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WO2009109071A1 - Imidazopyridine compounds - Google Patents

Imidazopyridine compounds Download PDF

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Publication number
WO2009109071A1
WO2009109071A1 PCT/CN2008/000517 CN2008000517W WO2009109071A1 WO 2009109071 A1 WO2009109071 A1 WO 2009109071A1 CN 2008000517 W CN2008000517 W CN 2008000517W WO 2009109071 A1 WO2009109071 A1 WO 2009109071A1
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WIPO (PCT)
Prior art keywords
substituted
group
fluorenyl
alkyl
phenyl
Prior art date
Application number
PCT/CN2008/000517
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French (fr)
Chinese (zh)
Inventor
张嘉杰
王广发
伍小云
吴少瑜
刘中秋
万山河
庞建新
徐伟
游文玮
吴曙光
Original Assignee
南方医科大学
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Publication of WO2009109071A1 publication Critical patent/WO2009109071A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Protein kinases are a class of phosphotransferases that act to transfer the Y phosphate group of ATP to a specific amino acid residue of a substrate to phosphorylate the protein. Protein kinase plays a major role in signal transduction in two ways: First, phosphorylation regulates protein activity, phosphorylation and dephosphorylation are common mechanisms for reversible activation of most signaling pathway components, and some proteins are phosphorylated. After the activity, some are active after dephosphorylation; the second is through the phosphorylation of the protein, the signal is amplified step by step, causing cell reaction.
  • protein kinase activity is not only directly related to tumors, but also lead to a range of other human diseases associated with inflammation or proliferative responses, such as rheumatoid arthritis, cardiovascular and neurological diseases, asthma, psoriasis. The main reason for waiting. More than 400 human diseases are known to be directly or indirectly related to protein kinases. This makes protein kinases another important class of drug targets following G-protein coupled receptors.
  • the protein kinase family consists of more than 500 members and is usually classified into protein tyrosine kinases (PTKs) and serine-threonine kinases.
  • Receptor kinases are generally tyrosine kinases, also known as receptor tyrosine kinases (RTKs), which are composed of a receptor moiety, a transmembrane region, and an intracellular portion of the cell membrane surface. The kinase moiety is located within the cell. Serine - threonine kinase majority located intracellularly, or is a non-receptor kinases called cytoplasmic kinase (cytosolic kinases) 0
  • a typical representative of the RTKs family is growth factor receptors, which have at least 19 subfamilies. Here are a few major subfamilies:
  • HER family tyrosine receptor kinases including EGFR (epithelial growth factor receptor) ⁇ HER2, HER3 and HER4.
  • EGFR epidermal growth factor receptor
  • HER2 epidermal growth factor receptor
  • HER3 epidermal growth factor receptor
  • EGFR epidermal growth factor receptor
  • IGF-1R insulin-like growth factor I receptor
  • IRR insulin receptor-associated receptors
  • the PDGFRs family including PDGFRc PDGFRp, CSF1R, c_kit, and c-fms.
  • One of the members is the molecular target of the leukemia treatment Gleevec®.
  • VEGFRs vascular endothelial growth factor receptors
  • FLT1 Fms-like tyrosine kinase 1 or VEGFR1
  • KDR or VEGFR-2
  • FLT4 or VEGFR3
  • Avastin® is the molecular target of the colorectal cancer treatment drug Avastin®.
  • FGFRs Family of fibroblast growth factor receptors (FGFRs), including FGFR1, FGFR2, FGFR3 and FGFR4 and seven ligands FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7.
  • FGFRs fibroblast growth factor receptors
  • FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7 members of the drug as molecular targets are still in clinical trials.
  • MET family including c-Met or human hepatocyte growth factor receptor or hHGFR and RON.
  • c-Met plays an important role in the growth and metastasis of initial tumors. Its drug as a molecular target is still in clinical trials.
  • the activity of protein kinases is associated with many diseases in humans and is a drug target for the treatment of these diseases.
  • receptor kinases there are many kinds of receptor kinases, and it is necessary to constantly seek new drugs.
  • imidazopyridines are a wide variety of compounds that are widely used in medicine, and there are many kinds of imidazoles which inhibit the activity of protein kinases (such as VEGFR2, FLT3, c-KIT, CSF1R, etc.).
  • a pyridine compound such as an imidazole as a PAF/Hi antagonist, described in an invention patent entitled "Imidazopyridine PAF/H, Antagonist” (CN1064275), which was issued by the National Science and Technology Bureau on September 9, 1992.
  • a pyridine compound for treating allergic inflammation the molecular structure of which is shown in the following formula;
  • Imidazopyridine as a cell cycle-dependent kinase inhibitor described in the patent application of the "New imidazopyridine as a cell cycle-dependent kinase inhibitor" disclosed by the National Patent Office on November 30, 2005 a compound for controlling diseases associated with cell cycle-dependent kinases, such as various cancers, tumors, and leukemias, the molecular structure of which is shown below;
  • the molecular structure of the novel imidazopyridine compound provided by the present invention is as shown in Formula I,
  • R1 and R2 are independent, respectively:
  • R3 means:
  • fluorenyl substituted fluorenyl group a 3-12 membered saturated or partially saturated heterocyclic substituted fluorenyl group, a 3-12 membered saturated or partially saturated heterocyclic substituted Cm fluorenyl substituted fluorenyl group, Cw 2 a mercapto-substituted fluorenyl-substituted fluorenyl group, d.
  • (9) a 3-12 membered saturated or partially saturated heterocyclic group, a 12 fluorenyl substituted 3-12 membered saturated or partially saturated heterocyclic group, an amino group, a hydroxy group, a cyano group, a halogen, a nitro group, a carboxy group or a fluorenyl group substituted d.
  • 12 alkoxy substituted 3-12 membered saturated or partially saturated heterocyclic group d 12 alkyl substituted amino substituted d.
  • Q 2 is alkyl with a substituted amino group substituted alkylsulfinyl _ 12 alkyl with a substituted 3-12-membered saturated or Partially saturated heterocyclyl, Q). 12 alkyl substituted aminosulfonyl group substituted with a d. 12 alkyl substituted 3-12 membered saturated or partially saturated heterocyclic group, Q). 12 embankment substituted ureas substituted .
  • X represents oxygen, sulfur, N-CN, or N-N0 2 ;
  • Ar and Ar' are each independently and represent an aryl or heteroaryl group, and 1 to 4 hydrogens on the aromatic ring or heteroaryl ring may be substituted by R3, aryl or heteroaryl.
  • the compounds of the present invention also include racemates and enantiomers of the structure of formula I.
  • R1 in the compound represents hydrogen
  • R2 represents an amino group.
  • R1 in the compound represents an amino group
  • R2 represents hydrogen.
  • X in the compound represents oxygen.
  • Ar and Ar' in the compound are a benzene ring, a pyridine, a pyridone, a tetrahydropyridone, an acetidine, a pyrazine, a pyridazine, an imidazole, a thiazole, a thiophene, a furan, Any one of hydrazine, azaindene, benzimidazole, porphyrin or fluorenone, and 1 to 4 hydrogens on the benzene ring or heterocyclic ring may be substituted by R3, aryl or heteroaryl.
  • R1 in the compound represents hydrogen or an amino group
  • R2 represents hydrogen or an amino group
  • X represents oxygen
  • Ar represents a benzene ring
  • Ar' represents a benzene ring or is 1 or 2 identical or different groups.
  • a group-substituted benzene ring the group being a halogen, a methyl group, a methoxy group, a halogen-substituted methyl group or a halogen-substituted methoxy group; the compound described in the present scheme may be further selected from any one of Table 1. .
  • the compound of the present invention is a 1-aminoimidazo[1, 5-a] pyridine compound, the compound The chemical synthesis method is as shown in the following formula II.
  • compound 11 is equivalent to a compound when R1 in formula I is an amino group.
