WO2020135765A1 - Cxcr4抑制剂及其应用 - Google Patents

Cxcr4抑制剂及其应用 Download PDF

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WO2020135765A1
WO2020135765A1 PCT/CN2019/129362 CN2019129362W WO2020135765A1 WO 2020135765 A1 WO2020135765 A1 WO 2020135765A1 CN 2019129362 W CN2019129362 W CN 2019129362W WO 2020135765 A1 WO2020135765 A1 WO 2020135765A1
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group
alkyl
amino
cycloalkyl
heteroaryl
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PCT/CN2019/129362
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English (en)
French (fr)
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黄子为
聂凛凛
徐岩
谭嘉文
梁柏强
杨虹
叶辉
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珠海诺贝尔国际生物医药研究院有限公司
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Publication of WO2020135765A1 publication Critical patent/WO2020135765A1/zh

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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/04—Antineoplastic agents specific for metastasis
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    • C12N2503/00—Use of cells in diagnostics
    • C12N2503/02—Drug screening
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • the invention relates to the field of medicine.
  • the invention relates to CXCR4 inhibitors and their use.
  • the present invention relates to compounds, the use of compounds in the preparation of pharmaceuticals, pharmaceutical compositions, pharmaceutical carriers, combinations of drugs, screening drugs, and methods of screening targets.
  • CXC chemokine receptor 4 CXCR4
  • SDF-1 stromal cell-derived factor 1
  • CXCR4 is an important chemokine receptor, widely expressed in a variety of hematopoietic cells (neutrophils, monocytes and macrophages, T, B lymphocytes), hematopoietic stem cells in blood and bone marrow, endothelial precursors Cells, blood-derived dendritic cells and Langerhans cells. At the same time, it is also highly expressed in vascular endothelial cells, neurons and neural stem cells in the central and peripheral nervous system, and microglia and astrocytes.
  • CXCR4 is a specific receptor for SDF-1 ⁇ , and the two constitute the biological axis of CXCR4-SDF-1 ⁇ , which can regulate the proliferation and migration of cells by activating various signaling pathways in the cell.
  • CXCR4-SDF-1 ⁇ axis plays an important role in regulating the body's immune system, circulatory system and nervous system, and their interactions and their mediated signal transduction are associated with viral infections, tumorigenesis and metastasis, inflammation and Autoimmune diseases and other diseases are closely related.
  • CXCR4 inhibitors to interfere or block the interaction between SDF-1 ⁇ and CXCR4 has the following effects: 1) It can mobilize the hematopoietic stem cells in the bone marrow to peripheral blood to facilitate the collection of hematopoietic stem cells for multiple myeloma and non-Hoge
  • the treatment of gold lymphoma 2) can block the invasion of HIV-1 T cells, thereby inhibiting the progression of AIDS; 3) can provide new treatments for anti-tumor metastasis; 4) can protect and inhibit the destruction of the bone marrow microenvironment
  • Leukemia cells migrate into and infiltrate the bone marrow, mobilize leukemia cells into the peripheral blood and increase their sensitivity to chemotherapy drugs, used in the treatment of leukemia; 5) can be used in combination with tumor immunotherapy drugs or therapies to treat tumors; 6) can be treated Immune deficiency diseases, such as WHIM syndrome.
  • the present invention aims to solve at least one of the technical problems existing in the prior art at least to a certain extent.
  • the invention proposes a compound.
  • the compound is a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites 2.
  • L is selected from C 2 ⁇ 10 alkylene group, C 2 ⁇ 10 alkynyl group, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 6 heterocyclic group, an aryl group, C 1 ⁇ 5 heteroaryl, C 1 ⁇ 12 fused Cyclic group, C 1-12 condensed heterocyclic group, C 1-12 spirocyclic group or C 1-12 spiro heterocyclic group, or L, And with The connected N and R 2 form a ring structure;
  • R 1 is selected from bond, hydrogen, sulfonyl, sulfinyl, C 1-6 alkylsulfonyl, amino C 1-6 alkyl, C 1-6 alkylsulfinyl, carbonyl, C 1-6 alkylcarbonyl, amino acid, amide bond, or Where A, B, C, D, E, F, and G are independently C, N, O, and S atoms, or C, N and R 7 in the ring form a ring structure, or R 1 and R 2 and the same N atom to form a ring structure; or R 2 , N, Forming a ring structure with L;
  • R 2, R 3 and R 4 are each independently selected from hydrogen, a hydroxyl group, an amino group, a sulfonyl group, a sulfinyl group, a carbonyl group, C 1 ⁇ 6 alkyl group, C 2 ⁇ 10 alkylene group, C 2 ⁇ 10 alkynyl, C 1 to 6 alkoxy, amino C 1-6 alkyl, C 1-6 alkyl phosphoryl group, a C 1-6 alkylcarbonyl group, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 heterocyclyl, aryl , C 1-10 heteroaryl, C 1-12 fused ring group, C 1-12 fused heterocyclic group, C 1-12 spiro ring group or C 1-12 spiro heterocyclic group; or R 3 , R 4 . And with N atoms connected at both ends form a ring;
  • R 5 and R 6 are each independently selected from hydrogen, a sulfonyl group, a sulfinyl group, a carbonyl group, an amino group, C 1 ⁇ 10 alkyl group, C 2 ⁇ 10 alkylene group, C 2 ⁇ 10 alkynyl group, C 1 ⁇ 6 alkoxycarbonyl group, an amino C 1 ⁇ 6 alkyl group, C 1 ⁇ 6 alkyl phosphoryl group, C 1 ⁇ 6 alkylcarbonyl, aryl C 1 ⁇ 6 alkyl group, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 heterocycle group, C 1 ⁇ 4 alkyl C 3 ⁇ 8 heterocyclyl, aryl, C 1 ⁇ 10 heteroaryl, C 1 ⁇ 12 fused cyclic group, C 1 ⁇ 12 fused heterocyclic group, C 1 ⁇ 12 Spirocyclic group or C 1-12 spiro heterocyclic group;
  • R 7 is selected from hydrogen, an amino group, a sulfonyl group, a sulfinyl group, a carbonyl group, C 1 ⁇ 6 alkyl group, C 2 ⁇ 10 alkylene group, C 2 ⁇ 10 alkynyl group, C 1 ⁇ 6 alkoxy, amino C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkyl phosphoryl group, C 1 ⁇ 6 alkylcarbonyl group, C 1 ⁇ 6 alkyl aryl, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 heterocyclyl, aryl, C 1-10 heteroaryl groups, C 1-12 fused ring groups, C 1-12 fused heterocyclic groups, C 1-12 spirocyclic groups, C 1-12 spiro heterocyclic groups;
  • alkenyl group, alkynyl group, alkoxy group, amino group, alkyl group, aminoalkyl group, cycloalkyl group, alkylphosphoryl group, heterocyclic group, aryl group, heteroaryl group, alkylcarbonyl group, alkyl heterocyclic group , Alkylaryl, fused ring group, fused heterocyclic group, spiro ring group, spiro heterocyclic group, sulfonyl group and sulfinyl group can be independently independently one or more alkyl, alkenyl, alkynyl, Fluorine, chlorine, bromine, iodine, haloalkyl, haloaryl, haloheteroaryl, hydroxy, amino, carbonyl, carboxyl, guanidino, amidino, sulfonyl, sulfinyl, alkoxy, aminoalkyl , Alkylphosphoryl, alkylcarbonyl, cycl
  • n 1 , n 2 and n 3 are each independently an integer of 0-10.
  • the compound of the present invention shows a strong inhibitory activity on the CXCR4-SDF-1 ⁇ axis, and shows good absorption, high biological activity and availability in animal pharmacokinetic tests, low toxicity, especially in the body It has strong stability, is not easy to decompose, and has a long drug effect. It can effectively interfere or block the interaction between SDF-1 ⁇ and CXCR4. It can effectively mobilize hematopoietic stem cells and provide new treatments for various blood tumors. It can also treat leukemia by destroying the protection of the bone marrow microenvironment, inhibiting the migration and infiltration of leukemia cells to the inside and outside of the bone marrow, mobilizing leukemia cells into the peripheral blood and increasing their sensitivity to chemotherapy drugs.
  • CXCR4-SDF-1 ⁇ It also plays an important physiological and pathological role in solid tumors, AIDS, autoimmune diseases and inflammatory diseases. It can be used as the target of the above diseases or as a means of adjuvant therapy, and has very good application prospects.
  • the above compounds may also have the following additional technical features:
  • R 1 is selected from the group consisting of bond, hydrogen, sulfonyl, sulfinyl, amide bond, amino acid, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl,
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, amino C 1-4 alkyl or C 1-5 heteroaryl, the alkyl, Cycloalkyl, heterocyclyl, aminoalkyl or heteroaryl can be optionally substituted by one or more H, C 1-4 alkyl, fluorine, chlorine, bromine, iodine, amino or C 1-5 heteroaryl Replaced by
  • R 3 and R 4 are each selected from hydrogen or C 1-6 alkyl, or R 3 , R 4 , And with The N atoms connected at both ends form a C 2-6 heterocyclic group, which may be optionally substituted by one or more hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or C 3 ⁇ 6 heterocyclic groups;
  • R 5 is selected from C 1-6 alkyl, aryl, C 3-6 cycloalkyl, C 3-6 heterocyclyl or C 1-5 heteroaryl, wherein the alkyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl can be optionally substituted by one or more fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 cycloalkyl, aryl, C 1-5 heteroaryl Group or C 1-6 heterocyclic group substitution;
  • R 6 is selected from C 1 ⁇ 4 alkyl group, an amino group, a sulfonyl group, a sulfinyl group, a carbonyl group, an amino C 1 ⁇ 6 alkyl, aryl C 1 ⁇ 6 alkyl group, C 1 ⁇ 4 alkyl C 3 ⁇ 8 hetero Aromatic ring group, C 3-6 cycloalkyl group or C 3-6 heterocyclic group, wherein the alkyl, amino, carbonyl, sulfonyl, sulfinyl, aminoalkyl, alkylaryl, alkyl hetero
  • the cyclic group, cycloalkyl group or heterocyclic group may be optionally substituted by one or more hydrogen, fluorine, chlorine, bromine, iodine, amino, aryl, C 1-5 heteroaryl, halogenated C 1-5 heteroaryl Group, C 2-6 heterocyclic group or C 1-4 alkylphosphoryl substitution;
  • R 7 is selected from C 1-6 alkyl, aryl, C 1-6 alkyl aryl, C 1-5 heteroaryl, C 1-6 alkenyl, C 3-6 cycloalkyl, C 3-6 Heterocyclyl, sulfonyl or sulfinyl, the alkyl, aryl, heteroaryl, alkylaryl, alkenyl, cycloalkyl or heterocyclyl can be optionally substituted by one or more hydrogen, fluorine , Chlorine, bromine, iodine, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, C 1-5 heteroaryl, amidino, guanidino or amino;
  • L is selected from aryl, C 1-5 heteroaryl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-12 fused ring or C 1-12
  • a fused heterocyclic group, the aryl, heteroaryl, alkynyl, cycloalkyl, fused ring or fused heterocyclic group may be optionally substituted by one or more hydrogen, fluorine, chlorine, bromine, iodine , C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclic, amino, hydroxyl, carboxyl, aryl, C 1-5 heteroaryl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 aminoalkyl or Replaced by.
  • L is selected from one of the following structures: or
  • the fused ring groups may be optionally substituted with one or more hydrogen, fluoro, chloro, bromo, iodo, C 1 ⁇ 10 alkyl group, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 a heterocyclic group, an amino group, Hydroxy, carboxy, aryl, C 1-5 heteroaryl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 aminoalkyl or substituted, where A, B, C, D, E, F, G, H and I are each independently H, C, N, O and S atoms.
  • L is selected from one of the following structures: or
  • A, B, C, D, E, F, G, H and I are independently H, C, N, O, S atoms;
  • R 8 , R 9 or R 10 are each independently hydrogen, fluorine, chlorine, bromine, iodine, C 1-4 alkyl, amino C 1-4 alkyl or C 1-4 alkoxy.
  • L is a fused ring group selected from one of the following:
  • the fused ring group is substituted with one or more of H, C 1-3 alkyl, fluorine, chlorine, bromine, iodine, or C 1-3 alkoxy.
  • the L is aryl and R 1 is When the compound meets at least one of the following conditions:
  • R 2 is C 3-6 cycloalkyl, halogenated C 1-4 alkyl or amino C 1-4 alkyl; or L, And with Connected N and R 2 form
  • R 3 or R 4 is C 1-6 alkyl, or R 3 , R 4 , And with C 2 ⁇ 8 is formed between the N atom a heterocyclic group at both ends;
  • R 5 is cycloalkyl, the cycloalkyl is substituted by one or more fluorine, chlorine, bromine, iodine, hydroxy, amino, aryl, C 1-4 alkyl, C 1-8 cycloalkyl or C 1-8 heterocyclic group substitution;
  • R 6 is a carbonyl, sulfonyl, sulfinyl, amino, or amino C 1-4 alkyl group, and the carbonyl, sulfonyl, sulfinyl, amino, or amino C 1-4 alkyl group may be optionally substituted
  • R 7 is a C 1-4 alkyl group, a C 1-4 alkenyl group, a C 1-5 heteroaryl group or a C 3-6 cycloalkyl group, wherein the alkyl group cannot be substituted by an alkyl group, amidinyl group, Substituted by amino, C 1-5 heteroaryl.
  • the compound is one of the following compounds, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceuticals Acceptable salts or prodrugs:
  • the pharmaceutically acceptable salts include selected from trifluoroacetate, hydrochloride, acetate, phosphate, hydrobromide, lactate, and dihydroxythenate , Sulfate, mesylate, tosylate, citrate, tartrate, fumarate, maleate and malate.
  • the present invention proposes the use of the aforementioned compounds in the preparation of medicaments.
  • the medicine is used to treat tumor diseases, AIDS, bone marrow transplantation, sickle cell anemia, hematopoietic stem cell transplantation, trauma, myocardial infarction, neutropenia, ischemic disease, neurological Disease, retinal vein occlusion, respiratory system disease, gastrointestinal disease, skin disease, inflammatory response or immunodeficiency disease.
  • the compound of the present invention shows a strong inhibitory activity on the CXCR4-SDF-1 ⁇ axis, and shows good absorption, high biological activity and availability, low toxicity, especially in the pharmacokinetic test in animals It has strong stability in the body and has a long drug effect. It can effectively interfere or block the interaction between SDF-1 ⁇ and CXCR4. It can effectively mobilize hematopoietic stem cells and provide new treatments for various blood tumors. By destroying the protection of the bone marrow microenvironment, inhibiting the migration and infiltration of leukemia cells to the inside and outside of the bone marrow, mobilizing leukemia cells into peripheral blood and increasing their sensitivity to chemotherapy drugs, it has the effect of treating leukemia.
