[go: up one dir, main page]

WO2019101178A1 - 作为c-MET/AXL抑制剂的尿嘧啶类化合物 - Google Patents

作为c-MET/AXL抑制剂的尿嘧啶类化合物 Download PDF

Info

Publication number
WO2019101178A1
WO2019101178A1 PCT/CN2018/117269 CN2018117269W WO2019101178A1 WO 2019101178 A1 WO2019101178 A1 WO 2019101178A1 CN 2018117269 W CN2018117269 W CN 2018117269W WO 2019101178 A1 WO2019101178 A1 WO 2019101178A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
pharmaceutically acceptable
acceptable salt
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/117269
Other languages
English (en)
French (fr)
Inventor
李金平
徐雄彬
李刚
胡利红
丁照中
周亚玲
胡国平
黎健
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medshine Discovery Inc
Original Assignee
Medshine Discovery Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medshine Discovery Inc filed Critical Medshine Discovery Inc
Priority to JP2020528451A priority Critical patent/JP7377798B2/ja
Priority to CN201880075156.2A priority patent/CN111372925B/zh
Priority to EP18880588.1A priority patent/EP3719012B1/en
Priority to US16/766,510 priority patent/US11623923B2/en
Publication of WO2019101178A1 publication Critical patent/WO2019101178A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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

Definitions

  • the present invention relates to a class of uracil compounds which are c-MET/AXL inhibitors, and specifically discloses a compound of the formula (IV) and a pharmaceutically acceptable salt thereof.
  • the proto-oncogene Met-encoded c-Met is a highly binding receptor tyrosine kinase belonging to the RON subfamily and the only known receptor for scattering factors or hepatocyte growth factor (HGF).
  • the c-Met protein is a heterodimer linked by a disulfide bond of a 50 kD alpha subunit and a 145 kD beta subunit, and is divided into an extracellular domain and an intracellular domain.
  • the extracellular domain contains three functionally distinct domains: an N-terminal ligand binding domain (SEMA region) covering the entire alpha chain and a portion of the beta chain, a cystine enrichment region with four conserved disulfide bonds, and immunity. Globulin-like domain.
  • SEMA region N-terminal ligand binding domain
  • the intracellular domain is also composed of three regulatory regions: the juxtamembrane domain with Tyr1003 phosphorylation site, the tyrosine kinase catalytic domain with Tyr1234 and Tyr1235 phosphorylation sites, and Tyr1349 and Tyr1356 binding tyrosine C-terminal multifunctional bonding area
  • Binding of HGF to the extracellular domain of c-Met induces phosphorylation of c-Met and recruits a variety of interstitial factors such as GAB1 (growth factor receptor binding protein-1) and GAB2 (growth factor) in the C-terminal multifunctional region.
  • Receptor binding protein-2 etc., further attracts SHP2, PI3K and other molecules to bind thereto, thereby activating RAS/MAPK, PI3K/AKT, JAK/STAT pathway, etc., thereby regulating cell growth, migration, proliferation and survival.
  • Abnormal c-Met pathway induces tumorigenesis and metastasis, and abnormally high levels of c-Met are found in various human malignancies such as bladder cancer, gastric cancer, lung cancer, and breast cancer.
  • c-Met is also associated with tumor resistance to multiple kinase inhibitors.
  • c-Met there is a crosstalk between c-Met and various membrane receptors, which constitutes a complex network system.
  • the interaction between c-Met and the adhesion receptor CD44 amplifies the response of the signal peptide; interaction with the brain protein receptor from the protein activates the non-dependent ligand HGF c-Met, enhancing the invasion;
  • the interaction between the pro-apoptotic receptor FAS accelerates apoptosis; interaction with various receptor tyrosine kinases such as EGFR, VEGFR, etc., causes activation between each other to be regulated, and the angiogenesis process is affected.
  • the interaction between c-Met and these membrane receptors promotes tumorigenesis and metastasis, and induces drug resistance.
  • AXL is a transmembrane protein.
  • the extracellular domain includes two immunoglobulin-like regions and two fibronectin-like regions.
  • the ligand binding region is an immunoglobulin-like region.
  • AXL and Tyro3 and Mer belong to the TAM receptor.
  • the family of lysin kinases is a protein molecule encoded by growth arrest specific gene 6 (Gas6) and human plasma anticoagulant protein S as a ligand.
  • AXL can cause activation of GRB2, which in turn affects tumor cell proliferation through RAS-RAF-MEK-ERK signaling pathway, and phosphorylates PI3K to activate AKT, thereby enhancing tumor cell survival.
  • AXL can directly activate SRC or promote the migration and invasion of tumor cells by interacting with EGFR, VEGFR and MET, which leads to the deterioration of tumor metastasis.
  • High expression of AXL protein is associated with worsening of breast cancer, lung cancer, and acute myelogenous leukemia. Studies have shown that AXL signaling activation is one of the main mechanisms of epithelial-mesenchymal transition (EMT) in tumor cells, and it is also one of the main mechanisms of cancer cell resistance to target drugs and chemotherapeutic drugs.
  • EMT epithelial-mesenchymal transition
  • anti-tumor drugs such as alkylating agents, anti-metabolites, anti-tumor antibiotics, immunomodulators, etc., but most of them are due to toxicity and patient intolerance.
  • alkylating agents such as alkylating agents, anti-metabolites, anti-tumor antibiotics, immunomodulators, etc.
  • Molecular targeted therapy for a variety of malignant tumors has received extensive attention and high attention.
  • Molecular targeted drugs are highly selective, broad-spectrum effective, and their safety is superior to cytotoxic chemotherapy drugs, which is a new direction in the field of cancer therapy.
  • the multi-target c-Met inhibitor is represented by BMS777607 (US2008114033), MGCD265 (WO2006010264), LY2801653 (US2010022529), and NPS-1034 (US2011183983).
  • Patent US2009094427 discloses the following series of compounds of the general formula (A).
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from the group consisting of H, halogen, and C 1-6 alkyl
  • R 2 is selected from the group consisting of H, NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein The C 1-6 alkyl group, the C 1-6 heteroalkyl group, the C 2-6 alkenyl group, and the 3-6 membered heterocycloalkyl group are optionally substituted by 1, 2 or 3 R;
  • R 3 is selected from the group consisting of H, C 1-4 alkyl and C 3-6 cycloalkyl;
  • R 2 and R 3 are bonded to form a 5-6 membered saturated heterocyclic ring, wherein the 5-6 membered saturated heterocyclic ring is optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from the group consisting of H, halogen, C 1-4 alkyl, C 1-4 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl;
  • R is independently selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring
  • An alkyl group wherein said C 1-4 alkyl group, C 1-4 heteroalkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally substituted by 1, 2 or 3 R';
  • R' is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CF 3 , CHF 2 , CH 3 O, CH 3 CH 2 , CH 3 CH 2 O, COOH, NH(CH 3 ) , NH(CH 3 ) 2 ,
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CF 3 , CHF 2 , CH 3 O, CH 3 CH 2 , CH 3 CH 2 O , COOH, NH(CH 3 ), NH(CH 3 ) 2 ,
  • R 1 is selected from H.
  • R 2 above is selected from the group consisting of H, NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl, and C 2-4 alkenyl, said C 1-4 alkyl, C The 1-4 heteroalkyl group and the C 2-4 alkenyl group are optionally substituted by 1, 2 or 3 R groups.
  • R 2 is selected from the group consisting of H, CH 3 ,
  • R 3 above is selected from the group consisting of H, C 1-3 alkyl, and C 3-4 cycloalkyl.
  • R 3 is selected from the group consisting of H, CH 3 , CH 3 CH 2 and
  • R 4 is selected from the group consisting of Cl.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CF 3 , CHF 2 , CH 3 O, CH 3 CH 2 , CH 3 CH 2 O , COOH, NH(CH 3 ), NH(CH 3 ) 2 ,
  • Other variables are as defined above.
  • R 1 above is selected from H, and other variables are as defined above.
  • R 2 above is selected from the group consisting of H, NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl, and C 2-4 alkenyl, said C 1-4 alkyl, C The 1-4 heteroalkyl and C 2-4 alkenyl are optionally substituted by 1, 2 or 3 R, and the other variables are as defined above.
  • R 2 is selected from the group consisting of H, CH 3 , Other variables are as defined above.
  • R 3 above is selected from the group consisting of H, C 1-3 alkyl, and C 3-4 cycloalkyl, and other variables are as defined above.
  • R 3 is selected from the group consisting of H, CH 3 , CH 3 CH 2 and Other variables are as defined above.
  • R 4 above is selected from Cl, and other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the above compound is selected from the group consisting of
  • R 3 is selected from the group consisting of C 1-4 alkyl and C 3-6 cycloalkyl, and R, R 1 and R 4 are as defined above.
  • the above compound is selected from the group consisting of
  • R 2 is selected from the group consisting of NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl and C 2-6 alkenyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 2
  • the -6 alkenyl group is optionally substituted by 1, 2 or 3 R, and R, R 1 and R 4 are as defined above.
  • the present invention provides a compound of the formula (IV) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from the group consisting of H, halogen, and C 1-6 alkyl
  • R 2 is selected from the group consisting of H, NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein The C 1-6 alkyl group, the C 1-6 heteroalkyl group, the C 2-6 alkenyl group, and the 3-6 membered heterocycloalkyl group are optionally substituted by 1, 2 or 3 R;
  • R 3 is selected from H, C 1-4 alkyl and C 3-6 cycloalkyl, and the C 1-4 alkyl and C 3-6 cycloalkyl are optionally substituted by 1, 2 or 3 R';
  • R 2 and R 3 are bonded to form a 5-6 membered saturated heterocyclic ring, wherein the 5-6 membered saturated heterocyclic ring is optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from the group consisting of H, CN, halogen, C 1-4 alkyl, C 1-4 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl;
  • R 5 and R 6 are each independently selected from the group consisting of H, NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
  • R is independently selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring
  • An alkyl group wherein said C 1-4 alkyl group, C 1-4 heteroalkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally substituted by 1, 2 or 3 R';
  • R' is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CF 3 , CHF 2 , CH 3 O, CH 3 CH 2 , CH 3 CH 2 O, COOH, NH(CH 3 ) , NH(CH 3 ) 2 ,
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CF 3 , CHF 2 , CH 3 O, CH 3 CH 2 , CH 3 CH 2 O , COOH, NH(CH 3 ), N(CH 3 ) 2 ,
  • R 1 is selected from H.
  • R 2 above is selected from the group consisting of H, NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl, and C 2-4 alkenyl, said C 1-4 alkyl, C The 1-4 heteroalkyl group and the C 2-4 alkenyl group are optionally substituted by 1, 2 or 3 R groups.
  • the above R 2 is selected from the group consisting of H, NH 2 , CH 3 , CH 3 CH 2 , The CH 3 , CH 3 CH 2 , Optionally substituted by 1, 2 or 3 R.
  • R 2 is selected from the group consisting of H, CH 3 ,
  • R 3 is selected from the group consisting of H, C 1-3 alkyl and C 3-4 cycloalkyl, the C1-3 alkyl and C3-4 cycloalkyl optionally being 1, 2 Or 3 R' substitutions.
  • R 3 is selected from the group consisting of H, CH 3 , CH 3 CH 2 and
  • R 4 is selected from the group consisting of H, Cl, and CN.
  • R 5 and R 6 are each independently selected from the group consisting of H, NH 2 , CH 3 , CH 3 CH 2 , The CH 3 , CH 3 CH 2 , Optionally substituted by 1, 2 or 3 R.
  • R 5 and R 6 are each independently selected from the group consisting of H, NH 2 , CH 3 , CH 3 CH 2 ,
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CF 3 , CHF 2 , CH 3 O, CH 3 CH 2 , CH 3 CH 2 O , COOH, NH(CH 3 ), N(CH 3 ) 2 ,
  • Other variables are as defined by the present invention.
  • R 1 above is selected from H, and other variables are as defined herein.
  • R 2 above is selected from the group consisting of H, NH 2 , C 1-4 alkyl, C 1-4 heteroalkyl, and C 2-4 alkenyl, said C 1-4 alkyl, C The 1-4 heteroalkyl and C2-4 alkenyl are optionally substituted by 1, 2 or 3 R, and other variables are as defined herein.
  • the above R 2 is selected from the group consisting of H, NH 2 , CH 3 , CH 3 CH 2 , The CH 3 , CH 3 CH 2 , Optionally substituted by 1, 2 or 3 R, other variables are as defined by the present invention.
  • R 2 is selected from the group consisting of H, CH 3 , Other variables are as defined by the present invention.
  • R 3 is selected from the group consisting of H, C 1-3 alkyl and C 3-4 cycloalkyl, the C1-3 alkyl and C3-4 cycloalkyl optionally being 1, 2 Or 3 R' substitutions, other variables are as defined by the present invention.
  • R 3 is selected from the group consisting of H, CH 3 , CH 3 CH 2 and Other variables are as defined by the present invention.
  • R 4 above is selected from the group consisting of H, Cl, and CN, and other variables are as defined herein.
  • R 5 and R 6 are each independently selected from the group consisting of H, NH 2 , CH 3 , CH 3 CH 2 , The CH 3 , CH 3 CH 2 , Optionally substituted by 1, 2 or 3 R, other variables are as defined by the present invention.
  • R 5 and R 6 are each independently selected from the group consisting of H, NH 2 , CH 3 , CH 3 CH 2 , Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 3 is selected from the group consisting of C 1-4 alkyl and C 3-6 cycloalkyl, and L 1 , L 2 , R 1 , R 4 , R 5 and R 6 are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 2 is selected from the group consisting of NH 2 , C 1-6 alkyl, C 1-6 heteroalkyl, and C 2-6 alkenyl, said C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6
  • the alkenyl group is optionally substituted by 1, 2 or 3 R;
  • L 1 , L 2 , R 1 , R 4 , R 5 , R 6 and R are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • L 1 , L 2 , R 1 , R 4 , R 5 and R 6 are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 4 and R 5 are as defined in the present invention.
  • the present invention also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the above claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a c-MET/AXL inhibitory drug.
  • the above c-MET/AXL inhibitory drug is a therapeutic agent for cancer.
  • the compound of the present invention has an increased half-life, an extended action time for the target, enhanced metabolic stability, and more excellent inhibitory activity.
  • the prolongation of the half-life will keep the blood concentration for a longer period of time. It can be predicted that the compound will be used in tumor treatment, and the patient's medication dose or dose will be reduced compared with the same drug, and patient compliance will be significantly improved.
  • c-MET binds to HGF, it activates cell signaling pathways such as MAPK, PI3K/AKT, and Cdc42/Rac1, which leads to cancer cell survival and proliferation, thereby accelerating tumor growth. Therefore, uracil compounds as c-MET inhibitors have great application prospects in targeted therapeutic drugs such as liver cancer, non-small cell lung cancer, and gastric cancer. Therefore, the compound of the present invention acts as a c-MET inhibitor of uracil, and AXL is also involved in tumor metastasis, tumor stem cell phenotype, tumor cell drug resistance, and suppression of immunity, as AXL inhibitors.
  • the uracil compound has great application prospects in the treatment of acute lymphocytic myeloma, non-small cell lung cancer, gastric cancer and breast cancer. In view of its remarkable inhibitory activity in vivo and in vitro and good pharmacokinetic properties, it is expected to become a new drug with better therapeutic effect than similar products.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of atoms of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in conjunction with another term, is represented by a number of carbon atoms and at least A stable, linear, branched or cyclic hydrocarbon radical consisting of a hetero atom or a combination thereof.
  • heteroalkyl by itself or in conjunction with another term, refers to a stable straight or branched alkyl radical or composition thereof consisting of a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including the position at which the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy).
  • alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • heterocycloalkyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkyl”, respectively, and further, in the case of the "heterocycloalkyl", a heteroatom may occupy a heterocycloalkyl group.
  • the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkane.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetra Hydropyranyl, piperidinyl, piperazinyl, morpholinyl, dioxoalkyl, dithiaalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2- Thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or oxetanyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • reaction product 1b 2.3 g of 1a (16.77 mmol, 1.89 mL, 1.05 eq) was dissolved in 20 mL of 1,2-dichloroethane at room temperature, followed by the addition of 3 g of diethylaminomethylmalonate (16.03 mmol, 1.00 eq) and 2.49 g of diisopropylethylamine (19.23 mmol, 3.35 mL, 1.2 eq), and the reaction mixture was stirred at 100 ° C for 12 hours. After the reaction was completed, it was filtered, and the obtained cake was obtained as reaction product 1b.
  • Step 1 3d was obtained as the intermediate 1d method.
  • Step 2 3e is obtained as in the intermediate 1e method.
  • Step 3: 3f is obtained as the intermediate 1f method.
  • Step 4 3 g was obtained as in the intermediate 1 g method.
  • Step 1 As the intermediate 1d method, 8d was obtained.
  • Step 2 8e is obtained as in the intermediate 1e method.
  • Step 3 As the intermediate 1f method, 8f is obtained.
  • Step 4 8 g was obtained as in the intermediate 1 g method.
  • reaction mixture is diluted with 30 mL of water, extracted with ethyl acetate (50 mL ⁇ 1), then the organic phase is discarded, and the organic phase is saturated with ammonium chloride solution (30 mL ⁇ 1), saturated sodium carbonate solution (30 mL ⁇ 1) and saturated brine were washed with anhydrous sodium sulfate, and the solvent was evaporated to give 11 g.
  • aqueous ammonia 60 ⁇ L was added to the reaction solution obtained in the step 1, and the reaction solution was stirred at 20 ° C for 24 hours. After the reaction was completed, 10 mL of water and 10 mL of dichloromethane were added to the reaction solution, respectively, and the mixture was stirred for 5 minutes, and the organic phase was separated. Saturated brine (10 mL * 2) was washed with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Example 5 After dissolving 200 mg of Example 5 (395.67 ⁇ mol, 1 eq) in 2 mL of tetrahydrofuran, 153.14 mg of N,N-diisopropylethylamine (1.19 mmol, 3 eq) and 37.27 mg of acetyl chloride (474.80 ⁇ mol, 1.2) were sequentially added to the reaction system.
  • reaction mixture was diluted with 100 mL of ethyl acetate, saturated ammonium chloride (60 mL*3) and saturated brine (100 mL*3) After washing, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford product 22d.
  • the intermediate 22d method is 24d.
  • Reaction buffer 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO and corresponding cofactors
  • test compound was dissolved in 0.3% ⁇ M with 100% DMSO, and subjected to a 3-fold dilution using a fully automated microplate pretreatment system ECHO, 10 concentration gradients.
  • the compound of the present invention has strong inhibitory activity against c-MET/AXL enzyme.
  • Example 1 Compound AXL IC 50 (nM) c-MET IC 50 (nM) Example 1 2.07 2.17 Example 2 2.64 1.76 Example 4 17.7 2.89 Example 5 2.51 2.51 Example 6 4.6 16.9 Example 7 2.06 3.77 Example 9 3.11 12.4 Example 11 3.11 1.43 Example 12 3.18 7.18 Example 13 6.69 7.35 Example 14 3.52 4.79 Example 15 3.74 4.05 Example 16 3.81 9.35 Example 17 4.41 2.01 Example 18 5.59 1.44 Example 21 1.07 14.63 Example 22 43.99 13.36 Example 23 5 26.15 Example 24 19.03 59.26
  • Cell culture DMEM medium, fetal bovine serum, DPBS
  • Detection reagent live cell detection kit CellTiter-Glo
  • the amount of ATP directly reflects the number of cells and the state of the cells, and the number of living cells can be detected by quantitatively measuring ATP.
  • the live cell assay kit contains luciferase and its substrate. Through the participation of ATP, luciferase can catalyze the substrate, emit a stable optical signal, and determine the amount of ATP in the cell by detecting the intensity of the signal. The light signal is proportional to the amount of ATP in the cell, and ATP is positively correlated with the number of living cells, so that the cell proliferation can be detected.
  • the assay plate was analyzed using PE company's Envision. experimental method:
  • MKN45 cells were separately seeded in 384-well plates containing 200 cells per well. The cell plates were placed in a carbon dioxide incubator for overnight culture.
  • Compounds were transferred to cell plates at a starting concentration of 10 [mu]M.
  • the cell plates were incubated in a carbon dioxide incubator for 3 days.
  • the Promega CellTiter-Glo reagent was added to the cell plate and incubated for 10 minutes at room temperature to stabilize the luminescence signal. Readings were performed using a PerkinElmer Envision multi-label analyzer.
  • the compounds of the present invention show good inhibitory activity against MKN45 cells.
  • Example 16 Test compound MKN45 cell IC 50 (nM) BMS777607 436 Example 1 54 Example 2 78 Example 3 27 Example 5 11 Example 8 374 Example 9 365 Example 11 240 Example 12 315 Example 13 38 Example 14 30 Example 15 12.6 Example 16 50.7
  • Example 17 7.64 Example 18 12.1 Example 19 41 Example 20 29.1
  • MKN45 cells were cultured in vitro in a single layer, cultured in RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 1% penicillin-streptomycin double antibody, and cultured at 37 ° C, 5% CO 2 . Passage was routinely digested with trypsin-EDTA twice a week. When the cells are in the exponential growth phase, the cells are harvested, counted, and inoculated.
  • mice BALB/c nude mice, male. 6-8 weeks old, weighing 18-22 grams.
  • 0.2 ml of a suspension containing 5 x 10 ⁇ 6 MKN45 cells was subcutaneously inoculated into the right back of each mouse. Group administration was initiated when the average tumor volume reached approximately 160 mm 3 .
  • TGI antitumor effect
  • the compounds of the present invention show better tumor inhibition than BMS777607 in the pharmacodynamic experiments of the subcutaneous xenograft tumor model of MKN45 gastric cancer cells.
  • the b.p value is calculated from the tumor volume.
  • Human gastric cancer Hs746t cells were cultured in vitro in a single layer.
  • the culture conditions were 10% fetal bovine serum, 100 U/mL penicillin and 100 U/mLL streptomycin in DMEM medium, and cultured in 37 ° C, 5% CO 2 incubator. Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, when the number reaches the requirement, the cells are collected, counted, and inoculated.
  • mice BALB/c nude mice, male. 6-8 weeks old, weighing 18-22 grams.
  • HS 746T cells were subcutaneously inoculated into the right back of each mouse, and group administration was started when the average tumor volume reached about 100-150 mm 3 .
  • TGI antitumor effect
  • Example 17 of the present invention was effective at a dose of 1.5 mpk; at the same 4.5 mpk dose, Example 5 and Example 17 showed more than BMS777607 and LY2801653. Good tumor inhibition; Compounds 5 and 17 of the present invention abolish tumors at a dose of 9 mpk.
  • the compounds of the invention have good tumor suppressing activity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