  • Compound 1 is reduced to a primary amine containing 2 with a reducing agent in an organic solvent;
  • the organic solvent is methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, Ether, propyl ether, toluene, benzene, xylene, tetrahydrofuran, acetonitrile, 1,2-dimethoxyacetamidine, etc.
  • the reducing agent is hydrogen, lithium tetrahydrogenate, sodium borohydride, diisobutylaluminum hydride, Red aluminum, etc.;
  • the agent is hydrogen, lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, red aluminum or the like.
  • the starting material in the above reaction that is, the compound 1 is R3 substituted 3-bromo-2-cyanopyridine, is commercially available.
  • the compound of the present invention is a 3-aminoimidazo[1,5-a] pyridine compound, and the chemical synthesis method of the compound is as shown in Formula III. .
  • the starting material a in the above reaction is R3 substituted 2-bromo-6-formylpyridine, which is commercially available; the starting materials a and b are subjected to metal-catalyzed coupling reaction to obtain compound c; c is reductively aminated to obtain compound b.
  • VEGFR2 vascular endothelial growth factor receptor 2
  • FLT3 tyrosine kinase 3
  • c-Kit human stem cell factor receptor
  • for the preparation of drugs for the treatment of diseases caused by abnormal increase in VEGFR2, FLT3 and c-Kit activity, such as cancer, psoriasis, cirrhosis, diabetes Eye diseases such as AMD, rheumatoid arthritis and other inflammations, immune system diseases (such as autoimmune diseases), cardiovascular diseases (such as atherosclerosis) and kidney diseases.
  • the compounds of the present invention are useful for treating diseases caused by abnormalities in the activity of VEGFR2, FLT3 and c-kit,
  • the effective dose is 0.1 to 100 mg per kilogram of body weight per day, and the optimized dose is 1 to 70 mg per kilogram of body weight per day; the frequency of administration depends on different diseases, usually 1 to 4 times per day, preferably 2 to 3 times.
  • the medicament for treating diseases caused by abnormal activity of VEGFR2, FLT3 and c-kit of the present invention mainly consists of the compound of the present invention and a pharmaceutically acceptable adjuvant, and may also contain other auxiliary drugs, such as antibacterial agents, One or more of an antifungal agent, an antimicrobial agent, a vitamin, an antitumor drug, and the like, the compound of the present invention may be present in the drug by the following means:
  • a pharmaceutically acceptable salt that is, a salt formed by reacting a compound of the present invention with a medically acceptable acid or base, and the acid may be an inorganic acid or an organic acid such as hydrochloric acid or hydrobromic acid.
  • a solvate that is, a stable substance formed by covalent bond, ionic bond, hydrogen bond, van der Waals force, complexation, inclusion, and the like of the compound of the present invention and a pharmaceutically-usual solvent
  • the solvent may be Is methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, etc.;
  • a prodrug that is, a compound of the present invention is converted into another compound by chemical synthesis or physical means, and when the compound is administered to a mammal, it is converted into a compound of the invention in its body.
  • the "prodrug” method is usually used to overcome the poor or poor physicochemical properties or drug-forming properties of the drug compound itself.
  • the compounds of the present invention may also exist in their tautomeric form (Tautomers), rotamers (rotamers), cis and trans isomers and the like, these concepts can be in J. March in "Advanced Organic Chemistry," 4 th edition Found and understood.
  • these isomers have the same effect of inhibiting protein kinase activity as the compounds of the present invention, these isomers are also encompassed by the present invention.
  • the compound of the present invention is administered to a mammal such as a human, it is highly known in the art that it is metabolized into various metabolites by different enzymes in the animal as long as these metabolites have the same properties as the compounds of the present invention.
  • the effect of inhibiting protein kinase activity, these metabolites are also encompassed by the present invention.
  • the medicament of the present invention can be administered orally, for example, into tablets, capsules, syrups, gels, pills, oral liquids, etc.; and can also be administered by injection, such as preparation into sterile solutions, suspensions, emulsions. Etc.; can also be administered by anal plug, such as preparation of a suppository, gel, etc.; can also be administered by inhalation through the nostrils, such as preparation into a spray, an aerosol, and the like.
  • the packaging and preservation of the medicament of the invention are similar to those of a general western medicine.
  • the solid dosage form of the medicine can be directly loaded into a glass, a plastic, a paper or a metal bottle, and a desiccant or the like is preferably placed in the bottle to maintain the quality of the drug;
  • the dosage form of the drug is generally contained in a glass, plastic or metal bottle or hose;
  • the aerosol type drug is generally contained in a metal or plastic container with a pressure-resistant device such as a pressure reducing valve.
  • Mercapto refers to a straight chain, branched chain, and cyclic hydrocarbon group having the specified number of carbon atoms.
  • c 1-12 fluorenyl refers to a straight chain, branched chain having a minimum of 1 and a maximum of 12 carbon atoms.
  • C. Represents a covalent chemical bond.
  • the fluorenyl group in the present invention includes, but is not limited to, methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, isopropyl, neopentyl, 2-methyl-1-hexyl and the like.
  • One or all of the hydrogen atoms in the fluorenyl group may be substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, decyl, oxy (OXO) and the like.
  • oxiranyloxy group in the present invention includes, but is not limited to, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a cyclopentyloxy group, a cyclohexyloxy group, an isopropoxy group, a neopentyloxy group, a 2-methyl group. Ke-1-hexyloxy and the like.
  • One or all of the hydrogen atoms in the alkoxy group may be substituted by the following groups: halogen, amino, hydroxy, cyano, nitro, carboxy, decyl, oxy (0X0) and the like.
  • Halogen means fluoro, chloro, bromo, iodo.
  • the "3-12 membered saturated or partially saturated heterocyclic group” means a monocyclic or polycyclic fluorenyl group composed of 3 to 12 atoms, wherein at least one of the atoms is 0, N, S, S0, S0 2 , P or Si.
  • these monocyclic or polycyclic fluorenyl groups may contain double or triple bonds, but do not constitute all conjugated aromatic structures.
  • These monocyclic or polycyclic fluorenyl groups may exist in the form of fused rings, bridged rings or spiro rings.
  • the 3-12 membered saturated or partially saturated heterocyclic group in the present invention includes, but is not limited to, piperidine, morpholine, piperazine, pyrrolidine, porphyrin, tetrahydropyridine, tetrahydrofuran, tropinol, etc., as shown in Table 2.
  • One or all of the hydrogen atoms in the heterocyclic group may be substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, decyl, oxy (0X0) and the like.
  • Aryl means a monocyclic or polycyclic structure consisting of 5 to 12 carbon atoms, at least one of which has a conjugated aromatic structure (i.e., conforms to the N+2 rule), but the entire structure does not have to be fully conjugated.
  • the aryl group may also be present in the form of a subunit, i.e., two points of attachment to other groups in the conjugated aromatic structure.
  • the aryl group in the present invention includes, but is not limited to, a phenyl group, a naphthyl group, an anthracenyl group, an indanyl group, a tetrahydronaphthalene or the like.
  • One or all of the hydrogen atoms in the aryl group may be substituted with a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a decyl group, an oxy group (OXO) or the like.
  • Heteroaryl means a monocyclic or polycyclic structure consisting of 5-12 atoms, wherein at least one atom is 0, N, S, S0, S0 2 , P or Si, and at least one ring has a conjugation
  • the aromatic structure ie conforms to the N+2 rule, but the entire structure does not have to be fully conjugated.
  • Heteroaryl groups can also occur in the form of subunits, that is, two points of attachment to other groups in the conjugated aromatic structure.
