WO2017167150A1 - Composé hétérocyclique 3-fluoropyridine et son application - Google Patents

Composé hétérocyclique 3-fluoropyridine et son application Download PDF

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WO2017167150A1
WO2017167150A1 PCT/CN2017/078305 CN2017078305W WO2017167150A1 WO 2017167150 A1 WO2017167150 A1 WO 2017167150A1 CN 2017078305 W CN2017078305 W CN 2017078305W WO 2017167150 A1 WO2017167150 A1 WO 2017167150A1
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group
substituted
alkyl
hydrogen atom
unsubstituted
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PCT/CN2017/078305
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Chinese (zh)
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张小虎
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苏州云轩医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to a 3-fluoropyridine heterocyclic compound and an application thereof, and belongs to the technical field of medicine.
  • the Wnt gene was discovered in 1982 and was originally identified as a site for preferential integration of mouse mammary tumor virus. This gene is capable of transmitting proliferation and differentiation information between cells. It is an oncogene and was named the Int gene at that time. Mouse Int-1 and Int-3). It was subsequently found to belong to the same source gene (orthologous gene) as the wingless gene of Drosophila, thereby naming the two as the Wnt gene.
  • the Wnt pathway is a very conserved signaling pathway.
  • Members of the lower biological flies to higher mammals have a high degree of homology.
  • the Wnt signaling pathway is involved in the regulation of a variety of biological processes, including embryo growth and morphogenesis, tissue stability, energy metabolism balance, and stem cell maintenance (Logan et al., Annu. Rev. Cell. Dev. Biol. , 2004, 20, 781-810).
  • Wnt signaling pathway plays an important role in the regulation of epidermal stem cells, intestinal stem cells, hematopoietic stem cells, neural stem cells, embryonic stem cells, and cancer stem cells (Reya et al., Nature, 2005, 434, 843-850).
  • the classical Wnt signaling pathway is driven by the extracellular ligand Wnts protein simultaneously binding to the 7-cell transmembrane Frizzled receptor and the helper receptor LRP5/6 to initiate Wnt/ ⁇ -catenin signaling pathway and activate cytoplasmic Dsh protein
  • activated Dsh protein can inhibit the activity of GSK-3 ⁇ , a key component in the degradation complex formed by APC protein, GSK-3 ⁇ , Axin, ⁇ -catenin, etc., so that ⁇ -catenin is not phosphorylated by GSK-3 ⁇ .
  • the recognition and degradation of the ubiquitin proteasome is avoided, which in turn accumulates in the cytoplasm (Boutros et al, Mech.
  • ⁇ -catenin When ⁇ -catenin accumulates to a certain concentration in the cytoplasm, it begins to transfer to the nucleus, and binds to the transcription factor TCF/LEFs in the nucleus, causing the promoter of the downstream target gene of ⁇ -catenin to be exposed and activated. Activation of c-myc, cyclin-D1, survivin, gasstrin, VEGF, ASEF, etc. leads to abnormal cell proliferation.
  • cytoplasmic ⁇ -catenin binds to the membrane adhesion proteins E-cadherin and ⁇ -catenin to form a complex that participates in the regulation of the cytoskeleton, maintains the adhesion of the same type of cells, and prevents cell migration.
  • a small amount of free ⁇ -catenin is recognized and degraded by the ubiquitin proteasome after being phosphorylated by the degradation complex in the cytoplasm, keeping the intracellular The ⁇ -catenin is in a low level state, thereby turning the Wnt signaling pathway off.
  • Wnt gene itself or any other member of the pathway changes to cause abnormal activation, it may cause tumors.
  • regulators of the Wnt pathway including mutations in genes such as APC, ⁇ -catenin, Axin, and TCF, are widely present in colon cancer patients, resulting in overexpression of growth-related genes (Klaus et al., Nat. Rev. Cancer, 2008, 8, 387-398).
  • Lozzo et al. found that overexpression of Wnt-5a mRNA, especially in breast cancer, was found in breast cancer, lung cancer, prostate cancer, and melanoma by studying more than 100 normal and tumor tissues and 10 human tumor cell lines. Abnormally apparent (Lozzo et al., Cancer Research, 1995, 55, 3495).
  • Wnt signaling pathway has a better anti-tumor targeting effect.
  • Activation of the Wnt signaling pathway by ⁇ -catenin increases the circulation and expansion of neural progenitor cells, whereas deletions result in the loss of progenitor cell spacing (Chenn et al., Science, 2002, 297, 365-369).
  • Abnormal activation of the Wnt signal is tumorigenic in the nervous system (Dahmen et al, Cancer Res., 2001, 61, 7039-7043).
  • the Wnt signaling pathway promotes the renewal and maintenance of pluripotent hematopoietic stem cells, and abnormal Wnt signaling is responsible for various diseases and other blood-related cancers caused by pluripotent hematopoietic stem cells (Reya et al, Nature, 2005, 434, 843- 850; Willert et al, Nature, 2003, 423, 448-452).
  • Deregulation of Wnt signaling also leads to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakage, and neovascularization.
  • tumor immunotherapy has become a research hotspot.
  • the main strategy of tumor immunotherapy is to block the activation of immunosuppressive receptors on T cells using immunological checkpoint inhibitors such as CTLA-4, PD-1 and PD-L1 monoclonal antibodies.
  • This strategy is effective in patients with a variety of tumors, such as melanoma and lung cancer (especially T cell infiltrating tumors), whereas in tumor tissue without T cell infiltration, it is often anti-tumor immunity.
  • the object of the present invention is to propose a 3-fluoropyridine heterocyclic compound and its use, which can effectively antagonize the Wnt signaling pathway and can be used for treating or preventing disorders caused by Wnt signaling pathway disorders. .
  • A is a 5-14 membered heteroaryl ring having 1 to 4 hetero atoms, a 6-12 membered aromatic ring, a 3-6 membered cycloalkyl group or 3-substituted or substituted with 1 to 6 R 6 groups.
  • a 6-membered heterocycloalkyl group, the hetero atom of the heteroaryl ring and the heterocycloalkyl group comprising one or more of N, O and S; or A being unsubstituted or 1-2 R 6 groups replaced Wherein X 1 is N or CR 6 ;
  • B is selected from a hydrogen atom, a cyano group, a halogeno group, a hydroxyl group, a C 3-8 cycloalkyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group, a C 1-8 sulfonyl group, a C 1-8 sulfonamide.
