WO2020125759A1 - 作为wnt信号通路抑制剂的化合物及其医学应用 - Google Patents

作为wnt信号通路抑制剂的化合物及其医学应用 Download PDF

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WO2020125759A1
WO2020125759A1 PCT/CN2019/127056 CN2019127056W WO2020125759A1 WO 2020125759 A1 WO2020125759 A1 WO 2020125759A1 CN 2019127056 W CN2019127056 W CN 2019127056W WO 2020125759 A1 WO2020125759 A1 WO 2020125759A1
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compound
methylpyridin
alkyl
methyl
substituted
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PCT/CN2019/127056
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French (fr)
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邢洪涛
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汇瀚医疗科技有限公司
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Priority claimed from CN201811573629.XA external-priority patent/CN111349093B/zh
Priority claimed from CN201910152552.7A external-priority patent/CN111620874B/zh
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Publication of WO2020125759A1 publication Critical patent/WO2020125759A1/zh

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicine, and relates to 5,6-bicyclic compounds and substituted 5,6-biheterocyclic amino compounds having WNT signaling pathway inhibitory activity, and applications thereof.
  • the WNT signaling pathway plays an important role in both embryogenesis and adult homeostasis.
  • the Wnt gene family is responsible for encoding a large class of secreted WNT ligands (Cadigen and Nusse., (1997) Genes & Development 11: 3286-3305 related to Int1/Wnt1 proto-oncogene and Drosophila wingless (Wg, corresponding to Drosophila Wnt1) ).
  • Wg corresponding to Drosophila Wnt1
  • Wnt pathway regulation disorders exist in different diseases, such as cancer, malformation syndrome, osteoporosis, diabetic retinopathy and Pulmonary fibrosis (MacDonald et al (2009) Dev. Cell 17: 9-26; Williams and Insogna (2009) J. Bone Miner. Res. 24: 171-178; Polaskis (2007) Curr. Opin. Genet. Dev. 17:45-51; Chen et al., (2009) Am. J. Pathol. 175: 2676-2685).
  • WNT ligands determine the activity of the WNT signaling pathway.
  • the first step in WNT protein synthesis is to complete translation in the endoplasmic reticulum (ER), followed by ER-intrinsic enzyme Porcupine (PORCN, a membrane-bound O-acyltransferase (MBOAT)) mediated post-translational acylation (palm Acylation) (Proffitt and Virshup., (2012) J of Biol. Chem. 287: 34167-34178), WNT protein has palmitoylation at 1 or 2 highly conserved sites (Zhai et al., (2004) J. Biol. Chem. 279: 33220-33227; Takada et al., (2006) Dev Cell 11: 791-801).
  • WNT protein transport, secretion and protein activity are closely related to WNT protein post-translational acylation, and PORCN has high selectivity and precise regulation for Wnt post-translational acylation (Proffitt and Virshup., (2012) J of Biol. Chem. 287:34167-34178), this modification process is necessary for WNT protein secretion and connection carrier protein WLS.
  • palmitoylation is crucial for the interaction between the WNT protein and the Frizzled receptor on the cell surface (Coombs et al., (2010) J. Cell Sci. 123: 3357-3367; Herr and Basler (2012) Dev. Biol. 361: 392-402; Janda et al., (2012) Dev. Biol. 361: 392-402).
  • the typical WNT pathway is activated by the binding of WNT ligands to Frizzled receptors on the cell surface (Bhanot et al., (1996) Nature 382:225-230), which in turn activates the cytoplasmic protein Dishevelled (Boutros, et al., (1999) Mech.Dev.83:27-37) and phosphorylation of LRP5/6, leading to the accumulation of ⁇ -catenin in the nucleus and interaction with TCF/LCF family transcription factors, promoting the transcription process of specific genes (Uthoff et al., (2001) Mol. Carcinog., 31: 56-62).
  • ⁇ -catenin In the non-activated state of the WNT pathway, free cytosolic ⁇ -catenin enters a complex system composed of scaffold protein Axin, colon adenoma-like polyp protein APC, and glycogen synthesis kinase (GSK)-3 ⁇ .
  • Axin, APC and ⁇ -catenin are successively phosphorylated by GSK-3 ⁇ , eventually leading to ⁇ -catenin entering the ubiquitination pathway and being degraded by the proteasome (Uthoff et al., (2001) Mol. Carcinog., 31: 56-62 ; Matsuzawa et al., (2001) Mol. Cell, 7:915-926).
  • the WNT signaling pathway plays a beneficial role in the survival of many types of cells (Orford et al., (1999) J. Cell Bio, 146: 855-868; Satoh et. al., (2000) Nat. Genet, 24: 245-250; Ioannidis et. (2001) Nat. Immunol, 2: 691-697). Changes in WNT pathway activity are closely related to tumorigenesis and development. For example, the high activity of the classical WNT pathway can cause abnormal cell growth (Reya and Clevers, (2005) Nature 434:843-850).
  • colorectal cancers have a deletion of the APC gene, which is an inhibitor of the WNT/ ⁇ -catenin signaling pathway (Kinzler and Vogelstein, (1996) Cell 87:159-170).
  • abnormal activity of the WNT signaling pathway is associated with a variety of human tumors, accompanied by C-Myc overexpression (Polakis et al., (2000) Genes Dev, 14: 1837-1851; Bienz et al., (2000) Cell :311-320).
  • the abnormal WNT signaling pathway is also associated with various disorders, including but not limited to bone and cartilage diseases, such as osteoporosis, osteoarthritis, obesity-related type 2 diabetes, etc. (Hoeppner, (2009) Expert Opin. Ther.
  • the present invention provides a 5,6-bicyclic compound of structural formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • B is -CONH-, or -NHCO-
  • R 1 and R 2 represent H, D, F, Cl, Br, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylene hydroxy, or R 1 and R 2 Connecting to form a substituted or unsubstituted 3-6 membered saturated ring containing 0-1 heteroatoms, wherein the heteroatoms are selected from one of O, S or N;
  • R 3, R 4, R ' 3, R' 4 may be substituted at any location ring positions, wherein R 3, R 4, R ' 3, R' 4 independently represent H, D, F, Cl, Br, I, NH 2 , NO 2 , CN, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, OR 5 , COR 5 , CONR 5 R 6 , NR 5 R 6 , NR 5 COR 6 , NR 5 CONHR 6 , NHSO 2 R 5 , SO 2 NHR 5 , SO 2 (C 1 -C 6 alkyl), substituted or unsubstituted C 3 -C 7 heterocycle Alkyl, the C 3 -C 7 heterocycloalkyl is a heterocycloalkyl containing O, S and/or N, and is connected to the ring by a C atom;
  • R 5 and R 6 may independently represent H, D, C 1 -C 6 alkyl, C 2 -C 4 alkylene hydroxy, C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl, amino C 1 -C 6 alkyl, or substituted amino C 1 -C 6 alkyl, or R 5 and R 6 can be linked to the attached group to form a substituted or unsubstituted 3-6 containing 1-2 heteroatoms Elementary saturated ring, wherein the heteroatom is further selected from O, S or N atoms;
  • substituted means that the group is further substituted with F, Cl, Br, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylene hydroxy;
  • X, Y, Z, X 1 , Y 1 , Z 1 can independently represent C, N;
  • A is selected from aryl or heteroaryl represented by the following structural formula,
  • R 3 and R 4 are at any substitutable position of the connected ring, and the definitions of R 3 and R 4 are the same as above;
  • R 7 may be selected from H, F, Cl, Br, I, C 1 -C 6 alkyl.
  • the present invention protects a compound of formula I, wherein B is -CONH- structure, X is C, Y is N, and Z is C, that is, the compound of formula Ia:
  • the present invention protects a compound of formula I, wherein B is a -CONH- structure, X is N, Y is N, and Z is C, that is, a compound of formula Ib:
  • the present invention protects a compound of formula I, wherein B is a -CONH- structure, X is C, Y is C, and Z is N, that is, a compound of formula Ic:
  • R 1 and R 2 represent H, D, F, Cl, Br, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylene hydroxy;
  • R 3, R 4, R ' 3, R' 4 may be substituted at any location ring positions, wherein R 3, R 4, R ' 3, R' 4 independently represent H, D, F, Cl, Br, I, NH 2 , NO 2 , CN, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, OR 5 , COR 5 , CONR 5 R 6 , NR 5 R 6 , NR 5 COR 6 , NR 5 CONHR 6 , NHSO 2 R 5 , SO 2 NHR 5 , SO 2 (C 1 -C 6 alkyl), substituted or unsubstituted C 3 -C 7 heterocycle Alkyl, the C 3 -C 7 heterocycloalkyl is a heterocycloalkyl containing O, S and/or N, and is connected to the ring by a C atom;
  • R 5 and R 6 may independently represent H, D, C 1 -C 6 alkyl, C 2 -C 4 alkylene hydroxy, C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl, amino C 1 -C 6 alkyl, or substituted amino C 1 -C 6 alkyl, or R 5 and R 6 can be linked to the attached group to form a substituted or unsubstituted 3-6 containing 1-2 heteroatoms Elementary saturated ring, wherein the heteroatom is further selected from O, S and/or N atoms;
  • substituted means that the group is further substituted with F, Cl, Br, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylene hydroxy;
  • A is selected from aryl or heteroaryl represented by the following structural formula,
  • R 3 and R 4 are at any substitutable position of the connected ring, and the definitions of R 3 and R 4 are the same as above;
  • R 7 may be selected from H, F, Cl, Br, I, C 1 -C 6 alkyl.
  • the present invention protects a compound of formula I, wherein B is -NHCO- structure, X is C, Y is N, and Z is C, that is, the compound of formula IIa:
  • B is -NHCO- structure
  • X is N
  • Y is N
  • Z is C, which is the compound of formula IIb:
  • B is -NHCO- structure
  • X is C
  • Y is C
  • Z is N, which is the compound of formula IIc structure:
  • R 1 and R 2 represent H, D, F, Cl, Br, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylene hydroxy;
  • R 3, R 4, R ' 3, R' 4 may be substituted at any location ring positions, wherein R 3, R 4, R ' 3, R' 4 independently represent H, D, F, Cl, Br, I, NH 2 , NO 2 , CN, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, OR 5 , COR 5 , CONR 5 R 6 , NR 5 R 6 , NR 5 COR 6 , NR 5 CONHR 6 , NHSO 2 R 5 , SO 2 NHR 5 , SO 2 (C 1 -C 6 alkyl), substituted or unsubstituted C 3 -C 7 heterocycle Alkyl, the C 3 -C 7 heterocycloalkyl is a heterocycloalkyl containing O, S and/or N, and is connected to the ring by a C atom;
  • R 5 and R 6 may independently represent H, D, C 1 -C 6 alkyl, C 2 -C 4 alkylene hydroxy, C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl, amino C 1 -C 6 alkyl, or substituted amino C 1 -C 6 alkyl, or R 5 and R 6 can be linked to the attached group to form a substituted or unsubstituted 3-6 containing 1-2 heteroatoms Elementary saturated ring, wherein the heteroatom is further selected from O, S and/or N atoms;
  • substituted means that the group is further substituted with F, Cl, Br, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylene hydroxy;
  • A is selected from aryl or heteroaryl represented by the following structural formula,
  • R 3 and R 4 are at any substitutable position of the connected ring, and the definitions of R 3 and R 4 are the same as above;
  • R 7 may be selected from H, F, Cl, Br, I, C 1 -C 6 alkyl.
  • B is -CONH- structure
  • B has the structure -NHCO-.
  • the present invention further protects the preparation method of the compound of formula I, which comprises: an organic acid compound and its derivative reacting with an organic amine compound to obtain an amide compound of formula I.
  • the organic amine compound is selected from the following compounds:
  • M is selected from the group consisting of -OH, halogen, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, metal ions or similar structural groups, substituents X, Y, Z, X 1 , Y 1 , Z 1, R 1, R 2, R 3, R 4, R '3, R' 4, R 5, R 6, R 7, A defined with reference to the above definitions.
  • the present invention also provides a substituted 5,6-biheterocyclic amino compound of structural formula X, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
  • R 11 and R 12 represent H, D, F, Cl, Br, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylene hydroxy, or R 11 and R 12 Connecting to form a substituted or unsubstituted 3-6 membered saturated ring containing 0-1 heteroatoms, wherein the heteroatoms are selected from one of O, S or N;
  • R 13 and R 14 can be substituted at any position on the ring.
  • R 13 and R 14 independently represent H, D, F, Cl, Br, I, NH 2 , NO 2 , CN, and C 1 -C 6 alkyl.
  • a 1 represents the following 6-membered aryl or heteroaryl group
  • R 13 and R 14 can be substituted at any position on the ring, and the definition is the same as above
  • R 18 may be selected from H, D, C 1 -C 6 alkyl
  • R 15 and R 16 may independently represent H, D, C 1 -C 6 alkyl, C 2 -C 4 alkylene hydroxy, C 3 -C 7 cycloalkyl or C 3 -C 7 heterocycloalkyl, amino C 1 -C 6 alkyl, or substituted amino C 1 -C 6 alkyl, or R 15 and R 16 can be linked to the attached group to form a substituted or unsubstituted 3-containing 1-2 heteroatoms 6-membered saturated heterocycloalkyl, wherein the heteroatom is further selected from O, S and/or N atoms;
  • X 11 , Y 11 , Z 11 , X 12 , Y 12 , Z 12 , Z 13 can independently represent C or N, wherein at least one of X 12 , Y 12 is N, Z 12 , at least one of Z 13 is N ;
  • R 17 may represent a 5- or 6-membered substituted or unsubstituted heterocyclic alkyl group containing 1 or 2 N at any substitution position of the ring in which R 17 includes the following examples, but not limited to:
  • substituted means that the group is further substituted with F, Cl, Br, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 alkylene hydroxy;
  • heterocyclic alkyl group is a heterocyclic alkyl group containing one or more heteroatoms independently selected from O, S, or N, and is connected to other groups through C atoms.