  • Heteroaryl groups in the present invention include, but are not limited to, pyridine, pyridone, tetrahydropyridone, imidazine, pyrazine, pyridazine, imidazole, thiazole, thiophene, furan, anthraquinone, azaindole, benzimidazole, Porphyrin, anthrone, quinone, etc., as shown in Table 3; one or all of the hydrogen atoms in the aryl group may be substituted by the following groups: halogen, amino, hydroxy, cyano, nitro, carboxy, fluorenyl, Oxyl (OXO) and the like.
  • High performance liquid chromatography was performed using a Waters 2695 Z0RBAX high performance liquid chromatograph (Bx_C 8 5 ⁇ 150 x 4. 6 mm column).
  • the melting point was determined using an Electrothermal digital melting point apparatus IA9100 and was uncorrected.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • the results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) ⁇ 8.39 (d, IH), 7.74 (s, IH), 7.54 (d, 2H), 7.43 (d, 2H), 7.27 - 7.40 (m, 3H), 6.60-6.72 (m, 2H), 2.32 (s, 3H).
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • (6) Preparation of the final product l-[4-(l-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-bromophenyl)urea: 4 -(1 -Nitroimidazole [1, 5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 2-bromophenylisocyanate (386 mg, 2 mmol). After 5 hours, the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Steps (1) to (5) are the same as in Example 1.
  • Acetic acid (480 mg, 8 mmol) and EDC.HC1 (1.917 g, 10 mmol) were suspended in DCM (20 mL) and diisopropylethylamine (2.585 g, 20 mmol) was added dropwise with stirring After the addition was completed, the mixture was stirred at room temperature for half an hour, (3 - bromopyridin-2-yl)methylamine hydrochloride (0. 894 g, 4 mmol) was added and stirring was continued for 2 hr. The solvent was removed by rotary evaporation and the residue was applied to silica gel column .
  • Phosphorus oxychloride (1 mL) was added to a solution of (3-bromopyridin-2-yl)methylacetamide (0. 687 g, 3 mmol) in toluene (4 mL). The mixture was refluxed for 7 hours. Excess phosphorus oxychloride and solvent were removed by rotary evaporation, and the resulting viscous liquid was hydrolyzed with ice water at 0 ° C and basified with concentrated aqueous ammonia. The aqueous phase was extracted with EtOAc (EtOAc)EtOAc.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (5) are the same as in Example 24.
  • Steps (1) to (4) are the same as in Example 30;
  • Steps (1) to (4) are the same as in Example 30;
  • Steps (1) to (4) are the same as in Example 30;
  • Steps (1) to (4) are the same as in Example 30;
  • Step (1:) ⁇ (4) is the same as in Example 30;
  • Steps (1) to (4) are the same as in Example 30;
  • the concentration of the peptide substrate (Biotin-Ahx-AEEEYFFLFA-amide) is 4 ⁇ , and the concentration of adenosine triphosphate (ATP) is 1 mM, the corresponding kinase and urea compound inhibitor was reacted in the following solution for 1 hour at room temperature: 50 mM Hepes/NaOH H 7. 5, 10 mM MgCl 2 , 2 mM MnCl 2 , 2. 5 mM DTT, 0.1 mM orthovanadate, and 0.
  • the inhibitor of the present invention was added to the wells of a 96-well plate at a final concentration of 3.2 nM to 50 ⁇ M with 5% DMS0 as a co-solvent.
  • the reaction was stopped by the following method: 10 ⁇ M per well of 0.5 M EDTA, followed by containing streptavidin-allophycocyanin (prozyme; 1. 1 g/mL and PT66 antibody europium cryptate (Ci s-Bio; 0.1 g/mL) Plate reading method: After adding the detection reagent for 1-4 hours, the fluorescence was measured with a Packard Discovery instrument (the ratio of 665 to 615). The detected signal-to-noise ratio is between 10 and 15.
  • the semi-inhibitory concentration is at least two tests.
  • the average value of the biochemical semi-inhibitory concentrations (IC 5 ) of VEGFR, FLT3, and c-KIT of the compounds obtained in Examples 1 to 38 are shown in Table 4.
  • Example 11 Compound 8 23 15
  • Example 12 Compound 370 43 79
  • the compounds of the present invention have a good inhibitory effect on VEGFR, FLT3, c-KIT, and the biochemical half-inhibitory concentration (IC 5 ) is mostly less than 100 ⁇ , wherein 1- [4- (1-amino) Imidazole [l,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea, 1-[4-(1-aminoimidazole[1, 5- a]pyridin-8-yl)phenyl]-3-(4-fluoro-3-methylphenyl)urea, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8 -yl)phenyl]-3-(3-fluorophenyl)urea, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3 -Methylphenyl)urea, 1-[4-(1-aminoimidazo[1,5
  • the target compound 1_[4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl]-3-(2-fluoride) of Example 32 was compared with the model group. After the administration of 5-methylphenyl)urea, the medium- and high-dose oral administration had a significant inhibitory effect on the subcutaneous transplantation of human colon cancer Colo205 cells in BALB/c nude mice, and the tumor inhibition rate was 11.8% and 16.
  • tumor volume they were randomly divided into model group, high (20 mg/kg), medium (10 mg/kg), and low dose group (5 mg/kg), with 8 rats in each group, half male and half female. It was administered by intragastric administration for 12 consecutive days. The long and short diameters of the tumor were measured on the 4th, 7th, and 12th day after administration, and the tumor volume and tumor inhibition rate were calculated.
  • Tumor volume /6 (long diameter short diameter 2).
  • Tumor inhibition rate (average volume of the model group - average volume of the administration group) / average volume of the model group X 100%.
  • the target compound of Example 2 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-), was compared with the model group. 4 days after the administration of fluoro-5-methylphenyl) urea, medium and high doses of oral administration of human gastric cancer HS-746T cells BALB/c nude mice subcutaneously transplanted tumors have a significant inhibitory effect, the tumor inhibition rate was 11.
  • Example 1 Dropping pills (dosage: 25 mg/granule) [Formulation prescription]
  • Example 2 target compound 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl] 3-(2-Fluoro-5-methylphenyl)urea 2. 5g
  • a total of 100 capsules were prepared, each containing 25 rag of the compound.
  • [Preparation method] Weigh the compound 2. 5 g, 5 ml of absolute ethanol (37 ° C), and set aside. Another PGE6000 was dissolved in a water bath at 80 ° C, mixed with PEG400, and stirred. Insulation, slowly add the prepared compound ethanol solution, stir while stirring, make it fully mixed and have no alcohol flavor, add glycerin, filter with gauze while hot, place in a storage bottle, keep warm at 80 °C, use the inside of the tube , the outer diameter of 9. 0mm, 9.
  • Example 2 Dropping pills (dosage: 50 mg/granule) [Formulation prescription]
  • Example 2 target compound 1 - [4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl] -3 - (2-Fluoro-5-methylphenyl)urea 5g
  • a total of 100 capsules were prepared, each containing 50 mg of the compound.
  • the dropping speed is 40 drops / min, dripping into the liquid paraffin (the outer layer is ice water bath) in the cooling liquid, condensing into pellets, sucking off the paper with burrs Attached liquid paraffin, that is, (every 0. 2g), quality inspection, packaging, that is.
  • Example 3 Tablet (dosage: 25 mg/tablet)
  • Example 2 target compound 1- [4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl] -3 - (2-Fluoro-5-methylphenyl)urea 2. 5 g
  • a total of 100 tablets were prepared, each containing 25 mg of the compound.
  • [Preparation method] Weigh the compound 2. 5g, ball milled into a very fine powder, and set aside. Take PVP water bath heating (80 ⁇ ) to dissolve, add the prepared compound fine powder, stir the hook, then add microcrystalline cellulose, wheat starch, add appropriate amount of anhydrous ethanol to soft material, use 14 mesh sieve to make granules, set 70- After drying at 80 ° C, the granules were sieved on a 12-mesh sieve, and talc powder was added thereto, and the tablets were granulated (0.25 g/tablet), and quality inspection was obtained.
