WO2023088477A1 - 一种可降解btk激酶的多功能化合物、组合物及应用 - Google Patents

一种可降解btk激酶的多功能化合物、组合物及应用 Download PDF

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WO2023088477A1
WO2023088477A1 PCT/CN2022/133404 CN2022133404W WO2023088477A1 WO 2023088477 A1 WO2023088477 A1 WO 2023088477A1 CN 2022133404 W CN2022133404 W CN 2022133404W WO 2023088477 A1 WO2023088477 A1 WO 2023088477A1
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amino
piperidin
alkyl
cycloalkyl
methyl
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French (fr)
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周星露
李佳
刘兴国
周宇波
胡苗
罗小敏
谢江峰
阚伟娟
吴一哲
胡小蓓
苏明波
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杭州和正医药有限公司
中国科学院上海药物研究所
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Publication of WO2023088477A1 publication Critical patent/WO2023088477A1/zh

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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • 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
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    • 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
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a multifunctional compound capable of degrading BTK kinase, a composition and an application.
  • BTK Bruton's tyrosine kinase BTK
  • Tec protein family Tec, Txk, Itk & Bmx
  • BTK Tec protein family
  • BCR cell surface B cell receptor
  • BTK plays a role in numerous other hematopoietic cell signaling pathways, such as Toll like receptor (TLR) and cytokine receptor-mediated TNF- ⁇ production in macrophages, mast cells Immunoglobulin E receptor (Fc ⁇ R1) signaling, signaling that inhibits Fas/APO-1 apoptosis in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation.
  • TLR Toll like receptor
  • Fc ⁇ R1 cytokine receptor-mediated TNF- ⁇ production in macrophages
  • Fas/APO-1 apoptosis in B-lineage lymphoid cells
  • collagen-stimulated platelet aggregation See eg C.A. Jeffries et al., J.Bio.Chem. (2003) 278:26258-26264, N.J. Horwood et al., J.Exp.Med. (2003) 197:1603-1611.
  • BTK signaling pathway is a new hotspot in the clinical treatment of non-Hodgkin's lymphoma (NHL), especially chronic lymphocytic leukemia (CLL), B-cell lymphoma and autoimmune diseases.
  • Small molecule BTK inhibitors act on the BCR signaling pathway, bind to BTK to inhibit BTK autophosphorylation, prevent BTK activation, thereby blocking cell conduction and inducing cell apoptosis.
  • BTK C481 mutations have occurred in some CLL patients, resulting in acquired drug resistance to BTK drugs.
  • a new generation of BTK drugs is urgently needed to solve this acquired drug resistance.
  • the purpose of the present invention is to provide novel Bruton's tyrosine kinase BTK degradation agent or its optical isomers, stereoisomers, Stereoisomer mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, prodrugs, and uses in BTK-associated diseases B cell or plasma cell proliferative diseases and autoimmune diseases.
  • the first aspect of the present invention provides the compound shown in formula I, or its pharmaceutically acceptable salt, prodrug;
  • L is selected from: the chemical group and the chemical bond connecting ring A and E3 ;
  • E3 is selected from the group consisting of: E3 ubiquitin ligase ligands;
  • Ring A is selected from: 3-12 membered heterocyclic ring, 6-10 membered aromatic ring, 5-12 membered heteroaryl ring, 3-12 membered cycloalkane, 4-12 membered cycloalkyne, 3-12 membered cycloalkene, wherein all The above-mentioned heterocycle and heteroaryl ring have 1-3 heteroatoms independently selected from N, O or S;
  • R 2 is selected from: H, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkoxy, C 3 -C 8 cycloalkoxy, C 3 -C 8 heterocyclyl, C 1 -C 4 alkylamino, -COOH, -NH 2 , OH, NO 2 ;
  • n is selected from: 0, 1, 2, 3, 4;
  • Y 1 is selected from: N, CR 4 ;
  • Y 2 is selected from: N, CR 5 ;
  • Y 3 is selected from: N, CR 5 ;
  • R 4 is selected from: halogen, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 haloalkyl, C 3 -C 8 halocycloalkyl, C 1 -C 4 alkoxy group, amino group, carboxyl group, hydroxyl group, cyano group;
  • R 5 is selected from: H, halogen, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 haloalkyl, C 3 -C 8 halocycloalkyl, C 1 -C 4 Alkoxy, amino, carboxyl, hydroxyl, cyano;
  • R 3 is selected from: H, C 1 -C 8 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 alkene, C 3 -C 8 alkyne, cycloalkyl, heterocyclyl, aryl;
  • R 6 and R 7 are each independently selected from H, C 1 -C 8 alkyl, aminoalkyl, hydroxyalkyl, C 3 -C 8 cycloalkyl, heterocyclic, aromatic ring, heteroaryl;
  • the above-mentioned alkyl, aminoalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aromatic ring, heteroaryl can be further substituted by one or more substituents, substituents include H, halogen, hydroxyl, amino, Cyano, oxo, carboxyl, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, -C(O)Ra, - C(O)ORa, -C(O)NRaRb, ORa, OC(O)Ra, OC(O)NRaRb, SRa, S(O)Ra, S(O)(
  • Ra, Rb, and Rc are each independently selected from H, halogen, alkyl, amino, hydroxyl, cyano, C 3 -C 8 cycloalkyl, alkylamino, and alkoxy.
  • R 5 in the two substitutions is independent of each other and may be the same or different.
  • Y 1 , Y 2 and Y 3 are N at the same time.
  • Ring A is selected from: 6-10 membered aromatic rings, 5-12 membered heteroaromatic rings; wherein the heterocyclic rings and heteroaryl rings have 1-3 heteroatoms independently selected from N, O or S, wherein:
  • Ring A is selected from:
  • the preferred compound of the present invention has the structure of general formula II(a) ⁇ II(i):
  • preferred compounds of the present invention have the structure of general formula III(a)-III(c):
  • R 1 is preferably selected from: NR 6 R 7 , OR 6 , C 1 -C 8 alkyl, 3-12 membered heterocycle, 5-6 membered heteroaromatic ring, C 3 -C 8 cycloalkyl, aromatic ring group; wherein The alkyl, heterocycle, heteroaryl, cycloalkyl, and aryl rings can be further substituted by one or more substituents selected from R 8 ;
  • Ra, Rb, and Rc are each independently preferably selected from H, halogen, alkyl, amino, hydroxyl, cyano, C 3 -C 8 cycloalkyl, alkylamino, and alkoxy.
  • preferred examples of R2 are: H, F.
  • the fragments in general formula (I), II(a)-II(i), III(a), III(b) or III(c) preferably is further preferably
  • R is preferably selected from:
  • L is preferably selected from:
  • Re is selected from: H, F, Cl, -CH 3 , -OMe, -CN, -CF 3 ;
  • Rd is selected from: H, L 2 R g ;
  • L2 is selected from:
  • R 9 is selected from: H, C 1 -C 5 alkyl (preferably methyl, );
  • q is selected from: 1, 2, 3, 4 or 5;
  • R g is selected from: H, C 1 -C 8 alkyl, substituted C 1 -C 8 alkyl (preferably tert-butyl, isobutyl, etc.); substituents are selected from amino, hydroxyl, cyano, halogen.
  • E3 is selected from:
  • the compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt, prodrug is selected from the following compounds:
  • the compound is the following compound:
  • Substituted means that a hydrogen atom is replaced by a substituent. Note that the substituents on a particular atom are restricted by its valence.
  • C ij means an inclusive range where i and j are integers representing the number of carbon atoms. For example, C 1-4 , C 1-10 , C 3-10 , etc.
  • C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopes.
  • the C, H, O, S, N, F, Cl, Br, and I involved in the groups and compounds of the present invention may optionally be substituted by one or more of their corresponding isotopes, including but not limited to Carbon isotopes 12 C, 13 C, 14 C, hydrogen isotopes protium (H), deuterium (D), tritium (T), oxygen isotopes 16 O, 17 O, 18 O, sulfur isotopes 32 S, 33 S , 34 S, 36 S, nitrogen isotopes 14 N, 15 N, fluorine isotopes 17 F, 19 F, chlorine isotopes 35 Cl, 37 Cl, bromine isotopes 79 Br, 81 Br, etc.
  • alkyl used in the present invention refers to a straight-chain or branched saturated hydrocarbon group containing 1 to 8 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl Base, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, pentyl, n-hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octane base, isooctyl, etc.
  • the alkyl group can be substituted by one or more substituents, and the substituents can be the same or different when multiple substitutions are made; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, amino Alkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, sulfonyl, alkylamide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 - C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycloalkyl, cycloalkenyl
  • Alkenyl can be substituted by one or more substituents, and the substituents can be the same or different when multiple substitutions are made; the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halo Hydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, Amide, sulfonamide, spiroalkyl.
  • alkynyl and “alkyne” used in the present invention refer to a straight or branched hydrocarbon chain group containing 1 to 8 carbon atoms and at least one C ⁇ C triple bond, including but not limited to ethynyl, 1 -propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl Alkynyl, 3-methyl-1-butynyl, 4-methyl-1-butynyl, 2-methyl-3-butynyl, 1-methyl-4-butynyl, 1-hexyl Alkynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4- Pentynyl, 2-methyl-3-pentyl, 2-
  • the alkynyl group can be substituted by one or more substituents, and the substituents can be the same or different when multiple substitutions are made; the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halo Hydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, Amide, sulfonamide, spiroalkyl.
  • cycloalkane and “cycloalkyl” used in the present invention refer to a monocyclic or polycyclic ring (two monocyclic rings are connected by a chemical bond or bridged ring or spiro ring or fused) with 3 to 12 carbon atoms.
  • Aromatic monovalent hydrocarbon group, and one or more chemical bonds may be double bonds or triple bonds.
  • Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydroindene, decahydronaphthalene, bicyclo[ 1.1.0] Butyl, Bicyclo [2.1.0] Pentyl, Bicyclo [2.2.0] Hexyl, Bicyclo [3.2.0] Heptyl, Bicyclo [4.2.0] Octyl, Bicyclo [ 1.1.1] pentyl, bicyclo [2.1.1] hexane, bicyclo [3.1.1] heptyl, bicyclo [2.2.1] heptyl, bicyclo [4.1.1] octane, bicyclo [ 3.2.1]octyl, bicyclo[3.2.1]octyl, bicyclo[5.1.1]non
  • the cycloalkyl group can be substituted by one or more substituents, and the substituents can be the same or different during multiple substitutions; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, Aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, sulfonyl, alkylamide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycloalkyl, cycloal
  • Cycloalkenes and cycloalkenyls can be substituted by one or more substituents, and the substituents can be the same or different when multi-substituted; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl , aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, methylsulfone, alkylamido, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino , halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycl
  • cycloalkyne and “cycloalkynyl” used in the present invention refer to a monocyclic or polycyclic ring (two monocyclic rings are connected by a chemical bond or bridged ring or spiro ring or fused) with 4 to 12 carbon atoms
  • Non-aromatic hydrocarbon group containing at least one triple bond preferably cyclobutynyl, cyclopentynyl, cyclohexynyl, etc., wherein one or two carbon atoms can be replaced by an oxygen atom.
  • the cycloalkynyl group can be unsubstituted or substituted, and its substituents are selected from D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate group, acyl group, amido group, methylsulfonyl group, alkylamido group, C 1 -C 8 alkyl group, C 1 -C 8 alkoxy group, C 1 -C 8 hydroxyalkyl group, C 1 -C 8 alkylamino group, Halogenated C 1 -C 8 alkyl, Halogenated C 1 -C 8 Alkoxy, Halogenated C 1 -C 8 Hydroxyalkyl, Halogenated C 1 -C 8 Alkylamino, C 3 -C 12 Cycloalkyl , halogenated C 3 -C 12 cycloalkyl, cycloalkenyl, cycloalky
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.
  • alkoxy refers to alkyl-O-, wherein alkyl is as defined above.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy , 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc.
  • Alkoxy also includes substituted alkoxy, whose substituents can be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamide, spiroalkyl, C 1 - C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 hydroxyalkane Base, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • hydroxyalkyl refers to -alkyl-OH, wherein alkyl is as defined above.
  • alkyl is as defined above.
  • examples of "hydroxyalkyl” as used in the present invention include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like.
  • Haldroxyalkyl also includes substituted hydroxyalkyl groups whose substituents can be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamide, spiroalkyl, C 1 - C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 hydroxyalkane Base, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • alkylamino refers to alkyl-NH-, wherein alkyl is as defined above.
  • alkylamino used in the present invention include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like.
  • Alkylamino also includes substituted alkylamino, whose substituents can be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamide, spiroalkyl, C 1 -C 8 Alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 hydroxyalkyl, Halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aryl, C 5 - C 14 heteroaryl, its substituent can be substituted on the alkyl or N.
  • aminoalkyl refers to NH2 -alkyl-, wherein alkyl is as defined above.
  • alkyl is as defined above.
  • aminoalkyl as used in the present invention include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, and the like.
  • Aminoalkyl also includes substituted aminoalkyl groups whose substituents can be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamide, spiroalkyl, C 1 - C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 hydroxyalkane Base, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl, its substituent can be substituted on the alkyl or N.
  • cycloalkoxy refers to a cycloalkyl group wherein one or more carbon atoms are replaced by one or more oxygen atoms, wherein cycloalkyl is as defined above.
  • alkylamino used in the present invention include, but are not limited to, oxetane, tetrahydrofuran, tetrahydropyran, dioxane, and the like.
  • aromatic ring and "aryl” used in the present invention refer to a full-carbon monocyclic or condensed polycyclic aromatic ring group with 6 to 12 carbon atoms (one of the fused rings may be partially saturated when fused to polycyclic rings) ), including but not limited to benzene ring, naphthalene ring, anthracene ring, indene ring, dihydroindenyl (indanyl), dihydronaphthalene ring, tetrahydronaphthalene ring, etc.
  • the aryl group can be unsubstituted or substituted, can be monosubstituted (such as ortho, meta, para substituted), can also be disubstituted or trisubstituted, etc., and the substituents can be the same or different during multiple substitutions;
  • the substituents are independently D (deuterium), halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, acyl, amido, alkylamido, C 1 -C 8 alkyl , C 1 -C 8 alkoxy, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl,
  • heteroaryl ring and “heteroaryl” used in the present invention refer to a monocyclic or fused polycyclic aromatic ring group with 5 to 14 ring atoms (one of the fused rings may be partially saturated when fused to polycyclic rings) , which corresponds to the replacement of one or more carbons in the above “aryl” by heteroatoms such as N, O, S, etc.
  • Heteroaryl rings can be monocyclic or bicyclic, ie formed by the fusion of two rings.
  • Heteroaryl includes, but is not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, thienyl, furyl, triazolyl , oxazolyl, imidazolyl, indazolyl, indolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl , Dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, pteridinyl, purinyl, benzimidazolyl, Benzof
  • Heteroaryl can be unsubstituted or monosubstituted or multi-substituted, and the substituents can be the same or different when multi-substituted; the substituents are independently D (deuterium), halogen, cyano, nitro, amino, aminoalkyl , hydroxyl, carboxyl, carboxylate, acyl, amido, alkylamide, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, spiroalkyl, C 1 - C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 hydroxyalkane radical, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkylamino,
  • heterocyclic group used in the present invention refers to a non-aromatic ring group with a monocyclic or polycyclic ring (two monocyclic rings are connected by a chemical bond or bridged ring or spiro ring or fused) with 3 to 12 ring atoms , has one or more heteroatoms selected from N, O, and S, and one or more chemical bonds may be double bonds or triple bonds.
  • Heterocyclyl includes, but is not limited to, pyranyl, piperidinyl, piperazinyl, morpholinyl, dioxane, oxiranyl, oxetanyl, oxetanyl, oxepeptyl oxetyl, aziridyl, azetidinyl, azepanyl, azepanyl, azepanyl, thietanyl, thiiridine , azacyclooctyl, oxazepine base, diazepine base, thiazepine base, dihydrofuryl, dihydrothienyl, dihydropyranyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiazolyl, tetrahydroimidazolyl, hex
  • the heterocyclic group can be substituted by one or more substituents, and the substituents can be the same or different when they are more substituted; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, Aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, sulfonyl, alkylamide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycloalkyl, alkoxycarbony
  • spiro ring and “spiro ring group” used in the present invention refer to a polycyclic structure, in which at least two rings share an atom (generally a C atom), in this polycyclic structure
  • one or more chemical bonds may be double bonds or triple bonds, and one or more heteroatoms may be present.