  • the compound of formula X has the structure of formula Xa:
  • R 11 , R 12 , R 13 , R 14 , R 17 , X 11 , Y 11 and Z 11 are as defined above.
  • the compound of formula X has the structure of structural formula Xa, Xb, Xc or Xd, wherein R 11 and R 12 respectively represent H, D, F, Cl, Br, C 1 -C 3 alkyl, C 1- C 3 alkoxy, C 1 -C 3 alkylene hydroxy;
  • a 1 is selected from the following structures:
  • R 13 and R 14 can be substituted at any position on the ring, R 13 and R 14 independently represent H, D, F, Cl, Br, I, NH 2 , NO 2 , CN, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl;
  • R 18 may be selected from H, C 1 -C 6 alkyl
  • X 11 , Y 11 and Z 11 can independently represent C or N;
  • R 17 is selected from the following substituent groups:
  • R 11 and R 12 represent H, D, F, Cl, Br, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylene hydroxy;
  • a 1 is R 13 and R 14 independently represent H, C 1 -C 3 alkyl, which may be substituted at any position on the ring;
  • X 11 , Y 11 or Z 11 are C or N;
  • the present invention is further preferred to protect the compound of formula X with the following specific structure, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • the present invention protects the following compounds, or pharmaceutically acceptable salts, solvates, and stereoisomers thereof:
  • the protective structure of formula X preferably of the formula Xa, formula Xb, Xc and Xd compound of structural formula, or above specific compounds, wherein at least one atom is replaced by its corresponding isotope elements, the isotope is selected from 2 H, 3 H, 11 C , 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F or 36 Cl.
  • the present invention further protects the preparation method of the compound of formula X, which includes reacting an organic aldehyde compound XIIa and its derivatives with an organic amine compound XIIIb or XIIIb' to obtain a compound of formula X'.
  • the preparation route includes synthetic route 1 and synthetic route 2,
  • B 1 is selected from -OH, halogen; the substituents A 1 , X 11 , Y 11 , Z 11 , X 12 , Y 12 , Z 12 , Z 13 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 refer to the above definitions.
  • the compound of formula I, the compound of formula X or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof of the present invention have WNT signaling pathway inhibitory activity and can be used for the treatment of WNT signaling pathway related diseases.
  • the present invention provides the use of the compound of formula I, the compound of formula X or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the preparation of a medicament for the treatment of diseases related to the WNT signaling pathway.
  • the diseases related to the WNT signaling pathway include, but are not limited to: tumors, deformity syndromes, bone or cartilage diseases, diabetes or its complications, tissue fibrosis, and the like.
  • the bone or cartilage diseases include but are not limited to: osteoporosis, osteoarthritis, osteochondrosis.
  • the diabetes or its complications include, but are not limited to: type II diabetes, diabetic retinopathy, diabetic nephropathy, and diabetic cerebrovascular disease.
  • the tumors include but are not limited to solid tumors or non-solid tumors.
  • the solid tumors include but are not limited to: colorectal cancer, colon cancer, gastric cancer, esophageal cancer, osteosarcoma, breast cancer, cervical squamous cell carcinoma, endometrial cancer, mesothelioma, pancreatic cancer, bladder cancer, prostate Cancer, lung cancer, hepatocellular carcinoma, medulloblastoma, hepatoblastoma, gastrointestinal carcinoid, ovarian cancer, melanoma, squamous cell carcinoma of the head and neck, thyroid cancer, nephroblastoma, retinoblastoma, Glioma.
  • the non-solid tumors include but are not limited to: leukemia, such as chronic myelogenous leukemia; lymphoma.
  • Tissue fibrosis can occur in a variety of organs.
  • the main pathological change is the increase of fibrous connective tissue and the decrease of parenchymal cells in organ tissues. Continued progress can lead to the destruction of organ structure and loss of function. It includes but is not limited to: pulmonary fibrosis, liver fibrosis, kidney fibrosis, bone marrow fibrosis, etc.
  • the present invention provides a pharmaceutical composition characterized by comprising a compound of Formula I, or a compound of Formula X, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the pharmaceutical composition can be used to treat diseases related to the WNT signaling pathway.
  • the definition of the diseases related to the WNT signaling pathway is as described above.
  • the pharmaceutical composition further contains a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is various auxiliary materials commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH adjusting agents, preservatives, lubricants, disintegrating agents, etc. .
  • Examples of the diluent include lactose, starch, cellulose derivatives, inorganic calcium salts, and sorbitol.
  • Examples of the binder include starch, gelatin, sodium carboxymethyl cellulose, and polyvinylpyrrolidone.
  • the antioxidants are, for example, vitamin E, sodium bisulfite, sodium sulfite, butylated hydroxyanisole, and the like.
  • the pH adjusting agent is, for example, hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate and the like.
  • preservatives examples include: methylparaben, ethylparaben, m-cresol, benzalkonium chloride and the like.
  • the lubricant is, for example, magnesium stearate, micropowder silica gel, talc powder and the like.
  • examples of the disintegrant include starch, methyl cellulose, xanthan gum, and croscarmellose sodium.
  • the pharmaceutical composition contains the compound of formula I, or the compound of formula X, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in an amount of 0.1-1000 mg, preferably 1-500 mg, more preferably 5- 100mg.
  • the compound of formula I, or the compound of formula X, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the pharmaceutical composition accounts for 10%-90% of the mass of the pharmaceutical composition, preferably 20%- 80%, more preferably 30%-70%.
  • the dosage form of the pharmaceutical composition may be in the form of oral preparations, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; it may also be in the form of injections, such as injections, powder injections, etc. , Administered by intravenous, intraperitoneal, subcutaneous or intramuscular route. All dosage forms used are well known to those of ordinary skill in the pharmaceutical arts.
  • the route of administration of the pharmaceutical composition includes, but is not limited to: oral; buccal; sublingual; transdermal; transmucosal; intranasal; ophthalmic; pulmonary; rectal; vaginal; gastrointestinal External, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital , Intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; by implantation in a reservoir or reservoir.
  • the pharmaceutical composition can be used in combination with other drugs or treatments for treating diseases related to the WNT signaling pathway.
  • the pharmaceutical composition may further contain a second therapeutic agent, and the second therapeutic agent is another medicine for treating diseases related to the WNT signaling pathway.
  • the present invention provides a method for treating WNT signaling pathway-related diseases, characterized in that a therapeutically effective amount of a compound of formula I, or a compound of formula X, or a pharmaceutically acceptable salt, solvate, or the like is administered to a patient in need Stereoisomers.
  • the route of administration of the compound of formula I, or the compound of formula X, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof includes, but is not limited to: oral; buccal; sublingual; transdermal ; Transmucosal; intranasal; ophthalmic; pulmonary; rectal; vaginal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial , Intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; By implanting the reservoir or reservoir.
  • the dosage of the compound of formula I, or the compound of formula X, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof will depend on the age, health, and weight of the recipient, the type of combination drug, the frequency of treatment, Route of administration, etc.
  • the drug can be administered in a single daily dose, once a day, once every two days, once every three days, once every four days, or the total daily dose is administered in divided doses of two, three or four times a day .
  • the dosage can be administered one or more times, and the administration time can be from a single day to several months or more.
  • the dosage of the compound of formula I, or the compound of formula X, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is 0.01-1000 mg/kg/day, preferably 0.1-100 mg/kg/day, such as 0.5mg/kg/day, 1mg/kg/day, 2mg/kg/day, 5mg/kg/day, etc.
  • the method further includes administering other drugs for treating WNT signaling pathway-related diseases to patients in need, or using other treatments in combination.
  • drugs that treat WNT signaling pathway-related diseases include, but are not limited to: drugs that disrupt DNA structure and function, nucleotide synthetase inhibitors, DNA polymerase inhibitors, dihydrofolate reductase inhibitors, nucleotide reductase inhibitors Agents, drugs that inhibit RNA synthesis, topoisomerase inhibitors, tubulin inhibitors, drugs that affect hormone balance, tyrosine kinase inhibitors, epidermal growth factor receptor inhibitors, vascular endothelial growth factor receptor inhibitors , Immunomodulators, etc.
  • the drugs that disrupt DNA structure and function include, but are not limited to: nitrogen mustard, cyclophosphamide, cisplatin, carboplatin, and oxaliplatin.
  • the nucleotide synthetase inhibitors include, but are not limited to: 5-fluorouracil, capecitabine, raltitrexed, 6-mercaptopurine.
  • the DNA polymerase inhibitors include but are not limited to: cytarabine, gemcitabine.
  • the dihydrofolate reductase inhibitors include but are not limited to: methotrexate and pemetrexed.
  • the nucleotide reductase inhibitor includes but is not limited to: hydroxyurea.
  • the drugs that inhibit RNA synthesis include, but are not limited to: doxorubicin, daunorubicin, epirubicin, and pirarubicin.
  • the topoisomerase inhibitors include but are not limited to: hydroxycamptothecin, irinotecan, and topotecan.
  • tubulin inhibitors include but are not limited to: vincristine, vindesine, vinorelbine, paclitaxel, and docetaxel.
  • the drugs that affect hormone balance include but are not limited to: toremifene, exemestane, letrozole, bicalutamide, enzalutamide, medroxyprogesterone, megestrol, testosterone propionate, Goserelin and leuprolide.
  • the tyrosine kinase inhibitors include but are not limited to: imatinib, gefitinib, erlotinib, sorafenib, sunitinib, lapatinib, apatinib.
  • the epidermal growth factor receptor inhibitors include, but are not limited to: trastuzumab, panitumumab, cetuximab, and pertuzumab.
  • vascular endothelial growth factor receptor inhibitors include but are not limited to: bevacizumab and ramucirumab.
  • the immunomodulators include but are not limited to: rituximab, pembrolizumab, and ipilimumab.
  • the other treatments include but are not limited to: radiotherapy, surgical resection.
  • the inhibitory activity of the compound of formula I and the compound of formula X as WNT signaling pathways of the present invention was determined by detection using a luciferase reporter gene system, as described in the examples below.
  • the compound of the present invention has an IC50 value of ⁇ 1 ⁇ M detected by the method.
  • the IC50 value of the preferred compounds of the present invention is ⁇ 0.8 ⁇ M.
  • the IC50 value of a further preferred compound of the present invention is ⁇ 0.1 ⁇ M.
  • HATU N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate, English name O-(7-Azabenzotriazol-1-yl )-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIEA N,N-diisopropylethylamine
  • DIPEA N,N-diisopropylethylamine
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • Et ethyl
  • Ac acetyl
  • ETOH is ethanol
  • LCMS liquid-mass spectrometry, liquid chromatography-mass spectrometry
  • the compound 11 is prepared by reacting I-10 with the compound of the above formula, and the preparation procedure is similar to the preparation method of compound 1.
  • ESIMS found: m/z 387.0 (M+1).
  • the compound 102 synthesis method is similar to the compound 101 synthesis method.
  • ESIMS found: m/z 443.4 (M+1).
  • Example 40 4-(3-(((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)amino)-[1,2,4]triazole Preparation of [4,3-c]pyrimidin-7-yl)piperazin-2-one (compound 104)
  • Example 41 4-(3-(((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)amino)-[1,2,4]triazole Preparation of [4,3-c]pyrimidin-7-yl)-1-methylpiperazin-2-one (Compound 105).
  • Example 42 4-(3-(((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)amino)-[1,2,4]triazole Preparation of [4,3-c]pyrimidin-7-yl)-1-acetylpiperazine (Compound 106).
  • Example 43 N-((2',3-dimethyl-[2,4'-bipyridyl]-5-yl)methyl)-7-(2-methylpyridin-4-yl)-[ Preparation of 1,2,4]triazolo[4,3-c]pyrimidin-3-amine (Compound 107).
  • a luciferase reporter gene system was selected to complete the detection.
  • the following experiment uses L-Wnt3a cells and HEK293/STF cells to co-culture, in which L-Wnt3a cells are WNT protein-producing cells, and HEK293/STF cells are WNT protein-responsive cells.
  • the classical WNT signaling pathway requires ⁇ -catenin to enter the nucleus, and then forms a complex with the transcription factor TCF/LEF to jointly initiate the transcription of downstream regulatory genes.
  • the HEK293/STF cell line carries the SuperTopflash (STF) reporter gene (7 LEF/TCF tandem DNA binding sites in the reporter gene drive firefly luciferase expression), which can express luciferase under the induction of Wnt/Norrin signal, so it can The level of activation of Wnt/Norrin- ⁇ -catenin signaling pathway can be conveniently detected by detecting the expression level of luciferase.
  • STF SuperTopflash
  • human embryonic kidney 293 cells (HEK293) (American culture collection, ATCC, Mansassas, VA) were co-transfected with STF-reporter 5-8 xTCF/Lef-luc plus pcDNA3.1-Neo (Invitrogen, Carlsbad, CA ) And FuGENE6 (Roche Diagnostics, Indianapolis, IL).
  • HEK293/STF cell line was added to Dulbecco's modified Eagle's complete medium (DMEM) (Gibco/Invitrogen, Carlsbad, supplemented with 10% FBS (Hyclone), 50 unit/ml penicillin, 50 ⁇ g/ml streptomycin (Invitrogen, Carlsbad, CA) CA) at 37 ° C, 5% CO 2, by G418 selection to obtain stable cell lines.
  • DMEM Dulbecco's modified Eagle's complete medium
  • FBS Hyclone
  • penicillin 50 unit/ml
  • streptomycin Invitrogen, Carlsbad, CA
  • the compound was diluted with DMEM medium to different concentrations, and the culture medium was replaced with fresh medium at 100 ⁇ l/well overnight, and the cells were cultured under compound treatment for 24 hours. Remove the medium from the cell culture plate at 50 ⁇ l/well, add 50 ⁇ l/well Bright-Glo reagent (Bright-Glo Luciferase Assay Kit, Promega, Madison, WI), mix for 60 seconds and incubate at room temperature in the dark for 10 minute. The plate was read on Envision, and the IC50 value of the dose response was calculated by GraphPad Prism 6 software.