  • Example 4 Tablet (dosage: 50 mg/tablet) [Formulation Formulation]
  • Example 2 target compound 1- [4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl] -3 - (2-Fluoro-5-methylphenyl)urea 5g
  • a total of 100 tablets were prepared, each containing 50 n) g of the compound.
  • [Preparation method] 5 g of the compound was weighed and ball-milled into a very fine powder for use. Take PVP water bath heating (80 ° C) to dissolve, add the prepared compound fine powder, stir well, then add microcrystalline cellulose, wheat starch, add appropriate amount of anhydrous ethanol to soft material, use 14 mesh sieve to make the grain, set After drying at 70-80 ° C, the granules were sieved on a 12-mesh sieve, and talc powder was added, and the tablets were compressed (0.3 g/tablet). Check, that is.
  • Example 2 target compound 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl) Urea 2.5 g
  • a total of 100 capsules of hard capsules were prepared, each containing 25 mg of the compound.
  • [Preparation method] Take the compound into a fine powder, pass through a 80 mesh sieve, and set aside; take a 10% starch slurry and add a small amount of edible orange (maximum dosage is one ten thousandth) to make a yellow paste; After mixing the wheat starch, add yellow paste, make soft material, granulate through 14 mesh nylon sieve, dry at 70 °C to below 3% of water, fill it into empty capsule after whole grain, get (5 capsules, each capsule 0.1 g), quality inspection, packaging, that is.
  • Example 6 Capsule [prescription]
  • Example 2 target compound 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea 5 g wheat Starch 19g

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Abstract

The present invention provides imidazopyridines of formula (I). The compounds show inhibitory activity against protein kinase, especially VEGFR2, FLT3, and C-KIT receptors and so on, and can be used for the preparation of the medicament for treating diseases associated with abnormal high level of kinase activity, such as cancer.

Description

一种咪唑并吡啶类化合物 技术领域  Imidazopyridine compound
本发明涉及有机化学领域, 具体涉及咪唑并吡啶类化合物。 背景技术 蛋白激酶是一类磷酸转移酶, 其作用是将 ATP 的 Y磷酸基转移到底物特定的氨基 酸残基上, 使蛋白质磷酸化。 蛋白激酶在信号转导中主要作用有两个方面: 其一是通过 磷酸化调节蛋白质的活性,磷酸化和去磷酸化是绝大多数信号通路组分可逆激活的共同 机制, 有些蛋白质在磷酸化后具有活性, 有些则在去磷酸化后具有活性; 其二是通过蛋 白质的逐级磷酸化, 使信号逐级放大, 引起细胞反应。 已有研究表明, 蛋白激酶活性的 异常不仅与肿瘤直接相关, 也是导致一系列其他与炎症或增殖反应有关的人类疾病,例 如类风湿性关节炎、 心血管和神经系统疾病、 哮喘、 银屑病等的主要原因。 目前已知有 四百多种人类疾病与蛋白激酶直接或间接相关。 这使得蛋白激酶成为继 G -蛋白偶联受 体之后的另一大类重要的药物靶标。 蛋白激酶大家庭有 500 多个成员组成, 通常可分为蛋白酪氨酸激酶(protein tyrosine kinases or PTKs)及丝氣酸-苏氨酸激酶 (serine- threonine kinases) 两类。 按照激酶在细胞中所处的位置, 又可分为受体激酶 (receptor kinases)及非受体激酶, 又称细胞内激酶。 受体激酶一般属酪氨酸激酶, 也称酪氨酸受体激酶(receptor tyrosine kinases or RTKs) , 这类激酶由细胞膜表面的受体部分、 跨膜区及细胞内部 分组成, 具有催化活性的激酶部分位于细胞内。 丝氨酸-苏氨酸激酶绝大多数位于细胞 内, 属非受体激酶或称细胞质激酶(cytosolic kinases) 0 The present invention relates to the field of organic chemistry, and in particular to imidazopyridine compounds. BACKGROUND OF THE INVENTION Protein kinases are a class of phosphotransferases that act to transfer the Y phosphate group of ATP to a specific amino acid residue of a substrate to phosphorylate the protein. Protein kinase plays a major role in signal transduction in two ways: First, phosphorylation regulates protein activity, phosphorylation and dephosphorylation are common mechanisms for reversible activation of most signaling pathway components, and some proteins are phosphorylated. After the activity, some are active after dephosphorylation; the second is through the phosphorylation of the protein, the signal is amplified step by step, causing cell reaction. Studies have shown that abnormalities in protein kinase activity are not only directly related to tumors, but also lead to a range of other human diseases associated with inflammation or proliferative responses, such as rheumatoid arthritis, cardiovascular and neurological diseases, asthma, psoriasis. The main reason for waiting. More than 400 human diseases are known to be directly or indirectly related to protein kinases. This makes protein kinases another important class of drug targets following G-protein coupled receptors. The protein kinase family consists of more than 500 members and is usually classified into protein tyrosine kinases (PTKs) and serine-threonine kinases. According to the location of the kinase in the cell, it can be divided into receptor kinases and non-receptor kinases, also known as intracellular kinases. Receptor kinases are generally tyrosine kinases, also known as receptor tyrosine kinases (RTKs), which are composed of a receptor moiety, a transmembrane region, and an intracellular portion of the cell membrane surface. The kinase moiety is located within the cell. Serine - threonine kinase majority located intracellularly, or is a non-receptor kinases called cytoplasmic kinase (cytosolic kinases) 0
RTKs 家族中的典型代表为生长因子受体(growth factor receptors) , 至少存在 19个亚家族(subfamily) , 以下是几个主要的亚家族: A typical representative of the RTKs family is growth factor receptors, which have at least 19 subfamilies. Here are a few major subfamilies:
(a) HER家族酪氨酸受体激酶, 包括 EGFR (epithelial growth factor receptor) ^ HER2、 HER3及 HER4。 EGFR为治疗非小细胞肺癌的合成小分子药 Tarceva®及单克隆抗体 Erbitux®的靶标。 (a) HER family tyrosine receptor kinases, including EGFR (epithelial growth factor receptor) ^ HER2, HER3 and HER4. EGFR is a target for the treatment of non-small cell lung cancer, the synthetic small molecule drug Tarceva® and the monoclonal antibody Erbitux®.
(b)由胰岛素受体(insulin receptor or IR)、 像胰岛素的生长因子 I 型受体 (insulin-like growth factor I receptor or IGF- 1R)及与胰岛素受体相关的受体 确认本 (insulin receptor-related receptor or IRR)组成。 其中的 IGF-1R是公认的好的抗 癌靶标, 但由于它与 IR太相似, 尤其是细胞内的激酶部分为 100%相同, 抑制— IGF-1R 的活性, 通常也会抑制 IR的活性, 后者将引起血糖的升高。 现在尚未有批准上市的药 物。 (c)血小板源性生长因子受体 (platelet- derived growth factor receptor or(b) Confirmation of the receptor by insulin receptor or IR, insulin-like growth factor I receptor (IGF-1R) and insulin receptor-associated receptors (insulin receptor-related receptor or IRR) composition. Among them, IGF-1R is a well-recognized good anti-cancer target, but because it is too similar to IR, especially the intracellular kinase fraction is 100% identical, inhibiting the activity of IGF-1R usually inhibits IR activity. The latter will cause an increase in blood sugar. There are no drugs approved for marketing. (c) platelet-derived growth factor receptor (platelet-derived growth factor receptor or
PDGFRs)家族, 包括 PDGFRc PDGFRp, CSF1R、 c_kit及 c-fms。 其中的成员是白血病治 疗药物 Gleevec®的分子靶标。 The PDGFRs family, including PDGFRc PDGFRp, CSF1R, c_kit, and c-fms. One of the members is the molecular target of the leukemia treatment Gleevec®.