  • B is selected from a benzene ring which is unsubstituted or substituted with 1-3 R 9 groups, unsubstituted or substituted with 1-3 R 10 groups 5-6 membered heteroaromatic ring containing 1-3 heteroatoms, unsubstituted or substituted with 1-3 R 11 groups containing 5-7 membered 1-3 a saturated heterocyclic ring of a hetero atom, the hetero atom of the heteroaromatic ring and the saturated heterocyclic ring including one or more of N, O and S;
  • U 6 is unsubstituted or substituted with R 13 6-12 membered aromatic ring, unsubstituted or substituted with 1-6 R 13 groups substituted 5-14 membered heteroaryl ring, unsubstituted or 1-6 R 13 groups, and substituted with 5-7 membered heterocyclic ring, unsubstituted or substituted with 1-6 R 13 substituted 5-7 membered aromatic heterocycle and 5-6 membered heteroaryl a ring, -OR 14 , -NR 14 R 15 , wherein the heterocyclic or heteroaromatic ring is a heterocyclic or heteroaromatic ring containing from 1 to 4 heteroatoms, and the hetero atom of the heterocyclic or heteroaromatic ring includes N Or one or more of O and S; or U is a C 2-8 alkenyl or C 2-8 alkynyl group substituted by a 5-6 membered aromatic or heteroaryl ring, said heterocyclic ring, heteroaromatic ring a heterocyclic
  • L is the price key or Wherein Y is a valence bond, -O-, -S-, -N(R 18 )- or -C(R 18 )(R 19 )-;
  • R 1, R 2, R 3 are each independently selected from hydrogen atom, C 1-6 alkyl, 1 to 3 groups independently selected from halo, hydroxy, cyano, C 1-3 alkyl, C 3- a C 1-6 alkyl group substituted with a 5- cycloalkyl group and a C 1-3 alkoxy group;
  • R 4 and R 5 are each independently selected from the group consisting of a hydrogen atom, a cyano group, an amino group, a halogen group, a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a C 1-8 alkoxy group, and -NH-C 1-3. alkyl;
  • R 6 is selected from a hydrogen atom, a halogeno group, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group; or R 6 is selected from the group consisting of 1-3 An amino group substituted with a substituent selected from a halogeno group, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group or a C 1-6 alkoxy group base;
  • R 7 and R 8 are each independently selected from a hydrogen atom which is unsubstituted or substituted with 1-3 R 12 , a C 1-8 alkyl group, a C 3-8 cycloalkyl group; or an atom to which R 7 and R 8 are bonded together Loop into
  • R 9 and R 10 are each independently selected from a hydrogen atom, a halogeno group, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group; or R 9 , R 10 each selected from an amino group substituted with 1 to 3 substituents selected from a halogeno group, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group Or a C 1-6 alkoxy group;
  • R 11 is selected from a hydrogen atom, a halogen group, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group, an oxo group, a C 1 which is unsubstituted or substituted by a halogen group. -6 alkyl;
  • R 12 is selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkoxy group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 ureido group, and a C 2-6 oxo group.
  • Urea -S(O) 2 -C 1-3 alkyl, -N(R 16 )S(O) 2 -C 1-3 alkyl, -N(R 16 )C(O)-C 1- 3- alkyl;
  • R 13 is selected from the group consisting of a hydrogen atom, a cyano group, a halogeno group, a hydroxyl group, an amino group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group, a -S(O) 2 -C 1-3 alkyl group, -C (O)-C 1-3 alkyl, -C(O)OC 1-3 alkyl, oxo, C 1-6 alkyl unsubstituted or substituted by halo;
  • R 14 and R 15 are each independently selected from the group consisting of a hydrogen atom, a C 3-6 cycloalkyl group, a C 1-6 alkyl group, a 5-6 membered aromatic ring, a 5-6 membered heteroaryl ring having 1-3 hetero atoms, and 5 6-membered heterocyclic ring having 1-3 heteroatoms, 20 is substituted with 1-3 R C 3-6 cycloalkyl, 20 substituted with 1-3 R C 1-6 alkyl, 1- 3 R 20 substituted 5-6 membered aromatic ring substituted with 1 to 3 R 20 is 5-6 membered heteroaromatic ring containing 1-3 heteroatoms, and is substituted with 1-3 R & lt 20 5-6 a heterocyclic ring containing 1-3 heteroatoms; the hetero atom comprising one or more of N, O and S; or R 14 and R 15 together with the N atom to which they are attached;
  • R 16 , R 17 , R 18 , and R 19 are each independently selected from a hydrogen atom, a C 1-6 alkyl group which is unsubstituted or substituted with a halogen group;
  • R 20 is selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkoxy group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a 5-6 membered aromatic ring, and a 5-6 member containing 1 a heteroatom ring of 3 heteroatoms comprising one or more of N, O and S;
  • R 21 is selected from a hydrogen atom or a C 1-6 alkyl group.
  • B is selected from the group consisting of a hydrogen atom, a cyano group, a halogeno group, a hydroxyl group, a C 1-8 sulfonyl group, a C 1-8 sulfonylamino group, a C 1-8 alkoxy group, a C 1-8 acyl group, and a C 1-8 amide group.
  • B is selected from benzene which is unsubstituted or substituted with 1-3 R 9 groups ring, unsubstituted or substituted with 1 to 3 R 10 groups substituted with a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms, unsubstituted or substituted with 1-3 R 11 groups 5- a 7-membered saturated heterocyclic ring having 1 to 3 hetero atoms, the hetero atom of the heteroaromatic ring and the saturated heterocyclic ring including one or more of N, O and S;
  • R 1 is a hydrogen atom
  • R 2 and R 3 are each independently selected from a hydrogen atom and a C 1-6 alkyl group
  • R 4 and R 5 are each independently selected from a hydrogen atom, a cyano group, a halogeno group, and a C 1-8 alkyl group;
  • R 6 is selected from a hydrogen atom, a halogeno group, a cyano group, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group; or R 6 is selected from the group consisting of 1-3 An amino group substituted with a substituent selected from a halogeno group, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group or a C 1-6 alkoxy group base;
  • R 7 and R 8 are each independently selected from the group consisting of a hydrogen atom, a C 3-8 cycloalkyl group, a C 1-8 alkyl group unsubstituted or substituted with 1-3 R 12 groups; or R 7 and R 8 together with an atom to which they are attached Loop into
  • R 9, R 10 are independently selected from hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy; or R 9, R 10 are independently selected from 1-3 halo groups Substituted C 1-6 alkyl or C 1-6 alkoxy;
  • R 11 is selected from a hydrogen atom, an oxo group, a C 1-6 alkyl group which is unsubstituted or substituted by a halogen group;
  • R 12 is selected from a hydrogen atom, a cyano group, C 1-6 alkyl, C 1-6 sulfonamido group;
  • R 13 is selected from the group consisting of a hydrogen atom, a cyano group, a halogeno group, an oxo group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group, a C 1-6 acyl group, which is unsubstituted or substituted by a halogen group.
