(5-氟-2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(600mg,2.52mmol)，醋酸铜(688mg,3.8mmol)，2,2’-联吡啶(590mg,3.8mmol)，碳酸钠(534mg,5.0mmol)，混合于1,2-二氯乙烷(5mL)中，室温下加入环丙基硼酸(865mg,10.0mmol)，加热至85℃搅拌过夜。反应液冷却至室温后，加入大量乙酸乙酯稀释。有机相用饱和食盐水洗涤多次，然后分离有机相用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得到标题化合物1-环丙基-3-(5-氟-2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(260mg,38％)。3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (600mg, 2.52mmol), copper acetate (688mg, 3.8mmol), 2,2 '-Bipyridine (590mg, 3.8mmol), sodium carbonate (534mg, 5.0mmol), mixed in 1,2-dichloroethane (5mL), add cyclopropylboronic acid (865mg, 10.0mmol) at room temperature, heat Stir at 85°C overnight. After the reaction solution was cooled to room temperature, it was diluted by adding a large amount of ethyl acetate. 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 1-cyclopropyl-3-(5-fluoro-2-methyl). (Oxy-3-nitrophenyl)-1H-1,2,4-triazole (260 mg, 38%).
1H NMR(400MHz,CDCl 3)δ1.16-1.20(m,2H),1.24-1.27(m,2H),3.64-3.73(m,1H),3.94(s,3H),7.52-7.54(m,1H),7.98-8.01(m,1H),8.23(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 1.16-1.20 (m, 2H), 1.24-1.27 (m, 2H), 3.64-3.73 (m, 1H), 3.94 (s, 3H), 7.52-7.54 (m ,1H),7.98-8.01(m,1H),8.23(s,1H);
MS m/z(ESI):279.0[M+H] +. MS m/z(ESI): 279.0[M+H] + .
第四步3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧基苯胺的的制备The fourth step is the preparation of 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline
Figure PCTCN2020073152-appb-000170
Figure PCTCN2020073152-appb-000170
往1-环丙基-3-(5-氟-2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(260mg,0.93mmol)的甲醇(5mL)溶液中加入钯/碳(60mg)，在常温常压氢气氛下反应8小时后，用硅藻土滤除催化剂。滤液减压浓缩有机溶剂得标题化合物3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧基苯胺(230mg)，直接用于下一步反应。To 1-cyclopropyl-3-(5-fluoro-2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (260mg, 0.93mmol) in methanol (5mL) Palladium/carbon (60 mg) was added to the mixture, and after reacting for 8 hours under a hydrogen atmosphere at room temperature and pressure, the catalyst was filtered off with Celite. The filtrate was concentrated under reduced pressure to obtain the title compound 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline (230mg), which was used directly In the next step.
MS m/z(ESI):249.2[M+H] +. MS m/z(ESI): 249.2[M+H] + .
第五步6-氯-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的的制备The fifth step 6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)- Preparation of N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000171
Figure PCTCN2020073152-appb-000171
室温下，往3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧基苯胺(230mg,0.93mmol)和4,6-二氯-N-(甲基-d3)哒嗪-3-甲酰胺(194mg,0.93mmol)的四氢呋喃(8mL)溶液中，滴加LiHMDS(1M,2.78mL,2.78mmol)的四氢呋喃溶液,反应液室温下搅拌2小时后，用饱和氯化铵水溶液淬灭。二氯甲烷稀释反应液，有机相用饱和食盐水洗涤多次，然后分离有机相用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得到标题化合物6-氯-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(290mg,74％)。At room temperature, to 3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyaniline (230mg, 0.93mmol) and 4,6- Dichloro-N-(methyl-d3)pyridazine-3-carboxamide (194mg, 0.93mmol) in tetrahydrofuran (8mL) solution, dropwise add LiHMDS (1M, 2.78mL, 2.78mmol) in tetrahydrofuran solution, reaction solution After stirring for 2 hours at room temperature, it was quenched with saturated aqueous ammonium chloride solution. The 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%).
MS m/z(ESI):421.2[M+H] +. MS m/z(ESI): 421.2[M+H] + .
第六步6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的的制备The sixth step 6-(cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxy Preparation of phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000172
Figure PCTCN2020073152-appb-000172
6-氯-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(155mg,0.37mmol)，环丙基酰胺(62mg,0.74mmol)，碳酸铯(360mg,1.1mmol)，混合于二氧六环(5mL)中，加入三(二亚苄基丙酮)二钯(101mg,0.11mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(127mg,0.22mmol)，氮气除氧5分钟，微波145℃反应2小时。用二氯甲烷稀释反应液，有机相用饱和食盐水洗涤多次，然后分离有机相用无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得到标题化合物6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(116mg,67％)。6-chloro-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-( Methyl-d3)pyridazine-3-carboxamide (155mg, 0.37mmol), cyclopropylamide (62mg, 0.74mmol), cesium carbonate (360mg, 1.1mmol), mixed in dioxane (5mL), Add tris(dibenzylideneacetone)dipalladium (101mg, 0.11mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (127mg, 0.22mmol), deoxygenate with nitrogen for 5 minutes , Microwave reaction at 145°C for 2 hours. The 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-(cyclopropanamide )-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl -d3) Pyridazine-3-carboxamide (116 mg, 67%).
1H NMR(400MHz,CDCl 3)δ0.90-0.95(m,2H),1.11-1.16(m,4H),1.21-1.26(m,2H),1.74-1.80(m,1H),3.65-3.71(m,1H),3.80(s,3H),7.22-7.25(m,1H), 7.51-7.54(m,1H),8.03(s,1H),8.19(s,1H),8.29(s,1H),9.59(s,1H),11.21(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.90-0.95 (m, 2H), 1.11-1.16 (m, 4H), 1.21-1.26 (m, 2H), 1.74-1.80 (m, 1H), 3.65-3.71 (m,1H),3.80(s,3H),7.22-7.25(m,1H), 7.51-7.54(m,1H),8.03(s,1H),8.19(s,1H),8.29(s,1H) ),9.59(s,1H),11.21(s,1H);
MS m/z(ESI):470.2[M+H] +. MS m/z(ESI): 470.2[M+H] + .
实施例89Example 89
6-(环丙甲酰胺基)-4-((2-甲氧基-5-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺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
Figure PCTCN2020073152-appb-000173
Figure PCTCN2020073152-appb-000173
6-(环丙甲酰胺基)-4-((2-甲氧基-5-甲基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。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.
MS m/z(ESI):440.2[M+H] +. MS m/z(ESI): 440.2[M+H] + .
实施例90Example 90
6-(环丙甲酰胺基)-4-((2-氟-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((2-fluoro-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( Methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000174
Figure PCTCN2020073152-appb-000174
6-(环丙甲酰胺基)-4-((2-氟-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-4-((2-fluoro-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( Refer to Example 1 for the preparation method of methyl-d3)pyridazine-3-carboxamide.
1H NMR(400MHz,CDCl 3)δ0.86-0.93(m,2H),1.06-1.11(m,2H),1.78-1.87(m,1H),4.04(s,3H),7.27-7.33(m,1H),7.46-7.52(m,1H),7.90-7.96(m,1H),8.03(s,1H),8.08-8.15(m,2H),9.99(s,1H),10.95(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.86-0.93 (m, 2H), 1.06-1.11 (m, 2H), 1.78-1.87 (m, 1H), 4.04 (s, 3H), 7.27-7.33 (m ,1H),7.46-7.52(m,1H),7.90-7.96(m,1H),8.03(s,1H),8.08-8.15(m,2H),9.99(s,1H),10.95(s,1H) );
MS m/z(ESI):414.2[M+H] +. MS m/z(ESI): 414.2[M+H] + .
实施例91Example 91
4-((3-(1-烯丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropylcarboxamido)-N -(Methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000175
Figure PCTCN2020073152-appb-000175
第一步3-(2-甲氧基-3-硝基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑的制备The first step 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- Preparation of triazole
Figure PCTCN2020073152-appb-000176
Figure PCTCN2020073152-appb-000176
-20℃下，往3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(1.00g,4.54mmol)、DMAP(55.0mg,0.454mmol)和DIPEA(1.05mL,6.36mmol)的二氯甲烷溶液(20mL)里，缓慢滴加入SEM-Cl(0.964mL,5.45mmol)的二氯甲烷溶液(10mL)。滴加完毕，缓慢升至-10℃，并在该温度下搅拌过夜。反应液用饱和食盐水洗涤，分离有机相并干燥，过滤后减压浓缩有机溶剂，得到的粗品3-(2-甲氧基-3-硝基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑直接用于下一步反应。At -20℃, to 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00g, 4.54mmol), DMAP (55.0mg, 0.454mmol) and To the dichloromethane solution (20 mL) of DIPEA (1.05 mL, 6.36 mmol), slowly dropwise add SEM-Cl (0.964 mL, 5.45 mmol) in dichloromethane solution (10 mL). After the addition is complete, slowly increase to -10°C and stir overnight at this temperature. The reaction solution was washed with saturated brine, the organic phase was separated and dried. After filtration, the organic solvent was concentrated under reduced pressure to obtain crude 3-(2-methoxy-3-nitrophenyl)-1-((2-(三Methylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was directly used in the next reaction.
MS m/z(ESI):351.2[M+H] +. MS m/z(ESI): 351.2[M+H] + .
第二步2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯胺的制备The second step 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline Preparation
Figure PCTCN2020073152-appb-000177
Figure PCTCN2020073152-appb-000177
上述粗品溶于乙醇(30mL)和水(5mL)的混合液里，再依次加入氯化铵固体(1.60g,30.0mmol)和还原铁粉(1.67g,30.0mmol)，然后在50℃下搅拌2小时，然后冷却反应体系，用硅藻土滤除不溶物，滤液浓缩后，残余物用二氯甲 烷溶解，再用饱和食盐水洗涤，分离有机相后用干燥剂干燥，过滤后减压浓缩有机溶剂，柱层析分离得到标题化合物2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯胺(650mg，两步收率：45％)。The above crude product is dissolved in a mixture of ethanol (30mL) and water (5mL), then ammonium chloride solid (1.60g, 30.0mmol) and reduced iron powder (1.67g, 30.0mmol) are added in sequence, and then stirred at 50℃ After 2 hours, the reaction system was cooled, and the insoluble matter was filtered with Celite. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. The organic phase was separated and dried with a desiccant, filtered and concentrated under reduced pressure Organic solvent, column chromatography to obtain the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-tri Azol-3-yl)aniline (650 mg, two-step yield: 45%).
MS m/z(ESI):321.2[M+H] +. MS m/z(ESI): 321.2[M+H] + .
第三步6-氯-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The third step 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- Preparation of triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000178
Figure PCTCN2020073152-appb-000178
0℃，往2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯胺(640mg,2.00mmol)、4,6-二氯-N-(甲基-d3)哒嗪-3-甲酰胺(417mg,2.00mmol)的THF溶液(20mL)里，滴加入LiHMDS(1M in THF,5.00mL)，滴加完毕，再慢慢升至室温，在室温下搅拌2小时。加入饱和食盐水淬灭，再用DCM萃取两次，合并有机相，干燥后减压浓缩有机溶剂，柱层析分离得到标题化合物6-氯-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(780mg,79％)。0℃, to 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl) Aniline (640mg, 2.00mmol), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417mg, 2.00mmol) in THF solution (20mL), dropwise add LiHMDS (1M in THF, 5.00mL), after the addition is complete, slowly warm to room temperature, and stir at room temperature for 2 hours. It was quenched by adding saturated brine, and then extracted twice with DCM. The organic phases were combined, dried, and the organic solvent was concentrated under reduced pressure. The title compound 6-chloro-4-((2-methoxy-3-( 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3 ) Pyridazine-3-carboxamide (780 mg, 79%).
MS m/z(ESI):493.2[M+H] +. MS m/z(ESI): 493.2[M+H] + .
第四步6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The fourth step 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Preparation of 1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000179
Figure PCTCN2020073152-appb-000179
6-氯-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(850mg,1.73mmol)，环丙酰胺(372mg,4.38mmol)和碳酸铯(2.14g,6.57mmol)混合于1,4-dioxane(20mL)中，用氮气洗脱反应溶液除氧5分钟，再依次加入Pd 2(dba) 3(400mg,0.438mmol)和Xantphos(506mg,0.876mmol)。在氮气保护下，微波130℃加热反应90分钟，冷却至室温，减压浓缩有机溶剂后柱层析分离得到标题化合物6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(680mg,73％)。 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole- 3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (850mg, 1.73mmol), cyclopropanamide (372mg, 4.38mmol) and cesium carbonate (2.14g, 6.57mmol) ) Was mixed in 1,4-dioxane (20 mL), the reaction solution was eluted with nitrogen to deoxygenate for 5 minutes, and then Pd 2 (dba) 3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added sequentially. Under the protection of nitrogen, the reaction was heated in a microwave at 130°C for 90 minutes, cooled to room temperature, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound 6-(cyclopropylcarboxamido)-4-((2-methoxy- 3-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(form -D3)pyridazine-3-carboxamide (680 mg, 73%).
MS m/z(ESI):542.3[M+H] +. MS m/z(ESI): 542.3[M+H] + .
第五步6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The fifth step 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( Preparation of methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000180
Figure PCTCN2020073152-appb-000180
0℃下，往6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(630mg,1.16mmol)的DCM溶液里加入TFA(6.0mL)，然后在室温下搅拌过夜。次日减压浓缩有机溶剂，残余物用DCM溶解，再依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，有机相干燥后减压浓缩，柱层析分离得到标题化合物6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(270mg，57％)。At 0℃, to 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (630mg, 1.16mmol) in DCM was added TFA (6.0 mL), and then stirred overnight at room temperature. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, and then washed with saturated aqueous sodium bicarbonate solution and saturated brine successively. The organic phase was dried and concentrated under reduced pressure. The title compound 6-(cyclopropanamide was obtained by column chromatography. Yl)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3- Formamide (270 mg, 57%).
1H NMR(400MHz,CDCl 3)δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H)； 1H NMR (400MHz, CDCl 3 ) δ 0.99-1.03 (m, 2H), 1.10-1.14 (m, 2H), 1.80-1.88 (m, 1H), 3.71 (s, 3H), 7.29-7.38 (m, 1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H);
MS m/z(ESI):412.2[M+H] +. MS m/z(ESI): 412.2[M+H] + .
第六步4-((3-(1-烯丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺 基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备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
Figure PCTCN2020073152-appb-000181
Figure PCTCN2020073152-appb-000181
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(30mg,0.073mmol),烯丙基溴(8.7mg，0.073mmol)和碳酸钾(20mg,0.15mmol)混合于MeCN(3mL)里，在0℃下搅拌2天。减压浓缩反应液，柱层析分离得到标题化合物4-((3-(1-烯丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺(12mg,39％)。6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl- d3) Pyridazine-3-carboxamide (30mg, 0.073mmol), allyl bromide (8.7mg, 0.073mmol) and potassium carbonate (20mg, 0.15mmol) were mixed in MeCN (3mL) and stirred at 0°C for 2 day. The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 4-((3-(1-allyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino )-6-(Cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (12 mg, 39%).
1H NMR(400MHz,CDCl 3)δ0.88-0.92(m,2H),1.10-1.12(m,2H),1.80-1.85(m,1H),3.80(s,3H),4.86-4.88(m,2H),5.35-5.38(m,2H),6.03-6.11(m,1H),7.27-7.31(m,1H),7.52(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),8.03(s,1H),8.15(s,1H),8.24(s,1H),9.88(br s,1H),11.05(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.88-0.92 (m, 2H), 1.10-1.12 (m, 2H), 1.80-1.85 (m, 1H), 3.80 (s, 3H), 4.86-4.88 (m ,2H),5.35-5.38(m,2H),6.03-6.11(m,1H),7.27-7.31(m,1H),7.52(d,J=8.0Hz,1H),7.80(d,J=8.0 Hz,1H),8.03(s,1H),8.15(s,1H),8.24(s,1H),9.88(br s,1H),11.05(s,1H);
MS m/z(ESI):452.2[M+H] +. MS m/z(ESI): 452.2[M+H] + .