  • CXCR4-SDF-1 ⁇ is in the entity Tumors, AIDS, autoimmune diseases and inflammatory diseases also have important physiological and pathological effects. They can be used as targets or adjuvant treatments for the above diseases, and have very good application prospects.
  • the drug inhibits the expression of CXCR4 or blocks the interaction between CXCR4 and SDF-1 ⁇ .
  • the compounds of the present invention can antagonistically bind to CXCR4 to block the interaction between CXCR4 and the natural ligand SDF-1 ⁇ .
  • the drug is used to mobilize hematopoietic stem cells in bone marrow for autologous or allogeneic hematopoietic stem cell transplantation, and for the treatment of multiple myeloma and non-Hodgkin's lymphoma diseases.
  • the drug is used to mobilize stem cells in bone marrow and used for the treatment of leukemia.
  • the drug is used to mobilize cancer cells of acute myeloid leukemia in bone marrow to peripheral blood, and is used for the treatment of leukemia.
  • the drug inhibits tumor cell metastasis and is used for tumor treatment.
  • the drug inhibits the invasion of HIV-1 into T cells and is used for the treatment of AIDS.
  • the medicine is used for the treatment of autoimmune deficiency diseases.
  • the drug is used as a tumor marker in the preparation of hematopoietic stem cell/progenitor cell mobilization agent and/or in tumor tissue overexpressing CXCR4.
  • the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition includes the aforementioned compound.
  • the compound of the present invention shows a strong inhibitory activity on the CXCR4-SDF-1 ⁇ axis, and shows good drug formation in the in vitro and in vivo pharmacokinetics and pharmacodynamic experiments, especially in the body with strong stability .
  • Long drug effect time can effectively interfere or block the interaction between SDF-1 ⁇ and CXCR4, can not only provide a new treatment for hematological tumors, but also can prevent the migration and infiltration of leukemia cells to the inside and outside of the bone marrow by destroying the protection of the bone marrow microenvironment 2.
  • the pharmaceutical composition further includes pharmaceutically acceptable excipients, carriers, excipients, vehicles, or a combination thereof.
  • the pharmaceutical composition further comprises a therapeutic agent selected from at least one of the following: maraviro, enfuvirtide, zidovudine, zalcitabine, and Tavudine, Lamivudine, Navirapine, Derivadine, Abacavir, Efavirenz, Tenofovir, Estracitabine, Etravirum, Lipivirum, Shun Platinum, cyclophosphamide, cytarabine, 5-fluorouracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, Gleevec, trocaine, sorafenib, dasatinib, lapatinib , Sunitinib, erlotinib, gefitinib, Tisagenlecleucel, echililide, ale
  • the present invention provides a pharmaceutical carrier.
  • the pharmaceutical carrier includes the aforementioned compound.
  • the compound of the present invention shows a strong inhibitory activity on the CXCR4-SDF-1 ⁇ axis, and it shows good drugability data in the absorption, distribution, metabolism and excretion (ADME) of pharmacokinetic tests in animals, showing good Absorption, high biological activity and availability, low toxicity, especially strong stability in the body, long drug effect time, can effectively interfere or block the interaction between SDF-1 ⁇ and CXCR4, can be Hematological tumors provide new treatments. They can also mobilize leukemia cells into peripheral blood and increase their sensitivity to chemotherapeutic drugs. They have the effect of treating tumor diseases, immunodeficiency diseases, AIDS and inflammatory reactions. Application prospects.
  • the invention proposes a drug combination.
  • the drug combination comprises: the aforementioned compound or pharmaceutical composition; and one or more drugs for treating tumor diseases, AIDS, inflammatory reactions, and immunodeficiency diseases.
  • the compound of the present invention shows a strong inhibitory activity on the CXCR4-SDF-1 ⁇ axis, and shows good absorption, high biological activity and availability in animal pharmacokinetic tests, low toxicity, especially in the body It has strong stability and long effect time. It can effectively interfere or block the interaction between SDF-1 ⁇ and CXCR4. It can not only provide new treatments for hematological tumors, but also protect and inhibit the destruction of the bone marrow microenvironment.
  • Leukemia cells migrate into and infiltrate the bone marrow, mobilize leukemia cells into the peripheral blood and increase their sensitivity to chemotherapy drugs, which has the effect of treating tumor diseases, immunodeficiency diseases, AIDS and inflammatory reactions, and has good application prospects. .
  • the drug is selected from at least one of the following: maraviro, enfuvirtide, zidovudine, zalcitabine, stavudine, lamivudine, navir Rapapine, Delavirdine, Abacavir, Efavirenz, Tenofovir, Estravitabine, Etravirum, Lipivirum, Cisplatin, Cyclophosphamide, Cytarabine, 5-fluorouracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, gleevec, trocaine, sorafenib, dasatinib, lapatinib, sunitinib, erlotinib, Gefitinib, Tisagenlecleucel, echililen, alemtuzumab, atizumab, avilizumab, ipilimumab, ofatumumab, nivolu
  • FIG. 1 shows a schematic diagram of the effect of NIC108 mobilizing tumor cells of AML model mice and synergistically enhancing the chemotherapy drug cytarabine according to an embodiment of the present invention
  • FIG. 2 shows a schematic diagram of quantitative analysis of colonies formed by mobilized hematopoietic stem cells according to an embodiment of the present invention.
  • Stereoisomer refers to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Chiral refers to molecules that have the property that they cannot overlap with their mirror images; while “achiral” refers to molecules that can overlap with their mirror images.
  • Enantiomer refers to two isomers of a compound that cannot overlap but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Diastereomer mixtures can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds that is, they have the ability to rotate the plane of plane polarized light.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to one or more chiral centers.
  • the prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane polarized light caused by a compound, where (-) or l indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or d are right-handed.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atoms (for example, carbon, etc.) of the compounds disclosed in the present invention can exist in racemic or enantiomerically enriched forms, such as (R)-, (S)-, or (R,S)-configuration forms exist.
  • each asymmetric atom has an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, at least in the (R)- or (S)-configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention may be in one of the possible isomers or their mixtures, such as racemates and diastereomer mixtures (this depends on the number of asymmetric carbon atoms) Form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography Method and/or step crystallization method.
  • racemates of any resulting end products or intermediates can be resolved into optical enantiomers by methods known to those skilled in the art using known methods, for example, by obtaining the diastereomeric salts obtained Separate. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents.
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis ( 2nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be interconverted by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomer (valence tautomer) includes interconversion through the recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • C 1-6 alkyl particularly refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl groups.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition for the variable lists “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” represents the linked group, respectively An alkylene group or an arylene group.
  • the compounds of the present invention may be independently and optionally substituted with one or more substituents, such as the compounds of the general formula above, or as specific examples, subclasses, and inclusions of the present invention in the examples.
  • substituents such as the compounds of the general formula above, or as specific examples, subclasses, and inclusions of the present invention in the examples.
  • substituents such as the compounds of the general formula above, or as specific examples, subclasses, and inclusions of the present invention in the examples.
  • a class of compounds A class of compounds.
  • Substituent 1 can be further monosubstituted by Substituent 2 or multiple substituted by the same or different.
  • alkyl used in the present invention includes a monovalent hydrocarbon group saturated with a linear or branched chain of 1 to 20 carbon atoms, wherein the alkyl group may be independently substituted with one or more substituents described in the present invention. Some of these embodiments are that the alkyl group contains 1-10 carbon atoms; other embodiments are that the alkyl group contains 1-8 carbon atoms; other embodiments are that the alkyl group contains 1-6 In other embodiments, the alkyl group contains 1-4 carbon atoms; in other embodiments, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), isopropyl ( -CH(CH 3 ) 2 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (-CH 2 CH(CH 3 ) 2 ), 1-methyl Propyl or sec-butyl (-CH(CH 3 )CH 2 CH 3 ), tert-butyl (-C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2 -Pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3
  • haloalkyl means that the alkyl group may be substituted with one or more same or different halogen atoms. Where the alkyl group has the meaning as described in the present invention, such examples include, but are not limited to, trifluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, and the like.
  • the haloalkyl group may be substituted with the substituents described in the present invention.
  • aminoalkyl means that the alkyl group may be substituted with one or more identical or different amino groups or the amino groups are independently substituted with one or two alkyl groups, wherein the alkyl group has the meaning as described in the present invention .
  • alkoxy used in the present invention refers to an alkyl group, as defined in the present invention, is connected to the main carbon chain through an oxygen atom. Such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
  • the alkoxy group may be substituted by the substituent described in the present invention.
  • cycloalkyl refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring, and does not contain heteroatoms, including a single ring of 3-12 carbon atoms or 7-12 carbon atoms Two or three rings.
  • Bicarbon rings with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, and bicarbon rings with 9 or 10 atoms It can be a bicyclic [5,6] or [6,6] system.
  • Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • cycloalkyl groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1 -Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cyclo Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl and the like.
  • the cycloalkyl group may be a monovalent group or a divalent group, that is, a cycloalkylene group.
  • C 4 cycloalkyl refers to cyclobutyl
  • C 5 cycloalkyl refers to cyclopentyl
  • C 7 cycloalkyl refers to cycloheptyl.
  • the cycloalkyl group may be substituted with the substituents described in the present invention.
  • aryl can be monocyclic, bicyclic, and tricyclic carbocyclic systems, where at least one ring system is aromatic, where each ring system contains 3-7 atoms, and there is only one attachment point with the molecule The rest of the connection.
  • aryl may be used interchangeably with the term "aromatic ring".
  • the aromatic ring may include phenyl, naphthyl, and anthracene.
  • the aryl group may be a monovalent group or a divalent group, that is, an arylene group.
  • the aryl group may be substituted with the substituents described in the present invention.
  • heteroaryl and “heteroaryl ring” are used interchangeably herein, and all refer to monocyclic, bicyclic, tricyclic or tetracyclic systems, where bicyclic heteroaryl ring, tricyclic heteroaryl ring or tetracyclic hetero ring Aromatic ring systems form rings in fused form. Among them, at least one ring system of the heteroaromatic ring system is aromatic, one or more atoms on the ring are optionally substituted by heteroatoms (heteroatoms are selected from N, O, P, S, where S or P is independent Optionally substituted by one or more oxygen atoms to give groups like SO, SO 2 , PO, PO 2 ).
  • the heteroaromatic system can be connected to the main structure at any heteroatom or carbon atom to form a stable compound.
  • the heteroaromatic system group may be a monocyclic ring composed of 3-7 atoms, or a bicyclic ring composed of 7-10 atoms, or a tricyclic ring composed of 10-15 atoms.
  • Bicyclic rings with 7-10 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, tricyclic rings with 10-15 atoms can be tricyclic [5,5,6], [5,7,6] or [6,5,6] system.
  • heterocyclic refers to monocyclic, bicyclic, tricyclic or tetracyclic systems, where one of the rings Or multiple atoms are independently optionally substituted with heteroatoms, the ring may be fully saturated or contain one or more unsaturations, but by no means are aromatic.
  • Heterocyclic systems can be attached to the main structure at any heteroatom or carbon atom to form a stable compound.
  • the hydrogen atoms on one or more rings are independently optionally substituted with one or more substituents described in the present invention.
  • the "heterocyclyl”, “heterocyclic”, “heteroalicyclic” or “heterocyclic” group is a 3-7 membered monocyclic ring (1-6 carbon atoms and selected from 1-3 heteroatoms of N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to obtain groups like SO, SO 2 , PO, PO 2 , and at the same time,
  • heterocyclic group may be a carbon group or a heteroatom group.
  • Heterocyclyl also includes groups formed by the combination of a heterocyclic group with a saturated or partially unsaturated carbocyclic or heterocyclic ring.
  • heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Thioxanyl, azetidinyl, oxetanyl, thiatanyl, piperidinyl, homopiperidinyl, epoxypropyl, N-morpholinyl, N-piperazinyl, 2 -Piperazinyl, 3-piperazinyl, homopiperazinyl, oxazepinyl, diazepinyl, thioazazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrole Porphyrinyl, dihydroindolyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl,
  • spirocyclic group means that one ring originates from a special cyclic carbon on another ring.
  • a saturated bridge ring system (rings D and B') is called a "fused bicyclic ring”
  • ring A'and ring D share a carbon atom in two saturated ring systems, It is called a "spiral ring”.
  • Each ring in the spiro ring is either carbocyclic or heteroalicyclic.
  • Such examples include, but are not limited to, spiro[2.4]heptan-5-yl, spiro[4.4]nonanyl, and the like.
  • spiroheterobicyclyl means that one ring originates from a special cyclic carbon on the other ring.
  • a saturated bridge ring system (rings D and B') is called a "fused bicyclic ring”
  • ring A'and ring D share a carbon atom in two saturated ring systems, It is called a "spiral ring”.
  • fused bicyclic means a saturated or unsaturated fused ring system, which refers to a non-aromatic bicyclic system, at least one ring is non-aromatic of. Such a system may contain independent or conjugated unsaturated states.
  • Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic.
  • Examples include, but are not limited to, hexahydro-furan[3,2-b]furanyl, 2,3,3a,4 ,7,7a-Hexahydro-1H-indenyl, 7-azabicyclo[2.2.1]heptanyl, fused bicyclic[3.3.0]octyl, fused bicyclic[3.1.0]hexane , 1,2,3,4,4a,5,8,8a-octahydronaphthyl, 1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, these are included in the fused bicyclic Within the system.
  • fused heterobicyclic group means a saturated or unsaturated fused ring system, which refers to a non-aromatic bicyclic system, at least one ring is non-aromatic. Such a system may contain independent or conjugated unsaturated states.
  • the fused heterobicyclic group may be substituted with the substituents described in the present invention.
  • the ring system formed by the substituent R'connected to the central ring by a bond means that the substituent R'can be substituted at any substitutable or any reasonable position on the ring.
  • formula a represents that any position on the A'ring or B'ring that may be substituted can be substituted by R', as shown in formula b, formula c, formula d, formula e, formula f, formula g, and formula h .
  • the attachment point can be connected to the rest of the molecule at any connectable position on the ring.
  • formula i means that any position on the A'ring or B'ring that may be connected can be used as a connection point.
  • the attachment point can be connected to the rest of the molecule at any connectable position on the fused ring, and the two ends of the connection can be interchanged.
  • formula y means that any position on the ring that may be connected can be used as a connection point, and the two ends of the connection point can be interchanged.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similarly inappropriate reactions, such as gastrointestinal discomfort, dizziness, and the like.
  • pharmaceutically acceptable refers to use in animals, more particularly in humans, approved by the federal regulatory agency or national government or listed in the US Pharmacopeia or other generally recognized pharmacopeia.
  • carrier refers to a diluent, adjuvant, excipient or base for administration with the compound.
  • These pharmaceutical carriers can be sterile liquids, such as water and oils, including petroleum, animal, plant, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Water and aqueous solutions Saline solutions and aqueous glucose and glycerin solutions are preferably used as carriers, especially injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceuticals" by E.W. Martin.