  • R 14 and R 15 are each independently selected from a hydrogen atom, a C 3-6 cycloalkyl group, a C 1-6 alkyl group which is unsubstituted or substituted with 1-3 R 20 groups; or R 14 and R 15 together with the N to which they are attached Atom into a ring;
  • R 16 , R 17 , R 18 , R 19 are each independently selected from a hydrogen atom, a C 1-6 alkyl group which is unsubstituted or substituted with a halogen group;
  • R 20 is selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a 5-6 membered aromatic ring, and a 5-6 member having 1-3.
  • a heteroatom heteroaromatic ring comprising one or more of N, O and S;
  • R 21 is selected from a hydrogen atom or a C 1-6 alkyl group.
  • A is one of the following groups which are unsubstituted or substituted by 1-6 R 6 groups:
  • R 6 is as defined above.
  • A is one of the following groups which are unsubstituted or substituted by one R 6 group:
  • R 6 is as defined above.
  • A is one of the following groups which are unsubstituted or substituted by one R 6 group:
  • R 6 is as defined above.
  • A is one of the following groups that are unsubstituted or substituted with one R 6 group:
  • R 6 is a hydrogen atom, a halogeno group (preferably F), a cyano group or a C 1-6 alkoxy group (preferably a methoxy group).
  • B is one of the following groups:
  • n 0, 1, or 2
  • R 10 is as defined above.
  • n 0, 1, or 2
  • R 10 is as defined above.
  • Scheme 8 Among the 3-fluoropyridine heterocyclic compounds of Scheme 6, most preferably, B is Wherein n is 1, and R 10 is a C 1-6 alkyl group (preferably a methyl group).
  • L is a valence bond.
  • the 3-fluoropyridine heterocyclic compound in a 3-fluoropyridine heterocyclic compound according to any one of the above aspects 1 to 9, preferably, the 3-fluoropyridine heterocyclic compound, and a pharmaceutically acceptable salt thereof, have the formula II structure:
  • X 3 is N or CR 22 ;
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from N or CR 6 ;
  • U 6 is unsubstituted or substituted with R 13 6-12 membered aromatic ring, unsubstituted or substituted with 1-6 R 13 groups substituted 5-14 membered heteroaryl ring, unsubstituted or 1-6 R 13 groups, and substituted with 5-7 membered heterocyclic ring, unsubstituted or substituted with 1-6 R 13 substituted 5-7 membered aromatic heterocycle and 5-6 membered heteroaryl a ring, -OR 14 or -NR 14 R 15 , wherein the heterocyclic or heteroaromatic ring is a heterocyclic or heteroaromatic ring containing from 1 to 4 heteroatoms, and the hetero atom of the heterocyclic or heteroaromatic ring includes N Or one or more of O and S; or U is a C 2-8 alkenyl or C 2-8 alkynyl group substituted by a 5-6 membered aromatic or heteroaryl ring, said heterocyclic ring, heteroaromatic ring a heterocyclic or
  • L is a valence bond
  • R 1 and R 4 are a hydrogen atom
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-3 alkyl group
  • R 5 is selected from the group consisting of a hydrogen atom, a halogeno group, a cyano group, and a C 1-3 alkyl group;
  • R 6 is selected from the group consisting of a hydrogen atom, a halogeno group, a cyano group, a hydroxyl group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group; or R 6 is selected from the group consisting of 1-3 from halo, C 1-3 alkyl, C 3-6 cycloalkyl substituted with a substituent C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy;
  • R 10 is selected from a hydrogen atom, a halogeno group, a C 1-6 alkyl group which is unsubstituted or substituted by a halogen group;
  • R 13 is selected from the group consisting of a hydrogen atom, a cyano group, a halogeno group, an oxo group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group, a C 1-6 acyl group, which is unsubstituted or substituted by a halogen group.
  • R 14 and R 15 are each independently selected from a hydrogen atom, a C 3-6 cycloalkyl group, a C 1-6 alkyl group which is unsubstituted or substituted with 1-3 R 20 groups; or R 14 and R 15 together with the N to which they are attached Atom into a ring;
  • R 20 is selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a 5-6 membered aromatic ring, and a 5-6 member having 1-3.
  • a heteroatom heteroaromatic ring comprising one or more of N, O and S;
  • R 21 and R 22 are each independently selected from a hydrogen atom or a C 1-6 alkyl group.
  • Scheme 11 In the 3-fluoropyridine heterocyclic compound of Scheme 10, preferably, for Wherein the group is unsubstituted or substituted by 1 R 6 wherein R 6 is a hydrogen atom, a halo group (preferably F), a cyano group or a C 1-6 alkoxy group (preferably a methoxy group). .
  • R 6 is a hydrogen atom, a halo group (preferably F), a cyano group or a C 1-6 alkoxy group (preferably a methoxy group).
  • 3-fluoropyridine heterocyclic compound according to any one of the above aspects 1 to 11, preferably, the 3-fluoropyridine heterocyclic compound, and a pharmaceutically acceptable salt thereof, have the formula III Structure:
  • Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 are each independently selected from N or CR 6 ;
  • B is a cyano group
  • U 6 is unsubstituted or substituted with R 13 6-12 membered aromatic ring, unsubstituted or substituted with 1-6 R 13 groups substituted 5-14 membered heteroaryl ring, unsubstituted or 1-6 R 13 groups, and substituted with 5-7 membered heterocyclic ring, unsubstituted or substituted with 1-6 R 13 substituted 5-7 membered aromatic heterocycle and 5-6 membered heteroaryl a ring, -OR 14 or -NR 14 R 15 , wherein the heterocyclic or heteroaromatic ring is a heterocyclic or heteroaromatic ring containing from 1 to 4 heteroatoms, and the hetero atom of the heterocyclic or heteroaromatic ring includes N Or one or more of O and S; or U is a C 2-8 alkenyl or C 2-8 alkynyl group substituted by a 5-6 membered aromatic or heteroaryl ring, said heterocyclic ring, heteroaromatic ring a heterocyclic or
  • L is a valence bond
  • R 1 and R 4 are a hydrogen atom
  • R 2 and R 3 are each selected from a hydrogen atom and a methyl group
  • R 5 is selected from the group consisting of a hydrogen atom, a halogeno group, a cyano group, and a C 1-3 alkyl group;
  • R 6 is selected from the group consisting of a hydrogen atom, a halogeno group, a cyano group, a hydroxyl group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group; or R 6 is selected from the group consisting of 1-3 from halo, C 1-3 alkyl, C 3-6 cycloalkyl substituted with a substituent C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy;
  • R 13 is selected from the group consisting of a hydrogen atom, a cyano group, a halogeno group, an oxo group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group, a C 1-6 acyl group, which is unsubstituted or substituted by a halogen group.