实施例92Example 92
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺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
Figure PCTCN2020073152-appb-000182
Figure PCTCN2020073152-appb-000182
第一步3-(2-甲氧基-3-硝基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑的制备The first step 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- Preparation of triazole
Figure PCTCN2020073152-appb-000183
Figure PCTCN2020073152-appb-000183
-20℃下，往3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(1.00g,4.54mmol)、DMAP(55.0mg,0.454mmol)和DIPEA(1.05mL,6.36mmol)的二氯甲烷溶液(20mL)里，缓慢滴加入SEM-Cl(0.964mL,5.45mmol)的二氯甲烷溶液(10mL)。滴加完毕，缓慢升至-10℃，并在该温度下搅拌过夜。反应液用饱和食盐水洗涤，分离有机相并干燥，过滤后减压浓缩有机溶剂，得到的粗品3-(2-甲氧基-3-硝基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑直接用于下一步反应。At -20℃, to 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00g, 4.54mmol), DMAP (55.0mg, 0.454mmol) and To the dichloromethane solution (20 mL) of DIPEA (1.05 mL, 6.36 mmol), slowly dropwise add SEM-Cl (0.964 mL, 5.45 mmol) in dichloromethane solution (10 mL). After the addition is complete, slowly increase to -10°C and stir overnight at this temperature. The reaction solution was washed with saturated brine, the organic phase was separated and dried. After filtration, the organic solvent was concentrated under reduced pressure to obtain crude 3-(2-methoxy-3-nitrophenyl)-1-((2-(三Methylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was directly used in the next reaction.
MS m/z(ESI):351.2[M+H] +. MS m/z(ESI): 351.2[M+H] + .
第二步2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯胺的制备The second step 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline Preparation
Figure PCTCN2020073152-appb-000184
Figure PCTCN2020073152-appb-000184
上述粗品溶于乙醇(30mL)和水(5mL)的混合液里，再依次加入氯化铵固体(1.60g,30.0mmol)和还原铁粉(1.67g,30.0mmol)，然后在50℃下搅拌2小时，然后冷却反应体系，用硅藻土滤除不溶物，滤液浓缩后，残余物用二氯甲烷溶解，再用饱和食盐水洗涤，分离有机相后用干燥剂干燥，过滤后减压浓缩有机溶剂，柱层析分离得到标题化合物2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯胺(650mg，两步收率：45％)。The above crude product is dissolved in a mixture of ethanol (30mL) and water (5mL), then ammonium chloride solid (1.60g, 30.0mmol) and reduced iron powder (1.67g, 30.0mmol) are added in sequence, and then stirred at 50℃ After 2 hours, the reaction system was cooled, and the insoluble matter was filtered with Celite. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. The organic phase was separated and dried with a desiccant, filtered and concentrated under reduced pressure Organic solvent, column chromatography to obtain the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-tri Azol-3-yl)aniline (650 mg, two-step yield: 45%).
MS m/z(ESI):321.2[M+H] +. MS m/z(ESI): 321.2[M+H] + .
第三步6-氯-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The third step 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- Preparation of triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000185
Figure PCTCN2020073152-appb-000185
0℃，往2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯胺(640mg,2.00mmol)、4,6-二氯-N-(甲基-d3)哒嗪-3-甲酰胺(417mg,2.00mmol)的THF溶液(20mL)里，滴加入LiHMDS(1M in THF,5.00mL)，滴加完毕，再慢慢升至室温，在室温下搅拌2小时。加入饱和食盐水淬灭，再用DCM萃取两次，合并有机相，干燥后减压浓缩有机溶剂，柱层析分离得到标题化合物6-氯-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(780mg,79％)。0℃, to 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl) Aniline (640mg, 2.00mmol), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417mg, 2.00mmol) in THF solution (20mL), dropwise add LiHMDS (1M in THF, 5.00mL), after the addition is complete, slowly warm to room temperature, and stir at room temperature for 2 hours. It was quenched by adding saturated brine, and then extracted twice with DCM. The organic phases were combined, dried, and the organic solvent was concentrated under reduced pressure. The title compound 6-chloro-4-((2-methoxy-3-( 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3 ) Pyridazine-3-carboxamide (780 mg, 79%).
MS m/z(ESI):493.2[M+H] +. MS m/z(ESI): 493.2[M+H] + .
第四步6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The fourth step 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Preparation of 1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000186
Figure PCTCN2020073152-appb-000186
6-氯-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(850mg,1.73mmol)，环丙酰胺(372mg,4.38mmol)和碳酸铯(2.14g,6.57mmol)混合于1,4-dioxane(20mL)中，用氮气洗脱反应溶液除氧5分钟，再依次加入Pd 2(dba) 3(400mg,0.438mmol)和Xantphos(506mg,0.876mmol)。在氮气保护下，微波130℃加热反应90分钟，冷却至室温，减压浓缩有机溶剂后柱层析分离得到标题化合物6-(环丙甲酰胺 基)-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(680mg,73％)。 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole- 3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (850mg, 1.73mmol), cyclopropanamide (372mg, 4.38mmol) and cesium carbonate (2.14g, 6.57mmol) ) Was mixed in 1,4-dioxane (20 mL), the reaction solution was eluted with nitrogen to deoxygenate for 5 minutes, and then Pd 2 (dba) 3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added sequentially. Under the protection of nitrogen, the reaction was heated in a microwave at 130°C for 90 minutes, cooled to room temperature, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound 6-(cyclopropylcarboxamido)-4-((2-methoxy- 3-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(form -D3)pyridazine-3-carboxamide (680 mg, 73%).
MS m/z(ESI):542.3[M+H] +. MS m/z(ESI): 542.3[M+H] + .
第五步6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The fifth step 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( Preparation of methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000187
Figure PCTCN2020073152-appb-000187
0℃下，往6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(630mg,1.16mmol)的DCM(20mL)溶液里加入TFA(6.0mL)，然后在室温下搅拌过夜。次日减压浓缩有机溶剂，残余物用DCM溶解，再依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，有机相干燥后减压浓缩，柱层析分离得到标题化合物6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(270mg，57％)。At 0℃, to 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (630mg, 1.16mmol) in DCM (20mL) TFA (6.0 mL), then stirred overnight at room temperature. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, and then washed with saturated aqueous sodium bicarbonate solution and saturated brine successively. The organic phase was dried and concentrated under reduced pressure. The title compound 6-(cyclopropanamide was obtained by column chromatography. Yl)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3- Formamide (270 mg, 57%).
1H NMR(400MHz,CDCl 3)δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.99-1.03 (m, 2H), 1.10-1.14 (m, 2H), 1.80-1.88 (m, 1H), 3.71 (s, 3H), 7.29-7.38 (m ,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H);
MS m/z(ESI):412.2[M+H] +. MS m/z(ESI): 412.2[M+H] + .
第六步6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备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
Figure PCTCN2020073152-appb-000188
Figure PCTCN2020073152-appb-000188
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(30mg,0.073mmol),溴丙炔(8.7mg，0.073mmol)和碳酸钾(20mg,0.15mmol)混合于MeCN(3mL)里，在0℃下搅拌2天。减压浓缩反应液，柱层析分离得到标题化合物6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(10mg,31％)。6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl- d3) Pyridazine-3-carboxamide (30mg, 0.073mmol), bromopropyne (8.7mg, 0.073mmol) and potassium carbonate (20mg, 0.15mmol) were mixed in MeCN (3mL) and stirred at 0°C for 2 days . The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 6-(cyclopropanamide)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)- 1H-1,2,4-Triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (10 mg, 31%).
1H NMR(400MHz,CDCl 3)δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),2.62(s,1H),3.81(s,3H),5.07(s,2H),7.26-7.30(m,1H),7.52(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),8.00(s,1H),8.23(s,1H),8.38(s,1H),9.88(br s,1H),11.13(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.88-0.93 (m, 2H), 1.10-1.14 (m, 2H), 1.75-1.82 (m, 1H), 2.62 (s, 1H), 3.81 (s, 3H) ),5.07(s,2H),7.26-7.30(m,1H),7.52(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),8.00(s,1H),8.23 (s,1H),8.38(s,1H),9.88(br s,1H),11.13(s,1H);
MS m/z(ESI):450.2[M+H] +. MS m/z(ESI): 450.2[M+H] + .
实施例93Example 93
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(2,2,2-三氟乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺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
Figure PCTCN2020073152-appb-000189
Figure PCTCN2020073152-appb-000189
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(2,2,2-三氟乙基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。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.
MS m/z(ESI):494.2[M+H] +. MS m/z(ESI): 494.2[M+H] + .
实施例94Example 94
4-((3-(1-(叔-丁基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲 基-d3)哒嗪-3-甲酰胺4-((3-(1-(tert-butyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanamide )-N-(Methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000190
Figure PCTCN2020073152-appb-000190
4-((3-(1-(叔-丁基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。4-((3-(1-(tert-butyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanamide The preparation method of )-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):468.2[M+H] +. MS m/z(ESI): 468.2[M+H] + .
实施例95Example 95
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(1,1,1-三氟-2-甲基丙烷-2-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropanamide)-4-((2-Methoxy-3-(1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1, 2,4-Triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000191
Figure PCTCN2020073152-appb-000191
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(1,1,1-三氟-2-甲基丙烷-2-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropanamide)-4-((2-Methoxy-3-(1-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-1, Refer to Example 1 for the preparation method of 2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
MS m/z(ESI):522.2[M+H] +. MS m/z(ESI): 522.2[M+H] + .
实施例96Example 96
4-((3-(1-(二环[1.1.1]戊烷-1-基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺4-((3-(1-(Bicyclo[1.1.1]pentan-1-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino) -6-(Cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000192
Figure PCTCN2020073152-appb-000192
4-((3-(1-(二环[1.1.1]戊烷-1-基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。4-((3-(1-(Bicyclo[1.1.1]pentan-1-yl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino) The preparation method of -6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):478.2[M+H] +. MS m/z(ESI): 478.2[M+H] + .
实施例97Example 97
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(噻丁环-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((2-Methoxy-3-(1-(thiabutan-3-yl)-1H-1,2,4-triazol-3-yl) (Phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000193
Figure PCTCN2020073152-appb-000193
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(噻丁环-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-4-((2-Methoxy-3-(1-(thiabutan-3-yl)-1H-1,2,4-triazol-3-yl) Refer to Example 1 for the preparation method of phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
MS m/z(ESI):484.2[M+H] +. MS m/z(ESI): 484.2[M+H] + .
实施例98Example 98
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(3-甲基噁丁环-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((2-Methoxy-3-(1-(3-Methyloxbutan-3-yl)-1H-1,2,4-triazole- 3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000194
Figure PCTCN2020073152-appb-000194
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(3-甲基噁丁环-3-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-4-((2-Methoxy-3-(1-(3-Methyloxbutan-3-yl)-1H-1,2,4-triazole- The preparation method of 3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CDCl 3)δ0.91-0.93(m,2H),1.08-1.13(m,2H),1.72-1.75(m,1H),2.07(s,3H),3.86(s,3H),4.71(d,J＝6.6Hz,2H),5.25(d,J＝6.4Hz,2H),7.28-7.30(m,1H),7.52-7.55(m,1H),7.82-7.85(m,1H)8.05(s,1H),8.23-8.25(m,2H),9.31(s,1H),11.16(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.91-0.93 (m, 2H), 1.08-1.13 (m, 2H), 1.72-1.75 (m, 1H), 2.07 (s, 3H), 3.86 (s, 3H) ), 4.71(d,J=6.6Hz,2H), 5.25(d,J=6.4Hz,2H), 7.28-7.30(m,1H),7.52-7.55(m,1H),7.82-7.85(m, 1H)8.05(s,1H),8.23-8.25(m,2H),9.31(s,1H),11.16(s,1H);
MS m/z(ESI):482.2[M+H] +. MS m/z(ESI): 482.2[M+H] + .
实施例99Example 99
6-(环丙甲硫代酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylmethylthioamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000195
Figure PCTCN2020073152-appb-000195
6-(环丙甲硫代酰氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropylmethylthioamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino) -N-(methyl-d3)pyridazine-3-carboxamide is prepared according to Example 1.
MS m/z(ESI):442.2[M+H] +. MS m/z(ESI): 442.2[M+H] + .
实施例100Example 100
6-(环丙甲酰胺基)-4-((2-(二甲基磷基)-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((2-(Dimethylphosphoryl)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) Amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000196
Figure PCTCN2020073152-appb-000196
6-(环丙甲酰胺基)-4-((2-(二甲基磷基)-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-4-((2-(dimethylphosphorus)-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl) The preparation method of amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):472.2[M+H] +. MS m/z(ESI): 472.2[M+H] + .
实施例101Example 101
6-(环丙甲酰胺基)-N-(甲基-d3)-4-((3-(1-甲基-1H-1,2,4-三唑-3-基)-2-(甲磺酰)苯基)氨基)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-( Methanesulfonyl)phenyl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000197
Figure PCTCN2020073152-appb-000197
6-(环丙甲酰胺基)-N-(甲基-d3)-4-((3-(1-甲基-1H-1,2,4-三唑-3-基)-2-(甲磺酰)苯基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-N-(methyl-d3)-4-((3-(1-methyl-1H-1,2,4-triazol-3-yl)-2-( Refer to Example 1 for the preparation method of methanesulfonyl)phenyl)amino)pyridazine-3-carboxamide.
MS m/z(ESI):474.2[M+H] +. MS m/z(ESI): 474.2[M+H] + .
实施例102Example 102
4-((3-(1-(氰基甲基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺4-((3-(1-(cyanomethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanamide )-N-(Methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000198
Figure PCTCN2020073152-appb-000198
4-((3-(1-(氰基甲基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺 基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。4-((3-(1-(cyanomethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanamide The preparation method of )-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):451.2[M+H] +. MS m/z(ESI): 451.2[M+H] + .
实施例103Example 103
4-((3-(1-(二环[1.1.1]戊烷-1-基甲基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺4-((3-(1-(Bicyclo[1.1.1]pentan-1-ylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl) Amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000199
Figure PCTCN2020073152-appb-000199
4-((3-(1-(二环[1.1.1]戊烷-1-基甲基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-6-(环丙甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。4-((3-(1-(Bicyclo[1.1.1]pentan-1-ylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl) Amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide is prepared according to Example 1.
MS m/z(ESI):492.2[M+H] +. MS m/z(ESI): 492.2[M+H] + .
实施例104Example 104
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(噁丁环-3-基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(oxbutan-3-ylmethyl)-1H-1,2,4-triazole-3- (Yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000200
Figure PCTCN2020073152-appb-000200
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(噁丁环-3-基甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例92。6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-(oxbutan-3-ylmethyl)-1H-1,2,4-triazole-3- The preparation method of phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 92.
1H NMR(400MHz,CDCl 3)δ0.91-0.94(m,2H),1.08-1.14(m,2H),3.55-3.62(m,1H),3.81(s,3H),4.54-4.59(m,4H),4.80-4.90(m,2H),7.27-7.29(m,1H),7.50-7.52(m,1H),7.80-7.82(m,1H),8.06(s,1H),8.13(s,1H),8.20(s,1H),9.14(s,1H),11.09(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.91-0.94 (m, 2H), 1.08-1.14 (m, 2H), 3.55-3.62 (m, 1H), 3.81 (s, 3H), 4.54-4.59 (m , 4H), 4.80-4.90 (m, 2H), 7.27-7.29 (m, 1H), 7.50-7.52 (m, 1H), 7.80-7.82 (m, 1H), 8.06 (s, 1H), 8.13 (s ,1H),8.20(s,1H),9.14(s,1H),11.09(s,1H);
MS m/z(ESI):482.2[M+H] +. MS m/z(ESI): 482.2[M+H] + .
实施例105Example 105
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(4-羰基-5-氮杂螺[2.4]庚烷-5-基)哒嗪-3-甲酰胺4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6- (4-carbonyl-5-azaspiro[2.4]heptan-5-yl)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000201
Figure PCTCN2020073152-appb-000201
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-(4-羰基-5-氮杂螺[2.4]庚烷-5-基)哒嗪-3-甲酰胺的制备方法参照实施例1。4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6- The preparation method of (4-carbonyl-5-azaspiro[2.4]heptan-5-yl)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):452.2[M+H] +. MS m/z(ESI): 452.2[M+H] + .
实施例106Example 106
6-((氰基(环丙基)甲基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) (Phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000202
Figure PCTCN2020073152-appb-000202
6-((氰基(环丙基)甲基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) Refer to Example 1 for the preparation method of phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
MS m/z(ESI):437.2[M+H] +. MS m/z(ESI): 437.2[M+H] + .