  • the spirocyclic group can be unsubstituted or monosubstituted or multi-substituted, and the substituents can be the same or different when multi-substituted; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl , amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, methylsulfone, alkylamido, C 1 -C 8 alkyl, C 1 -C 8 alkoxy , C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, Halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3
  • bridged ring group used in the present invention refers to a polycyclic structure. In this polycyclic structure, at least 2 rings share 2 or more atoms. In this polycyclic structure, there may be One or more of the bonds is a double or triple bond, and one or more heteroatoms may be present.
  • the bridging ring group can be unsubstituted or monosubstituted or multi-substituted, and the substituents can be the same or different when multi-substituted; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl , amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, methylsulfone, alkylamido, C 1 -C 8 alkyl, C 1 -C 8 alkoxy , C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, Halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3
  • haloalkyl refers to straight or branched chain alkyl in which one or more hydrogens are replaced by one or more halogen atoms (preferably fluorine, chlorine, bromine, iodine), wherein alkyl is as defined above .
  • halocycloalkyl refers to a cycloalkyl group in which one or more hydrogens are replaced by one or more halogen atoms (preferably fluorine, chlorine, bromine, iodine), wherein cycloalkyl is as defined above .
  • salts of the compounds described in the present invention can be prepared by methods well known to those skilled in the art.
  • “Pharmaceutically acceptable salt” refers to a salt formed of a compound of the present invention with an acid or a base which is suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, hydroiodic, sulfuric, nitric, phosphoric, carbonic, formic, acetic, trifluoroacetic, propionic, oxalic, propionic Diacid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, wolfberry acid , isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, sulfanilic acid, isethionic acid, pa
  • a preferred class of salts are the salts of the compounds of the invention with bases.
  • Bases suitable for forming salts include but are not limited to: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate and other inorganic bases, ammonia, triethylamine, diethylamine, piperazine, guanidine, diethanolamine, etc. organic base.
  • the second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any one of the above technical schemes.
  • the pharmaceutical composition of the present invention can be composed of one or more of the compounds described in any one of the above technical schemes and other compounds, or one or more of the compounds described in any of the above technical schemes composition.
  • the present invention provides a pharmaceutical preparation, comprising at least one active component, and the active component is one or more of the compounds described in any one of the above technical schemes.
  • the pharmaceutical preparation comprises at least one active component and one or more pharmaceutically acceptable carriers or excipients, and the active component may be the BTK inhibitor compound of the present invention, the optically isotropic compound of the compound Any one or more of the conformers, the pharmaceutically acceptable salt of the compound or its optical isomer, the solvate of the compound or its optical isomer.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and fragrances can also be added if necessary agents, sweeteners, etc.
  • the medicine of the present invention can be made into various forms such as tablets, powders, granules, capsules, oral liquids and injections, and the medicines in the above dosage forms can be prepared according to conventional methods in the field of pharmacy.
  • the present invention provides the use of compounds described in general formulas I to III disclosed herein and their optical isomers or pharmaceutically acceptable salts or solvates thereof to inhibit Bruton's tyrosine Kinase (Btk) activity or treatment of a disease, disorder or condition that would benefit from inhibition of Bruton's tyrosine kinase (Btk) activity.
  • the present invention provides for inhibiting Bruton's tyrosine kinase activity in a subject in need thereof by administering to the subject in need thereof a composition comprising a therapeutically effective amount of at least one compound method, wherein the structural formula of the compound is general formula I to general formula III.
  • the subject in need thereof suffers from an autoimmune disease, such as inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease (Still's disease), juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, rheumatoid arthritis Syndrome ( syndrome), multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, optic clonus-myoclonus syndrome, obsessive Spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, immune thrombocytopenic purpura (ITP), optic nerve Inflammation, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takaya
  • the subject in need thereof suffers from cancer.
  • the cancer is a B-cell or plasma cell proliferative disorder, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia ( macroglobulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, multiple myeloma, or lymphomatoid granulomatous disease.
  • the present invention also provides the application of the compound or the pharmaceutically acceptable salt thereof in the preparation of BTK inhibitors, especially in the preparation and treatment of cell proliferation diseases.
  • Said cell proliferative diseases include cancer.
  • the present invention also provides compounds described in general formulas I to III, and optical isomers thereof or pharmaceutically acceptable salts or solvates thereof for use alone or in combination with other drugs in the treatment of proliferative diseases (such as application in cancer).
  • antitumor drugs that can be used in combination with the compounds provided by the present invention or their pharmaceutically acceptable salts include but are not limited to at least one of the following types: mitosis inhibitors (such as vinblastine, vindesine and vinorelbine); tubulin catabolic inhibitors (such as taxol); alkylating agents (such as cisplatin, carboplatin, and cyclophosphamide); antimetabolites (such as 5-fluorouracil, tegafur, methotrexate, cytarabine, and hydroxyurea); insertable antibiotics (e.g., alcisol, mitomycin, and bleomycin)); enzymes (e.g., aspartase); topoisomerase inhibitors (e.g., etoposide and camptothecin); biological Response modifiers (such as interferon); immune checkpoint inhibitors (such as PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors); CD20 monoclonal
  • the inventors of the present invention have confirmed through experiments that the compound of the present invention has degrading activity on BTK.
  • the inventors of the present invention have confirmed through experiments that the compound of the present invention has anti-proliferation and inhibitory effects on tumor cell lines such as Mino and OCI-LY10.
  • the inventors of the present invention have confirmed through experiments that the compound of the present invention is metabolically stable in liver microparticles.
  • the inventors of the present invention have confirmed through experiments that the compound of the present invention can be taken orally.
  • the inventors of the present invention have confirmed through experiments that the compound of the present invention has a better effect of inhibiting tumor growth in the OCI-LY10 in vivo drug effect model.
  • tert-butyl 4-formylpiperidine-1-carboxylate (7.3 g, 34.27 mmol) was dissolved in 20 mL of DCM, trifluoroacetic acid (30 mL) was added to the system, and stirred at room temperature for one hour. After the reaction was completed, it was concentrated under reduced pressure to obtain yellow liquid piperidine-4-carbaldehyde.
  • the above product was dissolved in 50 mL DMF, and cesium carbonate (3.0 g, 9.21 mmol) and 2,4-difluoro-1-nitrobenzene (5.5 g, 31.44 mmol) were successively added to the system, and reacted at 90° C. for 2 h.
  • Synthetic step 2 tert-butyl 4-(2',6'-bis(benzyloxy)-[3,3'-bipyridyl]-6-yl)piperazine-1-carboxylate (intermediate 40-2 )
  • Example 1 5-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- Base) pyrrolidin-3-yl) methyl) piperidin-4-yl)-3-fluorophenyl) amino)-3-(piperidin-1-yl)-1,2,4-triazine-6 - Formamide (002)
  • 002-3 (200mg, 0.29mmol) was dissolved in 10mL 1,4-dioxane, and N,N-diisopropylethylamine (1.5g, 11.50mmol) and phosphorus oxychloride ( 2mL), react at 105°C for 0.2h.
  • Example 2 5-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- Base) pyrrolidin-3-yl) methyl) piperidin-4-yl) phenyl) amino)-3-(piperidin-1-yl)-1,2,4-triazine-6-carboxamide ( 001)
  • Example 3 5-((4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- Base) pyrrolidin-3-yl) methyl) piperazin-1-yl)-3-fluorophenyl) amino)-3-(piperidin-1-yl)-1,2,4-triazine-6 - Formamide (003)
  • Example 4 5-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- Base) piperidin-4-yl)methyl)piperidin-4-yl)-3-fluorophenyl)amino)-3-(piperidin-1-yl)-1,2,4-triazine-6 - Formamide (007)
  • Example 5 5-((4-(1-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- Dihydro-1H-benzo[d]imidazol-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-3-(piperidin-1-yl)- 1,2,4-Triazine-6-carboxamide (011)
  • Dissolve 016-1 in 5 mL of DCM, add trifluoroacetic acid (1 mL) to the system, react at room temperature for 1 h, and concentrate under reduced pressure to obtain a colorless liquid (R)-N-(piperidin-3-yl)acetamide, used directly in the next reaction.
  • Dissolve 016-2 (50mg, 0.07mmol) in 3mL DMF, add (R)-N-(piperidin-3-yl)acetamide (50mg, 0.21mmol), N,N-diisopropyl Ethylamine (40mg, 0.31mmol) was reacted at room temperature for 0.5h. After the reaction was completed, water was added until no yellow solid was precipitated in the system.
  • Example 7 3-((R)-3-aminopiperidin-1-yl)-5-((4-(1-((1-(2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindoline-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-1,2,4-tri Oxazine-6-carboxamide (029)
  • Example 39 5-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- Base) pyrrolidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-3-(thiazol-2-yl)-1,2,4-triazine-6-carboxamide (024 )
  • Example 42 5-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- Base) pyrrolidin-3-yl) methyl) piperidin-4-yl) phenyl) amino) -3-(3-hydroxyphenoxy) -1,2,4-triazine-6-carboxamide ( 027)
  • Example 43 3-(2,3-Difluorophenoxy)-5-((4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindoline-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-1,2,4-triazine-6- Formamide (028)
  • Example 44 5-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine- 4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-(piperidin-1-yl)-1,2,4-triazine-6-carboxamide (075 )
  • Synthetic step 2 5-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine- 4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-(piperidin-1-yl)-1,2,4-triazine-6-carboxamide (075 )
  • Example 45 5-((4-(4-((1-(6-((2,6-dioxopiperidin-3-yl)amino)pyridin-3-yl)piperidin-4-yl )Methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-(piperidin-1-yl)-1,2,4-triazine-6-carboxamide (077)
  • Example 46 5-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- Base) piperazin-1-yl) methyl) piperidin-1-yl)-3-fluorophenyl) amino)-3-(piperidin-1-yl)-1,2,4-triazine-6 - Formamide (044)
  • Example 87 5-((4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl )pyrrolidin-3-carbonyl)piperidin-4-yl)phenyl)amino)-3-(piperidin-1-yl)-1,2,4-triazine-6-carboxamide (055)
  • Example 94 (3-(5-(3-((4-(4-((6-carbamoyl-3-(piperidin-1-yl)-1,2,4-triazine-5- Base) amino) phenyl) piperidin-1-yl) methyl) pyrrolidin-1-yl)-1,3-dioxoisoindoline-2-yl)-2,6-dioxopiper Pyridin-1-yl) methyl pivalate (062)
  • 500,000-1,000,000/well cells of Mino cell line were planted in 6-well plates. Compounds were diluted to different concentrations, added to the plate, and after incubation for 24-72 hours, the cells were harvested. After the cells were lysed, the total protein concentration in each well was determined with a BCA kit. The amount of BTK was determined using Western blot or Elisa method.
  • Compound number DC 50 Compound number DC 50 Compound number DC 50 Compound number DC 50 Compound number DC 50 001 A 002 A 003 A 004 A 005 A 006 A 007 A 008 A 009 A 010 A 011 A 012 A 013 A 014 A 015 A 016 A 017 A 018 A 019 A 020 A 021 A 022 A 023 A 024 A 025 A 026 A 027 A 028 A 029 A 030 A 031 A 032 A 033 A 034 A 035 A 036 A 037 A 038 A 039 A 040 A 041 A 042 A 043 A 044 A 045 A 046 A 047 A 048 A 049 A 050 A 051 A 052 A 053 A 054 A 055 A 056 A 057 A 058 A 059 A 060 A 061 A 062 A 063 A 064 A 065 A 066 A 067 A 068 A 069 A 070 A
  • Compound a is from Compound 149 in patent WO2021113557A1;
  • Compound b is from Compound 44 in patent WO2021113557A1;
  • the compounds of the present invention have a degrading effect on BTK.
  • OCI-LY10 and Mino cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. The cells were digested, and the cells were seeded in a 96-well plate at a concentration of OCI-LY10 and Mino 10000/well; incubated overnight at 37°C and 5% CO 2 . Compounds of different concentrations (1000nM, 4-fold dilution, 8 points) were added to the 96-well plate and incubated at 37°C, 5% CO 2 for 72 hours or 7 days, and then 20uL MTS was added to each well.
  • Table 2 and Table 3 show that the compound of the present invention has obvious anti-proliferation activity on tumor cells.
  • mice were used as experimental animals, and 10 mg/kg (5% DMSO+5% Solutol+90% normal saline) was administered orally.
  • the time points of blood collection for intragastric administration were 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours.
  • 0.3ml of whole blood was taken, and 0.1ml of plasma was taken after centrifugation for analysis by LC-MS.
  • DNAUC means AUC (h*ng/mL)/dose (mg/kg).
  • SD rats were used as experimental animals, and 10 mg/kg (5% DMSO+5% Solutol+90% normal saline) was administered orally.
  • the time points of blood collection for intragastric administration were 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours.
  • 0.3ml of whole blood was taken, and 0.1ml of plasma was taken after centrifugation for analysis by LC-MS.
  • DNAUC means AUC (h*ng/mL)/dose (mg/kg).
  • Example 111 In Vivo Antitumor Drug Efficacy
  • NOD/SCID mice were subcutaneously inoculated with OCL-LY10 cells to establish a tumor model, and when the tumor grew to about 100mm3 , they were divided into groups for administration, and the administration method was as follows: Group A, the control group, was given a corresponding volume of CMC-Na solution; Give 3mg/kg test compound; C group is given 10mg/kg test compound by intragastric administration; D group is given 30mg/kg test compound by intragastric administration; Weigh mouse body weight and tumor size change twice every week, after 3 weeks, use cervical spine The mice were sacrificed by dislocation, and the drug effect of the compound on the transplanted tumor of OCL-LY10 mice was investigated.