  • R 14 and R 15 are each independently selected from a hydrogen atom, a C 3-6 cycloalkyl group, a C 1-6 alkyl group which is unsubstituted or substituted with 1-3 R 20 groups; or R 14 and R 15 together with the N to which they are attached Atom into a ring;
  • R 20 is selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a 5-6 membered aromatic ring, and a 5-6 member having 1-3.
  • a heteroatom heteroaromatic ring comprising one or more of N, O and S;
  • R 21 is a hydrogen atom or a C 1-6 alkyl group.
  • U is one of the following groups which are unsubstituted or substituted by 1 to 6 R 13 groups. :
  • R 13 is as defined above.
  • R 13 is as defined above.
  • R 13 is halogen (preferably F or Cl), C 1-6 alkyl (preferably methyl), C 1-6 alkoxy (preferably methoxy) or cyano.
  • the 3-fluoropyridine heterocyclic compound in a 3-fluoropyridine heterocyclic compound according to any one of the above aspects 1 to 13, preferably, the 3-fluoropyridine heterocyclic compound, and a pharmaceutically acceptable salt thereof, have Formula IV or Formula V The structure shown:
  • X 4 , X 5 , X 6 , X 7 , X 8 , X 9 are each independently selected from N or CR 13 ;
  • L is a valence bond
  • R 1 and R 4 are a hydrogen atom
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-3 alkyl group
  • R 5 is selected from the group consisting of a hydrogen atom, a halogeno group, a cyano group, and a C 1-3 alkyl group;
  • R 6 is selected from the group consisting of a hydrogen atom, a halogeno group, a cyano group, a hydroxyl group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group; or R 6 is selected from the group consisting of 1-3 from halo, C 1-3 alkyl, C 3-6 cycloalkyl substituted with a substituent C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy;
  • R 10 is selected from a hydrogen atom, a halogeno group, a C 1-6 alkyl group which is unsubstituted or substituted by a halogen group;
  • R 13 is selected from the group consisting of a hydrogen atom, a cyano group, a halogeno group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group, a C 1-6 alkyl group which is unsubstituted or substituted with a halogen group;
  • R 23 and R 24 are each independently selected from a hydrogen atom, a C 1-3 alkyl group; or R 23 and R 24 are combined into an oxo group;
  • R 25 , R 26 , R 27 and R 28 are each independently selected from a hydrogen atom or a C 1-3 alkyl group.
  • the 3-fluoropyridine heterocyclic compound includes one or more of the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above 3-fluoropyridine heterocyclic compound and a pharmaceutically acceptable carrier therefor.
  • the present invention also provides a pharmaceutical combination product of a 3-fluoropyridine heterocyclic compound, which comprises the 3-fluoropyridine heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof, and an antitumor drug, an antibacterial drug, and an antiviral agent.
  • a combination of one or a combination of a drug, an anti-parasitic drug, a central nervous system drug, an anti-osteogenesis drug, and a diabetes drug is used in combination.
  • the present invention also provides the use of the above 3-fluoropyridine heterocyclic compound for the preparation of a medicament for treating or preventing a disease associated with abnormal Wnt signaling pathway;
  • the diseases associated with abnormal Wnt signaling pathway include breast cancer, lung cancer, Bladder cancer, pancreatic cancer, liver cancer, head and neck squamous cell carcinoma, thyroid cancer, sarcoma, osteosarcoma, dural fibroma, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, myeloma, Lymphoma, mantle cell lymphoma, cutaneous T-cell lymphoma, chronic and non-progressive anemia, spontaneous or essential thrombocytosis, idiopathic bone Myeloid fibrosis, pulmonary fibrosis, renal fibrosis, liver fibrosis, cirrhosis, diabetic retinopathy, macroglobulinemia, leukemia, acute
  • the above pharmaceutical composition means a composition comprising the above 3-fluoropyridine heterocyclic compound and a pharmaceutically acceptable salt or carrier thereof as a component, or the above 3-fluoropyridine heterocyclic compound and pharmaceutically acceptable thereof a combination of the accepted salt and a combination of one or more of an anti-tumor drug, an antibacterial drug, an antiviral drug, an anti-parasitic drug, a central nervous system drug, an anti-osteogenesis drug, and a diabetes drug Things.
  • the 3-fluoropyridine heterocyclic compound of the present invention is capable of effectively antagonizing the Wnt signaling pathway and can be used for treating or preventing a disorder caused by a malfunction of the Wnt signaling pathway or a disease associated with abnormal Wnt signaling pathway.
  • Fig. 2 is a graph showing the results of cytostatic test of 3-fluoropyridine heterocyclic compound B7 in Example 25.
  • Alkyl means a straight or branched saturated aliphatic hydrocarbon group.
  • the alkyl group includes an alkyl group containing 1 to 18, such as 1 to 12, further such as 1 to 10, still more preferably 1 to 6 carbon atoms, examples of which are selected from methyl, ethyl, 1-propyl or N-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1- Propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”) and 1,1-dimethylethyl or tert-butyl ("t-Bu” ").
  • alkyl groups may be selected from the group consisting of 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-Butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl (-CH, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- Methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2 - butyl.
  • Alkynyl means a straight or branched hydrocarbon radical comprising at least one C ⁇ C triple bond and 2-18 such as 2-8, 2-6 or 2-4 carbon atoms.
  • alkynyl groups include ethynyl, 1-propynyl, propargyl, 1-butynyl, 2-butynyl and 3-butynyl.
  • Cycloalkyl means a saturated or partially unsaturated, cyclic aliphatic hydrocarbon group including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups.