实施例107Example 107
(R)-6-((氰基(环丙基)甲基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(R)-6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole- 3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000203
Figure PCTCN2020073152-appb-000203
(R)-6-((氰基(环丙基)甲基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。(R)-6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole- The preparation method of 3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):437.2[M+H] +. MS m/z(ESI): 437.2[M+H] + .
实施例108Example 108
(S)-6-((氰基(环丙基)甲基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(S)-6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole- 3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000204
Figure PCTCN2020073152-appb-000204
(S)-6-((氰基(环丙基)甲基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。(S)-6-((cyano(cyclopropyl)methyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole- The preparation method of 3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):437.2[M+H] +. MS m/z(ESI): 437.2[M+H] + .
实施例109Example 109
6-(1-氟环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(1-fluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzene (Yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000205
Figure PCTCN2020073152-appb-000205
6-(1-氟环丙烷-1-甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(1-fluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzene The preparation method of (yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CDCl 3)δ1.38-1.50(m,4H),3.81(s,3H),4.00(s,3H),7.23-7.29(m,1H),7.49(dd,J＝7.9,1.4Hz,1H),7.81(dd,J＝7.9,1.5Hz,1H),8.09-8.22(m,3H),9.09(s,1H),11.00(s,1H)； 1 H NMR(400MHz, CDCl 3 )δ1.38-1.50(m,4H), 3.81(s,3H), 4.00(s,3H), 7.23-7.29(m,1H), 7.49(dd,J=7.9 ,1.4Hz,1H),7.81(dd,J=7.9,1.5Hz,1H),8.09-8.22(m,3H),9.09(s,1H),11.00(s,1H);
MS m/z(ESI):444.2[M+H] +. MS m/z(ESI): 444.2[M+H] + .
实施例110Example 110
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-((3-乙烯基噁丁环-3-基)氨基)哒嗪-3-甲酰胺4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6- ((3-Vinyloxbutan-3-yl)amino)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000206
Figure PCTCN2020073152-appb-000206
4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)-6-((3-乙烯基噁丁环-3-基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6- The preparation method of ((3-vinyloxbutacyclo-3-yl)amino)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):440.2[M+H] +. MS m/z(ESI): 440.2[M+H] + .
实施例111Example 111
6-((3-乙炔基噁丁环-3-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-((3-ethynyloxbutan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3- (Yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000207
Figure PCTCN2020073152-appb-000207
6-((3-乙炔基噁丁环-3-基)氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-((3-ethynyloxbutan-3-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3- The preparation method of phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
MS m/z(ESI):438.2[M+H] +. MS m/z(ESI): 438.2[M+H] + .
实施例112Example 112
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl- d3) Pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000208
Figure PCTCN2020073152-appb-000208
第一步3-(2-甲氧基-3-硝基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑的制备The first step 3-(2-methoxy-3-nitrophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- Preparation of triazole
Figure PCTCN2020073152-appb-000209
Figure PCTCN2020073152-appb-000209
-20℃下，往3-(2-甲氧基-3-硝基苯基)-1H-1,2,4-三唑(1.00g,4.54mmol)、DMAP(55.0mg,0.454mmol)和DIPEA(1.05mL,6.36mmol)的二氯甲烷溶液(20mL)里，缓慢滴加入SEM-Cl(0.964mL,5.45mmol)的二氯甲烷溶液(10mL)。滴加完毕，缓慢升至-10℃，并在该温度下搅拌过夜。反应液用饱和食盐水洗涤，分离有机相并干燥，过滤后减压浓缩有机溶剂，得到的粗品3-(2-甲氧基-3-硝基苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑直接用于下一步反应。At -20℃, to 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.00g, 4.54mmol), DMAP (55.0mg, 0.454mmol) and To the dichloromethane solution (20 mL) of DIPEA (1.05 mL, 6.36 mmol), slowly dropwise add SEM-Cl (0.964 mL, 5.45 mmol) in dichloromethane solution (10 mL). After the addition is complete, slowly increase to -10°C and stir overnight at this temperature. The reaction solution was washed with saturated brine, the organic phase was separated and dried. After filtration, the organic solvent was concentrated under reduced pressure to obtain crude 3-(2-methoxy-3-nitrophenyl)-1-((2-(三Methylsilyl)ethoxy)methyl)-1H-1,2,4-triazole was directly used in the next reaction.
MS m/z(ESI):351.2[M+H] +. MS m/z(ESI): 351.2[M+H] + .
第二步2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯胺的制备The second step 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)aniline Preparation
Figure PCTCN2020073152-appb-000210
Figure PCTCN2020073152-appb-000210
上述粗品溶于乙醇(30mL)和水(5mL)的混合液里，再依次加入氯化铵固体(1.60g,30.0mmol)和还原铁粉(1.67g,30.0mmol)，然后在50℃下搅拌2小时，然后冷却反应体系，用硅藻土滤除不溶物，滤液浓缩后，残余物用二氯甲烷溶解，再用饱和食盐水洗涤，分离有机相后用干燥剂干燥，过滤后减压浓缩有机溶剂，柱层析分离得到标题化合物2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯胺(650mg，两步收率：45％)。The above crude product is dissolved in a mixture of ethanol (30mL) and water (5mL), then ammonium chloride solid (1.60g, 30.0mmol) and reduced iron powder (1.67g, 30.0mmol) are added in sequence, and then stirred at 50℃ After 2 hours, the reaction system was cooled, and the insoluble matter was filtered with Celite. After the filtrate was concentrated, the residue was dissolved in dichloromethane and washed with saturated brine. The organic phase was separated and dried with a desiccant, filtered and concentrated under reduced pressure Organic solvent, column chromatography to obtain the title compound 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-tri Azol-3-yl)aniline (650 mg, two-step yield: 45%).
MS m/z(ESI):321.2[M+H] +. MS m/z(ESI): 321.2[M+H] + .
第三步6-氯-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The third step 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- Preparation of triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000211
Figure PCTCN2020073152-appb-000211
0℃，往2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯胺(640mg,2.00mmol)、4,6-二氯-N-(甲基-d3)哒嗪-3-甲酰胺(417mg,2.00mmol)的THF溶液(20mL)里，滴加入LiHMDS(1M in THF,5.00mL)，滴加完毕，再慢慢升至室温，在室温下搅拌2小时。加入饱和食盐水淬灭，再用DCM萃取两次，合并有机相，干燥后减压浓缩有机溶剂，柱层析分离得到标题化合物6-氯-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(780mg,79％)。0℃, to 2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl) Aniline (640mg, 2.00mmol), 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (417mg, 2.00mmol) in THF solution (20mL), dropwise add LiHMDS (1M in THF, 5.00mL), after the addition is complete, slowly warm to room temperature, and stir at room temperature for 2 hours. It was quenched by adding saturated brine, and then extracted twice with DCM. The organic phases were combined, dried, and the organic solvent was concentrated under reduced pressure. The title compound 6-chloro-4-((2-methoxy-3-( 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3 ) Pyridazine-3-carboxamide (780 mg, 79%).
MS m/z(ESI):493.2[M+H] +. MS m/z(ESI): 493.2[M+H] + .
第四步6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The fourth step 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Preparation of 1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000212
Figure PCTCN2020073152-appb-000212
6-氯-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(850mg,1.73mmol)，环丙酰胺(372mg,4.38mmol)和碳酸铯(2.14g,6.57mmol)混合于1,4-dioxane(20mL)中，用氮气洗脱反应溶液除氧5分钟，再依次加入Pd 2(dba) 3(400mg,0.438mmol)和Xantphos(506mg,0.876mmol)。在氮气保护下，微波130℃下反应90分钟，冷却至室温，减压浓缩有机溶剂后柱层析分离得到标题化合物6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(680mg,73％)。 6-chloro-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole- 3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (850mg, 1.73mmol), cyclopropanamide (372mg, 4.38mmol) and cesium carbonate (2.14g, 6.57mmol) ) Was mixed in 1,4-dioxane (20 mL), the reaction solution was eluted with nitrogen to deoxygenate for 5 minutes, and then Pd 2 (dba) 3 (400 mg, 0.438 mmol) and Xantphos (506 mg, 0.876 mmol) were added sequentially. Under the protection of nitrogen, the reaction was carried out in a microwave at 130°C for 90 minutes, cooled to room temperature, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound 6-(cyclopropylcarboxamido)-4-((2-methoxy- 3-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(form -D3)pyridazine-3-carboxamide (680 mg, 73%).
MS m/z(ESI):542.3[M+H] +. MS m/z(ESI): 542.3[M+H] + .
第五步6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备The fifth step 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-( Preparation of methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000213
Figure PCTCN2020073152-appb-000213
0℃下，往6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(630mg,1.16mmol)的DCM溶液里加入TFA(6.0mL)，然后在室温下搅拌过夜。次日减压浓缩有机溶剂，残余物用DCM溶解，再依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，有机相干燥后减压浓缩，柱层析分离得到标题化合物6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(270mg，57％)。At 0℃, to 6-(cyclopropylcarboxamido)-4-((2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (630mg, 1.16mmol) in DCM was added TFA (6.0 mL), and then stirred overnight at room temperature. The organic solvent was concentrated under reduced pressure the next day, the residue was dissolved in DCM, and then washed with saturated aqueous sodium bicarbonate solution and saturated brine successively. The organic phase was dried and concentrated under reduced pressure. The title compound 6-(cyclopropanamide was obtained by column chromatography. Yl)-4-((2-methoxy-3-(1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3- Formamide (270 mg, 57%).
1H NMR(400MHz,CDCl 3)δ0.99-1.03(m,2H),1.10-1.14(m,2H),1.80-1.88(m,1H),3.71(s,3H),7.29-7.38(m,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.99-1.03 (m, 2H), 1.10-1.14 (m, 2H), 1.80-1.88 (m, 1H), 3.71 (s, 3H), 7.29-7.38 (m ,1H),7.42-7.50(m,1H),7.98-8.10(m,4H),11.37(br s,1H);
MS m/z(ESI):412.2[M+H] +. MS m/z(ESI): 412.2[M+H] + .
实施例113Example 113
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine -3-carboxamide
Figure PCTCN2020073152-appb-000214
Figure PCTCN2020073152-appb-000214
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine Refer to Example 1 for the preparation method of -3-formamide.
1H NMR(400MHz,DMSO)δ0.79-0.86(m,4H),2.04-2.12(m,1H),3.71(s,3H),3.95(s,3H),7.24-7.25(m,1H),7.49-7.52(m,1H),7.63-7.67(m,1H),7.89(s,1H),8.16(s,1H),8.53-8.58(m,2H),11.06(s,1H),11.33(s,1H)； 1 H NMR(400MHz,DMSO)δ0.79-0.86(m,4H), 2.04-2.12(m,1H), 3.71(s,3H), 3.95(s,3H), 7.24-7.25(m,1H) ,7.49-7.52(m,1H),7.63-7.67(m,1H),7.89(s,1H),8.16(s,1H),8.53-8.58(m,2H),11.06(s,1H),11.33 (s,1H);
MS m/z(ESI):409.2[M+H] +. MS m/z(ESI): 409.2[M+H] + .
实施例114Example 114
6-(环丙甲酰胺基)-4-((5-氟-2-甲氧基-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropanamide)-4-((5-fluoro-2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-tri (Azol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000215
Figure PCTCN2020073152-appb-000215
6-(环丙甲酰胺基)-4-((5-氟-2-甲氧基-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例92。6-(Cyclopropanamide)-4-((5-fluoro-2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-tri The preparation method of azol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 92.
1H NMR(400MHz,DMSO-d 6)δ0.84-0.87(m,2H),1.23-1.34(m,2H),2.09-2.12(m,1H),3.60(s,1H),3.75(s,3H),5.24(s,2H),7.39-7.47(m,2H),8.26(s,1H),8.72(s,1H),9.19(s,1H),11.20(s,1H),11.41(s,1H)； 1 H NMR (400MHz, DMSO-d 6 ) δ 0.84-0.87 (m, 2H), 1.23-1.34 (m, 2H), 2.09-2.12 (m, 1H), 3.60 (s, 1H), 3.75 (s ,3H),5.24(s,2H),7.39-7.47(m,2H),8.26(s,1H),8.72(s,1H),9.19(s,1H),11.20(s,1H),11.41( s,1H);
MS m/z(ESI):468.2[M+H] +. MS m/z(ESI): 468.2[M+H] + .
实施例115Example 115
6-(环丙甲酰胺基)-4-((3-(1-(环丙基甲基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl) Amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000216
Figure PCTCN2020073152-appb-000216
6-(环丙甲酰胺基)-4-((3-(1-(环丙基甲基)-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-4-((3-(1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl) The preparation method of amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CDCl 3)δ0.44-0.48(m,2H),0.70-0.76(m,2H),0.86-0.93(m,2H),1.08-1.11(m,2H),1.33-1.40(m,1H),1.82-1.89(m,1H),3.82(s,3H),4.10(d,J＝7.2Hz,2H),7.25-7.30(m,1H),7.50-7.54(m,1H),7.80-7.83(m,1H),8.02(s,1H),8.23-8.25(m,2H),9.98(s,1H),11.04(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.44-0.48 (m, 2H), 0.70-0.76 (m, 2H), 0.86-0.93 (m, 2H), 1.08-1.11 (m, 2H), 1.33-1.40 (m,1H),1.82-1.89(m,1H),3.82(s,3H),4.10(d,J=7.2Hz,2H),7.25-7.30(m,1H),7.50-7.54(m,1H ),7.80-7.83(m,1H),8.02(s,1H),8.23-8.25(m,2H),9.98(s,1H),11.04(s,1H);
MS m/z(ESI):466.2[M+H] +. MS m/z(ESI): 466.2[M+H] + .
实施例116Example 116
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺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
Figure PCTCN2020073152-appb-000217
Figure PCTCN2020073152-appb-000217
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例92，实施例116是第六步反应的产物之一。6-(Cyclopropanamide)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole-3- The preparation method of phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 92. Example 116 is one of the products of the sixth step.
1H NMR(400MHz,CDCl 3)δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),2.39(s,1H),3.48(s,3H),4.94(d,J＝6.4Hz,2H),7.26-7.36(m,1H),7.43(d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),8.07(s,1H),8.12(s,1H),9.64(br s,1H),11.07(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.88-0.93 (m, 2H), 1.10-1.14 (m, 2H), 1.75-1.82 (m, 1H), 2.39 (s, 1H), 3.48 (s, 3H) ), 4.94(d,J=6.4Hz,2H),7.26-7.36(m,1H),7.43(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),8.07(s ,1H),8.12(s,1H),9.64(br s,1H),11.07(s,1H);
MS m/z(ESI):450.2[M+H] +. MS m/z(ESI): 450.2[M+H] + .
实施例117Example 117
6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-5-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-5-yl)-5-fluoro-2-methoxyphenyl) Amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000218
Figure PCTCN2020073152-appb-000218
6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-5-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-5-yl)-5-fluoro-2-methoxyphenyl) The preparation method of amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 1.
1H NMR(400MHz,CDCl 3)δ0.93-1.02(m,4H),1.05-1.11(m,4H),1.75-1.82(m,1H),3.48(s,3H),3.61-3.70(m,1H),7.13-7.17(m,1H),7.29-7.33(m,1H),7.93(s,2H),8.18(s,1H),10.61(s,1H),11.59(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.93-1.02 (m, 4H), 1.05-1.11 (m, 4H), 1.75-1.82 (m, 1H), 3.48 (s, 3H), 3.61-3.70 (m ,1H),7.13-7.17(m,1H),7.29-7.33(m,1H),7.93(s,2H),8.18(s,1H),10.61(s,1H),11.59(s,1H);
MS m/z(ESI):470.1[M+H] +. MS m/z(ESI): 470.1[M+H] + .
实施例118Example 118
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(4-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺6-(Cyclopropanamide)-4-((2-methoxy-3-(4-(prop-2-yn-1-yl)-1H-1,2,4-triazole-3- (Yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
Figure PCTCN2020073152-appb-000219
Figure PCTCN2020073152-appb-000219
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(4-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的制备方法参照实施例92，实施例118是第六步反应的产物之一。6-(Cyclopropanamide)-4-((2-methoxy-3-(4-(prop-2-yn-1-yl)-1H-1,2,4-triazole-3- The preparation method of phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide refers to Example 92, and Example 118 is one of the products of the sixth step.
