WO2024131918A1 - 一种取代草酰胺类衍生物、其制备方法及用途 - Google Patents

一种取代草酰胺类衍生物、其制备方法及用途 Download PDF

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WO2024131918A1
WO2024131918A1 PCT/CN2023/140814 CN2023140814W WO2024131918A1 WO 2024131918 A1 WO2024131918 A1 WO 2024131918A1 CN 2023140814 W CN2023140814 W CN 2023140814W WO 2024131918 A1 WO2024131918 A1 WO 2024131918A1
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membered
alkyl
compound
substituted
alkyloxy
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French (fr)
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宾华超
刘春池
应文
杨国良
王琼
曹洪益
李莉
向永哲
陈洪
王颖
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成都苑东生物制药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, and in particular to a substituted oxalamide derivative as a protein arginine methyltransferase 5 (PRMT5) inhibitor or a pharmaceutically acceptable salt thereof, and a preparation method and use thereof.
  • a substituted oxalamide derivative as a protein arginine methyltransferase 5 (PRMT5) inhibitor or a pharmaceutically acceptable salt thereof, and a preparation method and use thereof.
  • PRMT5 protein arginine methyltransferase 5
  • PRMT Protein arginine methyltransferase
  • Methylthioadenosine phosphorylase is an important catalytic enzyme for the synthesis of methionine in vivo.
  • the loss of the MTAP gene will lead to the obstruction of the synthesis of downstream methylated arginine, so in order to obtain sufficient methylated arginine, it is more dependent on the PRMT5 pathway.
  • the loss of the MTAP gene will lead to the accumulation of methylthioadenosine (MTA), and a large amount of MTA will compete with SAM, resulting in a decrease in the activity of PRMT5. Therefore, in MTAP-deficient cells, MTA-mediated PRMT5 small molecule inhibitors can inhibit PRMT5 activity when the MTA concentration increases.
  • the present application relates to a substituted oxamide derivative as an MTA-mediated PRMT5 small molecule inhibitor, and a preparation method and medical application thereof, in particular to a substituted oxamide derivative as shown in Formula I below and its use in the preparation of drugs for MTA-PRMT5-mediated diseases, more specifically, its use in the preparation of drugs suitable for tumors.
  • One object of the present application is to provide a compound having a structure as shown in the following formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R1 is selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted amino, carboxyl, hydroxyl, C1 - C6 alkyl, C1 - C6 alkyloxy, C3 - C8 carbocyclyl or C3 - C8 carbocyclyloxy, wherein the C1 - C6 alkyl, C1 - C6 alkyloxy, C3 - C8 carbocyclyl or C3 - C8 carbocyclyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, C1 - C6 alkyl or C1 - C6 alkyloxy;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted amino, C 1 -C 6 hydrocarbon group, C 1 -C 6 hydrocarbon groupoxy group, C 3 -C 8 carbocyclyl group or C 3 -C 8 carbocyclyloxy group, wherein C1 - C6 hydrocarbon group, C1 - C6 hydrocarbon groupoxy group, C3 - C8 carbocyclyl group or C3 - C8 carbocyclyloxy group is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, C1 - C6 alkyl or C1 - C6 alkyloxy group; R2 and R3 can form a 5-8 membered carbocyclic ring or a 5-8 membered heterocyclic ring;
  • R5 is selected from: C3 - C10 carbocyclyl or 3-10 membered heterocyclyl, wherein the C3 - C10 carbocyclyl or 3-10 membered heterocyclyl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C1 - C6 alkyl, C1-C6 haloalkyl , C1 - C6 alkyloxy, C1 - C6 alkylamino , C1- C6 haloalkyloxy, C3 - C10 carbocyclyl, C3- C10 cycloalkyloxy, C3- C10 cycloalkylamino, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, 3-10 membered heterocyclylamino, The C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alky
  • R6 is selected from: C1 - C6 alkyl, C3 - C8 cycloalkyl, C6 - C10 aryl or 4-10 membered heterocyclyl, wherein the C1- C6 alkyl, C3 - C8 cycloalkyl, C6 - C10 aryl or 4-10 membered heterocyclyl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkyloxy, C1 - C6 alkylamino, C1- C6 haloalkyloxy, C3 - C8 cycloalkyl, C3 -C8 cycloalkyloxy, C3 - C10 cycloalkylamino , 3-10 membered heterocyclylamino,
  • X is selected from: a single bond, -CH 2 -, wherein -CH 2 - may be further substituted by 1 or 2 methyl groups or halogen;
  • n is selected from: 0 or 1.
  • R 5 is selected from: C 3 -C 10 carbocyclyl or 3-10 membered heterocyclyl, wherein the C 3 -C 10 carbocyclyl or 3-10 membered heterocyclyl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylamino, C 1 -C 6 haloalkyloxy, C 3 -C 10 carbocyclyl, C 3 -C 10 cycloalkyloxy, C 3 -C 10 cycloalkylamino, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, 3-10 membered heterocyclylamino,
  • R 1 is selected from: hydrogen, halogen, cyano, substituted or unsubstituted amino, carboxyl, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 3 -C 8 carbocyclyl or C 3 -C 8 carbocyclyloxy, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 3 -C 8 carbocyclyl or C 3 -C 8 carbocyclyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkyloxy;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted amino, C 1 -C 6 hydrocarbon group, C 1 -C 6 hydrocarbon groupoxy group, C 3 -C 8 carbocyclyl group or C 3 -C 8 carbocyclyloxy group, wherein C1 - C6 hydrocarbon group, C1 - C6 hydrocarbon groupoxy group, C3 - C8 carbocyclyl group or C3 - C8 carbocyclyloxy group is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, C1 - C6 alkyl or C1 - C6 alkyloxy group; R2 and R3 can form a 5-8 membered carbocyclic ring or a 5-8 membered heterocyclic ring;
  • R 5 is selected from: C 3 -C 10 carbocyclyl or 3-10 membered heterocyclyl, wherein the C 3 -C 10 carbocyclyl or 3-10 membered heterocyclyl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy or C 1 -C 6 haloalkyloxy;
  • R6 is selected from: C1 - C6 alkyl, C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl, wherein the C1 - C6 alkyl, C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkyloxy or C1 - C6 haloalkyloxy;
  • X is selected from: a single bond or -CH 2 -, wherein -CH 2 - may be further substituted by 1 or 2 methyl groups or halogen;
  • n is selected from: 0 or 1.
  • R 1 is selected from: hydrogen, halogen, cyano, substituted or unsubstituted amino, carboxyl, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkyloxy, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyloxy, wherein the C 1 -C 3 alkyl, C 1 -C 3 alkyloxy, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 alkyloxy;
  • R 1 is selected from: hydrogen, halogen, cyano, substituted or unsubstituted amino;
  • R 1 is selected from amino.
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted amino, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyloxy, wherein C1 - C6 alkyl, C1 - C6 alkyloxy, C3 - C8 cycloalkyl or C3 - C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, C1 - C6 alkyl or C1 - C6 alkyloxy; R2 and R3 can form a 5-8 membered carbocyclic ring or a 5-8 membered heterocyclic ring;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, substituted or unsubstituted amino, C 1 -C 3 alkyl or C 1 -C 3 alkyloxy, wherein C 1 -C 3 alkyl or C 1 -C 3 alkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, C 1 -C 3 alkyl or C 1 -C 3 alkyloxy; R 2 and R 3 can form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring;
  • R 2 , R 3 , and R 4 are independently selected from: hydrogen, halogen, or C 1 -C 3 alkyl;
  • R 5 is selected from: C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl or C 6 -C 10 aryl, wherein the C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl or C 6 -C 10 aryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkyloxy, C 1 -C 4 alkylamino, C 1 -C 4 haloalkyloxy , C 3 -C 6 carbocyclyl, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylamino, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylamino, The C 1 -C 4 alkyl, C 1 -C 4 al
  • R5 is further preferably selected from: C6 - C10 aryl or 5-8 membered heteroaryl, wherein the C6 - C10 aryl or 5-8 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C1 - C3 alkyl, C1- C3 haloalkyl, C1 - C3 alkyloxy, C1- C3 alkylamino, C1 - C3 haloalkyloxy, C3 - C6 carbocyclyl, C3 - C6 cycloalkyloxy, C3 - C6 cycloalkylamino, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylamino, The C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyloxy, C 1 -C 3 alkyl, C
  • R5 is further preferably selected from: C6 - C10 aryl or 5-8 membered heteroaryl, wherein the C6 - C10 aryl or 5-8 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C1 - C3 alkyl, C1 - C3 haloalkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and the C1 - C3 alkyl, C1 - C3 haloalkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl may be further substituted by 1, 2 or 3 F, Cl, Br, C1 - C4 alkyl.
  • R 6 is selected from: C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-8 membered heterocycloalkyl or 5-10 membered heteroaryl.
  • C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-8 membered heterocycloalkyl or 5-10 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkyloxy, C 1 -C 4 alkylamino, C 1 -C 4 haloalkyloxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylamino , 3-6 membered heterocyclylamino ,
  • R6 is preferably selected from: C1 - C3 alkyl, C3 - C6 cycloalkyl, C6- C10 aryl or 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is selected from 4-6 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C1 - C3 alkyl, C3 - C6 cycloalkyl, C6 - C10 aryl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C1 - C4 alkyl, C1- C4 haloalkyl, C1 - C4 alkyloxy, C1 - C4 alkylamino, C1 - C4 haloalkyloxy , C3 - C6 cycloalkyl, C3 - C6 cycloalkyl, C3
  • R6 is further preferably selected from: C3 - C6 cycloalkyl, C6 - C10 aryl, 4-6 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the C3 - C6 cycloalkyl, C6 - C10 aryl, 4-6 membered heterocycloalkyl or 5-10 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C1 - C3 alkyl, C1-C3 haloalkyl , C1 - C3 alkyloxy, C1 - C3 alkylamino, C1 - C3 haloalkyloxy, C3 - C6 cycloalkyl, C3 -C6 cycloalkyloxy, C3-C6 cycloalkylamino , 3-6 membered heterocyclylamino,
  • R6 is further preferably selected from: C3 - C6 cycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl, wherein the C3 - C6 cycloalkyl, C6- C10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from F, Cl, Br, cyano, C1 - C3 alkyl, C1 - C3 alkyloxy or C1 - C3 haloalkyloxy.
  • a compound having a structure shown in the following formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided:
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkyloxy, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkyloxy, wherein C1- C3 alkyl, C1 - C3 alkyloxy, C3 - C8 cycloalkyl or C3 - C8 cycloalkyloxy is unsubstituted or substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, C1 - C3 alkyl or C1 - C3 alkyloxy; R2 and R3 can form a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring;
  • R5 is selected from: C3 - C8 cycloalkyl, 3-10 membered heterocyclyl, C6 - C10 aryl or 5-10 membered heteroaryl, wherein the C3 - C8 cycloalkyl, 3-10 membered heterocyclyl, C6- C10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C1 - C4 alkyl, C1-C4 haloalkyl, C1 - C4 alkyloxy, C1 - C4 alkylamino, C1 - C4 haloalkyloxy, C3 - C6 carbocyclyl, C3 - C6 cycloalkyloxy, C3 - C6 cycloalkylamino, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylamino, C 1
  • R6 is selected from: C1 - C3 alkyl, C3 - C6 cycloalkyl, C6- C10 aryl or 5-10 membered heterocyclyl, wherein the 5-10 membered heterocyclyl is selected from 4-6 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C1 - C3 alkyl, C3 - C6 cycloalkyl, C6 - C10 aryl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C1 - C4 alkyl, C1- C4 haloalkyl, C1 - C4 alkyloxy, C1 - C4 alkylamino, C1 - C4 haloalkyloxy, C3 - C6 cycloalkyl, C3 -C6 cycloalkyloxy, C3 - C
  • n is selected from: 0 or 1.
  • R 2 , R 3 , and R 4 are each independently preferably selected from: hydrogen, halogen, cyano, or C 1 -C 3 alkyl.
  • R 2 is selected from C 1 -C 3 alkyl; R 3 and R 4 are both hydrogen;
  • R2 is selected from methyl or ethyl.
  • R 5 is preferably selected from: C 6 -C 10 aryl or 5-8 membered heteroaryl, wherein the C 6 -C 10 aryl or 5-8 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from halogen, cyano, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, and the C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl may be further substituted by 1-3 F, Cl, Br or C 1 -C 4 alkyl;
  • R 5 is preferably selected from:
  • the above substituents may be further substituted by one or more substituents independently selected from F, Cl, Br or C 1 -C 4 alkyl.
  • R 6 is further selected from: C 3 -C 6 cycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein the C 3 -C 6 cycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by one or more substituents selected from F, Cl, Br, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkyloxy or C 1 -C 3 haloalkyloxy;
  • R 6 The above substituents may be further substituted by one or more substituents independently selected from F, Cl, Br, C 1 -C 3 alkyl, C 1 -C 3 alkyloxy or C 1 -C 3 haloalkyloxy.