  • stereochemistry in the present invention generally refer to the following documents: SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S ., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
  • the compound of the present invention may contain an asymmetric center or a chiral center, so different stereoisomers exist. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention Part.
  • optically active compounds that is, they have the ability to rotate the plane of plane polarized light.
  • the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center.
  • the prefixes d, l, or (+), (-) are used to designate the symbol for the rotation of the plane polarized light of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed.
  • the chemical structures of these stereoisomers are the same, but their stereostructures are different.
  • the specific stereoisomer may be an enantiomer, and a mixture of isomers is usually called a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomers, lacking optical activity.
  • “Isomers” are different compounds with the same molecular formula. “Stereoisomers” are isomers that differ only in the spatial arrangement of atoms.
  • the term “isomer” as used herein includes any and all geometric isomers and stereoisomers. For example, “isomer” includes cis and trans isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (d) isomers , (L)-isomers, their racemic mixtures, and other mixtures falling within the scope of this specification.
  • the "hydrate” of the present invention refers to the compound or salt thereof provided by the present invention, which also includes stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces, and it can also be said that the solvent molecule is formed by water Association.
  • solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • N-oxide means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (such as peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • an oxidizing agent such as hydrogen peroxide or a peracid (such as peroxycarboxylic acid)
  • N-oxide can be prepared by the method of LWDeady (Syn. Comm. 1977, 7,509-514), in which, for example, in an inert solvent such as methylene chloride, the amine compound and m-chloroperoxybenzoic acid (MCPBA) reaction.
  • prodrug used in the present invention means that a compound is converted into a compound represented by formula (I)-formula (III) in vivo. Such conversion is affected by prodrug hydrolysis in the blood or enzymatic conversion into the parent structure in the blood or tissue.
  • the prodrug compounds of the present invention may be esters.
  • esters may be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters, as these phosphate ester compounds are obtained by phosphorylation of hydroxyl groups on the parent.
  • prodrugs please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJHecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
  • Metal refers to a product obtained by metabolizing a specific compound or its salt in the body.
  • the metabolite of a compound can be identified by techniques well known in the art, and its activity can be characterized by an experimental method as described in the present invention.
  • Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like.
  • the present invention includes metabolites of the compound, including metabolites produced by bringing the compound of the present invention into full contact with a mammal for a period of time.
  • compositions can be prepared by using active ingredients and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known to us in the field, as described in the literature: S.M. Berge, et al., describe, acceptable, salts, details in J. Pharmaceutical Sciences, 66: 1-19, 1977.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, Nitrate, etc., and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citric acid Salt, benzoate, mandelate, methanesulfonate, ethanesulfonate, tosylate, sulfosalicylic acid salt, etc., or obtained by other methods such as ion exchange in the literature These salts.
  • salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate Salt, glucoheptonic salt, glycerol phosphate, gluconate, hemisulfate, enanthate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate , Laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, parathionate, Pectate
  • the present invention also contemplates the formation of quaternary ammonium salts of any compound containing N groups.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • the alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt and the like.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1 -8 sulfonate and aromatic sulfonate.
  • Amine salts such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucose Amine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine And tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as but not limited to barium, calcium and magnesium; transition metal salts such as but not limited to zinc.
  • alkaline earth metal salts such as but not limited to barium, calcium and magnesium
  • transition metal salts such as but not limited to zinc.
  • any abbreviations of protecting groups, amino acids and other compounds used in the present invention are based on their commonly used and recognized abbreviations, or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11:942-944).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, carrier, excipient, vehicle or a combination thereof.
  • a mammal such as a human in the form of a medicine
  • it may be administered in the form of the compound itself or may contain, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient and pharmaceutically acceptable
  • the carrier is administered in the form of a pharmaceutical composition.
  • “Combination” means a fixed combination in a single dosage unit form or a kit of parts for combined administration, in which the compound disclosed in the present invention and the combination partner (medicines for treating tumor diseases, AIDS, inflammatory reactions, and immunodeficiency diseases) can be They can be administered independently at the same time or can be administered separately within a certain time interval, in particular to make the joint partners show cooperation, such as synergy.
  • pharmaceutical composition as used herein means a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.
  • the term “fixed combination” means that the active ingredients such as the disclosed compounds and combination partners of the present invention are administered to a patient simultaneously in the form of a single entity or dose.
  • non-fixed combination means that the active ingredients such as the compounds disclosed in the present invention and the combination partners are administered to the patient as separate entities simultaneously, jointly or without a specific time limit.
  • pharmaceutically acceptable carrier includes pharmaceutically acceptable materials, compositions or carriers suitable for administering the compounds of the present invention to mammals.
  • the carrier includes liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that are involved in carrying the subject substance or transferring it from one part of the organ or body to another part of the organ or body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient.
  • materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, Ethyl cellulose and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil , Olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffer Agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution;
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances may also be present in the composition , Preservatives and antioxidants.
  • antioxidants examples include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxybenzene Methyl ether (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, etc.; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid , Phosphoric acid, etc.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxybenzene Methyl ether (BHA), butylated hydroxytoluen
  • compositions of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal and/or parenteral administration.
  • the formulations can conveniently be presented in unit dosage form and can be prepared by any method known in the pharmaceutical art.
  • the amount of active ingredient that can be combined with a carrier material to prepare a single dosage form is generally that amount of the compound that produces a therapeutic effect. In general, the amount is from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10 to about 30%, in units of one percent.
  • treatment is used to refer to obtaining the desired pharmacological and/or physiological effect.
  • the effect may be preventive in terms of completely or partially preventing the disease or its symptoms, and/or may be therapeutic in terms of partially or completely curing the disease and/or the adverse effects caused by the disease.
  • Treatment covers diseases of mammals, especially humans, including: (a) preventing the occurrence of diseases or disorders in individuals who are susceptible to disease but have not been diagnosed with the disease; (b) inhibiting the disease, such as retarding the development of the disease; Or (c) alleviate the disease, for example, reduce the symptoms associated with the disease.
  • Treatment encompasses any medication for the administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, alleviate or inhibit the disease of the individual, including but not limited to the administration of a drug containing the compound described herein to an individual in need.
  • the cell line used for the detection of the affinity activity of CXCR4 is a CHO cell line constructed in vitro stably transfected with CXCR4.