1H NMR(400MHz,CDCl 3)δ0.88-0.93(m,2H),1.10-1.14(m,2H),1.75-1.82(m,1H),1.71(s,1H),3.81(s,3H),5.71(d,J＝6.4Hz,2H),7.22-7.30(m,1H),7.52(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),8.07(s,1H),8.20(s,1H),8.29(s,1H),9.10(br s,1H),11.07(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.88-0.93 (m, 2H), 1.10-1.14 (m, 2H), 1.75-1.82 (m, 1H), 1.71 (s, 1H), 3.81 (s, 3H) ), 5.71(d,J=6.4Hz,2H),7.22-7.30(m,1H),7.52(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),8.07(s ,1H),8.20(s,1H),8.29(s,1H),9.10(br s,1H),11.07(s,1H);
MS m/z(ESI):450.2[M+H] +. MS m/z(ESI): 450.2[M+H] + .
实施例119Example 119
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)尼克酰胺6-(Cyclopropanamide)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole-3- (Yl)phenyl)amino)-N-(methyl-d3)nicotamide
Figure PCTCN2020073152-appb-000220
Figure PCTCN2020073152-appb-000220
6-(环丙甲酰胺基)-4-((2-甲氧基-3-(1-(丙-2-炔-1-基)-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)尼克酰胺的制备方法参照实施例92。6-(Cyclopropanamide)-4-((2-methoxy-3-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazole-3- For the preparation method of phenyl)amino)-N-(methyl-d3)nicotamide, refer to Example 92.
1H NMR(400MHz,DMSO-d 6)δ0.88-0.91(m,2H),1.03-1.09(m,2H),1.55-1.65(m,1H),3.81(s,3H),5.06(s,2H),6.79(s,1H),7.26-7.77(m,2H),8.06-8.37(m,3H),9.01(br s,1H),10.63(br s,1H)； 1 H NMR (400MHz, DMSO-d 6 ) δ 0.88-0.91 (m, 2H), 1.03-1.09 (m, 2H), 1.55-1.65 (m, 1H), 3.81 (s, 3H), 5.06 (s ,2H),6.79(s,1H),7.26-7.77(m,2H),8.06-8.37(m,3H),9.01(br s,1H),10.63(br s,1H);
MS m/z(ESI):449.2[M+H] +. MS m/z(ESI): 449.2[M+H] + .
实施例120Example 120
6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d3)尼克酰胺6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N -(Methyl-d3) Nicotinamide
Figure PCTCN2020073152-appb-000221
Figure PCTCN2020073152-appb-000221
6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-2-甲氧苯基)氨基)-N-(甲基-d3)尼克酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-N -(Methyl-d3) Nicotinamide is prepared according to Example 1.
1H NMR(400MHz,CDCl 3)δ0.84-0.89(m,2H),1.03-1.08(m,2H),1.11-1.14(m,2H),1.21-1.25(m,2H),1.51-1.57(m,1H),3.63-3.70(m,1H),3.81(s,3H),6.46(s,1H),7.19-7.24(m,1H),7.51-7.54(m,1H),7.68-7.70(m,1H),8.06(s,1H),8.17(s,1H),8.30(s,1H),8.60(s,1H),10.41(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.84-0.89 (m, 2H), 1.03-1.08 (m, 2H), 1.11-1.14 (m, 2H), 1.21-1.25 (m, 2H), 1.51-1.57 (m,1H),3.63-3.70(m,1H),3.81(s,3H),6.46(s,1H),7.19-7.24(m,1H),7.51-7.54(m,1H),7.68-7.70 (m,1H),8.06(s,1H),8.17(s,1H),8.30(s,1H),8.60(s,1H),10.41(s,1H);
MS m/z(ESI):451.1[M+H] +. MS m/z(ESI): 451.1[M+H] + .
实施例121Example 121
6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)尼克酰胺6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl) Amino)-N-(methyl-d3) Nicotinamide
Figure PCTCN2020073152-appb-000222
Figure PCTCN2020073152-appb-000222
6-(环丙甲酰胺基)-4-((3-(1-环丙基-1H-1,2,4-三唑-3-基)-5-氟-2-甲氧苯基)氨基)-N-(甲基-d3)尼克酰胺的制备方法参照实施例1。6-(Cyclopropylcarboxamido)-4-((3-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-5-fluoro-2-methoxyphenyl) Refer to Example 1 for the preparation method of amino)-N-(methyl-d3)nicotamide.
1H NMR(400MHz,CDCl 3)δ0.87-0.94(m,2H),1.06-1.16(m,4H),1.20-1.25(m,2H),1.56-1.66(m,1H),3.65-3.69(m,1H),3.81(s,3H),6.84(s,1H),7.44-7.50(m,1H),8.13-8.17(m,2H),8.47(s,1H),9.12(s,1H),10.77(s,1H)； 1 H NMR (400MHz, CDCl 3 ) δ 0.87-0.94 (m, 2H), 1.06-1.16 (m, 4H), 1.20-1.25 (m, 2H), 1.56-1.66 (m, 1H), 3.65-3.69 (m,1H),3.81(s,3H),6.84(s,1H),7.44-7.50(m,1H),8.13-8.17(m,2H),8.47(s,1H),9.12(s,1H) ),10.77(s,1H);
MS m/z(ESI):469.2[M+H] +. MS m/z(ESI): 469.2[M+H] + .
生物学测试评价Biological test evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发 明的范围。The following further describes the present invention in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.
测试例1、本发明化合物对细胞TYK2信号通路抑制作用的测定Test Example 1. Determination of the inhibitory effect of the compound of the present invention on the cellular TYK2 signal pathway
实验目的：该测试例的目的是测试化合物对细胞TYK2信号通路抑制的活性。Experimental purpose: The purpose of this test case is to test the inhibitory activity of the compound on the cellular TYK2 signaling pathway.
实验仪器：laboratory apparatus:
离心机(5702R)购自Eppendorf公司，The centrifuge (5702R) was purchased from Eppendorf,
移液器购自Eppendorf公司，The pipette was purchased from Eppendorf,
酶标仪购自美国BioTek公司，型号为SynergyH1全功能酶标仪。The microplate reader was purchased from BioTek, USA, and the model was SynergyH1 full-function microplate reader.
实验方法：本实验采用表达TYK2的U266细胞系，通过INF-α刺激激活TYK2信号通路，检测化合物对其下游STAT3磷酸化的抑制活性，并得出化合物对TYK2信号通路活性的半数抑制浓度IC 50。 Experimental method: In this experiment, the U266 cell line expressing TYK2 was used to activate the TYK2 signaling pathway through INF-α stimulation, to detect the inhibitory activity of the compound on its downstream STAT3 phosphorylation, and to obtain the half inhibitory concentration IC 50 of the compound on the TYK2 signaling pathway activity .
具体实验操作如下：The specific experimental operations are as follows:
384孔检测板中铺入U266细3-12μL，每孔细胞个数为100-300K，加入2μL梯度稀释好的化合物溶液，二氧化碳培养箱孵育2小时。2小时后加入2μL INF-α，INF-α终浓度1000U/mL，室温震荡20min。加入2-5μL(5X)LANCE Ultra Lysis Buffer 2溶液，室温度震荡2h。2h后加入5μL终浓度为2nM的LANCE Ultra Eu-labeled Anti-STAT5(Y694/Y699)Antibody(PerkinElmer)和终浓度为20nM的LANCE Ultra ULight-labeled Anti-STAT5 Antibody(PerkinElmer)溶液，室温孵育过夜。酶标仪测定各板孔的665nm荧光信号值，通过荧光信号值计算抑制率，根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50。 Pour 3-12μL of U266 into the 384-well detection plate, the number of cells per well is 100-300K, add 2μL of the diluted compound solution, and incubate for 2 hours in a carbon dioxide incubator. After 2 hours, add 2μL of INF-α, the final concentration of INF-α is 1000U/mL, and shake at room temperature for 20min. Add 2-5μL (5X) LANCE Ultra Lysis Buffer 2 solution and shake the room temperature for 2h. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT5 (Y694/Y699) Antibody (PerkinElmer) with a final concentration of 2 nM and LANCE Ultra ULight-labeled Anti-STAT5 Antibody (PerkinElmer) with a final concentration of 20 nM were added, and incubated overnight at room temperature. The microplate reader measures the 665nm fluorescence signal value of each well, calculates the inhibition rate from the fluorescence signal value, and obtains the IC 50 of the compound by curve fitting according to the inhibition rate of different concentrations.
实验数据处理方法：Experimental data processing method:
通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不加细胞)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC 50值。 Calculate the percentage inhibition data of the wells treated with the compound through the positive control wells (DMSO control wells) and negative control wells (without cells) on the plate {% inhibition rate = 100-[(test compound value-negative control value)]/ (Positive control value-negative control value)×100}. Use GraphPad prism to fit data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC 50 value.
实验结论：Experimental results:
通过以上方案得出本发明所示的化合物在细胞TYK2信号通路抑制的活性试验数据如下表所示：Through the above scheme, the activity test data of the compound shown in the present invention in inhibiting the cell TYK2 signaling pathway are shown in the following table:
化合物编号Compound number 细胞活性U266 pSTAT3(nM)Cell activity U266 pSTAT3 (nM)
实施例3Example 3 4.364.36
实施例4Example 4 4.224.22
实施例53Example 53 2.432.43
实施例58Example 58 1.411.41
实施例60Example 60 6.016.01
实施例88Example 88 0.830.83
实施例89Example 89 4.954.95
实施例91Example 91 0.340.34
实施例92Example 92 0.130.13
实施例98Example 98 0.900.90
实施例104Example 104 1.881.88
实施例112Example 112 4.64.6
实施例114Example 114 2.102.10
实施例115Example 115 3.433.43
实施例118Example 118 1.271.27
实施例119Example 119 4.224.22
实施例120Example 120 1.651.65
实施例121Example 121 3.013.01
测试例2、本发明化合物对细胞JAK2信号通路抑制作用的测定Test Example 2. Determination of the inhibitory effect of the compound of the present invention on the cellular JAK2 signal pathway
实验目的：该测试例的目的是测试化合物对细胞JAK2信号通路抑制的活性。Experimental purpose: The purpose of this test case is to test the inhibitory activity of the compound on the cellular JAK2 signaling pathway.
实验仪器：laboratory apparatus:
离心机(5702R)购自Eppendorf公司，The centrifuge (5702R) was purchased from Eppendorf,
移液器购自Eppendorf公司，The pipette was purchased from Eppendorf,
酶标仪购自美国BioTek公司，型号为SynergyH1全功能酶标仪。The microplate reader was purchased from BioTek, USA, and the model was SynergyH1 full-function microplate reader.
实验方法：本实验采用TF-1细胞系，通过IL6刺激激活JAK2信号通路，检测化合物对其下游STAT3磷酸化的抑制活性，并得出化合物对JAK2信号通路活性的半数抑制浓度IC 50。 Experimental method: This experiment TF-1 cell lines, activation of the JAK2 signaling pathway by stimulation of IL6, its downstream test compound STAT3 phosphorylation inhibitory activity of the compound and draw half JAK2 signaling pathway activity inhibitory concentration IC 50.
具体实验操作如下：The specific experimental operations are as follows:
384孔检测板中铺入TF-1细胞3-12μL，每孔细胞个数为100-300K，加入2μL梯度稀释好的化合物溶液，二氧化碳培养箱孵育2小时。2小时后加入2μL IL6，IL6终浓度30ng/mL，室温震荡20min。加入2-5μL(5X)LANCE Ultra Lysis Buffer2溶液，4度震荡2h。2h后加入5μL终浓度为2nM的LANCE Ultra Eu-labeled Anti-STAT3(Tyr705)Antibody(PerkinElmer)和终浓度为20nM的LANCE Ultra ULight-labeled Anti-STAT3 Antibody(PerkinElmer)溶液，室温孵育过夜。酶标仪测定各板孔的665nm荧光信号值，通过荧光信号值计算抑制率，根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50。 Pour 3-12μL of TF-1 cells in the 384-well detection plate, the number of cells per well is 100-300K, add 2μL of the compound solution with gradient dilution, and incubate for 2 hours in a carbon dioxide incubator. After 2 hours, add 2μL IL6, the final concentration of IL6 is 30ng/mL, and shake at room temperature for 20min. Add 2-5μL (5X) LANCE Ultra Lysis Buffer2 solution and shake at 4°C for 2h. After 2h, 5μL of LANCE Ultra Eu-labeled Anti-STAT3 (Tyr705) Antibody (PerkinElmer) with a final concentration of 2nM and LANCE Ultra ULight-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 20nM were added and incubated overnight at room temperature. The microplate reader measures the 665nm fluorescence signal value of each plate well, calculates the inhibition rate from the fluorescence signal value, and obtains the IC 50 of the compound by curve fitting according to the inhibition rate of different concentrations.
实验数据处理方法：Experimental data processing method:
通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不加细胞)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC 50值。 Calculate the percentage inhibition data of the wells treated with the compound through the positive control wells (DMSO control wells) and negative control wells (without cells) on the plate {% inhibition rate = 100-[(test compound value-negative control value)]/ (Positive control value-negative control value)×100}. Use GraphPad prism to fit data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC 50 value.
实验结论：Experimental results:
通过以上方案得出本发明所示的化合物在细胞JAK2信号通路抑制的活性试验数据如下表所示：Through the above scheme, the activity test data of the compound shown in the present invention in inhibiting the cell JAK2 signal pathway are shown in the following table:
Figure PCTCN2020073152-appb-000223
Figure PCTCN2020073152-appb-000223
实验结论：从表中数据可以看出，实施例化合物对JAK2细胞活性与TYK2细胞活性相比的选择性较高。Experimental conclusion: It can be seen from the data in the table that the compounds of the examples have higher selectivity for JAK2 cell activity compared with TYK2 cell activity.
测试例3、小鼠的血浆蛋白结合率试验Test Example 3. Plasma protein binding rate test of mice
1.研究目的：1. Research purpose:
本实验目的是采用平衡透析法评价实施例58，实施例88和实施例92(5μM)在小鼠血浆中的蛋白结合率情况。The purpose of this experiment is to evaluate the protein binding rate of Example 58, Example 88 and Example 92 (5 μM) in mouse plasma by using the balanced dialysis method.
2.化合物与实验材料：2. Compounds and experimental materials:
1).受试化合物用DMSO配置为10mM储备液，于-20℃冰箱保存待用；1). The test compound is prepared as a 10mM stock solution with DMSO and stored in a refrigerator at -20°C until use;
2).所需种属的冷冻血浆、透析液(100mM磷酸缓冲液(Lot#SLBS7904和Lot#SLBR3106V)，pH 7.4)。2). Frozen plasma and dialysate of the required species (100mM phosphate buffer (Lot#SLBS7904 and Lot#SLBR3106V), pH 7.4).
3.实验仪器3. Experimental instrument
96孔板(Lot#07917415)、检测膜装置(Lot#SD2369421)、液相色谱联用串联质谱仪(LC-MS/MS)(LC-20AD,API4000)、离心机(Eppendorf 5804R/5424R)、涡旋仪(IKA VORTEX GENIUS 3)、移液枪(Eppendorf 10～100μL(PIP-100-002),Eppendorf 100～1000μL(PIP-1000-002)，RAININ 0.5～10μL(PIP-10-002))、水浴锅(上海恒科)。96-well plate (Lot#07917415), detection membrane device (Lot#SD2369421), liquid chromatography coupled with tandem mass spectrometer (LC-MS/MS) (LC-20AD, API4000), centrifuge (Eppendorf 5804R/5424R), Vortex (IKA VORTEX GENIUS 3), Pipette (Eppendorf 10～100μL (PIP-100-002), Eppendorf 100～1000μL (PIP-1000-002), RAININ 0.5～10μL (PIP-10-002)) , Water bath (Shanghai Hengke).
4.实验步骤4. Experimental steps
4.1配制透析液4.1 Preparation of dialysate
取1M的K2HPO4(AR级)4.01mL，1M的KH2PO4(AR级)0.99mL，用超纯水稀释至50mL，制备100mM磷酸缓冲液(pH＝7.4)作为透析液。Take 4.01 mL of 1M K2HPO4 (AR grade) and 0.99 mL of 1M KH2PO4 (AR grade), and dilute to 50 mL with ultrapure water to prepare 100 mM phosphate buffer (pH=7.4) as a dialysate.