  • the compound of the structure shown in Formula I, its stereoisomers or pharmaceutically acceptable salts thereof, the compound is selected from:
  • Another object of the present application is to provide a method for preparing the compound of the structure shown in the above formula I and its stereoisomers, the method comprising the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and n are as defined above for the compound of the structure shown in Formula I;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from dichloromethane, acetonitrile, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the base may be selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, preferably triethylamine.
  • the reaction is preferably carried out at a suitable temperature, preferably 0-50°C.
  • the reaction is preferably carried out for a suitable time, such as 0-4 hours.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, water and any combination thereof, preferably tetrahydrofuran aqueous solution.
  • the base may be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, preferably lithium hydroxide.
  • the reaction is preferably carried out at a suitable temperature, preferably 0-50°C.
  • the reaction is preferably carried out for a suitable time, such as 8-12 hours.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable condensing agent.
  • the condensing agent may be selected from HATU, HBTU, T 3 P, etc.
  • the reaction is preferably carried out at a suitable temperature, preferably 0-70° C.
  • the reaction is preferably carried out for a suitable time, such as 2-8 hours.
  • the present application also relates to the use of the above-mentioned compound of formula I in the preparation of drugs for preventing or treating diseases related to PRMT5.
  • the PRMT5-related disease or condition is selected from a tumor or cancer, such as breast cancer, pancreatic cancer, ovarian cancer, colorectal cancer, lung cancer, prostate cancer, lymphoma, malignant sarcoma, cervical cancer, oral cancer, brain cancer, gastric cancer, liver cancer, skin cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, mesothelioma, melanoma, glioma, glioblastoma, papillary malignant tumor, head and neck tumor, myeloma or leukemia. Blood disease.
  • a tumor or cancer such as breast cancer, pancreatic cancer, ovarian cancer, colorectal cancer, lung cancer, prostate cancer, lymphoma, malignant sarcoma, cervical cancer, oral cancer, brain cancer, gastric cancer, liver cancer, skin cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, mesothelioma, melanoma, glioma, glioblasto
  • This application reports a new type of PRMT5 inhibitor with a structure as shown in Formula I, which has good activity.
  • alkoxy refers to an -O-alkyl group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cycloalkyloxy refers to an -O-cycloalkyl group.
  • substituted or unsubstituted amino group encompasses unsubstituted amino group or amino group substituted by a group selected from C 1 -C 6 alkyl group or C 3 -C 8 cycloalkyl group.
  • Carbocyclic group also known as “carbocycle” refers to a cyclic group of a single ring or multiple rings (fused, bridged, spiro) with multiple carbon atoms and no ring heteroatoms; including saturated cycloalkyl, unsaturated cyclic hydrocarbon and aryl.
  • Unsaturated hydrocarbon refers to a cyclic group with unsaturated double bonds; aryl is usually a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group with multiple carbon atoms.
  • carbocyclyloxy refers to -O-carbocyclyl.
  • heterocyclyl also referred to as “heterocycle” refers to a cyclic group containing at least one heteroatom
  • the cyclic group may be a single ring or multiple rings (fused, bridged, spiro)
  • the ring may be a saturated heterocycloalkyl, cycloalkyl, unsaturated heterocycloalkyl, aryl or heteroaryl, wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, and when multiple rings (fused, bridged, spiro) form a cyclic group, the heteroatom may be on any ring, or multiple rings may contain heteroatoms at the same time;
  • the term "heterocycloalkyl” also includes the case where an aromatic ring containing at least one heteroatom is fused with a non-aromatic ring to form a partially saturated cyclic group, and the connection site may be located at a non-aromatic carbon atom
  • Heteroaryl groups include, for example, pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzothiophenyl, benzopyranyl, benzothiapyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, and the like.
  • C m -C n means that the moiety modified by the term has mn carbon atoms (n is greater than m, and both are integers).
  • C 1 -C 6 means that the moiety modified by the term has 1-6 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • the structures of the compounds were determined by mass spectrometry (MS) or nuclear magnetic resonance ( 1 H NMR).
  • Nuclear magnetic resonance ( 1 H NMR) shift ( ⁇ ) is given in parts per million (ppm); Nuclear magnetic resonance ( 1 H NMR) measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ) as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are given in The units are given as 10 -6 (ppm).
  • Mass spectrometry (MS) measurements were performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).
  • Thin layer silica gel uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel sheet.
  • nitrogen atmosphere in the present application means, for example, connecting the reaction bottle to a 1 L nitrogen balloon.
  • hydrogen atmosphere in the present application means, for example, connecting the reaction bottle to a 1 L hydrogen balloon.
  • the solution mentioned in the reaction of the present invention is an aqueous solution.
  • room temperature in the present application refers to a temperature between 10°C and 25°C.
  • Step 7 Preparation of N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -((3-chloropyridin-2-yl)methyl)-N 2 -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (1)
  • Step 5 Preparation of N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -(2-methoxyphenyl)-N 2 -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (15)
  • Step 8 Preparation of N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -((1R,2R)-2-(trifluoromethoxy)cyclohexyl)-N 2 -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (16)
  • Step 1 Using compound 17 and compound 20a as starting materials, the preparation process was the same as Example 13 to obtain the title compound 20b.
  • Step 2 Using compound 20b as the starting material, the title compound 20 was obtained by palladium carbon hydrogenation.
  • Compound 17 was used as the starting material to obtain the title compound through Suziki coupling reaction.
  • Example 15 Using compound 42a as the starting material, the preparation process was the same as in Example 15 to obtain intermediate 42c, which was then subjected to Suziki coupling and then referred to Example 15 to obtain the title compound.
  • Example 15 Using compound 43a as the starting material, the preparation process was the same as in Example 15 to obtain intermediate 43c, which was then subjected to Suziki coupling and then referred to Example 15 to obtain the title compound.
  • Compound 38e was used as the starting material to obtain the title compound through Suziki coupling reaction and BOC removal.
  • Compound 38e was used as the starting material to obtain the title compound through Suziki coupling reaction, hydrogen reduction and BOC removal.
  • Compound 38e was used as the starting material to obtain the title compound through Suziki coupling reaction, hydrogen reduction and BOC removal.
  • Compound 38e was used as the starting material to obtain the title compound through Suziki coupling reaction, hydrogen reduction and BOC removal.
  • Compound 17 was used as the starting material to obtain the title compound through Suziki coupling reaction and hydrogen reduction.
  • Compound 17 was used as the starting material to obtain the title compound through Suziki coupling reaction and hydrogen reduction.
  • Compound 38e was used as the starting material to obtain the title compound through Suziki coupling reaction and hydrogen reduction.
  • Compound 17 was used as the starting material to obtain the title compound through Suziki coupling reaction and hydrogen reduction.
  • Compound 17 was used as the starting material to obtain the title compound through Suziki coupling reaction.
  • Compound 53 was used as the starting material and reduced with hydrogen to obtain the title compound.
  • Test Example 1 HCT116 cell proliferation inhibition test
  • This experiment tested the inhibitory effect of the compounds on the proliferation of HCT116 mutant (MTAP-null) and wild-type (WT) cells.
  • test compounds were prepared in sequence according to the corresponding examples.
  • Preparation of 10 mM compound stock solution Dissolve the compound powder in 100% DMSO to prepare 10 mM compound stock solution.
  • the logarithm of the concentration was used as the X-axis and the percentage survival rate was used as the Y-axis.
  • the log (inhibitor) vs. response-Variable slop (Four parameters) formula of the analysis software Graphpad Prism 9 was used to fit the dose-effect curve to obtain the IC 50 value of each compound.
  • Table 1 The inhibitory activity of the patented compounds on HCT116 mutant (MTAP-null) cell proliferation and HCT116 wild type/mutant (WT/MTAP-null) selectivity data
  • MTase-Glo Assay is a bioluminescence-based detection method that monitors the formation of the reaction product s-adenosyl homocysteine (SAH) and can detect changes in the activity of multiple methyltransferases, including DNA, protein, RNA, and small molecule methyltransferases.
  • SAH s-adenosyl homocysteine
  • test compounds were prepared in sequence according to the corresponding examples.
  • Preparation of 10 mM compound stock solution Dissolve the compound powder in 100% DMSO to prepare 10 mM compound stock solution.
  • Compound concentration configuration The final concentration of the compound IC50 test starts at 1000 nM, with 3-fold dilutions and 10 concentrations, and duplicate wells are set for each concentration.
  • Inhibition percentage (%) ave high control–compounds)/(ave high control–ave low control)*100%
  • the logarithm of the concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis.
  • the log (inhibitor) vs. response-Variable slop (Four parameters) formula of the analysis software Graphpad Prism 5 was used to fit the dose-effect curve to obtain the IC 50 value of each compound on the enzyme activity.
  • the inhibitory activity of the compounds of the present invention on PRMT5-MTA enzyme is shown in Table 2.
  • Test Example 3 Oral pharmacokinetic study in rats
  • SD rats were used as test animals, and the LC-MS/MS method was used to determine the plasma concentration of the compound of the present invention at different times after oral administration to the rats, to obtain the pharmacokinetic parameters of the compound of the present invention in rats, and to study its pharmacokinetic characteristics.
  • test compounds were prepared in sequence according to the corresponding examples.
  • each group was gavaged with the corresponding test drug.
  • a fixed volume of blood was collected through the jugular vein and placed in an EDTA-K2 anticoagulant tube.
  • the blood was centrifuged at 4500rpm for 10min, and the plasma was separated in a centrifuge tube and frozen in a -80°C refrigerator.
  • the plasma at each time point stored at -80°C was taken out, and a fixed volume of methanol was added. After vortexing at 1500 rpm for 2 min, the plasma was centrifuged for 15 min (3500 r/min), and a fixed volume of the supernatant was taken for LC-MS/MS analysis.
  • the pharmacokinetic behavior of the test compound was fitted with a non-compartmental model, and the main pharmacokinetic parameters (T 1/2 , T max , C max , AUC last , etc.) were calculated using DAS3.31 software.