  • CTG CellTiter-Glo
  • HEK293/STF cells were co-cultured with L-Wnt 3a cells, and the culture method was as described above.
  • STSP staurosporine
  • the results showed that during the gradual increase of the compound concentration from 10 -11 to 10 -6 mol/L, the cell survival rate of STSP treatment gradually decreased from 100% to 60%
  • the cell survival rate of the tested compound of the present invention can be maintained between 90% and 110%, indicating that the inhibitory effect of the tested compound of the present invention on WNT signaling pathway has nothing to do with cell death.

Abstract

本发明提供了具有WNT信号通路抑制活性的5,6双环结构的化合物和取代5,6杂双环氨基化合物，可以用于WNT信号通路相关疾病的治疗。相关疾病包括但不限于：肿瘤、畸形综合症、骨或软骨疾病、糖尿病或其并发症、组织纤维化等。

Description

作为WNT信号通路抑制剂的化合物及其医学应用
本申请要求2018年12月21日向中国国家知识产权局提交的专利申请号为201811573629.X，发明名称为“5,6-双环化合物作为WNT信号通路抑制剂及其医学应用”，和2019年2月28日向中国国家知识产权局提交的专利申请号为201910152552.7，发明名称为“取代5,6-双杂环氨基化合物作为WNT信号通路抑制剂及其治疗应用”的在先申请的优先权。所述两份在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于医药技术领域，涉及具有WNT信号通路抑制活性的5,6-双环化合物和取代5,6-双杂环氨基化合物，及其应用。
背景技术
WNT信号通路在胚胎发生和成体的稳态调节中都起着重要作用。Wnt基因家族负责编码一大类与Int1/Wnt1原癌基因及无翅果蝇(Wg，对应果蝇Wnt1)相关的分泌型WNT配体(Cadigen and Nusse.,(1997)Genes&Development 11：3286-3305)。多种Wnt-激发的通路协同调节关键的发育过程，以及成人组织的稳态及修复过程，不同疾病中均存在Wnt通路调节失调，例如癌症、畸形综合症、骨质疏松症、糖尿病视网膜病变以及肺纤维化(MacDonald et al(2009)Dev.Cell 17：9-26；Williams and Insogna(2009)J.Bone Miner.Res.24：171-178；Polaskis(2007)Curr.Opin.Genet.Dev.17：45-51；Chen et al.,(2009)Am.J.Pathol.175：2676-2685)。WNT配体决定了WNT信号通路的活性。WNT蛋白合成的第一步是在内质网(ER)完成翻译，接着由ER固有的酶Porcupine(PORCN，一种膜结合的O-酰基转移酶(MBOAT))介导翻译后酰化(棕榈酰化)(Proffitt and Virshup.,(2012)J of Biol.Chem.287：34167-34178)，WNT蛋白在1或2个高度保守位点上存在棕榈酰化(Zhai et al.,(2004)J.Biol.Chem.279：33220-33227；Takada et al.,(2006)Dev Cell 11：791-801)。WNT蛋白转运、分泌以及蛋白活性与WNT蛋白翻译后酰化紧密相关，而PORCN对于Wnt的翻译后酰化具有高选择性及精密调节作用(Proffitt and Virshup.,(2012)J of Biol.Chem.287：34167-34178)，这一修饰过程是WNT蛋白分泌以及连接载体蛋白WLS所必须。除此之外，棕榈酰化对于WNT蛋白与细胞表面的Frizzled受体间的相互作用至关重要(Coombs et al.,(2010)J.Cell Sci 123：3357-3367；Herr and Basler(2012)Dev.Biol.361：392-402；Janda et al.,(2012)Dev.Biol.361：392-402)。
典型的WNT通路由WNT配体与细胞表面Frizzled受体结合而活化(Bhanot et al.,(1996) Nature 382：225-230)，继而激活胞浆蛋白Dishevelled(Boutros,et al.,(1999)Mech.Dev.83：27-37)以及LRP5/6的磷酸化，导致β-catenin在细胞核内的聚集并与TCF/LCF家族转录因子相互作用，促进特定基因的转录过程(Uthoff et al.,(2001)Mol.Carcinog.,31：56-62)。WNT通路非活化状态下，游离的胞浆β-catenin进入支架蛋白Axin、结肠腺瘤样息肉蛋白APC以及糖原合成激酶(GSK)-3β组成的复杂体系中。Axin、APC以及β-catenin被GSK-3β接连磷酸化，最终导致β-catenin进入泛素化途径，并被蛋白酶体降解(Uthoff et al.,(2001)Mol.Carcinog.,31：56-62；Matsuzawa et al.,(2001)Mol.Cell,7：915-926)。
众所周知，WNT信号通路对于多种类型的细胞的存活起到有利作用(Orford et al.,(1999)J.Cell Bio,146：855-868；Satoh et.al.,(2000)Nat.Genet,24：245-250；Ioannidis et al.,(2001)Nat.Immunol,2：691-697)。WNT通路活性的改变与肿瘤的发生发展紧密相关。例如，经典WNT通路高活性会导致细胞生长异常(Reya and Clevers,(2005)Nature 434：843-850)。另外，90％的结直肠癌有APC基因(其是WNT/β-catenin信号通路抑制剂)的缺失(Kinzler and Vogelstein,(1996)Cell 87：159-170)。再比如，WNT信号通路的活性异常与多种人体肿瘤相关，同时伴随C-Myc过度表达(Polakis et al.,(2000)Genes Dev,14：1837-1851；Bienz et al.,(2000)Cell：311-320)。C-Myc现已证实为结直肠癌β-caternin/TCF通路中的一个翻译靶点(He et al.,(1998)Science,281：1509-1512；de La Coste et al.,(1998)Proc Natl Acad Sci USA,95：8847-8851；Miller et al.,(1999)Oncogene,18：7860-7872；Uoi et al.,(2002)J.Cell Biol,157：429-440)。除此之外，WNT蛋白表达增强以及细胞外WNT蛋白功能抑制剂的缺失，可能会导致WNT依赖的肿瘤产生(Polaskis(2007)Curr.Opin.Genet.Dev.17：45-51)。近期研究发现，WNT信号通路在肿瘤干细胞中发挥作用(Takahashi-Yanaga and Kahn,(2010)Clin.Cancer Res 16：3153-62)，并与干细胞自我更新相关(Kretzachmar and Clevers,(2017)Dev.Biol.428：273-282；Prieur et al.,(2017)Clin.Cancer Res.23：5267-5280)。
应用基因或化学方法，阻断多种肿瘤中的WNT信号通路，能够使异常的细胞生长停滞(Herbst and Kolligs,(2007)Methods Mol.Biol 361：63-91)。此外，抑制此信号通路可能直接影响支持肿瘤细胞生长和转移的细胞，其中肿瘤转移被认为是肿瘤细胞对传统化疗药耐药的重要因素。异常的WNT信号通路还与多种紊乱相关，包括但不限于骨和软骨疾病，例如骨质疏松症、骨关节炎、肥胖相关的II型糖尿病等(Hoeppner,(2009)Expert Opin.Ther.Targets 13：485-96；Ouchi et al.,(2010)Science 329：454-457；Blom et al.,(2010)Curr.Drug Targets 11：620-629)。因此，调节WNT信号通路的物质或方法，具有潜在的治疗、预防以及改善WNT通路相关疾病的疗效。
发明内容
本发明提供一种结构式I的5,6-双环化合物，或其药学上可接受的盐，溶剂化物，或立体异构体：
Figure PCTCN2019127056-appb-000001
其中：B为-CONH-，或-NHCO-，
R 1，R 2分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基，或者R 1和R 2连接形成一个包含0-1个杂原子的取代的或未取代3-6元饱和环，其中所述杂原子选自O，S或N之一；
R 3，R 4，R’ 3，R’ 4可在所在环的任意取代位置，其中R 3，R 4，R’ 3，R’ 4独立代表H，D，F，Cl，Br，I，NH 2，NO 2，CN，C 1-C 6烷基，取代的C 1-C 6烷基，取代或非取代的C 3-C 7环烷基，OR 5，COR 5，CONR 5R 6，NR 5R 6，NR 5COR 6，NR 5CONHR 6，NHSO 2R 5，SO 2NHR 5，SO 2(C 1-C 6烷基)，取代或非取代的C 3-C 7杂环烷基，所述C 3-C 7杂环烷基为含O，S和/或N的杂环烷基，以C原子与环相连接；
R 5，R 6可独立代表H，D，C 1-C 6烷基，C 2-C 4亚烷基羟基，C 3-C 6环烷基或C 3-C 6杂环烷基，氨基C 1-C 6烷基，或取代氨基C 1-C 6烷基，或R 5和R 6与所连接的基团可连接形成包含1-2个杂原子的取代或未取代的3-6元饱和环，其中，所述杂原子进一步选自O，S或N原子；
上述“取代的”表示所述基团进一步被F，Cl，Br，C 1-C 6烷基，C 1-C 6烷氧基或C 1-C 6亚烷基羟基所取代；
X，Y，Z，X 1，Y 1，Z 1可独立代表C，N；
A选自下列结构式代表的芳基或杂芳基，
Figure PCTCN2019127056-appb-000002
Figure PCTCN2019127056-appb-000003
等，
其中R 3，R 4在所连接环的任意可取代位置，R 3，R 4的定义和上述相同；
R 7可选自H，F，Cl，Br，I，C 1-C 6烷基。
进一步，本发明保护一种结构式I的化合物，其中，B为-CONH-结构，X为C，Y为N，Z为C，即为式Ia结构化合物：
Figure PCTCN2019127056-appb-000004
或，本发明保护一种式I结构化合物，其中B为-CONH-结构，X为N，Y为N，Z为C，即为式Ib结构化合物：
Figure PCTCN2019127056-appb-000005
或，本发明保护一种式I结构化合物，其中B为-CONH-结构，X为C，Y为C，Z为N，即为式Ic结构化合物：
Figure PCTCN2019127056-appb-000006
其中，所述R 1，R 2分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基；
R 3，R 4，R’ 3，R’ 4可在所在环的任意取代位置，其中R 3，R 4，R’ 3，R’ 4独立代表H，D，F，Cl，Br，I，NH 2，NO 2，CN，C 1-C 6烷基，取代的C 1-C 6烷基，取代或非取代的C 3-C 7环烷基，OR 5，COR 5，CONR 5R 6，NR 5R 6，NR 5COR 6，NR 5CONHR 6，NHSO 2R 5，SO 2NHR 5，SO 2(C 1-C 6烷基)，取代或非取代的C 3-C 7杂环烷基，所述C 3-C 7杂环烷基为含O，S和/或N的杂环烷基，以C原子与环相连接；
R 5，R 6可独立代表H，D，C 1-C 6烷基，C 2-C 4亚烷基羟基，C 3-C 6环烷基或C 3-C 6杂环烷基，氨基C 1-C 6烷基，或取代氨基C 1-C 6烷基，或R 5和R 6与所连接的基团可连接形成包含1-2个杂原子的取代或未取代的3-6元饱和环，其中，所述杂原子进一步选自O，S和/或N原子；
所述“取代的”表示所述基团进一步被F，Cl，Br，C 1-C 6烷基，C 1-C 6烷氧基或C 1-C 6亚烷基羟基所取代；
A选自下列结构式代表的芳基或杂芳基，
Figure PCTCN2019127056-appb-000007
Figure PCTCN2019127056-appb-000008
其中R 3，R 4在所连接环的任意可取代位置，R 3，R 4的定义和上述相同；
R 7可选自H，F，Cl，Br，I，C 1-C 6烷基。
进一步，本发明保护一种结构式I的化合物，其中，B为-NHCO-结构，X为C，Y为N，Z为C，即为式IIa结构化合物：
Figure PCTCN2019127056-appb-000009
或，B为-NHCO-结构，X为N，Y为N，Z为C，即为式IIb结构化合物：
Figure PCTCN2019127056-appb-000010
或，B为-NHCO-结构，X为C，Y为C，Z为N，即为式IIc结构化合物：
Figure PCTCN2019127056-appb-000011
其中，所述R 1，R 2分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基；
R 3，R 4，R’ 3，R’ 4可在所在环的任意取代位置，其中R 3，R 4，R’ 3，R’ 4独立代表H，D，F，Cl，Br，I，NH 2，NO 2，CN，C 1-C 6烷基，取代的C 1-C 6烷基，取代或非取代的C 3-C 7环烷基，OR 5，COR 5，CONR 5R 6，NR 5R 6，NR 5COR 6，NR 5CONHR 6，NHSO 2R 5，SO 2NHR 5，SO 2(C 1-C 6烷基)，取代或非取代的C 3-C 7杂环烷基，所述C 3-C 7杂环烷基为含O，S和/或N的杂环烷基，以C原子与环相连接；
R 5，R 6可独立代表H，D，C 1-C 6烷基，C 2-C 4亚烷基羟基，C 3-C 6环烷基或C 3-C 6杂环烷基，氨基C 1-C 6烷基，或取代氨基C 1-C 6烷基，或R 5和R 6与所连接的基团可连接形成包含 1-2个杂原子的取代或未取代的3-6元饱和环，其中，所述杂原子进一步选自O，S和/或N原子；
所述“取代的”表示所述基团进一步被F，Cl，Br，C 1-C 6烷基，C 1-C 6烷氧基或C 1-C 6亚烷基羟基所取代；
A选自下列结构式代表的芳基或杂芳基，
Figure PCTCN2019127056-appb-000012
其中R 3，R 4在所连接环的任意可取代位置，R 3，R 4的定义和上述相同；
R 7可选自H，F，Cl，Br，I，C 1-C 6烷基。
进一步，本发明保护如下式I具体化合物，该具体化合物选自：
Figure PCTCN2019127056-appb-000013
Figure PCTCN2019127056-appb-000014
Figure PCTCN2019127056-appb-000015
上述所述化合物中B为-CONH-结构，
Figure PCTCN2019127056-appb-000016
Figure PCTCN2019127056-appb-000017
Figure PCTCN2019127056-appb-000018
上述所述化合物中B为-NHCO-结构。
优选保护如下具体化合物：
N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)乙酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)乙酰胺、
N-(4-(2-甲基吡啶-4-基)苯基甲基)-7-乙酰基-咪唑[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-(三氟甲基)吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺，或
N-(4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺。
进一步，保护上述通式I化合物或具体化合物，其中原子相应的同位素是 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 35S， 18F和 36Cl的同位素化合物。
本发明进一步保护式I化合物的制备方法，其包括：有机酸化合物及其衍生物与有机胺化合物反应得到式I结构的酰胺化合物，所述有机酸化合物及其衍生物选自下式化合物：
Figure PCTCN2019127056-appb-000019
所述有机胺化合物选自下式化合物：