4.2准备血浆4.2 Prepare plasma
于室温或37℃水浴解冻冷冻的血浆，3500rpm离心5min，取上清。Thaw the frozen plasma in a water bath at room temperature or 37°C, centrifuge at 3500 rpm for 5 min, and take the supernatant.
4.3配制反应终止液4.3 Preparation of reaction stop solution
用含有内标的乙腈(或其他合适的溶液)做终止液，储存在2-8℃冰箱，内标的具体浓度见最终报告。Use acetonitrile (or other suitable solution) containing the internal standard as the stop solution, store it in a refrigerator at 2-8°C, and see the final report for the specific concentration of the internal standard.
4.4配制化合物工作液4.4 Preparation of compound working solution
化合物的工作液配制：用DMSO稀释储备液至终浓度1mM。Compound working solution preparation: Dilute the stock solution with DMSO to a final concentration of 1mM.
4.5配制血浆溶液4.5 Preparation of plasma solution
取4μL化合物工作液加入到796μL空白血浆中，终浓度为5μM，震荡混匀。Take 4μL of compound working solution and add it to 796μL of blank plasma, the final concentration is 5μM, shake and mix.
4.6平衡透析4.6 Balanced dialysis
1).准备平衡透析装置，将检测膜装置放入平衡透析96孔板中；1). Prepare the balanced dialysis device, put the detection membrane device into the balanced dialysis 96-well plate;
2).在膜内加入200μL配制好的血浆溶液，n＝2；2). Add 200μL of the prepared plasma solution into the membrane, n=2;
3).另取4μL血浆溶液，用36μL相同种属的空白血浆稀释10倍后，加入160μL含有内标的乙腈终止液，储存于-20℃冰箱，得到T0(Total)样品；3). Take another 4μL plasma solution, dilute 10 times with 36μL blank plasma of the same species, add 160μL acetonitrile stop solution containing internal standard, and store in the refrigerator at -20℃ to obtain a T0 (Total) sample;
4).在膜外加入350μL透析液(100mM磷酸缓冲液)；4). Add 350μL of dialysate (100mM phosphate buffer) outside the membrane;
5).将透析板密封好，放入37℃度水浴锅内孵育6小时；5). Seal the dialysis plate well and incubate it in a 37℃ water bath for 6 hours;
6).透析结束后，自膜内样品孔分别取出4μL，用36μL相同种属的空白血浆稀释10倍；自膜外样品孔分别取出40μL透析液，加入160μL有内标的乙腈终止液，得到T6(Total)样品和F6(Total)样品；6). After dialysis, take out 4μL from the sample hole in the membrane and dilute it with 36μL blank plasma of the same species 10 times; take out 40μL dialysate from the sample hole outside the membrane, add 160μL of acetonitrile stop solution with internal standard to obtain T6 (Total) sample and F6 (Total) sample;
7).T0(Total)和T6(Total)样品离心后取上清液；7). Take the supernatant after centrifugation of T0 (Total) and T6 (Total) samples;
8).LC-MS分析。8). LC-MS analysis.
5.实验结果5. Experimental results
Figure PCTCN2020073152-appb-000224
Figure PCTCN2020073152-appb-000224
测试例4、Balb/C小鼠药代动力学测定Test Example 4, Balb/C mouse pharmacokinetic determination
1.研究目的：1. Research purpose:
以Balb/C小鼠为受试动物，研究化合物实施例58，实施例88和实施例92，在5mg/kg剂量下口服给药在小鼠体内血浆的药代动力学行为。Balb/C mice were used as test animals to study the pharmacokinetic behavior of compound Example 58, Example 88 and Example 92 at a dose of 5 mg/kg in the plasma of mice.
2.试验方案2. Test plan
2.1试验药品：2.1 Test drugs:
本发明实施例58，实施例88和实施例92，自制。Example 58, Example 88 and Example 92 of the present invention are self-made.
2.2试验动物：2.2 Experimental animals:
Balb/C Mouse 18只(6只/实施例)，雄性，上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006 N0.311620400001794)。Balb/C Mouse 18 (6 mice/example), male, Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 No 0.311620400001794).
2.3给药：2.3 Administration:
Balb/C小鼠18只，雄性；禁食一夜后分别p.o.，剂量为5mg/kg，给药体积10mL/kg。18 Balb/C mice, male; p.o. after fasting overnight, the dose was 5 mg/kg, and the administration volume was 10 mL/kg.
2.4样品采集：2.4 Sample collection:
小鼠给药前和给药后，在0、0.5、1、2、4、6、8和24小时，采用眼眶采血0.1mL，置于EDTA-K 2试管中，4℃6000rpm离心6min分离血浆，于-80℃保存。 Before and after the administration of the mice, at 0, 0.5, 1, 2 , 4, 6, 8 and 24 hours, 0.1 mL of blood was collected from the orbit, placed in an EDTA-K 2 test tube, and centrifuged at 4°C at 6000 rpm for 6 minutes to separate plasma , Store at -80℃.
2.5样品处理：2.5 Sample processing:
1)血浆样品40uL加入160uL乙腈沉淀，混合后3500×g离心5～20分钟。1) 40uL of plasma sample was precipitated by adding 160uL of acetonitrile, mixed and centrifuged at 3500×g for 5-20 minutes.
2)取处理后上清溶液100uL进行LC/MS/MS分析待测化合物的浓度。2) Take 100 uL of the supernatant solution after treatment to analyze the concentration of the test compound by LC/MS/MS.
2.6液相分析2.6 Liquid phase analysis
●液相条件：Shimadzu LC-20AD泵●Liquid phase conditions: Shimadzu LC-20AD pump
●质谱条件:AB Sciex API 4000质谱仪Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer
●色谱柱：phenomenex Gemiu 5um C18 50×4.6mm●Chromatography column: phenomenex Gemiu 5um C18 50×4.6mm
●移动相：A液为0.1％甲酸水溶液，B液为乙腈●Mobile phase: A solution is 0.1% formic acid aqueous solution, B solution is acetonitrile
●流速：0.8mL/min●Flow rate: 0.8mL/min
●洗脱时间：0-4.0分钟，洗脱液如下：●Elution time: 0-4.0 minutes, the eluent is as follows:
Figure PCTCN2020073152-appb-000225
Figure PCTCN2020073152-appb-000225
3.试验结果与分析3. Test results and analysis
药代动力学主要参数用WinNonlin 6.1计算得到，小鼠药代实验结果见下表：The main pharmacokinetic parameters are calculated with WinNonlin 6.1, and the mouse pharmacokinetic experiment results are shown in the following table:
化合物Compound t max(h) t max (h) C max(ng/mL) C max (ng/mL) AUC 0-t(ng/mL*h) AUC 0-t (ng/mL*h) AUC 0-∞(ng/mL*h) AUC 0-∞ (ng/mL*h) t 1/2(h) t 1/2 (h) MRT 0-∞(h) MRT 0-∞ (h)
BMS-986165BMS-986165 1.01.0 696696 19871987 20382038 1.41.4 2.32.3
实施例53Example 53 0.50.5 20432043 62506250 63486348 1.31.3 2.32.3
实施例58Example 58 0.50.5 39303930 1359013590 1447314473 1.91.9 3.03.0
实施例88Example 88 1.01.0 21902190 2099120991 2100121001 2.12.1 5.65.6
实施例92Example 92 1.01.0 939939 24662466 26372637 2.02.0 2.82.8
实施例118Example 118 0.50.5 19271927 33913391 37193719 2.72.7 2.52.5
实验结论：从表中数据可以看出，实施例化合物在小鼠体内药代暴露量AUC 0-t(ng/mL*h)优于参比化合物BMS-986165，特别是实施例58和实施例88，药代暴露量远优于参比化合物BMS-986165，比参比化合物优6倍和10倍以上。 Experimental conclusion: It can be seen from the data in the table that the pharmacokinetic exposure AUC 0-t (ng/mL*h) of the example compounds in mice is better than that of the reference compound BMS-986165, especially the example 58 and the examples. 88. The pharmacokinetic exposure is much better than the reference compound BMS-986165, 6 times and 10 times better than the reference compound.
测试例5、本发明化合物在咪喹莫特诱导的小鼠银屑病样模型中药效的测定Test Example 5. Determination of the efficacy of the compound of the present invention in a mouse psoriasis-like model induced by imiquimod
1.实验目的：1. Experiment purpose:
评价化合物在咪喹莫特诱导的小鼠银屑病样模型中药效。To evaluate the efficacy of the compound in a mouse psoriasis-like model induced by imiquimod.
2.实验主要仪器和试剂2. The main instruments and reagents of the experiment
2.1仪器2.1 Instrument
仪器设备名称Equipment name 型号model 厂家factory
电子天平Electronic balance SQP型SECURA225D-1CNSQP type SECURA225D-1CN SartoriusSartorius
电子天平Electronic balance MP5002型MP5002 type 上海舜宇恒平Shanghai Sunny Hengping
2.2试剂2.2 Reagents
名称name 批号batch number 品牌/货号Brand/Item No.
Imiquimod CreamImiquimod Cream GRI015AGRI015A AldaraAldara
CMC-NaCMC-Na 079K0054V079K0054V Sigma-C9481-500GSigma-C9481-500G
3.实验步骤3. Experimental steps
3.1造模3.1 Modeling
Day 0对动物背部测试部位剃毛。Day 1～Day 6在动物背部测试部位每天涂抹一次62.5mg咪喹莫特。Day 0 Shave the test site on the animal's back. From Day 1 to Day 6, apply 62.5 mg of imiquimod on the test site on the animal's back once a day.
3.2给药3.2 Administration
Day 1～Day 7根据实验方案对各组动物分别给药，咪喹莫特诱导的小鼠银屑病样模型实验设计见下表：From Day 1 to Day 7, each group of animals was administered separately according to the experimental protocol. The experimental design of the mouse psoriasis-like model induced by imiquimod is shown in the following table:
Figure PCTCN2020073152-appb-000226
Figure PCTCN2020073152-appb-000226
3.3皮炎皮肤损伤严重指数评分3.3 Dermatitis skin damage severity index score
Day 1～Day 7对动物背部测试部位的发红、结垢和增厚程度分别按0～4分进行评分。0，无损伤；1，轻微；2，中度的；3，明显的；4，非常明显的。总分表示损伤的严重程度From Day 1 to Day 7, the degree of redness, scaling and thickening of the test site on the back of the animal was scored on a scale of 0 to 4 points. 0, no damage; 1, slight; 2, moderate; 3, obvious; 4, very obvious. The total score indicates the severity of the injury
4.试验数据4. Test data
4.1不同化合物在咪喹莫特诱导的小鼠银屑病模型中PASI评分的比较结果见下表：4.1 The comparison results of PASI scores of different compounds in the mouse psoriasis model induced by imiquimod are shown in the following table:
Figure PCTCN2020073152-appb-000227
Figure PCTCN2020073152-appb-000227
4.2不同化合物在咪喹莫特诱导的小鼠银屑病模型中PASI评分结果如图1所示，其中数据点代表组内PASI评分均值，N＝8，运用One-way ANOVA与Vehicle组比较，***p<0.001。4.2 The PASI score results of different compounds in the mouse psoriasis model induced by imiquimod are shown in Figure 1, where the data points represent the average PASI score within the group, N=8, using One-way ANOVA to compare with the Vehicle group, ***p<0.001.
5.实验结果5. Experimental results
从上述结果中可以看出，本专利的实施例58、88和92在咪喹莫特诱导的小鼠银屑病样模型中能有效改善银屑病症状，与Vehicle组比较具有非常显著性差异，P<0.001，优于参比化合物BMS-986165(P<0.01)。It can be seen from the above results that Examples 58, 88 and 92 of this patent can effectively improve the symptoms of psoriasis in a mouse psoriasis-like model induced by imiquimod, which has very significant differences compared with the Vehicle group. , P<0.001, better than the reference compound BMS-986165 (P<0.01).

Claims (29)

  1. 通式(I)所示的化合物、其立体异构体或其药学上可接受盐，The compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt,
    Figure PCTCN2020073152-appb-100001
    Figure PCTCN2020073152-appb-100001
    其中：among them:
    R选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、氧代基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR aa、-SR aa、-C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb； 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 1选自环烷基、杂环基、芳基、杂芳基、-R aa、-(CH 2) n1OR bb、-(CH 2) n1NR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) m1R bb、-NR aaCR bb＝NR cc、-NR aaCR bb＝CR ccR dd、-(CH 2) n1S(O) m1NR aaR bb、-(CH 2) n1C(O)R aa、-NR aaC(O)OR bb、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaC(O)C(O)R aa或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、氘代烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R 1 is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -R aa , -(CH 2 ) n1 OR bb , -(CH 2 ) n1 NR aa R bb , -NR aa C(O) R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m1 R bb , -NR aa CR bb =NR cc , -NR aa CR bb =CR cc R dd , -(CH 2 ) n1 S(O) m1 NR aa R bb , -(CH 2 ) n1 C(O)R aa , -NR aa C(O)OR bb , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa C(O)C(O)R aa or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkane Group, heterocyclic group, aryl group and heteroaryl group, optionally further selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano Group, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or One or more substituents in the unsubstituted heteroaryl group;
    R 2选自环烷基、杂环基、芳基、杂芳基、-R aa、-C(O)R aa、-(CH 2) n1OR bb、-(CH 2) n1NR aaR bb、-NR aaC(O)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaS(O) m1R bb、-NR aaCR bb＝NR cc、-NR aaCR bb＝CR ccR dd、-(CH 2) n1S(O) m1NR aaR bb、-(CH 2) n1C(O)R aa、-NR aaC(O)OR bb、-(CH 2) n1S(O) m1R aa或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、氘代烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R 2 is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, -R aa , -C(O)R aa , -(CH 2 ) n1 OR bb , -(CH 2 ) n1 NR aa R bb , -NR aa C(O)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa S(O) m1 R bb , -NR aa CR bb = NR cc , -NR aa CR bb =CR cc R dd , -(CH 2 ) n1 S(O) m1 NR aa R bb , -(CH 2 ) n1 C(O)R aa , -NR aa C(O) OR bb , -(CH 2 ) n1 S(O) m1 R aa or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclic, aryl and heteroaromatic Group, optionally further selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, alkenyl, alkynyl, alkane One or more of oxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl Substituted by a substituent;
    R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基或炔基； 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和R 7存在或不存在，存在时选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、氧代基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-SR aa、 -(CH 2) n1C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb； The presence or absence of 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) m1 R bb ;
    或者，R 4和R 6或R 6和R 7链接形成一个环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, R 4 and R 6 or R 6 and R 7 are linked to form a cycloalkyl, heterocyclic, aryl, and heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are Optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, Substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R aa、R bb、R cc和R dd各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； 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, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkane Substituted by one or more substituents in the group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;
    或者，任意两个相邻或者不相邻的R aa、R bb、R cc和R dd链接形成一个环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Or, 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, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy Substituted by one or more substituents in the group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    x为0、1、2或3；x is 0, 1, 2 or 3;
    m1为0、1或2；且m1 is 0, 1 or 2; and
    n1为0、1、2、3、4或5。n1 is 0, 1, 2, 3, 4, or 5.