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Abstract

本申请公开了一种如式I所示的取代草酰胺类衍生物，及其作为蛋白精氨酸甲基转移酶5(PRMT5)抑制剂或其药学上可接受的盐、其制备方法及用途。

Description

一种取代草酰胺类衍生物、其制备方法及用途 技术领域
本发明涉及药物化学领域，具体涉及一种取代草酰胺类衍生物作为蛋白精氨酸甲基转移酶5(PRMT5)抑制剂或其药学上可接受的盐、其制备方法及用途。
背景技术
蛋白精氨酸甲基转移酶(PRMT)能够使多种蛋白甲基化，并在基因表达、剪接和DNA损伤修复等生物学过程中发挥重要作用。目前，已发现了11种PRMT家族的成员，主要的研究热点集中在PRMT5上。PRMT5参与组蛋白甲基化，与SAM结合，将其甲基基团转移到蛋白质精氨酸侧链的胍基氮原子上，生成甲基化精氨酸。
甲硫腺苷磷酸化酶(MTAP)是体内合成甲硫氨酸的重要催化酶。MTAP基因的缺失，将导致下游甲基化精氨酸的合成受阻，因此为了得到足够的甲基化精氨酸就更加依赖PRMT5途径。此外，MTAP基因的缺失，将导致甲硫腺苷(MTA)的累积，大量的MTA将于SAM竞争，导致PRMT5的活性降低。因此在MTAP缺陷细胞中，MTA介导的PRMT5小分子抑制剂，能够在MTA浓度升高的情况下抑制PRMT5活性。
研究发现MTAP基因缺失在全部肿瘤类型中发生率约为10％，包括胰腺癌、肺癌、膀胱癌及其他多种肿瘤类型。下调PRMT5表达或抑制其活性可明显抑制肿瘤细胞生长。
因此，开发一种高效、特异性的MTA介导的PRMT5小分子抑制剂，对于实现肿瘤的精准治疗、降低毒副作用具有重要的意义。
发明内容
本申请涉及一种取代草酰胺类衍生物作为MTA介导的PRMT5小分子抑制剂，及其制备方法和在医药上的应用，特别是如下式I所示的取代草酰胺类衍生物及其在制备MTA-PRMT5介导的疾病的药物中的用途，更具体而言，在制备适用于肿瘤药物中的用途。
本申请的一个目的在于，提供了如下式I所示结构的化合物、其立体异构体或其药学上可接受的盐：
其中，
R1选自：氢、卤素、氰基、取代或未被取代的氨基、羧基、羟基、C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基，其中所述C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；
R2、R3、R4分别独立选自：氢、卤素、氰基、取代或未被取代的氨基、C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基，其中所述C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；R2和R3可成环形成5-8元碳环或5-8元杂环；
R5选自：C3-C10碳环基或3-10元杂环基，其中所述C3-C10碳环基或3-10元杂环基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6卤代烷基氧基、C3-C10碳环基、C3-C10环烷基氧基、C3-C10环烷基氨基、3-10元杂环基、3-10元杂环基氧基、3-10元杂环基氨基、其中所述C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6卤代烷基氧基、C3-C10碳环基、C3-C10环烷基氧基、C3-C10环烷 基氨基、3-10元杂环基、3-10元杂环基氧基、3-10元杂环基氨基、 可进一步被卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基或氨基取代；
R6选自：C1-C6烷基、C3-C8环烷基、C6-C10芳基或4-10元杂环基，其中所述C1-C6烷基、C3-C8环烷基、C6-C10芳基或4-10元杂环基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6卤代烷基氧基、C3-C8环烷基、C3-C8环烷基氧基、C3-C10环烷基氨基、3-10元杂环基氨基、
X选自：单键、-CH2-，其中-CH2-可进一步被1或2个甲基或卤素取代；
n选自：0或1。
在一些实施方案中，R5选自：C3-C10碳环基或3-10元杂环基，其中所述C3-C10碳环基或3-10元杂环基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6卤代烷基氧基、C3-C10碳环基、C3-C10环烷基氧基、C3-C10环烷基氨基、3-10元杂环基、3-10元杂环基氧基、3-10元杂环基氨基、
在另外一些实施方案中，R1选自：氢、卤素、氰基、取代或未被取代的氨基、羧基、羟基、C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基，其中所述C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；
R2、R3、R4分别独立地选自：氢、卤素、氰基、取代或未被取代的氨基、C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基，其中所述C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；R2和R3可成环形成5-8元碳环或5-8元杂环；
R5选自：C3-C10碳环基或3-10元杂环基，其中所述C3-C10碳环基或3-10元杂环基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C6卤代烷基、C1-C6烷基、C1-C6烷基氧基或C1-C6卤代烷基氧基；
R6选自：C1-C6烷基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基或5-10元杂芳基，其中所述C1-C6烷基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基或C1-C6卤代烷基氧基；
X选自：单键或-CH2-，其中-CH2-可进一步被1或2个甲基或卤素取代；
n选自：0或1。
在一些实施方式中，R1选自：氢、卤素、氰基、取代或未被取代的氨基、羧基、羟基、C1-C3烃基、C1-C3烷基氧基、C3-C6环烷基或C3-C6环烷基氧基，其中所述C1-C3烃基、C1-C3烷基氧基、C3-C6环烷基或C3-C6环烷基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；
优选地，R1选自：氢、卤素、氰基、取代或未被取代的氨基；
更为优选地，R1选自氨基。
在另一些实施方式中，R2、R3、R4分别独立地选自：氢、卤素、氰基、取代或未被取代的氨基、 C1-C6烷基、C1-C6烷基氧基、C3-C8环烷基或C3-C8环烷基氧基，其中所述C1-C6烷基、C1-C6烷基氧基、C3-C8环烷基或C3-C8环烷基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；R2和R3可成环形成5-8元碳环或5-8元杂环；
更为优选地，R2、R3、R4分别独立选自：氢、卤素、氰基、取代或未被取代的氨基、C1-C3烷基或C1-C3烷基氧基，其中所述C1-C3烷基或C1-C3烷基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C3烷基或C1-C3烷基氧基；R2和R3可成环形成5-6元碳环或5-6元杂环；
更为优选地，R2、R3、R4分别独立地选自：氢、卤素或C1-C3烷基；
在一些实施方式中，R5选自：C3-C8环烷基、3-10元杂环基或C6-C10芳基，其中所述C3-C8环烷基、3-10元杂环基或C6-C10芳基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、 所述C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、可进一步被卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基或氨基取代；
在另一些实施方式中，R5进一步优选自：C6-C10芳基或5-8元杂芳基，其中所述C6-C10芳基或5-8元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷基氧基、C1-C3烷基氨基、C1-C3卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、所述C1-C3烷基、C1-C3卤代烷基、C1-C3烷基氧基、C1-C3烷基氨基、C1-C3卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、 可进一步被任选1个、2个或3个F、Cl、Br、C1-C4烷基取代；
在另一些实施方式中，R5进一步优选自：C6-C10芳基或5-8元杂芳基，其中所述C6-C10芳基或5-8元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C3烷基、C1-C3卤代烷基、3-6元环烷基或3-6元杂环基，所述C1-C3烷基、C1-C3卤代烷基、3-6元环烷基或3-6元杂环基可进一步被任选1个、2个或3个F、Cl、Br、C1-C4烷基取代。
在一些实施方式中，R6选自：C1-C6烷基、C3-C8环烷基、C6-C10芳基、4-8元杂环烷基或5-10元杂芳基，所述 C1-C6烷基、C3-C8环烷基、C6-C10芳基、4-8元杂环烷基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6环烷基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基氨基、
在另一些实施方式中，R6优选自：C1-C3烷基、C3-C6环烷基、C6-C10芳基或5-10元杂环基，其中5-10元杂环基选自4-6元杂环烷基或5-10元杂芳基，其中所述C1-C3烷基、C3-C6环烷基、C6-C10芳基、4-6元杂环烷基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6环烷基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基氨基、
在另一些实施方式中，R6进一步优选自：C3-C6环烷基、C6-C10芳基、4-6元杂环烷基或5-10元杂芳基，其中所述C3-C6环烷基、C6-C10芳基、4-6元杂环烷基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷基氧基、C1-C3烷基氨基、C1-C3卤代烷基氧基、C3-C6环烷基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基氨基、
在另一些实施方式中，R6进一步优选自：C3-C6环烷基、C6-C10芳基或5-10元杂芳基，其中所述C3-C6环烷基、C6-C10芳基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是F、Cl、Br、氰基、C1-C3烷基、C1-C3烷基氧基或C1-C3卤代烷基氧基。
在一些实施方式中，提供了如下式II所示结构的化合物、其立体异构体或其药学上可接受的盐：
其中，
R2、R3、R4分别独立地选自：氢、卤素、氰基、C1-C3烷基、C1-C3烷基氧基、C3-C8环烷基或C3-C8环烷基氧基，其中所述C1-C3烷基、C1-C3烷基氧基、C3-C8环烷基或C3-C8环烷基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C3烷基或C1-C3烷基氧基；R2和R3可成环形成5-6元碳环或5-6元杂环；
R5选自：C3-C8环烷基、3-10元杂环基、C6-C10芳基或5-10元杂芳基，其中所述C3-C8环烷基、3-10元杂环基、C6-C10芳基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、 C1-C3烷基、C1-C3卤代烷基、C1-C3烷基氧基、C1-C3烷基氨基、C1-C3卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、可进一步被1-3个F、Cl、Br或C1-C4烷基取代；
R6选自：C1-C3烷基、C3-C6环烷基、C6-C10芳基或5-10元杂环基，其中5-10元杂环基选自4-6元杂环烷基或5-10元杂芳基，其中所述C1-C3烷基、C3-C6环烷基、C6-C10芳基、4-6元杂环烷基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6环烷基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基氨基、
n选自：0或1。
在一些实施方式中，R2、R3、R4分别独立地优选自：氢、卤素、氰基或C1-C3烷基。
进一步，在另外一些实施方式中，R2选自C1-C3烷基；R3、R4均为氢；
进一步优选地，R2选自甲基或乙基。
在一些实施方式中，R5优选自：C6-C10芳基或5-8元杂芳基，其中所述C6-C10芳基或5-8元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C3烷基、C1-C3卤代烷基、3-6元环烷基或3-6元杂环基，所述C1-C3烷基、C1-C3卤代烷基、3-6元环烷基或3-6元杂环基可进一步被1-3个F、Cl、Br或C1-C4烷基取代；
进一步地，R5优选自： 以上取代基可进一步被一个或多个独立地选自F、Cl、Br或C1-C4烷基的取代基取代。
在另外一些实施方式中，R6进一步选自：C3-C6环烷基、C6-C10芳基或5-10元杂芳基，其中所述C3-C6环烷基、C6-C10芳基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是F、Cl、Br、氰基、C1-C3烷基、C1-C3烷基氧基或C1-C3卤代烷基氧基；
进一步地，R6自 以上取代基可进一步被一个或多个独立地选自F、Cl、Br、C1-C3烷基、C1-C3烷基氧基或C1-C3卤代烷基氧基的取代基取代。
在一些具体实施方式中，式I所示结构的化合物、其立体异构体或其药学上可接受的盐，所述化合物选自：



本申请的另一目的在于，提供了制备上述式I所示结构的化合物及其立体异构体的制备方法，所述方法包括以下步骤：
其中，R1、R2、R3、R4、R5、R6、X和n如上面对式I所示结构的化合物所定义；
(1)使化合物I-1与化合物I-2经缩合反应得到I-3；
所述反应优选在合适的有机溶剂中进行。所述有机溶剂可选自二氯甲烷、乙腈、N,N-二甲基甲酰胺及其任意组合，优选二氯甲烷。所述碱可选自三乙胺、二异丙基乙胺、碳酸钾、碳酸钠，优选三乙胺。所述反应优选在适合的温度下进行，所述温度优选为0-50℃。所述反应优选进行合适的时间，例如0-4小时。
(2)使化合物I-3经水解反应得到I-4；
所述反应优选在合适的有机溶剂中进行。所述有机溶剂可选自甲醇、乙醇、四氢呋喃、N,N-二甲基甲酰胺、水及其任意组合，优选四氢呋喃水溶液。所述碱可选自氢氧化钠、氢氧化钾、氢氧化锂，优选氢氧化锂。所述反应优选在适合的温度下进行，所述温度优选为0-50℃。所述反应优选进行合适的时间，例如8-12小时。
(3)使化合物I-4与化合物I-5经缩合反应得到式I所示结构的化合物；
所述反应优选在适合的有机溶剂中进行。所述有机溶剂可选自二氯甲烷、乙腈、四氢呋喃、N,N-二甲基甲酰胺及其任意组合，优选N,N-二甲基甲酰胺。所述反应优选在适合的缩合剂存在下进行。所述缩合剂可选自HATU、HBTU、T3P等。所述反应优选在适合的温度下进行，所述温度优选为0-70℃。所述反应优选进行合适的时间，例如2-8小时。
上述各反应步骤的具体条件为本领域公知，对此本申请不做具体限定。如本申请的教导结合本领域公知常识，本领域技术人员可以对通式中的各取代基进行选择替换以制备得到不同的化合物，这些选择和替换均在本申请的保护范围之内。
本申请还涉及上述式I化合物在制备预防或治疗与PRMT5相关疾病的药物中的用途。
在一些实施例方式中，所述与PRMT5相关疾病或病症选自肿瘤或癌症，例如乳腺癌、胰腺癌、卵巢癌、结直肠癌、肺癌、前列腺癌、淋巴瘤、恶性肉瘤、宫颈癌、口腔癌、脑癌、胃癌、肝癌、皮肤癌、骨癌、肾癌、膀胱癌、输卵管肿瘤、间皮瘤、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、乳突状恶性瘤、头颈部肿瘤、骨髓瘤或白 血病。
本申请报道一类结构全新，具有如式I所示结构的PRMT5抑制剂，其具有较好的活性。
具体实施方式
为了使本申请的目的和技术方案更加清楚，以下结合具体实施例进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明范围。并且，下列实施例中未提及的具体实验方法，均按照常规实验方法进行。
在本申请中，当化学名称和结构式不一致时，应当以结构式所示为准，除非如上下文可以推断化学名称而非结构式是正确的。
定义和说明
非另有说明，本申请中所用的术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。
在本文中，除非另有说明，“烷氧基”指-O-烷基。
在本文中，除非另有说明，“卤素”是指氟、氯、溴或碘。
在本文中，除非另有说明，“环烷基氧基”基指-O-环烷基。
在本文中，除非另有说明，“取代或未被取代的氨基”是涵盖未被取代的氨基或被选自如下的基团取代的氨基：C1-C6烷基或C3-C8环烷基。
在本文中，除非另有说明，“碳环基”，也称为“碳环”，指具有多个碳原子且没有环杂原子的单个环或多个环(稠合、桥连、螺合)的环状基团；含饱和环烷基、不饱和环烃基和芳基。不饱和烃基指环状基团上有不饱和双键；芳基通常是具有多个碳原子的单环、二环或三环芳烃基团。
在本文中，除非另有说明，“碳环基氧基”指-O-碳环基。
在本文中，除非另有说明，“杂环基”，也称为“杂环”，指包含至少一个杂原子的环状基团，所述环状基团可以是单个环或多个环(稠合、桥连、螺合)的，所述环可以是饱和的杂环烷基、环烷基、不饱和的杂环烃基、芳基或杂芳基，其中杂原子指氮原子、氧原子、硫原子，且当多个环(稠合、桥连、螺合)形成环状基团时，杂原子可在任一环上，或多个环同时含有杂原子；术语“杂环烷基”还包括包含至少一个杂原子的芳香环与非芳香环稠合形成的部分饱和环状基团的情形，其连接位点可以位于非芳族碳原子、芳族碳原子或杂原子。杂芳基例如代表：吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基等。
在本文中，除非另有说明，使用的术语“Cm-Cn”是指由该术语修饰的该部分中具有m-n个碳原子(n大于m，且二者为整数)。例如，C1-C6表示其修饰的部分中具有1-6个碳原子，例如1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