Figure PCTCN2019127056-appb-000020
其中M选自-OH，卤素，C 1-C 6烷氧基，C 3-C 7环烷氧基，金属离子或类似结构基团，取代基团X，Y，Z，X 1，Y 1，Z 1，R 1，R 2，R 3，R 4，R’ 3，R’ 4，R 5，R 6，R 7，A定义参照上述定义。
本发明还提供了一种结构式X的取代5,6-双杂环氨基化合物，或其药学上可接受的盐，溶剂化物，或立体异构体，
Figure PCTCN2019127056-appb-000021
其中：
R 11，R 12分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基，或者R 11和R 12连接形成一个包含0-1个杂原子的取代的或未取代的3-6元饱和环，其中所述杂原子选自O，S或N之一；
R 13，R 14可在所在环的任意取代位置，R 13，R 14独立代表H，D，F，Cl，Br，I，NH 2， NO 2，CN，C 1-C 6烷基，取代的C 1-C 6烷基，取代或非取代的C 3-C 7环烷基，OR 15，COR 15，CONR 15R 16，NR 15R 16，NR 15COR 16，NR 15CONHR 16，NHSO 2R 15，SO 2NHR 15，SO 2(C 1-C 6烷基)，取代或非取代的C 3-C 7杂环烷基；
A 1代表下面的6元芳基或杂芳基，
Figure PCTCN2019127056-appb-000022
Figure PCTCN2019127056-appb-000023
等，
R 13，R 14可在所在环的任意取代位置，定义与上述相同；
R 18可选自H，D，C 1-C 6烷基；
R 15，R 16可独立代表H，D，C 1-C 6烷基，C 2-C 4亚烷基羟基，C 3-C 7环烷基或C 3-C 7杂环烷基，氨基C 1-C 6烷基，或取代的氨基C 1-C 6烷基，或R 15和R 16与所连接的基团可连接形成包含1-2个杂原子的取代或未取代的3-6元饱和杂环烷基，其中，所述杂原子进一步选自O，S和/或N原子；
X 11，Y 11，Z 11，X 12，Y 12，Z 12，Z 13可独立代表C或N，其中，X 12，Y 12至少有一个是N，Z 12，Z 13至少有一个是N；
R 17可在所在环的任意取代位置，代表5或6-元取代或非取代含1或2个N的杂环烷基，所述杂环烷基包括下面的例子，但不限于：
Figure PCTCN2019127056-appb-000024
所述“取代的”表示所述基团进一步被F，Cl，Br，C 1-C 6烷基，C 1-C 6烷氧基或C 1-C 6亚烷基羟基所取代；
所述“杂环烷基”为含1个或多个，独立的选自O，S或N的杂原子的杂环烷基，以C原子与其它基团相连接。
一个优选实例，所述式X化合物具有结构式Xa的结构：
Figure PCTCN2019127056-appb-000025
或，具有结构式Xb的结构：
Figure PCTCN2019127056-appb-000026
或，具有结构式Xc的结构：
Figure PCTCN2019127056-appb-000027
或，具有结构式Xd的结构：
Figure PCTCN2019127056-appb-000028
其中：R 11，R 12，R 13，R 14，R 17，X 11，Y 11，Z 11的定义如前所述。
进一步优选，所述式X化合物具有结构式Xa、Xb、Xc或Xd的结构，其中，R 11，R 12分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基；
A 1选自如下结构：
Figure PCTCN2019127056-appb-000029
R 13，R 14可在所在环的任意取代位置，R 13，R 14独立代表H，D，F，Cl，Br，I，NH 2，NO 2，CN，C 1-C 6烷基，取代的C 1-C 6烷基；
R 18可选自H，C 1-C 6烷基；
X 11，Y 11，Z 11可独立代表C或N；
R 17选自如下取代基团：
Figure PCTCN2019127056-appb-000030
进一步，本发明保护式Xa化合物：
Figure PCTCN2019127056-appb-000031
其中，R 11，R 12分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基；A 1为
Figure PCTCN2019127056-appb-000032
R 13，R 14独立地代表H，C 1-C 3烷基，可在所在环上任意位置取代；X 11，Y 11或Z 11为C或N；
R 17为
Figure PCTCN2019127056-appb-000033
本发明进一步优选，保护如下具体结构的式X化合物，或其药学上可接受的盐，溶剂化物，立体异构体：
Figure PCTCN2019127056-appb-000034
Figure PCTCN2019127056-appb-000035
Figure PCTCN2019127056-appb-000036
Figure PCTCN2019127056-appb-000037
Figure PCTCN2019127056-appb-000038
Figure PCTCN2019127056-appb-000039
Figure PCTCN2019127056-appb-000040
最优选，本发明保护如下化合物，或其药学上可接受的盐，溶剂化物，立体异构体：
4-(3-((3-甲基-4-(2-甲基吡啶-4-基)苄基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)哌嗪-2-酮，
1-甲基-4-(3-((3-甲基-4-(2-甲基吡啶-4-基)苄基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)哌嗪-2-酮，
4-(3-((3-甲基-4-(2-甲基吡啶-4-基)苄基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)-1-乙酰基哌嗪，
4-(3-(((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)哌嗪-2-酮，
4-(3-(((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)-1-甲基哌嗪-2-酮，
4-(3-(((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)-1-乙酰基哌嗪，
N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-7-(2-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-3-胺。
进一步，保护结构式X，优选结构式Xa、结构式Xb、结构式Xc和结构式Xd化合物或上述具体化合物，其中至少一个原子被其相应的同位素元素替换，所述同位素选自 2H、 3H、 11C、 13C、 14C、 15N、 17O、 18O、 35S、 18F或 36Cl。
本发明进一步保护式X化合物的制备方法，包括，有机醛类化合物XIIa及其衍生物与有机胺化合物XIIIb或XIIIb’反应得到式X’结构的化合物，所述制备路线包括合成路线1和合成路线2，
Figure PCTCN2019127056-appb-000041
根据需要，进一步增加R 11或R 12的取代基团，得到式X化合物；
其中B 1选自-OH，卤素；取代基团A 1，X 11，Y 11，Z 11，X 12，Y 12，Z 12，Z 13，R 11，R 12， R 13，R 14，R 15，R 16，R 17定义参照上述定义。
本发明的式I化合物、式X化合物或其药学上可接受的盐，溶剂化物，或立体异构体具有WNT信号通路的抑制活性，可以用于WNT信号通路相关疾病的治疗。
本发明提供式I化合物、式X化合物或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗WNT信号通路相关疾病的药物中的用途。
所述WNT信号通路相关疾病包括但不限于：肿瘤、畸形综合症、骨或软骨疾病、糖尿病或其并发症、组织纤维化等。
所述骨或软骨疾病包括但不限于：骨质疏松症、骨关节炎、骨软骨病。
所述糖尿病或其并发症包括但不限于：II型糖尿病、糖尿病性视网膜病变、糖尿病性肾病、糖尿病性脑血管病。
所述肿瘤包括但不限于：实体瘤或非实体瘤。所述实体瘤包括但不限限于：结肠直肠癌、结肠癌、胃癌、食道癌、骨肉瘤、乳腺癌、宫颈鳞状细胞癌、子宫内膜癌、间皮瘤、胰腺癌、膀胱癌、前列腺癌、肺癌、肝细胞癌、髓母细胞瘤、肝母细胞瘤、胃肠类癌、卵巢癌、黑色素瘤、头颈部鳞状细胞癌、甲状腺癌、肾母细胞瘤、视网膜母细胞瘤、胶质瘤。所述非实体瘤包括但不限于：白血病，例如慢性粒细胞性白血病；淋巴瘤。
组织纤维化可发生于多种器官，主要病理改变为器官组织内纤维结缔组织增多，实质细胞减少，持续进展可致器官结构破坏和功能减退。其包括但不限于：肺纤维化、肝纤维化、肾纤维化、骨髓纤维化等。
本发明提供一种药物组合物，其特征在于，包括式I化合物、或式X化合物、或其药学上可接受的盐，溶剂化物，或立体异构体。
所述药物组合物可以用于治疗WNT信号通路相关疾病。所述WNT信号通路相关疾病的定义如前文所述。
所述药物组合物进一步含有药学上可接受的载体。
所述药学上可接受的载体是制药领域中常用或已知的各种辅料，包括但不限于：稀释剂、粘合剂、抗氧化剂、pH调节剂、防腐剂、润滑剂、崩解剂等。
所述稀释剂例如：乳糖、淀粉、纤维素衍生物、无机钙盐、山梨醇等。所述粘合剂例如：淀粉、明胶、羧甲基纤维素钠、聚乙烯吡咯烷酮等。所述抗氧化剂例如：维生素E、亚硫酸氢钠、亚硫酸钠、丁羟基茴香醚等。所述pH调节剂例如：盐酸、氢氧化钠、柠檬酸、酒石酸、Tris、乙酸、磷酸二氢钠、磷酸氢二钠等。所述防腐剂例如：对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、间甲酚、苯扎氯铵等。所述润滑剂例如：硬脂酸镁、微粉硅胶、滑石粉等。所述崩解剂例如：淀粉、甲基纤维素、黄原胶、交联羧甲基纤维素钠等。
所述药物组合物中含有式I化合物、或式X化合物、或其药学上可接受的盐，溶剂化物，或立体异构体的量为0.1-1000mg，优选1-500mg，更优选为5-100mg。
所述药物组合物中式I化合物、或式X化合物、或其药学上可接受的盐，溶剂化物，或立体异构体占药物组合物的质量百分比为10％-90％，优选为20％-80％，更优选为30％-70％。
所述药物组合物的剂型可以是口服剂的形式，例如片剂、胶囊、丸剂、粉剂、颗粒剂、悬浮剂、糖浆剂等；也可以是注射给药的剂型，例如注射液、粉针剂等，通过静脉内、腹膜内、皮下或肌肉内的途径注射给药。所有使用的剂型形式都是药学领域普通技术人员所熟知的。
所述药物组合物的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；经黏膜的；鼻内的；眼用的；肺的；直肠的；阴道的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的、动脉内的、心内的、鞘内的、脊柱内的、囊内的、囊下的、眼眶内的、腹膜内的、气管内的、表皮下的、关节内的、蛛网膜下的和胸骨内的；通过植入储库或储液器。
所述药物组合物可以和其他的治疗WNT信号通路相关疾病的药物或治疗手段联合应用。
所述药物组合物可以进一步含有第二种治疗剂，所述第二种治疗剂是其他的治疗WNT信号通路相关疾病的药物。
本发明提供一种治疗WNT信号通路相关疾病的方法，其特征在于，对有需要的患者施用治疗有效量的式I化合物、或式X化合物、或其药学上可接受的盐，溶剂化物，或立体异构体。
所述式I化合物、或式X化合物、或其药学上可接受的盐，溶剂化物，或立体异构体的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；经黏膜的；鼻内的；眼用的；肺的；直肠的；阴道的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的、动脉内的、心内的、鞘内的、脊柱内的、囊内的、囊下的、眼眶内的、腹膜内的、气管内的、表皮下的、关节内的、蛛网膜下的和胸骨内的；通过植入储库或储液器。
式I化合物、或式X化合物、或其药学上可接受的盐，溶剂化物，或立体异构体的施用剂量将取决于接受者的年龄、健康和体重，联用药物的种类，治疗频率，给药途径等。药物可以单一日剂量施用，每天给药一次、每两天给药一次、每三天给药一次、每四天给药一次，或者总日剂量以每天两次、三次或四次的分开剂量施用。剂量可以施用一次或多次，施药时间可以单日至几个月或更长时间。式I化合物、或式X化合物、或其药学上可接受的盐，溶剂化物，或立体异构体的用药量为0.01-1000mg/kg/天，优选为0.1-100mg/kg/天，例如为0.5mg/kg/天，1mg/kg/天、2mg/kg/天、5mg/kg/天等等。
所述方法进一步包括，对有需要的患者给予其他的治疗WNT信号通路相关疾病的药物，或者联合使用其他的治疗手段。
其他的治疗WNT信号通路相关疾病的药物包括但不限于：破坏DNA结构和功能的药物、核苷酸合成酶抑制剂、DNA多聚酶抑制剂、二氢叶酸还原酶抑制剂、核苷酸还原酶抑制剂、抑制RNA合成的药物，拓扑异构酶抑制剂、微管蛋白抑制剂、影响激素平衡的药物、酪氨酸激酶抑制剂、表皮生长因子受体抑制剂、血管内皮生长因子受体抑制剂、免疫调节剂等。
所述破坏DNA结构和功能的药物包括但不限于：氮芥、环磷酰胺、顺铂、卡铂、奥沙利铂。
所述核苷酸合成酶抑制剂包括但不限于：5-氟尿嘧啶、卡培他滨、雷替曲塞、6-巯嘌呤。
所述DNA多聚酶抑制剂包括但不限于：阿糖胞苷、吉西他滨。
所述二氢叶酸还原酶抑制剂包括但不限于：氨甲喋呤、培美曲塞。
所述核苷酸还原酶抑制剂包括但不限于：羟基脲。
所述抑制RNA合成的药物包括但不限于：阿霉素、柔红霉素、表柔比星、吡柔比星。
所述拓扑异构酶抑制剂包括但不限于：羟喜树碱、伊立替康、拓扑替康。
所述微管蛋白抑制剂包括但不限于：长春新碱、长春地辛、长春瑞滨、紫杉醇、多西紫杉醇。
所述影响激素平衡的药物包括但不限于：托瑞米芬、依西美坦、来曲唑、比卡鲁胺、恩杂鲁胺、甲羟孕酮、甲地孕酮、丙酸睾丸酮、戈舍瑞林、亮丙瑞林。
所述酪氨酸激酶抑制剂包括但不限于：伊马替尼、吉非替尼、埃罗替尼、索拉菲尼、舒尼替尼、拉帕替尼、阿帕替尼。
所述表皮生长因子受体抑制剂包括但不限于：曲妥珠单抗、帕尼单抗、西妥昔单抗、帕妥珠单抗。
所述血管内皮生长因子受体抑制剂包括但不限于：贝伐单抗、雷莫芦单抗。
所述免疫调节剂包括但不限于：利妥昔单抗、派姆单抗、伊匹单抗。
所述其他治疗手段包括但不限于：放疗、手术切除。
本发明的式I化合物，式X化合物作为WNT信号通路的抑制活性是通过使用荧光素酶报告基因系统检测确定的，所述方法如下文实施例中所描述的。本发明的化合物采用所述方法检测的活性IC50值≤1μM。本发明的优选化合物的IC50值≤0.8μM。本发明的进一步优选的化合物的IC50值≤0.1μM。
具体实施方式
实施例中使用的化学试剂均为市售化合物，其中
DMF：N,N-二甲基甲酰胺；
BrCN：溴氰；
EA：乙酸乙酯；
HATU：N,N,N',N'-四甲基-O-(7-氮杂苯并三唑-1-基)脲六氟磷酸盐，英文名O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
DIEA：N,N-二异丙基乙胺；
DIPEA：N,N-二异丙基乙基胺；
TFAA：三氟乙酸酐
DCM：二氯甲烷
THF：四氢呋喃
Pyridine：吡啶
Pd(PPh 3) 4：四(三苯基膦)钯
Et：乙基，Ac：乙酰基；如EtOAc为乙酸乙酯或醋酸乙酯，ETOH为乙醇；
LCMS：液质联用，液相色谱质谱联用仪；
ESIMS：电喷雾质谱。
5,6双环化合物的制备实施例
中间体合成实施例
2-(4-(2-甲基吡啶-4-基)苯基)乙酸乙酯(I-1)的制备
Figure PCTCN2019127056-appb-000042
室温下，2-(4-溴苯基)乙酸乙酯(0.50克,2.06毫摩尔)溶解在20毫升无水THF，然后加入2-甲基-4-(4,4,5,5-甲基1,3,2-二杂氧戊硼烷-2基)吡啶(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine)(0.45克，2.06毫摩尔)，Pd(PPh3)4(0.58克，0.1毫摩尔)和碳酸铯(1.34克，4.0毫摩尔)。反应混合物通氮气5分钟，然后在75℃搅拌过夜。反应冷却后，用饱和NaHCO 3稀释并用EtOAc(3×100毫升)提取。有机层用盐水洗涤，Na 2SO 4干燥，过滤，并减压下浓缩。硅胶色谱纯化提供0.4克(76％)的I-1。
2-(4-(2-甲基吡啶-4-基)苯基)乙酸(I-2)的制备
Figure PCTCN2019127056-appb-000043
室温下，10mL LiOH(0.19克，7.92毫摩尔)水溶液加到20毫升I-1(0.40克，1.57毫摩尔)的THF溶液中。反应混合物搅拌过夜，浓缩。残留物用1N盐酸中和到pH值6，EtOAc(3×100毫升)提取。有机层用盐水洗涤，Na 2SO 4干燥，过滤，并减压浓缩。硅胶色谱纯化提供0.2克(56％)的I-2。ESIMS发现：m/z 228.0(M+1)。
2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酸(I-3)的制备.