式(IV)所示的尿嘧啶类化合物或其药学上可接受的盐，其药物组合物。其作为c-MET/AXL抑制剂在制备c-MET/AXL抑制药物或者治疗肿瘤的药物中的用途。

Description

作为c-MET/AXL抑制剂的尿嘧啶类化合物
本申请主张如下优先权：
CN201711190571.6，申请日2017年11月24日；
CN201811159913.2，申请日2018年9月30日。
技术领域
本发明涉及一类作为c-MET/AXL抑制剂的尿嘧啶类化合物，具体公开了式(IV)和所示化合物或其药学上可接受的盐。
背景技术
原癌基因Met编码的c-Met是一种具有高度结合性的受体酪氨酸激酶，属于RON亚族，是散射因子或肝细胞生长因子(HGF)唯一已知的受体。c-Met蛋白是由50kD的α亚基和145kD的β亚基通过二硫键相连的异二聚体，分为胞外域和胞内域。胞外域包含有3个功能不同的结构域:覆盖整个α链和部分β链的N-端配体结合域(SEMA区域)、有4个保守二硫键的胱氨酸富集区域、以及免疫球蛋白样结构域。胞内域同样由3个调控区域组成:有Tyr1003磷酸化位点的近膜结构域、有Tyr1234和Tyr1235磷酸化位点的酪氨酸激酶催化结构域、以及有Tyr1349和Tyr1356结合酪氨酸的C-端多功能结合区域
HGF与c-Met胞外域结合后，诱导c-Met发生磷酸化，在C-端多功能区域募集多种细胞间质因子，如GAB1(生长因子受体结合蛋白-1)、GAB2(生长因子受体结合蛋白-2)等，进一步吸引SHP2、PI3K等分子结合在此，由此激活RAS/MAPK、PI3K/AKT、JAK/STAT通路等，从而调控着细胞的生长、迁移、增殖和存活。c-Met通路异常会诱发肿瘤的发生和转移，在多种人类恶性肿瘤如膀胱癌、胃癌、肺癌、乳腺癌中发现异常高水平表达的c-Met。此外，c-Met还与肿瘤对多种激酶抑制剂的耐药性相关。
c-Met和多种膜受体之间存在相互作用(crosstalk)，构成了复杂的网络体系。c-Met和黏附受体CD44之间的相互作用，放大了信号肽的应答作用；与脑蛋白受体从蛋白的相互作用激活了非依赖配体HGF的c-Met，增强了侵袭作用；与促凋亡受体FAS之间的相互作用加快了细胞凋亡；与多种受体酪氨酸激酶如EGFR、VEGFR等的作用使得彼此间激活受到调控，血管生成过程受到影响。c-Met与这些膜受体之间的相互作用促进了肿瘤的发生和转移，诱导产生耐药性。
AXL是一种跨膜蛋白，胞外区包括两个免疫球蛋白样区以及两个纤维连接蛋白样区，配体结合区域为免疫球蛋白样区，AXL与Tyro3以及Mer同属于TAM受体酪氨酸激酶家族，均以生长停滞特异性基因6(Gas6)所编码的蛋白分子以及人血浆抗凝蛋白S为配体。当AXL与Gas6结合时，AXL的构象发生变化，形成二聚体。膜内段酪氨酸残基被磷酸化，激活AXL本身的酪氨酸蛋白激酶活性，进一步磷酸化下游蛋白，起到信号传导作用。AXL激活后可引起GRB2激活，进而通过RAS-RAF-MEK-ERK信号通路影响肿瘤细胞增殖，也可以磷酸化PI3K进而激活AKT，增强肿瘤细胞存活能力。此外AXL可直接激活SRC或是通过与与EGFR、VEGFR以及MET产生交互影响促进肿瘤细胞的迁移与侵入，进而导致肿瘤转移恶化。AXL蛋白高表达与乳腺癌、肺癌、急性骨髓性白血病病情恶化相关。有研究表明，AXL信号激活是肿瘤细胞发生上皮-间充质转化(EMT)的主要机制之一，也是癌细胞对靶 向药物和化疗药物产生耐药性的主要机制之一。
目前已上市的抗肿瘤药物较多，如烷化剂药物、抗代谢药物、抗肿瘤抗生素、免疫调节剂等，但是大多由于毒性较大，病人不耐受。随着肿瘤分子生物学研究的深入，对肿瘤的发生发展的分子机制越来越清楚，分子靶向治疗多种恶性肿瘤受到了广泛的关注和高度重视。分子靶向药物具有选择性高、广谱有效，其安全性优于细胞毒性化疗药物，是目前肿瘤治疗领域发展的新方向。
目前在研的c-Met抑制剂可分为选择性抑制剂以及多靶点抑制剂，其中，选择性抑制剂Tepotinib(EMD1214063)(WO2009006959,公开日2009.1.15)抗肿瘤活性最优，对多种c-MET高表达的肿瘤细胞有很强的抑制作用(c-MET酶活性IC50＝3.67nM,MHCC97H细胞IC 50＝6.2nM)，目前已经进入临床Ⅱ期研究阶段。多靶点c-Met抑制剂以BMS777607(US2008114033)、MGCD265(WO2006010264)、LY2801653(US2010022529)、NPS-1034(US2011183983)为代表。专利US2009094427公开了如下结构通式(A)的化合物系列。
Figure PCTCN2018117269-appb-000001
发明内容
本发明提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2018117269-appb-000002
其中，
R 1选自H、卤素和C 1-6烷基；
R 2选自H、NH 2、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 3-6环烷基和3-6元杂环烷基，其中，所述C 1-6烷基、C 1-6杂烷基、C 2-6烯基和3-6元杂环烷基任选被1、2或3个R取代；
R 3选自H、C 1-4烷基和C 3-6环烷基；
或者R 2和R 3连接形成一个5-6元饱和杂环，其中，所述5-6元饱和杂环任选被1、2或3个R取代；
R 4选自H、卤素、C 1-4烷基、C 1-4杂烷基、C 3-6环烷基、3-6元杂环烷基和5-6元杂芳基；
R分别独立地选自F、Cl、Br、I、OH、CN、NH 2、C 1-4烷基、C 1-4杂烷基、C 3-6环烷基和3-6元杂环烷基，其中，所述C 1-4烷基、C 1-4杂烷基、C 3-6环烷基和3-6元杂环烷基任选被1、2或3个R’取代；
R’选自F、Cl、Br、I、OH、CN、NH 2、CH 3、CF 3、CHF 2、CH 3O、CH 3CH 2、CH 3CH 2O、COOH、NH(CH 3)、NH(CH 3) 2、
Figure PCTCN2018117269-appb-000003
所述C 1-6杂烷基、3-6元杂环烷基、5-6元饱和杂环、C 1-4杂烷基和5-6元杂芳基分别独立地包含1、2或者3个选自-NH-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝O)NH-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-、-C(＝NH)-、-S(＝O) 2NH-、-S(＝O)NH-、和-NHC(＝O)NH-的杂原子或杂原子团。
在本发明的一些方案中，上述R选自F、Cl、Br、I、OH、CN、NH 2、CH 3、CF 3、CHF 2、CH 3O、CH 3CH 2、CH 3CH 2O、COOH、NH(CH 3)、NH(CH 3) 2、
Figure PCTCN2018117269-appb-000004
在本发明的一些方案中，上述R 1选自H。
在本发明的一些方案中，上述R 2选自H、NH 2、C 1-4烷基、C 1-4杂烷基和C 2-4烯基，所述C 1-4烷基、C 1-4杂烷基和C 2-4烯基任选被1、2或3个R取代。
在本发明的一些方案中，上述R 2选自H、CH 3、
Figure PCTCN2018117269-appb-000005
Figure PCTCN2018117269-appb-000006
在本发明的一些方案中，上述R 3选自H、C 1-3烷基和C 3-4环烷基。
在本发明的一些方案中，上述R 3选自H、CH 3、CH 3CH 2和
Figure PCTCN2018117269-appb-000007
在本发明的一些方案中，上述R 4选自Cl。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018117269-appb-000008
选自
Figure PCTCN2018117269-appb-000009
在本发明的一些方案中，上述R选自F、Cl、Br、I、OH、CN、NH 2、CH 3、CF 3、CHF 2、CH 3O、CH 3CH 2、CH 3CH 2O、COOH、NH(CH 3)、NH(CH 3) 2、
Figure PCTCN2018117269-appb-000010
其他变量如上述所定义。
在本发明的一些方案中，上述R 1选自H，其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自H、NH 2、C 1-4烷基、C 1-4杂烷基和C 2-4烯基，所述C 1-4烷基、C 1-4杂烷基和C 2-4烯基任选被1、2或3个R取代，其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自H、CH 3、
Figure PCTCN2018117269-appb-000011
Figure PCTCN2018117269-appb-000012
其他变量如上述所定义。
在本发明的一些方案中，上述R 3选自H、C 1-3烷基和C 3-4环烷基，其他变量如上述所定义。
在本发明的一些方案中，上述R 3选自H、CH 3、CH 3CH 2和
Figure PCTCN2018117269-appb-000013
其他变量如上述所定义。
在本发明的一些方案中，上述R 4选自Cl，其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018117269-appb-000014
选自
Figure PCTCN2018117269-appb-000015
其他变量如上述所定义。
本发明还有一些方案是由上述各变量任意组合而来。
在本发明的一些方案中，上述化合物选自
Figure PCTCN2018117269-appb-000016
其中，R 3选自C 1-4烷基和C 3-6环烷基，R、R 1和R 4如上述所定义。
在本发明的一些方案中，上述化合物选自
Figure PCTCN2018117269-appb-000017
其中，R 2选自NH 2、C 1-6烷基、C 1-6杂烷基和C 2-6烯基，所述C 1-6烷基、C 1-6杂烷基、C 2-6烯基任选被1、2或3个R取代，R、R 1和R 4如上述所定义。
本发明提供式(IV)所示化合物或其药学上可接受的盐，
Figure PCTCN2018117269-appb-000018
其中，
R 1选自H、卤素和C 1-6烷基；
R 2选自H、NH 2、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 3-6环烷基和3-6元杂环烷基，其中，所述C 1-6烷基、C 1-6杂烷基、C 2-6烯基和3-6元杂环烷基任选被1、2或3个R取代；
R 3选自H、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基和C 3-6环烷基任选被1、2或3个R’取代；
或者R 2和R 3连接形成一个5-6元饱和杂环，其中，所述5-6元饱和杂环任选被1、2或3个R取代；
R 4选自H、CN、卤素、C 1-4烷基、C 1-4杂烷基、C 3-6环烷基、3-6元杂环烷基和5-6元杂芳基；
R 5和R 6分别独立地选自H、NH 2、C 1-6烷基、C 1-6杂烷基、C 3-6环烷基和3-6元杂环烷基，所述C 1-6烷基、C 1-6杂烷基、C 3-6环烷基和3-6元杂环烷基任选被1、2或3个R取代；
L 1和L 2分别独立地选自单键和-C(＝O)-；
R分别独立地选自F、Cl、Br、I、OH、CN、NH 2、C 1-4烷基、C 1-4杂烷基、C 3-6环烷基和3-6元杂环烷基，其中，所述C 1-4烷基、C 1-4杂烷基、C 3-6环烷基和3-6元杂环烷基任选被1、2或3个R’取代；
R’选自F、Cl、Br、I、OH、CN、NH 2、CH 3、CF 3、CHF 2、CH 3O、CH 3CH 2、CH 3CH 2O、COOH、NH(CH 3)、NH(CH 3) 2、
Figure PCTCN2018117269-appb-000019
所述C 1-6杂烷基、3-6元杂环烷基、5-6元饱和杂环、C 1-4杂烷基和5-6元杂芳基分别独立地包含1、2或者3个选自N、-NH-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝O)NH-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-、-C(＝NH)-、-S(＝O) 2NH-、-S(＝O)NH-、和-NHC(＝O)NH-的杂原子或杂原子团。
在本发明的一些方案中，上述R选自F、Cl、Br、I、OH、CN、NH 2、CH 3、CF 3、CHF 2、CH 3O、CH 3CH 2、CH 3CH 2O、COOH、NH(CH 3)、N(CH 3) 2、
Figure PCTCN2018117269-appb-000020
Figure PCTCN2018117269-appb-000021
在本发明的一些方案中，上述R 1选自H。
在本发明的一些方案中，上述R 2选自H、NH 2、C 1-4烷基、C 1-4杂烷基和C 2-4烯基，所述C 1-4烷基、C 1-4杂烷基和C 2-4烯基任选被1、2或3个R取代。
在本发明的一些方案中，上述R 2选自H、NH 2、CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000022
所述CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000023
任选被1、2或3个R取代。
在本发明的一些方案中，上述R 2选自H、CH 3、
Figure PCTCN2018117269-appb-000024
Figure PCTCN2018117269-appb-000025
在本发明的一些方案中，上述R 3选自H、C 1-3烷基和C 3-4环烷基，所述C1-3烷基和C3-4环烷基任选被1、2或3个R’取代。
在本发明的一些方案中，上述R 3选自H、CH 3、CH 3CH 2和
Figure PCTCN2018117269-appb-000026
在本发明的一些方案中，上述R 4选自H、Cl和CN。
在本发明的一些方案中，上述R 5和R 6分别独立地选自H、NH 2、CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000027
Figure PCTCN2018117269-appb-000028
Figure PCTCN2018117269-appb-000029
所述CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000030
Figure PCTCN2018117269-appb-000031
Figure PCTCN2018117269-appb-000032
任选被1、2或3个R取代。
在本发明的一些方案中，上述R 5和R 6分别独立地选自H、NH 2、CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000033
Figure PCTCN2018117269-appb-000034
在本发明的一些方案中，上述结构单元
Figure PCTCN2018117269-appb-000035
选自
Figure PCTCN2018117269-appb-000036
Figure PCTCN2018117269-appb-000037
在本发明的一些方案中，上述结构单元
Figure PCTCN2018117269-appb-000038
选自
Figure PCTCN2018117269-appb-000039
Figure PCTCN2018117269-appb-000040
在本发明的一些方案中，上述R选自F、Cl、Br、I、OH、CN、NH 2、CH 3、CF 3、CHF 2、CH 3O、CH 3CH 2、CH 3CH 2O、COOH、NH(CH 3)、N(CH 3) 2、
Figure PCTCN2018117269-appb-000041
Figure PCTCN2018117269-appb-000042
其他变量如本发明所定义。
在本发明的一些方案中，上述R 1选自H，其他变量如本发明所定义。
在本发明的一些方案中，上述R 2选自H、NH 2、C 1-4烷基、C 1-4杂烷基和C 2-4烯基，所述C 1-4烷基、C 1-4杂烷基和C 2-4烯基任选被1、2或3个R取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 2选自H、NH 2、CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000043
所述CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000044
任选被1、2或3个R取代，其他变量如本发明 所定义。
在本发明的一些方案中，上述R 2选自H、CH 3、
Figure PCTCN2018117269-appb-000045
Figure PCTCN2018117269-appb-000046
其他变量如本发明所定义。
在本发明的一些方案中，上述R 3选自H、C 1-3烷基和C 3-4环烷基，所述C1-3烷基和C3-4环烷基任选被1、2或3个R’取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 3选自H、CH 3、CH 3CH 2和
Figure PCTCN2018117269-appb-000047
其他变量如本发明所定义。
在本发明的一些方案中，上述R 4选自H、Cl和CN，其他变量如本发明所定义。
在本发明的一些方案中，上述R 5和R 6分别独立地选自H、NH 2、CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000048
Figure PCTCN2018117269-appb-000049
Figure PCTCN2018117269-appb-000050
所述CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000051
Figure PCTCN2018117269-appb-000052
Figure PCTCN2018117269-appb-000053
任选被1、2或3个R取代，其他变量如本发明所定义。
在本发明的一些方案中，上述R 5和R 6分别独立地选自H、NH 2、CH 3、CH 3CH 2、
Figure PCTCN2018117269-appb-000054
Figure PCTCN2018117269-appb-000055