本文中的缩写具有以下含义：
化合物的结构是通过质谱(MS)或者核磁共振(1H NMR)来确定的。
核磁共振(1H NMR)位移(δ)以百万分之一(ppm)的单位给出；核磁共振(1H NMR)的测定是用BrukerAVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，内标为四甲基硅烷(TMS)，化学位移是以 10-6(ppm)作为单位给出。
质谱(MS)的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Therm，型号：Finnigan LCQ advantage MAX)进行。
薄层硅胶使用烟台黄海HSGF254或青岛GF254硅胶板。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
在本申请未给出特殊说明的情况下，本发明中所提及的反应均在氮气氛围下进行。
在本申请的术语“氮气氛围”是指例如将反应瓶连接一个1L容积的氮气气球。
在本申请的术语“氢气氛围”是指例如将反应瓶连接一个1L容积的氢气气球。
在本申请未给出特殊说明的情况下，本发明反应中提及的溶液是水溶液。
在本申请的术语“室温”是指温度处于10℃-25℃之间。
实施例1 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((3-氯吡啶-2-基)甲基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(1)的制备
第一步：化合物1b的制备
将化合物1a(5g,32.7mmol)溶于二氯甲烷(100mL)中，依次加入4-二甲氨基吡啶(0.8g,6.5mmol)、二碳酸二叔丁酯(15.7g,71.9mmol)，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物10g，收率：86.7％。
LC-MS(ESI)m/z(M+H)+：354.2
第二步：化合物1c的制备
将化合物1b(10g,28.3mmol)溶于甲醇(300mL)中，然后加入10％钯碳(0.5g)，氢气氛围下，反应体系在室温下搅拌反应12小时。反应液滤除钯碳，减压浓缩滤液，得标题化合物8.8g，收率：96.5％。
LC-MS(ESI)m/z(M+H)+：324.2
第三步：化合物1d的制备
将化合物1c(8.8g,27.3mmol)溶于二氯甲烷(150mL)中，依次加入草酰氯单乙酯(5.6g,41.0mmol)、三乙胺(2.8g,27.3mmol)，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物10.5g，收率：90.8％。
LC-MS(ESI)m/z(M+H)+：424.2
第四步：化合物1e的制备
将化合物1d(10.5g,24.8mmol)溶于四氢呋喃-水(1:10)混合溶液(300mL)中，加入氢氧化锂(0.7g,27.3mmol)，反应体系在室温下搅拌反应12小时。反应液用2％稀盐酸水溶液调pH至6～7后，乙酸乙酯萃取3次，有机相合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩滤液，得标题化合物9.2g，收率：94.3％。
LC-MS(ESI)m/z(M+H)+：396.2
第五步：化合物1h的制备
将化合物1f(500mg,3.5mmol)、化合物1g(625mg,3.5mmol)溶于甲醇(30mL)中，滴加冰乙酸(0.01mL)，反应体系在室温下搅拌反应0.5小时。再加入三乙酰氧基硼氢化钠(2.3g,10.6mmol)，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物420mg，收率：39.4％。
LC-MS(ESI)m/z(M+H)+：302.1
第六步：化合物1i的制备
将化合物1h(100mg,0.3mmol)、化合物1e(132mg,0.3mmol)溶于N,N-二甲基甲酰胺(5mL)中，随后依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(165mg,0.4mmol)、三乙胺(68mg,0.7mmol)，反应体系在室温下搅拌反应12小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物32mg，收率：14.2％。
LC-MS(ESI)m/z(M+H)+：679.2
第七步：N1-(6-氨基-5-甲基吡啶-3-基)-N2-((3-氯吡啶-2-基)甲基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(1)的制备
将化合物1i(32mg,0.05mmol)溶于二氯甲烷-三氟乙酸(1:2)混合溶液(6mL)中，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物21mg，收率：93.5％。
LC-MS(ESI)m/z(M+H)+：479.1
1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.90(s,1H),8.49(d,J＝4.8,Hz,1H),8.19(d,J＝8.0Hz,1H),7.97(s,1H),7.90(d,J＝8.0Hz,1H),7.66(d,J＝8.3Hz,1H),7.48–7.40(m,1H),7.36(d,J＝8.1Hz,1H),5.63(s,2H),5.16(s,2H),4.86(s,2H),1.99(s,3H).
实施例2 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(3,3-二氟环丁基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(2)的制备
以化合物2a、化合物2b为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：444.2
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.88(s,1H),8.18(d,J＝9.2Hz,1H),8.01(s,1H),7.56(d,J＝9.2Hz,1H),7.45(s,1H),5.63(s,2H),4.90(s,2H),4.66–4.30(m,1H),2.02(s,3H),1.25–1.17(m,4H).
实施例3 N1-(6-氨基-5-三氟甲基吡啶-3-基)-N2-((3-氯吡啶-2-基)甲基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(3)的制备
以化合物3a为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：533.1
1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.90(s,1H),8.47(d,J＝4.8Hz,1H),8.37(d,J＝4.8Hz,1H),8.18(s,1H),7.96(s,1H),7.89(d,J＝6.6Hz,1H),7.64(s,1H),7.39–7.33(m,1H),6.39(s,2H),5.19(s,2H),4.87(s,2H).
实施例4 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(环丙基甲基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(4)的制备
以化合物4a、化合物2a为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：408.2
1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.94(s,1H),8.22(d,J＝8.4Hz,1H),8.04(s,1H),7.62(d,J＝8.4Hz,1H),7.53(s,1H),5.73(s,2H),4.85(s,2H),3.30(d,J＝7.0Hz,2H),2.04(s,3H),1.06–1.02(m,1H),0.45–0.32(m,2H),0.18–0.14(m,2H).
实施例5 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基环己基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(5)的制备
以化合物5a、化合物2a为起始原料，制备过程同实施例1，获得标题化合物，通过柱层析制备获得化合物5-2。化合物5-2经过SFC制备获得化合物5-2-P1(Rt＝3.789min)、5-2-P2(Rt＝4.987min)。
5-2-P2：
LC-MS(ESI)m/z(M+H)+：466.2
1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.91(s,1H),8.20(d,J＝11.2Hz,1H),8.06(s,1H),7.57–7.51(m,2H),5.65(s,2H),4.78(d,J＝16.8Hz,1H),4.66(d,J＝16.8Hz,1H),3.96–3.88(m,1H),3.24–3.19(m,1H),3.08(s,3H),2.04(s,3H),1.65-1.59(m,2H),1.56–1.41(m,2H),1.36–1.25(m,2H),1.14(d,J＝8.2Hz,2H).
实施例6 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(1-(嘧啶-2-基)乙基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(6)的制备
以化合物6a、化合物1g为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：460.2
1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.78(d,J＝12.2Hz,1H),8.74(s,1H),8.72(s,1H),8.10(d,J＝8.4Hz,1H),7.94(s,1H),7.66(d,J＝8.4Hz,1H),7.50(s,1H),7.39–7.32(m,1H),5.69(t,J＝7.0Hz,1H),5.61(s,2H),5.17–4.50(m,2H),1.97(s,3H),1.57(d,J＝6.9Hz,3H).
实施例7 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(1-甲基-1H-吡唑-4-基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(7)的制备
以化合物7a、化合物2a为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：434.2
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.01(s,1H),8.24(d,J＝8.4Hz,1H),8.04(s,1H),7.78(s,1H),7.64(d,J＝8.4Hz,1H),7.56(s,1H),7.40(s,1H),5.65(s,2H),5.08(s,2H),3.71(s,3H),2.00(s,3H).
实施例8 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基环己基)-N2-((5-溴吡啶-2-基)甲基)草酰胺(8)的制备
以化合物5a、化合物8a为起始原料，制备过程同实施例1，获得标题化合物，通过柱层析制备获得化合物8-2。化合物8-2经过SFC制备获得化合物8-2-P1(RT＝3.525min)、8-2-P2(RT＝4.732min)。
8-2-P2：
LC-MS(ESI)m/z(M+H)+：476.38
1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.64(s,1H),8.03(d,J＝12.2Hz,2H),7.52(s,1H),7.32(s,1H),5.60(d,J＝17.2Hz,2H),4.69(d,J＝16.4Hz,1H),4.51(d,J＝16.4Hz,1H),3.95–3.78(m,1H),3.18(td,J＝10.2,4.4Hz, 1H),3.08(s,3H),2.04(s,3H),1.63–1.59(m,2H),1.52–1.35(m,2H),1.23–1.07(m,4H).
实施例9 N1-(6-氨基-5-甲基吡啶-3-基)-N2-环己基-N2-((5-溴吡啶-2-基)甲基)草酰胺(9)的制备
以化合物9a、化合物2a为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：436.3
1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.92(s,1H),8.20(dd,J＝8.4,2.2Hz,1H),8.03(s,1H),7.53(d,J＝8.4Hz,1H),7.50(d,J＝3.0Hz,1H),5.67(s,2H),4.71(s,2H),3.85–3.71(m,1H),2.06(s,3H),1.78–1.73(m,2H),1.60–1.49(m,4H),1.24–1.13(m,4H).
实施例10 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(10)的制备
以化合物10a、化合物2a为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：504.1
1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.88(s,1H),8.15(d,J＝5.6Hz,1H),7.95(d,J＝2.5Hz,1H),7.57–7.39(m,2H),6.88–6.81(m,1H),6.68–6.60(m,1H),5.63(d,J＝15.2Hz,2H),4.91(d,J＝2.9Hz,2H),4.65(s,2H),4.53(t,J＝8.8Hz,2H),3.18(t,J＝8.8Hz,2H),1.99(s,3H).
实施例11 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(环戊基甲基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(11)的制备
以化合物11a、化合物2a为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：436.3
1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.92(s,1H),8.22(t,J＝9.6Hz,1H),7.98(s,1H),7.58(d,J＝8.4Hz,1H),7.51–7.38(m,1H),5.63(s,2H),4.86(s,2H),3.47(d,J＝7.6Hz,2H),2.28–2.16(m,1H),2.02(s,3H),1.62–1.58(m,2H),1.53–1.43(m,3H),1.24–1.18(m,3H).
实施例12 N1-(6-氨基-5-甲基吡啶-3-基)-N2-环戊基-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(12)的制备
以化合物12a、化合物2a为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：422.2
1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.90(s,1H),8.23–8.17(m,1H),7.96(s,1H),7.54(s,1H),7.42(s, 1H),5.66(s,2H),4.77(s,2H),3.55–3.51(m,1H),2.01(s,3H),1.91–1.81(m,2H),1.65–1.47(m,6H).
实施例13 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基环己基)-N2-((5-环丙基吡啶-2-基)甲基)草酰胺(13)的制备
将化合物8-2(47.5mg,0.1mmol)、化合物13a(25.8mg,0.3mmol)溶于1，4-二氧六环(20mL)中，依次加入1,1-双(二苯基膦)二荗铁二氯化钯(7.3mg,0.01mmol)、碳酸钾(41.5mg,0.3mmol)，氮气保护下，反应体系在100℃下搅拌反应4小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物21mg，收率：47.9％。
LC-MS(ESI)m/z(M+H)+：438.2
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.31(s,1H),8.01(s,1H),7.49(s,1H),7.41–7.35(m,1H),7.19(s,1H),5.59(s,2H),4.71(d,J＝16.0Hz,1H),4.45(d,J＝16.0Hz,1H),3.93–3.81(m,1H),3.22–3.15(m,1H),3.10(s,3H),2.01(s,3H),1.97–1.88(m,1H),1.61–1.42(m,4H),1.16–0.89(m,6H),0.77–0.64(m,2H).
实施例14 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(5,6,7,8-四氢喹啉-8-基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(12)的制备
以化合物14a、化合物2a为起始原料，制备过程同实施例1，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：485.2
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.81(s,1H),8.40(s,1H),8.16(s,1H),8.00(s,1H),7.67–7.48(m,2H),7.35–7.20(m,2H),5.64(s,2H),5.50–5.35(m,1H),5.12–4.68(m,2H),2.84–2.69(m,2H),2.00(s,3H),1.98–1.91(m,2H),1.81–1.70(m,2H).