Abstract

本发明公开了一种布鲁顿酪氨酸激酶降解剂，其具有通式I的结构；或其立体异构体，或其立体异构体混合物，或其药学上可接受的盐、前药；还公开了该化合物以及包含该化合物的药物组合物在制备治疗与布鲁顿酪氨酸激酶相关疾病如B细胞或浆细胞增殖性疾病。本发明的化合物具有强效的细胞增殖抑制活性，有效降解布鲁顿酪氨酸激酶，肝微粒代谢稳定性好，较好的口服吸收性质。可应用于在单独或与其他药物联合应用治疗从布鲁顿酪氨酸激酶活性的抑制或降解中获益的疾病、障碍或病症药物中的应用。

Description

一种可降解BTK激酶的多功能化合物、组合物及应用 技术领域
本发明属于医药合成技术领域，具体是涉及一种可降解BTK激酶的多功能化合物、组合物及应用。
背景技术
布鲁顿氏酪氨酸激酶BTK作为Tec蛋白家族中的一员(BTK,Tec,Txk,Itk&Bmx)，是在除了T淋巴细胞之外的所有造血细胞类型中表达的关键信号酶，主要表达在B淋巴细胞中，BTK在连接细胞表面B细胞受体(B-cell receptor,BCR)刺激至下游细胞内应答的B细胞信号传导途径中扮演至关重要的角色，已被临床证实为重要的药物靶标。BTK是B细胞发育、激活、信号传导和存活的关键调节物。另外，BTK在众多其他造血细胞信号传导途径中起作用，例如在巨噬细胞中的Toll样受体(Toll like receptor，TLR)和细胞因子受体介导的TNF-α产生、在肥大细胞中的免疫球蛋白E受体(FcεR1)信号传导、在B-谱系淋巴样细胞中抑制Fas/APO-1细胞凋亡的信号传导以及胶原刺激的血小板聚集。参见例如C.A.Jeffries等，J.Bio.Chem.(2003)278:26258-26264、N.J.Horwood等，J.Exp.Med.(2003)197:1603-1611。近年来研究显示，BTK信号通路是目前非霍奇金淋巴瘤(NHL)，特别是慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤及自身免疫疾病临床治疗研究中的新热点。小分子BTK抑制剂通过作用于BCR信号通路，与BTK结合而抑制BTK自身磷酸化，阻止BTK的激活，从而阻断细胞传导并诱导细胞凋亡。
随着共价BTK抑制在临床上的使用，部分CLL患者已经出现BTK C481突变，而造成的BTK药物获得性耐药问题，亟需新一代BTK药物解决这一获得性耐药。
靶向蛋白降解嵌合分子(PROTAC)技术取得了重大的进展，该技术通过其通过泛素-蛋白酶体***诱导致癌蛋白泛素化从而被降解。采用该技术的药物，无需持续占据靶蛋白，催化浓度即可实现靶点降解。因此开发针对BTK的靶向降解分子，有望解决BTK获得性耐药问题。
发明内容
本发明的目的是提供新颖的、未见文献报道的具有BTK降解活性，并具有优良口服PK性质优良的布鲁顿氏酪氨酸激酶BTK降解剂或其光学异构体、立体异构体、或其立体异构体混合物，或其药学上可接受的盐或溶剂合物，前药，以及在BTK相关疾病B细胞或浆细胞增殖性疾病和自身免疫性疾病中的用途。
本发明的第一方面，提供了如式I所示的化合物，或其药学上可接受的盐，前药；
Figure PCTCN2022133404-appb-000001
其中：
L选自：连接环A和E 3的化学基团和化学键；
E 3选自：E 3泛素连接酶配体；
环A选自：3-12元杂环、6-10元芳环、5-12元杂芳环，3-12元环烷、4-12元环炔、3-12元环烯，其中所述的杂环、杂芳环具有1-3个独立选自N、O或S的杂原子；
R 2选自：H、卤素、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 8环烷基、C 1-C 4烷氧基、C 3-C 8环烷氧基、C 3-C 8杂环基、C 1-C 4烷氨基、-COOH、-NH 2、OH、NO 2；
n选自：0、1、2、3、4；
Y 1选自：N,CR 4；
Y 2选自：N,CR 5；
Y 3选自：N,CR 5；
R 4选自：卤素、C 1-C 4烷基、C 3-C 8环烷基、C 1-C 4卤代烷基、C 3-C 8卤代环烷基、C 1-C 4烷氧基、氨基、羧基、羟基、氰基；
R 5选自：H、卤素、C 1-C 4烷基、C 3-C 8环烷基、C 1-C 4卤代烷基、C 3-C 8卤代环烷基、C 1-C 4烷氧基、氨基、羧基、羟基、氰基；
R 3选自：H、C 1-C 8烷基、C 1-C 6卤代烷基、C 3-C 8烯烃、C 3-C 8炔烃、环烷基、杂环基、芳基；
R 1选自：NR 6R 7、OR 6、SR 6、-C(O)R 6、-C(O)OR 6、-C(O)NR 6R 7、OC(O)R 6、OC(O)NR 6R 7、S(O)R 6、S(O)(＝NH)R 6、S(O) 2NR 6R 7、N(R 6)C(O)R 7、N(R 6)C(O)OR 7、C 1-C 8烷基、3-12元杂环、5-6元杂芳环、C 3-C 8环烷基、芳环基，其中所述的烷基、杂环、杂芳环、环烷基、芳环基可进一步被一个或者多个选自R 8的取代基取代；
R 8选自：H、卤素、羟基、氨基、氰基、氧代、羧基、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 3-C 8环烷基、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、ORa、OC(O)Ra、OC(O)NRaRb、SRa、S(O)Ra、S(O)(＝NH)Ra、S(O) 2NRaRb、NRaRb、N(Ra)C(O)Rb、N(Ra)C(O)ORb、N(Rc)C(O)NRaRb、-N(Ra)S(O) 2Rb、-N(Ra)S(O) 2NRbRc；其中所述的烷基、烷氧基、环烷基可进一步被一个或者多个取代基取代，取代基包括：H、卤素、羟基、氨基、氰基、氧代、羧基、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 3-C 8环烷基；
R 6、R 7各自独立的选自H、C 1-C 8烷基、胺烷基、羟烷基、C 3-C 8环烷基、 杂环基、芳环基、杂芳基；所述的烷基、胺烷基、羟烷基、环烷基、杂环基、芳环基、杂芳基可进一步被一个或者多个取代基取代，取代基包括H、卤素、羟基、氨基、氰基、氧代、羧基、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 3-C 8环烷基、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、ORa、OC(O)Ra、OC(O)NRaRb、SRa、S(O)Ra、S(O)(＝NH)Ra、S(O) 2NRaRb、NRaRb、N(Ra)C(O)Rb、N(Ra)C(O)ORb、N(Rc)C(O)NRaRb、-N(Ra)S(O) 2Rb、-N(Ra)S(O) 2NRbRc；
Ra、Rb、Rc各自独立的选自H、卤素、烷基、氨基、羟基、氰基、C 3-C 8环烷基、烷氨基、烷氧基。
Y 2、Y 3同时选择CR 5时，两个取代中R 5相互独立，可以相同，也可以不相同。
作为优选，Y 1、Y 2、Y 3同时为N。
进一步地，本发明优选的化合物：
环A选自：6-10元芳环、5-12元杂芳环；其中所述的杂环、杂芳环具有1-3个独立选自N、O或S的杂原子，其中：
环A选自：
Figure PCTCN2022133404-appb-000002
Figure PCTCN2022133404-appb-000003
进一步地，本发明优选的化合物具有通式II(a)～II(i)的结构：
Figure PCTCN2022133404-appb-000004
或其立体异构体，或其立体异构体混合物，或其药学上可接受的盐，前药。
进一步，本发明优选的化合物具有通式III(a)-III(c)的结构：
Figure PCTCN2022133404-appb-000005
或其立体异构体，或其立体异构体混合物，或其药学上可接受的盐，前药；
R 1优选自：NR 6R 7、OR 6、C 1-C 8烷基、3-12元杂环、5-6元杂芳环、C 3-C 8环烷基、芳环基；其中所述的烷基、杂环、杂芳环、环烷基、芳环基可进一步被一个或者多个选自R 8的取代基取代；
R 8优选自：H、卤素、羟基、氨基、氰基、氧代、羧基、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 3-C 8环烷基、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、ORa、OC(O)Ra、OC(O)NRaRb、SRa、S(O)Ra、S(O)(＝NH)Ra、S(O) 2NRaRb、NRaRb、N(Ra)C(O)Rb、N(Ra)C(O)ORb、N(Rc)C(O)NRaRb、-N(Ra)S(O) 2Rb、-N(Ra)S(O) 2NRbRc；其中所述的烷基、烷氧基、环烷基可进一步被一个或者多个取代基取代，取代基包括：H、卤素、羟基、氨基、氰基、氧代、羧基、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 3-C 8环烷基；
R 6、R 7优选自：H、C 1-C 8烷基、胺烷基、羟烷基、C 3-C 8环烷基、杂环基、芳环基、杂芳基；所述的烷基、胺烷基、羟烷基、环烷基、杂环基、芳环基、杂芳基可进一步被一个或者多个取代基取代，取代基包括H、卤素、羟基、氨基、氰基、氧代、羧基、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 3-C 8环烷基、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、ORa、OC(O)Ra、OC(O)NRaRb、SRa、S(O)Ra、S(O)(＝NH)Ra、S(O) 2NRaRb、NRaRb、N(Ra)C(O)Rb、N(Ra)C(O)ORb、N(Rc)C(O)NRaRb、-N(Ra)S(O) 2Rb、-N(Ra)S(O) 2NRbRc；
Ra、Rb、Rc各自独立的优选自H、卤素、烷基、氨基、羟基、氰基、C 3-C 8环烷基、烷氨基、烷氧基。
在一些实施方案中，R 2的优选为：H、F。
在一些实施方案中，通式(I)、II(a)～II(i)、III(a)、III(b)或III(c)中的片段
Figure PCTCN2022133404-appb-000006
优选为
Figure PCTCN2022133404-appb-000007
进一步优选为
Figure PCTCN2022133404-appb-000008
在一些实施方案中，R 1优选自：
Figure PCTCN2022133404-appb-000009
更一步地，作为优选方案：
L优选自:
Figure PCTCN2022133404-appb-000010
Figure PCTCN2022133404-appb-000011
E3选自：
Figure PCTCN2022133404-appb-000012
Figure PCTCN2022133404-appb-000013
Re选自：H、F、Cl、-CH 3、-OMe、-CN、-CF 3；
Rd选自：H、L 2R g；
L 2选自：
Figure PCTCN2022133404-appb-000014
Figure PCTCN2022133404-appb-000015
R 9选自：H、C 1-C 5烷基(优选为甲基、)；
q选自：1、2、3、4或5；
R g选自：H、C 1-C 8烷基、取代的C 1-C 8烷基(优选为叔丁基、异丁基等)；取代基选自氨基、羟基、氰基、卤素。
更一步地，E3选自：
Figure PCTCN2022133404-appb-000016
Figure PCTCN2022133404-appb-000017
作为优选，所述的化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐，前药，选自下列化合物：
Figure PCTCN2022133404-appb-000018
Figure PCTCN2022133404-appb-000019
Figure PCTCN2022133404-appb-000020
Figure PCTCN2022133404-appb-000021
Figure PCTCN2022133404-appb-000022
Figure PCTCN2022133404-appb-000023
或其立体异构体或其立体异构体混合物或其药学上可接受的盐、前药。作为优选，所述化合物为如下化合物：
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺001
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺002
5-((4-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基) 甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺003
5-((6-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)哒嗪-3-基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺004
5-((2-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)嘧啶-5-基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺005
5-((4-(4-((1-(2-(2,6-d二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁烷-3-基)甲基)哌嗪-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺006
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺007
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-羧酰胺008
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-羧酰胺009
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1-氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺010
5-((4-(1-((1-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺011
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1-氧代-1,2-二氢异喹啉-6-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺012
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1-氧代-1,2,3,4-四氢异喹啉-6-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺013
5-((4-(1-((1-(5-((2,6-二氧代哌啶-3-基)氨基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺014
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-((R)-3-羟基哌啶-1-基)-1,2,4-三嗪-6-甲酰胺015
3-((R)-3-乙酰氨基哌啶-1-基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺016
3-(((S)-1-氨基-1-氧代丁烷-2-基)氨基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺017
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(4-甲基哌嗪-1-基)-1,2,4-三嗪-6-甲酰胺018
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-吗啉代-1,2,4-三嗪-6-甲酰胺019
3-((3-氰基苯基)氨基)-5-((4-(1-((1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲 哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺020
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(吡啶-2-基氨基)-1,2,4-三嗪-6-甲酰胺021
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-((R)-3-羟基吡咯烷-1-基)-1,2,4-三嗪-6-甲酰胺022
3-((R)-3-乙酰氨基哌啶-1-基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺023
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(噻唑-2-基)-1,2,4-三嗪-6-甲酰胺024
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(1H-咪唑-2-基)-1,2,4-三嗪-6-甲酰胺025
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(吡啶-3-基)-1,2,4-三嗪-6-甲酰胺026
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(3-羟基苯氧基)-1,2,4-三嗪-6-甲酰胺027
3-(2,3-二氟苯氧基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺028
3-((R)-3-氨基哌啶-1-基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺029
3-(((1S，2R)-2-氨基环己基)氨基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺030
5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌嗪-1-基)-1,2,4-三嗪-6-甲酰胺031
2-(((1S,2R)-2-氨基环己基)氨基)-4-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)嘧啶-5-甲酰胺032
4-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-2-(哌啶-1-基)嘧啶-5-甲酰胺033
4-((4-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-2-(哌啶-1-基)嘧啶-5-甲酰胺034
4-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-2-((R)-3-羟基哌啶-1-基)嘧啶-5-甲酰胺035
4-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-2-(哌啶-1-基)嘧啶-5-甲酰胺036
4-((4-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-6-(哌啶-1-基)烟酰胺037
4-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-6-(哌啶-1-基)烟酰胺038
3-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-6-甲基-5-(哌啶-1-基)吡嗪-2-甲酰胺039
4-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-6-(哌啶-1-基)哒嗪-3-甲酰胺040
4-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-6-((R)-3-羟基哌啶-1-基)哒嗪-3-甲酰胺041
3-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-6-氟-5-(哌啶-1-基)吡嗪-2-甲酰胺042
3-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-6-甲氧基-5-(哌啶-1-基)吡嗪-2-甲酰胺043
5-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺044
5-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺045
5-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺046
5-((6-(4-((4-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌嗪-1-基)甲基)哌啶-1-基)吡啶-3-基)氨基)-3-(4-甲基哌嗪-1-基)-1,2,4-三嗪-6-甲酰胺047
5-((6-(4-((4-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌嗪-1-基)甲基)哌啶-1-基)吡啶-3-基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺048
5-((4-(3-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)氮杂环丁烷-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺049
5-((4-(4-((4-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌嗪-1-基)甲基)哌啶-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺050
4-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-3-氟苯基)氨基)-2-(哌啶-1-基)嘧啶-5-甲酰胺051
5-((4-(4-((4-(4-(2,6-二氧代哌啶-3-基)苯基)哌嗪-1-基)甲基)哌啶-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺052