Figure PCTCN2019127056-appb-000044
I-3的合成和I-2的合成方法一致。ESIMS发现：m/z 242.4(M+1)。
7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-胺(I-4)的制备
Figure PCTCN2019127056-appb-000045
4-甲氧基吡啶-2-胺用O-乙基三异硫氰酸酯处理，得到的中间体用氨水处理得到7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-胺(I-4)，ESIMS发现：m/z 165.3(M+1)。
6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-胺(I-5)的制备
Figure PCTCN2019127056-appb-000046
I-5的合成参考了I-4的合成。ESIMS发现：m/z 165.4(M+1)
5-甲氧基吡唑并[1,5-a]吡啶-2-胺(I-6)的制备.
Figure PCTCN2019127056-appb-000047
在0℃下，3mL二氯甲烷中，依次加入2,4,6-三甲基苯磺酰羟胺和2-(4-甲氧基吡啶-2-)乙腈，搅拌一小时。除掉溶剂，并加入了10ml的甲醇。在0℃下加入碳酸钾，搅拌1小时，去除溶 剂后，用清水清洗残渣，提取到乙酸乙酯中，干燥浓缩。硅胶色谱纯化得到I-6。1H核磁共振(亚砜,400兆赫)：7.98(d,1H,J＝3hz),7.18(d,1H,J＝5hz),6.82(d,1H,J＝5Hz),5.56(s,1H),5.03(s,2H),3.74(s,3H)
7-甲氧基咪唑并[1,2-a]吡啶-2-胺(I-7)的制备
Figure PCTCN2019127056-appb-000048
在15mL吡啶中，依次加入1g 2-氨基-4-甲氧基吡啶和1.7g对甲苯磺酰氯，加热到50℃14小时。冷却后，加入30mL水，过滤得到的固体干燥后溶解在DMF中，依次加入0.5g碘乙酰胺和0.4g DIEA，室温搅拌过夜。硅胶柱纯化得到中间体E溶解在20mL二氯甲烷中，加入1mL三氟乙酸酐，回流14小时，冷却后硅胶柱纯化后得中间体F。碱性条件下水解得到中间体I-7。ESIMS发现：m/z 164.4(M+1)。
6-甲氧基咪唑并[1,2-a]吡啶-2-胺(I-8)的制备
Figure PCTCN2019127056-appb-000049
I-8的合成和I-7类似。ESIMS：m/z 164.4(M+1)。1H NMR(DMSO,400MHz)：8.04(d,1H,J＝3Hz),7.07(d,1H,J＝5Hz),6.94(s,1H),6.76(d,1H,J＝5Hz),4.90(bs,2H),3.73(s,3H).
实施例1：N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物1)的制备
Figure PCTCN2019127056-appb-000050
在0℃下2-(4-(2-甲基吡啶-4-基)苯基)乙酸(I-2)(0.04克,0.18毫摩尔)溶解在2mL无水DMF。然后依次加入7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2胺(I-4)(0.035克，0.21毫摩尔)，HATU(0.074克，0.19毫摩尔)和DIEA(0.068克，0.53毫摩尔)。混合物室温搅拌1小时。用饱和NaHCO 3稀释，并提取到EtOAc。有机层用盐水洗两次，Na 2SO 4干燥，过滤，减压浓缩。硅胶色谱纯化得到12毫克(18％)的化合物1。ESIMS发现：m/z 374.3(M+1)。1H核磁共振(亚砜,400兆赫)：δ10.95(s,1H),8.64(d,1H,J＝5Hz),8.50(d,1H,J＝5Hz),7.77(d,2H,j＝5Hz),7.64(s,1H),7.55(d,1H,j＝5hz),7.47(d,2H,j＝5hz),7.07(d,1H,J＝3hz),6.75(d,1H,J＝5Hz),3.89(s,3H),3.83(s,2H),2.55(s,3H)
实施例2：N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物2)的制备
Figure PCTCN2019127056-appb-000051
在0℃下2-(3-甲基,4-(2-甲基吡啶-4基)苯基)乙酸(I-3)(0.06克，0.25毫摩尔)溶解在2mL无水DMF。然后依次加入7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2胺(I-4)(0.049克，0.30毫摩尔)，HATU(0.104克，0.27毫摩尔)和DIEA(0.097克，0.75毫摩尔)。混合物室温搅拌1小时。用饱和NaHCO 3稀释，并提取到EtOAc。有机层用盐水洗两次,Na 2SO 4干燥，过滤，减压浓缩。硅胶色谱纯化得到18毫克(19％)化合物2。ESIMS发现：m/z 388.2(M+1)。1H核磁共振(亚砜,400兆赫)：δ10.93(s,1H),8.64(d,1H,J＝5Hz),8.57(d,1H,J＝3Hz),7.45(s,1H),7.38(s,1H),7.30(m,3H),7.07(d,1H,J＝3hz),6.75(d,1H,J＝5hz),3.89(s,3H),3.78(s,2H),2.58(s,3H),2.33(s,3H)。
实施例3：N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物3)的制备
Figure PCTCN2019127056-appb-000052
化合物3的制备同化合物1。ESIMS发现：m/z 373.3(M+1)。
实施例4：N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物4)的制备
Figure PCTCN2019127056-appb-000053
化合物4的制备同化合物1。ESIMS发现：m/z 374.0(M+1)。
实施例5：N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物5)的制备
Figure PCTCN2019127056-appb-000054
化合物5的制备同化合物1。ESIMS发现：m/z 388.5(M+1).1H NMR(二甲亚枫,400MHz)：δ10.92(s,1H),8.61(s,1H),8.49(d,1H,J＝3Hz),7.60(d,1H,J＝5Hz),7.40(d,1H,J＝5Hz),7.26(m,3H),7.19(d,2H,J＝5Hz),3.85(s,3H),3.79(s,2H),2.52(s,3H),2.25(s,3H)。
实施例6：N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物6)的制备
Figure PCTCN2019127056-appb-000055
化合物6的制备同化合物1。ESIMS发现：m/z 387.3(M+1).1H NMR(二甲亚枫,400MHz)：δ10.92(s,1H),8.47(d,1H,J＝3Hz),8.20(s,1H),7.49(d,1H,J＝5Hz),7.16–7.49(m,5H),7.01(d,1H,J＝3Hz),6.76(s,1H),3.81(s,3H),3.71(s,2H),2.51(s,3H),2.25(s,3H)。
实施例7：N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺 (化合物7)的制备
Figure PCTCN2019127056-appb-000056
化合物7的制备同化合物1。ESIMS发现：m/z 387.3(M+1).1H NMR(二甲亚枫,400MHz)：δ10.87(s,1H),8.48(s,1H),8.27(d,1H,J＝3Hz),8.00(s,1H),7.25–7.35(m,3H),7.18(d,2H,J＝5Hz),6.98(d,1H,J＝5Hz),3.76(s,3H),3.70(s,2H),2.52(s,3H),2.25(s,3H)。
实施例8：N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物8)的制备
Figure PCTCN2019127056-appb-000057
化合物8的制备同化合物1。ESIMS发现：m/z 373.0(M+1).1H NMR(二甲亚枫,400MHz)：δ10.91(s,1H),8.48(s,1H),8.27(S,1H),8.01(s,1H),7.73(d,2H,J＝5Hz),7.32–7.56(m,4H),6.97(d,1H,J＝7.5Hz),3.76(s,5H),2.52(s,3H)。
实施例9：N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物9)的制备
Figure PCTCN2019127056-appb-000058
化合物9的制备同化合物1。ESIMS发现：m/z 373.1(M+1).1H NMR(二甲亚枫,400MHz)：δ10.92(s,1H),8.49(d,1H,J＝3Hz),8.38(d,1H,J＝5Hz),7.75(d,2H,J＝5Hz),7.60(s,1H),7.52(d,1H,J＝3Hz),7.40(d,1H,J＝5Hz),7.12(d,1H,J＝3Hz),6.63(d,1H,J＝5Hz),6.48(s,2H),4.25(s,2H),3.91(s,3H),2.52(s,3H)。
实施例10：N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺(化合物10)的制备
Figure PCTCN2019127056-appb-000059
化合物10的制备同化合物1。ESIMS发现：m/z 387.4(M+1).1H NMR(二甲亚枫,400MHz)：δ10.92(s,1H),8.47(d,1H,J＝3Hz),8.38(d,1H,J＝5Hz),7.13–7.24(m,5H),6.63(d,1H,J＝5Hz),6.48(s,2H),4.19(s,2H),3.91(s,3H),2.52(s,3H),2.24(s,3H)。
中间体化合物制备
(4-(2-甲基吡啶-4-基)苯基)甲胺(I-9)的制备
Figure PCTCN2019127056-appb-000060
室温下(4-溴苯基)甲胺(0.74克,4.0毫摩尔)溶解在40毫升无水THF中。依次加入2-甲基-4-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶(0.90克，4.0毫摩尔)，Pd(PPh 3) 4(0.95克，1.0毫摩尔)和碳酸铯(2.68克，8.0毫摩尔)。反应混合物氮气下脱氧5分钟，氮气保护下加热到75℃搅拌过夜。反应冷却后，饱和NaHCO 3稀释并提取成到EtOAc(3×100毫升)。有机层用盐水洗涤,Na 2SO 4干燥，过滤，减压浓缩。硅胶色谱纯化得到0.4克(49％)的I-9。ESIMS发现：m/z 199.2(M+1)。
(3-甲基-4-(2-甲基吡啶-4-基)苯基)甲胺(I-10)的制备
Figure PCTCN2019127056-appb-000061
室温下(4-溴-3-甲基苯基)甲胺(1.00克，5.0毫摩尔)溶解在无水THF中，依次加入2-甲基-4-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)吡啶(1.10克，5.0毫摩尔)，Pd(PPh 3) 4(1.16克,1.0毫摩尔)和碳酸铯(3.26克,10.0毫摩尔)。反应混合物氮气下脱氧5分钟，氮气保护下加热到75℃搅拌过夜。反应冷却后，饱和NaHCO 3稀释并提取成到EtOAc(3×100毫升)。有机层用盐水洗涤，Na 2SO 4干燥，过滤，减压浓缩。硅胶色谱纯化得到0.45克(42％)的I-10。ESIMS发现：m/z 213.0(M+1)。
7-乙酰基咪唑并[1,2-a]吡啶-2-羧酸(I-11)的制备
Figure PCTCN2019127056-appb-000062
4-乙酰基-2-氨基吡啶(1.2克，9.0毫摩尔)溶解在无水四氢呋喃(60毫升)中，慢慢滴加3-溴-2-氧代丙酸乙酯(2.5克，13.0毫摩尔)。产生的悬浊液回流加热6小时，冷却到室温，过滤干燥得到粗产物。酯(0.5克，2.0毫摩尔)溶解在THF(10毫升)。然后滴加氢氧化锂(0.5g，22.0毫摩尔)水溶液(10毫升)。室温搅拌过夜，浓缩。残渣酸化至pH 5。固体过滤收集，然后干燥，得到I-11。1H核磁共振(亚砜,400兆赫)：8.60(d,1H,J＝5Hz),8.46(s,1H),8.30(s,1H),7.36(d,1H,J＝3Hz),2.65(s,3H)。
7-甲氧基咪唑并[1,2-a]吡啶-2-羧酸(I-12)的制备
Figure PCTCN2019127056-appb-000063
I-12的制备同I-11。ESIMS发现：m/z 193.2(M+1)。
7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-羧酸(I-13)的制备
Figure PCTCN2019127056-appb-000064
冷却2,4,6-三甲基苯磺酰羟胺(0.87g，4mmol)的二氯甲烷溶液到0℃。然后分批慢慢加入4-甲氧基吡啶-2-胺(0.5g，4mmol)。1小时后，用乙醚稀释悬浮液，过滤收集，用乙醚清洗干燥。然后将0.5g的白色固体与2-氯-2-氧乙酸乙酯混合在吡啶中，在100℃加热18h。冷却后加入饱和碳酸钾(sat.)溶液，搅拌2小时。过滤收集固体，然后用水清洗干燥，得到产品0.3g。然后碱性条件下水解，得到中间体I-13。ESIMS发现：m/z 194.1(M+1)。
6-甲氧基咪唑并[1,2-a]吡啶-2-羧酸(I-14)的制备
Figure PCTCN2019127056-appb-000065
I-14的制备同I-11。ESIMS发现：m/z 193.2(M+1).。
6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-羧酸(I-15)的制备
Figure PCTCN2019127056-appb-000066
I-15的制备同I-13。ESIMS发现：m/z 194.1(M+1)。
6-氰基咪唑并[1,2-a]吡啶-2-羧酸(I-16)的制备
Figure PCTCN2019127056-appb-000067
I-16的制备同I-11。ESIMS发现：m/z 188.2(M+1)。
7-氰基咪唑并[1,2-a]吡啶-2-羧酸(I-17)的制备
Figure PCTCN2019127056-appb-000068
I-17的制备同I-11。ESIMS发现：m/z 188.2(M+1)。
实施例11：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物11)的制备
Figure PCTCN2019127056-appb-000069