(d)血管内皮生长因子受体 (vascular endothelial growth factor receptors or VEGFRs)家族, 包括 FLTl (Fms- like tyrosine kinase 1或 VEGFR1)、 KDR (或 VEGFR- 2) 及 FLT4 (或 VEGFR3)。 其中的成员为结直肠癌治疗药物 Avastin®的分子靶标。 (d) A family of vascular endothelial growth factor receptors (VEGFRs), including FLT1 (Fms-like tyrosine kinase 1 or VEGFR1), KDR (or VEGFR-2), and FLT4 (or VEGFR3). One of the members is the molecular target of the colorectal cancer treatment drug Avastin®.
(e)成纤细胞生长因子受体(fibroblast growth factor receptors or FGFRs)家 族, 包括 FGFR1、 FGFR2、 FGFR3及 FGFR4及 7个配体 FGF1、 FGF2、 FGF3、 FGF4、 FGF5、 FGF6及 FGF7。 其中的成员作为分子靶标的药物还在临床实验阶段。 (e) Family of fibroblast growth factor receptors (FGFRs), including FGFR1, FGFR2, FGFR3 and FGFR4 and seven ligands FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7. Among them, members of the drug as molecular targets are still in clinical trials.
(f) MET 家族, 包括 c-Met或称人类肝细胞生长因子受体家族 (human hepatocyte growth factor receptor or hHGFR)及 RON。其中 c-Met在初始肿瘤的生长及转移中扮演重 要的角色。 其作为分子靶标的药物还处于临床实验阶段。 综上所述, 蛋白激酶的活性与人类的很多疾病有关, 是治疗这些疾病的药物靶标, 但是受体激酶的种类繁多, 有必要不断地寻求新的药物。在已知的化合物中, 咪唑并吡 啶类化合物一类医药用途较广泛的化合物, 其种类繁多, 但未见具有抑制蛋白激酶(如 VEGFR2、 FLT3、 c-KIT、 CSF1R等) 活性作用的咪唑并吡啶类化合物, 如: 国知局 1992年 9月 9日授权公告的一项 "咪唑并吡啶 PAF/H,拮抗剂"的发明专利 (CN1064275 ) 所记载的一种作为 PAF/Hi拮抗剂的咪唑并吡啶类化合物, 用于治疗过 敏性炎症, 其分子结构如下式所示; (f) MET family, including c-Met or human hepatocyte growth factor receptor or hHGFR and RON. Among them, c-Met plays an important role in the growth and metastasis of initial tumors. Its drug as a molecular target is still in clinical trials. In summary, the activity of protein kinases is associated with many diseases in humans and is a drug target for the treatment of these diseases. However, there are many kinds of receptor kinases, and it is necessary to constantly seek new drugs. Among the known compounds, imidazopyridines are a wide variety of compounds that are widely used in medicine, and there are many kinds of imidazoles which inhibit the activity of protein kinases (such as VEGFR2, FLT3, c-KIT, CSF1R, etc.). A pyridine compound, such as an imidazole as a PAF/Hi antagonist, described in an invention patent entitled "Imidazopyridine PAF/H, Antagonist" (CN1064275), which was issued by the National Science and Technology Bureau on September 9, 1992. a pyridine compound for treating allergic inflammation, the molecular structure of which is shown in the following formula;
Figure imgf000005_0001
国知局 2005年 11月 30日公开的一项 "用作细胞周期依赖性激酶抑制剂的新颖咪 唑并吡啶"的发明专利申请所记载的一种作为细胞周期依赖性激酶抑制剂的咪唑并吡啶 化合物, 用于防治与细胞周期依赖性激酶相关联的疾病, 如各种癌症、 肿瘤和白血病, 其其分子结构如下所示;
Figure imgf000005_0001
Imidazopyridine as a cell cycle-dependent kinase inhibitor described in the patent application of the "New imidazopyridine as a cell cycle-dependent kinase inhibitor" disclosed by the National Patent Office on November 30, 2005 a compound for controlling diseases associated with cell cycle-dependent kinases, such as various cancers, tumors, and leukemias, the molecular structure of which is shown below;
Figure imgf000005_0002
国知局 2007 年 4 月 18 日公开的一项 "咪唑并吡啶化合物" 的发明专利申请 (CN1950372A, 优先权日为 2004年 5月 10日)所记载的一种作为黑色素凝集激素受 体拮抗剂的咪唑并吡啶化合物, 用于治疗肥胖症, 其分子结构如下所示;
Figure imgf000005_0002
A melanin agglutinin receptor antagonist described in the invention patent application (CN1950372A, priority date of May 10, 2004) of the "Imidazopyridine Compound" published by the National Knowledge Bureau on April 18, 2007. Imidazopyridine compound for the treatment of obesity, the molecular structure of which is shown below;
Figure imgf000005_0003
发明内容
Figure imgf000005_0003
Summary of the invention
本发明的目的是提供一种新的的咪唑并吡啶类化合物,该化合物具有抑制蛋白激酶 的药物活性。 本发明所提供的新的咪唑并吡啶类化合物的分子结构如式 I所示, It is an object of the present invention to provide a novel imidazopyridine compound which has a pharmaceutical activity of inhibiting protein kinase. The molecular structure of the novel imidazopyridine compound provided by the present invention is as shown in Formula I,
Figure imgf000006_0001
Figure imgf000006_0001
其中,  among them,
R1和 R2各自独立, 分别选自:  R1 and R2 are independent, respectively:
(1) 氢; 或者  (1) hydrogen; or
(2) 氨基或 d.12垸基取代的氨基; 或者 (2) an amino group or a d. 12 fluorenyl substituted amino group; or
(3) .12烷基, 羟基取代的 Q.12烷基, (^_12垸氧基取代的 d.12垸基, 氨基取代的(3) . 12 alkyl, hydroxy substituted Q. 12 alkyl, (^ -12 methoxy substituted d. 12 fluorenyl, amino substituted
C 12烷基, Cw2垸基取代的氨基取代的 Cw2垸基, 或 3-12元饱和 /部分饱和杂环取代 的 Ci-i2院基; a C 12 alkyl group, a Cw 2 fluorenyl substituted amino substituted Cw 2 fluorenyl group, or a 3-12 membered saturated/partially saturated heterocyclic substituted Ci-i 2 aryl group;
R3表示:  R3 means:
(1) 氢, 氨基, 羟基, 氰基, ,硝基, 羧基, 巯基, 或 垸基; 或者 (1) hydrogen, amino, hydroxy, cyano, nitro, carboxy, fluorenyl, or fluorenyl;