实施例15 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(15)的制备
第一步：化合物15b的制备
将化合物15a(500mg,4.1mmol)、化合物2a(711mg,4.1mmol)溶于甲醇(30mL)中，滴加冰乙酸(0.01mL)，反应体系在室温下搅拌反应0.5小时。再加入三乙酰氧基硼氢化钠(2.6g,12.3mmol)，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物740mg，收率：64.0％。
LC-MS(ESI)m/z(M+H)+：283.2
第二步：化合物15c的制备
将化合物15b(740mg,2.6mmol)溶于二氯甲烷(50mL)中，依次加入草酰氯单乙酯(425mg,3.1mmol)、三乙胺(316mg,2.6mmol)，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化 合物934mg，收率：93.2％。
LC-MS(ESI)m/z(M+H)+：383.2
第三步：化合物15d的制备
将化合物15c(934mg,2.4mmol)溶于四氢呋喃-水(1:10)混合溶液(50mL)中，加入氢氧化锂(65mg,2.7mmol)，反应体系在室温下搅拌反应12小时。反应液用2％稀盐酸水溶液调pH至6～7后，乙酸乙酯萃取3次，有机相合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩滤液，得标题化合物848mg，收率：91.3％。
LC-MS(ESI)m/z(M+H)+：355.1
第四步：化合物15e的制备
将化合物15d(100mg,0.3mmol)、化合物1c(92mg,0.3mmol)溶于N,N-二甲基甲酰胺(5mL)中，随后依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(152mg,0.4mmol)、三乙胺(70mg,0.7mmol)，反应体系在室温下搅拌反应12小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物69mg，收率：34.7％。
LC-MS(ESI)m/z(M+H)+：660.3
第五步：N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(15)的制备
将化合物15e(69mg,0.1mmol)溶于二氯甲烷-三氟乙酸(1:2)混合溶液(6mL)中，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物46mg，收率：90.7％。
LC-MS(ESI)m/z(M+H)+：460.2
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.88(s,1H),8.22(dd,J＝8.4,2.4Hz,1H),7.83(d,J＝2.5Hz,1H),7.71(d,J＝8.4Hz,1H),7.34–7.21(m,3H),7.06–7.01(m,1H),6.91–6.82(m,1H),5.57(s,2H),5.26(d,J＝16.4Hz,1H),4.80(d,J＝16.4Hz,1H),3.74(s,3H),1.96(s,3H).
实施例16 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((1R,2R)-2-(三氟甲氧基)环己基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(16)的制备
第一步：化合物16b的制备
将化合物16a(1g,8.7mmol)溶于二氯甲烷(100mL)中，依次加入4-二甲氨基吡啶(212mg,1.7mmol)、二碳酸二叔丁酯(5.7g,26.0mmol)，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物2.3g，收率：83.2％。
LC-MS(ESI)m/z(M+H)+：316.2
第二步：化合物16c的制备
将化合物16b(2.3g,7.3mmol)乙酸乙酯(100mL)中，依次加入三氟甲基三甲基硅烷(3.1g,21.9mmol)、三氟甲磺酸银(3.7g,14.6mmol)、1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(3.9g,10.9mmol)、氟化钾(1.3g,21.9mmol)、2-氟吡啶(2.1g,21.9mmol)，氮气保护下，反应体系在室温下搅拌反应24小时.减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物1.9g，收率：67.8％。
LC-MS(ESI)m/z(M+H)+：384.2
第三步：化合物16d的制备
将化合物16c(1.9g,4.9mmol)溶于二氯甲烷-三氟乙酸(1:2)混合溶液(6mL)中，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物849mg，收率：93.7％。
LC-MS(ESI)m/z(M+H)+：184.1
第四步：化合物16e的制备
将化合物16d(849mg,4.6mmol)、化合物2a(811mg,4.6mmol)溶于甲醇(30mL)中，滴加冰乙酸(0.01mL)，反应体系在室温下搅拌反应0.5小时。再加入三乙酰氧基硼氢化钠(2.9g,13.9mmol)，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物600mg，收率：38.1％。
LC-MS(ESI)m/z(M+H)+：343.1
第五步：化合物16f的制备
将化合物16e(600mg,1.8mmol)溶于二氯甲烷(50mL)中，依次加入草酰氯单乙酯(286mg,2.1mmol)、三乙胺(213mg,2.1mmol)，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物732mg，收率：94.2％。
LC-MS(ESI)m/z(M+H)+：443.1
第六步：化合物16g的制备
将化合物16f(732mg,1.7mmol)溶于四氢呋喃-水(1:10)混合溶液(50mL)中，加入氢氧化锂(44mg,1.8mmol)，反应体系在室温下搅拌反应12小时。反应液用2％稀盐酸水溶液调pH至6～7后，乙酸乙酯萃取3次，有机相合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩滤液，得标题化合物630mg，收率：92.1％。
LC-MS(ESI)m/z(M+H)+：415.1
第七步：化合物16h的制备
将化合物15g(125mg,0.3mmol)、化合物1c(92mg,0.3mmol)溶于N,N-二甲基甲酰胺(5mL)中，随后依次加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(152mg,0.4mmol)、三乙胺(70mg,0.7mmol)，反应体系在室温下搅拌反应12小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物73mg，收率：33.8％。
LC-MS(ESI)m/z(M+H)+：720.3
第八步：N1-(6-氨基-5-甲基吡啶-3-基)-N2-((1R,2R)-2-(三氟甲氧基)环己基)-N2-((5-(三氟甲基)吡啶-2-基)甲基)草酰胺(16)的制备
将化合物16h(73mg,0.1mmol)溶于二氯甲烷-三氟乙酸(1:2)混合溶液(6mL)中，反应体系在室温下搅拌反应3小时。减压浓缩反应液，粗品经硅胶柱层析纯化得到标题化合物49mg，收率：93.2％。
LC-MS(ESI)m/z(M+H)+：520.2
1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.93(s,1H),8.19(dd,J＝8.4,2.4Hz,1H),8.07(d,J＝2.4Hz,1H),7.56–7.52(m,1H),7.48(d,J＝8.4Hz,1H),5.66(s,2H),4.80(t,J＝17.6Hz,2H),4.73–4.65(m,1H),4.56–4.46(m,1H),2.04(s,3H),1.67–1.58(m,4H),1.55–1.44(m,2H),1.35–1.27(m,2H).
实施例17 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((5-溴代-吡啶-2-基)甲基)草酰胺(17)的制备
以化合物15a、化合物17a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：470.1
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.60(d,J＝2.4Hz,1H),8.07–8.03(m,1H),7.82(d,J＝2.4Hz,1H),7.44(d,J＝8.4Hz,1H),7.28(d,J＝2.4Hz,1H),7.25–7.18(m,2H),7.02(d,J＝8.4Hz,1H),6.84(td,J＝7.6,1.2Hz,1H),5.57(s,2H),5.19(d,J＝15.6Hz,1H),4.64(d,J＝15.6Hz,1H),3.74(s,3H),1.96(s,3H).
实施例18 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((5-环丙基-吡啶-2-基)甲基)草酰胺(18)的制备
以化合物17、化合物13a为起始原料，制备过程同实施例13，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：432.2
1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.27(s,1H),7.86(s,1H),7.38(dd,J＝8.4,2.4Hz,1H),7.31(d,J＝8.4Hz,1H),7.28(d,J＝2.4Hz,1H),7.21(t,J＝8.0Hz,1H),7.15(dd,J＝7.6,1.6Hz,1H),7.01(d,J＝8.0Hz,1H),6.81(t,J＝7.6Hz,1H),5.56(s,2H),5.21(d,J＝15.6Hz,1H),4.56(d,J＝15.6Hz,1H),3.74(s,3H),1.96(s,3H),1.91(td,J＝8.4,4.4Hz,1H),0.99–0.92(m,2H),0.72–0.68(m,2H).
实施例19 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-异丙氧基苯基)-N2-((5-三氟甲基-吡啶-2-基)甲基)草酰胺(19)的制备
以化合物19a、化合物2a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：488.2
1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.87(s,1H),8.23(d,J＝9.0Hz,1H),7.89(d,J＝2.5Hz,1H),7.73(d,J＝8.2Hz,1H),7.36(d,J＝2.5Hz,1H),7.31(dd,J＝7.8,1.7Hz,1H),7.19(t,J＝7.8Hz,1H),6.99(d,J＝8.3Hz,1H),6.84(t,J＝7.6Hz,1H),5.56(s,2H),5.11(d,J＝16.1Hz,1H),4.96(d,J＝16.1Hz,1H),4.59(p,J＝5.9Hz,1H),1.97(s,3H),1.15(dd,J＝17.1,6.0Hz,6H).
实施例20 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((5-环戊基-吡啶-2-基)甲基)草酰胺(20)的制备
第一步：以化合物17、化合物20a为起始原料，制备过程同实施例13，获得标题化合物20b。
LC-MS(ESI)m/z(M+H)+：458.2
1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.35(d,J＝2.4Hz,1H),7.82(d,J＝2.4Hz,1H),7.64(dd,J＝8.0,2.4Hz,1H),7.37(d,J＝8.0Hz,1H),7.28(d,J＝2.4Hz,1H),7.21(t,J＝8.4Hz,2H),7.05–6.97(m,1H),6.92–6.77(m,1H),5.56(s,2H),5.21(d,J＝15.6Hz,1H),4.58(d,J＝15.6Hz,1H),3.74(s,3H),3.01–2.92(m,1H),2.02–1.99(m,2H),1.96(s,3H),1.80–1.72(m,2H),1.69–1.59(m,2H),1.56–1.46(m,2H).
第二步：以化合物20b为起始原料，经钯碳氢化获得标题化合物20。
LC-MS(ESI)m/z(M+H)+：460.2
1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.35(d,J＝2.4Hz,1H),7.82(d,J＝2.4Hz,1H),7.64(dd,J＝8.0,2.4Hz,1H),7.37(d,J＝8.0Hz,1H),7.28(d,J＝2.4Hz,1H),7.21(t,J＝8.4Hz,2H),7.05–6.97(m,1H),6.92–6.77(m,1H),5.56(s,2H),5.21(d,J＝15.6Hz,1H),4.58(d,J＝15.6Hz,1H),3.74(s,3H),3.05–2.86(m,1H),2.02(d,J＝6.8Hz,2H),1.96(s,3H),1.76(d,J＝7.6Hz,2H),1.65(dd,J＝7.6,4.7Hz,2H),1.52(d,J＝9.8Hz,2H).
实施例21 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((6-(3,3-二氟吡咯烷-1-基)-吡啶-3-基)甲基)草酰胺(21)的制备
以化合物21a、化合物15a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：497.2
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.91(d,J＝2.4Hz,1H),7.79(d,J＝2.4Hz,1H),7.40(dd,J＝8.6,2.4Hz,1H),7.24(dd,J＝5.0,2.0Hz,1H),7.23–7.18(m,1H),7.00(td,J＝8.0,1.6Hz,2H),6.81(td,J＝7.6,1.6Hz,1H),6.47(d,J＝8.6Hz,1H),5.54(s,2H),5.03(d,J＝14.4Hz,1H),4.44(d,J＝14.4Hz,1H),3.78(t,J＝13.4Hz,2H),3.72(s,3H),3.56(t,J＝7.2Hz,2H),1.95(s,3H),1.25(d,J＝9.4Hz,2H).
实施例22 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基-5-甲基-苯基)-N2-((5-三氟甲基-吡啶-2-基)甲基)草酰胺(22)的制备
以化合物22a、化合物2a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：474.2
1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.89(s,1H),8.23(dd,J＝8.4,2.4Hz,1H),7.83(d,J＝2.4Hz,1H),7.71(d,J＝8.4Hz,1H),7.29(d,J＝1.8Hz,1H),7.13(d,J＝2.2Hz,1H),7.06–7.01(m,1H),6.91(d,J＝8.4Hz,1H),5.58(s,2H),5.19(d,J＝15.6Hz,1H),4.84(d,J＝15.6Hz,1H),3.68(s,3H),2.14(s,3H),1.97(s,3H).
实施例23 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基-5-氯代-苯基)-N2-((5-三氟甲基-吡啶-2-基)甲基)草酰胺(23)的制备
以化合物23a、化合物2a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：494.1
1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.90(s,1H),8.23(d,J＝8.4Hz,1H),7.85(d,J＝2.0Hz,1H),7.70(d,J＝8.4Hz,1H),7.45(d,J＝2.8Hz,1H),7.32–7.28(m,2H),7.06(d,J＝8.6Hz,1H),5.60(s,2H),5.20(d,J＝15.0Hz,1H),4.88(d,J＝15.0Hz,1H),3.71(s,3H),1.98(s,3H).
实施例24 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基-4-氯代-苯基)-N2-((5-三氟甲基-吡啶-2-基)甲基)草酰胺(24)的制备
以化合物24a、化合物2a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：494.1
1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.89(s,1H),8.23(dd,J＝8.4,2.4Hz,1H),7.86(d,J＝2.4Hz,1H),7.69(d,J＝8.4Hz,1H),7.32(d,J＝2.4Hz,1H),7.29(d,J＝8.4Hz,1H),7.14(d,J＝2.4Hz,1H),6.96(dd,J＝8.4,2.3Hz,1H),5.60(s,2H),5.24(d,J＝16.0Hz,1H),4.79(d,J＝16.0Hz,1H),3.76(s,3H),1.98(s,3H).
实施例25 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-氯代-苯基)-N2-((5-三氟甲基-吡啶-2-基)甲基)草酰胺(25)的制备
以化合物25a、化合物2a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：464.2
1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.91(d,J＝1.1Hz,1H),8.23(dd,J＝8.4,2.2Hz,1H),7.84(d,J＝2.5Hz,1H),7.73(d,J＝8.4Hz,1H),7.53(dd,J＝7.6,1.8Hz,1H),7.44(dd,J＝7.6,2.0Hz,1H),7.34(dd,J＝7.5,2.0 Hz,1H),7.30(dd,J＝7.2,2.0Hz,2H),5.60(s,2H),5.42(d,J＝15.6Hz,1H),4.70(d,J＝15.6Hz,1H),1.96(s,3H).