  • the CHO cell line was cultured in DMEM medium (containing 10% fetal bovine serum, 100 IU penicillin, 0.1 mg/ml streptomycin and 0.2 mg/ml G418). After trypsin digestion, washed and counted with FACS buffer (containing 0.5% BSA, 0.05% NaN3 in PBS) suspended cells and added to 96-well plates. A total of 100 ⁇ l of reaction system per well contains 5 ⁇ 10 5 cells, 250 ng/ml of 12G5 monoclonal antibody and different concentrations of tested compounds.
  • the cell migration experiment induced by SDF-1 ⁇ was detected using the SupT1 cell line that naturally expresses CXCR4.
  • the compound of the present invention has a significant ability to inhibit cell migration at a concentration of 500 nM.
  • Propantheline bromide was diluted to 1 mM with acetonitrile. Use propantheline bromide as a human control drug. Take 4 ⁇ L of 10 mM drug to be tested and add them to 96-well plates, then add 36 ⁇ L of DMSO to dilute the drug to 1 mM.
  • the human plasma stored at -80°C was thawed in a 37°C water bath and centrifuged at 4,000 rpm for 10 minutes to remove floating matter and clots. Use a pH meter to check the pH value of plasma. Only use plasma with a pH of 7.2-8.0. The plasma was pre-incubated in a 37°C water bath for 15 minutes. 398 ⁇ L of pre-incubated plasma was added to a new 96-well plate, and 2 ⁇ L of the test compound and the control drug were added respectively. The final concentration of the compound was 5 ⁇ M, and the concentration of the organic solvent was 0.2%. Two parallels for each compound. The samples were vortex mixed and placed in a 37°C water bath and incubated at 50 rpm.
  • a heterogeneous tumor model NSG mouse constructed using a cell line U937 with acute myeloid leukemia (AML) highly expressing CXCR4 and EGFP-Luc (luciferase reporter gene).
  • the model mice were injected with a 5 mg/kg dose of NIC108 compound, and peripheral blood was taken at different time points, mobilized AML cells were labeled with CD45-PE and 12G5-APC antibodies, and the number of AML cells was detected by flow cytometry.
  • the marketed CXCR4 antagonist AMD3100 was used as a positive control.
  • mice Inject 10 mg/kg of NIC108 into AML allogeneic model mice, and give 50 mg/kg of cytarabine to the mice within 3 hours after injection, 7 consecutive days of administration, and give on the 14th day Mice were injected with luciferase to detect the amount of AML cells in the mice.
  • NIC108 can effectively mobilize AML cells in the bone marrow of mice into peripheral blood, and the effect is similar to the positive control drug AMD3100.
  • Figure 1 right shows that NIC108 can effectively mobilize AML cells in bone marrow to peripheral blood, and can greatly enhance the effect of cytarabine to kill tumor cells.
  • NSG mice were injected subcutaneously with NIC108 at a dose of 5 mg/kg.
  • Peripheral blood of the mice was taken at 5 minutes, 15 minutes, 30 minutes, 1 hour and 2 hours after injection. After the red blood cells were broken, the remaining blood cells were planted in stem cell culture. In semi-solid medium. After culturing at 37 degrees for 14 days, the number of colonies formed by hematopoietic stem cells and progenitor cells (CFU) was counted using a stereo microscope.
  • CFU hematopoietic stem cells and progenitor cells
  • NIC108 can effectively mobilize hematopoietic stem cells and hematopoietic progenitor cells in the bone marrow of NSG mice, and the effect is better than the marketed drug AMD3100.

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Abstract

本发明涉及化合物及其在制备药物中的用途、含有该化合物的药物组合物、药物载体、及药物联用。所述化合物为如式(I)所示的化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。

Description

CXCR4抑制剂及其应用 技术领域
本发明涉及医药领域。具体地，本发明涉及CXCR4抑制剂及其应用。更具体地，本发明涉及化合物、化合物在制备药物中的用途、药物组合物、药物载体、药物联用、筛选药物和筛选目标物的方法。
背景技术
CXC趋化因子受体4(CXCR4)和基质细胞衍生因子1(SDF-1)分别属于趋化因子CXC亚家族和趋化因子受体G蛋白偶联受体超家族。CXCR4是一种重要的趋化因子受体，广泛表达于多种造血细胞(中性粒细胞、单核和巨噬细胞、T、B淋巴细胞)、血液和骨髓中的造血干细胞、内皮前体细胞、血液来源的树突状细胞和朗格汉斯细胞中。同时，也高表达于血管内皮细胞、中心和周围神经系统的神经元和神经干细胞及小胶质和星形胶质细胞中。CXCR4是SDF-1α的特异性受体，两者构成CXCR4-SDF-1α生物轴，通过激活细胞内多种信号传导通路，调节细胞的增殖和迁移能力。
大量研究发现CXCR4-SDF-1α轴在调节人体的免疫系统、循环系统和神经系统中发挥重要作用，而且它们的相互作用及其介导的信号传导与病毒感染、肿瘤发生发展和转移、炎症和自身免疫性疾病等多种疾病密切相关。利用CXCR4抑制剂干扰或阻断SDF-1α与CXCR4的相互作用，起到如下作用：1)可动员骨髓中的造血干细胞到外周血，便于采集造血干细胞，用于多发性骨髓瘤和非霍杰金淋巴瘤的治疗；2)可阻断HIV-1入侵T细胞，从而抑制艾滋病的疾病进展；3)可以为抗肿瘤转移提供新的治疗手段；4)可以通过破坏骨髓微环境的保护、抑制白血病细胞向骨髓内外迁移浸润、动员白血病细胞到外周血中并提高其对化疗药物的敏感性，用于白血病的治疗；5)可与肿瘤免疫治疗药物或疗法联合使用治疗肿瘤；6)可治疗免疫缺陷疾病，如WHIM综合征等。
目前对于干细胞动员、HIV感染、血液肿瘤、实体肿瘤和免疫缺陷疾病的药物有很大的需求，而已上市药物较少，且无法满足患者的需求。因此，高活性的CXCR4抑制剂亟待开发，为上述疾病患者提供更好的治疗。
发明内容
本发明旨在至少在一定程度上解决现有技术中存在的技术问题至少之一。
在本发明的一个方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物为如式(I)所示的化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药：
Figure PCTCN2019129362-appb-000001
L选自C 2～10烯基、C 2～10炔基、C 3～8环烷基、C 3～6杂环基、芳基、C 1～5杂芳基、C 1～12稠合环基、C 1～12稠合杂环基、C 1～12螺环基或者C 1～12螺杂环基，或者L、
Figure PCTCN2019129362-appb-000002
及与
Figure PCTCN2019129362-appb-000003
相连的N及R 2形成环状结构；
R 1选自键、氢、磺酰基、亚磺酰基、
Figure PCTCN2019129362-appb-000004
C 1～6烷基磺酰基、氨基C 1～6烷基、C 1～6烷基亚磺酰基、羰基、C 1～6烷基羰基、氨基酸、酰胺键、
Figure PCTCN2019129362-appb-000005
Figure PCTCN2019129362-appb-000006
或者
Figure PCTCN2019129362-appb-000007
其中A、B、C、D、E、F、G各自独立地为C、N、O、S原子，或者
Figure PCTCN2019129362-appb-000008
中的C、N及R 7形成环状结构，或者R 1与R 2以及连接的同一N原子形成环状结构；或者R 2、N、
Figure PCTCN2019129362-appb-000009
和L形成环状结构；
R 2、R 3和R 4各自独立地选自氢、羟基、氨基、磺酰基、亚磺酰基、羰基、C 1～6烷基、C 2～10烯基、C 2～10炔基、C 1～6烷氧基、氨基C 1～6烷基、C 1～6烷基磷酰基、C 1～6烷基羰基、C 3～8环烷基、C 3～8杂环基、芳基、C 1～10杂芳基、C 1～12稠合环基、C 1～12稠合杂环基、C 1～12螺环基或者C 1～12螺杂环基；或者R 3、R 4、
Figure PCTCN2019129362-appb-000010
及与
Figure PCTCN2019129362-appb-000011
两端相连的N原子之间形成环；
R 5和R 6各自独立地选自氢、磺酰基、亚磺酰基、羰基、氨基、C 1～10烷基、C 2～10烯基、C 2～10炔基、C 1～6烷氧基、氨基C 1～6烷基、C 1～6烷基磷酰基、C 1～6烷基羰基、C 1～6烷基芳基、C 3～8环烷基、C 3～8杂环基、C 1～4烷基C 3～8杂环基、芳基、C 1～10杂芳基、C 1～12稠合环基、C 1～12稠合杂环基、C 1～12螺环基或者C 1～12螺杂环基；
R 7选自氢、氨基、磺酰基、亚磺酰基、羰基、C 1～6烷基、C 2～10烯基、C 2～10炔基、C 1～6烷氧基、氨基C 1～6烷基、C 1～6烷基磷酰基、C 1～6烷基羰基、C 1～6烷基芳基、C 3～8环烷基、C 3～8杂环基、芳基、C 1～10杂芳基、C 1～12稠合环基、C 1～12稠合杂环基、C 1～12螺环基、C 1～12螺杂环基；
其中，
所述烯基、炔基、烷氧基、氨基、烷基、氨基烷基、环烷基、烷基磷酰基、杂环基、芳基、杂芳基、烷基羰基、烷基杂环基、烷基芳基、稠合环基、稠合杂环基、螺环基、螺杂环基、磺酰基和亚磺酰基可分别独立地被一个或者多个烷基、烯基、炔基、氟、氯、溴、碘、卤代烷基、卤代芳基、卤代杂芳基、羟基、氨基、羰基、羧基、胍基、脒基、磺酰基、亚磺酰基、烷氧基、氨基烷基、烷基磷酰基、烷基羰基、环烷基、杂环基、芳基、杂芳基、稠合环基、稠合杂环基、螺环基、螺杂环基所取代；
n 1、n 2和n 3各自独立地为0～10的整数。
本发明化合物对CXCR4-SDF-1α轴显示出很强的抑制活性，在动物体内的药代动力学试验中显示出良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，不易分解，药效时间长，可以有效地干扰或阻断SDF-1α与CXCR4的相互作用，既可以有效地动员造血干细胞，为多种血液肿瘤提供新的治疗手段，也可以通过破坏骨髓微环境的保护、抑制白血病细胞向骨髓内外迁移浸润、动员白血病细胞到外周血中并提高其对化疗药物的敏感性，起到治疗白血病的效果，同时，CXCR4-SDF-1α在实体瘤、艾滋病、自身免疫疾病和炎性类疾病也有很重要的生理和病理作用，可作为以上疾病的靶点或辅助治疗的手段，具有很好的应用前景。
根据本发明的实施例，上述化合物还可以具有下列附加技术特征：
根据本发明的实施例，R 1选自键、氢、磺酰基、亚磺酰基、酰胺键、氨基酸、C 1～6烷基磺酰基、C 1～6烷基亚磺酰基、
Figure PCTCN2019129362-appb-000012
Figure PCTCN2019129362-appb-000013
R 2选自氢、C 1～6烷基、C 3～6环烷基、C 3～6杂环基、氨基C 1～4烷基或C 1～5杂芳基，所述烷基、环烷基、杂环基、氨基烷基或杂芳基可任选的被一个或多个H、C 1～4烷基、氟、氯、溴、碘、氨基或C 1～5杂芳基所取代；
或者
Figure PCTCN2019129362-appb-000014
选自
Figure PCTCN2019129362-appb-000015
Figure PCTCN2019129362-appb-000016
或者
Figure PCTCN2019129362-appb-000017
或者L、
Figure PCTCN2019129362-appb-000018
及与
Figure PCTCN2019129362-appb-000019
相连的N和R 2形成
Figure PCTCN2019129362-appb-000020
R 3和R 4分别选自氢或C 1～6烷基，或者R 3、R 4、
Figure PCTCN2019129362-appb-000021
及与
Figure PCTCN2019129362-appb-000022
两端相连的N原子之间形成C 2～6杂环基，所述杂环基可任选地被一个或多个氢、C 1～4烷基、C 3～6环烷基或C 3～6杂环基；
R 5选自C 1～6烷基、芳基、C 3～6环烷基、C 3～6杂环基或C 1～5杂芳基，其中，所述烷基、环烷基、杂环基、芳基或杂芳基可任选地被一个或多个氟、氯、溴、碘、C 1～6烷基、C 1～6环烷基、芳基、C 1～5杂芳基或C 1～6杂环基取代；
R 6选自C 1～4烷基、氨基、磺酰基、亚磺酰基、羰基、氨基C 1～6烷基、C 1～6烷基芳基、C 1～4烷基C 3～8杂芳环基、C 3～6环烷基或C 3～6杂环基，其中，所述烷基、氨基、羰基、磺酰基、亚磺酰基、氨基烷基、烷基芳基、烷基杂环基、环烷基或杂环基可任选地被一个或多个氢、氟、氯、溴、碘、氨基、芳基、C 1～5杂芳基、卤代C 1～5杂芳基、C 2～6杂环基或C 1～4烷基磷酰基取代；
R 7选自C 1～6烷基、芳基、C 1～6烷基芳基、C 1～5杂芳基、C 1～6烯基、C 3～6环烷基、C 3～6杂环基、磺酰基或亚磺酰基，所述烷基、芳基、杂芳基、烷基芳基、烯基、环烷基或杂环基可任选地被一个或多个氢、氟、氯、溴、碘、C 1～6烷基、C 3～6环烷基、芳基、C 1～5杂芳基、脒基、胍基或氨基所取代；
L选自芳基、C 1～5杂芳基、C 2～4炔基、C 3～6环烷基、C 3～6杂环基、C 6～12稠合环基或C 1～12稠合杂环基，所述芳基、杂芳基、炔基、环烷基、稠合环基或稠合杂环基可任选地被一个或多个氢、氟、氯、溴、碘、 C 1～6烷基、C 3～6环烷基、C 3～6杂环基、氨基、羟基、羧基、芳基、C 1～5杂芳基、卤代C 1～6烷基、C 1～6烷氧基、C 1～6氨基烷基或
Figure PCTCN2019129362-appb-000023
所取代。
根据本发明的实施例，L选自以下之一的结构：
Figure PCTCN2019129362-appb-000024
Figure PCTCN2019129362-appb-000025
或者
Figure PCTCN2019129362-appb-000026
所述稠合环基可任选地被一个或多个氢、氟、氯、溴、碘、C 1～10烷基、C 3～8环烷基、C 3～8杂环基、氨基、羟基、羧基、芳基、C 1～5杂芳基、卤代C 1～6烷基、C 1～6烷氧基、C 1～6氨基烷基或所取代，其中A、B、C、D、E、F、G、H和I各自独立地为H、C、N、O、S原子。
根据本发明的实施例，L选自以下之一的结构：
Figure PCTCN2019129362-appb-000027
Figure PCTCN2019129362-appb-000028
Figure PCTCN2019129362-appb-000029
或者
Figure PCTCN2019129362-appb-000030
其中A、B、C、D、E、F、G、H和I各自独立地为H、C、N、O、S原子；
R 8、R 9或R 10各自独立地为氢、氟、氯、溴、碘、C 1～4烷基、氨基C 1～4烷基或C 1～4烷氧基。
根据本发明的实施例，L选自下列之一的稠合环基：
Figure PCTCN2019129362-appb-000031
Figure PCTCN2019129362-appb-000032
所述稠合环基被一个或多个H、C 1～3烷基、氟、氯、溴、碘或C 1～3烷氧基所取代。
根据本发明的实施例，所述L为芳基且R 1为
Figure PCTCN2019129362-appb-000033
时，所述化合物满足下列至少之一的条件：
(1)所述芳基上碳原子被非氢基的取代基所取代；
(2)R 2为C 3～6环烷基、卤代C 1～4烷基或氨基C 1～4烷基；或者L、
Figure PCTCN2019129362-appb-000034
及与
Figure PCTCN2019129362-appb-000035
相连的N和R 2形成
Figure PCTCN2019129362-appb-000036
(3)R 3或R 4为C 1～6烷基，或者R 3、R 4、
Figure PCTCN2019129362-appb-000037
及与
Figure PCTCN2019129362-appb-000038
两端相连的N原子之间形成C 2～8杂环基；
(4)R 5为环烷基，所述环烷基被一个或多个氟、氯、溴、碘、羟基、氨基、芳基、C 1～4烷基、C 1～8环烷基或C 1～8杂环基所取代；
(5)R 6为羰基、磺酰基、亚磺酰基、氨基或氨基C 1～4烷基，所述羰基、磺酰基、亚磺酰基、氨基或氨基C 1～4烷基可任选地被一个或多个氢、氟、氯、溴、碘、氨基、芳基、C 1～5杂芳基、卤代C 1～5杂芳基、C 2～6杂环基或C 1～4烷基磷酰基取代；
(6)R 7为C 1～4烷基、C 1～4烯基、C 1～5杂芳基或C 3～6环烷基，其中，所述烷基不可被烷基、脒基、氨基、C 1～5杂芳基所取代。
根据本发明的实施例，所述化合物为下列所示之一的化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药：
Figure PCTCN2019129362-appb-000039
Figure PCTCN2019129362-appb-000040
Figure PCTCN2019129362-appb-000041
Figure PCTCN2019129362-appb-000042
Figure PCTCN2019129362-appb-000043
Figure PCTCN2019129362-appb-000044
Figure PCTCN2019129362-appb-000045
Figure PCTCN2019129362-appb-000046
Figure PCTCN2019129362-appb-000047
Figure PCTCN2019129362-appb-000048
根据本发明的实施例，所述药学上可接受的盐，包括选自三氟乙酸盐、盐酸盐、醋酸盐、磷酸盐、氢溴酸盐、乳酸盐、双羟基茶酸盐、硫酸盐、甲磺酸盐、甲苯磺酸盐、柠檬酸盐、酒石酸盐、富马酸盐、马来酸盐和苹果酸盐的至少之一。
在本发明的又一方面，本发明提出了前面所述化合物在制备药物中的用途。根据本发明的实施例，所述药物用于治疗肿瘤疾病、艾滋病、骨髓移植、镰状细胞性贫血、造血干细胞移植、创伤、心肌梗死、嗜中性白血球减少症、缺血性疾病、神经性疾病、视网膜静脉阻塞、呼吸系统性疾病、肠胃疾病、皮肤疾病、炎症反应或免疫缺陷疾病。本发明化合物显示出对CXCR4-SDF-1α轴有很强的抑制活性，在动物体内的药代动力学试验中显示出良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，药效时间长，可以有效地干扰或阻断SDF-1α与CXCR4的相互作用，既可以有效地动员造血干细胞，为多种血液肿瘤提供新的治疗手段，也可以通过破坏骨髓微环境的保护、抑制白血病细胞向骨髓内外迁移浸润、动员白血病细胞到外周血中并提高其对化疗药物的敏感性，起到治疗白血病的效果，同时，CXCR4-SDF-1α在实体瘤、艾滋病、自身免疫疾病和炎性类疾病也有很重要的生理和病理作用，可作为以上疾病的靶点或辅助治疗的手段，具有很好的应用前景。