  • a cycloalkyl group can contain 3-12, such as 3-8, further such as 3-6, 3-5 or 3-4 carbon atoms.
  • examples of cycloalkyl groups are selected from monocyclic rings containing from 3 to 12, such as from 3 to 8, from 3 to 6 carbon atoms.
  • Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, Cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclodecyl , cyclodecyl, cyclodecyl and cyclododeyl.
  • bicyclic cycloalkyl group examples include a bicyclic cycloalkyl group having 7 to 12 carbon atoms, which are arranged to be selected from [4, 4], [4, 5], [5, 5], [5, 6] And a bicyclic ring of the [6,6] ring system, or a bridged bicyclic ring selected from the group consisting of bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] decane .
  • Other examples of bicyclic cycloalkyl groups include those arranged in a bicyclic ring selected from the group consisting of the [5,6] and [6,6] ring systems.
  • the ring may be saturated or have at least one double bond (ie, partially unsaturated), but not fully conjugated.
  • Aryl or “aryl ring” means a monocyclic or bicyclic aromatic hydrocarbon group containing from 6 to 10 carbon atoms.
  • Examples of the aryl or aromatic ring include a phenyl or benzene ring, a naphthyl group or a naphthalene ring (including 1-naphthyl or 2-naphthyl).
  • a divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is designated as a substituted phenylene group.
  • the divalent group derived from a monovalent polycyclic hydrocarbon group designated by a "- group” is removed by removing a hydrogen atom from a carbon atom having a free valence as follows: a "-subunit" is added to the corresponding monovalent group, for example A naphthyl group having two linked sites is referred to as a naphthylene group.
  • the aryl group does not encompass or overlap the heteroaryl group in any way, as defined separately below.
  • Halogen or "halo” or “halo” means F, Cl, Br or I.
  • Heteroaryl or “heteroaryl” refers to a group selected from the group consisting of:
  • a -5-7 membered aromatic monocyclic ring comprising at least one hetero atom selected from N, O and S, for example from 1 to 4, or in some embodiments from 1 to 3 heteroatoms, the remaining ring atoms being carbon ;
  • -8-12 membered bicyclic ring comprising at least one heteroatom selected from N, O and S, for example from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 Or 2 heteroatoms, the remaining ring atoms being carbon, and wherein at least one of the rings is aromatic and at least one heteroatom is present in the aromatic ring;
  • a -11-14 membered tricyclic ring comprising at least one heteroatom selected from N, O and S, for example from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 Or 2 heteroatoms, the remaining ring atoms are carbon, and at least one of the rings is aromatic and at least one heteroatom is present in the aromatic ring.
  • the hetero atoms in the heteroaryl group exceeds 1, the hetero atoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is at most 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is at most one.
  • heteroaryl groups include, but are not limited to, (numbered starting from the position of the linkage designated as priority 1), pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), porphyrinyl, pyridyl Azinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, Tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolyl, isodecyl, indanyl, pyridazinyl, pyrazine , pyridazinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, pyri
  • Heterocyclic or “heterocyclic” or “heterocyclyl” or “heterocycloalkyl” are mutually replaceable and refer to a 4-12 membered monocyclic, bicyclic, and tricyclic saturated or partially unsaturated non.
  • An aromatic ring comprising at least one carbon atom in addition to at least one (such as 1-4, again such as 1-3 or further such as 1 or 2) heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen .
  • the ring can be saturated or have at least one double bond (ie, partially unsaturated).
  • the heterocyclic ring is optionally substituted for oxo.
  • the site of attachment in the heterocycle can be carbon or a hetero atom.
  • the heterocyclic ring is not a heteroaryl group as defined herein.
  • the heterocyclic ring may also form a fused ring with an aromatic ring (e.g., a benzene ring) or a heteroaryl ring, such as a 5-7 membered heterocyclic benzophenone ring or a 5-7 membered heterocyclic ring and a 5-6 membered heteroaryl ring.
  • heterocycles include, but are not limited to, (numbered starting from the position specified as priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazole Alkyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl , oxacyclopropyl, azacyclopropyl, thioheteropropyl, azetidinyl, oxetanyl, thioheterobutyl, 1,2-dithiot-butyl, 1, 3-dithiot-butyl, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, oxathiaridyl, piperazinyl, homopiperazinyl, homopiperidinyl, piperaz
  • the substituted heterocyclic ring also includes a ring system substituted with one or more oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
  • oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
  • fused ring refers to a polycyclic ring system, for example, a bicyclic or tricyclic ring system in which two rings share only two ring atoms and one common bond.
  • the fused ring may include a fused bicyclic cycloalkyl ring such as a bicyclic cycloalkyl ring having 7 to 12 ring atoms, which is arranged to be selected from the above [4, 4], [4, 5] a bicyclic ring of the [5,5], [5,6] and [6,6] ring systems; a fused bicyclic aryl ring such as the above 7-12 membered bicyclic aryl ring system; fused three a cycloaryl ring such as the above 10-15 membered tricyclic aryl ring system; a fused bicyclic heteroaryl ring such as the above 8-12-membered bicyclic heteroaryl ring; a fused tricyclic heteroaryl group; A ring such as the above 11
  • Alkanoyl means a group formed by the combination of an alkyl group and a carbonyl group.
  • a C 1-8 acyl group means a C 1-8 alkyl acyl group.
  • Alkoxy means a group formed by the combination of an alkyl group and an oxygen atom.
  • amide or “amido” refers to an amide group attached through a nitrogen atom.
  • a C 1-8 amide group refers to a C 1-8 alkyl amide group.
  • Sulfonyl means RS(O) 2 -, wherein R includes alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, meaning alkyl, cycloalkyl, heterocycloalkyl, aryl
  • the base or heteroaryl is attached to the parent structure via -S(O) 2 -.
  • C 1-8sulfonyl represents a C 1-8 alkylsulfonyl group.
  • Sulfonylamino refers to a sulfonamide substituent attached to a nitrogen atom.
  • C 1-8 sulfonylamino means a C 1-8 alkylsulfonylamino group.
  • “Ureido” refers to a substituted or unsubstituted urea group.
  • Ester group means a group containing a carbonyloxy group.
  • a C 1-8 ester group means a C 1-8 alkylcarbonyloxy group.
  • the compounds described herein may contain asymmetric centers and may thus exist as enantiomers. When the compounds described herein have two or more asymmetric centers, they may also exist as diastereomers. Both enantiomers and diastereomers fall into a wider variety of stereoisomers.