由I-10与上式化合物反应制备得到化合物11，其制备方法操作步骤类似化合物1的制备方法。ESIMS发现：m/z 387.0(M+1).1H核磁共振(亚砜,400兆赫)：8.74(s,1H),8.47(m,2H),8.20(s,1H),7.16-7.28(m,4H),6.86(d,1H,J＝3hz),6.70(d,1H J＝5hz),4.48(d,2H,J＝3Hz),3.86(s,3H),2.52(s,3H),2.23(s,3H)。
实施例12：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺(化合物12)的制备
Figure PCTCN2019127056-appb-000070
化合物12的制备同化合物1。ESIMS发现：m/z 388.2(M+1).1H核磁共振(亚砜,400兆赫)：9.26(t,1H,J＝3hz),8.83(d,1H,J＝5hz),8.47(s,1H),7.15-7.29(m,5H),6.97(d,1H,J＝5hz),4.49(d,2H,J＝5hz),3.93(s,3H),2.52(s,3H),2.24(s,3H)。
实施例13：N-(4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺(化合物13)的制备
Figure PCTCN2019127056-appb-000071
化合物13的制备同化合物1。ESIMS找到：m/z 373.4(M+1).1H核磁共振(亚砜,400兆赫)：9.31(t,1H,J＝3hz),8.83(d,1H,J＝3hz),8.48(s,1H),7.75(d,2H,J＝5Hz),7.58(s,1H),7.47(m,3H),7.22(s,1H),6.97(d,1H,J＝5Hz),4.54(d,2H,J＝3hz),3.94(s,3H),2.53(s,3H)。
实施例14：N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物14)的制备
Figure PCTCN2019127056-appb-000072
化合物14的制备同化合物1。ESIMS发现：m/z 373.2(M+1).1H核磁共振(亚砜,400兆赫)：8.92(t,1H,J＝3Hz),8.47(d,1H,J＝5Hz),8.28(d,2H J＝5hz),7.73(d,2H,J＝5hz),7.47(m,4H),7.13(d,1H,J＝3hz),4.51(d,2H,J＝3hz),3.81(s,3H),2.52(s,3H)。
实施例15：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物15)的制备
Figure PCTCN2019127056-appb-000073
化合物15的制备同化合物1。ESIMS找到：m/z 387.2(M+1).1H核磁共振(CDCl3,400兆赫)：8.51(d,1H,J＝3Hz),8.13(s,1H),7.65(d,1H J＝5Hz),7.64(s,1H),7.42(d,1H,J＝5hz),7.28(d,1H,J＝3hz),7.15(d,1H,J＝5hz),7.03(m,3H),4.66(d,2H,J＝5Hz),3.84(s,3H),2.60(s,3H),2.25(s,3H)。
实施例16：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺(化合物16)的制备
Figure PCTCN2019127056-appb-000074
化合物16的制备同化合物1。ESIMS找到：m/z 388.4(M+1).1H核磁共振(亚砜,400兆赫)：9.29(t,1H,J＝3Hz),8.72(d,1H,J＝3hz),8.47(d,1H,J＝3hz),7.82(d,2H,J＝5hz),7.54(d,1H,J＝5Hz),7.20(m,4H),4.50(d,2H,J＝3Hz),3.90(s,3H),2.51(s,3H),2.24(s,3H)。
实施例17：N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺(化合物17)的制备
Figure PCTCN2019127056-appb-000075
化合物17的制备同化合物1。ESIMS发现：m/z 374.3(M+1).1H核磁共振(亚砜,400兆赫)：9.34(t,1H,J＝3Hz),8.72(d,1H,J＝3hz),8.48(d,1H,J＝3hz),7.82(d,2H,J＝5hz),7.75(d,2H,J＝5Hz),7.48(m,4H),4.54(d,2H,J＝5Hz),3.90(s,3H),2.52(s,3H)。
实施例18：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物18)的制备
Figure PCTCN2019127056-appb-000076
化合物18的制备同化合物1。ESIMS找到：m/z 399.2(M+1).1H核磁共振(CDCl 3,400兆赫)：8.85(s,1H),8.51(d,1H,J＝5Hz),8.29(s,1H),7.79(d,1H,J＝5Hz),7.74(s,1H),7.57(d,1H,J＝5hz),7.30(d,1H,J＝3hz),7.16(d,1H,J＝5hz),7.03(m,2H),4.68(d,2H,J＝5Hz),2.65(s,3H),2.61(s,3H),2.26(s,3H)。
实施例19：N-(4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物19)的制备
Figure PCTCN2019127056-appb-000077
化合物19的制备同化合物1。ESIMS找到：m/z 384.4(M+1).1H核磁共振(CDCl 3,400兆赫)：8.87(s,1H),8.53(d,1H,J＝3Hz),8.30(s,1H),7.79(d,1H,J＝5Hz),7.40-7.62(m,5H),7.35(s,1H),7.29(d,1H,J＝3hz),4.73(d,2H,J＝3hz),2.65(s,3H),2.62(s,3H)。
实施例20：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物20)的制备
Figure PCTCN2019127056-appb-000078
化合物20的制备同化合物1。ESIMS找到：m/z 382.3(M+1).1H核磁共振(CDCl 3,400兆赫)：8.64(s,1H),8.52(d,1H,J＝3Hz),8.28(s,1H),7.68(s,1H),7.64(d,1H,J＝5hz),7.35(d,1H,J＝5hz),7.29(m,1H),7.17(d,1H J＝5Hz),7.10(s,1H),7.04(d,1H,J＝5hz),4.68(d,2H,J＝5Hz),2.61(s,3H),2.26(s,3H)。
实施例21：N-(4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物21)的 制备
Figure PCTCN2019127056-appb-000079
化合物21的制备同化合物1。ESIMS发现：m/z 368.1(M+1).1H核磁共振(亚砜,400兆赫)：9.39(s,1H),9.18(t,1H,J＝5Hz),8.45(m,2H),7.75(m,3H),7.61(d,1H,J＝5Hz),7.56(s,1H),7.45(d,2H,J＝5hz),4.53(d,2H,J＝5hz),3.17(s,3H)。
2-(4-(2-甲基吡啶)-3-甲基吡啶)-乙酸(I-18)的制备.
Figure PCTCN2019127056-appb-000080
I-18的合成和I-2的合成方法一致。ESIMS发现：m/z 243.2(M+1)。
实施例22：2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺(化合物22)的制备
Figure PCTCN2019127056-appb-000081
化合物22的制备同化合物1。ESIMS发现：m/z 389.0(M+1).
实施例23：N-(4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物23)的制备
Figure PCTCN2019127056-appb-000082
化合物23的制备同化合物1。ESIMS找到：m/z 368.2(M+1).1H核磁共振(亚砜,400兆赫)：9.22(t,1H,J＝3Hz),8.75(d,1H,J＝5Hz),8.59(s,1H),8.49(d,1H,J＝3Hz),8.41(s,1H),7.73(d,2H,J＝5Hz),7.57(s,1H),7.46(m,2H),7.30(d,1H,J＝3Hz),4.53(d,2H,J＝5hz),3.17(d,3H,J＝3hz)。
实施例24 2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺(化合物24)的制备
Figure PCTCN2019127056-appb-000083
化合物24的制备同化合物1。ESIMS找到：m/z 389.4(M+1)。
实施例25：2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)乙酰胺(化合物25)的制备
Figure PCTCN2019127056-appb-000084
化合物25的制备同化合物1。ESIMS找到：m/z 388.3(M+1).1H核磁共振(亚砜,400兆赫)：8.52(d,1H,J＝5Hz),8.33(m,2H),8.58(s,1H),7.51(s,1H),7.45(s,1H),7.12(d,1H,J＝3hz),6.59(d,1H,J＝5hz),6.38(bs,2H),4.22(s,2H),3.86(s,3H),2.52(s,3H)。
实施例26：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物26)的制备
Figure PCTCN2019127056-appb-000085
化合物26的制备同化合物1。ESIMS找到：m/z 382.3(M+1).1H核磁共振(CDCl 3,400兆赫)：8.65(d,1H,J＝5Hz),8.31(s,1H),8.27(d,1H,J＝3Hz),7.98(s,1H),7.77(s,1H),7.29(m,3H),7.18(d,1H J＝5Hz),7.01(d,1H,J＝5hz),4.70(d,2H,J＝3Hz),2.72(s,3H),2.26(s,3H)。
实施例27：2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)乙酰胺(化合物27)的制备
Figure PCTCN2019127056-appb-000086
化合物27的制备同化合物1。ESIMS找到：m/z 388.0(M+1).1H核磁共振(CDCl 3,400兆赫)：11.01(s,1H),8.60(m,1H),8.25(s,1H),7.70(s,1H),7.62(d,1H,J＝3Hz),7.33(m,3H),7.07(d,1H,J＝5Hz),3.90(s,3H),3.80(s,2H),2.64(s,3H),2.36(s,3H)。
实施例28：N-(4-(2-甲基吡啶-4-基)苯基甲基)-7-乙酰基-咪唑[1,2-a]吡啶-2-甲酰胺(化合物28)的制备
Figure PCTCN2019127056-appb-000087
化合物28的制备同化合物1。ESIMS找到：m/z 388.0(M+1).1H核磁共振(亚砜,400兆赫)：9.09(t,1H,J＝3Hz),8.65(d,1H,J＝5Hz),8.56(s,1H),8.50(d,1H,J＝3Hz),8.27(s,1H),7.76(d,2H,J＝5Hz),7.62(s,1H),7.53(d,1H,J＝3Hz),7.48(d,1H,J＝5hz),7.40(d,1H,J＝5hz),4.55(d,2H,J＝5hz),2.67(s,3H),2.54(s,3H)。
实施例29：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺(化合物29)的制备
Figure PCTCN2019127056-appb-000088
化合物29的制备同化合物1。ESIMS找到：m/z 398.0(M+1).1H核磁共振(亚砜,400兆赫)：9.03(t,1H,J＝3Hz),8.65(d,1H,J＝5Hz),8.56(s,1H),8.52(d,1H,J＝3Hz),8.27(s,1H),7.40(d,1H,J＝5Hz),7.31(m,4H),4.51(d,2H,J＝5Hz),2.67(s,3H),2.55(s,3H),2.25(s,3H)。
5-甲氧基吡唑[1,5-a]吡啶-2-甲酸(I-19)的制备
Figure PCTCN2019127056-appb-000089
在3mL二氯甲烷中加入4-甲氧基吡啶(0.51克，5mmol)，在0℃下加入2,4,6-三甲基苯磺酰羟胺(1g，5mmol)。搅拌1小时。去除溶剂，并添加5ml DMSO。将反应液冷却至0℃后慢慢加入K 2CO 3。然后滴加丁炔二酸二乙酯(0.66g，5mmol)。由此产生的红色悬浮物在通入空气的情况下强烈搅拌3个小时。用冰水稀释，提取到乙酸乙酯中。有机相用盐水清洗，干燥，浓缩得到粗产品。然后加入5mL硫酸/水(1:1)加热到80℃ 3小时。用冰水冷却后，30％的NaOH中和后，用1N HCl酸化至pH 2～3。过滤和干燥得到固体酯。酯在LiOH中水解，得到中间体I-19。ESIMS发现：m/z 193.2(M+1)。
6-甲氧基吡唑并[1,5-a]吡啶-2-羧酸(I-20)的制备
Figure PCTCN2019127056-appb-000090
I-20的合成和I-19的合成方法一致。ESIMS发现：m/z 193.2(M+1)。
7-(三氟甲基)吡唑并[1,5-a]吡啶-2-羧酸(I-21)的制备
Figure PCTCN2019127056-appb-000091
I-21的合成和I-19的合成方法一致。ESIMS发现：m/z 231.2(M+1)。
5-(三氟甲基)咪唑并[1,2-a]吡啶-2-羧酸(I-22)的制备
Figure PCTCN2019127056-appb-000092
I-22的合成和I-16的合成方法一致。ESIMS发现：m/z 231.2(M+1)。
实施例30：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺(化合物30)的制备
Figure PCTCN2019127056-appb-000093
化合物30的制备同化合物1。ESIMS找到：m/z 387.0(M+1)。1H核磁共振(亚砜,400兆赫)：8.93(t,1H,J＝3hz),8.52(d,1H,J＝5hz),8.47(d,1H,J＝3hz),7.11-7 28(m,6H),6.80(s,1H),6.72(dd,1H,J＝5hz),4.47(d,2H,J＝5hz),3.85(s,3H),2.67(s,3H),2.52(s,3H),2.23(s,3H)。
实施例31：N-(4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺(化合物31)的制备
Figure PCTCN2019127056-appb-000094