根据本发明的实施例，所述药物抑制CXCR4的表达或者阻断CXCR4和SDF-1α之间的相互作用。本发明的化合物可以通过竞争性地与CXCR4拮抗性结合从而阻断CXCR4和天然配体SDF-1α之间的相互作用。
根据本发明的实施例，所述药物用于动员骨髓中的造血干细胞以用于自体或异体造血干细胞移植，用于多发性骨髓瘤和非霍杰金淋巴瘤疾病的治疗。
根据本发明的实施例，所述药物用于动员骨髓中的干细胞，用于白血病的治疗。
根据本发明的实施例，所述药物用于动员骨髓中的急性髓细胞白血病的癌细胞到外周血，用于白血病的治疗。
根据本发明的实施例，所述药物抑制肿瘤细胞转移，用于肿瘤的治疗。
根据本发明的实施例，所述药物抑制HIV-1入侵T细胞，用于艾滋病的治疗。
根据本发明的实施例，所述药物用于自身免疫缺陷疾病的治疗。
根据本发明的实施例，所述药物在制备造血干细胞/祖细胞动员剂和/或在过表达CXCR4的肿瘤组织中作为检测肿瘤标志物的应用。
本发明的又一方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物包括前面所述化合物。本发明化合物显示出对CXCR4-SDF-1α轴有很强的抑制活性，在动物的体外体内的药代和药效实验中表现出较好的成药性，尤其是在体内具有较强的稳定性，药效时间长可以有效地干扰或阻断SDF-1α与CXCR4的相互作用，既可以为血液肿瘤提供新的治疗手段，也可以通过破坏骨髓微环境的保护、抑制白血病细胞向骨髓内外迁移浸润、动员白血病细胞到外周血中并提高其对化疗药物的敏感性，起到治疗肿瘤疾病、免疫缺陷性疾病、艾滋病和炎性反应等效果，具有较好的应用前景。
根据本发明的实施例，所述药物组合物进一步包括药学上可接受的辅料、载体、赋形剂、溶媒或它们的组合。根据本发明的实施例，所述药物组合物进一步包含治疗剂，所述治疗剂选自下列的至少之一：马拉韦罗、恩夫韦肽、齐多夫定、扎西他宾、司他夫定、拉米夫定、萘韦拉平、地拉韦定、阿巴卡韦、依非韦伦、替诺福韦、乙曲西他槟、依曲韦润、利匹韦润、顺铂、环磷酰胺、阿糖胞苷、5-氟尿嘧啶、吉西他滨、紫杉醇、多西他赛、阿霉素、格列卫、特罗凯、索拉菲尼、达沙替尼、拉帕替尼、舒尼替尼、埃罗替尼、吉非替尼、Tisagenlecleucel、益基利仑赛、阿仑单抗、阿特珠单抗、阿维单抗、伊匹单抗、奥法木单抗、纳武利尤单抗、帕博利珠单抗、利妥昔单抗、度伐鲁单抗、卡瑞利珠单抗、特伦普利单抗、信迪利单抗、替雷利珠单抗、阿替利珠单抗、西妥昔单抗和曲妥珠单抗的赫赛汀。
在本发明的又一方面，本发明提出了一种药物载体。根据本发明的实施例，所述药物载体包括前面所述化合物。本发明化合物对CXCR4-SDF-1α轴显示出很强的抑制活性，在动物体内的药代动力学试验中吸收、分布、代谢和排泄(ADME)均表现出良好的成药性数据，显示出良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，药效时间长，可以有效地干扰或阻断SDF-1α与CXCR4的相互作用，既可以为血液肿瘤提供新的治疗手段，也可以通过动员白血病细胞到外周血中并提高其对化疗药物的敏感性，起到治疗肿瘤疾病、免疫缺陷性疾病、艾滋病和炎性反应等效果，具有较好的应用前景。
在本发明的又一方面，本发明提出了一种药物联合。根据本发明的实施例，所述药物联合包含：前面所述化合物或药物组合物；以及一种或多种用于治疗肿瘤疾病、艾滋病、炎症反应以及免疫缺陷疾病的药物。本发明化合物对CXCR4-SDF-1α轴显示出很强的抑制活性，在动物体内的药代动力学试验中显示出良好的吸收、较高的生物活性和利用度，低毒，尤其是在体内具有较强的稳定性，药效时间长，可以有效地干扰或阻断SDF-1α与CXCR4的相互作用，既可以为血液肿瘤提供新的治疗手段，也可以通过破坏骨髓微环境的保护、抑制白血病细胞向骨髓内外迁移浸润、动员白血病细胞到外周血中并提高其对化疗药物的敏感性，起到治疗肿瘤疾病、免疫缺陷性疾病、艾滋病和炎性反应等效果，具有较好的应用前景。
根据本发明的实施例，所述药物选自下列的至少之一：马拉韦罗、恩夫韦肽、齐多夫定、扎西他宾、司他夫定、拉米夫定、萘韦拉平、地拉韦定、阿巴卡韦、依非韦伦、替诺福韦、乙曲西他槟、依曲韦润、利匹韦润、顺铂、环磷酰胺、阿糖胞苷、5-氟尿嘧啶、吉西他滨、紫杉醇、多西他赛、阿霉素、格列卫、特罗凯、索拉菲尼、达沙替尼、拉帕替尼、舒尼替尼、埃罗替尼、吉非替尼、Tisagenlecleucel、益基利仑赛、阿仑单抗、阿特珠单抗、阿维单抗、伊匹单抗、奥法木单抗、纳武利尤单抗、帕博利珠单抗、利妥昔单抗、度伐鲁单抗、卡瑞利珠单抗、特伦普利单抗、信迪利单抗、替雷利珠单抗、阿替利珠单抗、西妥昔单抗或曲妥珠单抗的赫赛汀。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1显示了根据本发明一个实施例的NIC108动员AML模型小鼠的肿瘤细胞并协同提升化疗药物阿糖胞苷的效果示意图；
图2显示了根据本发明一个实施例的动员出的造血干细胞所形成集落的数量分析示意图。
具体实施方式
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
定义或一般术语
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体 包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；PrinciplesofAsymmetricSynthesis(2 nd Ed.Robert E.Gawley,JeffreyAubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1～6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
像本发明所描述的，本发明的化合物可以独立任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“独立任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子可以被具体取代基1所取代或未取代。除非其他方面表明，一个任选的取代基团可以有一个取代基1在基团的各个可取代的位置进行取代或未取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基1所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基1可以是，但并不限于：氧代(＝O)，氟，氯，溴，碘，羟基，氨基，羧基，烷基，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，氨基烷基，烷硫基，卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基烷氧基，苄基，环丙基，苯基，或烷氧基烷基等。在合理的情况下，取代基1能进一步被取代基2单取代或相同或不同的多取代。其中所述的取代基2可以是，但不限于：氧代(＝O)，氟，氯，溴，碘，羟基，氨基，羧基，烷基，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，氨基烷基，烷硫基，卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基烷氧基，苄基，环丙基，苯基，或烷氧基烷基等。
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-10个碳原子；另外一些实施例是，烷基基团含有1-8个碳原子；另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子；另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(-CH 3)，乙基(-CH 2CH 3)，正丙基(-CH 2CH 2CH 3)，异丙基(-CH(CH 3) 2)，正丁基(-CH 2CH 2CH 2CH 3)，2-甲基丙基或异丁基(-CH 2CH(CH 3) 2)，1-甲基丙基或仲丁基(-CH(CH 3)CH 2CH 3)，叔丁基(-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。烷基可以被本发明所述的取代基所取代。
术语“卤代烷基”表示烷基可以被一个或多个相同或不同卤素原子所取代的情况。其中烷基基团具有如本发明所述的含义，这样的实例包括，但并不限于三氟甲基，2,2-二氟乙基，3,3,3-三氟丙基等。卤代烷基可以被本发明所述的取代基所取代。
术语“氨基烷基”是指烷基可以被一个或多个相同或不同的氨基取代或者氨基分别独立地被一个或两个烷基基团所取代，其中烷基具有如本发明所述的含义。
本发明中所使用的术语“烷氧基”，涉及到烷基，像本发明所定义的，通过氧原子连接到主要的碳链上。这样的实施例包括，但并不限于，甲氧基，乙氧基，丙氧基等等。烷氧基可以被本发明所述的取代基所取代。
术语“环烷基”是指一价或多价、非芳香族、饱和或部分不饱和环，且不包含杂原子，其中包括3-12个碳原子的单环或7-12个碳原子的二环或三环。具有7-12个原子的双碳环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，同时具有9或10个原子的双碳环可以是二环[5,6]或[6,6]体系。合适的环烷基基团包括，但并不限于，环烷基，环烯基和环炔基。环烷基基团的实例进一步包括，但绝不限于，环丙基，环丁基，环戊基，1-环戊基-1-烯基，1-环戊基-2-烯基，1-环戊基-3-烯基，环己基，1-环己基-1-烯基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，环壬基，环癸基，环十一烷基，环十二烷基， 金刚烷基等等。视结构而定，环烷基可为单价基团或二价基团，即亚环烷基。C 4环烷基是指环丁基，C 5环烷基是指环戊基，C 7环烷基是指环庚基。环烷基可以被本发明所述的取代基所取代。
术语“芳基”可以是单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子，且只有一个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽。视结构而定，芳基可为单价基团或二价基团，即亚芳基。芳基可以被本发明所述的取代基所取代。
术语“杂芳基”，“杂芳环”在此处可交换使用，都是指单环，双环，三环或者四环体系，其中，双环杂芳环，三环杂芳环或者四环杂芳环体系以稠合的形式成环。其中，杂芳环体系至少一个环体系是芳香族的，环上一个或多个原子独立任选地被杂原子所取代(杂原子选自N，O，P，S，在此S或P独立任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团)。杂芳体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。杂芳体系基团可以是3-7个原子组成的单环，或7-10个原子组成的双环，或10-15个原子组成的三环。具有7-10个原子的双环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，具有10-15个原子的三环可以是三环[5,5,6]，[5,7,6]或[6,5,6]体系。
术语“杂环基”，“杂环”，“杂脂环族”或“杂环的”在此处可交换使用，都是指单环，双环，三环或者四环体系，其中环上一个或多个原子独立任选地被杂原子所取代，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类。杂环体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。一个或多个环上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，“杂环基”，“杂环”，“杂脂环族”或“杂环的”基团是3-7元环的单环(1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P独立任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团，同时，-CH 2-基团可以独立任选地被-C(＝O)-替代；当所述的环为三元环时，其中只有一个杂原子)，或7-10个原子组成的双环(4-9个碳原子和选自N，O，P，S的1-3个杂原子，在此N，S或P独立任选地被一个或多个氧原子所取代得到像NO，NO 2，SO，SO 2，PO，PO 2的基团，同时，-CH 2-基团可以独立任选地被-C(＝O)-替代；)。
“杂环基”可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和碳环或杂环并合所形成的基团。杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，噻噁烷基，氮杂环丁基，氧杂环丁基，硫杂环丁基，哌啶基，高哌啶基，环氧丙基，N-吗啉基，N-哌嗪基，2-哌嗪基，3-哌嗪基，高哌嗪基，氧氮杂卓基，二氮杂卓基，硫氮杂卓基，吡咯啉-1-基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，二氢苯并异噻嗪基，二氢苯并异噁嗪基，二氧戊环基，二氢吡嗪基，二氢吡啶基，二氢吡唑基，二氢嘧啶基，二氢吡咯基，呋喃酮基，呋喃基，咪唑烷基，咪唑啉基，咪唑基，咪唑并吡啶基，咪唑并噻唑基，吲唑基，，吲哚嗪基，吲哚基，吗啉基，噁唑烷二酮基，噁唑烷基，环氧乙烷基，哌嗪基，哌啶基，吡唑烷基，喹宁环基，四氢异喹啉基，四氢噻嗯基，硫吗啉基，噻唑烷基。
术语“螺环基”，“螺环”，“螺双环基”，“螺双环”表示一个环起源于另一个环上特殊的环状碳。例如，像下面所描述的，一个饱和的桥环体系(环D和B')被称为“稠合双环”，反之环A’和环D在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。螺环里面的每一个环要么是碳环要么是杂脂环族。这样的实例包括，但并不限于，螺[2.4]庚烷-5-基，螺[4.4]壬烷基，等。
Figure PCTCN2019129362-appb-000049
术语“螺杂双环基”表示一个环起源于另一个环上特殊的环状碳。例如，像上面所描述的，一个饱和的桥环体系(环D和B')被称为“稠合双环”，反之环A’和环D在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7个原子，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子,在此N，S或P独立任选地被一个或多个氧原子所取代得到像NO，NO 2，SO，SO 2，PO，PO 2的基团，-CH 2-基团可以独立任选地被-C(＝O)-替代。
术语“稠合双环”，“稠环”，“稠合双环基”或“稠环基”表示饱和或不饱和的稠环体系，涉及到非芳香族的双环体系，至少有一个环是非芳香性的。这样的体系可以包含独立的或共轭的不饱和状态。稠合双环中的每一个环要么是碳环要么是杂脂环族，这样的实例包括，但并不限于，六氢-呋喃[3,2-b]呋喃基，2,3,3a,4,7,7a-六氢-1H-茚基，7-氮杂双环[2.2.1]庚烷基，稠合双环[3.3.0]辛烷基，稠合双环[3.1.0]己烷基，1,2,3,4,4a,5,8,8a-八氢萘基，1,2,3,4-四氢萘，2,3-二氢茚，这些都包含在稠合双环的体系之内。
术语“稠合杂双环基”表示饱和或不饱和的稠环体系，涉及到非芳香族的双环体系，至少有一个环是非芳香性的。这样的体系可以包含独立的或共轭的不饱和状态。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7个原子组成的环，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此N，S或P独立任选地被一个或多个氧原子所取代得到像NO，NO 2，SO，SO 2，PO，PO 2的基团，-CH 2-基团可以独立任选地被-C(＝O)-替代。稠合杂双环基可以被本发明所述的取代基所取代。
如本发明所描述，取代基R’由一个键连接到中心的环上形成的环体系代表取代基R’可以在环上任何可取代或任何合理的位置进行取代。例如，式a代表A’环或B’环上任何可能被取代的位置均可被R’取代，如式b，式c，式d，式e，式f，式g，和式h所示。
Figure PCTCN2019129362-appb-000050
如本发明所描述，附着点可以在环上任何可连接的位置与分子其余部分连接。例如，式i代表A’环或B’环上任何可能被连接的位置均可作为连接的点。
Figure PCTCN2019129362-appb-000051
如本发明所描述，附着点可以在稠环上任何可连接的位置与分子其余部分连接，同时连接的两端可以互换。例如，式y代表环上任何可能被连接的位置均可作为连接的点，同时连接点的两端可以互换。
Figure PCTCN2019129362-appb-000052
另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各…和…独立地为”、“…和…各自独立地为”和“…和…分别独立地为”可以互换，应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，“H-(C(R 3) 2) n-O-(C(R 3) 2) n1-C(＝O)-(C(R 3) 2) n-”中“R 3”表示相同或不同的基团，且相互之间不影响；“n”表示相同或不同的取值，且相互之间不影响。
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液 体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。水和水性溶液盐水溶液和水性葡萄糖与甘油溶液优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′s Pharmaceutical Sciences”中。
本发明中立体化学的定义和惯例的使用通常参考以下文献：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。
“异构体”为具有相同分子式的不同化合物。“立体异构体”为仅仅原子的空间排列方式不同的异构体。如本文使用的术语“异构体”包括任何和所有的几何异构体和立体异构体。例如，“异构体”包括顺式和反式异构体、E-和Z-异构体、R-和S-对映异构体、非对映异构体、(d)异构体、(l)-异构体、其外消旋混合物、及落入本说明书范围的其它其混合物。
本发明的“水合物”是指本发明所提供的化合物或其盐，其还包括化学量或非化学当量通过非共价分子间力结合的水，也可说是溶剂分子是水所形成的缔合物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂例如二氯甲烷中，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
化合物可存在多种不同几何异构体和互变异构体，所述式(I)-式(III)化合物包括所有此类形式。为避免疑惑，当化合物以几种几何异构体或互变异构体之一存在并且只具体描述或显示一种时，显然所有其它形式包括在式(I)-式(III)中。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)-式(III)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分 接触一段时间所产生的代谢产物。
本发明化合物的各种药学上可接受的盐形式都是有用的。术语“药学上可接受的盐”是指那些盐形式对于制药化学家而言是显而易见的，即它们基本上无毒并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄。其他因素，在性质上更加实用，对于选择也很重要，这些是：原材料的成本、结晶的容易、产率、稳定性、吸湿性和结果原料药的流动性。简单地讲，药物组合物可以通过有效成分与药学上可接受的载体制备得到。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，硝酸盐等，和有机酸盐如乙酸盐，丙酸盐，乙醇酸盐，草酸盐，马来酸盐，丙二酸盐，琥珀酸盐，富马酸盐，酒石酸盐，枸橼酸盐，苯甲酸盐，扁桃酸盐，甲磺酸盐，乙磺酸盐，甲苯磺酸盐，磺基水杨酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。
其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐、等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。
本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。胺盐，例如但不限于N,N’-二苄基乙二胺，氯普鲁卡因，胆碱，氨，二乙醇胺和其它羟烷基胺，乙二胺，N-甲基还原葡糖胺，普鲁卡因，N-苄基苯乙胺，1-对-氯苄基-2-吡咯烷-1’-基甲基-苯并咪唑，二乙胺和其它烷基胺，哌嗪和三(羟甲基)氨基甲烷；碱土金属盐，例如但不限于钡，钙和镁；过渡金属盐，例如但不限于锌。
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参照IUPAC-IUB Commission on Biochemical Nomenclature(参见Biochem.1972，11：942-944)。
本发明提供药物组合物，包含治疗有效量的式(I)所示化合物或其药学上可接受的盐和药学上可接受的辅料、载体、赋形剂、溶媒或它们的组合。当本发明的化合物以药物的形式施用于哺乳动物例如人时，其可以以化合物本身的形式被给予或者可以以含有例如0.1至99.5％(更优选0.5至90％)活性成分以及药学可接受的载体的药物组合物的形式被给予。
“联合”表示在单个剂量单位形式中的固定组合或用于组合施用的部分的药盒，其中本发明公开化合物和组合伴侣(治疗肿瘤疾病、艾滋病、炎症反应以及免疫缺陷疾病的药物)可以在同一时间独立施用或者可以在一定的时间间隔内分别施用，特别是使联合合伴侣表现出合作、例如协同作用。如本文所用的术语“药物组合物”表示将一种以上活性成分混合或组合所得到的产品，并且既包括活性成分的固定组合也包括非固定组合。术语“固定联合”表示活性成分如本发明公开化合物和组合伙伴以单一实体或剂量的形式同时施用于患者。术语“非固定联合”表示活性成分如本发明公开化合物和组合伙伴均作为单独实体同时、共同或无特定时间限制地先后施用于患者。