(2)氨基、 羟基、 氰基、 卤素、 硝基、 羧基或巯基取代的 d.12烷基, d_12垸氧基 取代的 _12垸基, CL12烷基取代的氨基取代的 d_12烷基, 3- 12元饱和或部分饱和杂环 取代的垸基, Cw2垸基取代的巯基取代的 C 12烷基, Ci_12烷基取代的亚砜基取代的 d_12 垸基, Cw2垸基取代的砜基取代的 CL12垸基, CQ_12烷基取代的氨基羰基取代的 d_12烷基, QM2垸基取代的氨基亚磺酰基取代的 CW2院基, C(M2垸基取代的氨基磺酰基取代的 d_12 垸基, CQ.12垸基取代的脲基取代的 d.12垸基, CQ.12烷基取代的羰基氨基取代的 d.12烷基, C( 2烷基取代的亚磺酰基氨基取代的 烷基, Co_12垸基取代的磺酰基氨基取代的 CL12 垸基, CL12垸氧基取代的 d.12烷基, d.12烷基取代的氨基取代的 d_12垸基, 3-12元饱 和或部分饱和杂环取代的烷基, Cw2垸基取代的巯基取代的 d_12垸基, CL12烷基取代的 亚砜基取代的 Cw2垸基, 或 CL12垸基取代的砜基取代的 d_12垸基; 或者 (2) an amino, hydroxy, cyano, halogen, nitro, carboxy or fluorenyl substituted d. 12 alkyl, d 12 12 methoxy substituted -12 fluorenyl, CL 12 alkyl substituted amino substituted d 12 alkyl a 3-, 12-membered saturated or partially saturated heterocyclic substituted fluorenyl group, a Cw 2 fluorenyl substituted fluorenyl substituted C 12 alkyl group, a Ci 12 alkyl substituted sulfoxide group substituted d 12 fluorenyl group, Cw 2垸Substituted sulfone-substituted CL 12 fluorenyl, C Q -12 alkyl substituted aminocarbonyl substituted d- 12 alkyl, QM2 fluorenyl substituted aminosulfinyl substituted C W2 , C (M 2垸Substituted aminosulfonyl substituted d- 12 fluorenyl, C Q . 12 fluorenyl substituted ureido substituted d. 12 fluorenyl, C Q . 12 alkyl substituted carbonylamino substituted d. 12 alkyl, C ( 2 alkyl substituted sulfinylamino substituted alkyl, Co- 12 alkyl substituted sulfonylamino substituted CL 12 fluorenyl, CL 12 decyl substituted d. 12 alkyl, d. 12 alkyl substituted amino-substituted alkyl with d_ 12, 3-12 membered saturated or partially saturated heterocycle substituted alkyl, Cw 2 embankment substituted mercapto group substituted by alkyl with d_ 12, CL 12 alkyl substituted Sulfone-substituted alkyl with Cw 2, or CL 12 alkyl with a substituted sulfonyl group substituted d_ 12 embankment; or
(3) 乙烯基, 或 CW2垸基取代的乙烯基; 或者 (3) a vinyl group, or a C W2 fluorenyl substituted vinyl; or
(4) 乙炔基, 或 CW2垸基取代的乙炔基; 或者 (4) an ethynyl group, or a C W2 fluorenyl substituted ethynyl group;
(5)氨基、 羟基、 氰基、 卤素、 硝基、 羧基或巯基取代的 Cw2垸氧基, CW2烷氧 基取代的 C 12垸氧基, CW2垸基取代的氨基取代的 d.12垸氧基, 3-12元饱和或部分饱 和杂环取代的垸氧基, d.12垸基取代的巯基取代的 Cw2垸氧基, d_12垸基取代的亚砜 基取代的 C1-12垸氧基, -12垸基取代的砜基取代的 C1-12垸氧基, 3-12元饱和或部分饱 和杂环取代的 C1-12 ^氧基, Q 2垸基取代的氨基羰基取代的 CW2烷氧基, Q 2垸基取 代的氨基亚磺酰基取代的 C1-12垸氧基, QM2烷基取代的氨基磺酰基取代的 12垸氧基, c0-12垸基取代的脲基取代的 12垸氧基, CQ-12烷基取代的羰基氨基取代的 12垸氧基,(5) an amino, hydroxy, cyano, halogen, nitro, carboxy or fluorenyl substituted Cw 2 decyloxy group, a C W 2 alkoxy substituted C 12 decyloxy group, a C W 2 fluorenyl substituted amino substituted d. 12 decyloxy, 3-12 membered saturated or partially saturated heterocyclic substituted oxirane, d. 12 fluorenyl substituted fluorenyl substituted Cw 2 decyloxy, d- 12 12 fluorenyl substituted sulfoxide a substituted C 1-12 decyloxy group, a -12 fluorenyl substituted sulfone group substituted C 1-12 decyloxy group, a 3-12 membered saturated or partially saturated heterocyclic substituted C 1-12 ^oxy group, Q 2 fluorenyl substituted aminocarbonyl substituted C W2 alkoxy, Q 2 fluorenyl substituted aminosulfinyl substituted C 1-12 decyloxy, QM 2 alkyl substituted aminosulfonyl substituted 12 decyloxy a c 0-12 mercapto-substituted ureido-substituted 12- decyloxy group, a CQ -12 alkyl-substituted carbonylamino-substituted 12- decyloxy group,
C0-12垸基取代的亚磺酰基氨基取代的 C1-12垸氧基, 或 Q 2垸基取代的磺酰基氨基取代 的 Cw2垸氧基; 或者 a C 0-12 mercapto substituted sulfinylamino substituted C 1-12 decyloxy group, or a Q 2 fluorenyl substituted sulfonylamino substituted Cw 2 decyloxy group;
(6) C1-12垸基取代的氨基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基或巯基取代的 C1-12垸基取代的氨基, C1-12垸氧基取代的氨基, C1-12垸基取代的氨基取代的 d.12垸基 取代的氨基, 3-12元饱和或部分饱和杂环取代的氨基, 3-12元饱和或部分饱和杂环取代 的 C1-12烷基取代的氨基, C1-12垸基取代的巯基取代的氨基, C 12垸基取代的亚砜基取 代的氨基, C1-12烷基取代的砜基取代的氨基, Q 2烷基取代的氨基羰基取代的 CW2垸 基取代的氨基, QM2烷基取代的氨基亚磺酰基取代的 Cw2垸基取代的氨基, C(M2垸基 取代的氨基磺酰基取代的 C1-12垸基取代的氨基, QM2垸基取代的脲基取代的 CW2烷基 取代的氨基, C( 2垸基取代的羰基氨基取代的 Cw2垸基取代的氨基, QM2垸基取代的 亚磺酰基氨基取代的 Cw2垸基取代的氨基, 或 Q).12垸基取代的磺酰基氨基取代的 d.12 垸基取代的氨基; 或者 (6) C 1-12 mercapto substituted amino, amino, hydroxy, cyano, halogen, nitro, carboxy or fluorenyl substituted C 1-12 fluorenyl substituted amino, C 1-12 decyl substituted amino , a C 1-12 fluorenyl substituted amino substituted d. 12 fluorenyl substituted amino group, a 3-12 membered saturated or partially saturated heterocyclic substituted amino group, a 3-12 membered saturated or partially saturated heterocyclic substituted C 1 12 alkyl substituted amino group, C 1-12 fluorenyl substituted fluorenyl substituted amino group, C 12 fluorenyl substituted sulfoxide substituted amino group, C 1-12 alkyl substituted sulfone substituted amino group, Q 2 alkane Substituted aminocarbonyl substituted C W2 fluorenyl substituted amino group, QM 2 alkyl substituted amino sulfinyl substituted Cw 2 fluorenyl substituted amino group, C (M 2 fluorenyl substituted aminosulfonyl substituted C 1- 12 mercapto substituted amino group, QM 2 mercapto substituted ureido substituted C W2 alkyl substituted amino group, C ( 2 fluorenyl substituted carbonylamino substituted Cw 2 fluorenyl substituted amino group, QM 2 fluorenyl substituted sulfinylamino Cw 2-substituted alkyl with a substituted amino group, or Q). 12 alkyl with an amino substituted sulfonyl group substituted with a d. 12-substituted embankment Group; or
( 7 ) C1-12烷基取代的巯基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基、 巯基取代的 Cw2垸基取代的巯基, CL12烷氧基取代的巯基, CL12烷基取代的氨基取代的 d.12垸基取 代的巯基, 3-12元饱和或部分饱和杂环取代的巯基, 3-12元饱和或部分饱和杂环取代 的 Cm垸基取代的巯基, Cw2垸基取代的巯基取代的巯基, d.12垸基取代的亚砜基取代 的巯基, Cw2垸基取代的砜基取代的巯基, 0)_12垸基取代的氨基羰基取代的 垸基取 代的巯基, 0)_12垸基取代的氨基亚磺酰基取代的 CW2垸基取代的巯基, CQ.12烷基取代的 氨基磺酰基取代的 垸基取代的巯基, CQ.12垸基取代的脲基取代的 d_12垸基取代的 巯基, 0)_12垸基取代的羰基氨基取代的 垸基取代的巯基, 0>.12垸基取代的亚磺酰基 氨基取代的 C 12烷基取代的巯基, 或 0)_12烷基取代的磺酰基氨基取代的 Cw2烷基取代 的巯基; 或者 (7) C 1-12 alkyl-substituted fluorenyl, amino, hydroxy, cyano, halogen, nitro, carboxy, fluorenyl substituted Cw 2 fluorenyl substituted fluorenyl, CL 12 alkoxy substituted fluorenyl, CL 12 alkane a substituted amino group substituted d. 12 fluorenyl substituted fluorenyl group, a 3-12 membered saturated or partially saturated heterocyclic substituted fluorenyl group, a 3-12 membered saturated or partially saturated heterocyclic substituted Cm fluorenyl substituted fluorenyl group, Cw 2 a mercapto-substituted fluorenyl-substituted fluorenyl group, d. 12 -mercapto-substituted sulfoxide-substituted fluorenyl group, a Cw 2 fluorenyl-substituted sulfone-substituted fluorenyl group, and a 0)- 12 -yl-substituted aminocarbonyl-substituted fluorenyl group Sulfhydryl, 0) _ 12 mercapto substituted aminosulfinyl substituted C W2 fluorenyl substituted fluorenyl, C Q . 