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018117269-appb-000056
选自
Figure PCTCN2018117269-appb-000057
Figure PCTCN2018117269-appb-000058
Figure PCTCN2018117269-appb-000059
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018117269-appb-000060
选自
Figure PCTCN2018117269-appb-000061
Figure PCTCN2018117269-appb-000062
Figure PCTCN2018117269-appb-000063
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，化合物选自
Figure PCTCN2018117269-appb-000064
其中，R 3选自C 1-4烷基和C 3-6环烷基，L 1、L 2、R 1、R 4、R 5和R 6如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，化合物选自
Figure PCTCN2018117269-appb-000065
其中，
R 2选自NH 2、C 1-6烷基、C 1-6杂烷基和C 2-6烯基，所述C 1-6烷基、C 1-6杂烷基、C 2-6烯基任选被1、2或3个R取代；
L 1、L 2、R 1、R 4、R 5、R 6和R如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，化合物选自
Figure PCTCN2018117269-appb-000066
其中，L 1、L 2、R 1、R 4、R 5和R 6如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，化合物选自
Figure PCTCN2018117269-appb-000067
其中，R 1、R 4和R 5如本发明所定义。
本发明还提供化合物或其药学上可接受的盐，其中，化合物选自
Figure PCTCN2018117269-appb-000068
Figure PCTCN2018117269-appb-000069
Figure PCTCN2018117269-appb-000070
本发明还提供一种药物组合物，包含治疗有效量的根据权利要求上述的化合物或其药学上可接受的盐以及药学上可接受的载体。
本发明还提供上述化合物或其药学上可接受的盐或者上述组合物在制备c-MET/AXL抑制药物中的应用。
在本发明的一些方案中，上述c-MET/AXL抑制药物是治疗肿瘤药物。
本发明还有一些方案是由上述各变量任意组合而来。
技术效果
本发明化合物半衰期增大，针对靶点的作用时间延长，代谢稳定性增强，具有更优异的抑制活性。半衰期的延长将会使血药浓度维持更长时间，由此可以预测，该化合物运用于肿瘤治疗，与同类药物相比，将减少病人的服药量或服药次数，病人依从性将得到显著提高。
由于c-MET与HGF结合后,激活MAPK、PI3K/AKT、Cdc42/Rac1等细胞信号通路,导致癌细胞存活与增殖,从而加速肿瘤生长。因此，作为c-MET抑制剂的尿嘧啶类化合物在肝癌、非小细胞肺癌、胃癌等靶向治疗药物中具有较大的应用前景。所以，本发明化合物作为尿嘧啶类的c-MET抑制剂，而AXL过度激活后也涉及到肿瘤的转移、肿瘤干细胞的表型、肿瘤细胞耐药性的产生以及抑制免疫等，作为AXL抑制剂的尿嘧啶类化合物在急性淋巴性骨髓瘤、非小细胞肺癌、胃癌、乳腺癌等治疗领域有较大的应用前景。鉴于其在体内外的显著的抑制活性及良好的药代动力学性质，有望成为比同类产品治疗效果更好的新药。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、 材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2018117269-appb-000071
和楔形虚线键
Figure PCTCN2018117269-appb-000072
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2018117269-appb-000073
和直形虚线键
Figure PCTCN2018117269-appb-000074
表示立体中心的相对构型，用波浪线
Figure PCTCN2018117269-appb-000075
表示楔形实线键
Figure PCTCN2018117269-appb-000076
或楔形虚线键
Figure PCTCN2018117269-appb-000077
或用波浪线
Figure PCTCN2018117269-appb-000078
表示直形实线键
Figure PCTCN2018117269-appb-000079
和直形虚线键
Figure PCTCN2018117269-appb-000080
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊 乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018117269-appb-000081
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018117269-appb-000082
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018117269-appb-000083
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018117269-appb-000084
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为 环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另 一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示由一定数目的碳原子和至少一个杂原子组成的，稳定的直链、支链或环状的烃原子团或其组合。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示由一定数目的碳原子和至少一个杂原子组成的，稳定的直链或支链的烷基原子团或其组合物。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“杂环烷基”本身或者与其他术语联合分别表示环化的“杂烷基”，此外，就该“杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。在一些实施方案中，所述杂环烷基为4～6元杂环烷基；在另一些实施方案中，所述杂环烷基为5～6元杂环烷。杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、二恶烷基、二噻烷基、异恶唑烷基、异噻唑烷基、1,2-恶嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或氧杂环庚烷基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6- 喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；FA代表甲酸；ACN代表乙腈。
化合物经手工或者
Figure PCTCN2018117269-appb-000085
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2018117269-appb-000086
步骤1
室温下将2.3g 1a(16.77mmol,1.89mL,1.05eq)溶于20mL 1,2-二氯乙烷中，之后加入3g氨甲烯基丙二酸二乙酯(16.03mmol,1.00eq)以及2.49g二异丙基乙胺(19.23mmol,3.35mL,1.2eq)，反应液在100℃条件下搅拌12小时，反应完成后过滤，所得滤饼即反应产物1b，产物无需纯化可直接用于下一步， 1H NMR(400MHz,DMSO-d 6)δppm 1.26(dt,J＝12.05,7.09Hz,6H)4.16(q,J＝7.15Hz,2H)4.25(q,J＝7.03Hz,2H)7.15-7.24(m,2H)7.47-7.56(m,2H)8.47(d,J＝12.55Hz,1H)10.42(s,1H)10.58(d,J＝12.55Hz,1H)。
步骤2
室温下将3.4g 1b(10.26mmol,1eq)溶于15mL乙醇，搅拌条件下加入0.8g乙醇钠，反应液室温下搅拌0.5小时，反应完成后过滤，所得滤饼即产物1c。 1H NMR(400MHz,DMSO-d 6)δppm 1.21(t,J＝7.09Hz,4H)4.08(q,J＝7.05Hz,2H)7.05-7.10(m,2H)7.16-7.22(m,2H)8.46(s,1H)。
步骤3
室温下将0.5g 1c(1.80mmol,1eq),0.5g碳酸钾(3.62mmol,2.01eq)和0.45g 2-溴丙烷(3.66mmol,343.51μL,2.04eq)加入到5mL DMF中，氮气保护后，反应液在70℃条件下搅拌12小时，反应完成后加入30mL水稀释反应液，之后用30mL乙酸乙酯萃取反应液，所得有机相经10mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂后，残留物经柱层析(石油醚/乙酸乙酯＝3/1)纯化得1d. 1H NMR (400MHz,DMSO-d 6)δppm 1.25(t,J＝7.09Hz,3H)1.37(d,J＝6.72Hz,6H)4.22(q,J＝7.09Hz,2H)4.64-4.75(m,1H)7.26-7.37(m,4H)8.45(s,1H)。
步骤4
将0.46g 1d(1.44mmol,1eq)溶于9mL MeOH后加入到0.075g一水合氢氧化锂(1.79mmol,1.24eq)的3mL水溶液中，反应液在25℃条件下搅拌0.5小时，反应完成后浓缩反应液除去大部分甲醇，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)后弃去有机相，水相调pH＝3后用乙酸乙酯萃取(30mL×2),合并的有机相经10mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得1e。 1H NMR(400MHz,DMSO-d 6)δppm 1.39(d,J＝6.78Hz,6H)4.73(quin,J＝6.74Hz,1H)7.03-7.51(m,5H)8.39-8.77(m,1H)12.64(br s,1H)。
步骤5
将80mg 1e(259.93μmol,1eq)溶于5mL四氢呋喃，搅拌下先后滴加2μL DMF以及23μL草酰氯，20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，得油状粗产物1f，产品未经纯化，直接用于下一步。
步骤6
将50mg 1f1溶于(177.51μmol,1eq)5mL四氢呋喃后滴加60μL二异丙基乙胺(2.0eq)，将90mg1f产物溶于5mL四氢呋喃后滴加至上述溶液，反应液在20℃条件下搅拌0.5h，反应结束后浓缩除去溶剂，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)，有机相经饱和氯化铵溶液(40mL×1)、饱和碳酸钠溶液(40mL×1)及饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得1g。产物未经纯化直接用于下一步。LCMS M+1：566.0
步骤7
将150mg 1g(269.82μmol,1eq)溶于4mL乙腈以及4mL乙酸乙酯组成的混合溶剂后加入2mL水，搅拌条件下加入104.29mg醋酸碘苯(323.79μmol,1.2eq)，反应液在20℃条件下搅拌1小时，反应完成后经制备色谱分离(柱型:Luna C18 150*25mm×5μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:33％-57％,10min)得产物实施例1。 1H NMR(400MHz,DMSO-d 6)δppm 1.43(d,J＝6.78Hz,6H)4.73-4.81(m,1H)5.94(d,J＝5.40Hz,1H)6.43(s,2H)7.29-7.39(m,3H)7.39-7.39(m,1H)7.40-7.46(m,2H)7.48(br d,J＝8.28Hz,1H)7.76(d,J＝5.65Hz,1H)7.96(dd,J＝12.92,2.38Hz,1H)8.67(s,1H)11.01(s,1H)。
实施例2
Figure PCTCN2018117269-appb-000087
Figure PCTCN2018117269-appb-000088
步骤1
室温下将0.3g 1c(1.08mmol,1eq)、0.3g碳酸钾(2.17mmol,2.01eq)和0.26g 3-溴代丙烯(2.15mmol,1.99eq)加入到5mL DMF中，氮气保护后，反应液在70℃条件下搅拌2小时，反应完成后加入50mL水稀释反应液，之后用60mL乙酸乙酯萃取反应液，所得有机相经50mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂后得2d. 1H NMR(400MHz,DMSO-d 6)δppm 1.25(t,J＝7.09Hz,3H)4.21(q,J＝7.15Hz,2H)4.52(br d,J＝5.40Hz,2H)5.21-5.36(m,2H)5.88-6.01(m,1H)7.29-7.34(m,4H)8.59(s,1H)。
步骤2
将0.27g 2d(848.26μmol,1eq)溶于6mL乙醇后加入到0.096g氢氧化钾(1.79mmol,1.24eq)的2mL水溶液中，反应液在20℃条件下搅拌1小时，反应完成后浓缩反应液除去大部分乙醇，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)后弃去有机相，水相调pH＝3后用乙酸乙酯萃取(30mL×2),合并有机相后经40mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得2e。 1H NMR(400MHz,DMSO-d 6)δppm 4.57(d,J＝5.77Hz,1H)4.91(d,J＝13.05Hz,1H)5.10-5.43(m,2H)5.82-6.06(m,1H)6.96-7.12(m,1H)7.25-7.41(m,2H)7.53-7.62(m,1H)8.63(s,1H)。
步骤3
将110mg 2e(378.99μmol,1eq)溶于5mL四氢呋喃，搅拌下先后滴加3μL DMF以及40μL(COCl) 2。20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，得油状粗产物2f，产品未经纯化，直接用于下一步。
步骤4
将100mg 1f1(355.03μmol,0.9eq)溶于5mL四氢呋喃后滴加135μL二异丙基乙胺(2.0eq)，将120mg 2f(388.74μmol,1eq)溶于10mL四氢呋喃后滴加至上述溶液，反应液20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)，有机相经饱和氯化铵溶液(40mL×1)、饱和碳酸钠溶液(40mL×1)及饱和食盐水洗后用无水硫酸钠干燥，浓缩后用制备TLC纯化得2g。
步骤5
将30mg 2g(44.44μmol,1eq)溶于3mL乙腈以及3mL乙酸乙酯组成的混合溶剂后加入1mL水，搅拌条件下加入30mg醋酸碘苯(93.14μmol,2.10eq)，反应液20℃条件下搅拌1小时，反应完成后经制备色谱分离(柱型:Luna C18 150*25mm*5μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:35％-56％,10min)即得实施例2。 1H NMR(400MHz,DMSO-d 6)δppm 4.62(br s,2H)5.25-5.43(m,2H)5.90-6.04(m,2H)6.42(br d,J＝1.51Hz,2H)7.28-7.50(m,6H)7.73-7.79(m,1H)7.90-7.98(m,1H)8.37(br s,1H)8.80(d,J＝4.27Hz,1H)10.99(br d,J＝3.01Hz,1H)。
实施例3
Figure PCTCN2018117269-appb-000089
步骤1：如中间体1d方法得3d。LCMS(ESI)m/z:367.1(M+1)。
步骤2：如中间体1e方法得3e。
步骤3：如中间体1f方法得3f。
步骤4：如中间体1g方法得3g。LCMS(ESI)m/z:604.0(M+1)。
步骤5：如实施例1方法得实施例3。 1H NMR(400MHz,DMSO-d 6)δppm 1.502-1.816(m,2H)2.079(s,1H)2.241(br dd,J＝11.42,5.90Hz,1H)4.141(br d,J＝7.03Hz,2H)5.941(d,J＝5.65Hz,1H)6.411(s,2H)7.266-7.534(m,5H)7.284-7.518(m,1H)7.760(d,J＝5.65Hz,1H)7.956(dd,J＝12.86,2.20Hz,1H)8.861(s,1H)10.969(s,1H)。
实施例4
Figure PCTCN2018117269-appb-000090
步骤1
将0.2g 1c(848.26μmol,1eq)溶于6mL乙醇后加入到80mg氢氧化钾(1.79mmol,1.24eq)的2mL水溶液中，反应液25℃条件下搅拌12小时，反应完成后浓缩反应液除去大部分乙醇，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)后弃去有机相，水相调pH＝3后用乙酸乙酯萃取(40mL×1)，合并的有机相后经40mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得4e。粗产物直接用于下一步。
步骤2
将130mg 4e(516.33μmol,1eq)溶于5mL四氢呋喃，搅拌下先后滴加3μL DMF以及50μL草酰氯.20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，得粗产物4f，产品未经纯化，直接用于下一步。