实施例26 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-(吡啶-2-基甲基)草酰胺(26)的制备
以化合物26a、化合物15a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：392.2
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.46(d,J＝4.8Hz,1H),7.83(d,J＝2.5Hz,1H),7.77(td,J＝7.8,1.8Hz,1H),7.46(d,J＝7.8Hz,1H),7.29–7.27(m,1H),7.27–7.23(m,1H),7.22–7.17(m,2H),7.02(d,J＝8.0Hz,1H),6.85–6.79(m,1H),5.56(s,2H),5.26(d,J＝15.6Hz,1H),4.62(d,J＝15.6Hz,1H),3.75(s,3H),1.96(s,3H).
实施例27 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((5-(环戊-1-烯-1-基)吡啶-2-基)甲基)草酰胺(27)的制备
以化合物17、化合物20a为起始原料，制备过程同实施例20，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：458.2
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.55(d,J＝1.8Hz,1H),7.85–7.79(m,2H),7.41(d,J＝8.4Hz,1H),7.28(d,J＝3.0Hz,1H),7.24–7.19(m,1H),7.17(dd,J＝7.8,1.8Hz,1H),7.02(dd,J＝8.4,1.3Hz,1H),6.82(td,J＝7.8,1.2Hz,1H),6.44–6.36(m,1H),5.56(s,2H),5.25(d,J＝15.4Hz,1H),4.60(d,J＝15.4Hz,1H),3.75(s,3H),2.66(t,J＝6.2Hz,2H),2.01–1.92(m,7H).
实施例28 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((喹啉-2-基)甲基)草酰胺(28)的制备
以化合物28a、化合物15a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：442.2
1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.37(d,J＝8.4Hz,1H),7.95(d,J＝8.6Hz,1H),7.92(d,J＝8.2Hz,1H),7.84(d,J＝2.4Hz,1H),7.73(ddd,J＝8.4,6.9,1.5Hz,1H),7.64(d,J＝8.6Hz,1H),7.58(ddd,J＝8.2,6.8,1.2Hz,1H),7.29(d,J＝1.7Hz,1H),7.27(dd,J＝7.6,1.7Hz,1H),7.20(td,J＝8.0,1.7Hz,1H),7.02(dd,J＝8.4,1.3Hz,1H),6.81(td,J＝7.6,1.3Hz,1H),5.57(s,2H),5.44(d,J＝15.6Hz,1H),4.84(d,J＝15.6Hz,1H),3.76(s,3H),1.97(s,3H).
实施例29 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((苯并噻唑-5-基)甲基)草酰胺(29)的制备
以化合物29a、化合物15a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：448.1
1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),9.38(s,1H),8.09(d,J＝8.4Hz,1H),8.02(s,1H),7.97(s,1H),7.73(s,1H),7.37(d,J＝8.4Hz,1H),7.21(t,J＝7.8Hz,1H),7.11(d,J＝7.8Hz,1H),7.00(d,J＝8.2Hz,1H),6.82(t,J＝7.6Hz,1H),5.61(s,2H),5.29(d,J＝14.8Hz,1H),4.86(d,J＝14.8Hz,1H),3.74(s,3H),2.12(s,3H).
实施例30 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((6-氟吡啶-3-基)甲基)草酰胺(30)的制备
以化合物21a、化合物15a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：410.2
1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.08(d,J＝2.4Hz,1H),7.83(td,J＝8.4,2.4Hz,1H),7.79(d,J＝2.4Hz,1H),7.27–7.21(m,2H),7.16–7.09(m,2H),7.01(dd,J＝8.4,1.2Hz,1H),6.86(td,J＝7.6,1.2Hz,1H),5.56(s,2H),5.04(d,J＝15.0Hz,1H),4.74(d,J＝15.0Hz,1H),3.69(s,3H),1.96(s,3H).
实施例31 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((5-环丙基吡啶-2-基)甲基)-N2-(5-氟-2-甲氧基苯基)恶酰胺(31)的制备
以化合物31a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：450.2
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.30(d,J＝2.4Hz,1H),7.86(s,1H),7.43–7.36(m,1H),7.35–7.27(m,2H),7.18–7.13(m,1H),7.10–6.97(m,2H),5.58(s,2H),5.14(d,J＝15.4Hz,1H),4.67(d,J＝15.4Hz,1H),3.69(s,3H),1.97(s,3H),1.94–1.88(m,1H),1.00–0.95(m,2H),0.72–0.68(m,2H).
实施例32 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(异喹啉-3-基甲基)-N2-(2-甲氧基苯基)恶酰胺(32)的制备
以化合物32a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：442.2
1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.24(d,J＝1.1Hz,1H),8.10(d,J＝8.4Hz,1H),7.92(d,J＝8.4Hz,1H),7.87–7.82(m,2H),7.81–7.76(m,1H),7.65(ddd,J＝8.2,6.8,1.2Hz,1H),7.30(d,J＝2.4Hz,1H),7.26–7.17(m,2H),7.02(dd,J＝8.2,1.2Hz,1H),6.80(td,J＝7.6,1.2Hz,1H),5.56(s,2H),5.42(d,J＝15.6Hz,1H),4.80(d,J＝15.6Hz,1H),3.78(s,3H),1.97(s,3H).
实施例33 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((2'，6'-二甲基-[3,4'-联吡啶]-6-基)甲基)-N2-(2-甲氧基苯基)恶酰胺(33)的制备
以化合物17为起始原料，制备过程同实施例20，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：497.2
1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.86(d,J＝2.4Hz,1H),8.16(dd,J＝8.2,2.4Hz,1H),7.84(d,J＝2.4Hz,1H),7.58(d,J＝8.2Hz,1H),7.43(s,2H),7.29(d,J＝2.4Hz,1H),7.26–7.21(m,2H),7.05–6.98(m,1H),6.88–6.81(m,1H),5.56(s,2H),5.28(d,J＝15.6Hz,1H),4.73(d,J＝15.6Hz,1H),3.76(s,3H),2.48(s,6H),1.97(s,3H).
实施例34 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((5-(3,6-二氢-2H-吡喃-4-基)吡啶-2-基)甲基)-N2-(2-甲氧基苯基)恶酰胺(34)的制备
以化合物17为起始原料，制备过程同实施例20，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：474.2
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.56(d,J＝2.4Hz,1H),7.87–7.80(m,2H),7.43(d,J＝8.4Hz,1H),7.28(d,J＝2.4Hz,1H),7.23–7.18(m,2H),7.02(d,J＝8.4Hz,1H),6.83(t,J＝7.6Hz,1H),6.36(s,1H),5.56(s,2H),5.25(d,J＝15.6Hz,1H),4.62(d,J＝15.6Hz,1H),4.22(d,J＝2.9Hz,2H),3.85–3.81(m,2H),3.75(s,3H),2.46–2.43(m,2H),1.96(s,3H).
实施例35 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((5-(1-甲基-1H-吡唑-5-基)吡啶-2-基)甲基)草酰胺(35)的制备
以化合物17为起始原料，制备过程同实施例20，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：472.2
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.97(d,J＝2.4Hz,1H),7.79(d,J＝2.4Hz,1H),7.55(dd,J＝8.4,2.4Hz,1H),7.27–7.16(m,3H),7.07–7.00(m,2H),6.87(d,J＝17.4Hz,1H),6.82(d,J＝7.6Hz,1H),6.75(d,J＝8.4Hz,1H),5.55(s,2H),5.03(d,J＝14.8Hz,1H),4.57(d,J＝14.8Hz,1H),3.80(s,3H),3.70(s,3H),1.95(s,3H).
实施例36 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((5-甲基吡嗪-2-基)甲基)-N2-萘-2-基)恶酰胺(36)的制备
以化合物36a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：427.2
1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.60(s,1H),8.46(s,1H),7.92–7.85(m,3H),7.82–7.78(m,1H),7.71(d,J＝2.4Hz,1H),7.55–7.49(m,3H),7.15(d,J＝2.4Hz,1H),5.56(s,2H),5.20(s,2H),2.45(s,3H),1.90(s,3H).
实施例37 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((5-(4-氟苯基)吡啶-2-基)甲基)-N2-(2-甲氧基苯基)恶酰胺(37)的制备
以化合物17为起始原料，经Suziki偶联反应，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：486.3
1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.77(s,1H),8.07(d,J＝8.2Hz,1H),7.84(s,1H),7.80–7.74(m,2H),7.55(d,J＝8.2Hz,1H),7.36–7.28(m,3H),7.27–7.19(m,2H),7.04(d,J＝8.2Hz,1H),6.85(t,J＝7.6Hz,1H),5.57(s,2H),5.28(d,J＝15.4Hz,1H),4.69(d,J＝15.4Hz,1H),3.76(s,3H),1.97(s,3H).
实施例38 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(4-溴-2-氟苄基)-N2-(2-甲氧基苯基)恶酰胺(38)的制备
以化合物38a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：487.1
1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.79(d,J＝2.5Hz,1H),7.46(dd,J＝9.6,1.7Hz,1H),7.40–7.33(m,2H),7.26–7.20(m,2H),7.09(dd,J＝7.8,1.7Hz,1H),7.01(dd,J＝8.3,1.3Hz,1H),6.83(td,J＝7.6,1.3Hz,1H),5.56(s,2H),5.07(d,J＝14.9Hz,1H),4.67(d,J＝15.0Hz,1H),3.72(s,3H),1.95(s,3H).
实施例39 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((4-溴噻吩-2-基)甲基)-N2-(2-甲氧基苯基)恶酰胺(39)的制备
以化合物39a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：475.0
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),7.81(d,J＝2.6Hz,1H),7.55(d,J＝1.5Hz,1H),7.29–7.23(m,2H),7.11(dd,J＝7.7,1.7Hz,1H),7.07–7.02(m,1H),6.93(d,J＝1.5Hz,1H),6.88(td,J＝7.6,1.3Hz,1H),5.56(s,2H),5.19(d,J＝15.3Hz,1H),4.76(d,J＝15.3Hz,1H),3.72(s,3H),1.95(s,3H).
实施例40 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲基-2H-吲唑-4-基)-N2-((4-甲基噻唑-5-基)甲基)恶酰胺(40)的制备
LC-MS(ESI)m/z(M+H)+：436.2
1H NMR(400MHz,Chloroform-d)δ8.66(s,1H),7.88(d,J＝2.6Hz,1H),7.71(d,J＝8.8Hz,1H),7.63(s,1H),7.59(d,J＝2.0Hz,1H),7.20–7.16(m,1H),6.59(d,J＝7.0Hz,1H),5.26(d,J＝14.7Hz,1H),4.99(d,J＝14.3Hz,1H),4.34(s,2H),4.18(s,3H),2.02(s,3H),1.88(s,3H).
实施例41 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(1-(5-环丙基吡啶-2-基)乙基)-N2-(2-甲氧基苯基)恶酰胺(41)的制备
以化合物41a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：446.2
1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.37(s,1H),7.77(s,1H),7.44–7.41(m,1H),7.37–7.35(m,1H),7.33–7.30(m,1H),7.23–7.21(m,2H),7.02–7.00(m,1H),6.79(t,J＝7.8Hz,1H),5.75(q,J＝7.2Hz,1H),5.53(s,2H),3.74(s,3H),1.96–1.88(m,4H),1.27(d,J＝7.2Hz,3H),1.02–0.97(m,2H),0.78–0.72(m,2H).
实施例42 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((6-环丙基吡啶-2-基)甲基)-N2-(2-甲氧基苯基)恶酰胺(42)的制备
以化合物42a为起始原料，制备过程同实施例15，获得中间体42c后，经Suziki偶联，再参照实施列15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：432.2
1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),7.83(d,J＝2.6Hz,1H),7.60(t,J＝7.8Hz,1H),7.29(s,1H),7.21(td,J＝7.2,5.6Hz,2H),7.13(d,J＝7.8Hz,1H),7.03–6.99(m,1H),6.90(s,1H),6.86–6.82(m,1H),5.55(s,2H),5.14(d,J＝15.6Hz,1H),4.52(d,J＝15.6Hz,2H),3.74(s,3H),2.03–1.96(m,4H),1.04–0.99(m,2H),0.80–0.74(m,2H).
实施例43 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((4-环丙基吡啶-2-基)甲基)-N2-(2-甲氧基苯基)恶酰胺(43)的制备
以化合物43a为起始原料，制备过程同实施例15，获得中间体43c后，经Suziki偶联，再参照实施列15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：432.2
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.25(d,J＝5.1Hz,1H),7.85(s,1H),7.31(s,1H),7.24–7.18(m,2H),7.11(s,1H),7.01(d,J＝8.0Hz,1H),6.93(d,J＝5.2Hz,1H),6.85(t,J＝7.6Hz,1H),,5.56(s,2H),5.14(d,J＝15.6Hz,1H),4.68(d,J＝15.6Hz,1H),3.74(s,3H),1.97(s,3H),1.93–1.88(m,1H),1.08–1.04(m,2H),0.77–0.69(m,2H).