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the
    R选自氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、卤素、氨基、巯基、-OR aa、-SR aa、-S(O) m1R aa或-NR aaR bb，优选氢、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、氟、氯、溴、-OR aa、-SR aa、-S(O) m1R aa或-NR aaR bb，更优选氢、甲基、乙基、丙基、FCH 2-、F 2CH-、F 3C-、ClCH 2-、Cl 2CH-、Cl 3C-、CH 3O-、CH 3CH 2O-、CH 3CH 2CH 2O-、FCH 2O-、F 2CHO-、F 3CO-、氟、氯、-OR aa、-SR aa、-S(O) m1R aa或-NR aaR bb，进一步优选CH 3O-、(CH 3) 2N-、CH 3S-、F 3CO-、F 2HCO-、F-或CH 3S(O) 2-； R is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halo 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 alkane Oxy, 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 3 CH 2 CH 2 O-, FCH 2 O-, F 2 CHO-, F 3 CO-, fluorine, chlorine, -OR aa , -SR aa , -S(O) m1 R aa or -NR aa R bb , more preferably CH 3 O-, (CH 3 ) 2 N- , CH 3 S-, F 3 CO-, F 2 HCO-, F- or CH 3 S(O) 2 -;
    其中，R aa或R bb各自独立地选自氢、氘、羟基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、氰基、C 2-6烯基、C 2-6炔基、C 3-7环烷基或3-7元杂环基，优选氢、羟基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、氰 基、C 2-5烯基、C 2-5炔基、C 3-6环烷基或含1-3个N、O或S原子的3-6元杂环基，更优选氢、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、环丙基、环丁基、环己基、环氧乙基、环氧丙基、环氧丁基、环氧戊基、四氢吡咯基或哌啶基；进一步优选氢、甲基、乙基、丙基、环丙基或环丁基； Wherein, 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, Ethynyl, propynyl, FCH 2 -, F 2 CH-, F 3 C-, cyano, cyclopropyl, cyclobutyl, cyclohexyl, epoxyethyl, epoxypropyl, epoxybutyl, Epoxypentyl, tetrahydropyrrolyl or piperidinyl; more preferably hydrogen, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
    R 1选自C 3-7环烷基、3-7元杂环基、C 6-12芳基、3-7元杂芳基、-NR cC(O)R d、-NR cC(O)NR dR e、-NR cS(O) m1R d、-NR cCR d＝NR e、-NR cCR d＝CR eR f、-NR cC(O)OR d、-(CH 2) n1S(O) m1R c、-(CH 2) n1NR cC(O)C(O)R g或-(CH 2) n1NR cS(O) m1R d、-NR cCR dR eR f、-NR cC(S)R d、-OC＝ONR cR d或-CR eR fC＝ONR cR d，优选C 3-6环烷基、3-6元杂环基、C 6-10芳基、3-6元杂芳基、-NR cC(O)R d、-NR cC(O)NR dR e、-NR cS(O) m1R d、-NR cCR d＝NR e、-NR cCR d＝CR eR f、-NR cC(O)OR d、-(CH 2) n1S(O) m1R c、-(CH 2) n1NR cC(O)C(O)R g或-(CH 2) n1NR cS(O) m1R d、-NR cCR dR eR f、-NR cC(S)R d、-OC＝ONR cR d或-CR eR fC＝ONR cR d，更优选C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、苯基、萘基、含1-3个N、O或S原子的3-6元杂芳基、-NR cC(O)R d、-NR cC(O)NR dR e、-NR cS(O) m1R d、-NR cCR d＝NR e、-NR cCR d＝CR eR f、-NR cC(O)OR d、-(CH 2) n1S(O) m1R c、-(CH 2) n1NR cC(O)C(O)R g或-(CH 2) n1NR cS(O) m1R d、-NR cCR dR eR f、-NR cC(S)R d、-OC＝ONR cR d或–CR eR fC＝ONR cR d，进一步优选
    Figure PCTCN2020073152-appb-100002
    Figure PCTCN2020073152-appb-100003
    R 1 is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl, 3-7 membered heteroaryl, -NR c C(O)R d , -NR c C( O)NR d R e , -NR c S(O) m1 R d , -NR c CR d =NR e , -NR c CR d =CR e R f , -NR c C(O)OR d , -( CH 2 ) n1 S(O) m1 R c , -(CH 2 ) n1 NR c C(O)C(O)R g or -(CH 2 ) n1 NR c S(O) m1 R d , -NR c CR d R e R f , -NR c C(S)R d , -OC=ONR c R d or -CR e R f C=ONR c R d , preferably C 3-6 cycloalkyl, 3-6 member Heterocyclic group, C 6-10 aryl, 3-6 membered heteroaryl, -NR c C(O)R d , -NR c C(O)NR d R e , -NR c S(O) m1 R d , -NR c CR d =NR e , -NR c CR d =CR e R f , -NR c C(O)OR d , -(CH 2 ) n1 S(O) m1 R c , -(CH 2 ) n1 NR c C(O)C(O)R g or -(CH 2 ) n1 NR c S(O) m1 R d , -NR c CR d R e R f , -NR c C(S)R d , -OC=ONR c R d or -CR e R f C=ONR c R d , more preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms , Phenyl, naphthyl, 3-6 membered heteroaryl containing 1-3 N, O or S atoms, -NR c C(O)R d , -NR c C(O)NR d R e ,- NR c S(O) m1 R d , -NR c CR d ＝NR e , -NR c CR d ＝CR e R f , -NR c C(O)OR d , -(CH 2 ) n1 S(O) m1 R c , -(CH 2 ) n1 NR c C(O)C(O)R g or -(CH 2 ) n1 NR c S(O) m1 R d , -NR c CR d R e R f ,- NR c C(S)R d , -OC=ONR c R d or -CR e R f C=ONR c R d , more preferably
    Figure PCTCN2020073152-appb-100002
    Figure PCTCN2020073152-appb-100003
    R c、R d、R e、R f或R g各自独立地选自氢、氘、羟基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、C 6-12芳基和3-7元杂芳基，优选氢、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氰基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基和含1-3个N、O或S原子的3-6元杂芳基，更优选氢、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、氟、氯、CH 3O-、CH 3CH 2O-、环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2020073152-appb-100004
    Figure PCTCN2020073152-appb-100005
    Figure PCTCN2020073152-appb-100006
    进一步优选氢、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、氟、氯、CH 3O-、CH 3CH 2O-、环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2020073152-appb-100007
    Figure PCTCN2020073152-appb-100008
    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, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-10 aryl groups and 3-6 membered heteroaryl groups containing 1-3 N, O or S atoms, More preferably hydrogen, methyl, ethyl, -CD 3 , -CD 2 CD 3 , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH 2 -, F 2 CH-, F 3 C-, cyano, fluorine, chlorine, CH 3 O-, CH 3 CH 2 O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2020073152-appb-100004
    Figure PCTCN2020073152-appb-100005
    Figure PCTCN2020073152-appb-100006
    More preferably hydrogen, methyl, ethyl, -CD 3 , -CD 2 CD 3 , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH 2 -, F 2 CH-, F 3 C-, cyano, fluorine, chlorine, CH 3 O-, CH 3 CH 2 O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2020073152-appb-100007
    Figure PCTCN2020073152-appb-100008
    或者，任意两个相邻或者不相邻的R c、R d、R e或R f链接形成一个C 3-7环烷基、3-7元杂环基、芳基和3-7元杂芳基，优选C 3-6环烷基、3-6元杂环基、C 6-12芳基和3-6元杂芳基，更优选C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基和含1-2个N、O或S原子的3-6元芳基，进一步优选环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2020073152-appb-100009
    Figure PCTCN2020073152-appb-100010
    Figure PCTCN2020073152-appb-100011
    更进一步优选环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2020073152-appb-100012
    Figure PCTCN2020073152-appb-100013
    Alternatively, 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 aryl groups with 1-2 N, O or S atoms, more preferably cyclopropyl and cyclobutyl , Cyclopentyl, cyclohexyl,
    Figure PCTCN2020073152-appb-100009
    Figure PCTCN2020073152-appb-100010
    Figure PCTCN2020073152-appb-100011
    More preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2020073152-appb-100012
    Figure PCTCN2020073152-appb-100013
    R 2选自C 3-7环烷基、3-7元杂环基、C 6-12芳基、3-7元杂芳基、C 1-6羟烷基、-C(O)R hh、-(CH 2) n1OR ii、-(CH 2) n1NR hhR ii、-NR hhC(O)R ii、-NR hhC(O)NR iiR jj、-C(O)NR hhR ii、-NR hhS(O) m1R ii、-NR hhCR ii＝NR jj、-NR hhCR ii＝CR jjR kk、-(CH 2) n1S(O) m1NR hhR ii、-(CH 2) n1C(O)R hh、-NR hhC(O)OR ii、-(CH 2) n1S(O) m1R hh或 -(CH 2) n1NR hhS(O) m1R ii，其中所述的C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，任选被氢、氘、卤素、C 1-6烷基、C 1-6烷氧基或C 3-6环烷基中的一个或多个取代基取代；优选C 3-6环烷基、3-6元杂环基、C 6-10芳基、3-6元杂芳基、C 1-3羟烷基、-C(O)R hh、-(CH 2) n1OR ii、-(CH 2) n1NR hhR ii、-NR hhC(O)R ii、-NR hhC(O)NR iiR jj、-C(O)NR hhR ii、-NR hhS(O) m1R ii、-NR hhCR ii＝NR jj、-NR hhCR ii＝CR jjR kk、-(CH 2) n1S(O) m1NR hhR ii、-(CH 2) n1C(O)R hh、-NR hhC(O)OR ii、-(CH 2) n1S(O) m1R hh或-(CH 2) n1NR hhS(O) m1R ii，其中所述的C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，任选被氢、氘、氟、氯、溴、C 1-3烷基或C 3-5环烷基中的一个或多个取代基取代；更优选C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、苯基、萘基、含1-3个N、O或S原子的3-6元杂芳基、C 1-3羟烷基、-C(O)R hh、-(CH 2) n1OR ii、-(CH 2) n1NR hhR ii、-C(O)NR hhR ii、-(CH 2) n1S(O) m1NR hhR ii、-(CH 2) n1C(O)R hh、-(CH 2) n1S(O) m1R hh或-(CH 2) n1NR hhS(O) m1R ii，其中所述的C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，任选被氢、氘、氟、氯、溴、甲基、乙基、丙基、环丙基、环戊基或环己基中的一个或多个取代基取代；进一步优选HOCH 2-、HOCH 2CH 2-、HOCH 2C(O)-、CH 3NHC(O)-、D 3CNHC(O)-、CH 3NHS(O) 2-、D 3CNHS(O) 2-、
    Figure PCTCN2020073152-appb-100014
    R 2 is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl, 3-7 membered heteroaryl, C 1-6 hydroxyalkyl, -C(O)R hh , -(CH 2 ) n1 OR ii , -(CH 2 ) n1 NR hh R ii , -NR hh C(O)R ii , -NR hh C(O)NR ii R jj , -C(O)NR hh R ii , -NR hh S(O) m1 R ii , -NR hh CR ii =NR jj , -NR hh CR ii =CR jj R kk , -(CH 2 ) n1 S(O) m1 NR hh R ii , -(CH 2 ) n1 C(O)R hh , -NR hh C(O)OR ii , -(CH 2 ) n1 S(O) m1 R hh or -(CH 2 ) n1 NR hh S(O) m1 R ii , wherein said C 3-7 cycloalkyl group, 3-7 membered heterocyclic group, C 6-12 aryl group or 3-7 membered heteroaryl group is optionally substituted by hydrogen, deuterium, halogen, C 1- One or more substituents in 6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 3-6 membered heteroaryl, C 1-3 hydroxyalkyl, -C(O)R hh , -(CH 2 ) n1 OR ii , -(CH 2 ) n1 NR hh R ii , -NR hh C(O)R ii , -NR hh C(O)NR ii R jj , -C(O)NR hh R ii , -NR hh S(O) m1 R ii , -NR hh CR ii =NR jj ,- NR hh CR ii = CR jj R kk , -(CH 2 ) n1 S(O) m1 NR hh R ii , -(CH 2 ) n1 C(O)R hh , -NR hh C(O)OR ii ,- (CH 2 ) n1 S(O) m1 R hh or -(CH 2 ) n1 NR hh S(O) m1 R ii , wherein the C 3-7 cycloalkyl group, 3-7 membered heterocyclic group, C 6-12 aryl or 3-7 membered heteroaryl, optionally substituted by one or more substituents of hydrogen, deuterium, fluorine, chlorine, bromine, C 1-3 alkyl or C 3-5 cycloalkyl ; More preferably C 3-6 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, phenyl, naphthyl, containing 1-3 N, O or S atoms 3 -6 membered heteroaryl, C 1-3 hydroxyalkyl, -C(O)R hh , -(CH 2 ) n1 OR ii , -(CH 2 ) n1 NR hh R ii , -C(O)NR hh R ii , -(CH 2 ) n1 S(O) m1 NR hh R ii , -(CH 2 ) n1 C(O)R hh , -(CH 2 ) n1 S(O) m1 R hh or -(CH 2 ) n1 NR hh S(O) m1 R ii , wherein the C 3-7 cycloalkyl, 3-7 membered heterocyclic group, C 6-12 aryl or 3-7 member Heteroaryl, optionally substituted by one or more substituents of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, cyclopropyl, cyclopentyl or cyclohexyl; more preferably HOCH 2 -, HOCH 2 CH 2 -, HOCH 2 C(O)-, CH 3 NHC(O)-, D 3 CNHC(O)-, CH 3 NHS(O) 2 -, D 3 CNHS(O) 2 -,
    Figure PCTCN2020073152-appb-100014
    R hh、R ii、R jj或R kk各自独立地选自氢、氘、羟基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氰基、C 2-5烯基、C 2-5炔基、C 3-6环烷基或含1-3个N、O或S原子的3-6元杂环基，更优选氢、氘、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、氟、氯、CH 3O-、CH 3CH 2O-、环丙基、环丁基、环戊基、环己基、环氧丙基、环氧丁基、环氧戊基、环氧己基、四氢吡咯基或哌啶基； 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 heterocyclic group, more preferably hydrogen, deuterium, methyl, ethyl, -CD 3 , -CD 2 CD 3 , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propyl Alkynyl, FCH 2 -, F 2 CH-, F 3 C-, cyano, fluorine, chlorine, CH 3 O-, CH 3 CH 2 O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, tetrahydropyrrolyl or piperidinyl;
    R 3选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基或氰基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基或氰基，更优选氢、氘、甲基、乙基、丙基、甲氧基、 乙氧基、氟、氯、羟基或氰基； 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和R 7存在或不存在，存在时选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基、氰基、氧代基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-7元杂环基、芳基、3-7元杂芳基、-(CH 2) n1R ll、-(CH 2) n1OR ll、-SR ll、-(CH 2) n1C(O)R ll、-C(O)OR ll、-S(O) m1R ll、-NR llR mm、-C(O)NR llR mm、-NR llC(O)R mm或-NR llS(O) m1R mm，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基、氰基、氧代基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-12芳基、含1-3个N、O或S原子的3-6元杂芳基、-(CH 2) n1R ll、-(CH 2) n1OR ll、-SR ll、-(CH 2) n1C(O)R ll、-C(O)OR ll、-S(O) m1R ll、-NR llR mm、-C(O)NR llR mm、-NR llC(O)R mm或-NR llS(O) m1R mm，更优选氢、氘、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氨基、巯基、硝基、羟基、氰基、氧代基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基、含1-3个N、O或S原子的3-6元杂芳基、-(CH 2) n1R ll、-(CH 2) n1OR ll或-NR llR mm，进一步优选氢、甲基、乙基、丙基、异丙基、丁基、(CH 3) 3C-、CF 3CH 2-、氟、氯、环丙基、环丁基、环戊基、环丁基、乙烯基、CH 2＝CHCH 2-、乙炔基、
    Figure PCTCN2020073152-appb-100015
    氰基、CNCH 2-、CNCH 2CH 2-、CH 3OCH 2-、CH 3OCH 2CH 2-、CF 3C(CH 3) 2-、
    Figure PCTCN2020073152-appb-100016
    Figure PCTCN2020073152-appb-100017
    The presence or absence of 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 mm , -NR ll C(O ) R mm or -NR ll S(O) m1 R mm , 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, cyano, oxo, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 ring Alkyl groups, 3-6 membered heterocyclic groups containing 1-3 N, O or S atoms, C 6-12 aryl groups, 3-6 membered heteroaryl groups containing 1-3 N, O or S atoms, -(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 mm , -NR ll C(O)R mm or -NR ll S(O) m1 R mm , more preferably hydrogen, deuterium, C 1-3 alkane Group, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, fluorine, chlorine, bromine, amino, mercapto, nitro, hydroxyl, cyano, oxo, 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, containing 1-3 A 3-6 membered heteroaryl group containing N, O or S atoms, -(CH 2 ) n1 R ll , -(CH 2 ) n1 OR ll or -NR ll R mm , more preferably hydrogen, methyl, ethyl, Propyl, isopropyl, butyl, (CH 3 ) 3 C-, CF 3 CH 2 -, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, vinyl, CH 2 = CHCH 2 -, ethynyl,
    Figure PCTCN2020073152-appb-100015
    Cyano, CNCH 2 -, CNCH 2 CH 2 -, CH 3 OCH 2 -, CH 3 OCH 2 CH 2 -, CF 3 C(CH 3 ) 2 -,
    Figure PCTCN2020073152-appb-100016
    Figure PCTCN2020073152-appb-100017
    R ll或R mm各自独立地选自氢、氘、羟基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟烷基、C 1-6烷氧基、C 1-6卤代烷氧基、卤素、氰基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或3-6元杂环基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氰基、C 2-5烯基、C 2-5炔基、C 3-6环烷基或含1-3个N、O或S原子的3-6元杂环基，更优选氢、氘、甲基、乙基、-CD 3、-CD 2CD 3、丙基、羟甲基、羟乙基、乙烯基、丙烯基、乙炔基、丙炔基、FCH 2-、F 2CH-、F 3C-、氰基、氟、氯、环丙基、环丁基、环戊基、环己基、环氧丙基、环氧丁基、环氧戊基、环氧己基、四氢吡咯基或哌啶基； 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, methyl, ethyl, -CD 3 , -CD 2 CD 3 , propyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, ethynyl, propynyl, FCH 2- , F 2 CH-, F 3 C-, cyano, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxy Hexyl, tetrahydropyrrolyl or piperidinyl;
    或者，R 4和R 6或R 6和R 7链接形成一个杂环基或杂芳基，其中所述的杂环基或杂芳基，任选被氢、氘、卤素、C 1-6烷基或C 3-6环烷基中的一个或多个取代基取代；优选3-6元杂环基或3-7元杂芳基，其中所述的杂环基或杂芳基，任选被氢、氘、氟、氯、溴、C 1-3烷基或C 3-5环烷基中的一个或多个取代基取代；更优选含1-3个N、O或S原子的3-6元杂环基或含1-3个N、O或S原子的3-7 元杂芳基，其中所述的杂环基或杂芳基，任选被氢、氘、氟、氯、溴、甲基、乙基、丙基、环丙基、环戊基或环己基中的一个或多个取代基取代；进一步优选
    Figure PCTCN2020073152-appb-100018
    Alternatively, 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. Group or one or more substituents in 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
    Figure PCTCN2020073152-appb-100018
  3. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(II)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (II):
    Figure PCTCN2020073152-appb-100019
    Figure PCTCN2020073152-appb-100019
    其中：among them:
    R～R 6和x如权利要求1所述。 R to R 6 and x are as described in claim 1.