步骤3
将140mg 1f1(497.04μmol,1.03eq)溶于5mL四氢呋喃后滴加170μL二异丙基乙胺(2.0eq)，将 130mg 4f(388.74μmol,1eq)溶于10mL四氢呋喃后滴加至上述溶液，反应液在20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)，有机相后经饱和氯化铵溶液(40mL×1)、饱和碳酸钠溶液(40mL×1)及饱和食盐水洗后用无水硫酸钠干燥，浓缩后用制备TLC纯化得4g。 1H NMR(400MHz,CD 3OD)δppm 6.80-7.09(m,1H)7.19-7.49(m,9H)7.79-8.07(m,1H)8.32(d,J＝5.52Hz,1H)8.42(s,1H)8.49-8.80(m,1H)。
步骤4
将50mg 4g(97.31μmol,1eq)溶于3mL乙腈以及3mL乙酸乙酯组成的混合溶剂后加入1mL水，搅拌条件下加入63mg醋酸碘苯(195.59μmol,2.01eq)，反应液20℃条件下搅拌1小时，反应完成后经制备色谱分离(柱型:PhenomenexSynergi C18 150*25mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:17％-47％,10min)即产物实施例4。 1H NMR(400MHz,DMSO-d 6)δppm 5.93(d,J＝5.65Hz,1H)6.41(s,2H)7.26-7.46(m,7H)7.75(d,J＝5.77Hz,1H)7.95(dd,J＝12.99,2.45Hz,1H)8.47(s,1H)11.07(s,1H)。
实施例5
Figure PCTCN2018117269-appb-000091
步骤1
室温下将0.5g 1c(1.8mmol,1eq)、0.5g碳酸钾(3.62mmol,2.01eq)和0.49g环丙基甲基溴(3.59mmol,1.99eq)加入到10mL DMF中，氮气保护后，反应液在70℃条件下搅拌12小时，反应完成后加入40mL水稀释反应液，之后用60mL乙酸乙酯萃取反应液，所得有机相经50mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂后得5d。 1H NMR(400MHz,DMSO-d 6)δppm 0.23-0.31(m,2H)0.37-0.46(m,2H)1.03-1.10(m,1H)1.13(t,J＝7.09Hz,3H)2.77(s,9H)3.64(d,J＝7.09Hz,2H)4.09(q,J＝7.13Hz,2H)7.15-7.21(m,4H)8.56(s,1H)。
步骤2
将0.85g 5d(2.56mmol,1eq)溶于6mL乙醇后加入到0.22g氢氧化锂(1.79mmol,1.24eq)的2mL水溶液中，反应液20℃条件下搅拌1小时，反应完成后浓缩反应液除去大部分乙醇，之后加入30mL水稀释反应液，乙酸乙酯萃取(30mL×1)后弃去有机相，水相调pH＝3后用乙酸乙酯萃取(30mL×2),合并有机相后经40mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得5e。 1H NMR(400MHz,DMSO-d 6)δppm 0.37-0.45(m,2H)0.51-0.56(m,2H)1.15-1.29(m,1H)3.80(d,J＝7.15Hz,2H)7.30-7.42(m,4H)8.72-8.96(m,1H)12.63(br d,J＝1.51Hz,1H)。
步骤3
将300mg 5e(884.9μmol,1eq)溶于10mL四氢呋喃，搅拌下先后滴加3μL DMF以及100μL草酰氯，20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，得粗产物5f，产品未经纯化，直接用于下一步。
步骤4
将280mg 1f1(994.07μmol,1.13eq)溶于10mL四氢呋喃后滴加310μL二异丙基乙胺(2.0eq)，将285mg 5f(883.1μmol,1eq)溶于10mL THF后滴加至上述溶液，反应液20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，之后加入50mL水稀释反应液，乙酸乙酯萃取(80mL×1)，有机相后经饱和氯化铵溶液(40mL×1)、饱和碳酸钠溶液(40mL×1)及饱和食盐水洗后用无水硫酸钠干燥，所得即5g。 1H NMR(400MHz,DMSO-d 6)δppm 0.20(q,J＝4.65Hz,2H)0.30-0.35(m,2H)1.01(br s,1H)3.62(d,J＝7.21Hz,2H)6.61(d,J＝5.62Hz,1H)7.10-7.23(m,5H)7.30(dd,J＝8.93,1.22Hz,1H)7.52(s,1H)7.75-7.84(m,2H)8.10(d,J＝5.62Hz,1H)8.67(s,1H)10.80(s,1H)。
步骤5
将500mg 5g(880.4μmol,1eq)溶于9mL DMF后加入3mL水，搅拌条件下加入340mg醋酸碘苯(1.06mmol,1.2eq)，反应液20℃条件下搅拌3小时，反应完成后经制备色谱分离(柱型:Phenomenex luna C18 250*50mm*10μm；流动相:[A：水(0.05％HCl)，B：ACN]；B％:30％-60％,32min,40％min)即产物实施例5。 1H NMR(400MHz,DMSO-d 6)δppm 0.40-0.48(m,2H)0.52-0.61(m,2H)1.20-1.31(m,1H)3.86(d,J＝7.15Hz,2H)5.94(d,J＝5.40Hz,1H)6.42(s,2H)7.27-7.51(m,6H)7.76(d,J＝5.65Hz,1H)7.96(dd,J＝12.92,2.38Hz,1H)8.91(s,1H)11.00(s,1H)。
实施例6
Figure PCTCN2018117269-appb-000092
步骤1
室温下将0.496g 1c(1.54mmol,1eq),0.43g碳酸钾(3.09mmol,2.0eq)以及0.68g碘甲烷(4.82mmol,3.12eq)加入到10mL DMF中，氮气保护后，反应液在70℃条件下搅拌12小时，反应完成后加入30mL水稀释反应液，之后用50mL乙酸乙酯萃取反应液，所得有机相经30mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂后所得残留物经柱层析得6d。 1H NMR(400MHz,DMSO-d 6)δppm 1.25(t,J＝7.09Hz,3H)3.44(s,3H)4.21(q,J＝7.15Hz,2H)7.23-7.39(m,4H)8.66(s,1H)。
步骤2
将0.42g 6d(1.44mmol,1eq)溶于6mL甲醇以及6mL四氢呋喃后加入到0.22g氢氧化锂(1.79mmol,1.24eq)的3mL水溶液中，反应液20℃条件下搅拌1小时，反应完成后浓缩反应液除去大部分乙醇，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)后弃去有机相，水相调pH＝3后用乙酸乙酯萃取(30mL×2)，合并有机相后经40mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得6e。 1H NMR(400MHz,DMSO-d 6)δppm 3.48(s,3H)7.31-7.37(m,4H)8.82(s,1H)。
步骤3
将152mg 6e(569.9μmol,1eq)溶于8mL四氢呋喃，搅拌下先后滴加3μL DMF以及60μL草酰氯.10℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，得粗产物6f，产品未经纯化，直接用于下一步。
步骤4
将160mg 1f1(569.92μmol,1.0eq)溶于8mL四氢呋喃后滴加198μL二异丙基乙胺(2.0eq)，将6f溶于10mL四氢呋喃后滴加至上述溶液，反应液20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，之后加入50mL水稀释反应液，乙酸乙酯萃取(80mL×1)有机相后经1N盐酸(50mL×1)、饱和碳酸钠溶液(30mL×1)及饱和食盐水洗后用无水硫酸钠干燥，浓缩所得即6g。
步骤5
将250mg 6g(473.61μmol,1eq)溶于9mL DMF后加入3mL水，搅拌条件下加入183mg醋酸碘苯(568.3μmol,1.2eq)，反应液15℃条件下搅拌1小时，反应完成后经制备色谱分离(柱型:Boston Green ODS 150*30mm*5μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:27％-54％,10min)即产物实施例6. 1H NMR(400MHz,DMSO-d 6)δppm 3.54(s,3H)5.93(d,J＝5.65Hz,1H)6.42(s,2H)7.27-7.44(m,5H)7.48(dd,J＝8.85,1.07Hz,1H)7.76(d,J＝5.65Hz,1H)7.95(dd,J＝12.92,2.38Hz,1H)8.88(s,1H)11.00(s,1H)。
实施例7
Figure PCTCN2018117269-appb-000093
步骤1
如中间体1d方法得7d。LCMS(ESI)m/z:349.1(M+1)。
步骤2
如中间体1e方法得7e。LCMS(ESI)m/z:605(M+1)。
步骤3
如中间体1f方法得7f。
步骤4
如中间体1g方法得7g。LCMS(ESI)m/z:584.1(M+1)。
步骤5
如实施例1方法得实施例7  1H NMR(400MHz,DMSO-d 6)δppm 2.529(d,J＝1.88Hz,1H)4.292-4.310(d,J＝6.90Hz,2H)4.405-4.437(t,J＝6.27Hz,2H)4.616-4.651(dd,J＝7.91,6.15Hz,2H)5.928-5.941(d,J＝5.52Hz,1H)6.420(s,2H)7.310-7.400(m,5H)7.407-7.417(br d,J＝10.16Hz,1H)7.749(d,J＝5.65Hz,1H)7.763-7.931(m,1H)8.897(s,1H)10.985(s,1H)。
实施例8
Figure PCTCN2018117269-appb-000094
步骤1：如中间体1d方法得8d。 1H NMR(400MHz,DMSO-d 6)δppm 0.90(d,J＝6.72Hz,6H)1.24(t,J＝7.09Hz,3H)1.96-2.07(m,1H)3.71(d,J＝7.21Hz,2H)4.15-4.24(m,2H)7.25-7.33(m,4H)8.59(s,1H)
步骤2：如中间体1e方法得8e。LCMS(ESI)m/z:329.1(M+23)。
步骤3：如中间体1f方法得8f。
步骤4：如中间体1g方法得8g。 1H NMR(400MHz,DMSO-d 6)δppm 0.93(d,J＝6.65Hz,6H)2.05(dquin,J＝13.64,6.85,6.85,6.85,6.85Hz,1H)3.82(d,J＝7.15Hz,2H)6.84(d,J＝5.65Hz,1H)7.32-7.47(m,5H)7.54(dd,J＝9.03,1.25Hz,1H)7.74(s,1H)7.97-8.06(m,2H)8.34(d,J＝5.65Hz,1H)8.81(s,1H)11.05(s,1H)。
步骤5：如实施例1方法得实施例8。 1H NMR(400MHz,DMSO-d 6)δppm 0.92(br d,J＝6.53Hz,6H)2.03(br d,J＝6.40Hz,1H)3.81(br d,J＝7.03Hz,2H)5.93(br d,J＝5.52Hz,1H)6.41(br s,2H)7.25-7.51(m,6H)7.75(d,J＝5.52Hz,1H)7.95(br d,J＝12.67Hz,1H)8.32(br s,1H)8.79(s,1H)11.00(s,1H)。
实施例9
Figure PCTCN2018117269-appb-000095
步骤1
室温下将0.2g 1c(0.78mmol,1eq),0.2g碳酸钾(1.45mmol,2.01eq)以及0.42g 1,1-二氟-2-碘乙烷(2.16mmol,3.0eq)加入到5mL DMF中，氮气保护后，反应液在70℃条件下搅拌12小时，反应完成后加入30mL水稀释反应液，之后用40mL乙酸乙酯萃取反应液，所得有机相经50mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂后得9d。
步骤2
将0.2g 9d(0.58mmol,1eq)溶于6mL乙醇后加入到0.03g氢氧化锂(0.71mmol,1.2eq)的2mL水溶液中，反应液25℃条件下搅拌1小时，反应完成后浓缩反应液除去大部分乙醇，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)后弃去有机相，水相调pH＝3后用乙酸乙酯萃取(30mL×2)，合并有机相后经40mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得9e。 1H NMR(400MHz,DMSO-d 6)δppm 4.36-4.52(m,1H)4.44(td,J＝14.73,3.18Hz,2H)6.14-6.47(m,1H)7.31-7.40(m,4H)8.75(s,1H)。
步骤3
将100mg 9e(31.3μmol,1eq)溶于10mL四氢呋喃，搅拌下先后滴加1μL DMF以及30μL草酰氯，20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，得粗产物9f，产品未经纯化，直接用于下一步。
步骤4
将85mg 1f1(994.07μmol,1.13eq)溶于20mL四氢呋喃后滴加600μL二异丙基乙胺(2.0eq)，将100mg  9f(300μmol,1eq)溶于10mL THF后滴加至上述溶液，反应液20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，之后加入40mL水稀释反应液，乙酸乙酯萃取(80mL×1)，有机相后经饱和氯化铵溶液(40mL×1)、饱和碳酸钠溶液(40mL×1)及饱和食盐水洗后用无水硫酸钠干燥，所得固体即9g。
步骤5
将170mg 9g(294μmol,1eq)溶于3mL DMF后加入1mL水，搅拌条件下加入190mg醋酸碘苯(590μmol,2.0eq)，反应液25℃条件下搅拌1小时，反应完成后经制备色谱分离(柱型:Phenomenex Synergi C18 150*25mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:30％-60％,10min)即产物实施例9. 1H NMR(400MHz,DMSO-d 6)δppm 4.53(td,J＝14.81,3.26Hz,2H)5.94(d,J＝5.77Hz,1H)6.42(s,2H)7.28-7.52(m,7H)7.76(d,J＝5.65Hz,1H)7.95(dd,J＝12.92,2.38Hz,1H)8.86(s,1H)10.92(s,1H)。
实施例10
Figure PCTCN2018117269-appb-000096
步骤1
将0.095g 10c(298μmol,1eq)溶于3mL乙醇后加入到0.050g氢氧化钾(895μmol,3eq)的1mL水溶液中，反应液70℃条件下搅拌24小时，反应完成后浓缩反应液除去大部分乙醇，之后加入15mL水稀释反应液，乙酸乙酯萃取(20mL×1)后弃去有机相，水相调pH＝3后用乙酸乙酯萃取(20mL×2)，合并有机相后经30mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得10e。
步骤2
将85mg 10e(268μmol,1eq)溶于5mL四氢呋喃，搅拌下先后滴加1μL DMF以及29μL草酰氯，20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，得粗产物10f，产品未经纯化，直接用于下一步。
步骤3
将85mg 10f溶于(300μmol,1eq)5mL四氢呋喃后滴加100μL二异丙基乙胺(2.0eq)，将90mg1f产物溶于5mL四氢呋喃后滴加至上述溶液，反应液20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)，有机相后经饱和氯化铵溶液(30mL× 1)、饱和碳酸钠溶液(30mL×1)及饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂后用制备板分离得10g。 1H NMR(400MHz,DMSO-d 6)δppm 1.06-1.16(m,4H)1.97(t,J＝3.51Hz,1H)7.42-7.54(m,4H)7.56-7.64(m,1H)7.64-7.73(m,1H)7.97-8.05(m,2H)8.11(s,2H)8.38(d,J＝5.52Hz,2H)11.05(br s,1H)。
步骤4
将75mg 10g(124μmol,1eq)溶于3mL乙腈以及3mL乙酸乙酯组成的混合溶剂后加入1mL水，搅拌条件下加入80mg醋酸碘苯(248μmol,2.0eq)，反应液20℃条件下搅拌2小时，反应完成后经制备色谱分离(柱型:PhenomenexSynergi C18 150*25mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:18％-38％,10min)即产物实施例10。 1H NMR(400MHz,DMSO-d 6)δppm 0.72-0.85(m,2H)1.04(br s,2H)5.91(d,J＝5.65Hz,1H)6.40(s,2H)7.09-7.28(m,6H)7.74(d,J＝5.65Hz,1H)7.90-7.99(m,1H)8.34(s,2H)12.27(s,1H)。
实施例11
Figure PCTCN2018117269-appb-000097
步骤1
将0.14g 11c(479μmol,1eq)溶于6mL乙醇后加入到0.081g氢氧化钾(1.44mmol,1eq)的2mL水溶液中，反应液80℃条件下搅拌16小时，反应完成后浓缩反应液除去大部分乙醇，之后加入20mL水稀释反应液，乙酸乙酯萃取(30mL×1)后弃去有机相，水相调pH＝3后用乙酸乙酯萃取(30mL×2)，合并有机相后经30mL饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得11e。 1H NMR(400MHz,DMSO-d 6)δppm 2.56(s,3H)7.29-7.45(m,4H)12.30(br s,1H)13.34-13.53(m,1H)。