5-((4-(4-((4-(5-(2,6-二氧代哌啶-3-基)吡啶-2-基)哌嗪-1-基)甲基)哌啶-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺053
5-((4-(4-((4-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌嗪-1-基)甲基)哌啶-1-基)-3-氟苯基)氨基)-3-(4-甲基哌嗪-1-基)-1,2,4-三嗪-6-甲酰胺054
5-((4-(1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-羰基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺055
5-((4-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-羰 基)哌嗪-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺056
5-((4-(1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-羰基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺057
5-((4-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-羰基)哌嗪-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺058
5-((4-(1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁烷-3-羰基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺059
5-((4-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-羰基)哌啶-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺060
5-((4-(4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氮杂环丁烷-3-羰基)哌嗪-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺061
(3-(5-(3-((4-(4-((6-氨基甲酰基-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸甲酯062
(3-(5-(3-((4-(4-((6-氨基甲酰基-3-(4-甲基哌嗪-1-基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸甲酯063
(3-(5-(3-((4-(4-((6-氨基甲酰基-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌嗪-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸甲酯064
(3-(5-(3-((4-(4-((5-氨基甲酰基-2-(哌啶-1-基)嘧啶-4-基)氨基)苯基)哌啶-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸甲酯065
(3-(4-(4-((1-(4-((6-氨基甲酰基-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)苯基)-2,6-二氧代四氢嘧啶-1(2H)-基)新戊酸甲酯066
5-((4-(1-((1-(2-(二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-3-((R)-3-羟基哌啶-1-基)-1,2,4-三嗪-6-甲酰胺067
(3-(5-(3-((4-(4-((6-氨甲酰-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌啶-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸甲酯068
1-(3-(5-(3-((4-(4-((6-氨甲酰-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸乙酯069
1-(3-(5-(3-((4-(4-((6-氨甲酰-3-(4-甲基哌嗪-1-基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸乙酯070
1-(3-(5-(3-((4-(4-((6-氨甲酰-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌 嗪-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸乙酯071
1-(3-(5-(3-((4-(4-((6-氨甲酰-3-(4-甲基哌嗪-1-基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸乙酯072
(3-(5-(3-((4-(4-((6-氨甲酰-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)L-缬氨酸甲酯073
(3-(5-(3-((4-(4-((6-氨甲酰-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌嗪-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)L-缬氨酸甲酯074
5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺075
5-((4-(4-((4-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-甲基苯基)哌嗪-1-基)甲基)哌啶-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺076
5-((4-(4-((1-(6-((2,6-二氧代哌啶-3-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺077
5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺078
5-((4-(4-((1-(6-((2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)吡咯烷-3-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺079
5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺080
5-((3-氟-4-(4-((1-(5-(6-氧代-1,6-二氢哒嗪-3-基)-3-(三氟甲基)吡啶-2-基)哌啶-4-基)甲基)哌嗪-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺081
5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺082
5-((4-(4-((1-(4-((2,6-二氧代哌啶-3-基)氨基甲酰基)-3-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺083
5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺084
5-((4-(4-((1-(6-((2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺085
5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-2-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺086
5-((3-氟-4-(4-((1-(4-(6-氧代-1,6-二氢哒嗪-3-基)-2-(三氟甲基)苯基)哌啶-4-基)甲基)哌嗪-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺087
5-((4-(4-((1-(4-((2,6-二氧代哌啶-3-基)氨基)-3-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺088
5-((3-氟-4-(4-((4-(4-(6-氧代-1,6-二氢哒嗪-3-基)-2-(三氟甲基)苯基)哌嗪-1-基)甲基)哌啶-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺089
(R)-3-(3-乙酰氨基哌啶-1-基)-5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-1,2,4-三嗪-6-甲酰胺090
(R)-3-(3-乙酰氨基哌啶-1-基)-5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-1,2,4-三嗪-6-甲酰胺091
3-((R)-3-乙酰氨基哌啶-1-基)-5-((4-(4-((1-(6-((2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-1,2,4-三嗪-6-甲酰胺092
3-((R)-3-乙酰氨基哌啶-1-基)-5-((4-(4-((1-(4-((2,6-二氧代哌啶-3-基)氨基甲酰基)-3-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-1,2,4-三嗪-6-甲酰胺093
(R)-3-(3-乙酰氨基哌啶-1-基)-5-((3-氟-4-(4-((1-(5-(6-氧代-1,6-二氢哒嗪-3-基)-3-(三氟甲基)吡啶-2-基)哌啶-4-基)甲基)哌嗪-1-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺094
(R)-3-(3-乙酰氨基哌啶-1-基)-5-((3-氟-4-(4-((1-(4-(6-氧代-1,6-二氢哒嗪-3-基)-2-(三氟甲基)苯基)哌啶-4-基)甲基)哌嗪-1-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺095
3-((R)-3-乙酰氨基哌啶-1-基)-5-((4-(4-((1-(6-((2,6-二氧代哌啶-3-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-1,2,4-三嗪-6-甲酰胺096
3-((R)-3-乙酰氨基哌啶-1-基)-5-((4-(4-((1-(4-((2,6-二氧代哌啶-3-基)氨基)-3-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-1,2,4-三嗪-6-甲酰胺097
5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-吗啉基-1,2,4-三嗪-6-甲酰胺098
5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-吗啉基-1,2,4-三嗪-6-甲酰胺099
5-((4-(4-((1-(6-((2,6-二氧代哌啶-3-基)氨基甲酰基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-吗啉基-1,2,4-三嗪-6-甲酰胺100
5-((4-(4-((1-(4-((2,6-二氧代哌啶-3-基)氨基甲酰基)-3-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-吗啉基-1,2,4-三嗪-6-甲酰胺101
5-((3-氟-4-(4-((1-(5-(6-氧代-1,6-二氢哒嗪-3-基)-3-(三氟甲基)吡啶-2-基)哌啶-4-基)甲基)哌嗪-1-基)苯基)氨基)-3-吗啉基-1,2,4-三嗪-6-甲酰胺102
5-((3-氟-4-(4-((1-(4-(6-氧代-1,6-二氢哒嗪-3-基)-2-(三氟甲基)苯基)哌啶-4-基)甲基)哌嗪-1-基)苯基)氨基)-3-吗啉基-1,2,4-三嗪-6-甲酰胺103
5-((4-(4-((1-(6-((2,6-二氧代哌啶-3-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-吗啉基-1,2,4-三嗪-6-甲酰胺104
5-((4-(4-((1-(4-((2,6-二氧代哌啶-3-基)氨基)-3-氟苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-吗啉基-1,2,4-三嗪-6-甲酰胺105
术语说明
除非另有定义，本发明使用的所有技术和科学术语与该领域专业人员通常理解的含义相同。除非另有说明，本发明参考的所有专利文献、公开披露的资料等全文纳入参考文献。如本发明中同一术语有多个定义，以本节中的定义为准。
需要理解的是，前文的一般描述和后文的详细描述仅仅是示范性的和解释性的，对任何权利要求都无限制性。在本发明中，除非另有说明，使用的单数包含复数。需要注意的是，说明书和所附权利要求书中，除非文中另有说明，单数形式指代如“一”、“一个”、“这个”，包含复数指代。还需注意的是，除非另有说明，“或”代表“和/或”。此外，“包含”、“包括”等类似术语不是限制性的。
“取代”是指氢原子被取代基取代。需要注意的是，特定原子上的取代基是被其价态限制的。在定义部分，“C i-j”是指包括起点和终点的范围，其中i和j都是整数，表示碳原子的数目。例如，C 1-4，C 1-10，C 3-10等。
本发明所述基团和化合物中所涉及的C、H、O、S、N、F、Cl、Br、I等均包括它们的同位素情况。同时，本发明所述基团和化合物中所涉及的C、H、O、S、N、F、Cl、Br、I可任选的被一个或多个它们对应的同位素取代，包括但不限于碳的同位素 12C、 13C、 14C，氢的同位素氕(H)、氘(D)、氚(T)，氧的同位素 16O、 17O、 18O，硫的同位素 32S、 33S、 34S、 36S，氮的同位素 14N、 15N，氟的同位素 17F、 19F，氯的同位素 35Cl、 37Cl，溴的同位素 79Br、 81Br等。
本发明所用术语“烷基”是指含有1至8个碳原子的直链或支链的饱和烃基，包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、特戊基、正己基、异己基、新己基、庚烷基、异庚烷基、新庚烷基、辛基、异辛基等。烷基可被一个或者多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、环烯基、环炔基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 14杂芳基、C 3-C 12杂环基。
本发明所用术语“烯基”“烯烃”是指含有1至8个碳原子且含至少一个C＝C双键的直链或支链的烃链基团，包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、1-甲基-2-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、 5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、1-甲基-2-己烯基、2-甲基-2-己烯基、2-甲基-3-己烯基、3,5-二甲基-2-己烯基、3,3-二甲基-1-戊烯基、3-甲基-2-乙基-1-丁烯基、1-辛烯基、2-辛烯基等。烯基可被一个或者多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、烷氨基、卤代烷氨基、环烷基、卤代环烷基、杂环基、芳基、杂芳基、羟基、卤素、氰基、硝基、氨基、氨基烷基、羧基、酰胺基、磺酰胺基、螺烷基。
本发明所用术语“炔基”“炔烃”是指含有1至8个碳原子且含至少一个C≡C叁键的直链或支链的烃链基团，包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、3-甲基-1-丁炔基、4-甲基-1-丁炔基、2-甲基-3-丁炔基、1-甲基-4-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、1-甲基-2-戊炔基、1-甲基-3-戊炔基、1-甲基-4-戊炔基、2-甲基-3-戊炔基、2,2-二甲基-4-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、5-庚炔基、2-甲基-3-己炔基、3-甲基-1-己炔基、3,3-二甲基-1-己炔基、4-甲基-1-己炔基等。炔基可被一个或者多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、烷氨基、卤代烷氨基、环烷基、卤代环烷基、杂环基、芳基、杂芳基、羟基、卤素、氰基、硝基、氨基、氨基烷基、羧基、酰胺基、磺酰胺基、螺烷基。
本发明所用术语“环烷”“环烷基”是指具有3至12个碳原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性单价烃基，且可有一个或多个化学键为双键或三键。“环烷基”包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、八氢茚、十氢萘、双环[1.1.0]丁烷基、双环[2.1.0]戊烷基、双环[2.2.0]己烷基、双环[3.2.0]庚烷基、双环[4.2.0]辛烷基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[3.1.1]庚烷基、双环[2.2.1]庚烷基、双环[4.1.1]辛烷基、双环[3.2.1]辛烷基、双环[3.2.1]辛烷基、双环[5.1.1]壬烷基、双环[4.2.1]壬烷基、双环[4.3.1]壬烷基、双环[3.2.2]壬烷基、双环[5.2.1]癸烷基、双环[4.2.2]癸烷基、螺环[2.2]戊烷基、螺环[2.3]己烷基、螺环[2.4]庚烷基、螺环[2.5]辛烷基、螺环[2.6]壬烷基、螺环[3.5]壬烷基、螺环[3.4]辛烷基、螺环[3.3]庚烷基、螺环[4.5]癸烷基、螺环[4.4]壬烷基等。环烷基可被一个或多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、环烯基、环炔基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 14杂芳基、C 3-C 12杂环基。
本发明所用术语“环烯”“环烯基”是指具有3至12个碳原子且至少含有一个C＝C双键的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性单价烃基，包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环烯基、螺[2.2]戊-1-烯基、螺[2.2]戊-1,4-二烯基、螺[2.3]己-1-烯基、螺[2.3]己-1,4-二烯基、螺[3.3]庚-1-烯基、螺[3.3]庚-1,5-二烯基、螺[3.4]辛-1-烯基、螺[3.4]辛-1,6-二烯基、螺[3.4]辛-5-烯基、螺[3.4]辛-6-烯基、螺[3.4]辛-1-烯基、双环[2.1.1]己-1-烯基、双环[2.1.1]己-2-烯基、双环[3.1.1]庚-1-烯基、双环[3.1.1]庚-2-烯基、双环[2.2.1]庚-1-烯基、双环[2.2.1]庚-2-烯基等。环烯、环烯基可被一个或多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、环烯基、环炔基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 12杂芳基、C 3-C 12杂环基。
本发明所用术语“环炔”“环炔基”是指具有4个至12个碳原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性烃基且至少含有一个三键，优选为环丁炔基、环戊炔基、环己炔基等，其中一个或两个碳原子可以由一个氧原子替代。该环炔基可以是无取代或取代的，其取代基选自D(氘)、氧代、卤素、氰基、硝基、羟基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、环烯基、环炔基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 12杂芳基、C 3-C 12杂环基。
本发明所用术语“卤素”是指氟、氯、溴和碘，优选氟、氯或溴。
本发明所用术语“烷氧基”是指烷基-O-，其中烷基如上所定义。本发明所用“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基等。“烷氧基”还包括取代烷氧基，其取代基可为D、卤素、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、磺酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“羟烷基”是指-烷基-OH，其中烷基如上所定义。本发明所用“羟烷基”的实例包括但不限于羟甲基、羟乙基、羟丙基、羟异丙基等。“羟烷基”还包括取代羟烷基，其取代基可为D、卤素、氧代、氨基、羟基、氰基、硝基、 羧基、酰胺基、磺酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“烷氨基”是指烷基-NH-，其中烷基如上所定义。本发明所用“烷氨基”的实例包括但不限于甲氨基、乙氨基、丙氨基、异丙氨基等。“烷氨基”还包括取代烷氨基，其取代基可为D、卤素、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、磺酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基，其取代基可以取代在烷基上也可以取代在N上。
本发明所用术语“胺烷基”是指NH 2-烷基-，其中烷基如上所定义。本发明所用“氨基烷基”的实例包括但不限于氨基甲基、氨基乙基、氨基丙基、氨基异丙基等。“氨基烷基”还包括取代氨基烷基，其取代基可为D、卤素、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、磺酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基，其取代基可以取代在烷基上也可以取代在N上。
本发明所用术语“环烷氧基”是指其中一个或多个碳原子被一个或多个氧原子取代的环烷基，其中环烷基如上所定义。本发明所用“烷氨基”的实例包括但不限于氧杂环丁烷、四氢呋喃、四氢吡喃、二恶烷等。