  4. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(III)所示：The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, the general formula (I) is further represented by the general formula (III):
    Figure PCTCN2020073152-appb-100020
    Figure PCTCN2020073152-appb-100020
    其中：among them:
    R、R 1、R 3～R 6和x如权利要求1所述。 R, R 1 , R 3 to R 6 and x are as described in claim 1.
  5. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(IV)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (IV):
    Figure PCTCN2020073152-appb-100021
    Figure PCTCN2020073152-appb-100021
    其中：among them:
    环A选自环烷基、杂环基、芳基或杂芳基，优选杂芳基；Ring A is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, preferably heteroaryl;
    R 8选自氢、氘、烷基、氘代烷基、卤素、氰基、硝基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，优选氢、卤素、氨基、氰基、烷基、卤代烷基或环烷基，其中所述的烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 8 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogen, cyano, nitro, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Group, preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and hetero Aryl, optionally further selected from hydrogen, deuterium, alkyl, halogen, hydroxyl, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, One or more substituents in heterocyclic group, aryl group and heteroaryl group;
    y为0、1、2或3；y is 0, 1, 2 or 3;
    R、R 1、R 3～R 6和x如权利要求1所述。 R, R 1 , R 3 to R 6 and x are as described in claim 1.
  6. 根据权利要求5所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 5, wherein the
    环A选自C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，优选C 3-6环烷基、3-6元杂环基、C 6-10芳基或3-6元杂芳基，更优选C 3-6环烷基、3-6元含1-3个N、O或S原子的杂环基、苯基、萘基或含1-3个N、O或S原子的3-6元杂芳基，进一步优选
    Figure PCTCN2020073152-appb-100022
    Figure PCTCN2020073152-appb-100023
    Figure PCTCN2020073152-appb-100024
    更进一步优选
    Figure PCTCN2020073152-appb-100025
    Figure PCTCN2020073152-appb-100026
    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 Group, C 6-10 aryl group or 3-6 membered heteroaryl group, more preferably C 3-6 cycloalkyl group, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, phenyl group, Naphthyl or 3-6 membered heteroaryl containing 1-3 N, O or S atoms, more preferably
    Figure PCTCN2020073152-appb-100022
    Figure PCTCN2020073152-appb-100023
    Figure PCTCN2020073152-appb-100024
    Further preferred
    Figure PCTCN2020073152-appb-100025
    Figure PCTCN2020073152-appb-100026
    R 8选自氢、氘、C 1-6烷基、C 1-6氘代烷基、氟、氯、溴、氰基、硝基、C 1-6卤代烷基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-7元杂环基、C 6-12芳基和3-7元杂芳基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、氟、氯、溴、氰基、硝基、C 1-3卤代烷基、羟基、氨基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基和含1-3个N、O或S原子的3-6元杂芳基，更优选氢、氘、甲基、乙基、丙基、氯取代甲基、氯取代乙基、氟取代甲基、氟取代乙基、氟、氯、溴、氰基、硝基、羟基、氨基、乙烯基、丙烯基、乙炔基、丙炔基、环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2020073152-appb-100027
    Figure PCTCN2020073152-appb-100028
    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, deuterium, methyl, ethyl, propyl, chlorine-substituted methyl, chlorine-substituted ethyl, fluorine-substituted methyl, fluorine-substituted ethyl, fluorine, chlorine, bromine, cyano, nitro Group, hydroxyl, amino, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2020073152-appb-100027
    Figure PCTCN2020073152-appb-100028
  7. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(V)所示：The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, the general formula (I) is further represented by the general formula (V):
    Figure PCTCN2020073152-appb-100029
    Figure PCTCN2020073152-appb-100029
    其中：among them:
    R 9选自氢、氘、烷基、氘代烷基、卤素、氰基、硝基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-SR aa、-(CH 2) n1C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb，其中所述的烷基、卤代烷基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤代烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； 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, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, hydroxy, amino, oxo, Substituted by one or more substituents among nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R、R 3～R 6、R aa、R bb和x如权利要求1所述。 R, R 3 to R 6 , R aa , R bb and x are as claimed in claim 1.
  8. 根据权利要求7所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 7, wherein the
    R 9选自氢、氘、C 1-6烷基、C 1-6氘代烷基、氟、氯、溴、氰基、硝基、C 1-6卤代烷基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-SR aa、-(CH 2) n1C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、氟、氯、溴、氰基、硝基、C 1-3卤代烷基、羟基、氨基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、3-6元杂环基、C 6-10芳基或3-6元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-SR aa、-(CH 2) n1C(O)R aa、-C(O)OR aa、-S(O) m1R aa、-NR aaR bb、-C(O)NR aaR bb、-NR aaC(O)R bb或-NR aaS(O) m1R bb，更优选氢、氘、羟基取代的C 1-3烷基、C 1-3环烷基取代的C 1-3烷基、羟基取代的C 1-3氘代烷基、氟、氯、溴、氰基、硝基、C 1-3卤代烷基、羟基、C 3-6环烷基取代的氨基、卤素取代的C 2-5烯基、卤素取代的C 2-5炔基、卤素取代的C 3-6环烷基、C 1-3烷基取代的C 3-6环烷基、氰基取代的C 3-6环烷基、C 1-3烷氧基取代的C 3-6环烷基、C 1-3卤代烷基取代的C 3-6环烷基、3-7元含1-3个N、O或S原子的杂环基、苯基、萘基或3-7元含1-3个N、O或S原子的杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1C(O)R aa或-NR aaR bb，更进一步优选
    Figure PCTCN2020073152-appb-100030
    Figure PCTCN2020073152-appb-100031
    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 aa S(O) m1 R bb , preferably hydrogen, deuterium, C 1-3 alkyl, C 1-3 deuterated alkane Group, 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, C 6-10 aryl group or 3-6 membered heteroaryl group, -(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 , more preferably hydrogen, deuterium, hydroxy substituted C 1-3 alkyl, C 1-3 cycloalkyl substituted C 1-3 alkyl, hydroxy substituted C 1-3 deuterated Alkyl, fluorine, chlorine, bromine, cyano, nitro, C 1-3 haloalkyl, hydroxy, C 3-6 cycloalkyl substituted amino, halogen substituted C 2-5 alkenyl, halogen substituted C 2 -5 alkynyl, halogen-substituted C 3-6 cycloalkyl, C 1-3 alkyl substituted C 3-6 cycloalkyl, cyano substituted C 3-6 cycloalkyl, C 1-3 alkoxy Group substituted C 3-6 cycloalkyl, C 1-3 haloalkyl substituted C 3-6 cycloalkyl, 3-7 membered heterocyclic group containing 1-3 N, O or S atoms, phenyl, Naphthyl or 3-7 member heteroaryl containing 1-3 N, O or S atoms, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 C(O ) R aa or -NR aa R bb , more preferably
    Figure PCTCN2020073152-appb-100030
    Figure PCTCN2020073152-appb-100031
    R aa或R bb独立地选自氢、氘、C 1-6烷基、C 1-6氘代烷基、卤素、氰基、硝基、C 1-6卤代烷基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、氟、氯、溴、氰基、硝基、C 1-3卤代烷基、羟基、氨基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基或含1-3个N、O或S原子的3-6元杂芳基，更优选氢、甲基、乙基、丙基、氟、氯、环丙基、环丁基、环戊基、环己基、苯基、萘基或联苯基； 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 6-membered heteroaryl, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or biphenyl;
    m1为0、1、2或3；m1 is 0, 1, 2 or 3;
    n1为0、1、2或3。n1 is 0, 1, 2 or 3.
  9. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，所 述通式(I)进一步如通式(VI)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (VI):
    Figure PCTCN2020073152-appb-100032
    Figure PCTCN2020073152-appb-100032
    其中：among them:
    环B选自环烷基、杂环基、芳基或杂芳基，优选杂芳基；Ring B is selected from cycloalkyl, heterocyclic, aryl or heteroaryl, preferably heteroaryl;
    R 10选自氢、氘、烷基、氘代烷基、卤素、氰基、硝基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；优选氢、卤素、氨基、氰基、烷基、卤代烷基或环烷基； 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 the alkyl group, deuterated alkyl group, haloalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, optionally further selected from hydrogen, deuterium, alkyl One or more of, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one substituent; preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or cycloalkyl;
    z为0、1、2或3；z is 0, 1, 2 or 3;
    R、R 3～R 6和x如权利要求1所述。 R, R 3 to R 6 and x are as described in claim 1.
  10. 根据权利要求9所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 9, wherein the
    环B选自C 3-7环烷基、3-7元杂环基、C 6-12芳基或3-7元杂芳基，优选C 3-6环烷基、3-6元杂环基、C 6-10芳基或3-6元杂芳基，更优选C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、苯基、萘基或含1-3个N、O或S原子的3-6元杂芳基，进一步优选
    Figure PCTCN2020073152-appb-100033
    Figure PCTCN2020073152-appb-100034
    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 Group, C 6-10 aryl group or 3-6 membered heteroaryl group, more preferably C 3-6 cycloalkyl group, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, phenyl group, Naphthyl or 3-6 membered heteroaryl containing 1-3 N, O or S atoms, more preferably
    Figure PCTCN2020073152-appb-100033
    Figure PCTCN2020073152-appb-100034
    更进一步优选
    Figure PCTCN2020073152-appb-100035
    Further preferred
    Figure PCTCN2020073152-appb-100035
    R 10选自氢、氘、C 1-6烷基、C 1-6氘代烷基、氟、氯、溴、氰基、硝基、C 1-6卤代烷基、羟基、氨基、烯基、炔基、C 3-7环烷基、3-7元杂环基、C 6-12芳基和3-7元杂芳基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、氟、氯、溴、氰基、硝基、C 1-3卤代烷基、羟基、氨基、烯基、炔基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基、C 6-10芳基和含1-3个N、O或S原子的3-6元杂芳基，更优选氢、甲基、乙基、丙基、氟、氯、羟基、氨基、环丙基、环丁基、环戊基或环己基。 R 10 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 and 3-6 membered heteroaryl group containing 1-3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl Group, fluorine, chlorine, hydroxyl, amino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  11. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(VII)所示：The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, the general formula (I) is further represented by the general formula (VII):
    Figure PCTCN2020073152-appb-100036
    Figure PCTCN2020073152-appb-100036
    其中：among them:
    M为S、NR cc或CR ccR dd； M is S, NR cc or CR cc R dd ;
    R 11选自氢、氘、烷基、氘代烷基、卤素、氰基、硝基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，优选氢、卤素、氨基、氰基、烷基、卤代烷基或环烷基，任选进一步被选自氘代烷基、氘、烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； 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 groups are preferably hydrogen, halogen, amino, cyano, alkyl, haloalkyl or ring Alkyl group, optionally further selected from deuterated alkyl, deuterium, alkyl, halogen, hydroxyl, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, ring Substituted by one or more substituents in the alkyl group, heterocyclic group, aryl group and heteroaryl group;
    R cc和R dd各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基； 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;
    或者R cc和R dd链接形成一个环烷基或杂环基，其中所述的环烷基或杂环基任选进一步被选自氘代烷基、氘、烷基、卤素、羟基、氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Or 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～R 6和x如权利要求1所述。 R, R 3 to R 6 and x are as described in claim 1.
  12. 根据权利要求11所述化合物、其立体异构体或其药学上可接受盐，其特征在于，所述The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 11, wherein the
    M为S、NR cc或CR ccR dd，优选S、NCH 3、NOCH 3、NCN、CH 2、CHCH 3或
    Figure PCTCN2020073152-appb-100037
    M is S, NR cc or CR cc R dd , preferably S, NCH 3 , NOCH 3 , NCN, CH 2 , CHCH 3 or
    Figure PCTCN2020073152-appb-100037
    R 11选自氢、氘、C 1-6烷基、C 1-6氘代烷基、卤素、氰基、硝基、C 1-6卤代烷基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、C 6-12芳基和3-8元杂芳基，优选氢、C 1-3烷基、C 1-3氘代烷基、卤素、氨基、氰基、烷基、C 1-3卤代烷基或C 3-5环烷基，更优选甲基、乙基、丙基、环丙基、环丁基、环戊基、环己基、氟、氯、溴、二氟甲基、二氟乙基、三氟甲基或三氟乙基； 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和R dd各自独立地选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 1-6卤代烷氧基、氟、氯、溴、氰基、硝基、羟基、氨基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基、C 6-12芳基或3-6元杂芳基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3羟烷基、C 1-3卤代烷氧基、氟、氯、溴、氰基、硝基、羟基、氨基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、含1-3个N、O或S的3-6元杂环基、C 6-10芳基或含1-3个N、O或S的3-6元杂芳基，更优选氢、甲基、乙基、丙基、氟、氯、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氨基、羟基或氰基； 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 cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S, C 6-10 aryl group or containing 1-3 N, O or S 3 -6 membered heteroaryl, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, hydroxyl Or cyano;
    或者R cc和R dd链接形成一个C 3-6环烷基或3-6元杂环基，优选C 3-6环烷基或含1-3个N、O或S的3-6元杂环基，更优选环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2020073152-appb-100038
    Or 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,
    Figure PCTCN2020073152-appb-100038
  13. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，所述通式(I)进一步如通式(VIII)所示：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (I) is further represented by the general formula (VIII):
    Figure PCTCN2020073152-appb-100039
    Figure PCTCN2020073152-appb-100039
    其中：among them:
    R 3～R 6和x如权利要求1所述。 R 3 to R 6 and x are as described in claim 1.
  14. 根据权利要求13所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 13, wherein the
    R 3选自氢、氘、氟、氯或溴，优选氢、氘或氟，更优选氢或氟； R 3 is selected from hydrogen, deuterium, fluorine, chlorine or bromine, preferably hydrogen, deuterium or fluorine, more preferably hydrogen or fluorine;
    R 4选自C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基，其中所 述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6元杂环基，任选进一步选自甲基、乙基、氟或氯中的一个或多个取代基所取代；优选C 1-3烷基、C 2-5烯基、C 2-5炔基、C 3-5环烷基、3-5元杂环基，更优选C 1-3烷基、C 2-5烯基、C 2-5炔基、C 3-5环烷基、含1-3个N、O或S原子的3-5元杂环基，进一步优选甲基、乙基、丙基、环丙基、环丁基、环戊基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、
    Figure PCTCN2020073152-appb-100040
    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, cyclobutyl, cyclopentyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl,
    Figure PCTCN2020073152-appb-100040
    R 5或R 6各自独立地为氢或氘； R 5 or R 6 are each independently hydrogen or deuterium;
    x为0、1、2或3。x is 0, 1, 2 or 3.