12 alkyl substituted aminosulfonyl substituted fluorenyl substituted fluorenyl, C Q . 12 fluorenyl substituted ureas substituted D_ 12 alkyl with a substituted thiol group, 0) _ 12 alkyl with a substituted carbonyl group substituted with alkyl with a substituted thiol group, 0>. 12 alkyl with a substituted sulfinyl group substituted with C 12 alkyl substituted mercapto group, or 0) _ 12 alkyl substituted sulfonyl group substituted Cw 2 alkyl substituted mercapto Or
( 8 ) C 12烷基取代的亚砜基, 垸基取代的砜基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基、 巯基取代的 CW2烷基取代的亚砜基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基、 巯基取代的 CW2垸基取代的砜基, CW2烷氧基取代的亚砜基, C1-12烷氧基取代的 砜基, Cw2垸基取代的氨基取代的 Cw2垸基取代的亚砜基, C1-12垸基取代的氨基取代的 Cw2垸基取代的砜基, 3-12元饱和或部分饱和杂环取代的亚砜基, 3- 12元饱和或部分 饱和杂环取代的砜基, 3-12元饱和或部分饱和杂环取代的 垸基取代的亚砜基, 3-12 元饱和或部分饱和杂环取代的 Ci.12垸基取代的砜基, d_12垸基取代的巯基取代的亚砜 基, 12垸基取代的巯基取代的砜基, 12烷基取代的砜基取代的亚砜基, d.12烷基取 代的砜基取代的砜基, Co_12烷基取代的氨基羰基取代的 d_12垸基取代的亚砜基, C0_12 垸基取代的氨基羰基取代的 CL12垸基取代的砜基, 0)_12烷基取代的氨基磺酰基取代的 _12垸基取代的亚砜基, Co.12烷基取代的氨基磺酰基取代的 d—12垸基取代的砜基, C0-12 垸基取代的脲基取代的 Q_12烷基取代的亚砜基, CQ.12垸基取代的脲基取代的 .12烷基 取代的砜基, Q 2垸基取代的羰基氨基取代的 Cw2烷基取代的亚砜基, C( 2垸基取代 的羰基氨基取代的 CW2垸基取代的砜基, CQ.12烷基取代的磺酰基氨基取代的 d.12烷基 取代的亚砜基, 或 0)_12垸基取代的磺酰基氨基取代的 d_12垸基取代的砜基; 或者 (8) C 12 alkyl substituted sulfoxide group, fluorenyl substituted sulfone group, amino group, hydroxy group, cyano group, halogen, nitro group, carboxyl group, fluorenyl substituted C W 2 alkyl substituted sulfoxide group, amino group, Hydroxy, cyano, halogen, nitro, carboxy, fluorenyl substituted C W2 fluorenyl substituted sulfone group, C W2 alkoxy substituted sulfoxide group, C 1-12 alkoxy substituted sulfone group, Cw 2垸Substituted amino substituted Cw 2 fluorenyl substituted sulfoxide group, C 1-12 fluorenyl substituted amino substituted Cw 2 fluorenyl substituted sulfone group, 3-12 membered saturated or partially saturated heterocyclic substituted sulfoxide group, 3- 12 membered saturated or partially saturated heterocyclic substituted sulfone group, 3-12 membered saturated or partially saturated heterocyclic ring Substituted fluorenyl substituted sulfoxide group, 3-12 membered saturated or partially saturated heterocyclic substituted Ci. 12 fluorenyl substituted sulfone group, d- 12 12 substituted fluorenyl substituted sulfoxide group, 12 fluorenyl substituted mercapto-substituted sulfone groups, alkyl substituted sulfone group 12 substituted alkylene sulfone group, d. 12 alkyl substituted sulfone group substituted sulfone group, Co_ 12 alkyl substituted aminocarbonyl substituted with substituted alkyl with D_ 12 alkylene Sulfone group, C 0 _ 12 fluorenyl substituted aminocarbonyl substituted CL 12 fluorenyl substituted sulfone group, 0) -12 alkyl substituted sulfamoyl substituted -12 12 fluorenyl substituted sulfoxide group, Co. 12 Alkyl substituted sulfamoyl substituted d- 12 alkyl substituted sulfone group, C 0-12 mercapto substituted ureido substituted Q 12 alkyl substituted sulfoxide group, C Q . 12 fluorenyl substituted urea Substituted. 12 alkyl substituted sulfone group, Q 2 fluorenyl substituted carbonylamino substituted Cw 2 alkyl substituted sulfoxide group, C ( 2 fluorenyl substituted carbonyl group Amino substituted C W2 fluorenyl substituted sulfone group, C Q . 12 alkyl substituted sulfonylamino substituted d. 12 alkyl substituted sulfoxide group, or 0) _ 12 fluorenyl substituted sulfonylamino substituted D_ 12 mercapto substituted sulfone group; or
( 9 ) 3-12元饱和或部分饱和杂环基, .12垸基取代的 3-12元饱和或部分饱和杂环 基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基或巯基取代的 d.12垸基取代的 3-12元饱和 或部分饱和杂环基, d.12烷氧基取代的 3-12元饱和或部分饱和杂环基, d_12烷基取代 的氨基取代的 d.12烷基取代的 3-12元饱和或部分饱和杂环基, 3-12元饱和或部分饱和 杂环取代的 3-12元饱和或部分饱和杂环基, 3-12元饱和或部分饱和杂环取代的 _12垸 基取代的 3-12元饱和或部分饱和杂环基, d_12垸基取代的巯基取代的 3-12元饱和或部 分饱和杂环基, Cw2垸基取代的亚砜基取代的 3-12元饱和或部分饱和杂环基, CW2垸 基取代的砜基取代的 3-12元饱和或部分饱和杂环基, Co.12烷基取代的氨基羰基取代的 Cw2垸基取代的 3-12元饱和或部分饱和杂环基, Q 2垸基取代的氨基亚磺酰基取代的 _12垸基取代的 3-12元饱和或部分饱和杂环基, Q).12烷基取代的氨基磺酰基取代的 d.12 烷基取代的 3- 12元饱和或部分饱和杂环基, Q).12垸基取代的脲基取代的 .12烷基取代 的 3-12元饱和或部分饱和杂环基, C<M2烷基取代的羰基氨基取代的 d_12垸基取代的 3-12 元饱和或部分饱和杂环基, Q 2垸基取代的亚磺酰基氨基取代的 CW2垸基取代的 3-12 元饱和或部分饱和杂环基, 或 C(M2垸基取代的磺酰基氨基取代的 d.12垸基取代的 3-12 元饱和或部分饱和杂环基; (9) a 3-12 membered saturated or partially saturated heterocyclic group, a 12 fluorenyl substituted 3-12 membered saturated or partially saturated heterocyclic group, an amino group, a hydroxy group, a cyano group, a halogen, a nitro group, a carboxy group or a fluorenyl group substituted d. 12 mercapto substituted 3-12 membered saturated or partially saturated heterocyclic group, d. 12 alkoxy substituted 3-12 membered saturated or partially saturated heterocyclic group, d 12 alkyl substituted amino substituted d. 12 alkyl substituted 3-12 membered saturated or partially saturated heterocyclic group, 3-12 membered saturated or partially saturated heterocyclic substituted 3-12 membered saturated or partially saturated heterocyclic group, 3-12 membered saturated or partially saturated heterocyclic group Ring-substituted -12 12 -substituted 3-12-membered saturated or partially saturated heterocyclic group, d- 12 12 -substituted fluorenyl-substituted 3-12-membered saturated or partially saturated heterocyclic group, Cw2 fluorenyl-substituted sulfoxide group Substituted 3-12 membered saturated or partially saturated heterocyclic group, C W2 fluorenyl substituted sulfone group substituted 3-12 membered saturated or partially saturated heterocyclic group, Co. 12 alkyl substituted aminocarbonyl substituted Cw 2 fluorene substituted 3-12 membered saturated or partially saturated heterocyclic group, Q 2 is alkyl with a substituted amino group substituted alkylsulfinyl _ 12 alkyl with a substituted 3-12-membered saturated or Partially saturated heterocyclyl, Q). 