化合物31的制备同化合物1。ESIMS发现：m/z 373.0(M+1)。1H核磁共振(亚砜,400兆赫)：8.97(t,1H,J＝3Hz),8.52(d,1H,J＝5hz),8.47(d,1H,J＝5hz),7.74(d,2H,J＝5hz),7.48(m,4H),7.11(d,1H,J＝3Hz),6.80(s,1H),6.70(d,1H,J＝5Hz),4.52(d,2H,J＝3Hz),3.85(s,3H),2.52(s,3H)。
实施例32：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-(三氟甲基)吡唑并[1,5-a]吡啶-2-甲酰胺(化合物32)的制备
Figure PCTCN2019127056-appb-000095
化合物32的制备同化合物1。ESIMS发现：m/z 425.4(M+1)。1H核磁共振(CDCl3,400兆赫)：8.62(d,1H,J＝5hz),7.83(d,1H,J＝8Hz),7.69(m,2H),7.37(m,2H),7.28(m,3H),4.74(d,2H,J＝5Hz),2.96(s,3H),2.35(s,3H)。
实施例33：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺(化合物33)的制备
Figure PCTCN2019127056-appb-000096
化合物33的制备同化合物1。ESIMS发现：m/z 387.0(M+1)。1H核磁共振(亚砜,400兆赫)：9.02(t,1H,J＝3Hz),8.47(d,1H,J＝5hz),8.31(d,1H,J＝5Hz),7.22(m,4H),6.98(m,3H),6.71(d,1H,J＝5hz),4.48(d,2H,J＝3Hz),3.97(s,3H),2.52(s,3H),2.23(s,3H)。
实施例34：N-(4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺(化合物34)的制备
Figure PCTCN2019127056-appb-000097
化合物34的制备同化合物1。ESIMS发现：m/z 372.7(M+1)。1H核磁共振(亚砜,400兆赫)：9.06(t,1H,J＝3Hz),8.47(d,1H,J＝5hz),8.31(d,1H,J＝5Hz),7.74(d,2H,J＝5Hz),7.56(s,1H),7.46(m,3H),6.98(m,2H),6.72(d,1H,J＝3Hz),4.52(d,2H,J＝3Hz),3.97(s,3H),2.52(s, 3H)。
实施例35：N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺(化合物35)的制备
Figure PCTCN2019127056-appb-000098
化合物35的制备同化合物1。ESIMS发现：m/z 425.0(M+1)。1H核磁共振(亚砜,400兆赫)：9.16(t,1H,J＝3Hz),8.46(d,1H,J＝5hz),8.31(d,1H,J＝5hz),7.99(d,1H,J＝7hz),7.69(d,1H,J＝5Hz),7.54(m,1H),7.22(m,5H),4.52(d,2H,J＝3Hz),2.52(s,3H),2.23(s,3H)。
实施例36：N-(4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺(化合物36)的制备
Figure PCTCN2019127056-appb-000099
化合物36的制备同化合物1。ESIMS发现：m/z 411.1(M+1)。1H核磁共振(亚砜,400兆赫)：9.21(t,1H,J＝3Hz),8.47(d,1H,J＝5Hz),8.31(s,1H),8.00(d,1H,J＝75hz),7.74(d,2H,J＝5hz),7.69(d,1H,J＝5hz),7.54(m,5H),4.55(d,2H,J＝3Hz),2.52(s,3H)。
式X的取代5,6-双杂环氨基化合物的制备实施例
中间体合成实施例
中间体化合物X-1的制备
Figure PCTCN2019127056-appb-000100
4,6-二氯嘧啶(50g,0.336摩尔)溶解在500ml异丙醇。随后慢慢滴加水合肼(50.4克,3eq)。反应混合物室温搅拌5小时。LCMS显示没有起始反应原料存在后，在反应混合物加入400ml冷水，过滤。固体用冷水冲洗，干燥，得到47.5克氯代嘧啶肼的白色固体(产量96％)。
用上述氯代嘧啶肼(500mg)和BrCN(476毫克)依据文献(Bioorganic Med Chem,2009,17,4230-4240)所述方法进行反应，制备得到385毫克X-1化合物。
中间体化合物X-3的制备
Figure PCTCN2019127056-appb-000101
在氩气保护下，X-2(293.5毫克,1.17毫摩尔)，X-1(198.4毫克,1.17毫摩尔)与5ml无水DCM的混合物冷却到0℃。在0℃下慢慢滴加TiCl 4(333mg,1.75mmol)后，在室温下搅拌30分钟，然后降温到0℃，在0℃下慢慢滴加NaBH(Ac) 3(371毫克,1.75毫摩尔)。反应混合物在0℃搅拌30min，然后室温搅拌一小时。处理后，用硅胶柱纯化得到450毫克中间体X-3化合物(产量52.3％)。
实施例37：4-(3-((3-甲基-4-(2-甲基吡啶-4-基)苄基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)哌嗪-2-酮(化合物101)的制备
Figure PCTCN2019127056-appb-000102
在2ml异丙醇密封管中依次加入X-3(70毫克,0.19毫摩尔)，哌嗪-2-酮(0.35毫摩尔,1.8eq)，DIPEA(25毫克,0.19毫摩尔)，油浴加热120℃，加热反应4h。滴加加入3滴水后再加热120℃，反应2小时。用LCMS检测反应完成。硅胶柱提纯得到12毫克纯产品(纯度95％)。ESIMS发现:m/z 429.2(M+1)。
实施例38：1-甲基-4-(3-((3-甲基-4-(2-甲基吡啶-4-基)苄基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)哌嗪-2-酮(化合物102)的制备
Figure PCTCN2019127056-appb-000103
化合物102的合成方法与化合物101合成方法类似。ESIMS发现:m/z 443.4(M+1)。
实施例39：4-(3-((3-甲基-4-(2-甲基吡啶-4-基)苄基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)-1-乙酰基哌嗪(化合物103)的制备
Figure PCTCN2019127056-appb-000104
化合物103的合成和化合物101合成方法类似。ESIMS发现:m/z 457.2(M+1)。
中间体化合物X-4的制备
Figure PCTCN2019127056-appb-000105
X-4的合成和X-3类似。产量180mg(20.5％)为黄色固体。
实施例40:4-(3-(((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)哌嗪-2-酮(化合物104)的制备
Figure PCTCN2019127056-appb-000106
化合物104的合成和化合物101类似。ESIMS发现:m/z 430.2(M+1)。
实施例41：4-(3-(((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)-1-甲基哌嗪-2-酮(化合物105)的制备。
Figure PCTCN2019127056-appb-000107
化合物105的合成和化合物101类似。ESIMS发现:m/z 444.4(M+1)。
实施例42：4-(3-(((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)-1-乙酰基哌嗪(化合物106)的制备。
Figure PCTCN2019127056-appb-000108
化合物106的合成和化合物101类似。ESIMS发现:m/z 458.49(M+1)。
实施例43：N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-7-(2-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-3-胺(化合物107)的制备。
Figure PCTCN2019127056-appb-000109
在50ml二氧六环和10毫升水中，加入4,6-二氯嘧啶(3.0g,20.2毫摩尔)，2-甲基吡啶-4-硼酸(2.3g,16.8毫摩尔)，K 2CO 3(7g,50.4毫摩尔)，氩气鼓泡15分钟后，加入钯催化剂(970mg,0.84毫摩尔)，混合物加热回流3小时。冷却到室温，添加10毫升水。用乙酸乙酯(40ml×3)提取混合物。合并有机相用盐水冲洗，用硫酸钠干燥，过滤。滤液浓缩，用硅胶柱纯化得到1.2克(产量34％)红色油状产物中间体化合物X-5。
上述获得的X-5(1.2克,5.8毫摩尔)溶解在20毫升异丙醇。室温下加入水合肼(900毫克,18毫摩尔)。该混合物在室温中搅拌2小时，蒸发掉溶剂，得到1.6克粗中间体化合物，为X-6的黄色固体，直接用于下一步。
X-6(0.7克,2.6毫摩尔)和BrCN(0.7克,5.2毫摩尔)的混合物溶解在100毫升甲醇中，室温下搅拌过夜。加入碳酸钠溶液。在室温搅拌2小时后，用DCM(30ml×3)提取混合物。合并后的有机相，用盐水冲洗，经过硫酸钠干燥，过滤。滤液浓缩后硅胶柱纯化得到褐色固体X-7(170毫克,产量28％)。
氩气保护下，在5毫升干燥的DCM中混合X-7(80毫克,0.35毫摩尔)和醛(89毫克,0.42毫摩尔)。混合物冷却到0℃，慢慢滴加TiCl 4(132mg,0.7毫摩尔)。反应混合物搅拌过夜，然后降温到0℃，在0℃下慢慢滴加NaBH(Ac) 3(112毫克,0.53毫摩尔)。反应混合物在0℃搅拌30min，然后室温搅拌一小时。处理后，用硅胶柱提纯得到25毫克(产量17％)化合物107。ESIMS发现:m/z 423.1(M+1)。
生物学活性试验
WNT通路活性研究
为证实本发明化合物对WNT通路活性是否有抑制作用，选择荧光素酶报告基因系统完成检测。以下实验采用L-Wnt3a细胞和HEK293/STF细胞共培养，其中L-Wnt3a细胞是WNT蛋白生成细胞，HEK293/STF细胞为WNT蛋白响应细胞。
经典的WNT信号通路需要β-catenin入核，进而与转录因子TCF/LEF结合形成复合物，共同起始下游调控基因的转录。HEK293/STF细胞株携带SuperTopflash(STF)报告基因(在报告基因中7个LEF/TCF串联DNA结合位点驱动萤火虫荧光素酶表达)，能够在Wnt/Norrin信号诱导下表达荧光素酶，因此可以通过检测荧光素酶表达水平方便地检测Wnt/Norrin-β-catenin信号通路的活化程度。
材料和方法：
依据用户手册，人胚胎肾脏293细胞(HEK293)(美国培养收集,ATCC,Mansassas,VA)，共转染STF-reporter 5-8 xTCF/Lef-luc plus pcDNA3.1-Neo(Invitrogen,Carlsbad,CA)以及FuGENE6(Roche Diagnostics,Indianapolis,IL)。HEK293/STF细胞系于加有10％FBS(Hyclone)、50unit/ml青霉素、50μg/ml链霉素(Invitrogen,Carlsbad,CA)的Dulbecco’s modified Eagle’s完全培养基(DMEM)(Gibco/Invitrogen,Carlsbad,CA)中，在37摄氏度，5％CO 2下，经G418筛选，获得稳定细胞系。为验证WNT信号通路的作用，HEK293/STF稳定细胞系与L-Wnt3a细胞(
Figure PCTCN2019127056-appb-000110
CRL-2647 TM)以1：1比例混合，在37摄氏度，5％CO 2条件下，于96孔板中共培养(20K+20K)过夜。化合物用DMEM培养基稀释成不同浓度，与新鲜培养基一同以100μl/孔更换培养过夜的培养基，细胞在化合物处理下培养24小时。按50μl/孔从细胞培养板中取出培养基，加入50μl/孔的Bright-Glo试剂(Bright-Glo荧光素酶检测试剂盒，Promega，Madison，WI)，混匀60秒并常温避光孵育10分钟。在Envision上读板，剂量反应的IC50值由GraphPad Prism 6软件计算获得。
测试化合物以及它们的IC50值。
化合物 IC50(nM)
6 56.02
7 1.45
8 10.78
15 39.79
18 16.21
27 25.53
102 710.2
103 41.42
根据所示结果，共培养L-Wnt3a细胞诱导的STF报告基因活性会被化合物所抑制，这一现象不出现在单独培养的HEK293/STF细胞中，提示所述化合物具有抑制WNT信号通路的活性，且抑制作用发生在L-Wnt3a和受体作用的上游。
抑制作用与细胞死亡无关：
为证实STF报告分子的抑制作用并非源于细胞死亡，化合物使用CellTiter-Glo(CTG)(Promega,Madison,WI)进行测试。CTG实验采用HEK293/STF细胞与L-Wnt 3a细胞共培养，培养方法如上所述。实验中，直接加入50μl/孔CTG试剂，混匀60秒并常温避光孵育10分钟。用Envision读板。STSP(星形孢菌素，staurosporine)作为本实验参照化合物使用。实验使用Evision读板系统监测，重复样本的值用均数±标准误表示。剂量反应的IC50值由GraphPad Prism 6计算获得。
在5,6双环化合物的实验中，结果显示，化合物浓度在10 -11～10 -6mol/L逐渐上升过程中，STSP处理的细胞存活率由100％逐渐降至80％，而测试的本发明化合物处理的细胞存活率能够保持在100％～120％之间，说明测试的本发明化合物对WNT信号通路的抑制作用与细胞死亡无关。
在取代5,6-双杂环氨基化合物的实验中，结果显示，化合物浓度在10 -11～10 -6mol/L逐渐上升过程中，STSP处理的细胞存活率由100％逐渐降至60％，而测试的本发明化合物处理的细胞存活率能够保持在90％～110％之间，说明测试的本发明化合物对WNT信号通路的抑制作用与细胞死亡无关。

Claims (10)

  1. 一种结构式I的化合物，或药学上可接受的盐，溶剂化物，或立体异构体：
    Figure PCTCN2019127056-appb-100001
    其中：B为-CONH-，或-NHCO-，
    R 1，R 2分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基，或者R 1和R 2连接形成一个包含0-1个杂原子的取代的或未取代3-6元饱和环，其中所述杂原子选自O，S或N之一；