  15. 根据权利要求5、6、9或10中任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 5, 6, 9 or 10, characterized in that:
    环A和环B选自如下基团：Ring A and Ring B are selected from the following groups:
    Figure PCTCN2020073152-appb-100041
    Figure PCTCN2020073152-appb-100041
  16. 根据权利要求1～15中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 15, characterized in that:
    R选自氢、C 1-6烷氧基、C 1-6卤代烷氧基、-OR aa、-SR aa或-NR aaR bb； R is selected from hydrogen, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR aa , -SR aa or -NR aa R bb ;
    R 1选自3-8元杂环基、5-8元杂芳基、-(CH 2) n1NR aaR bb、-NR aaC(O)R bb、-NR aaC(＝S)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaC(O)OR bb、-NR aaS(O) m1R bb、-(CH 2) n1NR aaC(O)C(O)R aa、-NR aaCR bb＝NR cc或-NR aaCR bb＝CR ccR dd，其中所述的3-8元杂环基和5-8元杂芳基，任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氰基、氧代基和C 3-8环烷基中的一个或多个取代基所取代； R 1 is selected from 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, -(CH 2 ) n1 NR aa R bb , -NR aa C(O)R bb , -NR aa C(=S)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa C(O)OR bb , -NR aa S(O) m1 R bb , -(CH 2 ) n1 NR aa C(O)C(O)R aa , -NR aa CR bb =NR cc or -NR aa CR bb =CR cc R dd , wherein the 3-8 membered heterocyclic group and 5-8 membered Heteroaryl, optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxyl, amino, cyano, oxo and C 3-8 cycloalkyl Substituted by one or more substituents;
    R 2选自3-8元杂环基、5-8元杂芳基、-C(O)R aa、-(CH 2) n1OR aa、-C(O)NR aaR bb或-S(O) m1NR aaR bb，其中所述的3-8元杂环基和5-8元杂芳基，任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氰基和C 3-8环烷基中的一个或多个取代基所取代； 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 haloalkane Substituted by one or more substituents in the group, halogen, hydroxy, amino, cyano and C 3-8 cycloalkyl;
    R 3选自氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 3 is selected from hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    R 5选自氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    R 4和R 6各自独立的选自氢、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或-(CH 2) n1R aa；优选氢、环丙基或
    Figure PCTCN2020073152-appb-100042
    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
    Figure PCTCN2020073152-appb-100042
    或者R 4和R 6链接形成一个C 3-8环烷基，优选环戊烷基； Or R 4 and R 6 are linked to form a C 3-8 cycloalkyl group, preferably a cyclopentyl group;
    R 7存在或不存在，存在时选自氢、卤素、氰基、C 1-6烷基或C 1-6卤代烷基； The presence or absence of R 7 is selected from hydrogen, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl when present;
    或者R 6和R 7链接形成一个C 3-8环烷基，优选环戊烷基； Or R 6 and R 7 are linked to form a C 3-8 cycloalkyl group, preferably a cyclopentyl group;
    R 8和R 10各自独立的选自氢、卤素、氰基、C 1-6烷基、C 1-6卤代烷基或C 3-8环烷基； 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选自氢、C 1-6烷基、C 3-8环烷基、3-8元杂环基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1C(O)R aa、-C(O)OR aa、-NR aaR bb或-C(O)NR aaR bb，其中所述的C 1-6烷基、C 3-8环烷基和3-8元杂环基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氧代基、硝基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-8元杂芳基中的一个或多个取代基所取代； 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 heterocyclic group, C 6-10 One or more substituents in the aryl group and 5-8 membered heteroaryl group;
    R 11选自氢、氘、C 1-6烷基、C 1-6氘代烷基、卤素、氰基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基或5-8元杂芳基； 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和R dd各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基或5-8元杂芳基，其中所述的C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基和5-8元杂芳基任选进一步被选自氢、氘、C 1-6烷基、卤素、羟基、氨基、氧代基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-8元杂芳基中的一个或多个取代基所取代； 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 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-8 membered heteroaryl Substituted by a substituent;
    或者，R cc和R dd链接形成一个C 3-8环烷基，其中所述的C 3-8环烷基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、氨基、氧代基、氰基、羟基、C 1-6烷氧基、C 1-6卤代烷氧基和C 1-6羟烷基中的一个或多个取代基所取代。 Alternatively, 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.
  17. 根据权利要求1～16中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述通式(I)选自如下化合物：The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1-16, wherein the general formula (I) is selected from the following compounds:
    Figure PCTCN2020073152-appb-100043
    Figure PCTCN2020073152-appb-100043
    Figure PCTCN2020073152-appb-100044
    Figure PCTCN2020073152-appb-100044
    Figure PCTCN2020073152-appb-100045
    Figure PCTCN2020073152-appb-100045
    Figure PCTCN2020073152-appb-100046
    Figure PCTCN2020073152-appb-100046
    Figure PCTCN2020073152-appb-100047
    Figure PCTCN2020073152-appb-100047
  18. 通式(IX)所示的化合物、其立体异构体或其药学上可接受盐：The compound represented by the general formula (IX), its stereoisomer or its pharmaceutically acceptable salt:
    Figure PCTCN2020073152-appb-100048
    Figure PCTCN2020073152-appb-100048
    其中：among them:
    环C选自如下基团：Ring C is selected from the following groups:
    Figure PCTCN2020073152-appb-100049
    Figure PCTCN2020073152-appb-100049
    R 12独立地选自-OR ee、-C(O)NR eeR ff、-(CH 2) n1NR eeR ff或-S(O) m2NR eeR ff； 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选自氢、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或-(CH 2) n1R aa； 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和R ff各自独立地选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或5-8元杂芳基，其中所述的C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基和5-8元杂芳基，任选进一步被选自氢、氘、C 1-6烷基、卤素、羟基、氨基、氧代基、氰基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-8元杂芳基中的一个或多个取代基所取代； 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 Heterocyclic groups and 5-8 membered heteroaryl groups, optionally further selected from hydrogen, deuterium, C 1-6 alkyl, halogen, hydroxyl, amino, oxo, cyano, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-8 membered heteroaryl substituted by one or more substituents;
    n1为0、1或2；n1 is 0, 1 or 2;
    m2为0、1或2；且m2 is 0, 1, or 2; and
    q为0、1、2或3。q is 0, 1, 2 or 3.
  19. 根据权利要求18所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 18, wherein the
    R 12选自CD 3NHC(O)-、CH 3NHC(O)-、CH 3NHS(O) 2-、CH 3O-、D 3CNHS(O) 2-、
    Figure PCTCN2020073152-appb-100050
    Figure PCTCN2020073152-appb-100051
    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 -,
    Figure PCTCN2020073152-appb-100050
    Figure PCTCN2020073152-appb-100051
    R 17选自氢、卤素、氰基、C 1-3烷基、C 2-5烯基、C 2-5炔基、C 1-3卤代烷基、C 3-6环烷基、3-6元杂环基或-(CH 2) n1R aa，优选氢、卤素、氰基、C 1-3烷基、C 2-5烯基、C 2-5炔基、含1-3个氟、氯或溴原子取代的C 1-3烷基、C 3-6环烷基、含1-3个N、O或S原子的3-6元杂环基或-(CH 2) n1R aa，更优选氢、甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、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、氮杂环戊基、氮杂环己基、硫杂环丁基、硫杂环戊基、硫杂环己基、烯丙基、炔丙基、CF 3CH 2-、(CH 3) 2CF 3C-、CN-、CNCH 2-、CNCH 2CH 2-、
    Figure PCTCN2020073152-appb-100052
    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, cyclobutyl, cyclopentyl, cyclohexyl, oxa Cyclobutyl, oxalanyl, oxanyl, azetidinyl, azetidinyl, azetidinyl, thietanyl, thiolanyl, thiolanyl, alkene Propyl, propargyl, CF 3 CH 2 -, (CH 3 ) 2 CF 3 C-, CN-, CNCH 2 -, CNCH 2 CH 2 -,
    Figure PCTCN2020073152-appb-100052
    R aa选自烷氧基、羟烷基、卤代烷氧基、硝基、羟基、氰基、氨基、芳基或杂芳基，优选C 1-6烷氧基、C 1-6羟烷基、C 1-6卤代烷氧基、硝基、羟基、氰基、氨基、C 6-12芳基或3-12元杂芳基，更优选C 1-3烷氧基、C 1-3羟烷基、C 1-3卤代烷氧基、硝基、羟基、氰基、氨基、C 6-10芳基或5-8元杂芳基，进一步优选甲氧基、乙氧基、丙氧基、羟甲基、羟乙基、羟丙基、含1-3个氟、氯或溴原子取代的C 1-3烷氧基、硝基、羟基、氰基、氨基、苯基、萘基或含1-3个N、O或S原子的3-6元杂芳基； 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, phenyl, naphthyl or 1- 3-6 membered heteroaryl with 3 N, O or S atoms;
    n1选自1或2。n1 is selected from 1 or 2.
  20. 根据权利要求18所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述通式(IX)进一步选自如下化合物：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 18, wherein the general formula (IX) is further selected from the following compounds:
    Figure PCTCN2020073152-appb-100053
    Figure PCTCN2020073152-appb-100053
  21. 通式(X)所示的化合物、其立体异构体或其药学上可接受盐，The compound represented by the general formula (X), its stereoisomer or its pharmaceutically acceptable salt,
    Figure PCTCN2020073152-appb-100054
    Figure PCTCN2020073152-appb-100054
    其中：among them:
    R 13和R 14各自独立地选自氢、氘、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或5-8元杂芳基； 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 15选自3-8元杂环基、5-8元杂芳基、-(CH 2) n1NR aaR bb、-NR aaC(O)R bb、-NR aaC(＝S)R bb、-NR aaC(O)NR bbR cc、-C(O)NR aaR bb、-NR aaC(O)OR bb、-NR aaS(O) m1R bb、-(CH 2) n1NR aaC(O)C(O)R aa、-NR aaCR bb＝NR cc或-NR aaCR bb＝CR ccR dd，其中所述的3-8元杂环基和5-8元杂芳基任选进一步被选自氢、氘、C 1-6烷基、C 1-6卤代烷基、卤素、羟基、氨基、氰基和C 3-8环烷基中的一个或多个取代基所取代； R 15 is selected from 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, -(CH 2 ) n1 NR aa R bb , -NR aa C(O)R bb , -NR aa C(=S)R bb , -NR aa C(O)NR bb R cc , -C(O)NR aa R bb , -NR aa C(O)OR bb , -NR aa S(O) m1 R bb , -(CH 2 ) n1 NR aa C(O)C(O)R aa , -NR aa CR bb =NR cc or -NR aa CR bb =CR cc R dd , wherein the 3-8 membered heterocyclic group and 5-8 membered Heteroaryl is optionally further substituted with one or more selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxy, amino, cyano and C 3-8 cycloalkyl Substituted by
    R 16选自氢、卤素、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 3-8环烷基、3-8元杂环基或-(CH 2) n1R aa； 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和R dd各自独立地选自氢、氘、氰基、卤素、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基或5-8元杂芳基，其中所述的C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基和5-8元杂芳基任选进一步被选自氢、氘、C 1-6烷基、卤素、羟基、氨基、氧代基、氰基、C 2-6烯基、C 2-6炔基、C 1-6 烷氧基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-8元杂芳基中的一个或多个取代基所取代； 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 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-8 membered heteroaryl Substituted by a substituent;
    n1为0、1或2；且n1 is 0, 1 or 2; and
    m1为0、1或2。m1 is 0, 1, or 2.
  22. 根据权利要求21所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述通式(X)进一步为如下化合物：The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 21, wherein said general formula (X) is further the following compound:
    Figure PCTCN2020073152-appb-100055
    Figure PCTCN2020073152-appb-100055
  23. 一种通式(XI)所示的化合物、其立体异构体或其药学上可接受盐：A compound represented by general formula (XI), its stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2020073152-appb-100056
    Figure PCTCN2020073152-appb-100056
    其中：among them:
    R 18选自氢、氘、卤素、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-8环烷基、3-8元杂环基或-(CH 2) n1R aa，优选氢、氘、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、羟基、氰基、C 2-5烯基、C 2-5炔基、C 3-6环烷基、3-6元杂环基或-(CH 2) n1R aa，更优选氢、甲基、环丙基、
    Figure PCTCN2020073152-appb-100057
    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,
    Figure PCTCN2020073152-appb-100057
    R 19选自氢、氘、卤素、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、氨基、羟基或氰基，优选氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、氟、氯、溴、氨基、羟基或氰基，更优选氢、氘、甲基、乙基、丙基、甲氧基、乙氧基、氟、氯、羟基或氰基； 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选自氢、氘、氰基、羟基、卤素、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基或3-8元杂环基，优选 氢、氘、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3羟烷基、C 1-3烷氧基、氟、氯、溴、氰基、C 2-5烯基、C 2-5炔基或C 3-6环烷基，更优选氢、甲基、乙炔基或环丙基； 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为0、1或2；n1 is 0, 1 or 2;
    r为0、1、2或3。r is 0, 1, 2 or 3.
  24. 根据权利要求23所述的通式(XI)化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：The compound of general formula (XI), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 23, characterized in that they are selected from the following compounds:
    Figure PCTCN2020073152-appb-100058
    Figure PCTCN2020073152-appb-100058
  25. 一种制备权利要求7所述的通式(V)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，A method for preparing the compound represented by the general formula (V) according to claim 7 or its stereoisomers and pharmaceutically acceptable salts thereof, characterized by comprising the following steps:
    Figure PCTCN2020073152-appb-100059
    Figure PCTCN2020073152-appb-100059
    通式(V-1)与通式(V-2)反应，得到通式(V-3)，通式(V-3)进一步反应得到与通式(V)所示化合物或其立体异构体及其药学上可接受盐；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;
    其中：among them:
    X选自卤素；X is selected from halogen;
    R 3～R 6、R 9和x如权利要求7所述。 R 3 to R 6 , R 9 and x are as described in claim 7.
  26. 一种制备权利要求7所述的通式(V)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，A method for preparing the compound represented by the general formula (V) according to claim 7 or its stereoisomers and pharmaceutically acceptable salts thereof, characterized by comprising the following steps:
    Figure PCTCN2020073152-appb-100060
    Figure PCTCN2020073152-appb-100060
    通式(V-4)与通式(V-5)反应，得到通式(V-6)，通式(V-6)进一步与通式(V-2)反应，得到与通式(V)所示化合物或其立体异构体及其药学上可接受盐；General formula (V-4) reacts with general formula (V-5) to obtain general formula (V-6), and general formula (V-6) further reacts with general formula (V-2) to obtain general formula (V ) The compound or its stereoisomers and pharmaceutically acceptable salts thereof;
    其中：among them:
    X选自卤素；X is selected from halogen;
    R 3～R 6、R 9和x如权利要求7所述。 R 3 to R 6 , R 9 and x are as described in claim 7.
  27. 一种药用组合物，其包括治疗有效剂量的权利要求1～24中任一项所示的化合物、及其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition, which comprises a therapeutically effective dose of the compound according to any one of claims 1-24, and its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable Accepted carrier, diluent or excipient.
  28. 根据权利要求1～24中任一项所述的化合物、及其立体异构体或其药学上可接受的盐，或权利要求27所述的药物组合物在制备TYK2抑制剂药物中的应用。The compound according to any one of claims 1-24, and its stereoisomers or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical composition according to claim 27 in the preparation of TYK2 inhibitor drugs.
  29. 根据权利要求1～24中任一项所述的化合物、及其立体异构体或其药学上可接受的盐，或权利要求27所述的药物组合物在制备治疗炎性疾病和自身免疫疾病中的应用；其中所述炎性疾病和自身免疫疾病选自类风湿性关节炎、皮炎、银屑病或炎症性肠病。The compound according to any one of claims 1-24, and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 27 when preparing for the treatment of inflammatory diseases and autoimmune diseases The application in; wherein the inflammatory disease and autoimmune disease are selected from rheumatoid arthritis, dermatitis, psoriasis or inflammatory bowel disease.
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