步骤2
将120mg 11e(446μmol,1eq)溶于5mL四氢呋喃，搅拌下先后滴加1μL DMF以及47μL草酰氯.20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，得油状粗产物11f，产品未经纯化，直接用于下 一步。
步骤3
将150mg 1f1溶于(532μmol,1eq)20mL四氢呋喃后滴加880μL二异丙基乙胺(2.0eq)，将125mg10f产物溶于5mL四氢呋喃后滴加至上述溶液，反应液20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，之后加入30mL水稀释反应液，乙酸乙酯萃取(50mL×1)后弃去有机相，有机相后经饱和氯化铵溶液(30mL×1)、饱和碳酸钠溶液(30mL×1)及饱和食盐水洗后用无水硫酸钠干燥，旋蒸除去溶剂得后用得11g。
步骤4
将180mg 11g(341μmol,1eq)溶于6mLDMF后加入2mL水，搅拌条件下加入220mg醋酸碘苯(683μmol,2.0eq).反应液20℃条件下搅拌0.5小时.反应完成后经制备色谱分离(柱型:Phenomenex Synergi C18 150*25mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:16％-46％,10min)得产物实施例11. 1H NMR(400MHz,DMSO-d 6)δppm 2.47(s,3H)2.65-2.70(m,1H)5.92(d,J＝5.62Hz,1H)6.41(s,2H)7.24-7.43(m,6H)7.75(d,J＝5.62Hz,1H)7.90(dd,J＝13.14,2.38Hz,1H)8.17(s,1H)11.03(s,1H)。
实施例12
Figure PCTCN2018117269-appb-000098
步骤1
将5g 12a(58.8mmol,1eq)溶于200mL THF后加入14.3g劳森试剂(35.3mmol,0.6eq)，反应液 80℃条件下搅拌12小时.反应结束后浓缩除去溶剂，残余物经柱层析(PE:EA＝3:1).后,得产物12b。 1H NMR(400MHz,CDCl 3)δ＝8.47(br s,1H),3.68(t,J＝7.2Hz,2H),2.93(t,J＝8.0Hz,2H),2.24(quin,J＝7.6Hz,2H).
步骤2
将3g 12b(29.65mmol,1eq)溶于10mL四氢呋喃与10mL水的混合溶剂再加入5g碳酸氢钠(2.0eq)以及7.8g溴代丙二酸二乙酯(32.62mmol,1.1eq).反应液60℃条件下搅拌3小时.反应结束后加入30mL水稀释反应液，乙酸乙酯萃取(50mL×2)有机相后经饱和氯化铵溶液(30mL×1)、饱和碳酸钠溶液(30mL×1)及饱和食盐水洗后用无水硫酸钠干燥,旋蒸除去溶剂后残余物经柱层析(PE:EA＝3:1).后,得产物12c。 1H NMR(400MHz,CD 3OD)δ＝4.16(q,J＝7.0Hz,4H),3.63(t,J＝7.3Hz,2H),3.09(t,J＝7.8Hz,2H),2.05(quin,J＝7.6Hz,2H),1.29(t,J＝7.1Hz,6H)。
步骤3
将1g 12c(4.40mmol,1eq)溶于10mL四氢呋喃后再加入1.44g三光气(4.84mmol,1.1eq)。反应液25℃条件下搅拌12小时后加入1.47g对氟苯胺并搅拌0.5小时，水稀释反应液，乙酸乙酯萃取(50mL×2)有机相后经饱和氯化铵溶液(30mL×1)、饱和碳酸钠溶液(30mL×1)及饱和食盐水洗后用无水硫酸钠干燥,旋蒸除去溶剂后残余物经柱层析(PE:EA＝3:1).后,得产物12d。 1H NMR(400MHz,CD 3OD)δ＝7.33-7.18(m,4H),4.60(s,1H),4.37-4.25(m,2H),4.08(t,J＝7.5Hz,2H),3.50(t,J＝7.8Hz,2H),2.25(quin,J＝7.7Hz,2H),1.40-1.31(m,3H)。
步骤4
将0.17g 12d(282μmol,1eq)溶于2mL乙醇后加入到0.03g氢氧化钠(0.75mmol,2.6eq)的2mL水溶液中.反应液80℃条件下搅拌16小时。反应完成后浓缩反应液除去大部分乙醇，之后加入2mL水稀释反应液，乙酸乙酯萃取(2mL×1)后弃去有机相。水相调pH＝3后用乙酸乙酯萃取(10mL×2),合并有机相后经2mL饱和食盐水洗后用无水硫酸钠干燥,旋蒸除去溶剂得12e。 1H NMR(400MHz,CD 3ODδ＝7.42-7.20(m,4H),4.20-4.07(m,2H),3.68(t,J＝7.9Hz,2H),2.37-2.22(m,2H)。
步骤5
将80mg 12e(265μmol,1eq)溶于5mL四氢呋喃，搅拌下先后滴加1μL DMF以及46μL草酰氯.20℃条件下搅拌0.5小时，反应结束后浓缩除去溶剂，得粗产物11f，产品未经纯化，溶于5mL四氢呋喃。之后向溶液中加入75mg 1f1(265μmol,1eq)以及150μL三乙胺(1.06mmol,4eq).反应液25℃条件下搅拌1小时.反应结束后浓缩除去溶剂，之后加入10mL水稀释反应液，乙酸乙酯萃取(20mL×1)后弃去有机相，有机相后经饱和氯化铵溶液(30mL×1)、饱和碳酸钠溶液(30mL×1)及饱和食盐水洗后用无水硫酸钠干燥,旋蒸除去溶剂后残留物用2mL甲醇打浆得12f。 1H NMR(400MHz,DMSO-d6)δ＝11.40(s,1H),8.34(d,J＝5.6Hz,1H),8.14-7.96(m,2H),7.76(s,1H),7.49(br d,J＝7.4Hz,1H),7.42-7.35(m,5H),6.92-6.73(m,1H),4.00(t,J＝7.4Hz,2H),3.64(t,J＝8.0Hz,2H),2.27-2.09(m,2H)。
步骤6
将50mg 12f(87μmol,1eq)溶于0.5mL DMF后加入0.5mL水，搅拌条件下加入56mg醋酸碘苯(173.68μmol,2eq).反应液25℃条件下搅拌1小时.之后加入10mL水稀释反应液，乙酸乙酯萃取(20mL ×1)后弃去有机相，有机相后经饱和氯化铵溶液(30mL×1)、饱和碳酸钠溶液(30mL×1)及饱和食盐水洗后用无水硫酸钠干燥,旋蒸除去溶剂后，残留物经制备色谱(柱型:Phenomenex luna C18250*50mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:10％-40％,33min)纯化得实施例12。 1H NMR(400MHz,DMSO-d6)δ＝11.35(s,1H),7.93(dd,J＝2.4,13.2Hz,1H),7.75(d,J＝5.8Hz,1H),7.47-7.35(m,5H),7.31-7.26(m,1H),6.42(s,2H),5.92(d,J＝5.8Hz,1H),3.99(t,J＝7.4Hz,2H),3.64(t,J＝7.7Hz,2H),2.17(quin,J＝7.7Hz,2H)。
实施例13
Figure PCTCN2018117269-appb-000099
步骤1
将1g 13a(3.55mmol,1eq)和0.01g Pd/C(10％纯度)加入10mL甲醇中，反应液在氢气(1大气压)氛围中于25℃下搅拌12小时，反应完成后将反应液过滤，滤液浓缩后得化合物13b粗品直接用于下一步。
步骤2
将712.21mg 5e(2.34mmol,1eq)溶于5mL DMF，之后向反应体系依次加入1.33g HATU(3.51mmol,1.5eq),710.56mg三乙胺(7.02mmol,977.39μL,3eq)和640mg 13b(2.34mmol,1eq)，反应液在35℃下搅拌3小时，反应结束后反应液加入10mL水后过滤，收集滤饼干燥后得化合物13c粗品直接用于下一步。
步骤3
将200mg 13c(374.90μmol,1eq)溶于5mL DMF，向反应体系依次加入144.90mg醋酸碘苯(449.87 μmol,1.2eq)和97.98mg吗菲啉(1.12mmol,98.97μL,3eq).反应液在35℃下搅拌24小时。反应完成后将反应液过滤，滤液减压浓缩，残渣经制备色谱分离(柱型:Phenomenex luna C18 250*50mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:25％-55％,30min)得实施例13。 1H NMR(400MHz,DMSO-d6)δppm 0.44(br d,J＝4.89Hz,2H),0.57(br d,J＝8.19Hz,2H),1.24(br s,1H),3.54(br d,J＝5.26Hz,4H),3.60(br s,2H),3.86(br d,J＝7.09Hz,4H),6.63(br d,J＝3.42Hz,1H),7.28-7.33(m,1H),7.43(br d,J＝5.01Hz,2H),7.50(br d,J＝8.56Hz,1H),7.98(br d,J＝12.84Hz,1H),8.13(d,J＝5.99Hz,1H),8.12-8.14(m,1H),8.44(br s,2H),8.92(s,1H),9.30(s,1H),11.02(s,1H)。
实施例14
Figure PCTCN2018117269-appb-000100
步骤1
将200mg 14a(200mg,530.05μmol,1eq)和44.20mg NH 2OH.HCl(636.06μmol,1.2eq)溶于4mL乙醇和2mL水，向反应液中加入52.18mg醋酸钠(636.06μmol,1.2eq)。反应液在15℃下搅拌0.5小时后加热至70℃搅拌0.5小时。反应完成后减压浓缩除去乙醇后加入10mL水稀释，乙酸乙酯萃取(15mL×3，合并有机相经饱和食盐水(10mL)洗涤后用无水硫酸钠干燥，过滤，滤液减压浓缩后得14b粗品直接用于下一步反应。
步骤2
将200mg 14b(509.76μmol,1eq)溶于5mL二氯甲烷，0℃搅拌下向反应体系中加入128.96mg三乙胺(1.27mmol,2.5eq)和267.66mg三氟乙酸酐(1.27mmol,2.5eq)，反应液在0℃条件下搅拌1.5小时。反应完成后向反应液中加入6mL饱和碳酸氢钠溶液淬灭，减压浓缩除去溶剂。向残渣加入10mL水稀释用乙酸乙酯萃取(15mL×3)，合并有机相经饱和食盐水(10mL)洗涤后加入无水硫酸钠干燥，过滤，减压浓缩后残留物即14c粗品直接用于下一步反应。步骤3
将160mg 14c(316.30μmol,1eq)溶于5mL甲醇，向反应体系中加入67.32mg Pd/C(10％纯度，63.26μmol,0.2eq)，反应液在氢气氛围(1大气压)于15℃条件下搅拌1小时，反应完成后过滤除去催化剂，滤液减压浓缩，残留物经柱层析纯化后得化合物14d。
步骤4
15℃时将40mg 14d(102.22μmol,1eq).58mg和30mg 5e(102.22μmol,1eq)溶于5mL DMF中，向反应体系中依次加入31.03mg三乙胺(306.67μmol,3eq)和58.30mg HATU(153.34μmol,1.5eq)，反应液15C下搅拌0.5小时后加热至40C搅拌1小时，反应结束后向反应液中加入10mL水，过滤，所得固体用水洗涤、干燥后经制备薄层色谱纯化后得14e。
步骤5
将40mg 14e(52.65μmol,1eq)溶于2mL二氯甲烷，0℃条件下向反应液中加入0.67mL三氟乙酸，反应体系在15℃条件下搅拌2小时，反应完成后向反应液中加入2mL氨水淬灭，之后加入5mL水稀释，反应液经二氯甲烷萃取(8mL×3)，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用制备色谱分离(柱型:Phenomenex Synergi C18 150*30mm*4μm；流动相:[A：水(0.225％FA)-ACN]；B％:40％-70％,10min)得实施例14  1H NMR(400MHz,DMSO-d 6)δppm 0.44(br d,J＝4.77Hz,2H)0.56(br d,J＝7.58Hz,2H)1.24(br d,J＝6.24Hz,1H)3.86(br d,J＝7.09Hz,2H)5.89(d,J＝6.11Hz,1H)7.06(s,2H)7.33-7.51(m,6H)7.96-8.05(m,2H)8.91(s,1H)11.02(s,1H)。
实施例15
Figure PCTCN2018117269-appb-000101
Figure PCTCN2018117269-appb-000102
步骤1
将10g 15a(63.65mmol,1eq)溶于100mL甲醇，向反应体系中加入1g Pd/C(10％纯度)，反应液在氢气氛围(50psi)中于25℃下搅拌12小时，反应结束后反应液过滤，滤液减压蒸馏除去溶剂后得15b粗品直接用于下一步。
步骤2
将4.94g 15c(25.86mmol,1eq)溶于50mL DMF向反应体系中依次加入4.35g叔丁醇钾(38.79mmol,1.5eq)和4.1g 15b(29.74mmol,1.15eq)，反应液在55℃条件下搅拌3小时。反应结束后，向反应体系中加入150mL水后用乙酸乙酯(100mL*2)萃取，合并有机相依次用无水硫酸钠干燥后过滤滤液减压蒸馏除去溶剂后得15d粗品直接用于下一步。
步骤3
将7g 15d(23.71mmol,1eq)溶于100mL甲醇，向反应体系中加入0.2g Pd/C(10％purity)，反应液在氢气氛围(15psi)中于35℃下搅拌12小时，反应结束后反应液过滤，滤液减压蒸馏后除去溶剂后得15e粗品直接用于下一步。
步骤4
将3.4g 15e(13.75mmol,1eq)和5.05g 5e(16.50mmol,1.2eq)溶于50mL DMF中，向反应体系依次加入7.84g HATU(20.63mmol,1.5eq)和4.17g三乙胺(41.26mmol,3eq)，反应液25℃下搅拌3小时，反应结束后向反应液加入40mL水，过滤，滤饼干燥后经甲醇(10mL)打浆后所得固体经干燥即15f。
步骤5
将6.1g 15f(11.43mmol,1eq)溶于60mL DMF中，向反应体系依次加入后加入3.68g醋酸碘苯(11.43mmol,1eq)和10mL水。反应液30℃条件下搅拌3小时.反应结束向反应液加入50mL水，乙酸乙酯萃取(150mL×2)，合并有机相饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残渣经乙醇(20mL)打浆，所得固体干燥后即15g。
步骤6
将1g 15g(1.98mmol,1eq)溶于10mL二氯甲烷，向反应体系中依次加入600.57mg三乙胺(5.94mmol,3eq)和371.69mg 15i(2.37mmol,1.2eq),。反应液在20℃条件下搅拌1小时。反应液减压除去溶剂得15h粗品直接用于下一步。
步骤7
将1.3g 15h(2.08mmol,1eq)溶于15mL二氯甲烷，向反应体系中加入1.05g 15j 10.39mmol,5eq)，反应液在20℃条件下搅拌下1小时，反应结束后反应液减压浓缩，残渣经制备色谱分离(柱型:Phenomenex Synergi C18 150*25*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:27％-57％,10min)后得实施例15。1H NMR(400MHz,DMSO-d6)δppm 0.44(q,J＝4.77Hz,2H),0.52-0.63(m,2H),1.18-1.37(m,3H),1.62-1.77(m,2H),2.97-3.08(m,2H),3.64(br s,1H),3.74-3.82(m,2H),3.86(d,J＝7.09Hz,2H),4.72(br s,1H),6.59(dd,J＝5.75,2.32Hz,1H),7.30-7.34(m,1H),7.34-7.39(m,3H),7.40-7.46(m,2H),7.46-7.51(m,1H),7.96(dd,J＝12.84,2.32Hz,1H),8.09-8.16(m,1H),8.90(s,1H),9.16(s,1H),11.00(s,1H)。
实施例16
Figure PCTCN2018117269-appb-000103
步骤1
将100mg 15g(197.83μmol,1eq)溶于1mL二氯甲烷，之后向反应体系中依次加入30.03mg三乙胺(296.75μmol,1.5eq)以及30.97mg 15i(197.83μmol,1eq)，反应液在20℃条件下搅拌1小时,得到产物15h的二氯甲烷溶液直接用于下一步。
步骤2
向步骤1所得反应液中加入60μL氨水，反应液在20℃下搅拌下反应24小时，反应结束后向反应液中分别加入10mL水和10mL二氯甲烷并搅拌5分钟，分液，有机相经饱和食盐水(10mL*2)洗涤后用无水硫酸钠干燥，过滤后减压除去溶剂，残渣经制备色谱分离(柱型:Phenomenex Synergi C18150*25mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:25％-55％,10min)后得实施例16。1H NMR(400MHz,DMSO-d6)δppm 0.44(br s,2H)0.56(br d,J＝6.60Hz,1H)1.25(br s,1H)3.86(br d,J＝5.99Hz,2H)6.54(br s,1H)6.98(br s,1H)7.36(br t,J＝8.62Hz,3H)7.41-7.53(m,3H)7.97(br d,J＝11.74Hz,1H)8.07(br d,J＝4.77Hz,1H)8.91(s,1H)9.09(br s,1H)11.01(br s,1H)。
实施例17
Figure PCTCN2018117269-appb-000104
步骤1
将200mg 15g(395.67μmol,1eq)溶于2mL二氯甲烷，之后向反应体系中依次加入120mg三乙胺(1.19mmol,3eq)以及74.34mg 15i(474.80μmol,1.2eq)，反应液在10℃条件下搅拌2小时。之后减压除去溶剂即得15h，粗品未经纯化直接用于下一步。
步骤2