  • the present application is intended to include all possible stereoisomers, such as substantially pure analytical enantiomers, their racemic mixtures, and mixtures of diastereomers.
  • the present application is intended to include all stereoisomers of the compounds described herein and/or pharmaceutically acceptable salts thereof. Unless otherwise specified, reference to one isomer applies to any possible isomer. Wherever the composition of the isomer is not specified, all possible isomers are included.
  • the term “substantially pure” as used herein means that the target stereoisomer contains up to 35% by weight, such as at most 30% by weight, such as up to 25% by weight, and further such as up to 20% by weight of any one or more other stereoisomers. In some embodiments, the term “substantially pure” means that the target stereoisomer contains up to 10% by weight, such as up to 5% by weight, such as up to 1% by weight, of any one or more other stereoisomers.
  • Certain of the compounds described herein may exist as attachment sites for different hydrogens, referred to as tautomers.
  • the application is intended to cover both the keto form and the enol form, alone and in mixtures thereof.
  • the reaction products can advantageously be separated from each other and/or from the starting materials.
  • the desired product of each step or series of steps is separated and/or purified (hereinafter referred to as separation) to the desired degree of homogenization by conventional techniques in the art.
  • separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography.
  • Chromatography can involve a number of methods including, for example, reverse phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical chromatography; simulated moving bed (“SMB”) Chromatography and preparative thin or thick layer chromatography and small-scale thin layer and flash chromatography techniques.
  • SMB simulated moving bed
  • Diastereomeric mixtures can be separated into their individual diastereomers by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization, based on physicochemical differences in diastereomers. .
  • the enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric reaction by reaction with a suitably optically active compound (for example, a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride).
  • a suitably optically active compound for example, a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride.
  • the isomeric mixture is separated, the diastereomers are separated, and the individual diastereomers are then converted (e.g., hydrolyzed) to the corresponding pure enantiomers.
  • the enantiomers can also be separated using a chiral HPLC column.
  • a single stereoisomer for example, a substantially pure enantiomer
  • Mixture (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. "Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr., 113 (3) (1975): pp. 283-302).
  • the racemic mixture of the chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) formation of an ionic diastereomeric salt with a chiral compound, followed by fractional crystallization or other Method separation, (2) formation of diastereomeric compounds with a chiral derivatization reagent, separation of the diastereomers, then conversion to pure stereoisomers, (3) direct under chiral conditions The substantially pure or enriched stereoisomer is isolated. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
  • “Pharmaceutically acceptable salts” include, but are not limited to, salts formed with inorganic acids, and salts with organic acids.
  • the free base can be obtained by alkalizing a solution of the acid salt.
  • an addition salt such as a pharmaceutically acceptable addition salt
  • an addition salt can be prepared by dissolving the free base in a suitable organic solvent and then following the preparation of the acid addition salt from the base compound. The solution is treated with an acid in a conventional operation.
  • Treatment refers to administering to a subject deemed to have such a need (with, for example, a cancer) at least one compound described herein or a pharmaceutically acceptable thereof Salt.
  • an effective amount refers to an amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, that is effective to "treat” (as defined above) a disease or condition in a subject.
  • the solvent and the drug used were analytically pure or chemically pure; the solvent was re-distilled before use; and the anhydrous solvent was treated according to standard methods or literature methods.
  • Column chromatography silica gel (100-200 mesh) and thin layer chromatography silica gel (GF254) are products of Qingdao Ocean Chemical Plant and Yantai Chemical Plant; unless otherwise specified, petroleum ether (60-90 ° C) / ethyl acetate ( v / v) as eluant; color-developing agent with iodine or phosphomolybdic acid ethanol solution; all unexplained extraction solvent are dried over anhydrous Na 2 SO 4.
  • LC-MS High Performance Liquid Chromatography-Ion Trap Mass Spectrometer
  • DAD diode array detector
  • detection wavelengths 214 nm and 254 nm ion trap mass spectrometry (ESI source).
  • the HPLC column was AgelaDurashell C18 (4.6 x 50 mm, 3.5 ⁇ m); the mobile phase was 0.1% aqueous NH4HCO3: acetonitrile (from 5:95 to 95:5 in 5 min); the flow rate was 1.8 mL/min.
  • This embodiment provides a 3-fluoropyridine heterocyclic compound and a synthesis method thereof.
  • a heterocyclic compound B1 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B2 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B3 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B4 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B5 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B6 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B7 which is synthesized by the following method:
  • B7-1 (167 mg, 0.6 mmol) and 2,3-difluoropyridine-4-boronic acid (105 mg, 0.66 mmol) were dissolved in dioxane (4 mL) and water (1 mL), and Pd(dppf)Cl was added. 2 (39 mg, 0.048 mmol), dppf (26 mg, 0.048 mmol) and potassium phosphate (254 mg, 1.2 mmol). Under nitrogen protection, it was replaced with nitrogen five times, heated to 100 ° C, and reacted for 12 hours. After cooling to room temperature, the residue was evaporated.
  • This example provides a 3-fluoropyridine heterocyclic compound B8 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B9 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B10 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B11 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B12 which is synthesized by the following method:
  • B12-1 164 mg, 1.0 mmol
  • 2,3-difluoropyridine-4-boronic acid (175 mg, 1.1 mmol) were dissolved in dioxane (4 mL) and water (1 mL), and Pd(dppf)Cl was added.
  • 2 65 mg, 0.08 mmol
  • dppf 44 mg, 0.08 mmol
  • potassium phosphate 424 mg, 2.0 mmol
  • This example provides a 3-fluoropyridine heterocyclic compound B13 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B14 which is synthesized by the following method:
  • B14-1 (209 mg, 1.0 mmol) and 2,3-difluoropyridine-4-boronic acid (175 mg, 1.1 mmol) were dissolved in dioxane (4 mL) and water (1 mL), and Pd(dppf)Cl was added. 2 (65 mg, 0.08 mmol), dppf (44 mg, 0.08 mmol) and potassium phosphate (424 mg, 2.0 mmol). Under nitrogen protection, it was replaced with nitrogen five times, heated to 100 ° C, and reacted for 12 hours. After cooling to room temperature, it was concentrated under reduced vacuo.