本发明所用术语“芳环”“芳基”是指具有6到12个碳原子的全碳单环或稠合多环的芳香性环基(稠和多环时其中一个稠合环可以部分饱和)，包括但不限于苯环、萘环、蒽环、茚环、二氢茚基(茚满基)、二氢萘环、四氢萘环等。芳基可以是无取代或取代的，可以是单取代(比如邻位、间位、对位取代)，也可以是双取代或者三取代等，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、卤素、氰基、硝基、羟基、氨基、氨基烷基、烯基、炔基、羧基、酰基、酰胺基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 14杂芳基、C 3-C 12杂环基。
本发明所用术语“杂芳环”“杂芳基”指具有5到14个环原子的单环或稠合多环的芳香性环基(稠和多环时其中一个稠合环可以部分饱和)，相当于上述“芳基”中一个或多个碳被杂原子例如N、O、S等置换。杂芳环可以是单环，也可以是双环，即通过两个环稠合而成。杂芳基包括但不限于吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、异恶唑基、异噻唑基、吡唑基、噻唑基、噻吩基、呋喃基、***基、恶唑基、咪唑基、吲唑基、吲嗪基、吲哚基、二氢吲哚基、异吲哚啉基、喹啉基、异喹啉基、喹喔啉基、喹唑啉基、二氢喹啉基、四氢喹啉基、二氢异喹 啉基、二氢异喹啉基、四氢异喹啉基、噌啉基、蝶啶基、嘌呤基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并***基、苯并三嗪基、苯并噁二唑基、苯并噁唑基、苯并异噁唑基、咪唑并吡啶基、咪唑并噻唑基、吡咯并吡啶基、噻吩并吡咯基、噻吩并噻吩基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、吡咯并吡咯基、吡咯并嘧啶基、吡咯并哒嗪基、吡咯并吡嗪基、咪唑并嘧啶基、咪唑并吡嗪基、咪唑并哒嗪基、吡唑并吡啶基、吡唑并哒嗪基、吡唑并吡嗪基、嘧啶并吡啶基、嘧啶并吡嗪基、嘧啶并哒嗪基、嘧啶并嘧啶基、吡啶并吡啶基、吡啶并吡嗪基、吡啶并哒嗪基、哒嗪并哒嗪基、哒嗪并吡嗪基、吡嗪并吡嗪基等。杂芳基可以是无取代或单取代或多取代的，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、卤素、氰基、硝基、氨基、氨基烷基、羟基、羧基、羧酸酯基、酰基、酰胺基、烷基酰胺基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“杂环基”是指具有3至12个环原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性环基，具有一个及以上选自N、O、S的杂原子，且可有一个或多个化学键为双键或三键。杂环基包括但不限于吡喃基、哌啶基、哌嗪基、吗啉基、二氧六环基、氧杂环丙基、氧杂环丁基、氧杂环己基、氧杂环庚基、氧杂环辛基、氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环庚基、氮杂环辛基、硫杂环丁烷基、硫杂环丙烷基、氮杂环辛烷基、氧氮杂
Figure PCTCN2022133404-appb-000024
基、二氮杂
Figure PCTCN2022133404-appb-000025
基、硫氮杂
Figure PCTCN2022133404-appb-000026
基、二氢呋喃基、二氢噻吩基、二氢吡喃基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢噻唑基、四氢咪唑基、六氢哒嗪基、六氢嘧啶基、1-氮杂螺[2.2]戊烷基、1-氮杂螺[2.3]己烷基、4-氮杂螺[2.3]己烷基、5-氮杂螺[2.3]己烷基、2-氮杂螺[3.3]庚烷基、2,6-二氮杂螺[3.3]庚烷基、2-氧杂-6-氮杂螺[3.3]庚烷、1-氮杂螺[2.5]辛烷基、2-氮杂螺[3.4]辛烷基、6-氮杂螺[3.4]辛烷基、2,6-二氮杂螺[3.4]辛烷基、2-氮杂螺[3.5]壬烷基、6-氮杂螺[3.5]壬烷基、7-氮杂螺[3.5]壬烷基、2,7-二氮杂螺[3.5]壬烷基、2-氧杂-7-氮杂螺[3.5]壬烷基、1-氮杂螺[4.4]壬烷基、2-氮杂螺[4.4]壬烷基、8-氮杂螺[4.5]癸烷基、2,8-二氮杂螺[4.5]癸烷基、1-氧杂螺[2.2]戊烷基、1-氧杂螺[2.3]己烷基、4-氧杂螺[2.3]己烷基、5-氧杂螺[2.3]己烷基、2-氧杂螺[3.3]庚烷基、1-氧杂螺[2.5]辛烷基、2-氧杂螺[3.4]辛烷基、6-氧杂螺[3.4]辛烷基、2-氧杂螺[3.5]壬烷基、6-氧杂螺[3.5]壬烷基、7-氧杂螺[3.5]壬烷基、1-氧杂螺[4.4]壬烷基、2-氧杂螺[4.4]壬烷基、8-氧杂螺[4.5]癸烷基、十氢喹啉基、十氢异喹啉基、2-氮杂双环[1.1.1]戊烷基、2-氧杂双环[1.1.1]戊烷基、氮杂双环[2.1.1]己烷基、氧杂双环[2.1.1]己烷基、氮杂双环[3.1.1]庚烷基、氧杂双环[3.1.1]庚烷基、氮杂双环[2.2.1]庚烷基、氮杂双环[4.1.1]辛烷基、氮杂双环[3.2.1]辛烷基、氮杂双环[3.2.1]辛烷基等。杂环基可被一个或 多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 14杂芳基、C 3-C 12杂环基。
本发明所用术语“螺环”、“螺环基”是指一种多环结构，在这种多环结构中至少有2个环存在共用一个原子(一般为C原子)的情况，在这种多环结构中可以有一个或多个化学键是双键或者三键，且可以有一个或多个杂原子存在。该螺环基可以是无取代或单取代或多取代的，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、环烯基、环炔基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 14杂芳基、C 3-C 12杂环基。
本发明所用术语“桥环基”是指一种多环结构，在这种多环结构中至少有2个环存在共用2个或2个以上原子的情况，在这种多环结构中可以有一个或多个化学键是双键或者三键，且可以有一个或多个杂原子存在。该桥环基可以是无取代或单取代或多取代的，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、环烯基、环炔基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 14杂芳基、C 3-C 12杂环基。
本发明所用术语“卤代烷基”是指其中一个或多个氢被一或多个卤素原子(优选为氟、氯、溴、碘)取代的直链或支链烷基，其中烷基如上所定义。本发明所用“卤代烷基”的实例包括但不限于氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、2-氟乙基、2,2,2-三氟乙基、2-氯乙基、四氟乙基、五氟乙基、1,1,1-三氟丙-2-基等。
本发明所用术语“卤代环烷基”是指其中一个或多个氢被一或多个卤素原子(优选为氟、氯、溴、碘)取代的环烷基，其中环烷基如上所定义。
本发明采用本领域技术人员所熟知的方法可以制备本发明所述化合物的盐。
“药学上可接受的盐”是指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸 形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、氢碘酸、硫酸、硝酸、磷酸、碳酸等无机酸，甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、对甲苯磺酸、乙磺酸、苯磺酸、樟脑磺酸、枸杞酸、异烟酸、水杨酸、抗坏血酸、龙胆酸、葡萄糖酸、丙酮酸、萘磺酸、硬脂酸、苯乙酸、对氨基苯磺酸、羟乙磺酸、双羟萘酸，丹宁酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的盐。适合形成盐的碱包括但并不限于：氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱，氨水、三乙胺、二乙胺、哌嗪、胍、二乙醇胺等有机碱。
本发明的第二个目的是提供一种药物组合物，包括上述任意一项技术方案所述的化合物中的一种或多种。本发明所述的药物组合物可以是上述任意一项技术方案所述的化合物中的一种或多种与其他化合物组成，或者上述任意一项技术方案所述的化合物中的一种或多种组成。
本发明提供了一种药物制剂，包含至少一种活性组分，所述活性组分是如上述任意一项技术方案所述的化合物中的一种或多种。所述药物制剂包含至少一种活性组分以及一种或多种药学上可接受的载体或赋形剂，所述的活性组分可以是本发明的BTK抑制剂化合物、所述化合物的光学异构体、所述化合物或其光学异构体在药学上可接受的盐、所述化合物或其光学异构体的溶剂合物中的任意一种或任意多种。
所述载体包括药学领域的常规稀释剂，赋形剂，填充剂，粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂等，必要时还可以加入香味剂，甜味剂等。
本发明药物可以制成片剂，粉剂，粒剂，胶囊，口服液及注射用药等多种形式，上述各剂型的药物均可以按照药学领域的常规方法制备。
另一方面，本发明提供的是使用本文公开的通式I～通式III所述的化合物及其光学异构体或其药学上可接受的盐或溶剂合物来抑制布鲁顿酪氨酸激酶(Btk)活性或者治疗从布鲁顿酪氨酸激酶(Btk)活性的抑制中获益的疾病、障碍或病症。
在进一步优选的方案中，本发明提供的是通过给予有需要的治疗者一种含有治疗有效量的至少一种化合物的组合物、从而抑制所述受治疗者的布鲁顿酪氨酸激酶活性的方法，其中所述化合物的结构式为通式I～通式III。在一些实施方式中，有需要的受治疗者罹患自身免疫性疾病，例如炎性肠病、关节炎、狼疮、类风湿性关节炎、银屑病性关节炎、骨关节炎、斯蒂尔病(Still’s disease)、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎(Hashimoto’s thyroiditis)、奥德甲状腺炎(Ord’s thyroiditis)、格雷夫斯氏病(Graves’disease)、类风湿性关节炎综合征(
Figure PCTCN2022133404-appb-000027
syndrome)、多发性硬化症、传染性神经元炎(Guillain-Barré syndrome)、急性播散性脑脊髓炎、阿狄森病(Addison’s disease)、视性眼阵挛-肌阵挛综合征、强制性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻 (coeliac disease)、古德帕斯彻综合征(Goodpasture’s syndrome)、免疫性血小板减少性紫癜(ITP)、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征(Reiter’s syndrome)、高安动脉炎(Takayasu’s arteritis)、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病(Wegener’s granulomatosis)、银屑病、全身脱毛、贝赫切特病(
Figure PCTCN2022133404-appb-000028
disease)、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病或外阴痛和慢性移植物抗宿主病(cGvHD)。
在进一步的实施方式中，有需要的受治疗者罹患癌症。在一个实施方式中，所述癌症是B细胞或浆细胞增生性疾病，例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症(
Figure PCTCN2022133404-appb-000029
macroglobulinemia)、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、***边缘区B细胞淋巴瘤、外套细胞淋巴瘤、纵膈(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)/白血病、多发性骨髓瘤或淋巴瘤样肉芽肿病。
本发明还提供本发明所述的化合物或其可药用盐在制备BTK抑制剂中的应用，特别是在制备治疗细胞增生疾病中的应用。所述的细胞增生疾病包括癌症。换言之，本发明还提供通式I～通式III所述的化合物、及其光学异构体或其药学上可接受的盐或溶剂合物单独或和其他药物联合使用在治疗增生类疾病(如癌症)中的应用。能和本发明所提供的化合物或其可药用盐联合使用的抗肿瘤药包括但并非限定至少一种以下种类：有丝***抑制剂(如长春碱、长春地辛和长春瑞宾)；微管蛋白分解抑制剂(如泰素))；烷基化试剂(如顺铂、卡铂和环磷酰胺)；抗代谢物(如5-氟尿嘧啶、替加氟、甲氨蝶呤、阿糖胞苷和羟基脲)；可***抗生素(如阿雷素、丝裂霉素和争光霉素))；酶(如天门冬氨酶)；拓朴异构酶抑制剂(如依托伯苷和喜树碱)；生物反应调节剂(如干扰素)；免疫检查点抑制剂(如PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂)；CD20单抗；BCL2抑制剂。
本发明发明人通过实验证实，本发明化合物对BTK具有降解活性。
本发明发明人通过实验证实，本发明化合物对Mino、OCI-LY10等肿瘤细胞株具有抗增殖抑制作用。
本发明发明人通过实验证实，本发明化合物在肝微粒中代谢稳定。
本发明发明人通过实验证实，本发明化合物可口服。
本发明发明人通过实验证实，本发明化合物在OCI-LY10体内药效模型中具有较好的抑制肿瘤生长的效果。
具体实施方式
中间体1：4-(4-((6-氨甲酰-3-(甲硫基)-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌啶-1-羧酸叔丁酯
Figure PCTCN2022133404-appb-000030
将5-氯-3-(甲硫基)-1,2,4-三嗪-6-羧酸乙酯(760mg，3.40mmol)溶于10mL乙腈中，向体系依次加入4-(4-氨基-2-氟苯基)哌啶-1-羧酸叔丁酯(1.0g，3.40mmol)，N,N-二异丙基乙胺(1.2mL，6.80mmol)，室温反应0.5h，再向体系加入氨的甲醇溶液(25mL，1mmol/mL)，室温反应0.5h。反应结束后，加水过滤，减压浓缩得到中间体1固体1.3g，收率：86％。ESI-MS(M+H) +＝463。
中间体2：4-(4-((6-氨基甲酰基-3-(甲硫基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-羧酸叔丁酯
Figure PCTCN2022133404-appb-000031
参考中间体1的合成路线和方法，把4-(4-氨基-2-氟苯基)哌啶-1-羧酸叔丁酯替换为4-(4-氨基苯基)哌啶-1-羧酸叔丁酯，合成得到中间体2。ESI-MS(M+H) +＝445。
中间体3：4-(4-((5-氨基甲酰基-2-(甲硫基)嘧啶-4-基)氨基)-2-氟苯基)哌啶-1-羧酸叔丁酯
Figure PCTCN2022133404-appb-000032
参考中间体1的合成路线和方法，把5-氯-3-(甲硫基)-1,2,4-三嗪-6-羧酸乙酯替换为4-氯-2-甲硫基嘧啶-5-羧酸乙酯，合成得到中间体3。ESI-MS(M+H) +＝462。
参考中间体1的合成路线和方法，合成得到如下中间体结构：
Figure PCTCN2022133404-appb-000033
Figure PCTCN2022133404-appb-000034
中间体16：5-((3-氟-4-(4-甲酰基哌啶-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺
Figure PCTCN2022133404-appb-000035
合成步骤1：1-(2-氟-4-硝基苯基)哌啶-4-甲醛(中间体16-1)
将4-甲酰哌啶-1-羧酸叔丁酯(7.3g，34.27mmol)溶于20mL DCM中，向体系中加入三氟乙酸(30mL)，室温搅拌一小时。反应结束，减压浓缩，得黄色液体哌啶-4-甲醛。将上述产物溶于50mL DMF中，向体系中依次加入碳酸铯(3.0g，9.21mmol)，2,4-二氟-1-硝基苯(5.5g，31.44mmol)，90℃反应2h。反应结束，加水淬灭，EA萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，得黄色液体1-(2-氟-4-硝基苯基)哌啶-4-甲醛7.5g，收率94％。ESI-MS(M+H) +＝253。
合成步骤2：4-(1,3-二氧戊环-2-基)-1-(2-氟-4-硝基苯基)哌啶(中间体16-2)
将中间体16-1(7.5g，29.64mmol)溶于50mL甲苯中，向体系中依次加入对甲苯磺酸(563mg，2.96mmol)，乙二醇(18mL，296.40mmol)，于120℃反应12h。反应结束。加水淬灭，减压浓缩，加水有固体析出，过滤，得棕黑色固体4-(1,3-二氧戊环-2-基)-1-(2-氟-4-硝基苯基)哌啶7g，收率80％。ESI-MS(M+H) +＝297。
合成步骤3：4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-3-氟苯胺(中间体16-3)
将中间体16-2(7g，23.64mmol)溶于70mL四氢呋喃中，向体系中依次加入氯化铵(13g，236.48mmol)，水(10mL)，铁粉(12g，236.48mmol)，于70℃反应12h。反应结束，EA萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析(乙酸乙酯/石油醚)得黄色固体4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-3-氟苯胺3.4g，收率54％。ESI-MS(M+H) +＝267。
合成步骤4：5-((4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-3-氟苯基)氨基)-3-(甲硫基)-1,2,4-三嗪-6-甲酰胺(中间体16-4)
将中间体16-3(1.5g，5.63mmol)溶于15mL乙腈中，向体系中依次加入DIPEA(1.81g，14.07mmol)、5-氯-3-(甲硫基)-1,2,4-三嗪-6-羧酸乙酯(1.3g，5.63mmol)，室温反应30min后，向其加入氨的甲醇溶液(7mol/L，15mL)，10min内体系变浑浊，于室温下继续反应2h。反应结束，减压浓缩，石油醚打浆，过滤，得黄色固体5-((4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-3-氟苯基)氨基)-3-(甲硫基)-1,2,4-三嗪-6-甲酰胺2.1g，收率83％。ESI-MS(M+H) +＝435。
合成步骤5：5-((4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(中间体16-5)
将中间体16-4(1g，2.00mmol)溶于10mL NMP中，向体系中加入mCPBA(85％，1.8g，10.00mmol)，于室温搅拌2h。待反应结束，向体系中依次加入DIPEA(1.1mL，6.00mmol)，哌啶(653mg，3.00mmol)，于80℃反应2h。反应结束，加水淬灭，EA萃取五次，合并有机相，用饱和氯化钠水溶液洗涤有机相2次，无水硫酸钠干燥，减压浓缩，所得粗产物经柱层析(二氯甲烷/甲醇洗 脱)得黄色固体5-((4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺690mg，收率73％。ESI-MS(M+H) +＝472。
合成步骤6：5-((3-氟-4-(4-甲酰基哌啶-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(中间体16)
将中间体16-5(690mg，1.46mmol)溶于3mL四氢呋喃中，向体系中加入3N HCl(7mL)，于80℃反应3h。反应结束，向体系中加入饱和碳酸氢钠水溶液调至碱性，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析(甲醇/二氯甲烷体系)得中间体16黄色固体380mg，收率57％。ESI-MS(M+H) +＝428。
参考中间体16的合成路线和方法，合成得到如下中间体结构：
Figure PCTCN2022133404-appb-000036
中间体23：4-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022133404-appb-000037
合成步骤1：3-((4-溴苯基)氨基)丙酸(中间体23-1)
将4-溴苯胺(5.00g，29.06mmol)溶于40mL甲苯中，向体系中加入丙烯酸(2.50g，34.87mmol)，于100℃反应12h。反应结束，加水淬灭，减压浓缩，经柱层析(PE/EA洗脱)可得黄色固体3-((4-溴苯基)氨基)丙酸2.8g，收率39％。ESI-MS:m/z＝244[M+H] +。
合成步骤2：1-(4-溴苯基)二氢嘧啶-2,4(1H，3H)-二酮(中间体23-2)
将中间体23-1(2.80g，11.52mmol)溶于30mL醋酸中，向体系加入尿素(1.40g，23.04mmol)，于120℃反应12h。反应结束，加水有固体析出，过滤得黄色固体，加DCM溶解，用无水硫酸钠干燥，减压浓缩，经柱层析(DCM/MeOH洗脱)可得固体1-(4-溴苯基)二氢嘧啶-2,4(1H，3H)-二酮1.1g，收率35％。ESI-MS:m/z＝269[M+H] +。
合成步骤3：4-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌嗪-1-羧酸叔丁酯(中间体23)
将中间体23-2(150mg，0.55mmol)溶于3mL 1,4-二氧六环溶液中，向体系中依次加入哌嗪-1-羧酸叔丁酯(156mg，0.83mmol)，叔丁醇钠(162mg，1.65mmol)，碳酸铯(536mg，1.65mmol)，醋酸钯(12mg，0.05mmol)，三(二亚苄基丙酮)二钯(45mg，0.05mmol)、X-phos(52mg，0.11mmol)，于90℃反应12h。反应结束，加水淬灭，用EA萃取3次，合并有机相，无水硫酸钠干燥，浓缩经柱层析(PE/EA洗脱)可得4-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)苯基)哌嗪-1-羧酸叔丁酯80mg，收率38％。ESI-MS:m/z＝375[M+H] +。
中间体24：1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-羧酸
Figure PCTCN2022133404-appb-000038