将240mg 15h(383.65μmol,1eq)溶于3mL二氯甲烷后向反应体系中加入959μL二甲胺(2M四氢呋喃溶液，5eq)，反应液在20℃下搅拌下1小时，反应结束后减压除去溶剂，残渣经制备色谱分离(柱型:Phenomenex luna C18 250*50mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:35％-65％,20min,50％min)后得实施例17。1H NMR(400MHz,DMSO-d6)δppm 0.39-0.50(m,2H),0.52-0.61(m,2H),1.22-1.30(m,1H),2.89(s,6H),3.87(d,J＝7.21Hz,2H),6.60(dd,J＝5.69,2.38Hz,1H),7.29-7.34(m,1H),7.34-7.39(m,2H),7.40(d,J＝2.20Hz,1H),7.42-7.47(m,2H),7.49(dd,J＝8.93,1.34Hz,1H),7.97(dd,J＝12.90,2.38Hz,1H),8.12(d,J＝5.62Hz,1H),8.87(s,1H),8.91(s,1H),11.00(s,1H)。
实施例18
Figure PCTCN2018117269-appb-000105
步骤1
将0.2g 15g(395.67μmol,1eq)溶于2mL二氯甲烷，之后向反应体系中依次加入80.08mg三乙胺(791.34μmol,2eq)以及92.92mg 15i(474.80μmol,1.5eq)，反应液在20℃条件下搅拌2小时。之后 减压除去溶剂即得15h，粗品未经纯化直接用于下一步。
步骤2
将250mg 15h(399.63μmol,1eq)溶于3mL二氯甲烷后向反应体系中加入112.16mg氮杂环丁烷盐酸盐(1.20mmol，3eq)，反应液在20℃下搅拌下16小时，反应结束后减压除去溶剂，残渣经制备色谱分离(柱型:Phenomenex luna C18 250*50mm*10μm；流动相:[A：水(0.05％HCl)，B：ACN]；B％:25ACN％-55ACN％,27min)后得实施例18。1H NMR(400MHz,DMSO-d6)δppm 11.04(s,1H),9.68(br d,J＝2.3Hz,1H),8.91(s,1H),8.19(d,J＝6.4Hz,1H),8.01(dd,J＝2.3,12.8Hz,1H),7.54(dd,J＝1.4,8.9Hz,1H),7.47-7.33(m,3H),7.24-7.16(m,1H),6.86(br d,J＝5.5Hz,1H),3.99(br s,2H),3.86(d,J＝7.1Hz,2H),2.28-2.13(m,2H),1.30-1.21(m,1H),0.64-0.52(m,2H),0.48-0.38(m,2H)。
实施例19
Figure PCTCN2018117269-appb-000106
步骤1
将200mg实施例5(395.67μmol,1eq)溶于2mL四氢呋喃后向反应体系中依次加入153.14mg N,N-二异丙基乙胺(1.19mmol，3eq)和37.27mg乙酰氯(474.80μmol,1.2eq)，反应液在20℃下搅拌下2小时，反应结束后减压除去溶剂，残渣经制备色谱分离(柱型:Phenomenex luna C18 150*25 10μm；流动相:[A：(0.225％FA)，B：ACN]；B％:36％-66％,7.8min)后得实施例19。1H NMR(400MHz,DMSO-d6)δppm 0.44(br d,J＝3.67Hz,2H)0.52-0.60(m,2H)1.24(br d,J＝7.09Hz,1H)2.03(s,3H)3.86(d,J＝7.09Hz,2H)6.68(dd,J＝5.62,2.32Hz,1H)7.31-7.39(m,3H)7.44(dd,J＝8.80,5.14Hz,2H)7.50(br d,J＝11.25Hz,1H)7.65(s,1H)7.97(dd,J＝12.78,2.38Hz,1H)8.18(d,J＝5.62Hz,1H)8.91(s,1H)10.56(s,1H)11.01(s,1H)。
实施例20
Figure PCTCN2018117269-appb-000107
步骤1
将555mg 15g(960.24μmol,1eq)溶于6mL二氯甲烷，之后向反应体系中依次加入291.50mg三乙胺(2.88mmol,3eq)以及225.51mg 15i(1.44mmol,1.5eq)，反应液在25℃条件下搅拌2小时。得到产物15h的二氯甲烷溶液直接用于下一步。
步骤2
向步骤1所得反应液中加入341.07mg吡咯烷(4.80mmol，5eq)，反应液在25℃下搅拌下12小时，反应结束后减压除去溶剂，残渣经制备色谱分离(柱型:Phenomenex luna C18 150*25mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:26％-56％,7.8min)后得实施例20。1H NMR(400MHz,DMSO-d6)δppm 0.48-0.38(m,2H)0.39-0.48(m,2H)0.53-0.61(m,2H)1.20-1.31(m,1H)1.80(br s,4H)3.36-3.38(m,4H)3.86(d,J＝7.09Hz,2H)6.60(dd,J＝5.75,2.45Hz,1H)7.29-7.39(m,3H)7.41-7.51(m,4H)7.96(dd,J＝12.90,2.38Hz,1H)8.11(d,J＝5.75Hz,1H)8.67(s,1H)8.90(s,1H)11.00(s,1H)。
实施例21
Figure PCTCN2018117269-appb-000108
步骤1
室温下将20g 21a(181.63mmol,1eq)溶于200mL乙腈中，之后依次加入25.10g碳酸钾(181.63mmol,1eq)和32g 21b(201.14mmol,22.22mL,1.11eq)，反应液在50℃下搅拌16小时，反应完成后将反应液倾倒入600mL水中，搅拌2小时后过滤，收集滤饼干燥后得产物21c。 1HNMR(400MHz,DMSO-d 6)δppm 6.00(d,J＝2.32Hz,1H)6.10(s,2H)6.26(dd,J＝5.75,2.32Hz,1H)7.45-7.59(m,1H)7.90(d,J＝5.75Hz,1H)8.11-8.24(m,1H)8.39(dd,J＝10.45,2.75Hz,1H)。
步骤2
2g 21c(7.84mmol,1eq)和3.04g二异丙基乙胺(23.52mmol,4.10mL,3eq)溶于20mL四氢呋喃中，0℃下加入1.88g氯甲酸苯酯(12.01mmol,1.50mL,1.53eq)，反应液在0℃条件下搅拌3.5小时，反应完成后得21d的反应液直接用于下一步。
步骤3
向步骤2的反应液中加入1.64g 21e(16.03mmol,2.08mL,2eq)，反应液室温下搅拌16小时，反应完成后向反应液加入80mL乙酸乙酯稀释，经饱和食盐水(80mL*3)洗涤后收集有机相，无水硫酸钠干燥， 过滤，滤液减压浓缩，残渣经制备色谱分离(柱型:Phenomenex Synergi Max-RP 250*50mm*10um；流动相:[water(0.225％FA)-ACN]；B％:0％-30％,30MIN,70％min)后得产物21f。
步骤4
室温下将1g 21f(2.65mmol,1eq)溶于20mL乙醇和4mL水中，氮气保护后，加入739.92mg铁粉(13.52mmol,5eq)和708.74mg氯化铵(13.25mmol,5eq)，反应液在30℃下搅拌16小时，反应完成后过滤，收集滤液减压浓缩除去溶剂，残余物加入饱和碳酸钠溶液调节pH至11，加入30mL饱和食盐水稀释后经乙酸乙酯(30mL*3)萃取，收集有机相经无水硫酸钠干燥，过滤，减压浓缩后得产物21g，粗品未经纯化直接用于下一步。
步骤5
室温下将875.89mg 5e(2.88mmol,1eq)，1.31g HATU(3.45mmol,1.2eq)和1.12g二异丙基乙胺(8.64mmol,1.50mL,3eq)溶于10mL DMF中，搅拌0.5小时后加入1g 21g(2.88mmol,1eq)，反应液室温下搅拌15.5小时，反应完成后反应液加入50mL饱和食盐水稀释，经乙酸乙酯(50mL*3)萃取，收集有机相经无水硫酸钠干燥，过滤，滤液减压浓缩后残渣经制备色谱分离(柱型:Phenomenex Synergi Max-RP250*50mm*10μm；流动相:[A：水(0.225％FA)，B：ACN]；B％:10％-40％,35min)得产物实施例21。 1HNMR(400MHz,DMSO-d 6)δppm 11.01(s,1H),10.57-9.58(m,1H),8.91(s,1H),8.10(s,1H),7.97(br d,J＝13.0Hz,1H),7.51-7.30(m,7H),6.65-6.51(m,1H),3.87(br d,J＝7.0Hz,3H),2.89(s,4H),2.57(br s,2H),2.33(s,6H),1.34-1.14(m,1H),0.64-0.51(m,2H),0.49-0.33(m,2H)。
实施例22
Figure PCTCN2018117269-appb-000109
Figure PCTCN2018117269-appb-000110
步骤1
如中间体1d方法得22b。
步骤2
如中间体1e方法得22c。 1H NMR(400MHz,DMSO-d 6)δppm 12.70-12.29(m,1H),8.67(s,1H),7.43-7.27(m,4H),4.15-4.07(m,2H),3.66-3.58(m,2H),3.53-3.47(m,2H),1.12(t,J＝7.0Hz,3H)。
步骤3
室温下将500mg 22c(1.55mmol,1eq)，707.87mg HATU(1.86mmol,1.2eq)和601.53mg二异丙基乙胺(4.65mmol,0.81mL,3eq)溶于10mL DMF中，搅拌0.5小时后加入400mg 1f1(1.42mmol,0.92eq)，反应液室温下搅拌2小时，反应完成后反应液加入100mL乙酸乙酯稀释，经饱和氯化铵(60mL*3)和饱和食盐水(100mL*3)洗涤，收集有机相经无水硫酸钠干燥，过滤，滤液减压浓缩后得产物22d，粗品未经纯化直接用于下一步。
步骤4
如实施例1方法得实施例22。 1H NMR(400MHz,DMSO-d 6)δppm 10.97(s,1H),8.75(s,1H),8.02-7.88(m,1H),7.81-7.69(m,1H),7.49-7.28(m,6H),6.41(s,2H),5.98-5.90(m,1H),4.23-4.08(m,2H),3.65(t,J＝5.0Hz,2H),3.52(d,J＝7.0Hz,2H),1.13(t,J＝7.0Hz,3H)。
实施例23
Figure PCTCN2018117269-appb-000111
Figure PCTCN2018117269-appb-000112
步骤1
如中间体1d方法得23b。
步骤2
如中间体1e方法得23c。 1H NMR(400MHz,DMSO-d 6)δppm 12.78-12.37(m,1H),8.68(s,1H),7.41-7.30(m,4H),4.10-4.02(m,2H),3.67-3.57(m,3H),1.11-1.07(m,6H)。
步骤3
如中间体22d方法得23d。
步骤4
如实施例1方法得实施例23。 1H NMR(400MHz,DMSO-d 6)δppm 11.07-10.87(m,1H),8.77(s,1H),8.04-7.86(m,1H),7.82-7.70(m,1H),7.36(s,6H),6.41(s,2H),5.98-5.89(m,1H),4.21-4.06(m,2H),3.69-3.61(m,3H),1.11(d,J＝6.1Hz,6H))。
实施例24
Figure PCTCN2018117269-appb-000113
Figure PCTCN2018117269-appb-000114
步骤1
如中间体1d方法得24b。
步骤2
如中间体1e方法得24c。
步骤3
如中间体22d方法得24d。
步骤4
如实施例1方法得实施例24。 1H NMR(400MHz,DMSO-d 6)δppm 0.94(t,J＝7.03Hz,6H)2.64(s,2H)4.03(br t,J＝5.50Hz,2H)5.93(d,J＝5.75Hz,1H)6.41(s,2H)7.24-7.34(m,1H)7.38(d,J＝6.72Hz,4H)7.48(br d,J＝8.68Hz,1H)7.76(d,J＝5.62Hz,1H)7.95(dd,J＝12.90,2.02Hz,1H)8.28(s,1H)8.76(s,1H)10.97(s,1H)。
实验例1:c-MET酶结合活性实验
试剂和耗材:
反应缓冲液：20mM Hepes(pH 7.5)，10mM MgCl 2，1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na 3VO 4,2mM DTT,1％DMSO以及相应辅助因子
化合物配制：
将受试化合物用100％DMSO溶解至0.33μM，使用全自动微孔板预处理系统ECHO进行3倍稀释，10个浓度梯度.
反应操作：
1)将底物溶于新制缓冲液
2)在上述缓冲液中加入所需辅助因子
3)将酶加入上述溶液中，混合均匀
4)加入受试样品溶液，室温下孵育20min
5)将 33P-ATP加入反应液液中，之后室温孵育2小时
6)检测放射信号
7)用GraphPad Prism软件分析结果
实验结果:见表1。
结论：本发明化合物对c-MET/AXL酶有较强的抑制活性。
表1
化合物 AXL IC 50(nM) c-MET IC 50(nM)
实施例1 2.07 2.17
实施例2 2.64 1.76
实施例4 17.7 2.89
实施例5 2.51 2.51
实施例6 4.6 16.9
实施例7 2.06 3.77
实施例9 3.11 12.4
实施例11 3.11 1.43
实施例12 3.18 7.18
实施例13 6.69 7.35
实施例14 3.52 4.79
实施例15 3.74 4.05
实施例16 3.81 9.35
实施例17 4.41 2.01
实施例18 5.59 1.44
实施例21 1.07 14.63
实施例22 43.99 13.36
实施例23 5 26.15
实施例24 19.03 59.26
实验例2:细胞增殖的抑制效应测试
试剂和耗材:
1.细胞培养：DMEM培养基、胎牛血清、DPBS
2.细胞系：MKN45胃癌细胞系
3.检测试剂：活细胞检测试剂盒CellTiter-Glo
4.其他主要耗材及试剂：化合物稀释板，中间板，检测板，DMSO
实验原理:
ATP的含量直接反应了细胞的数量及细胞状态，通过对ATP进行定量测定可以检测活细胞的数目。活细胞检测试剂盒含有萤光素酶及其底物，通过ATP的参与，荧光素酶可以催化底物，发出稳定的光学信号，通过检测信号的强度来测定细胞中ATP的数量。其中光信号和细胞中ATP量成正比，而ATP又和活细胞数正相关，从而可以检测出细胞的增殖情况。检测板使用PE公司的Envision进行分析。实验方法:
1.制备细胞板
将MKN45细胞分别种于384孔板中，每孔包含200个细胞。细胞板置于二氧化碳培养箱中过夜培养。
2.准备化合物
用Echo进行5倍稀释，9个化合物浓度，设置双复孔实验。
3.化合物处理细胞
将化合物转移到细胞板中，化合物起始浓度为10μM。细胞板置于二氧化碳培养箱中培养3天。
4.检测
向细胞板中加入Promega CellTiter-Glo试剂，室温孵育10分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数。
实验结果:见表2。
结论：本发明化合物对MKN45细胞显示出较好的抑制活性。
表2
待测化合物 MKN45细胞IC 50(nM)
BMS777607 436
实施例1 54
实施例2 78
实施例3 27
实施例5 11
实施例8 374
实施例9 365
实施例11 240
实施例12 315
实施例13 38
实施例14 30
实施例15 12.6
实施例16 50.7
实施例17 7.64
实施例18 12.1
实施例19 41
实施例20 29.1
实验例3:MKN45胃癌细胞皮下异种移植肿瘤模型的药效实验
细胞培养：
MKN45细胞体外单层培养，培养条件为RPMI1640培养基中加10％热灭活胎牛血清、1％青霉素-链霉素双抗，37℃，5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞呈指数生长期时，收取细胞，计数，接种。
动物：
BALB/c裸小鼠，雄性。6－8周龄，体重18-22克。
肿瘤接种：
将0.2ml含5×10 ^6个MKN45细胞悬液皮下接种于每只小鼠的右后背。肿瘤平均体积达到约160mm 3时开始分组给药。
实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效(TGI)用T-C(天)和T/C(％)评价。
实验结果:见表3。
结论：本发明化合物在MKN45胃癌细胞皮下异种移植肿瘤模型的药效实验中显示比BMS777607更好的肿瘤抑制作用。
表3受试药物对人胃癌细胞异种移植瘤模型的抑瘤药效评价
(基于给药后第14天肿瘤体积计算得出)
Figure PCTCN2018117269-appb-000115
注：
a.平均值±SEM。
b.p值根据肿瘤体积计算。
实验例4:Hs746t胃癌细胞皮下异种移植肿瘤模型的药效实验
细胞培养：
人胃癌Hs746t细胞体外单层培养，培养条件为DMEM培养基中加10％胎牛血清，100U/mL青霉素和100U/mLL链霉素，37℃，5％CO 2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当 细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。
动物：
BALB/c裸小鼠，雄性。6－8周龄，体重18-22克。
肿瘤接种：
将0.2mL(20.2 6个，细胞：Matrigel＝1:1)HS 746T细胞皮下接种于每只小鼠的右后背，肿瘤平均体积达到约100-150mm 3时开始分组给药。
实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效(TGI)用T-C(天)和T/C(％)评价。
实验结果:见表4。
结论：在Hs746t胃癌细胞皮下异种移植肿瘤模型的药效实验中，本发明实施例17在1.5mpk剂量下起效；在同等4.5mpk剂量下，实施例5和实施例17显示比BMS777607和LY2801653更好的肿瘤抑制作用；在9mpk剂量下，本发明化合物实施例5和实施例17消除肿瘤。本发明化合物具有良好的肿瘤抑制活性。
表4受试药物对人Hs746t胃癌细胞异种移植瘤模型的抑瘤药效评价
(基于给药后第21天肿瘤体积计算得出)
Figure PCTCN2018117269-appb-000116
注：
a.平均值±SEM。