  • This example provides a 3-fluoropyridine heterocyclic compound B15 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B16 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B17 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B18 which is synthesized by the following method:
  • B18-1 200 mg, 1.0 mmol
  • B1-2 (238 mg, 1.5 mmol) were dissolved in dioxane (4 mL) and water (1 mL), and Pd(dppf)Cl 2 (65 mg, 0.08 mmol), Dppf (44 mg, 0.08 mmol) and potassium phosphate (424 mg, 2.0 mmol). Under nitrogen protection, it was replaced with nitrogen five times, heated to 100 ° C, and reacted for 12 hours. After cooling to room temperature, the residue was evaporated.
  • This example provides a 3-fluoropyridine heterocyclic compound B19 which is synthesized by the following method:
  • B19-1 (264 mg, 1.5 mmol) and B1-2 (358 mg, 2.25 mmol) were dissolved in dioxane (8 mL) and water (2 mL), and Pd(dppf)Cl 2 (55 mg, 0.075 mmol), Dppf (42 mg, 0.075 mmol) and potassium phosphate (798 mg, 3.0 mmol). Under nitrogen protection, it was replaced with nitrogen five times, heated to 100 ° C, and reacted for 12 hours. After cooling to room temperature, it was concentrated under reduced pressure and purified by column chromatography.
  • This example provides a 3-fluoropyridine heterocyclic compound B20 which is synthesized by the following method:
  • B20-1 (288 mg, 1.5 mmol) and B1-2 (358 mg, 2.25 mmol) were dissolved in dioxane (8 mL) and water (2 mL), and Pd(dppf)Cl 2 (55 mg, 0.075 mmol), Dppf (42 mg, 0.075 mmol) and potassium phosphate (798 mg, 3.0 mmol). Under nitrogen protection, it was replaced with nitrogen five times, heated to 100 ° C, and reacted for 12 hours. After cooling to room temperature, it was concentrated under reduced vacuo.
  • This example provides a 3-fluoropyridine heterocyclic compound B21 which is synthesized by the following method:
  • B21-2 (199 mg, 1.0 mmol) and B1-2 (191 mg, 1.2 mmol) were dissolved in dioxane (8 mL) and water (2 mL), and Pd(dppf)Cl 2 (37 mg, 0.05 mmol), Dppf (28 mg, 0.05 mmol) and potassium phosphate (532 mg, 2.0 mmol). Under nitrogen protection, it was replaced with nitrogen five times, heated to 100 ° C, and reacted for 12 hours. After cooling to room temperature, it was concentrated under reduced vacuo.
  • This example provides a 3-fluoropyridine heterocyclic compound B22 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B23 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B24 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B25 which is synthesized by the following method:
  • This example provides a 3-fluoropyridine heterocyclic compound B38 which is synthesized by the following method:
  • Table 1 lists the analytical structures and spectral data of the compounds B1-B38 obtained in Examples 1-26 and the like.
  • This example measures the inhibitory ability of the 3-fluoropyridine heterocyclic compounds B1-B25 and B38 prepared in Examples 1-26, and the compounds B26-B37 obtained according to the similar procedures of Examples 1-26, to the Wnt signaling pathway. .
  • LWnt3A cells (CRL-2647, ATCC) were cultured in DMEM medium (Gibico) containing 10% fetal bovine serum (Hyclone).
  • HEK293STF stable clonal cells (HEK293 cells transfected with "Super-TopFlash” TCF fluorescence reporter plasmid) were cultured in complete medium (containing 4mML-glutamine, 1.5g/L sodium bicarbonate, 4.5g/L glucose, 6 ⁇ g/ mL of blasticidin and 10% fetal bovine serum in DMEM medium).
  • LWnt3A cells and HEK293STF stable cloned cells were cultured to a confluence of 90%, they were harvested separately and mixed at a ratio of 1:1.
  • test compound 100 ⁇ L/well of the mixed cell culture medium was added to a 96-well plate to give a final cell concentration of 12,000 cells/well, followed by further culture for 24 hours.
  • the test compound was diluted stepwise with DMSO and then diluted to the desired concentration with DMEM medium. 20 ⁇ L of the compound solution was added to the aforementioned 96-well plate containing the cell culture medium, followed by incubation at 37 ° C for 48 hours. Finally, 50 ⁇ L of luciferase solution (Brigh-Glo, Promega) was added to each well, and shaken at room temperature for 5 minutes.
  • the luminescent signal was measured with a microplate reader (PHERAstar FS, BMG), and then the IC 50 value (potency) of the compound was calculated based on the inhibition of the luminescent signal by the compound at different concentrations.
  • a microplate reader PHERAstar FS, BMG
  • the IC 50 value potency
  • a graph of inhibition results is obtained; the test patterns of the remaining compounds are basically the same.
  • the overall results are shown in Table 2 (Results of the experiment for determining the ability of the heterocyclic compound B1-B38 to inhibit the Wnt signaling pathway).
  • Compound IC 50 (nM) Compound IC 50 (nM) Compound IC 50 (nM) Compound IC 50 (nM) B1 0.18 B2 0.06 B3 0.11 B4 0.27 B5 0.31 B6 0.54 B7 0.12 B8 0.11 B9 5.2 B10 0.24 B11 16 B12 1 B13 10 B14 1 B15 10 B16 10 B17 16 B18 8 B19 7 B20 8 B21 2 B22 318 B23 10 B24 12 B25 0.06 B26 0.13 B27 0.12 B28 0.12 B29 0.06 B30 0.04 B31 0.34 B32 1.8 B33 0.4 B34 0.11 B35 1.0 B36 0.25 B37 0.2 B38 0.5
  • the heterocyclic compound obtained in the examples of the present invention can be used as an effective antagonist of the Wnt signaling pathway, and can effectively block the Wnt signaling pathway, thereby being capable of treating or preventing diseases caused by abnormal Wnt signaling pathway. disease.
  • the cytochrome P450 enzyme inhibition rate of the substrate to be tested was carried out in human liver microsomes.
  • the five CYP isozymes and their respective probe substrates and their concentrations are as follows: CYP-1A2 (Phenacetin, 30 ⁇ M), CYP-2C9 (Tolutamide, 100 ⁇ M), CYP-2C19 (S-mephenytoin, 40 ⁇ M), CYP-2D6 (Dextromethorphan, 5 ⁇ M) and CYP-3A4 (Midazolam, 1 ⁇ M). All probe substrates were used at concentrations close to or below their Kms.
  • HLM 0.2 mg/mL
  • phosphate buffer 100 mM, pH 7.4
  • NADPH 1 ⁇ M
  • test compound 10 ⁇ M
  • substrate of each CYP enzyme was incubated in a constant temperature water bath at 37 ° C. .