将2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(500mg，1.81mmol)溶于8mL DMSO中，向体系中依次加入吡咯烷-3-羧酸(312mg，2.72mmol)、DIPEA(701mg，5.43mmol)，于90℃反应12h。反应结束，加水，DCM萃取三次，合并有机相，饱和氯化铵水溶液洗涤有机相，无水硫酸钠干燥，减压浓缩，经柱层析得中间体24，550mg，收率81％。ESI-MS(M+H) +＝372。
中间体25：4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022133404-appb-000039
参考中间体24合成路线和方法，把吡咯烷-3-羧酸替换为哌嗪-1-羧酸叔丁酯，合成得到中间体25。ESI-MS(M+H) +＝443。
中间体26：4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022133404-appb-000040
参考中间体25的合成路线和方法，把2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮替换为2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮，合成得到中间体26。ESI-MS(M+H) +＝461。
中间体27：1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-氟苯基)哌啶-4-甲醛
Figure PCTCN2022133404-appb-000041
合成步骤1：5-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-硝基苯胺(中间体27-1)
将5-氟-2-硝基苯胺(1g，6.41mmol)溶于10mL DMF中，向体系中依次加入4-(1,3-二氧戊环-2-基)哌啶(1.2g，7.69mmol)，碳酸铯(6.2g，19.23mmol)，80℃反应3h。反应结束，加水淬灭，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得5-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-硝基苯胺1.5g，收率79％，ESI-MS(M+H) +＝294。
合成步骤2：4-(1,3-二氧戊环-2-基)-1-(3-氟-4-硝基苯基)哌啶(中间体27-2)
将中间体27-1(1.5g，5.11mmol)溶于15mL浓盐酸，在0℃向体系中加入HF(70％，30mL)，室温反应至反应完全溶解，在-78℃下向体系中加入NaNO 2(423mg，6.13mmol)，0℃反应30min后升温至60℃反应15-30min。反应结束，加水淬灭，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得4-(1,3-二氧戊环-2-基)-1-(3-氟-4-硝基苯基)哌啶1g，收率66％。ESI-MS(M+H) +＝297。
合成步骤3：4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-氟苯胺(中间体27-3)
将中间体27-2(1g，3.37mmol)溶于10mL四氢呋喃中，向体系中依次加入氯化铵(2g，33.78mmol)，水(10mL)，铁粉(1.9g，33.78mmol)，70℃反应12h。反应结束，用硅藻土过滤除去铁粉，滤液用DCM萃取三次，合并有机相，无水 硫酸钠干燥，减压浓缩，经柱层析(EA/PE洗脱)纯化得4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-氟苯胺750mg，收率83％。ESI-MS(M+H) +＝267。
合成步骤4：3-(4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-氟苯基)氨基)丙酸(中间体27-4)
将中间体27-3(750mg，2.81mmol)溶于10mL甲苯中，向体系中加入丙烯酸(243mg，3.38mmol)，100℃反应12h，反应结束。DCM萃取五次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得黄色液体3-(4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-氟苯基)氨基)丙酸860mg，收率90％。ESI-MS(M+H) +＝339。
合成步骤5：1-(4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-氟苯基)二氢嘧啶-2,4(1H，3H)-二酮(中间体27-5)
将中间体27-4(860mg，2.54mmol)溶于10mL醋酸中，向体系加入尿素(315mg，5.08mmol)，120℃反应12h。反应结束，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析(DCM/MeOH洗脱)得棕黄色固体1-(4-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-氟苯基)二氢嘧啶-2,4(1H，3H)-二酮540mg，收率58％。ESI-MS(M+H) +＝364。
合成步骤6：1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-氟苯基)哌啶-4-甲醛(中间体27)
将中间体27-5(540mg，1.68mmol)溶于6mL TFA中，80℃反应1h后向体系中加入浓盐酸0.5mL，80℃反应3h。反应结束，加饱和碳酸钠水溶液调至偏碱性，MeOH/DCM萃取五次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得到中间体27固体490mg，收率91％。ESI-MS(M+H) +＝320。
参考中间体27的合成路线和方法，合成得到如下中间体结构：
Figure PCTCN2022133404-appb-000042
Figure PCTCN2022133404-appb-000043
中间体33：N-(2,6-二氧代哌啶-3-基)-5-(4-甲酰基哌啶-1-基)吡啶甲酰胺
Figure PCTCN2022133404-appb-000044
合成步骤1：5-(4-(1，3-二氧戊环-2-基)哌啶-1-基)吡啶甲酸甲酯(中间体33-1)
将5-氟吡啶-2-甲酸甲酯(2.2g，14.18mmol)溶于20mL DMF中，向体系中加入4-(1，3-二氧戊环-2-基)哌啶(2.7g，17.02mmol)，碳酸钾(5.8g，42.54mmol)，90℃反应2h。反应结束，加水淬灭，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得黄色固体5-(4-(1，3-二氧戊环-2-基)哌啶-1-基)吡啶-2-甲酸甲酯3.2g，收率78％。ESI-MS(M+H) +＝293。
合成步骤2：5-(4-(1，3-二氧戊环-2-基)哌啶-1-基)吡啶甲酸(中间体33-2)
将中间体33-1(1.5g，5.13mmol)溶于20mL四氢呋喃中，向体系中加入氢氧化锂(615mg，25.67mmol)、水(7.5mL)，室温反应2h，反应结束，浓缩至无溶剂，DCM打浆，过滤，浓缩滤液得到白色固体5-(4-(1，3-二氧戊环-2-基)哌啶-1-基)吡啶-2-甲酸1.3g，收率93％。ESI-MS(M+H) +＝279。
合成步骤3：5-(4-(1，3-二氧戊环-2-基)哌啶-1-基)-N-(2，6-二氧代哌啶-3-基)吡啶甲酰胺(中间体33-3)
将中间体33-2(500mg，1.08mmol)溶于10mL DMF中，向体系中依次加入3-氨基哌啶-2，6-二酮(255mg，1.97mmol)、HATU(752mg，1.97mmol)、三乙胺(0.75mL，5.39mmol)，室温反应1h。反应结束，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析(DCM/MeOH洗脱)得灰色固体5-(4-(1，3-二氧戊环-2-基)哌啶-1-基)-N-(2，6-二氧代哌啶-3-基)吡啶甲酰胺350g，收率51％。ESI-MS(M+H) +＝389。
合成步骤4：N-(2,6-二氧代哌啶-3-基)-5-(4-甲酰基哌啶-1-基)吡啶甲酰胺(中间体33)
将中间体33-3(100mg，0.26mmol)溶于2mL TFA中，80℃反应1h后，向体系中加入1mL浓盐酸，80℃反应3h。反应结束，加饱和碳酸钠水溶液调节体系至偏碱性，DCM萃取五次，合并有机相，无水硫酸钠干燥，减压浓缩，得中间体33黄色固体75mg，收率84％。ESI-MS(M+H) +＝345。
参考中间体33的合成路线和方法，合成得到如下中间体结构：
Figure PCTCN2022133404-appb-000045
中间体36：1-(6-((2,6-二氧代哌啶-3-基)氨基)吡啶-3-基)哌啶-4-甲醛
Figure PCTCN2022133404-appb-000046
合成步骤1：5-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-硝基吡啶(中间体36-1)
将5-氟-2-硝基吡啶(1.5g，10.56mmol)溶于20mL DMF中，向体系中加入4-(1,3-二氧戊环-2-基)哌啶(1.8g，12.67mmol)，碳酸铯(10g，31.68mmol)，80℃反应2h。反应结束，加水淬灭，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得固体5-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-2-硝基吡啶2g，收率69％。ESI-MS(M+H) +＝280。
合成步骤2：5-(4-(1,3-二氧戊环-2-基)哌啶-1-基)吡啶-2-胺(中间体36-2)
将中间体36-1(2g，7.31mmol)溶于25mL四氢呋喃中，向体系中依次加入氯化铵(3.9g，73.12mmol)，水(5mL)，铁粉(4.1g，73.12mmol)，于70℃反应12h。反应结束，趁热过滤掉大量的铁粉，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得5-(4-(1,3-二氧戊环-2-基)哌啶-1-基)吡啶-2-胺1.6g，收率89％。ESI-MS(M+H) +＝250。
合成步骤3：3-((5-(4-(1,3-二氧戊环-2-基)哌啶-1-基)吡啶-2-基)氨基)哌啶-2,6-二酮(中间体36-3)
将中间体36-2(1.6g，6.49mmol)溶于20mL DMF中，向体系中依次加入3-溴哌啶-2,6-二酮(1.9g，9.74mmol)，Pd(dppf)Cl 2(472mg，0.65mmol)，Na 2CO 3(2.1g，19.47mmol)，于100℃反应3h。反应结束，加水淬灭，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得3-((5-(4-(1,3-二氧戊环-2-基)哌啶-1-基)吡啶-2-基)氨基)哌啶-2,6-二酮1.9g，收率82％。ESI-MS(M+H) +＝361。
合成步骤4：1-(6-((2,6-二氧代哌啶-3-基)氨基)吡啶-3-基)哌啶-4-甲醛(中间体36)
将中间体36-3(1.9g，5.35mmol)溶于10mL TFA中，80℃反应1h。然后向体系中加入浓盐酸2mL，80℃反应3h。反应结束，加饱和碳酸钠水溶液调至偏碱性，DCM萃取五次，合并有机相，无水硫酸钠干燥，减压浓缩得到中间体36 固体1.4g，收率83％。ESI-MS(M+H) +＝317。
参考中间体36的合成路线和方法，合成得到如下中间体结构：
Figure PCTCN2022133404-appb-000047
中间体39：1-(5-(6-氧-1,6-二氢哒嗪-3-基)-3-(三氟甲基)吡啶-2-基)哌啶-4-甲醛
Figure PCTCN2022133404-appb-000048
合成步骤1：(6-氯-5-(三氟甲基)吡啶-3-基)硼酸(中间体39-1)
将5-溴-2-氯-3-(三氟甲基)吡啶(5g，19.20mmol)溶于50mL 1,4-二氧六环中，向体系中依次加入联硼酸频那醇酯(4.8g，19.20mmol)、醋酸钾(4.7g，48.12mmol)、Pd(dppf)Cl 2(1.39g，1.92mmol)，氩气氛围下于100℃反应6h，反应结束。DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，得(6-氯-5-(三氟甲基)吡啶-3-基)硼酸4g，收率92％，ESI-MS(M+H) +＝226。
合成步骤2：3-氯-6-(6-氯-5-(三氟甲基)吡啶-3-基)哒嗪(中间体39-2)
将中间体39-1(2g，8.88mmol)溶于20mL乙腈中，向体系中依次加入3,6-二氯哒嗪(1.7g，11.54mmol)、碳酸钾(3.4g，26.64mmol)、水(2mL)、PdCl 2(pph 3) 2(616mg，0.88mmol)，于80℃反应4h。反应结束后，减压浓缩，得3-氯-6-(6-氯-5-(三氟甲基)吡啶-3-基)哒嗪700mg，收率26％，ESI-MS(M+H) +＝294。
合成步骤3：6-(6-氯-5-(三氟甲基)吡啶-3-基)哒嗪-3-醇(中间体39-3)
将中间体39-2(700mg，2.38mmol)溶于9mL 1,4-二氧六环中，向体系中加入3M HCl，于110℃反应4h，反应结束。DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，得6-(6-氯-5-(三氟甲基)吡啶-3-基)哒嗪-3-醇440mg，收率67％，ESI-MS(M+H) +＝276。
合成步骤4：6-(6-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-5-(三氟甲基)吡啶-3-基)哒嗪-3(2H)-酮(中间体39-4)
将中间体39-3(440mg，1.60mmol)溶于5mL DMF中，向体系中加入4-(1,3-二氧戊环-2-基)哌啶(376mg，2.40mmol)、碳酸铯(1.5g，4.80mmol)，于120℃反应12h，反应结束。加水淬灭，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，得6-(6-(4-(1,3-二氧戊环-2-基)哌啶-1-基)-5-(三氟甲基)吡啶-3-基) 哒嗪-3(2H)-酮344mg，收率54％，ESI-MS(M+H) +＝397。
合成步骤5：1-(5-(6-氧-1,6-二氢哒嗪-3-基)-3-(三氟甲基)吡啶-2-基)哌啶-4-甲醛(中间体39)
将中间体39-4(140mg，0.35mmol)溶于2mL TFA中，于80℃反应1h后，向体系中加入浓盐酸0.1mL，继续80℃反应1h，反应结束。加饱和碳酸钠水溶液调至中性或偏碱性，DCM萃取五次，合并有机相，无水硫酸钠干燥，减压浓缩，得1-(5-(6-氧代-1,6-二氢哒嗪-3-基)-3-(三氟甲基)吡啶-2-基)哌啶-4-甲醛100mg，收率81％。ESI-MS(M+H) +＝353。
参考中间体39的合成路线和方法，合成得到如下中间体结构：
Figure PCTCN2022133404-appb-000049
实施例41：4-(5-(2,6-二氧代哌啶-3-基)吡啶-2-基)哌嗪-1-羧酸叔丁酯
Figure PCTCN2022133404-appb-000050
合成步骤1：(6-(4-(叔丁氧羰基)哌嗪-1-基)吡啶-3-基)硼酸(中间体40-1)
将4-(5-溴吡啶-2-基)哌嗪-1-甲酸叔丁酯(1.4g，4.09mmol)溶于15mL 1,4-二氧六环中，向体系中依次加入联硼酸频那醇酯(1.0g，4.09mmol)，醋酸钾(1.2g，12.27mmol)、Pd(dppf)Cl 2(232mg，0.32mmol)，氩气氛围下于100℃反应6h，反应结束。过滤后滤液加水，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得(6-(4-(叔丁氧羰基)哌嗪-1-基)吡啶-3-基)硼酸1.0g，收率79％。ESI-MS(M+H) +＝308。
合成步骤2：4-(2'，6'-双(苄氧基)-[3,3'-联吡啶]-6-基)哌嗪-1-羧酸叔丁酯(中间体40-2)
将中间体40-1(950mg，3.09mmol)溶于15mL 1,4-二氧六环中，向体系中依次加入2,6-双(苄氧基)-3-溴吡啶(2.29g，6.19mmol)，醋酸铯(3.0g，9.28mmol)，Pd(dppf)Cl 2(224mg，0.30mmol)，氩气氛围下于100℃反应12h，反应结束。过滤后滤液加水，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析得4-(2'，6'-双(苄氧基)-[3,3'-联吡啶]-6-基)哌嗪-1-羧酸叔丁酯1.2g，收率70％。ESI-MS(M+H) +＝553。
合成步骤3：4-(5-(2,6-二氧代哌啶-3-基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(中间体40)
将中间体40-2(1.0g，1.81mmol)溶于20mL甲醇中，向体系中依次加入Pd/C(400mg)，氢气环境下室温反应24h。反应结束后，过滤，减压浓缩，经柱层析得4-(5-(2,6-二氧代哌啶-3-基)吡啶-2-基)哌嗪-1-羧酸叔丁酯320mg，收率47％，ESI-MS(M+H) +＝375。
参考中间体41的合成路线和方法，合成得到如下中间体结构：
Figure PCTCN2022133404-appb-000051
实施例1：5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(002)
Figure PCTCN2022133404-appb-000052
合成步骤1：4-(4-((6-氨基甲酰基-3-羟基-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌啶-1-羧酸叔丁酯(002-1)
将中间体1(1.3g，2.81mmol)溶于20mL NMP中，向体系中加入mCPBA(85％，5.0g，28.93mmol)，于室温搅拌2h，然后向体系中依次加入DIPEA(4.5g，34.82mmol)，水(10mL)，继续室温反应2h。反应结束，加水25mL，过滤，滤饼经柱层析(二氯甲烷/甲醇洗脱)得橙黄色固体4-(4-((6-氨基甲酰基-3-羟基-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌啶-1-羧酸叔丁酯350mg，收率30％。ESI-MS(M+H) +＝433。
合成步骤2：3-((4-(4-((6-氨基甲酰基-3-羟基-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌啶-1-基)甲基)吡咯烷-1-羧酸叔丁酯(002-2)
将002-1(350mg，0.81mmol)溶于5mL DCM中，向体系中加入三氟乙酸(3mL)，于室温下搅拌1h。反应结束，减压浓缩，得黄色液体。将上述产物溶于10mL DCM中，依次加入DIPEA(314mg，2.43mmol)、3-甲酰基吡咯烷-1-羧酸叔丁酯(323mg，1.62mmol)，室温搅拌10min，向体系加入醋酸(0.5mL)，氰基硼氢化钠(101mg，1.62mmol)，继续室温反应1h。反应结束，加饱和碳酸氢钠水溶液淬灭，DCM萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析(DCM/MeOH洗脱)得黄色固体3-((4-(4-((6-氨基甲酰基-3-羟基-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌啶-1-基)甲基)吡咯烷-1-羧酸叔丁酯210mg，收率：50％。ESI-MS(M+H) +＝516。
合成步骤3：5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯 烷-3-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-3-羟基-1,2,4-三嗪-6-甲酰胺(002-3)
将002-2(210mg，0.41mmol)溶于5mL DCM中，向体系加入三氟乙酸(2mL)，室温搅拌1h。反应结束，减压浓缩，得黄色液体。将上述产物溶于5mL DMSO中，向体系依次加入DIPEA(1.48g，11.44mmol)，2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(280mg，1.02mmol)，于95℃反应12h。反应结束，加水有固体析出，过滤得黄色固体，加DCM溶解，无水硫酸钠干燥，减压浓缩。经柱层析(DCM/MeOH洗脱)得黄色固体5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-3-羟基-1,2,4-三嗪-6-甲酰胺200mg，收率：73％。ESI-MS(M+H) +＝672。
合成步骤4：3-氯-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-1,2,4-三嗪-6-甲酰胺(002-4)
将002-3(200mg，0.29mmol)溶于10mL 1,4-二氧六环中，向体系依次加入N,N-二异丙基乙胺(1.5g，11.50mmol)，三氯氧磷(2mL)，于105℃反应0.2h。反应结束后，缓慢倒入20mL水中，加碳酸氢钠调节至pH值大于7，过滤，滤饼即粗产物3-氯-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-1,2,4-三嗪-6-甲酰胺200mg，收率：99％。ESI-MS(M+H) +＝690。
合成步骤5：5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(002)
将002-4(100mg，0.14mmol)溶于3mL DMF，向体系依次加入哌啶(18mg，0.20mmol)，N,N-二异丙基乙胺(40mg，0.31mmol)，于75℃反应0.5h。反应结束后，加水至体系不再有黄色固体析出止，固体经柱层析后得到化合物002固体54mg，收率：53％。ESI-MS(M+H) +＝739。 1H-NMR(400MHz,CCl 3D)δ11.00(brs,1H),8.20(brs,1H),7.57-7.72(m,3H),7.22-7.23(m,2H),6.96-6.97(m,1H),6.68-6.71(m,1H),5.45(brs,1H),4.92-4.96(m,1H),3.70-4.01(m,4H),3.40-3.61(m,3H),3.17-3.22(m,1H),2.60-3.19(m,6H),2.41-2.48(m,2H),2.08-2.25(m,3H),1.73-1.89(m,10H),1.25-1.29(m,3H).