措辞“药学可接受的载体”在本领域中是公认的，包括适于将本发明的化合物施用于哺乳动物的药学可接受的材料、组合物或载体。所述载体包括参与携带主题物质或将其从一个器官或机体的一部分转移 到另一个器官或机体的另一部分的液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。各载体在与制剂中的其它成分相容和对患者无害的意义上必须是“可接受的”。可用作药学可接受的载体的材料的一些实例包括：糖类，如乳糖、葡萄糖和蔗糖；淀粉类，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；粉状西黄蓍胶；麦芽；明胶；滑石粉；赋形剂，如可可脂和栓剂蜡类；油类，如花生油、棉子油、红花油、芝麻油、橄榄油、玉米油和豆油；二醇类，如丙二醇；多元醇类，如甘油、山梨醇、甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等张盐水；林格氏溶液；乙醇；磷酸盐缓冲液；和药物制剂中所用的其它无毒的可相容的物质。
在组合物中也可以存在润湿剂、乳化剂和润滑剂如十二烷基硫酸钠和硬脂酸镁，以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂。
药学可接受的抗氧化剂的实例包括：水溶性抗氧化剂，如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等；油溶性抗氧化剂，如棕榈酸抗坏血酸酯、丁基化羟基苯甲醚(BHA)、丁化羟基甲苯(BHT)、卵磷脂、棓酸丙酯、α-生育酚等；和金属螯合剂，如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本发明的药物组合物包括适于口服、鼻、局部、口含、舌下、直肠和/或胃肠外施用的那些。制剂可以方便地以单位剂型形式存在并且可以通过药学领域公知的任何方法来制备。可以与载体物质组合来制备单剂量形式的活性成分的量一般是产生治疗作用的化合物的量。一般而言，以百分之一为单位，该量为约1％至约99％活性成分，优选约5％至约70％，最优选约10至约30％。
术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生；(b)抑制疾病，例如阻滞疾病发展；或(c)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述化合物的药物给予有需要的个体。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
Figure PCTCN2019129362-appb-000053
中间体71-2的合成：
将化合物71-1(500mg，2.92mmol)溶解在THF(30mL)和H 2O 30mL中，加入碳酸氢钠(294mg，3.50mmol)，二碳酸二叔丁酯(764mg，3.50mmol)，室温搅拌。TLC跟踪反应，至原料氨甲环酸甲酯消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(PE:EA＝3:1)，得到中间体6-2(751mg)。
中间体71-2的合成：
将71-1(750mg，2.77mmol)溶解在THF(30mL)中，降温至0℃搅拌，慢慢加入LiAlH4(211mg，5.54mmol)，搅拌,室温反应。TLC跟踪反应，至原料83-1消失，停止反应，饱和食盐水和EA萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(PE:EA＝3:1)，得到化合物83-2(754mg)。
中间体71-3的合成：
于100ml单口瓶中加入中间体71-2(750mg，3.08mmol)，DMSO(10ml)，IBX(1.04g，3.70mmol)，室温下反应过夜，TLC监控。常规萃取操作浓缩，过柱纯化(PE:EA＝1:2)得685mg黄色固体。
中间体71-4的合成：
将化合物71-3(650mg，2.70mmol)溶解在甲醇(30mL)中，搅拌，依次加入N-(3-氨丙基)环己胺(423mg，2.70mmol)，氰基硼氢化钠(171mg，2.71mmol)和醋酸(163mg，2.71mmol)，TLC跟踪反应，至原料71-4消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝10:1)，得到中间体71-4(847mg)。
中间体71-5的合成：
将化合物71-4(840mg)溶解在2M HCl/CH 3OH中，室温搅拌，TLC跟踪反应，至原料71-4消失，停止反应，浓缩除去溶剂，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝8:1)，得到化合物71-5(677mg)。
中间体71-6的合成：
将N-Boc-L-丙氨酸(717mg，2.31mmol)溶解于THF(50mL)中，搅拌，依次加入HATU(1.05g，2.77mmol)，HOBT(372mg，2.77mmol)，DIEA(593mg，4.59mmol)和化合物71-5(650mg，2.31mmol)，室温搅拌，TLC跟踪反应，至原料17-1消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩过柱纯化(DCM:CH 3OH＝10:1)，得到中间体71-6(836mg)。
中间体71-7的合成：
将化合物71-6(836mg)溶解在2M HCl/CH 3OH中，室温搅拌，TLC跟踪反应，至原料71-6消失，停止反应，浓缩除去溶剂，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，得到化合物71-7(654mg)。
终产物NIC71的合成：
将化合物71-7(600mg，1.70mmol)溶解在甲醇(30mL)中，搅拌，依次加入吡啶-2-甲醛(183mg，1.70mmol)，氰基硼氢化钠(129mg，2.05mmol)和醋酸(141mg，2.33mmol)，TLC跟踪反应，至原料71-7消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝20:1)，得到白色固体终产物NIC71(359mg)。
化合物NIC71： 1H NMR(400MHz,CDCl 3)δ8.59(d,J＝3.8Hz,1H),7.66(t,J＝7.6Hz,1H),7.52(s,1H),7.21(d,J＝7.7Hz,2H),3.87(d,J＝4.6Hz,2H),3.30–3.19(m,1H),3.12(t,J＝6.4Hz,2H),2.69(dt,J＝18.2,6.6Hz,4H),2.45(d,J＝6.3Hz,3H),1.89(d,J＝11.4Hz,3H),1.85–1.57(m,10H),1.56–1.39(m,3H),1.36(d,J＝6.9Hz,3H),1.33–0.86(m,10H)。
HRMS(ESI,m/z)：444.3713。
参考上述合成路线合成下表所示的化合物：
Figure PCTCN2019129362-appb-000054
Figure PCTCN2019129362-appb-000055
Figure PCTCN2019129362-appb-000056
Figure PCTCN2019129362-appb-000057
Figure PCTCN2019129362-appb-000058
Figure PCTCN2019129362-appb-000059
Figure PCTCN2019129362-appb-000060
Figure PCTCN2019129362-appb-000061
Figure PCTCN2019129362-appb-000062
实施例2
Figure PCTCN2019129362-appb-000063
中间体96-2的合成：
将化合物96-1(400mg，0.84mmol)溶解在10Ml THF中，依次加入2,4-二氯嘧啶(125mg，0.84mmol)和DIEA(129mg，1.00mmol)，室温搅拌，TLC跟踪反应，至原料96-1消失，停止反应，饱和食盐水和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝30:1)，得到黄色固体终产物96-2(392mg)。
中间体96-3的合成：
将化合物96-2(390mg，0.66mmol)溶解在20Ml 1,4-二氧六环中，依次加入2-氨甲基吡啶(71mg，0.66mmol)，碳酸铯(323mg，0.99mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(48mg，0.066mmol)，N2置换，加热至100℃反应。TLC跟踪反应，至原料96-2消失，停止反应，饱和食盐水和DCM萃取号西苑广场三楼、电脑城3楼)三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝30:1)，得到黄色固体终产物96-3(268mg)。
终产物NIC96的合成：
将化合物96-3(260mg)溶解在2M HCl/CH 3OH中，室温搅拌，TLC跟踪反应，至原料32-4消失，停止反应，浓缩除去溶剂，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩过柱坐公交车到童诺迷你世界)纯化(DCM:CH 3OH＝10:1)，得到终产物NIC32(168mg)。
化合物NIC32：HRMS(ESI,m/z)：460.3192。
参考上述合成路线合成下表所示的化合物：
Figure PCTCN2019129362-appb-000064
Figure PCTCN2019129362-appb-000065
实施例3
Figure PCTCN2019129362-appb-000066
中间体17-2合成：
将N-Fmoc-L-丙氨酸(295mg，0.95mmol)溶解于THF(20Ml)中，搅拌，依次加入HATU(431mg，1.14mmol)，HOBT(153mg，1.14mmol)，DIEA(244mg，1.89mmol)和化合物17-1(528mg，0.95mmol)，室温搅拌，TLC跟踪反应，至原料17-1消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩过柱纯化(PE:EA＝3:1)，得到中间体17-2(679mg)。
中间体17-3合成：
将化合物17-2(650mg)溶解在1M PIP/THF溶液中，室温搅拌。TLC跟踪反应，至原料17-2消失，停止反应，浓缩过柱纯化(DCM:CH 3OH＝10:1)，得到中间体17-3(451mg)。
中间体17-4合成：
将化合物17-3(450mg，0.82mmol)溶解在甲醇(20Ml)中，搅拌，依次加入2-乙酰基吡啶(100mg，0.82mmol)，氰基硼氢化钠(103mg，1.64mmol)和醋酸(98mg，1.64mmol)，TLC跟踪反应，至原料17-3消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝20:1)，得到中间体17-4(389mg)。
化合物NIC17的合成：
将化合物17-4(350mg)溶解在2M HCl/CH 3OH中，室温搅拌，TLC跟踪反应，至原料17-4消失，停止反应，浓缩除去溶剂，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝8:1)，得到化合物NIC17(139mg)。
化合物NIC17： 1H NMR(400MHz,DMSO)δ9.50(s,1H),8.80(t,J＝5.7Hz,1H),8.69(d,J＝4.2Hz,1H),7.89(td,J＝7.7,1.7Hz,1H),7.46(dd,J＝10.7,8.2Hz,3H),7.30(dd,J＝17.0,8.1Hz,2H),4.51(s, 1H),4.35(dd,J＝11.6,5.9Hz,2H),4.16(s,2H),3.67(s,2H),3.00(s,5H),1.99(s,4H),1.77(s,2H),1.62(d,J＝11.3Hz,1H),1.53(t,J＝6.2Hz,3H),1.42(t,J＝6.0Hz,3H),1.25(t,J＝10.0Hz,6H)。
HRMS(ESI,m/z)：452.3393。
参考上述合成路线合成下表所示的化合物：
Figure PCTCN2019129362-appb-000067
Figure PCTCN2019129362-appb-000068
实施例4
Figure PCTCN2019129362-appb-000069
中间体6-1的合成：
将化合物N-叔丁氧羰基-1,3-丙二胺(500mg，2.87mmol)溶解在40Ml甲醇中，室温搅拌，加入4-氰基苯甲醛(375mg，2.87mmol)，室温搅拌1h，加入氰基硼氢化钠(218mg,3.44mmol)和冰醋酸(206mg,3.44mmol),室温搅拌。TLC跟踪反应，至原料N-叔丁氧羰基-1,3-丙二胺消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝20:1)，得到中间体6-1(948mg)。
中间体6-2的合成：
将化合物6-1(900mg，3.11mmol)溶解在THF(20Ml)和H 2O 20Ml中，加入碳酸氢钠(270mg，3.22mmol)，二碳酸二叔丁酯(678mg，3.11mmol),,室温搅拌。TLC跟踪反应，至原料N-叔丁氧羰基-1,3-丙二胺消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(PE:EA＝3:1)，得到中间体6-2(1.3g)。
中间体6-3的合成：
将化合物6-2(1g)溶解在甲醇中，加入10％的Rany Ni，H2置换三次。室温搅拌反应。TLC跟踪反应，至原料6-2消失，停止反应，过滤，浓缩，得到中间体6-3(989mg)。
中间体6-4的合成：
将化合物6-3(980mg，2.49mmol)溶解于THF(20Ml)中，搅拌，依次加入HATU(941mg，2.49mmol)，HOBT(334mg，2.49mmol)，DIEA(1.01g，4.13mmol)和化合物N-芴甲氧羰基-L-丙氨酸五氟苯酯(1.19g，2.49mmol)，室温搅拌，TLC跟踪反应，至原料6-3消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩过柱纯化(PE:EA＝3:1)，得到中间体6-4(1.5g)。
中间体6-5的合成：
将化合物6-5(1.5g)溶解在20％PIP/THF溶液中，室温搅拌反应。TLC跟踪反应，至原料6-5消失，停止反应，浓缩，过柱纯化(DCM:CH 3OH＝20:1)，得到中间体6-3(972mg)。中间体6-6的合成：
将化合物6-6(900mg，1.94mmol)溶解在甲醇(30Ml)中，搅拌，依次加入吡啶-2-甲醛(208mg，1.94mmol)，氰基硼氢化钠(147mg，2.33mmol)和醋酸(141mg，2.33mmol)，TLC跟踪反应，至原料6-6消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝20:1)，得到中间体6-6(879mg)。
中间体6-7的合成：
将化合物6-5(850mg)溶解在2M HCl/CH 3OH中，室温搅拌，TLC跟踪反应，至原料6-5消失， 停止反应，浓缩除去溶剂，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝8:1)，得到化合物6-7(458mg)。
终产物NIC6的合成：
将化合物6-7(400mg，1.13mmol)溶解在甲醇(30Ml)中，搅拌，依次加入4,4-二氟环已酮(151mg，1.13mmol)，氰基硼氢化钠(86mg，1.36mmol)和醋酸(82mg，1.36mmol)，TLC跟踪反应，至原料6-7消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝20:1)，得到终产物NIC6(268mg)。
化合物NIC6： 1H NMR(400MHz,DMSO)δ9.46(s,1H),8.96(s,1H),8.69(d,J＝4.2Hz,1H),7.94(td,J＝7.7,1.7Hz,1H),7.57–7.46(m,3H),7.38(d,J＝8.1Hz,2H),4.43(d,J＝5.4Hz,2H),4.35(d,J＝9.7Hz,2H),4.18(s,2H),4.06(d,J＝6.8Hz,1H),3.25(s,1H),3.06(s,4H),2.12(d,J＝13.3Hz,4H),2.06–1.99(m,2H),1.92(dd,J＝22.7,8.9Hz,2H),1.62(d,J＝10.9Hz,2H),1.53(d,J＝7.0Hz,3H)。
HRMS(ESI,m/z)：474.3074。
参考上述合成路线合成下表所示的化合物：
Figure PCTCN2019129362-appb-000070
Figure PCTCN2019129362-appb-000071
Figure PCTCN2019129362-appb-000072
Figure PCTCN2019129362-appb-000073
实施例5
Figure PCTCN2019129362-appb-000074
中间体83-1的合成：
将2-哌嗪酮(400mg，3.00mmol)溶解在甲醇(30Ml)中，搅拌，依次加入吡啶-2-甲醛(321mg，3.00mmol)，氰基硼氢化钠(227mg，3.60mmol)和醋酸(216mg，3.60mmol)，TLC跟踪反应，至原料2-哌嗪酮消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝20:1)，得到化合物83-1(587mg)。
中间体83-2的合成：
将83-1(580mg，3.03mmol)溶解在THF(30Ml)中，降温至0℃搅拌，慢慢加入NaH(145mg，6.06mmol)，搅拌30min，加入4-溴甲基苯甲醛(603mg，3.03mmol)，室温反应。TLC跟踪反应，至原料83-1消失，停止反应，饱和食盐水和EA萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(PE:EA＝3:1)，得到化合物83-2(754mg)。
终产物NIC83的合成：
将化合物83-2(700mg，2.26mmol)溶解在甲醇(30Ml)中，搅拌，依次加入N-(3-氨丙基)环己胺(354mg，2.26mmol)，氰基硼氢化钠(171mg，2.71mmol)和醋酸(163mg，2.71mmol)，TLC跟 踪反应，至原料83-2消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝10:1)，得到终产物NIC83(468mg)。
化合物NIC83： 1H NMR(400MHz,DMSO)δ8.50(dt,J＝8.4,2.6Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.43(d,J＝7.8Hz,1H),7.34–7.25(m,3H),7.16(d,J＝8.0Hz,2H),4.48(s,2H),3.71–3.60(m,5H),3.22–3.15(m,3H),3.14(s,2H),2.70–2.63(m,2H),2.58–2.53(m,2H),2.32(d,J＝12.5Hz,2H),1.77(d,J＝10.2Hz,2H),1.63(d,J＝12.1Hz,2H),1.52(dd,J＝13.6,6.7Hz,3H),1.25–1.06(m,4H),0.95(d,J＝11.1Hz,2H)。
HRMS(ESI,m/z)：450.3232。
参考上述合成路线合成下表所示的化合物：
Figure PCTCN2019129362-appb-000075
Figure PCTCN2019129362-appb-000076
实施例6
Figure PCTCN2019129362-appb-000077
中间体32-2的合成：
将N-Fmoc-L-丙氨酸(271mg，0.87mmol)将溶解于THF(50Ml)中，搅拌，依次加入HATU(400mg，1.04mmol)，HOBT(141mg，1.04mmol)，DIEA(225mg，1.74mmol)和中间体32-1(400mg，0.87mmol)，室温搅拌，TLC跟踪反应，至原料17-1消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩过柱纯化(DCM:CH 3OH＝10:1)，得到中间体71-6(512mg)
中间体32-3的合成：
将化合物32-2(500mg)溶解在20％PIP/THF溶液中，室温搅拌。TLC跟踪反应，至原料32-2消失，停止反应，浓缩过柱纯化(DCM:CH 3OH＝10:1)，得到中间体32-3(368mg)。
中间体32-4的合成：
将3-吡啶磺酸(102mg，0.64mmol)将溶解于THF(50Ml)中，搅拌，依次加入HATU(296mg，0.77mmol)，HOBT(104mg，0.77mmol)，DIEA(167mg，1.29mmol)和中间体32-3(350mg，0.64mmol)，室温搅拌，TLC跟踪反应，至原料32-3消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩过柱纯化(DCM:CH 3OH＝10:1)，得到中间体32-4(385mg)。
终产物NIC32的合成：
将化合物32-4(380mg)溶解在2M HCl/CH 3OH中，室温搅拌，TLC跟踪反应，至原料32-4消失，停止反应，浓缩除去溶剂，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩过柱纯化(DCM:CH 3OH＝10:1)，得到终产物NIC32(168mg)。
化合物NIC32： 1H NMR(400MHz,DMSO)δ9.57(s,1H),8.79(t,J＝5.7Hz,1H),8.69(d,J＝4.2Hz,1H),7.89(td,J＝7.7,1.7Hz,1H),7.46(dd,J＝10.7,8.2Hz,3H),7.30(dd,J＝17.0,8.1Hz,2H),4.51(s,1H),4.35(dd,J＝11.6,5.9Hz,2H),4.16(s,2H),3.67(s,2H),3.00(s,5H),1.99(s,4H),1.77(s,2H),1.53(t,J＝6.2Hz,3H),1.42(t,J＝6.0Hz,3H),1.25(t,J＝10.0Hz,3H).