Claims (21)

  1. 式(IV)所示化合物或其药学上可接受的盐，
    Figure PCTCN2018117269-appb-100001
    其中，
    R 1选自H、卤素和C 1-6烷基；
    R 2选自H、NH 2、C 1-6烷基、C 1-6杂烷基、C 2-6烯基、C 3-6环烷基和3-6元杂环烷基，其中，所述C 1-6烷基、C 1-6杂烷基、C 2-6烯基和3-6元杂环烷基任选被1、2或3个R取代；
    R 3选自H、C 1-4烷基和C 3-6环烷基，所述C 1-4烷基和C 3-6环烷基任选被1、2或3个R’取代；
    或者R 2和R 3连接形成一个5-6元饱和杂环，其中，所述5-6元饱和杂环任选被1、2或3个R取代；
    R 4选自H、CN、卤素、C 1-4烷基、C 1-4杂烷基、C 3-6环烷基、3-6元杂环烷基和5-6元杂芳基；
    R 5和R 6分别独立地选自H、NH 2、C 1-6烷基、C 1-6杂烷基、C 3-6环烷基和3-6元杂环烷基，所述C 1-6烷基、C 1-6杂烷基、C 3-6环烷基和3-6元杂环烷基任选被1、2或3个R取代；
    L 1和L 2分别独立地选自单键和-C(＝O)-；
    R分别独立地选自F、Cl、Br、I、OH、CN、NH 2、C 1-4烷基、C 1-4杂烷基、C 3-6环烷基和3-6元杂环烷基，其中，所述C 1-4烷基、C 1-4杂烷基、C 3-6环烷基和3-6元杂环烷基任选被1、2或3个R’取代；
    R’选自F、Cl、Br、I、OH、CN、NH 2、CH 3、CF 3、CHF 2、CH 3O、CH 3CH 2、CH 3CH 2O、COOH、NH(CH 3)、NH(CH 3) 2、
    Figure PCTCN2018117269-appb-100002
    所述C 1-6杂烷基、3-6元杂环烷基、5-6元饱和杂环、C 1-4杂烷基和5-6元杂芳基分别独立地包含1、2或者3个选自N、-NH-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝O)NH-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-、-C(＝NH)-、-S(＝O) 2NH-、-S(＝O)NH-、和-NHC(＝O)NH-的杂原子或杂原子团。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R选自F、Cl、Br、I、OH、CN、NH 2、CH 3、CF 3、CHF 2、CH 3O、CH 3CH 2、CH 3CH 2O、COOH、NH(CH 3)、N(CH 3) 2、
    Figure PCTCN2018117269-appb-100003
    Figure PCTCN2018117269-appb-100004
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 1选自H。
  4. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 2选自H、NH 2、C 1-4烷基、C 1-4杂烷基和C 2-4烯基，所述C 1-4烷基、C 1-4杂烷基和C 2-4烯基任选被1、2或3个R取代。
  5. 根据权利要求4所述的化合物或其药学上可接受的盐，其中，R 2选自H、NH 2、CH 3、CH 3CH 2、
    Figure PCTCN2018117269-appb-100005
    Figure PCTCN2018117269-appb-100006
    所述CH 3、CH 3CH 2、
    Figure PCTCN2018117269-appb-100007
    任选被1、2或3个R取代。
  6. 根据权利要求5所述的化合物或其药学上可接受的盐，其中，R 2选自H、CH 3、
    Figure PCTCN2018117269-appb-100008
    Figure PCTCN2018117269-appb-100009
  7. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 3选自H、C 1-3烷基和C 3-4环烷基，所述C1-3烷基和C3-4环烷基任选被1、2或3个R’取代。
  8. 根据权利要求7所述的化合物或其药学上可接受的盐，其中，R 3选自H、CH 3、CH 3CH 2和
    Figure PCTCN2018117269-appb-100010
  9. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 4选自H、Cl和CN。
  10. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 5和R 6分别独立地选自H、NH 2、CH 3、CH 3CH 2、
    Figure PCTCN2018117269-appb-100011
    Figure PCTCN2018117269-appb-100012
    所述CH 3、CH 3CH 2、
    Figure PCTCN2018117269-appb-100013
    Figure PCTCN2018117269-appb-100014
    任选被1、2或3个R取代。
  11. 根据权利要求10所述的化合物或其药学上可接受的盐，其中，R 5和R 6分别独立地选自H、NH 2、
    Figure PCTCN2018117269-appb-100015
  12. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018117269-appb-100016
    选自
    Figure PCTCN2018117269-appb-100017
  13. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018117269-appb-100018
    选自
    Figure PCTCN2018117269-appb-100019
  14. 根据权利要求1～3、7～11、13任意一项所述的化合物或其药学上可接受的盐，化合物选自
    Figure PCTCN2018117269-appb-100020
    其中，R 3选自C 1-4烷基和C 3-6环烷基，L 1、L 2、R 1、R 4、R 5和R 6如权利要求1～3、7～11、13任意一项所定义。
  15. 根据权利要求1～6、9～11、13任意一项所述的化合物或其药学上可接受的盐，化合物选自
    Figure PCTCN2018117269-appb-100021
    其中，
    L 1和L 2如权利要求1所定义；
    R 1如权利要求1或3所定义；
    R 2选自NH 2、C 1-6烷基、C 1-6杂烷基和C 2-6烯基，所述C 1-6烷基、C 1-6杂烷基、C 2-6烯基任选被1、2或3个R取代；
    R 4如权利要求1或9所定义；
    R 5和R 6如权利要求1、10或11所定义；
    R如权利要求1或2所定义。
  16. 根据权利要求15所述的化合物或其药学上可接受的盐，化合物选自
    Figure PCTCN2018117269-appb-100022
    其中，L 1、L 2、R 1、R 4、R 5和R 6如权利要求15所定义。
  17. 根据权利要求16所述的化合物或其药学上可接受的盐，化合物选自
    Figure PCTCN2018117269-appb-100023
    其中，R 1、R 4和R 5如权利要求16所定义。
  18. 化合物或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2018117269-appb-100024
    Figure PCTCN2018117269-appb-100025
    Figure PCTCN2018117269-appb-100026
  19. 一种药物组合物，包含治疗有效量的根据权利要求1-18任意一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体。
  20. 根据权利要求1-18任意一项所述的化合物或其药学上可接受的盐或者权利要求19所述的组合物在制备c-MET/AXL抑制药物中的应用。
  21. 根据权利要求20所述的应用，其中，c-MET/AXL抑制药物是治疗肿瘤药物。
PCT/CN2018/117269 2017-11-24 2018-11-23 作为c-MET/AXL抑制剂的尿嘧啶类化合物 Ceased WO2019101178A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2020528451A JP7377798B2 (ja) 2017-11-24 2018-11-23 ｃ－ＭＥＴ／ＡＸＬ阻害剤としてのウラシル系化合物
CN201880075156.2A CN111372925B (zh) 2017-11-24 2018-11-23 作为c-MET/AXL抑制剂的尿嘧啶类化合物
EP18880588.1A EP3719012B1 (en) 2017-11-24 2018-11-23 N-[4-[(2-amino-4-pyridinyl)oxy]-3-fluorophenyl]-3-(4-fluorophenyl)-1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidinecarboxamide derivatives as c-met/axl inhibitors for the treatment of tumors
US16/766,510 US11623923B2 (en) 2017-11-24 2018-11-23 Uracil compound as c-MET/AXL inhibitor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201711190571 2017-11-24
CN201711190571.6 2017-11-24
CN201811159913 2018-09-30
CN201811159913.2 2018-09-30