实施例44 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((5-环丙基-3-甲基吡啶-2-基)甲基)-N2-(2-甲氧基苯基)恶酰胺(44)的制备
以化合物a为起始原料，制备过程同实施例15，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：446.21
1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.09(s,1H),7.78(s,1H),7.24(s,1H),7.18(t,J＝7.2Hz,1H),7.14(s,1H),7.06(d,J＝7.6Hz,1H),6.97(d,J＝7.6Hz,1H),6.75(t,J＝7.2Hz,1H),5.53(s,2H),5.32(d,J＝14.8Hz,1H),4.48(d,J＝14.8Hz,1H),3.73(s,3H),2.23(s,3H),1.95(s,3H),1.89–1.82(m,1H),0.97–0.93(m,2H),0.88–0.83(m,2H).
实施例45 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(4-环丙基-2-氟苄基)-N2-(2-甲氧基苯基)草酰胺(45)的制备
以化合物38e为起始原料，经Suziki偶联反应、脱BOC，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：449.2
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.79(s,1H),7.27–7.18(m,3H),7.04–6.98(m,2H),6.87(d,J＝8.0Hz,1H),6.83–6.75(m,2H),5.55(s,2H),5.10(d,J＝14.8Hz,1H),4.59(d,J＝14.8Hz,1H),3.72(s,3H),1.95(s,3H),1.91–1.85(m,1H),0.97–0.90(m,2H),0.68–0.63(m,2H).
实施例46 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(4-环戊基-2-氟苄基)-N2-(2-甲氧基苯基)草酰胺(46)的制备
以化合物38e为起始原料，经Suziki偶联反应、氢气还原和脱BOC，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：477.2
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.80(s,1H),7.30(t,J＝8.0Hz,1H),7.27–7.19(m,2H),7.07(d,J＝7.8Hz,1H),7.01(td,J＝8.4,1.5Hz,2H),6.97(d,J＝11.6Hz,1H),6.81(t,J＝7.6Hz,1H),5.55(s,2H),5.09(d,J＝14.9Hz,1H),4.62(d,J＝14.9Hz,1H),3.72(s,3H),3.00–2.87(m,1H),1.95(s,3H),1.76–1.14(m,8H).
实施例47 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(4-环己基-2-氟苄基)-N2-(2-甲氧基苯基)草酰胺(47)的制备
以化合物38e为起始原料，经Suziki偶联反应、氢气还原和脱BOC，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：491.2
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.79(d,J＝2.5Hz,1H),7.30(t,J＝8.0Hz,1H),7.26–7.19(m,2H),7.08(dd,J＝7.8,1.7Hz,1H),7.00(d,J＝8.1Hz,2H),6.95(dd,J＝11.5,1.7Hz,1H),6.81(td,J＝7.6,1.3Hz,1H),5.55 (s,2H),5.07(d,J＝14.9Hz,1H),4.63(d,J＝14.9Hz,1H),2.69–2.63(m,1H),1.95(s,3H),1.81–1.63(m,6H),1.38–1.30(m,4H).
实施例48 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-氟-4-(1-甲基哌啶-4-基)苄基)-N2-(2-甲氧基苯基)恶酰胺(48)的制备
以化合物38e为起始原料，经Suziki偶联反应、氢气还原和脱BOC，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：506.3
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.79(s,1H),7.33(t,J＝8.0Hz,1H),7.26–7.19(m,2H),7.09–6.96(m,4H),6.82(t,J＝7.6Hz,1H),5.55(s,2H),5.08(d,J＝14.8Hz,1H),4.63(d,J＝14.8Hz,1H),3.71(s,3H),3.00–2.88(m,2H),2.48–2.44(m,1H),2.27(s,3H),1.95(s,3H),1.77–1.53(m,6H).
实施例49 N1-(6-氨基-5-甲基吡啶-3-基)-N1-(2-甲氧基苯基)-N2-((5-(1-甲基哌啶-4-基)吡啶-2-基)甲基)草酰胺(49)的制备
以化合物17为起始原料，经Suziki偶联反应、氢气还原，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：489.3
1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.35(s,1H),7.82(s,1H),7.65(d,J＝8.2Hz,1H),7.38(d,J＝8.2Hz,1H),7.28(s,1H),7.20(d,J＝7.6Hz,2H),7.02(d,J＝8.2Hz,1H),6.83(t,J＝7.6Hz,1H),5.55(s,2H),5.20(d,J＝15.6Hz,1H),4.59(d,J＝15.6Hz,1H),3.73(s,3H),2.87–2.84(m,2H),2.48–2.43(m,1H),2.18(s,3H),1.96(s,3H),1.95–1.90(m,2H),1.71–1.62(m,4H).
实施例50 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((5-环己基吡啶-2-基)甲基)-N2-(2-甲氧基苯基)恶酰胺(50)的制备
以化合物17为起始原料，经Suziki偶联反应、氢气还原，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：474.2
1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.33(s,1H),7.83(s,1H),7.62(d,J＝8.1Hz,1H),7.37(d,J＝8.1Hz,1H),7.29(s,1H),7.20(d,J＝7.4Hz,2H),7.01(d,J＝8.2Hz,1H),6.83(t,J＝7.6Hz,1H),5.55(s,2H),5.20(d,J＝15.6Hz,1H),4.59(d,J＝15.6Hz,1H),3.73(s,3H),2.04–1.99(m,1H),1.96(s,3H),1.84–1.66(m,6H),1.41–1.33(m,4H).
实施例51 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-氟-4-(四氢-2H-吡喃-4-基)苄基)-N2-(2-甲氧基苯基)恶酰胺(51)的制备
以化合物38e为起始原料，经Suziki偶联反应、氢气还原，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：493.2
1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),7.79(s,1H),7.34(t,J＝8.0Hz,1H),7.25(s,1H),7.22(t,J＝7.8Hz,1H),7.08(d,J＝7.8Hz,1H),7.05(d,J＝8.0Hz,1H),7.02(s,1H),6.99(s,1H),6.82(t,J＝7.6Hz,1H),5.55(s,2H),5.09(d,J＝15.0Hz,1H),4.64(d,J＝14.9Hz,1H),4.02–3.84(m,4H),3.71(s,3H),2.79–2.71(m,1H),1.95(s,3H),1.69–1.60(m,4H).
实施例52 N1-(6-氨基-5-甲基吡啶-3-基)-N2-(2-甲氧基苯基)-N2-((5-(四氢-2H-吡喃-4-基)吡啶-2-基)甲基)草酰胺(52)的制备
以化合物17为起始原料，经Suziki偶联反应、氢气还原，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：476.2
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.37(s,1H),7.83(s,1H),7.67(d,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.30(s,1H),7.28–7.24(m,2H),7.02(d,J＝8.2Hz,1H),6.84(t,J＝7.8Hz,1H),5.60(s,2H),5.21(d,J＝15.6Hz,1H),4.60(d,J＝15.6Hz,1H),4.05–3.84(m,4H),3.74(s,3H),2.85–2.74(m,1H),1.97(s,3H),1.71–1.62(m,4H).
实施例53 N1-(6-氨基-5-甲基吡啶-3-基)-N2-((5-(4,4-二氟环己-1-烯-1-基)吡啶-2-基)甲基)-N2-(2-甲氧基苯基)恶酰胺(53)的制备
以化合物17为起始原料，经Suziki偶联反应，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：508.2
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.56(s,1H),7.87–7.80(m,2H),7.43(d,J＝8.2Hz,1H),7.28(s,1H),7.24–7.14(m,2H),7.02(d,J＝7.6Hz,1H),6.82(t,J＝7.6Hz,1H),6.11(s,1H),5.56(s,2H),5.25(d,J＝15.6Hz,1H),4.62(d,J＝15.6Hz,1H),3.75(s,3H),2.76–2.64(m,2H),2.22–2.13(m,2H),2.05–1.93(m,5H).
实施例54 N1-(6-氨基-5-甲基吡啶-3-基基)-N2-((5-(4,4-二氟环己基)吡啶-2-基)甲基)-N2-(2-甲氧基苯基)草酰胺(54)的制备
以化合物53为起始原料，经氢气还原，获得标题化合物。
LC-MS(ESI)m/z(M+H)+：510.2；
1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.37(s,1H),7.82(s,1H),7.67(d,J＝8.2Hz,1H),7.39(d,J＝8.2Hz,1H),7.29(s,1H),7.21(d,J＝7.6Hz,2H),7.01(d,J＝7.6Hz,1H),6.83(t,J＝7.6Hz,1H),5.56(s,2H),5.20(d,J＝15.4Hz,1H),4.61(d,J＝15.4Hz,1H),3.73(s,3H),2.16–2.05(m,2H),2.05–1.99(m,2H),1.96(s,3H),1.89–1.83(m,2H),1.73–1.60(m,2H)。
生物学评价
试验例1：HCT116细胞增殖抑制试验
1、试验目的
本次试验分别测试化合物对HCT116突变型(MTAP-null)、野生型(WT)细胞增殖抑制作用。
2、试验材料
2.1、化合物
受试化合物依次由对应实施例制备得到。
2.2、试剂及仪器
Cell-Titer Glo试剂，Promega；
RPMI1640培养基，Hyclone；
DMSO，Sigma；
胎牛血清，Gibco；
酶标仪(BMG)，POLARstar；
移液器，Eppendorf；
细胞计数仪，Countstar；
CO2恒温培养箱，Thermo；
生物安全柜，Thermo；
倒置显微镜，OLYMPUS；
3、试验方法
3.1、化合物配制
化合物10mM储存液配制：将化合物粉末溶解在100％DMSO中，分别配成10mM的化合物储存液。
3.2、试验方法
(1)处于对数生长期的细胞，去掉培养基，加PBS清洗2遍；
(2)0.25％胰酶消化细胞2min，至细胞变圆脱落，加完全培养基终止消化；
(3)将消化后的细胞转移至离心管中，1000rpm离心3min；
(4)去掉上清。加入10ml完全培养基重悬细胞，取20μL细胞悬液加20μL台盼蓝混匀后用细胞计数仪计数。选取3个视野计数并记录活细胞密度，细胞活力及细胞代次；
(5)稀释细胞密度为5.56*103个/mL，96孔板中接种90μL，每孔500个细胞；
(6)96孔板置于37℃、5％CO2条件下培养过夜；
(7)第二天，取化合物母液10mM，加含1％DMSO的完全培养基梯度稀释，使终浓度分别为3000、1000、300、100、30、10、3、1、0.3nM；30000、10000、3000、1000、300、100、30、10、3nM；
(8)化合物配制好后，取出细胞培养板，往细胞中加10μL稀释好的化合物；
(9)轻柔混匀后，于37℃5％CO2培养箱中培养；
(10)培养5天后，每孔加入50μL CTG检测液，于水平摇床避光裂解细胞10min，吸20μL到384孔白板中；
(11)使用BMG酶标仪Luminescence模块读数，并计算抑制率。
3.3、数据分析
细胞活率＝(As-Ab)/(Ac-Ab)*100％
As：实验孔吸光度(含细胞、培养基、CTG溶液和药物溶液)
Ac：对照孔吸光度(含细胞、培养基、CTG溶液，不含药物)
Ab：空白孔吸光度(含培养基、CTG溶液，不含细胞、药物)
以浓度的对数值作为X轴，百分比存活率为Y轴，采用分析软件Graphpad Prism 9的log(inhibitor)vs.response-Variable slop(Four parameters)公式拟合量效曲线，从而得出各个化合物IC50值。
4、试验结果
表1本申请专利化合物对HCT116突变型(MTAP-null)细胞增殖抑制活性和HCT116野生型/突变型(WT/MTAP-null)选择性数据

从表1示例性化合物对HCT116突变型(MTAP-null)细胞抑制活性和HCT116野生型/突变型(WT/MTAP-null)选择性验数据可知，本申请化合物具有明显的HCT116突变型(MTAP-null)细胞抑制活性，且对HCT116野生型(WT)细胞抑制活性较弱，对MTAP基因缺失型细胞具有较高的选择性。
试验例2：PRMT5-MTA酶学抑制试验
1、试验目的
MTase-Glo Assay是一种基于生物发光的检测方法，可监测反应产物s-腺苷型同型半胱氨酸(SAH)的形成，并能检测多种甲基转移酶的活性变化，包括DNA、蛋白质、RNA和小分子甲基转移酶。本次试验测试化合物对PRMT5-MTA酶活的影响，同时利用抑制率计算测试化合物对PRMT5-MTA酶的IC50值。
2、试验材料
2.1、化合物
受试化合物依次由对应实施例制备得到。
2.2、试剂及仪器
PRMT5/MEP50，active motife；
5'-Deoxy-5'-(methylthio)adenosine(MTA)，Sigma-Aidrich；
Bio-H4(1-21)，GenScript；
MTase_GloTM Methyltransferase Assay，Promega；
96孔板，Nunc；
384孔板，Greiner；
离心机，湘仪；
酶标仪，BMG。
3、试验方法
3.1、化合物配制
化合物10mM储存液配制：将化合物粉末溶解在100％DMSO中，分别配成10mM的化合物储存液。
3.2、试验方法
(1)化合物浓度配置：化合物IC50测试终浓度为1000nM起始，3倍稀释，10个浓度，每个浓度设置复孔检测。
(2)吸取20nL化合物到384孔板，384孔板以1000rpm离心。
(3)384孔板每孔加入2μL PRMT5-MEP50/MTA工作液，25℃孵育15min。