实施例2：5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(001)
Figure PCTCN2022133404-appb-000053
参考实施例1的合成路线和方法，把合成步骤1中的中间体1替换为中间体2，合成得到目标化合物001，ESI-MS(M+H) +＝721。 1H-NMR(400MHz,CCl 3D)δ10.89(brs,1H),8.02(brs,1H),7.60-7.71(m,4H),7.23-7.25(m,2H),6.97-6.98(m,1H),6.68-6.71(m,1H),5.36-5.38(m,1H),4.91-4.96(m,1H),3.77-4.02(m, 4H),3.38-3.62(m,3H),3.19-3.24(m,1H),2.94-3.08(m,2H),2.64-2.92(m,4H),2.41-2.51(m,3H),2.00-2.23(m,7H),1.71-1.86(m,8H).
实施例3：5-((4-(4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(003)
Figure PCTCN2022133404-appb-000054
参考实施例1的合成路线和方法，把合成步骤1中的中间体1替换为中间体4，合成得到目标化合物003，ESI-MS(M+H) +＝740。 1H-NMR(400MHz,CDCl 3)δ10.88(brs,1H),8.37(s,1H),7.60-7.71(m,3H),7.18-7.22(m,1H),6.92-6.96(m,2H),6.68-6.70(m,1H),5.53(brs,1H),4.91-4.96(m,1H),3.38-3.91(m,6H),3.09-3.23(m,5H),2.61-2.91(m,6H),2.40-2.53(m,2H),1.99-2.26(m,2H),1.68-1.89(m,7H),1.24-1.33(m,3H).
实施例4：5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-4-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(007)
Figure PCTCN2022133404-appb-000055
参考实施例1的合成路线和方法，把合成步骤2中的3-甲酰基吡咯烷-1-羧酸叔丁酯替换为4-甲酰基哌啶-1-羧酸叔丁酯，合成得到目标化合物007，ESI-MS(M+H) +＝753。 1H-NMR(400MHz,CDCl 3)δ11.00(brs,1H),8.34(s,1H),7.60-7.72(m,3H),7.28-7.29(m,1H),7.20-7.23(m,2H),7.03-7.05(m,1H),5.51(brs,1H),4.92-4.96(m,1H),3.94-3.96(m,4H),2.77-3.01(m,9H),1.91-2.27(m,6H),1.68-1.81(m,11H),1.28-1.35(m,4H).
实施例5：5-((4-(1-((1-(1-(2,6-二氧代哌啶-3-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(011)
Figure PCTCN2022133404-appb-000056
参考实施例1的合成路线和方法，把合成步骤3中的2-(2,6-二氧哌啶-3-基)-5-氟异吲哚啉-1,3-二酮替换为3-(5-氟-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-1-基) 哌啶-2,6-二酮，合成得到目标化合物011，ESI-MS(M+H) +＝722。
实施例6：3-((R)-3-乙酰氨基哌啶-1-基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺(016)
Figure PCTCN2022133404-appb-000057
合成步骤1：(R)-3-乙酰氨基哌啶-1-羧酸叔丁酯(016-1)
将(R)-3-氨基哌啶-1-羧酸叔丁酯(100mg，0.50mmol)溶于3mL DCM中，向体系中依次加入乙酸酐(76mg，0.75mmol)，三乙胺(86mg，0.85mmol)，于室温反应0.5h。反应结束，DCM萃取，合并有机相，饱和碳酸氢钠水溶液洗涤，饱和氯化铵水溶液洗涤，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，减压浓缩，得无色液体(R)-3-乙酰氨基哌啶-1-羧酸叔丁酯110mg，收率90％。ESI-MS(M+H) +＝243。
合成步骤2：3-氯-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺(016-2)
参考实施例1合成步骤1-4的合成路线和方法，把合成步骤1中的中间体1替换为中间体2，合成得到3-氯-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺，ESI-MS(M+H) +＝672。
合成步骤3：3-((R)-3-乙酰氨基哌啶-1-基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺(016)
将016-1溶于5mL DCM中，向体系中加入三氟乙酸(1mL)，室温反应1h，减压浓缩，得无色液体(R)-N-(哌啶-3-基)乙酰胺，直接用于下一步反应。将016-2(50mg，0.07mmol)溶于3mL DMF，向体系依次加入(R)-N-(哌啶-3-基)乙酰胺(50mg，0.21mmol)，N,N-二异丙基乙胺(40mg，0.31mmol)，于室温反应0.5h。反应结束后，加水至体系不再有黄色固体析出止，固体经柱层析后得到化合物016固体35mg，收率：60％。ESI-MS(M+H) +＝778。 1H-NMR(400MHz,CCl 3D)δ10.95(brs,1H),8.37(brs,1H),7.73(brs,1H),7.58-7.66(m,3H),7.24-7.27(m,2H),6.96-6.97(m,1H),6.68-6.70(m,1H),5.71-5.73(m,1H),5.57(brs,1H),4.92-4.96(m,1H),3.78-4.13(m,4H),3.38-3.61(m,3H),2.63-3.23(m,6H),2.38-2.51(m,3H),2.03-2.23(m,4H),1.93(s,3H),1.77-1.85(m,8H),1.27-1.31(m,3H).
实施例7：3-((R)-3-氨基哌啶-1-基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺(029)
Figure PCTCN2022133404-appb-000058
将016-2(145mg，0.22mmol)溶于5mL DCM，向体系依次加入(R)-哌啶-3-基氨基甲酸叔丁酯(65mg，0.32mmol)，N,N-二异丙基乙胺(40mg，0.31mmol)，于室温反应0.5h。反应结束后，加水淬灭，DCM萃取，饱和氯化铵水溶液洗涤，浓缩后经柱层析后得到纯化固体。将上述固体溶于3mL DCM，滴加氯化氢的1,4-二氧六环溶液(0.3mL，4.0mol/L)，室温搅拌0.5h。反应结束，减压浓缩，得到化合物029黄色固体35mg，收率97％。ESI-MS(M+H) +＝736。 1H-NMR(400MHz,DMSO-d6)δ11.52(brs,1H),11.07(brs,1H),8.31-8.39(m,3H),7.85(s,1H),7.65-7.70(m,3H),7.32-7.33(m,2H),6.95(s,1H),6.83-6.85(m,1H),5.03-5.08(m,1H),3.78-3.82(m,1H),3.60-3.68(m,4H),3.05-3.24(m,6H),2.83-2.92(m,3H),2.54-2.63(m,2H),2.16-2.32(m,2H),1.62-2.02(m,10H),1.23-1.27(m,3H).
参考实施例1-7的合成路线和方法，合成得到如下目标化合物：
Figure PCTCN2022133404-appb-000059
Figure PCTCN2022133404-appb-000060
Figure PCTCN2022133404-appb-000061
Figure PCTCN2022133404-appb-000062
Figure PCTCN2022133404-appb-000063
实施例39：5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯 烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(噻唑-2-基)-1,2,4-三嗪-6-甲酰胺(024)
Figure PCTCN2022133404-appb-000064
将016-2(50mg，0.07mmol)、2-(三丁基锡酰基)噻唑(45mg，0.12mmol)、碳酸钠(22mg，0.21mmol)、四(三苯基膦)钯(0)(25mg)和1,4-二氧六环溶液(1mL)的混合物置于50℃下搅拌过夜反应。反应结束，加水和DCM萃取，分离有机相，无水硫酸镁干燥，过滤浓缩，经柱层析纯化得到化合物024固体21mg，收率：43％。ESI-MS(M+H) +＝721。
参考实施例39的合成路线和方法，合成得到如下目标化合物：
Figure PCTCN2022133404-appb-000065
实施例42：5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-3-(3-羟基苯氧基)-1,2,4-三嗪-6-甲酰胺(027)
Figure PCTCN2022133404-appb-000066
将016-2(50mg，0.07mmol)溶于2mL DMSO中，向体系中依次加入间苯二酚(13mg，0.12mmol)、碳酸铯(39mg，0.12mmol)，于50℃反应3h。反应结束，加水和DCM萃取，分离有机相，无水硫酸镁干燥，过滤浓缩，经柱层析纯化得化合物027固体37mg，收率：70％。ESI-MS(M+H) +＝746。
实施例43：3-(2,3-二氟苯氧基)-5-((4-(1-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-基)甲基)哌啶-4-基)苯基)氨基)-1,2,4-三嗪-6-甲酰胺(028)
Figure PCTCN2022133404-appb-000067
参考实施例42的合成方法和路线，把间苯二酚替换为2,3-二氟苯酚，可合成得到化合物028，ESI-MS(M+H) +＝766。
实施例44：5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(075)
Figure PCTCN2022133404-appb-000068
合成步骤1：4-(4-((6-氨基甲酰基-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌嗪-1-羧酸叔丁酯(075-1)
将中间体4(1.6g，3.45mmol)溶于25mL NMP中，向体系中加入mCPBA(85％，2.9g，17.25mmol)，于室温搅拌2h。反应结束，向体系依次加入DIPEA(1.3g，10.35mmol)，哌啶(439mg，5.17mmol)，于80℃反应2h。反应结束，加水有固体析出，过滤得黄色固体，加DCM溶解，无水硫酸钠干燥，减压浓缩。经柱层析(DCM/MeOH洗脱)得黄色固体4-(4-((6-氨基甲酰基-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)-2-氟苯基)哌嗪-1-羧酸叔丁酯1.7g，收率98％。ESI-MS(M+H) +＝501.5。
合成步骤2：5-((4-(4-((1-(4-(2,4-二氧代四氢嘧啶-1(2H)-基)-3-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(075)
将075-1(100mg，0.25mmol)溶于3mL DCM中，向体系中加入1.5mL三氟乙酸，室温反应30min。反应结束，减压浓缩得5-((3-氟-4-(哌嗪-1-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺。将所得产物溶于2mL DCM中，向体系中加入中间体29(118mg，0.37mmol)，室温搅拌10min，向体系加入醋酸(0.1mL)，氰基硼氢化钠(47mg，0.75mmol)，室温反应0.5h。反应结束，加水淬灭，DCM萃取，合并有机相，无水硫酸钠干燥，减压浓缩。经柱层析(DCM/MeOH洗脱)得化合物075黄色固体50mg，收率28％。，ESI-MS(M+H) +＝700。 1H-NMR(400MHz,DMSO-d 6)δ11.30(brs,1H),10.25(s,1H),8.35(s,1H),7.62-7.72(m,2H),7.25-7.28(m,1H),7.01-7.06(m,2H),6.76-6.80(m,2H),3.62-3.83(m,7H),3.32-3.48(m,1H),2.98-3.00(m,4H),2.62-2.71(m,4H),2.49-2.52(m,4H),2.20-2.22(m,2H),2.11(s,3H),1.77-1.81(m,2H),1.59-1.67(m,6H),1.16-1.23(m,3H).
实施例45：5-((4-(4-((1-(6-((2,6-二氧代哌啶-3-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(077)
Figure PCTCN2022133404-appb-000069
参考实施例44的合成路线和方法，把合成步骤2中的中间体29替换为中间体36，合成得到目标化合物077，ESI-MS(M+H) +＝701。 1H-NMR(400MHz,DMSO-d 6)δ11.30(brs,1H),10.73(s,1H),8.35(s,1H),7.61-7.72(m,3H),7.19-7.28(m,2H),7.01-7.04(m,1H),6.51-6.53(m,1H),6.37-6.39(m,1H),4.60-4.66(m,1H),3.79-3.83(m,4H),3.34-3.36(m,3H),2.97-3.00(m,4H),2.68-2.77(m,1H),2.51-2.54(m,3H),2.20-2.22(m,2H),1.93-2.10(m,3H),1.75-1.81(m,2H),1.58-1.67(m,6H),1.22-1.26(m,5H).
实施例46：5-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-3-氟苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(044)
Figure PCTCN2022133404-appb-000070
参考实施例44合成步骤2的合成路线和方法，把075-1替换为中间体16，把中间体29替换为中间体25，合成得到化合物044黄色固体40mg，收率15％。ESI-MS(M+H) +＝754。 1H-NMR(400MHz,CCl 3D)δ10.85(brs,1H),8.04(brs,1H),7.69-7.70(m,2H),7.60-7.65(m,1H),7.28-7.29(m,1H),7.16-7.19(m,1H),7.05-7.08(m,1H),6.92-6.96(m,1H),5.38(brs,1H),4.92-4.97(m,1H),3.41-3.47(m,6H),2.59-2.92(m,9H),2.29-2.31(m,2H),2.11-2.17(m,3H),1.87-2.01(m,2H),1.65-1.74(m,8H),1.29-1.46(m,3H).