  • the compound was incubated for 10 min before the start of the reaction with NADPH to allow the enzyme-inhibitor to function adequately. It was then reacted within each CYP enzyme specific reaction time period (CYP1A2, CYP2D6 and CYP3A4 for 10 min; CYP2C9 and CYP2C19 for 30 min).
  • the reaction was quenched by the addition of an appropriate amount of an internal standard of ice-cold acetonitrile (100 ⁇ M). After high-speed centrifugation (13,000 rpm) for 10 min, the supernatant sample LC-MS/MS was used to quantitatively analyze the concentration of the unique metabolite formed by the probe substrate and the CYP enzyme to determine the CYP inhibition rate. Each test substrate was tested at least three times independently.
  • LC-MS/MS analysis conditions All samples were analyzed by LC-MS/MS system using API4000QTRAP mass spectrometer.
  • the instrument is equipped with two LC-20AD pumps and a CBM-20A controller, a DGU-20A solvent auto-degassing pump and a SIL-20A autosampler (Shimadzu, Columbia, MD, USA).
  • Bona Aigel's Venusil XBP C18 column (50 x 2.1 mm, 5 ⁇ M) was used as an HPLC separation column with a column temperature of 40 ° C, a flow rate of 0.3 mL/min, and a total run time of 6 min.
  • MS/MS Quantification of MS/MS: The API4000QTRAP mass spectrometer was operated in electrospray (ESI) positive ion mode with multiple reaction monitors (MRM). All compounds and internal standards were tested over a 100 ms residence time period. The remaining MS/MS parameters were set as follows: ion source curtain pressure, 30 psi; atomizing gas pressure, 55 psi; ion source spray voltage 4500V; ion source temperature 500 °C. For the detection of specific selected ions, the de-clustered voltage (DP) and collision energy (CE) need to be optimized according to the different detectors. The final data processing was performed using AB SCIEX Analysist 1.5.2 data collection and integration software.
  • ESI electrospray
  • MRM multiple reaction monitors

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Abstract

La présente invention décrit un composé hétérocyclique 3-fluoropyridine. Le composé hétérocyclique 3-fluoropyridine et un sel pharmaceutiquement acceptable de ce dernier présentent une structure telle que présentée dans la formule I. L'invention concerne en outre une composition pharmaceutique, qui comprend le composé hétérocyclique 3-fluoropyridine en une quantité thérapeutiquement efficace, et un support pharmaceutiquement acceptable. L'invention concerne également l'utilisation du composé hétérocyclique 3-fluoropyridine destiné à la préparation d'un médicament de traitement ou de prévention d'une anomalie dans la voie de signalisation Wnt. Le composé hétérocyclique 3-fluoropyridine de la présente invention permet d'antagoniser de manière efficace la voie de signalisation Wnt, et par conséquent peut être utilisé pour traiter ou prévenir les troubles provoqués par une anomalie de la voie de signalisation Wnt.
PCT/CN2017/078305 2016-03-31 2017-03-27 Composé hétérocyclique 3-fluoropyridine et son application WO2017167150A1 (fr)

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CN201610195733.4 2016-03-31
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CN201610850358.2A CN107286136B (zh) 2016-03-31 2016-09-26 一种3-氟吡啶杂环化合物及其应用

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WO2020007273A1 (fr) * 2018-07-02 2020-01-09 四川大学 Nouvel inhibiteur du récepteur des androgènes, son procédé de synthèse et son utilisation
WO2022086892A1 (fr) * 2020-10-21 2022-04-28 Calithera Biosciences, Inc. Inhibiteurs du gène 1 induit par l'interleukine 4 (il4) et leurs méthodes d'utilisation

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WO2013185353A1 (fr) * 2012-06-15 2013-12-19 Curegenix Inc. Composé comme inhibiteur de la voie de signalisation wnt, composition et utilisation associée
WO2014141038A2 (fr) * 2013-03-11 2014-09-18 Irm Llc Marqueurs associés à des inhibiteurs de la voie wnt
CN104876912A (zh) * 2015-04-08 2015-09-02 苏州云轩医药科技有限公司 Wnt信号通路抑制剂及其应用
WO2015140196A1 (fr) * 2014-03-20 2015-09-24 Bayer Pharma Aktiengesellschaft Inhibiteurs des voies de signalisation wnt
WO2015140195A1 (fr) * 2014-03-20 2015-09-24 Bayer Pharma Aktiengesellschaft Nouveaux composés
CN105142641A (zh) * 2013-03-12 2015-12-09 广州源生医药科技有限公司 用于治疗癌症的化合物
CN105254613A (zh) * 2015-10-08 2016-01-20 苏州云轩医药科技有限公司 具有Wnt信号通路抑制活性的杂环化合物及其应用

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WO2013185353A1 (fr) * 2012-06-15 2013-12-19 Curegenix Inc. Composé comme inhibiteur de la voie de signalisation wnt, composition et utilisation associée
WO2014141038A2 (fr) * 2013-03-11 2014-09-18 Irm Llc Marqueurs associés à des inhibiteurs de la voie wnt
CN105142641A (zh) * 2013-03-12 2015-12-09 广州源生医药科技有限公司 用于治疗癌症的化合物
WO2015140196A1 (fr) * 2014-03-20 2015-09-24 Bayer Pharma Aktiengesellschaft Inhibiteurs des voies de signalisation wnt
WO2015140195A1 (fr) * 2014-03-20 2015-09-24 Bayer Pharma Aktiengesellschaft Nouveaux composés
CN104876912A (zh) * 2015-04-08 2015-09-02 苏州云轩医药科技有限公司 Wnt信号通路抑制剂及其应用
CN105254613A (zh) * 2015-10-08 2016-01-20 苏州云轩医药科技有限公司 具有Wnt信号通路抑制活性的杂环化合物及其应用

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020007273A1 (fr) * 2018-07-02 2020-01-09 四川大学 Nouvel inhibiteur du récepteur des androgènes, son procédé de synthèse et son utilisation
CN110669049A (zh) * 2018-07-02 2020-01-10 四川大学 新型雄激素受体抑制剂及其合成方法和应用
CN110669049B (zh) * 2018-07-02 2022-03-04 四川大学 新型雄激素受体抑制剂及其合成方法和应用
WO2022086892A1 (fr) * 2020-10-21 2022-04-28 Calithera Biosciences, Inc. Inhibiteurs du gène 1 induit par l'interleukine 4 (il4) et leurs méthodes d'utilisation

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