    R 3，R 4，R’ 3，R’ 4可在所在环的任意取代位置，其中R 3，R 4，R’ 3，R’ 4独立代表H，D，F，Cl，Br，I，NH 2，NO 2，CN，C 1-C 6烷基，取代的C 1-C 6烷基，取代或非取代的C 3-C 7环烷基，OR 5，COR 5，CONR 5R 6，NR 5R 6，NR 5COR 6，NR 5CONHR 6，NHSO 2R 5，SO 2NHR 5,SO 2(C 1-C 6烷基)，取代或非取代的C 3-C 7杂环烷基，所述C 3-C 7杂环烷基为含O，S和/或N的杂环烷基，以C原子与环相连接；
    R 5，R 6可独立代表H，D，C 1-C 6烷基，C 2-C 4亚烷基羟基，C 3-C 6环烷基或C 3-C 6杂环烷基，氨基C 1-C 6烷基，或取代氨基C 1-C 6烷基，或R 5和R 6与所连接的基团可连接形成包含1-2个杂原子的取代或未取代的3-6元饱和环，其中，所述杂原子进一步选自O，S和/或N原子；
    所述“取代的”表示所述基团进一步被F，Cl，Br，C 1-C 6烷基，C 1-C 6烷氧基或C 1-C 6亚烷基羟基所取代；
    X，Y，Z，X 1，Y 1，Z 1可独立代表C，N；
    A选自下列结构式代表的芳基或杂芳基，
    Figure PCTCN2019127056-appb-100002
    其中R 3，R 4在所连接环的任意可取代位置，R 3，R 4的定义和上述相同；
    R 7可选自H，F，Cl，Br，I，C 1-C 6烷基；
    优选，R 1，R 2分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟 基；
    R 3，R 4，R’ 3，R’ 4可在所在环的任意取代位置，其中R 3，R 4，R’ 3，R’ 4独立代表H，D，F，Cl，Br，I，NH 2，NO 2，CN，C 1-C 6烷基，取代的C 1-C 6烷基，取代或非取代的C 3-C 7环烷基，OR 5，COR 5，CONR 5R 6，NR 5R 6，NR 5COR 6，NR 5CONHR 6，NHSO 2R 5，SO 2NHR 5，SO 2(C 1-C 6烷基)；
    R 5，R 6可独立代表H，D，C 1-C 6烷基，C 2-C 4亚烷基羟基，C 3-C 6环烷基；
    所述“取代的”表示所述基团进一步被F，Cl，Br，C 1-C 6烷基，C 1-C 6烷氧基或C 1-C 6亚烷基羟基所取代。
  2. 如权利要求1所述化合物，其中，所述化合物具有选自Ia、Ib、Ic、IIa、IIb或IIc结构的化合物：
    式Ia结构化合物：
    Figure PCTCN2019127056-appb-100003
    式Ib结构化合物：
    Figure PCTCN2019127056-appb-100004
    式Ic结构化合物：
    Figure PCTCN2019127056-appb-100005
    式IIa结构化合物：
    Figure PCTCN2019127056-appb-100006
    式IIb结构化合物：
    Figure PCTCN2019127056-appb-100007
    或，式IIc结构化合物：
    Figure PCTCN2019127056-appb-100008
  3. 如权利要求1-2任一项所述化合物，所述化合物选自：
    Figure PCTCN2019127056-appb-100009
    Figure PCTCN2019127056-appb-100010
    Figure PCTCN2019127056-appb-100011
    Figure PCTCN2019127056-appb-100012
    Figure PCTCN2019127056-appb-100013
    Figure PCTCN2019127056-appb-100014
    更优选，所述化合物选自：
    N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)-2-(3-甲基-4-(2-甲基吡啶-4-基)苯基)乙酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
    N-(4-(2-甲基吡啶-4-基)苯甲基)-7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
    N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
    N-(4-(2-甲基吡啶-4-基)苯甲基)-6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    N-(4-(2-甲基吡啶-4-基)苯甲基)-6-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    N-(4-(2-甲基吡啶-4-基)苯甲基)-6-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺、
    N-(4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺、
    2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(5-甲氧基吡唑并[1,5-a]吡啶-2-基)乙酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-氰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    2-(2',3-二甲基-[2,4'-联吡啶]-5-基)-N-(6-甲氧基咪唑并[1,2-a]吡啶-2-基)乙酰胺、
    N-(4-(2-甲基吡啶-4-基)苯基甲基)-7-乙酰基-咪唑[1,2-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-乙酰基-咪唑并[1,2-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
    N-(4-(2-甲基吡啶-4-基)苯甲基)-5-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-(三氟甲基)吡唑并[1,5-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
    N-(4-(2-甲基吡啶-4-基)苯甲基)-4-甲氧基-吡唑并[1,5-a]吡啶-2-甲酰胺、
    N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺，或
    N-(4-(2-甲基吡啶-4-基)苯甲基)-5-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲酰胺。
  4. 一种结构式X的化合物，或其药学上可接受的盐，溶剂化物，或立体异构体，
    Figure PCTCN2019127056-appb-100015
    其中：
    R 11，R 12分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基，或者R 11和R 12连接形成一个包含0-1个杂原子的取代的或未取代的3-6元饱和环，其中所述杂原子选自O，S或N之一；
    A 1代表下面的6元芳基或杂芳基，
    Figure PCTCN2019127056-appb-100016
    R 13，R 14可在所在环的任意取代位置，R 13，R 14独立代表H，D，F，Cl，Br，I，NH 2，NO 2，CN，C 1-C 6烷基，取代的C 1-C 6烷基，取代或非取代的C 3-C 7环烷基，OR 15，COR 15，CONR 15R 16，NR 15R 16，NR 15COR 16，NR 15CONHR 16，NHSO 2R 15，SO 2NHR 15，SO 2(C 1-C 6烷基)，取代或非取代的C 3-C 7杂环烷基；
    R 18选自H，D，C 1-C 6烷基；
    R 15，R 16可独立代表H，D，C 1-C 6烷基，C 2-C 4亚烷基羟基，C 3-C 7环烷基或C 3-C 7杂环烷基，氨基C 1-C 6烷基，或取代的氨基C 1-C 6烷基，或R 15和R 16与所连接的基团可连接形成包含1-2个杂原子的取代或未取代的3-6元饱和杂环烷基，其中，所述杂原子进一步选自O，S或N原子；
    X 11，Y 11，Z 11，X 12，Y 12，Z 12，Z 13可独立代表C或N，其中，X 12，Y 12至少有一个是N，Z 12，Z 13至少有一个是N；
    R 17可在所在环的任意取代位置，代表5或6-元取代或非取代含1或2个N的杂环烷基，所述杂环烷基选自如下基团：
    Figure PCTCN2019127056-appb-100017
    所述“取代的”表示所述基团进一步被F，Cl，Br，C 1-C 6烷基，C 1-C 6烷氧基或C 1-C 6亚烷基羟基所取代。
  5. 如权利要求4所述的化合物，其特征在于，所述化合物选自具有下列结构式Xa、Xb、Xc或Xd的化合物，所述结构式Xa、Xb、Xc或Xd结构如下：
    Figure PCTCN2019127056-appb-100018
    进一步优选，R 11，R 12分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基；
    A 1选自如下结构：
    Figure PCTCN2019127056-appb-100019
    R 13，R 14可在所在环的任意取代位置，R 13，R 14独立代表H，D，F，Cl，Br，I，NH 2，NO 2，CN，C 1-C 6烷基，取代的C 1-C 6烷基；
    R 18可选自H，C 1-C 6烷基；
    X 11，Y 11，Z 11可独立代表C或N；
    R 17选自如下取代基团：
    Figure PCTCN2019127056-appb-100020
  6. 如权利要求4或5的化合物，为具有结构式Xa的化合物，
    Figure PCTCN2019127056-appb-100021
    其中：R 11，R 12分别代表H，D，F，Cl，Br，C 1-C 3烷基，C 1-C 3烷氧基，C 1-C 3亚烷基羟基；
    A 1为
    Figure PCTCN2019127056-appb-100022
    R 13，R 14独立地代表H，C 1-C 3烷基，可在所在环上任意位置取代；
    X 11，Y 11或Z 11为C或N；
    R 17为
    Figure PCTCN2019127056-appb-100023
  7. 如权利要求4-6任一项的化合物，所述化合物选自：
    Figure PCTCN2019127056-appb-100024
    Figure PCTCN2019127056-appb-100025
    Figure PCTCN2019127056-appb-100026
    Figure PCTCN2019127056-appb-100027
    Figure PCTCN2019127056-appb-100028
    Figure PCTCN2019127056-appb-100029
    Figure PCTCN2019127056-appb-100030
    更优选，所述化合物选自：
    4-(3-((3-甲基-4-(2-甲基吡啶-4-基)苄基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)哌嗪-2-酮，
    1-甲基-4-(3-((3-甲基-4-(2-甲基吡啶-4-基)苄基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)哌嗪-2-酮，
    4-(3-((3-甲基-4-(2-甲基吡啶-4-基)苄基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)-1-乙酰基哌嗪，
    4-(3-(((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)哌嗪-2-酮，
    4-(3-(((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)-1-甲基哌嗪-2-酮，
    4-(3-(((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)氨基)-[1,2,4]三唑[4,3-c]嘧啶-7-基)-1-乙酰基哌嗪，
    N-((2',3-二甲基-[2,4'-联吡啶]-5-基)甲基)-7-(2-甲基吡啶-4-基)-[1,2,4]三唑并[4,3-c]嘧啶-3-胺。
  8. 如权利要求1-7任一项所述化合物，所述化合物是原子相应的同位素是 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 35S， 18F和/或 36Cl的同位素化合物。
  9. 权利要求1-8任一项所述化合物或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗WNT信号通路相关疾病的药物中的用途；优选，所述WNT信号通路相关疾病包括但不限于：肿瘤、畸形综合症、骨或软骨疾病、糖尿病或其并发症、组织纤维化；优选，所述骨或软骨疾病包括但不限于：骨质疏松症、骨关节炎、骨软骨病；优选，所述糖尿病或其并发症包括但不限于：II型糖尿病、糖尿病性视网膜病变、糖尿病性肾病、糖尿病性脑血管病；优选，所述肿瘤包括但不限于：实体瘤或非实体瘤；优选，所述实体瘤包括但不限限于：结肠直肠癌、结肠癌、胃癌、食道癌、骨肉瘤、乳腺癌、宫颈鳞状细胞癌、子宫内膜癌、间皮瘤、胰腺癌、膀胱癌、前列腺癌、肺癌、肝细胞癌、髓母细胞瘤、肝母细胞瘤、胃肠类癌、卵巢癌、黑色素瘤、头颈部鳞状细胞癌、甲状腺癌、肾母细胞瘤、视网膜母细胞瘤、胶质瘤；优选，所述非实体瘤包括但不限于：白血病，例如慢性粒细胞性白血病；淋巴瘤；优选，组织纤维化包括但不限于：肺纤维化、肝纤维化、肾纤维化、骨髓纤维化。
  10. 一种药物组合物，其包含权利要求1-8任一项所述的化合物或其药学上可接受的盐，溶剂化物，或立体异构体；优选，所述药物组合物进一步含有药学上可接受的载体；优选，所述的药物组合物，进一步含有第二种治疗剂，所述第二种治疗剂是其他的治疗WNT信号通路相关疾病的药物；优选，所述第二种治疗剂选自氮芥、环磷酰胺、顺铂、卡铂、奥沙利铂、5-氟尿嘧啶、卡培他滨、雷替曲塞、6-巯嘌呤、阿糖胞苷、吉西他滨、氨甲喋呤、培美曲塞、羟基脲、阿霉素、柔红霉素、表柔比星、吡柔比星、羟喜树碱、伊立替康、拓扑替康、长春新碱、长春地辛、长春瑞滨、紫杉醇、多西紫杉醇、托瑞米芬、依西美坦、来曲唑、比卡鲁胺、恩杂鲁胺、甲羟孕酮、甲地孕酮、丙酸睾丸酮、戈舍瑞林、亮丙瑞林、伊马替尼、吉非替尼、埃罗替尼、索拉菲尼、舒尼替尼、拉帕替尼、阿帕替尼、曲妥珠单抗、帕尼单抗、西妥昔单抗、帕妥珠单抗、贝伐单抗、雷莫芦单抗、利妥昔单抗、派姆单抗、伊匹单抗。
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