HRMS(ESI,m/z):488.3105。
参考上述合成路线合成下表所示的化合物：
Figure PCTCN2019129362-appb-000078
实施例7
Figure PCTCN2019129362-appb-000079
中间体40-1的合成：
将化合物2-氨甲基吡啶(500mg，4.64mmol)溶解在40Ml甲醇中，室温搅拌，加入4-氰基苯甲醛(606mg，4.64mmol)，室温搅拌1h，加入氰基硼氢化钠(353mg,5.57mmol)和冰醋酸(334mg,5.57mmol),室温搅拌。TLC跟踪反应，至原料4-氰基苯甲醛消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝20:1)，得到中间体40-2(756mg)。
中间体40-2的合成：
将化合物40-1(750mg)溶解在甲醇中，加入10％的Rany Ni，H2置换三次。室温搅拌反应。TLC跟踪反应，至原料40-1消失，停止反应，过滤，浓缩，得到中间体40-2(587mg)。
中间体40-3的合成：
将N-Fmoc-L-丙氨酸(548mg，1.76mmol)将溶解于THF(50Ml)中，搅拌，依次加入HATU(808mg，2.10mmol)，HOBT(285mg，2.10mmol)，DIEA(455mg，3.51mmol)和中间体40-2(400mg，1.76mmol)，室温搅拌，TLC跟踪反应，至原料40-2消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩过柱纯化(DCM:CH 3OH＝10:1)，得到中间体40-3(775mg)。
中间体40-4的合成：
将化合物40-3(770mg)溶解在20％PIP/THF溶液中，室温搅拌。TLC跟踪反应，至原料40-3消失，停止反应，浓缩过柱纯化(DCM:CH 3OH＝10:1)，得到中间体40-4(440mg)。
终产物NIC40的合成：
将化合物40-4(400mg，1.34mmol)溶解在甲醇(30Ml)中，搅拌，依次加入吡啶-2-甲醛(145mg，1.34mmol)，氰基硼氢化钠(102mg，1.62mmol)和醋酸(111mg，1.84mmol)，TLC跟踪反应，至原料40-4消失，停止反应，饱和碳酸氢钠和DCM萃取三次，合并有机相，无水硫酸钠干燥，浓缩，过柱纯化(DCM:CH 3OH＝20:1)，得到白色固体终产物NIC40(126mg)。
化合物NIC40： 1H NMR(400MHz,DMSO)δ8.76(s,1H),8.63(d,J＝4.8Hz,1H),8.56(d,J＝4.7Hz,1H),7.85(dtd,J＝21.6,7.7,1.7Hz,2H),7.45(ddd,J＝12.5,9.4,5.9Hz,5H),7.37–7.29(m,3H),4.36(d,J＝6.0Hz,2H),4.22(s,2H),4.15(s,2H),4.01(s,2H),3.55(t,J＝15.5Hz,1H),1.34(d,J＝6.8Hz,3H)。
HRMS(ESI,m/z)：390.2295。
参考上述合成路线合成下表所示的化合物：
Figure PCTCN2019129362-appb-000080
Figure PCTCN2019129362-appb-000081
Figure PCTCN2019129362-appb-000082
实施例8 CXCR4生物活性实验
1、化合物对CXCR4的亲和活性测试
(1)实验方法
CXCR4的亲和活性检测所用的细胞系为体外构建的稳定转染CXCR4的CHO细胞系。CHO细胞系经DMEM培养基(含10％胎牛血清，100IU青霉素，0.1mg/ml的链霉素和0.2mg/ml的G418)培养，胰蛋白酶消化后，清洗计数后用FACS缓冲液(含0.5％BSA，0.05％NaN3的PBS)悬浮细胞，加入96孔板中。每孔的反应体系共100μl，包含5×10 5个细胞，250ng/ml的12G5单抗以及不同浓度的检测的化合物。冰上孵育40min后，用FACS缓冲液洗涤后，加入抗鼠的FITC标记的IgG二抗(1：200)后冰上孵育30min，用FACS缓冲液洗涤两次，酶标仪(PerkinElmer)检测485nmEX/535nmEM的吸收，记录荧光强度值。计算每个化合物抑制12G5单抗与受体CXCR4结合的比例，即在0.1μM浓度下的结合抑制率。
(2)实验结果
部分化合物的亲和活性IC 50值如下表1所示，化合物活性数值分为以下几个区间：A：1-20nM,B:20-50nM,C:50-100nM,D:100-500nM。可以看出，本发明的化合物表现出较强抑制活性。
表1化合物的亲和活性实验结果
化合物名称 亲和活性 化合物名称 亲和活性 化合物名称 亲和活性
NIC6 B NIC80 B NIC181 D
NIC17 C NIC93 B NIC182 B
NIC203 A NIC91 C NIC183 B
NIC53 C NIC108 A NIC150 B
NIC63 A NIC100 A NIC161 C
NIC78 B NIC101 A NIC145 B
NIC163 B NIC96 B NIC152 C
NIC61 D NIC141 D NIC153 C
NIC135 D NIC167 B NIC154 B
NIC89 B NIC111 B NIC155 B
NIC119 A NIC122 C NIC156 B
NIC146 A NIC147 A NIC157 B
NIC120 A NIC144 A NIC158 B
NIC166 B NIC165 B NIC189 B
NIC168～NIC178 B NIC151 A NIC126 B
NIC49 C NIC46 B NIC127 C
NIC24 C NIC90 B NIC128 B
NIC21 B NIC98 B NIC129 B
NIC94 C NIC125 C NIC130 A
NIC92 C NIC124 C NIC116 B
NIC131 C NIC133 C NIC109 C
NIC132 C NIC134 C NIC110 C
NIC121 C NIC112 C NIC113 C
NIC117 B NIC190 A NIC191 A
NIC192 B NIC193 A NIC194 A
NIC195 A NIC196 A NIC197 B
NIC198 B NIC199 B NIC200 B
NIC201 B NIC202 B    
2、化合物抑制SDF-1α诱导的细胞迁移实验
(1)实验方法
SDF-1α诱导的细胞迁移实验是用天然表达CXCR4的SupT1细胞系检测的。首先收集RPMI 1640(含10％胎牛血清，100IU青霉素和0.1mg/ml的链霉素)培养的悬浮的SupT1细胞，用含0.5％BSA的RPMI 1640洗涤后计数，悬浮细胞至每毫升3.0×107个细胞，细胞和不同浓度的化合物混匀后，取75μl加入至tranwell小室中，37℃孵育30min后，在下层培养板的孔内加入200μl含2Nm SDF-1α的0.5％BSA的RPMI 1640(背景值的一组不含SDF-1α)，37℃孵育3小时后，去除上层的tranwell小室，在下层培养孔中每孔加入40μl的CellTiter 96(Promega)，孵育1-4小时后检测490nm处的吸收值。每组实验结果均经过至少三次的独立实验得到，抑制曲线由GraphPad软件制作。
(2)实验结果
如表2中所示，100％>A>70％,70％>B>30％,30％>C。在SDF-1α诱导的细胞迁移抑制实验中，本发明的化合物在500nM浓度下，具有显著的抑制细胞迁移能力。
表2 SDF-1α诱导的细胞迁移实验结果
Figure PCTCN2019129362-appb-000083
Figure PCTCN2019129362-appb-000084
3、血浆蛋白稳定性实验
(1)实验方法
用乙腈将溴丙胺太林(propantheline bromide)稀释到1mM。用propantheline bromide作为human的对照药。分别取4μL 10mM待测药加入到96孔板中，再加入36μL DMSO将待测药稀释到1mM。
将-80℃保存的人血浆置于37℃水浴中解冻，4,000rpm离心10分钟，去除漂浮物和凝块。用pH计检测血浆pH值，仅使用pH7.2-8.0的血浆。将血浆置于37℃水浴中预孵育15分钟。取398μL预孵育的血浆加入新的96孔板中，分别加入2μL待测化合物和对照药，化合物终浓度为5μM，有机溶剂浓度为0.2％，每个化合物2个平行。将样品涡旋混匀后放置在37℃水浴中，50rpm孵育。分别在孵育0、10、30、60、90和120分钟后各取出50μL样品至96孔板中，加入400μL含内标乙腈(100nM aprozolam,200nM caffeine,100nM tolbutamide)，涡旋10分钟后，于4,000rpm离心30min。吸取上清液300μL至新的96孔板中，于4,000rpm再次离心30min。吸取二次离心的上清液150μL，与等体积水混合稀释之后进行LC-MS/MS分析。
(2)实验结果
如表3中所示，在人源血浆蛋白稳定性实验中，与对照药Propantheline相比，化合物NIC80在2小时的血浆蛋白稳定性实验中表现出很好的稳定性。
表3血浆蛋白稳定性实验结果
Figure PCTCN2019129362-appb-000085
4、体内动员实验和化疗药物增敏实验
(1)实验方法
使用带有高度表达CXCR4和EGFP-Luc(荧光素酶报告基因)的急性髓细胞白血病(AML)的细 胞系U937构建的异体瘤模型NSG小鼠。给模式小鼠注射5mg/kg剂量的NIC108化合物，并在不同时间点取外周血，用CD45-PE和12G5-APC抗体标记动员出的AML细胞，并用流式细胞仪检测AML细胞数量。使用已上市的CXCR4拮抗剂AMD3100作为阳性对照。
在AML异体瘤模型小鼠注射10mg/kg的NIC108，并在注射后的3小时内给小鼠50mg/kg的阿糖胞苷，隔天给药连续给药7次，并在第14天给小鼠注射荧光素酶，检测小鼠体内的AML细胞量。
(2)实验结果
如图1左所示，NIC108可有效动员小鼠骨髓中的AML细胞到外周血中，效果与阳性对照药物AMD3100相类似。图1右可见NIC108可有效动员骨髓内AML细胞到外周血，并可大大提升阿糖胞苷杀死肿瘤细胞的效果。
5、干细胞动员实验
(1)实验方法
在NSG小鼠皮下注射NIC108，剂量为5mg/kg，在注射后的5分钟，15分钟，30分钟，1小时和2小时取小鼠外周血，破红细胞后，将剩余血细胞种植于干细胞培养的半固体培养基中。37度培养14天后，使用体视显微镜计数由造血干细胞和祖细胞形成的集落数量(CFU)。使用已上市的CXCR4拮抗剂AMD3100作为阳性对照。
(2)实验结果
由图2所示，NIC108可有效动员NSG小鼠骨髓中的造血干细胞和造血祖细胞，效果优于已上市药物AMD3100。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (10)

  1. 一种化合物，其特征在于，为如式(I)所示的化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药：
    Figure PCTCN2019129362-appb-100001
    L选自C 2～10烯基、C 2～10炔基、C 3～8环烷基、C 3～6杂环基、芳基、C 1～5杂芳基、C 1～12稠合环基、C 1～12稠合杂环基、C 1～12螺环基或者C 1～12螺杂环基，或者L、
    Figure PCTCN2019129362-appb-100002
    及与
    Figure PCTCN2019129362-appb-100003
    相连的N及R 2形成环状结构；
    R 1选自键、氢、磺酰基、亚磺酰基、
    Figure PCTCN2019129362-appb-100004
    C 1～6烷基磺酰基、氨基C 1～6烷基、C 1～6烷基亚磺酰基、羰基、C 1～6烷基羰基、氨基酸、酰胺键、
    Figure PCTCN2019129362-appb-100005
    Figure PCTCN2019129362-appb-100006
    或者
    Figure PCTCN2019129362-appb-100007
    其中A、B、C、D、E、F、G各自独立地为C、N、O、S原子，或者
    Figure PCTCN2019129362-appb-100008
    中的C、N及R 7形成环状结构，或者R 1与R 2以及连接的同一N原子形成环状结构；或者R 2、N、
    Figure PCTCN2019129362-appb-100009
    和L形成环状结构；
    R 2、R 3和R 4各自独立地选自氢、羟基、氨基、磺酰基、亚磺酰基、羰基、C 1～6烷基、C 2～10烯基、C 2～10炔基、C 1～6烷氧基、氨基C 1～6烷基、C 1～6烷基磷酰基、C 1～6烷基羰基、C 3～8环烷基、C 3～8杂环基、芳基、C 1～10杂芳基、C 1～12稠合环基、C 1～12稠合杂环基、C 1～12螺环基或者C 1～12螺杂环基；或者R 3、R 4、
    Figure PCTCN2019129362-appb-100010
    及与
    Figure PCTCN2019129362-appb-100011
    两端相连的N原子之间形成环；