参考实施例44-46的合成路线和方法，合成得到如下目标化合物：
Figure PCTCN2022133404-appb-000071
Figure PCTCN2022133404-appb-000072
Figure PCTCN2022133404-appb-000073
Figure PCTCN2022133404-appb-000074
Figure PCTCN2022133404-appb-000075
Figure PCTCN2022133404-appb-000076
Figure PCTCN2022133404-appb-000077
实施例87：5-((4-(1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-羰基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(055)
Figure PCTCN2022133404-appb-000078
合成步骤1：4-(4-((6-氨基甲酰基-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-羧酸叔丁酯(055-1)
参考实施例44合成步骤1的合成路线和方法，把中间体4替换为中间体2，合成得到4-(4-((6-氨基甲酰基-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-羧酸叔丁酯。ESI-MS(M+H) +＝482。
合成步骤2：5-((4-(1-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)吡咯烷-3-羰基)哌啶-4-基)苯基)氨基)-3-(哌啶-1-基)-1,2,4-三嗪-6-甲酰胺(055)
将055-1溶于3mL DCM中，向体系中加入1.5mL三氟乙酸，室温反应30min。反应结束，将所得产物(102mg，0.27mmol)溶于5mL DMF中，向体系中依次加入中间体24(100mg，0.27mmol)、HATU(112mg，0.29mmol)、TEA(81mg，0.80mmol)，于30℃反应2h，反应结束。加水淬灭，DCM萃取三次，合并有机相，饱和氯化铵水溶液洗涤有机相，无水硫酸钠干燥，减压浓缩，经柱层析得到化合物055固体60mg，收率30％，ESI-MS(M+H) +＝735。
参考实施例87的合成路线和方法，合成得到如下化合物：
Figure PCTCN2022133404-appb-000079
Figure PCTCN2022133404-appb-000080
实施例94：(3-(5-(3-((4-(4-((6-氨基甲酰基-3-(哌啶-1-基)-1,2,4-三嗪-5-基)氨基)苯基)哌啶-1-基)甲基)吡咯烷-1-基)-1,3-二氧代异吲哚啉-2-基)-2,6-二氧代哌啶-1-基)新戊酸甲酯(062)
Figure PCTCN2022133404-appb-000081
将化合物001(100mg，0.12mmol)溶于2mL DMF中，向体系中依次加入碳酸铯(46mg，0.14mmol)、新戊酸氯甲基酯(18mg，0.12mmol)，于室温反应12h。反应结束，加水淬灭，EA萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，得化合物062黄色固体30mg，收率：26％。ESI-MS(M+H) +＝835。 1H-NMR(400MHz,CDCl 3)δ10.89(brs,1H),7.60-7.70(m,4H),7.23-7.24(m,2H),6.96-6.97(m,1H),6.68-6.71(m,1H),5.79-5.84(m,2H),5.40(brs,1H),4.97-5.01(m,1H),3.86-3.95(m,4H),3.44-3.61(m,2H),3.19-3.23(m,1H),2.99-3.03(m,2H),2.79-2.86(m,2H),2.44-2.51(m,3H),2.03-2.24(m,5H),1.70-1.85(m,10H),1.25-1.32(m,3H),1.18(s,9H).
参考实施例94的合成路线和方法，合成得到如下目标化合物：
Figure PCTCN2022133404-appb-000082
Figure PCTCN2022133404-appb-000083
Figure PCTCN2022133404-appb-000084
实施例106.BTK降解活性测试
Mino细胞系细胞50～100万/孔种于6孔板中。化合物稀释到不同浓度，加入到板中，孵育24-72小时后，收取细胞。裂解细胞后，用BCA试剂盒测定各孔总蛋白浓度。使用Westernblot或Elisa法测定BTK的量。
表1化合物的BTK降解活性结果
化合物编号 DC 50 化合物编号 DC 50 化合物编号 DC 50
001 A 002 A 003 A
004 A 005 A 006 A
007 A 008 A 009 A
010 A 011 A 012 A
013 A 014 A 015 A
016 A 017 A 018 A
019 A 020 A 021 A
022 A 023 A 024 A
025 A 026 A 027 A
028 A 029 A 030 A
031 A 032 A 033 A
034 A 035 A 036 A
037 A 038 A 039 A
040 A 041 A 042 A
043 A 044 A 045 A
046 A 047 A 048 A
049 A 050 A 051 A
052 A 053 A 054 A
055 A 056 A 057 A
058 A 059 A 060 A
061 A 062 A 063 A
064 A 065 A 066 A
067 A 068 A 069 A
070 A 071 A 072 A
073 A 074 A 075 A
076 A 077 A 078 A
079 A 080 A 081 A
082 A 083 A 084 A
085 A 086 A 087 A
088 A 089 A 090 A
091 A 092 A 093 A
094 A 095 A 096 A
097 A 098 A 099 A
100 A 101 A 102 A
103 A 104 A 化合物a A
化合物b A        
注A:DC 50<10nM
化合物a来自专利WO2021113557A1中的Compound 149；
化合物b来自专利WO2021113557A1中的Compound 44；
本发明的化合物对BTK具有降解作用。
实施例107.肿瘤细胞增殖抑制活性测试
通过测定化合物对OCI-LY10和Mino细胞增殖的抑制作用，检测化合物对抗肿瘤药效。OCI-LY10和Mino细胞培养于含10％胎牛血清的RPMI-1640培养基中。消化细胞，将细胞按OCI-LY10和Mino 10000/孔；的细胞浓度接种于96孔板，37℃，5％CO 2孵育过夜。96孔板中加入不同浓度(1000nM,4倍稀释，8个点)的化合物于37℃，5％CO 2孵育72小时或7day后每孔加入20uL MTS。孵育2h后，每孔加入25μl10％SDS终止反应。用酶标仪测量490nm和650nm处的吸收。用GraphPad Prism 5.0计算IC 50。
表2本发明化合物对Mino肿瘤细胞增殖抑制活性
化合物编号 Mino IC 50(nM) 化合物编号 Mino IC 50(nM)
001 5.50 044 3.46
004 1.15 045 3.91
005 2.47 050 6.05
007 5.31 075 1.42
011 4.20 082 2.30
012 1.22 084 3.30
013 3.37 087 4.31
014 4.14 090 1.94
016 1.45 092 3.28
019 2.13 098 3.11
023 6.75 100 3.83
033 9.10 化合物a 10.56
表3本发明化合物对OCI-ly10肿瘤细胞增殖抑制活性
化合物编号 OCI-ly10IC 50(nM) 化合物编号 OCI-ly10IC 50(nM)
001 3.00 077 1.59
004 0.18 078 0.70
005 0.41 079 1.15
014 0.67 082 0.64
016 0.32 083 1.24
019 1.10 085 0.57
023 0.69 086 0.70
048 0.61 088 0.66
052 1.39 090 0.89
053 1.73 092 0.24
075 0.51 100 0.39
076 1.09 化合物a 10.96
表2和表3表明，本发明的化合物对肿瘤细胞具有明显增殖抑制活性。
实施例108.肝微粒体代谢稳定性
在冰浴下，将人、小鼠肝微粒1mg加入到PBS(1mL)缓冲液，再加入NADPH(20μL)，在37℃下孵育5min，加入待测试化合物10μL，用移液枪吸打多次，分成3份，每份330μL。然后分别在0，15、30、60、120min取点。每次用移液枪取出10μL溶液加入到490μL含有内标化合物的溶液中，涡旋后置于冰上，后继续另一个时间点的取样。所有样品在10000rpm下离心10min，取上清液进行LC/MS测试，通过峰面积计算化合物在肝微粒体中的代谢情况。
表4化合物对肝微粒代谢稳定性的测试
Figure PCTCN2022133404-appb-000085
由表4可知：本发明的化合物具有较好的代谢稳定性。
实施例109.小鼠吸收试验
实验方法：以小鼠为实验动物，灌胃给药10mg/kg(5％DMSO+5％Solutol+90％生理盐水)。灌胃给药的取血时间点为0.25、0.5、1、2、4、6、8、24h小时。取全血0.3ml，离心后取血浆0.1ml采用LC-MS进行分析。
表5本发明化合物的小鼠吸收结果
编号 DNAUC
001 2300
002 2223
003 1648
007 1955
044 1941
045 1686
046 1867
化合物b 1088
注：DNAUC表示AUC(h*ng/mL)/剂量(mg/kg)。
由表5可知，本发明的化合物在小鼠中具有较好的口服吸收。
实施例110.大鼠吸收试验
以SD大鼠为实验动物，灌胃给药10mg/kg(5％DMSO+5％Solutol+90％生理盐水)。灌胃给药的取血时间点为0.25、0.5、1、2、4、6、8、24h小时。取全血0.3ml，离心后取血浆0.1ml采用LC-MS进行分析。
表6本发明化合物的大鼠吸收结果
编号 DNAUC
002 252
003 456
045 716
075 1125
077 285
079 6611
081 372
085 579
化合物a 164
注：DNAUC表示AUC(h*ng/mL)/剂量(mg/kg)。
由表6可知，本发明的化合物在大鼠中具有较好的口服吸收。
实施例111.体内抗肿瘤药效
采用NOD/SCID小鼠皮下接种OCL-LY10细胞建立肿瘤模型，当肿瘤长至100mm 3左右分组给药，给药方式如下：A组control组灌胃相应体积的CMC-Na溶液；B组灌胃给予3mg/kg受试化合物；C组灌胃给予10mg/kg受试化合物；D组灌胃给予30mg/kg受试化合物；每周两次秤量老鼠体重和肿瘤大小变化，3周后，用颈椎脱臼法处死小鼠，考察了化合物对OCL-LY10小鼠移植瘤的药效。

Claims (13)

  1. 一种化合物，其特征在于，具有通式(I)所示的结构：
    Figure PCTCN2022133404-appb-100001
    或其立体异构体，或其立体异构体混合物，或其药学上可接受的盐，前药；
    其中：
    L选自：连接环A和E 3的化学基团或化学键；
    E 3选自：E3泛素连接酶配体；
    环A选自：3-12元杂环、6-10元芳环、5-12元杂芳环，3-12元环烷、4-12元环炔、3-12元环烯，其中所述的杂环、杂芳环中具有1-3个独立选自N、O或S的杂原子；
    R 2选自：H、卤素、氰基、C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 8环烷基、C 1-C 4烷氧基、C 3-C 8环烷氧基、C 3-C 8杂环基、C 1-C 4烷氨基、-COOH、-NH 2、OH、NO 2；
    n选自：0、1、2、3、4；
    Y 1选自：N、CR 4；
    Y 2选自：N、CR 5；
    Y 3选自：N、CR 5；
    R 4选自：卤素、C 1-C 4烷基、C 3-C 8环烷基、C 1-C 4卤代烷基、C 3-C 8卤代环烷基、C 1-C 4烷氧基、氨基、羧基、羟基、氰基；
    R 5选自：H、卤素、C 1-C 4烷基、C 3-C 8环烷基、C 1-C 4卤代烷基、C 3-C 8卤代环烷基、C 1-C 4烷氧基、氨基、羧基、羟基、氰基；
    R 3选自：H、C 1-C 8烷基、C 1-C 6卤代烷基、C 3-C 8烯烃、C 3-C 8炔烃、环烷基、杂环基、芳基；
    R 1选自：NR 6R 7、OR 6、SR 6、-C(O)R 6、-C(O)OR 6、-C(O)NR 6R 7、OC(O)R 6、OC(O)NR 6R 7、S(O)R 6、S(O)(＝NH)R 6、S(O) 2NR 6R 7、N(R 6)C(O)R 7、N(R 6)C(O)OR 7、C 1-C 8烷基、3-12元杂环、5-6元杂芳环、C 3-C 8环烷基、芳环基，其中所述的烷基、杂环、杂芳环、环烷基、芳环基可进一步被一个或者多个选自R 8的取代基取代；
    R 8选自：H、卤素、羟基、氨基、氰基、氧代、羧基、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 3-C 8环烷基、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、ORa、OC(O)Ra、OC(O)NRaRb、SRa、S(O)Ra、S(O)(＝NH)Ra、S(O) 2NRaRb、NRaRb、N(Ra)C(O)Rb、N(Ra)C(O)ORb、N(Rc)C(O)NRaRb、-N(Ra)S(O) 2Rb、-N(Ra)S(O) 2NRbRc；其中所述的烷基、烷氧基、环烷基可进一步被一个或者多个取代基取代，取代基包括：H、卤素、羟基、氨基、氰基、氧代、羧基、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 3-C 8环烷基；
    R 6、R 7各自独立的选自H、C 1-C 8烷基、胺烷基、羟烷基、C 3-C 8环烷基、杂环基、 芳环基、杂芳基；所述的烷基、胺烷基、羟烷基、环烷基、杂环基、芳环基、杂芳基可进一步被一个或者多个取代基取代，取代基包括H、卤素、羟基、氨基、氰基、氧代、羧基、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8烷氧基、C 3-C 8环烷基、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、ORa、OC(O)Ra、OC(O)NRaRb、SRa、S(O)Ra、S(O)(＝NH)Ra、S(O) 2NRaRb、NRaRb、N(Ra)C(O)Rb、N(Ra)C(O)ORb、N(Rc)C(O)NRaRb、-N(Ra)S(O) 2Rb、-N(Ra)S(O) 2NRbRc；
    Ra、Rb、Rc各自独立的选自H、卤素、烷基、氨基、羟基、氰基、C 3-C 8环烷基、烷氨基、烷氧基。
  2. 根据权利要求1所述的化合物，其特征在于：
    Y 1选自：N；
    Y 2选自：N；
    Y 3选自：N。
  3. 根据权利要求2所述的化合物，其特征在于：
    环A选自：6-10元芳环、5-12元杂芳环；其中所述的杂环、杂芳环具有1-3个独立选自N、O或S的杂原子，其中：
    环A选自：
    Figure PCTCN2022133404-appb-100002
    Figure PCTCN2022133404-appb-100003
  4. 根据权利要求3所述的化合物，其特征在于，具有通式II(a)～II(i)所示的结构：
    Figure PCTCN2022133404-appb-100004
    或其立体异构体，或其立体异构体混合物，或其药学上可接受的盐，前药。
  5. 根据权利要求4所述的化合物，其特征在于，具有通式III(a)-III(c)所示的结构：
    Figure PCTCN2022133404-appb-100005
    或其立体异构体，或其立体异构体混合物，或其药学上可接受的盐，前药；
    R 1选自：NR 6R 7、OR 6、C 1-C 8烷基、3-12元杂环、5-6元杂芳环、C 3-C 8环烷基、芳环基；其中所述的烷基、杂环、杂芳环、环烷基、芳环基可进一步被一个或者多个选自R 8的取代基取代。
  6. 根据权利要求1-5任一项所述的化合物，其特征在于，
    L选自：
    Figure PCTCN2022133404-appb-100006
    Figure PCTCN2022133404-appb-100007
    E 3选自：
    Figure PCTCN2022133404-appb-100008
    Figure PCTCN2022133404-appb-100009
    Re选自：H、F、Cl、-CH 3、-OMe、-CN、-CF 3；
    Rd选自：H、L 2R g；
    L 2选自：
    Figure PCTCN2022133404-appb-100010
    Figure PCTCN2022133404-appb-100011
    R 9选自：H、C 1-C 5烷基；
    q选自：1、2、3、4或5；
    R g选自：H、取代或未取代的C 1-C 8烷基；取代基选自氨基、羟基、氰基、卤素。
  7. 根据权利要求1所述的化合物，其特征在于，选自下列化合物：
    Figure PCTCN2022133404-appb-100012
    Figure PCTCN2022133404-appb-100013
    Figure PCTCN2022133404-appb-100014
    Figure PCTCN2022133404-appb-100015
    Figure PCTCN2022133404-appb-100016
    Figure PCTCN2022133404-appb-100017
    Figure PCTCN2022133404-appb-100018
    或其立体异构体，或其立体异构体混合物，或其药学上可接受的盐，前药。
  8. 一种药物组合物，其特征在于，包括如权利要求1至7中任意一项所述的化合物中的一种或多种。
  9. 一种如权利要求1至7中任意一项所述的化合物或权利要求8所述组合物在制备单独或与其他药物联合应用治疗从布鲁顿酪氨酸激酶活性的抑制中获益的疾病、障碍或病症药物中的应用。
  10. 如权利要求9所述的应用，其特征在于，所述的疾病、障碍或病症为从抑制布鲁顿酪氨酸激酶突变中获益的疾病、障碍或病症。
  11. 如权利要求9所述的应用，其特征在于，所述疾病选自B细胞或浆细胞增殖性疾病和自身免疫性疾病中的一种或多种。
  12. 如权利要求11所述的应用，其特征在于，所述B细胞或浆细胞增殖性疾病包括弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞淋巴瘤、慢性淋巴细胞白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、浆细胞性骨髓瘤、浆细胞瘤、结外边缘区B细胞淋巴瘤、***边缘区B细胞淋巴瘤、外套细胞淋巴瘤、纵膈(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病或淋巴瘤样肉芽肿病、多发性骨髓瘤。
  13. 如权利要求11所述的应用，其特征在于，所述自身免疫性疾病包括炎性肠病、关节炎、狼疮、类风湿性关节炎、银屑病性关节炎、骨关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎奥德甲状腺炎、格雷夫斯氏病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性播散性脑脊髓炎、阿狄森病、视性眼阵挛-肌阵挛综合征、强制性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻、古德帕斯彻综合征、免疫性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征、高安动脉炎、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病、银屑病、全身脱毛、贝赫切特病、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病或外阴痛和慢性移植物抗宿主病。
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