Publications (1)

Publication Number Publication Date
WO2019101178A1 true WO2019101178A1 (zh) 2019-05-31

Family

ID=66630504

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/117269 Ceased WO2019101178A1 (zh) 2017-11-24 2018-11-23 作为c-MET/AXL抑制剂的尿嘧啶类化合物

Country Status (5)

Country Link
US (1) US11623923B2 (zh)
EP (1) EP3719012B1 (zh)
JP (1) JP7377798B2 (zh)
CN (1) CN111372925B (zh)
WO (1) WO2019101178A1 (zh)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019213340A1 (en) * 2018-05-03 2019-11-07 Bristol-Myers Squibb Company Uracil derivatives as mer-axl inhibitors
CN110563697A (zh) * 2019-03-27 2019-12-13 江西科技师范大学 2-吡啶甲酰胺类化合物的制备及应用
WO2020238802A1 (zh) * 2019-05-24 2020-12-03 南京明德新药研发有限公司 一种c-MET/AXL抑制剂的晶型
CN112457295A (zh) * 2019-09-06 2021-03-09 中国科学院上海药物研究所 具有Axl与c-Met激酶抑制活性的化合物及其制备和应用
US11104676B2 (en) 2018-08-30 2021-08-31 Array Biopharma Inc. Pyrazolo[3,4-b]pyridine compounds as inhibitors of TAM and MET kinases
JP2022533440A (ja) * 2019-05-24 2022-07-22 メッドシャイン ディスカバリー インコーポレイテッド ｃ－ＭＥＴ／ＡＸＬ阻害剤の結晶形
EP4011885A4 (en) * 2019-08-02 2023-01-18 Wellmarker Bio Co., Ltd. CONDENSED CYCLE OXO-PYRIDINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING THEM
CN116283920A (zh) * 2023-03-31 2023-06-23 贵州医科大学 2,4-二取代吡啶类化合物及其应用
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020038460A1 (zh) * 2018-08-24 2020-02-27 南京药捷安康生物科技有限公司 一种新型的喹啉衍生物抑制剂
JPWO2023286719A1 (zh) * 2021-07-13 2023-01-19
IT202100022682A1 (it) * 2021-09-01 2023-03-01 Luigi Frati Derivati pirimidinici e loro uso nel trattamento di tumori
CN114573553B (zh) * 2022-01-27 2023-11-10 广州六顺生物科技有限公司 杂芳环类衍生物及其制备方法和应用
US12421207B2 (en) * 2022-02-16 2025-09-23 Cmg Pharmaceutical Co., Ltd. Pyrimidinedione-based compounds as AXL, c-MET, and Mer inhibitors and methods of use thereof
WO2024134516A1 (ko) * 2022-12-23 2024-06-27 주식회사 엘지화학 Ron 억제제로서 신규한 화합물
KR20240101432A (ko) * 2022-12-23 2024-07-02 주식회사 엘지화학 Ron 억제제로서 신규한 화합물

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006010264A1 (en) 2004-07-30 2006-02-02 Methylgene, Inc. Inhibitors of vegf receptor and hgf receptor signaling
US20080114033A1 (en) 2006-11-08 2008-05-15 Bristol-Myers Squibb Company Pyridinone compounds
WO2009006959A1 (de) 2007-07-12 2009-01-15 Merck Patent Gmbh Pyridazinonderivate
US20090094427A1 (en) 2007-10-05 2009-04-09 Takanori Sano Capacity expansion control method for storage system
US20100022529A1 (en) 2008-07-24 2010-01-28 Tiechao Li Amidophenoxyindazoles useful as inhibitors of c-met
US20110183983A1 (en) 2008-10-14 2011-07-28 Neopharm Co., Ltd. Heterocyclic compound as protein kinase inhibitor
WO2013074633A1 (en) * 2011-11-14 2013-05-23 Cephalon, Inc. Uracil derivatives as axl and c-met kinase inhibitors
CN106543145A (zh) * 2016-10-28 2017-03-29 山西医科大学 c‑Met激酶抑剂3‑(4‑氟苯基)嘧啶酮‑5‑甲酸酰胺衍生物、制备方法与应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2680886B1 (en) 2011-02-28 2016-08-10 Calitor Sciences, LLC Substituted quinoline compounds
DK3087070T3 (en) 2013-12-26 2017-12-04 Ignyta Inc PYRAZOLO [1,5-A] PYRIDINE DERIVATIVES AND PROCEDURES FOR THEIR USE
US9718841B2 (en) 2014-04-22 2017-08-01 Calitor Sciences, Llc Bicyclic pyrazolone compounds and methods of use
US12037323B2 (en) * 2018-05-03 2024-07-16 Bristol-Myers Squibb Company Uracil derivatives as Mer-AXL inhibitors

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006010264A1 (en) 2004-07-30 2006-02-02 Methylgene, Inc. Inhibitors of vegf receptor and hgf receptor signaling
US20080114033A1 (en) 2006-11-08 2008-05-15 Bristol-Myers Squibb Company Pyridinone compounds
WO2009006959A1 (de) 2007-07-12 2009-01-15 Merck Patent Gmbh Pyridazinonderivate
US20090094427A1 (en) 2007-10-05 2009-04-09 Takanori Sano Capacity expansion control method for storage system
US20100022529A1 (en) 2008-07-24 2010-01-28 Tiechao Li Amidophenoxyindazoles useful as inhibitors of c-met
US20110183983A1 (en) 2008-10-14 2011-07-28 Neopharm Co., Ltd. Heterocyclic compound as protein kinase inhibitor
WO2013074633A1 (en) * 2011-11-14 2013-05-23 Cephalon, Inc. Uracil derivatives as axl and c-met kinase inhibitors
CN106543145A (zh) * 2016-10-28 2017-03-29 山西医科大学 c‑Met激酶抑剂3‑(4‑氟苯基)嘧啶酮‑5‑甲酸酰胺衍生物、制备方法与应用

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12037323B2 (en) 2018-05-03 2024-07-16 Bristol-Myers Squibb Company Uracil derivatives as Mer-AXL inhibitors
WO2019213340A1 (en) * 2018-05-03 2019-11-07 Bristol-Myers Squibb Company Uracil derivatives as mer-axl inhibitors
US11104676B2 (en) 2018-08-30 2021-08-31 Array Biopharma Inc. Pyrazolo[3,4-b]pyridine compounds as inhibitors of TAM and MET kinases
US11780835B2 (en) 2018-08-30 2023-10-10 Array Biopharma Inc. Pyrazolo[3,4-b]pyridine compounds as inhibitors of TAM and MET kinases
CN110563697A (zh) * 2019-03-27 2019-12-13 江西科技师范大学 2-吡啶甲酰胺类化合物的制备及应用
JP2022533440A (ja) * 2019-05-24 2022-07-22 メッドシャイン ディスカバリー インコーポレイテッド ｃ－ＭＥＴ／ＡＸＬ阻害剤の結晶形
WO2020238802A1 (zh) * 2019-05-24 2020-12-03 南京明德新药研发有限公司 一种c-MET/AXL抑制剂的晶型
JP7293404B2 (ja) 2019-05-24 2023-06-19 メッドシャイン ディスカバリー インコーポレイテッド ｃ－ＭＥＴ／ＡＸＬ阻害剤の結晶形
EP4011885A4 (en) * 2019-08-02 2023-01-18 Wellmarker Bio Co., Ltd. CONDENSED CYCLE OXO-PYRIDINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING THEM
CN116283916B (zh) * 2019-09-06 2024-06-11 中国科学院上海药物研究所 具有Axl与c-Met激酶抑制活性的化合物及其制备和应用
JP7542613B2 (ja) 2019-09-06 2024-08-30 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズ Ａｘｌとｃ－Ｍｅｔキナーゼ阻害活性を有する化合物およびその製造と使用
CN112457295B (zh) * 2019-09-06 2022-07-26 中国科学院上海药物研究所 具有Axl与c-Met激酶抑制活性的化合物及其制备和应用
CN116283916A (zh) * 2019-09-06 2023-06-23 中国科学院上海药物研究所 具有Axl与c-Met激酶抑制活性的化合物及其制备和应用
US12479850B2 (en) 2019-09-06 2025-11-25 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Compound having Axl and c-Met kinase inhibitory activity, preparation thereof and application thereof
CN112457295A (zh) * 2019-09-06 2021-03-09 中国科学院上海药物研究所 具有Axl与c-Met激酶抑制活性的化合物及其制备和应用
KR102826937B1 (ko) * 2019-09-06 2025-07-01 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 Axl 및 c-Met 키나아제 억제 활성을 갖는 화합물 및 이의 제조와 응용
KR20220058931A (ko) * 2019-09-06 2022-05-10 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 Axl 및 c-Met 키나아제 억제 활성을 갖는 화합물 및 이의 제조와 응용
WO2021043217A1 (zh) * 2019-09-06 2021-03-11 中国科学院上海药物研究所 具有Axl与c-Met激酶抑制活性的化合物及其制备和应用
JP2022547915A (ja) * 2019-09-06 2022-11-16 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズ Ａｘｌとｃ－Ｍｅｔキナーゼ阻害活性を有する化合物およびその製造と使用
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
CN116283920B (zh) * 2023-03-31 2024-04-16 贵州医科大学 2,4-二取代吡啶类化合物及其应用
CN116283920A (zh) * 2023-03-31 2023-06-23 贵州医科大学 2,4-二取代吡啶类化合物及其应用
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder

Also Published As

Publication number Publication date
EP3719012A4 (en) 2021-08-04
EP3719012A1 (en) 2020-10-07
JP7377798B2 (ja) 2023-11-10
CN111372925A (zh) 2020-07-03
EP3719012B1 (en) 2024-03-06
JP2021504367A (ja) 2021-02-15
US11623923B2 (en) 2023-04-11
US20210371395A1 (en) 2021-12-02
CN111372925B (zh) 2022-09-02

Similar Documents

Publication Publication Date Title
CN111372925B (zh) 作为c-MET/AXL抑制剂的尿嘧啶类化合物
CN113121530B (zh) 作为krasg12c突变蛋白抑制剂的吡啶酮并嘧啶类衍生物
CN110944989B (zh) 作为egfr激酶抑制剂的芳基磷氧化合物
CN111683928B (zh) 作为fgfr抑制剂的吡嗪-2(1h)-酮类化合物
WO2018184590A1 (zh) 作为A 2A受体抑制剂的[1,2,4]三唑并[1,5-c]嘧啶衍生物
EP3470409B1 (en) Benzotriazole-derived alpha and beta-unsaturated amide compound used as tgf-beta ri inhibitor
WO2018108064A1 (zh) 作为第四代egfr激酶抑制剂的螺环芳基磷氧化合物
WO2019085933A1 (zh) 作为Wee1抑制剂的大环类化合物及其应用
CN109661395B (zh) Pde4抑制剂
WO2018233696A1 (zh) 作为mek抑制剂的类香豆素环类化合物及其应用
JP6836693B2 (ja) Ａ２ａ受容体アンタゴニストとしての縮合環誘導体
WO2019062637A1 (zh) 喹啉衍生物及其作为酪氨酸激酶抑制剂的应用
WO2018192493A1 (zh) 作为pcsk9抑制剂的哌啶类化合物
WO2019228404A1 (zh) 一种新型磷酸肌醇3-激酶抑制剂及其制备方法和用途
WO2019134662A1 (zh) 作为csf-1r抑制剂的杂环化合物及其应用
WO2021197467A1 (zh) 多靶点的抗肿瘤化合物及其制备方法和应用
WO2018036470A1 (zh) 作为pde4抑制剂的并环类化合物
WO2019091492A1 (zh) 用作iap抑制剂的smac模拟物及其用途
WO2017215588A1 (zh) 作为Akt抑制剂的二氢吡唑氮杂卓类化合物
HK40038950A (zh) 用於肿瘤治疗的作为c-met/axl抑制剂的n-[4-[(2-氨基-4-吡啶基)氧基]-3-氟苯基]-3-(4-氟苯基)-1，2，3，4-四氢-2，4-二氧代-5-嘧啶羧酰胺衍生物
HK40038950B (zh) 用於肿瘤治疗的作为c-met/axl抑制剂的n-[4-[(2-氨基-4-吡啶基)氧基]-3-氟苯基]-3-(4-氟苯基)-1，2，3，4-四氢-2，4-二氧代-5-嘧啶羧酰胺衍生物
HK40000494A (zh) 作为TGF-βR1抑制剂的苯并三氮唑衍生的α，β不饱和酰胺类化合物
HK40000494B (zh) 作为TGF-βR1抑制剂的苯并三氮唑衍生的α，β不饱和酰胺类化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18880588

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2020528451

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018880588

Country of ref document: EP

Effective date: 20200624