    R 5和R 6各自独立地选自氢、磺酰基、亚磺酰基、羰基、氨基、C 1～10烷基、C 2～10烯基、C 2～10炔基、C 1～6烷氧基、氨基C 1～6烷基、C 1～6烷基磷酰基、C 1～6烷基羰基、C 1～6烷基芳基、C 3～8环烷基、C 3～8杂环基、C 1～4烷基C 3～8杂环基、芳基、C 1～10杂芳基、C 1～12稠合环基、C 1～12稠合杂环基、C 1～12螺环基或者C 1～12螺杂环基；
    R 7选自氢、氨基、磺酰基、亚磺酰基、羰基、C 1～6烷基、C 2～10烯基、C 2～10炔基、C 1～6烷氧基、氨基C 1～6烷基、C 1～6烷基磷酰基、C 1～6烷基羰基、C 1～6烷基芳基、C 3～8环烷基、C 3～8杂环基、芳基、C 1～10杂芳基、C 1～12稠合环基、C 1～12稠合杂环基、C 1～12螺环基、C 1～12螺杂环基；
    其中，
    所述烯基、炔基、烷氧基、氨基、烷基、氨基烷基、环烷基、烷基磷酰基、杂环基、芳基、杂芳基、烷基羰基、烷基杂环基、烷基芳基、稠合环基、稠合杂环基、螺环基、螺杂环基、磺酰基和亚磺酰基可分别独立地被一个或者多个烷基、烯基、炔基、氟、氯、溴、碘、卤代烷基、卤代芳基、卤代杂芳基、羟基、氨基、羰基、羧基、胍基、脒基、磺酰基、亚磺酰基、烷氧基、氨基烷基、烷基磷酰基、烷基羰基、环烷基、杂环基、芳基、杂芳基、稠合环基、稠合杂环基、螺环基、螺杂环基所取代；
    n 1、n 2和n 3各自独立地为0～10的整数。
  2. 根据权利要求1所述的化合物，其特征在于，R 1选自键、氢、磺酰基、亚磺酰基、酰胺键、氨基酸、C 1～6烷基磺酰基、C 1～6烷基亚磺酰基、
    Figure PCTCN2019129362-appb-100012
    Figure PCTCN2019129362-appb-100013
    R 2选自氢、C 1～6烷基、C 3～6环烷基、C 3～6杂环基、氨基C 1～4烷基或C 1～5杂芳基，所述烷基、环烷基、杂环基、氨基烷基或杂芳基可任选的被一个或多个H、C 1～4烷基、氟、氯、溴、碘、氨基或C 1～5杂芳基所取代；
    或者
    Figure PCTCN2019129362-appb-100014
    选自
    Figure PCTCN2019129362-appb-100015
    Figure PCTCN2019129362-appb-100016
    或者
    Figure PCTCN2019129362-appb-100017
    或者L、
    Figure PCTCN2019129362-appb-100018
    及与
    Figure PCTCN2019129362-appb-100019
    相连的N和R 2形成
    Figure PCTCN2019129362-appb-100020
    R 3和R 4分别选自氢或C 1～6烷基，或者R 3、R 4、
    Figure PCTCN2019129362-appb-100021
    及与
    Figure PCTCN2019129362-appb-100022
    两端相连的N原子之间形成C 2～6杂环基，所述杂环基可任选地被一个或多个氢、C 1～4烷基、C 3～6环烷基或C 3～6杂环基；
    R 5选自C 1～6烷基、芳基、C 3～6环烷基、C 3～6杂环基或C 1～5杂芳基，其中，所述烷基、环烷基、杂环基、芳基或杂芳基可任选地被一个或多个氟、氯、溴、碘、C 1～6烷基、C 1～6环烷基、芳基、C 1～5杂芳基或C 1～6杂环基取代；
    R 6选自C 1～4烷基、氨基、磺酰基、亚磺酰基、羰基、氨基C 1～6烷基、C 1～6烷基芳基、C 1～4烷基C 3～8杂芳环基、C 3～6环烷基或C 3～6杂环基，其中，所述烷基、氨基、羰基、磺酰基、亚磺酰基、氨基烷基、烷基芳基、烷基杂环基、环烷基或杂环基可任选地被一个或多个氢、氟、氯、溴、碘、氨基、芳基、C 1～5杂芳基、卤代C 1～5杂芳基、C 2～6杂环基或C 1～4烷基磷酰基取代；
    R 7选自C 1～6烷基、芳基、C 1～6烷基芳基、C 1～5杂芳基、C 1～6烯基、C 3～6环烷基、C 3～6杂环基、磺酰基或亚磺酰基，所述烷基、芳基、杂芳基、烷基芳基、烯基、环烷基或杂环基可任选地被一个或多个氢、氟、氯、溴、碘、C 1～6烷基、C 3～6环烷基、芳基、C 1～5杂芳基、脒基、胍基或氨基所取代；
    L选自芳基、C 1～5杂芳基、C 2～4炔基、C 3～6环烷基、C 3～6杂环基、C 6～12稠合环基或C 1～12稠合杂环基，所述芳基、杂芳基、炔基、环烷基、稠合环基或稠合杂环基可任选地被一个或多个氢、氟、氯、溴、碘、C 1～6烷基、C 3～6环烷基、C 3～6杂环基、氨基、羟基、羧基、芳基、C 1～5杂芳基、卤代C 1～6烷基、C 1～6烷氧基、C 1～6氨基烷基或
    Figure PCTCN2019129362-appb-100023
    所取代。
  3. 根据权利要求1所述的化合物，其特征在于，L选自以下之一的结构：
    Figure PCTCN2019129362-appb-100024
    Figure PCTCN2019129362-appb-100025
    或者
    Figure PCTCN2019129362-appb-100026
    L可任选地被一个或多个氢、氟、氯、溴、碘、C 1～10烷基、C 3～8环烷基、C 3～8杂环基、氨基、羟基、羧基、芳基、C 1～5杂芳基、卤代C 1～6烷基、C 1～6烷氧基、C 1～6氨基烷基或所取代，其中A、B、C、D、E、F、G、H和I各自独立地为H、C、N、O、S原子；
    优选地，L选自以下之一的结构：
    Figure PCTCN2019129362-appb-100027
    Figure PCTCN2019129362-appb-100028
    Figure PCTCN2019129362-appb-100029
    Figure PCTCN2019129362-appb-100030
    或者
    Figure PCTCN2019129362-appb-100031
    其中A、B、C、D、E、F、G、H和I各自独立地为H、C、N、O、S原子；
    R 8、R 9或R 10各自独立地为氢、氟、氯、溴、碘、C 1～4烷基、氨基C 1～4烷基或C 1～4烷氧基。
  4. 根据权利要求1所述的化合物，其特征在于，L选自下列之一的稠合环基：
    Figure PCTCN2019129362-appb-100032
    Figure PCTCN2019129362-appb-100033
    所述稠合环基被一个或多个H、C 1～3烷基、氟、氯、溴、碘或C 1～3烷氧基所取代。
  5. 根据权利要求1所述的化合物，其特征在于，所述L为芳基且R 1为
    Figure PCTCN2019129362-appb-100034
    时，所述化合物满足下列至少之一的条件：
    (1)所述芳基上碳原子被非氢基的取代基所取代；
    (2)R 2为C 3～6环烷基、卤代C 1～4烷基或氨基C 1～4烷基；或者L、
    Figure PCTCN2019129362-appb-100035
    及与
    Figure PCTCN2019129362-appb-100036
    相连的N和R 2形成
    Figure PCTCN2019129362-appb-100037
    (3)R 3或R 4为C 1～6烷基，或者R 3、R 4、
    Figure PCTCN2019129362-appb-100038
    及与
    Figure PCTCN2019129362-appb-100039
    两端相连的N原子之间形成C 2～8杂环基；
    (4)R 5为环烷基，所述环烷基被一个或多个氟、氯、溴、碘、羟基、氨基、芳基、C 1～4烷基、C 1～8环烷基或C 1～8杂环基所取代；
    (5)R 6为羰基、磺酰基、亚磺酰基、氨基或氨基C 1～4烷基，所述羰基、磺酰基、亚磺酰基、氨基或氨基C 1～4烷基可任选地被一个或多个氢、氟、氯、溴、碘、氨基、芳基、C 1～5杂芳基、卤代C 1～5杂芳基、C 2～6杂环基或C 1～4烷基磷酰基取代；
    (6)R 7为C 1～4烷基、C 1～4烯基、C 1～5杂芳基或C 3～6环烷基，其中，所述烷基不可被烷基、脒基、氨基、C 1～5杂芳基所取代。
  6. 根据权利要求1所述的化合物，其特征在于，为下列所示之一的化合物、其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药：
    Figure PCTCN2019129362-appb-100040
    Figure PCTCN2019129362-appb-100041
    Figure PCTCN2019129362-appb-100042
    Figure PCTCN2019129362-appb-100043
    Figure PCTCN2019129362-appb-100044
    Figure PCTCN2019129362-appb-100045
    Figure PCTCN2019129362-appb-100046
    Figure PCTCN2019129362-appb-100047
    Figure PCTCN2019129362-appb-100048
    Figure PCTCN2019129362-appb-100049
  7. 权利要求1～6任一项所述化合物在制备药物中的用途，其特征在于，所述药物用于治疗肿瘤疾病、艾滋病、骨髓移植、镰状细胞性贫血、造血干细胞移植、创伤、心肌梗死、嗜中性白血球减少症、缺血性疾病、神经性疾病、视网膜静脉阻塞、呼吸系统性疾病、肠胃疾病、皮肤疾病、炎症反应或免疫缺陷疾病；
    任选地，所述药物抑制CXCR4的表达或者阻断CXCR4和SDF-1α之间的相互作用；
    任选地，所述药物用于动员骨髓中的造血干细胞以用于自体或异体造血干细胞移植，用于多发性骨髓瘤和非霍杰金淋巴瘤疾病的治疗；
    任选地，所述药物用于动员骨髓中的干细胞，用于白血病的治疗；
    任选地，所述药物用于动员骨髓中的急性髓细胞白血病的癌细胞到外周血，用于白血病的治疗；
    任选地，所述药物抑制肿瘤细胞转移，用于肿瘤的治疗；
    任选地，所述药物抑制HIV-1入侵T细胞，用于艾滋病的治疗；
    任选地，所述药物用于自身免疫缺陷疾病的治疗；
    任选地，所述药物在制备造血干细胞/祖细胞动员剂和/或在过表达CXCR4的肿瘤组织中作为检测肿瘤标志物的应用。
  8. 一种药物组合物，其特征在于，包括权利要求1～6任一项所述化合物；
    任选地，所述药物组合物进一步包括药学上可接受的辅料、载体、赋形剂、溶媒或它们的组合；
    任选地，所述药物组合物进一步包含治疗剂，所述治疗剂选自下列的至少之一：马拉韦罗、恩夫韦肽、齐多夫定、扎西他宾、司他夫定、拉米夫定、萘韦拉平、地拉韦定、阿巴卡韦、依非韦伦、替诺福韦、乙曲西他槟、依曲韦润、利匹韦润、顺铂、环磷酰胺、阿糖胞苷、5-氟尿嘧啶、吉西他滨、紫杉醇、多西他赛、阿霉素、格列卫、特罗凯、索拉菲尼、达沙替尼、拉帕替尼、舒尼替尼、埃罗替尼、吉非替尼、Tisagenlecleucel、益基利仑赛、阿仑单抗、阿特珠单抗、阿维单抗、伊匹单抗、奥法木单抗、纳武利尤单抗、帕博利珠单抗、利妥昔单抗、度伐鲁单抗、卡瑞利珠单抗、特伦普利单抗、信迪利单抗、替雷利珠单抗、阿替利珠单抗、西妥昔单抗和曲妥珠单抗的赫赛汀。
  9. 一种药物联合，其特征在于，包含：
    权利要求1～6任一项所述化合物或权利要求8所述药物组合物；以及
    一种或多种用于治疗肿瘤疾病、艾滋病、炎症反应以及免疫缺陷疾病的药物；
    任选地，所述药物选自下列的至少之一：马拉韦罗、恩夫韦肽、齐多夫定、扎西他宾、司他夫定、拉米夫定、萘韦拉平、地拉韦定、阿巴卡韦、依非韦伦、替诺福韦、乙曲西他槟、依曲韦润、利匹韦润、顺铂、环磷酰胺、阿糖胞苷、5-氟尿嘧啶、吉西他滨、紫杉醇、多西他赛、阿霉素、格列卫、特罗凯、索拉菲尼、达沙替尼、拉帕替尼、舒尼替尼、埃罗替尼、吉非替尼、Tisagenlecleucel、益基利仑赛、阿仑单抗、阿特珠单抗、阿维单抗、伊匹单抗、奥法木单抗、纳武利尤单抗、帕博利珠单抗、利妥昔单抗、度伐鲁单抗、卡瑞利珠单抗、特伦普利单抗、信迪利单抗、替雷利珠单抗、阿替利珠单抗、西妥昔单抗或曲妥珠单抗的赫赛汀。
  10. 一种药物载体，其特征在于，包括权利要求1～6任一项所述化合物。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101242848A (zh) * 2005-06-14 2008-08-13 太景生物科技股份有限公司 嘧啶化合物
CN107602450A (zh) * 2017-09-28 2018-01-19 清华大学 氨基酸骨架类新型cxcr4拮抗剂及其制备与生物医学应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101242848A (zh) * 2005-06-14 2008-08-13 太景生物科技股份有限公司 嘧啶化合物
CN107602450A (zh) * 2017-09-28 2018-01-19 清华大学 氨基酸骨架类新型cxcr4拮抗剂及其制备与生物医学应用

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