(4)每孔加入2μL Bio-H4(1-21)&SAM工作液，25℃孵育180min。
(5)每孔加入1μL 5X MTase-Glo试剂，384孔板1000rpm离心，25℃孵育30min。
(6)每孔加入5μL MTase-Glo检测液，384孔板1000rpm离心，25℃孵育30min。
(7)酶标仪检测生物发光值。
3.3、数据处理
计算公式
抑制百分率(％)＝ave high control–compounds)/(ave high control–ave low control)*100％
以浓度的对数值作为X轴，百分比抑制率为Y轴，采用分析软件Graphpad Prism 5的log(inhibitor)vs.response-Variable slop(Four parameters)公式拟合量效曲线，从而得出各个化合物对酶活性的IC50值。
4、试验结果
本发明化合物对PRMT5-MTA酶抑制活性见表2。
表2本发明化合物对PRMT5-MTA酶抑制活性
从表2化合物对PRMT5-MTA酶抑制活性试验数据可知，本申请示例性化合物具有较强的PRMT5-MTA酶抑制活性。
试验例3：大鼠口服药代动力学研究
1、试验原理
以SD大鼠为受试动物，应用LC-MS/MS法测定大鼠口服给药后，本发明化合物在不同时刻血浆中的血药浓度，获取本发明的化合物在大鼠体内的药代动力学参数，研究其药代动力学特征。
2、试验材料
2.1化合物
受试化合物依次由对应实施例制备得到。
2.2、试验仪器：
岛津LC-30A AB API4500串联质谱仪、真空采血管、采血针、滤纸、注射器等。
2.3、试验动物
SD大鼠，雌性，体重180-220g，每组3只。动物购回后饲养于动物房，适应期至少3天，检疫合格后用于试验。
3、试验方法
3.1、分组：根据表6随机分组，分组后，SD大鼠体重组间无统计学差异。
3.2、溶媒PO：0.5％MC+0.2％Tween 80+5％DMSO
表3试验分组及给药方案
3.3、血样采集测定：
按照表3分别对各组灌胃给予相应受试药，给药前、给药后0.25h、0.5h、0.75h、1h、1.5h、2h、4h、6h、24h，经颈静脉采血取固定体积的血量，置于EDTA-K2抗凝管中，4500rpm，离心10min，分离血浆于离心管中，-80℃冰箱冷冻。
3.4、分析方法
取出-80℃保存的各时间点血浆，再加入固定体积的甲醇，涡旋1500转2min后，离心15min(3500r/min)，取固定体积的溶液上清液进行LC-MS/MS分析。
4、药代动力学参数计算：
对受试化合物的药代动力学行为进行非房室模型拟合，并采用DAS3.31软件计算主要药代动力学参数(T1/2、Tmax、Cmax、AUClast等)。
5、试验结果：
表4实施例化合物药代动力学参数
从表4试验结果可以看出，本申请示例性化合物具有较好的药代动力学性质。

Claims (12)

  1. 一种具有式I结构的化合物、其立体异构体或其药学上可接受的盐，
    其中，
    R1选自：氢、卤素、氰基、取代或未被取代的氨基、羧基、羟基、C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基，其中所述C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；
    R2、R3、R4分别独立地选自：氢、卤素、氰基、取代或未被取代的氨基、C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基，其中所述C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；R2和R3可成环形成5-8元碳环或5-8元杂环；
    R5选自：C3-C10碳环基或3-10元杂环基，其中所述C3-C10碳环基或3-10元杂环基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6卤代烷基氧基、C3-C10碳环基、C3-C10环烷基氧基、C3-C10环烷基氨基、3-10元杂环基、3-10元杂环基氧基、3-10元杂环基氨基、其中所述C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6卤代烷基氧基、C3-C10碳环基、C3-C10环烷基氧基、C3-C10环烷基氨基、3-10元杂环基、3-10元杂环基氧基、3-10元杂环基氨基、 可进一步被卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基或氨基取代；
    R6选自：C1-C6烷基、C3-C8环烷基、C6-C10芳基或4-10元杂环基，其中所述C1-C6烷基、C3-C8环烷基、C6-C10芳基或4-10元杂环基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6卤代烷基氧基、C3-C8环烷基、C3-C8环烷基氧基、C3-C10环烷基氨基、3-10元杂环基氨基、
    X选自：单键或-CH2-，其中-CH2-可进一步被1或2个甲基或卤素取代；
    n选自：0或1。
  2. 如权利要求1所述的式I化合物、其立体异构体或其药学上可接受的盐，其特征在于：
    R5选自：C3-C10碳环基或3-10元杂环基，其中所述C3-C10碳环基或3-10元杂环基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6卤代烷基氧基、C3-C10碳环基、C3-C10环烷基氧基、C3-C10环烷基氨基、3-10元杂环基、3-10元杂环基氧基、3-10元杂环基氨基、
  3. 如权利要求1所述的式I化合物、其立体异构体或其药学上可接受的盐，其特征在于：
    R1选自：氢、卤素、氰基、取代或未被取代的氨基、羧基、羟基、C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基，其中所述C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；
    R2、R3、R4分别独立地选自：氢、卤素、氰基、取代或未被取代的氨基、C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基，其中所述C1-C6烃基、C1-C6烃基氧基、C3-C8碳环基或C3-C8碳环基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C6烷基或C1-C6烷基氧基；R2和R3可成环形成5-8元碳环或5-8元杂环；
    R5选自：C3-C10碳环基或3-10元杂环基，其中所述C3-C10碳环基或3-10元杂环基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C6卤代烷基、C1-C6烷基、C1-C6烷基氧基或C1-C6卤代烷基氧基；
    R6选自：C1-C6烷基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基或5-10元杂芳基，其中所述C1-C6烷基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基氧基或C1-C6卤代烷基氧基；
    X选自：单键或-CH2-，其中-CH2-可进一步被1或2个甲基或卤素取代；
    n选自：0或1。
  4. 如权利要求1-3任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其特征在于：
    R5选自：C3-C8环烷基、3-10元杂环基或C6-C10芳基，其中所述C3-C8环烷基、3-10元杂环基或C6-C10芳基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、 所述C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、可进一步被卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基或氨基取代；
    优选地，R5选自：C6-C10芳基或5-8元杂芳基，其中所述C6-C10芳基或5-8元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷基氧基、C1-C3烷基氨基、C1-C3卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、所述C1-C3烷基、C1-C3卤代烷基、C1-C3烷基氧基、C1-C3烷基氨基、C1-C3卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、 可进一步被任选1个、2个或3个F、Cl、Br、C1-C4烷基取代；
    进一步优选地，R5选自：C6-C10芳基或5-8元杂芳基，其中所述C6-C10芳基或5-8元杂芳基是未取代的或 被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C3烷基、C1-C3卤代烷基、3-6元环烷基或3-6元杂环基，所述C1-C3烷基、C1-C3卤代烷基、3-6元环烷基或3-6元杂环基可进一步被任选1个、2个或3个F、Cl、Br、C1-C4烷基取代。
  5. 如权利要求1-4任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其特征在于：
    R6选自：C1-C6烷基、C3-C8环烷基、C6-C10芳基、4-8元杂环烷基或5-10元杂芳基，所述C1-C6烷基、C3-C8环烷基、C6-C10芳基、4-8元杂环烷基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6环烷基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基氨基、
    R6优选自：C1-C3烷基、C3-C6环烷基、C6-C10芳基或5-10元杂环基，其中5-10元杂环基选自4-6元杂环烷基或5-10元杂芳基，其中所述C1-C3烷基、C3-C6环烷基、C6-C10芳基、4-6元杂环烷基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6环烷基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基氨基、
    R6进一步优选自：C3-C6环烷基、C6-C10芳基、4-6元杂环烷基或5-10元杂芳基，其中所述C3-C6环烷基、C6-C10芳基、4-6元杂环烷基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷基氧基、C1-C3烷基氨基、C1-C3卤代烷基氧基、C3-C6环烷基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基氨基、
    R6进一步优选自：C3-C6环烷基、C6-C10芳基或5-10元杂芳基，其中所述C3-C6环烷基、C6-C10芳基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是F、Cl、Br、氰基、C1-C3烷基、C1-C3烷基氧基或C1-C3卤代烷基氧基。
  6. 如权利要求1-4任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其特征在于：
    R1选自氢、卤素、氰基、取代或未被取代的氨基。
  7. 如权利要求1-5任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其特征在于：
    R2、R3、R4分别独立选自：氢、卤素、氰基、取代或未被取代的氨基、C1-C3烷基或C1-C3烷基氧基，其中所述C1-C3烷基或C1-C3烷基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C3烷基或C1-C3烷基氧基；R2和R3可成环形成5-6元碳环或5-6元杂环。
  8. 一种具有式II结构的化合物、其立体异构体或其药学上可接受的盐，
    其中，
    R2、R3、R4分别独立地选自：氢、卤素、氰基、C1-C3烷基、C1-C3烷基氧基、C3-C8环烷基或C3-C8环烷基氧基，其中所述C1-C3烷基、C1-C3烷基氧基、C3-C8环烷基或C3-C8环烷基氧基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、羟基、氨基、C1-C3烷基或C1-C3烷基氧基；R2和R3可成环形成5-6元碳环或5-6元杂环；
    R5选自：C3-C8环烷基、3-10元杂环基、C6-C10芳基或5-10元杂芳基，其中所述C3-C8环烷基、3-10元杂环基、C6-C10芳基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、 C1-C3烷基、C1-C3卤代烷基、C1-C3烷基氧基、C1-C3烷基氨基、C1-C3卤代烷基氧基、C3-C6碳环基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基、3-6元杂环基氧基、3-6元杂环基氨基、可进一步被1-3个F、Cl、Br或C1-C4烷基取代；
    R6选自：C1-C3烷基、C3-C6环烷基、C6-C10芳基或5-10元杂环基，其中5-10元杂环基选自4-6元杂环烷基或5-10元杂芳基，其中所述C1-C3烷基、C3-C6环烷基、C6-C10芳基、4-6元杂环烷基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是卤素、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基氧基、C1-C4烷基氨基、C1-C4卤代烷基氧基、C3-C6环烷基、C3-C6环烷基氧基、C3-C6环烷基氨基、3-6元杂环基氨基、
    n选自：0或1；
    优选地，R2、R3、R4分别独立地选自：氢、卤素、氰基或C1-C3烷基；
    进一步优选地，R2选自C1-C3烷基；R3、R4均为氢；
    优选地，R5选自：C6-C10芳基或5-8元杂芳基，其中所述C6-C10芳基或5-8元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基选自卤素、氰基、C1-C3烷基、C1-C3卤代烷基、3-6元环烷基或3-6元杂环基，所述C1-C3烷基、C1-C3卤代烷基、3-6元环烷基或3-6元杂环基可进一步被1-3个F、Cl、Br或C1-C4烷基取代；
    优选地，R6进一步选自：C3-C6环烷基、C6-C10芳基或5-10元杂芳基，其中所述C3-C6环烷基、C6-C10芳基或5-10元杂芳基是未取代的或被选自一个或者多个取代基取代，所述取代基是F、Cl、Br、氰基、C1-C3烷基、C1-C3烷基氧基或C1-C3卤代烷基氧基。
  9. 如权利要求1所述化合物、其立体异构体或其药学上可接受的盐，所述化合物选自：




  10. 如权利要求1-9中任一项所述化合物、其立体异构体的的制备方法，包括以下步骤：
    (1)化合物I-1与化合物I-2经缩合反应得到I-3；
    (2)化合物I-3经水解反应得到I-4；
    (3)化合物I-4与化合物I-5经缩合反应得到式I所示结构的化合物；
    其中，R1、R2、R3、R4、R5、R6、X和n如权利要求1-9中对各取代基的定义。
  11. 一种药物组合物，其特征在于，包含权利要求1-9任一项中所述的化合物、其立体异构体或其药学上可接受的盐，以及药学上可以接受的辅料。
  12. 如权利要求1-9任一项中的化合物、其立体异构体或其药学上可接受的盐在制备用于预防或治疗蛋白质精氨酸甲基转移酶5(PRMT5)介导的疾病的药物中的用途；优选地，所述蛋白质精氨酸甲基转移酶5(PRMT5)介导的疾病选自肿瘤或癌症；更优选地，所述PRMT5的疾病选自肿瘤或癌症；更优选地，所述疾病选自乳腺癌、胰腺癌、卵巢癌、结直肠癌、肺癌、前列腺癌、淋巴瘤、恶性肉瘤、宫颈癌、口腔癌、脑癌、胃癌、肝癌、皮肤癌、骨癌、肾癌、膀胱癌、输卵管肿瘤、间皮瘤、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、乳突状恶性瘤、头颈部肿瘤、骨髓瘤或白血病。
PCT/CN2023/140814 2022-12-22 2023-12-22 一种取代草酰胺类衍生物、其制备方法及用途 WO2024131918A1 (zh)

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