12 alkyl substituted aminosulfonyl group substituted with a d. 12 alkyl substituted 3-12 membered saturated or partially saturated heterocyclic group, Q). 12 embankment substituted ureas substituted . 12 alkyl substituted 3-12 membered saturated or partially saturated heterocyclic group, C < M 2 alkyl substituted carbonylamino substituted d 12 12 fluorenyl substituted 3-12 membered saturated or partially saturated heterocyclic group, Q 2垸a substituted sulfinylamino substituted C W 2 fluorenyl substituted 3-12 membered saturated or partially saturated heterocyclic group, or C (M 2 fluorenyl substituted sulfonylamino substituted d. 12 fluorenyl substituted 3- 12-membered saturated or partially saturated heterocyclic group;
X表示氧, 硫, N-CN, 或 N-N02; X represents oxygen, sulfur, N-CN, or N-N0 2 ;
Ar和 Ar' 各自独立, 表示芳基或杂芳基, 该芳环或杂芳环上的 1〜4个氢可被 R3、 芳基或杂芳基取代。 本发明所述的化合物, 还包括如式 I所示结构的消旋体和对映异构体。 作为本发明的优选方案, 所述的化合物中的 R1表示氢, R2表示氨基。 本发明的另一优选方案, 所述的化合物中的 R1表示氨基, R2表示氢。 Ar and Ar' are each independently and represent an aryl or heteroaryl group, and 1 to 4 hydrogens on the aromatic ring or heteroaryl ring may be substituted by R3, aryl or heteroaryl. The compounds of the present invention also include racemates and enantiomers of the structure of formula I. As a preferred embodiment of the present invention, R1 in the compound represents hydrogen, and R2 represents an amino group. In another preferred embodiment of the present invention, R1 in the compound represents an amino group, and R2 represents hydrogen.
本发明的另一优选方案, 所述的化合物中的 X表示氧。 本发明的另一优选方案, 所述的化合物中的 Ar和 Ar'分别为苯环、 吡啶、 吡啶酮、 四氢吡啶酮、 咪啶、 吡嗪、 哒嗪、 咪唑、 噻唑、 噻吩、 呋喃、 吲哚、 氮杂吲哚、 苯并咪 唑、 吲哚啉、 吲哚酮中的任何一种, 苯环或杂环上的 1〜4个氢可被 R3、 芳基或杂芳基 取代。 本发明的另一优选方案, 所述的化合物中的 R1表示氢或氨基, R2表示氢或氨基, X 表示氧, Ar表示苯环, Ar'表示苯环或者被 1〜2个相同或不同基团取代的苯环, 所述的 基团是卤素、 甲基、 甲氧基、 卤素取代的甲基或卤素取代的甲氧基; 本方案所述的化合 物可进一步选自表 1中任一种。  In another preferred embodiment of the invention, X in the compound represents oxygen. In another preferred embodiment of the present invention, Ar and Ar' in the compound are a benzene ring, a pyridine, a pyridone, a tetrahydropyridone, an acetidine, a pyrazine, a pyridazine, an imidazole, a thiazole, a thiophene, a furan, Any one of hydrazine, azaindene, benzimidazole, porphyrin or fluorenone, and 1 to 4 hydrogens on the benzene ring or heterocyclic ring may be substituted by R3, aryl or heteroaryl. In another preferred embodiment of the present invention, R1 in the compound represents hydrogen or an amino group, R2 represents hydrogen or an amino group, X represents oxygen, Ar represents a benzene ring, Ar' represents a benzene ring or is 1 or 2 identical or different groups. a group-substituted benzene ring, the group being a halogen, a methyl group, a methoxy group, a halogen-substituted methyl group or a halogen-substituted methoxy group; the compound described in the present scheme may be further selected from any one of Table 1. .
表 1  Table 1
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
根据 Rl、 R2和 R3的不同, 本发明所述的化合物可分为两个小类:
Figure imgf000017_0001
Figure imgf000018_0001
Depending on R1, R2 and R3, the compounds of the invention can be divided into two subclasses:
1、 当 R1为氨基, R2和 R3分别为前面所定义的基团中的任一种时, 本发明所述的 化合物是 1-氨基咪唑 [1, 5- a]并吡啶类化合物, 该化合物的化学合成方法如下述式 II所 1. When R1 is an amino group, and R2 and R3 are each of the groups defined above, the compound of the present invention is a 1-aminoimidazo[1, 5-a] pyridine compound, the compound The chemical synthesis method is as shown in the following formula II.
Figure imgf000019_0001
其中, 化合物 11等同于当式 I中的 R1为氨基时的化合物。
Figure imgf000019_0001
Wherein compound 11 is equivalent to a compound when R1 in formula I is an amino group.
式 II所示的合成方法由以下步骤组成:  The synthesis method shown in Formula II consists of the following steps:
( 1 )在氮气保护下, 化合物 1在有机溶剂中用还原剂还原成含伯胺 2; 所述的有机 溶剂为甲醇、 乙醇、 异丙醇、 正丁醇、 叔丁醇、 乙酸乙酯、 乙醚、 丙醚、 甲苯、 苯、 二 甲苯、 四氢呋喃、 乙氰、 1,2-二甲氧基乙垸等, 还原剂为氢气、 四氢铝锂、 硼氢化钠、 二异丁基铝氢、 红铝等;  (1) Under a nitrogen atmosphere, Compound 1 is reduced to a primary amine containing 2 with a reducing agent in an organic solvent; the organic solvent is methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, Ether, propyl ether, toluene, benzene, xylene, tetrahydrofuran, acetonitrile, 1,2-dimethoxyacetamidine, etc., the reducing agent is hydrogen, lithium tetrahydrogenate, sodium borohydride, diisobutylaluminum hydride, Red aluminum, etc.;
(2) 伯胺 2通过与酸、 酰氯或酯 3反应进一步转化成酰胺 4;  (2) primary amine 2 is further converted to amide 4 by reaction with an acid, acid chloride or ester 3;
(3 ) 酰胺 4与三氯氧磷反应生成双环咪唑 [1, 5-a]并吡啶中间体 5,  (3) amide 4 is reacted with phosphorus oxychloride to form a bicyclic imidazole [1, 5-a] pyridine intermediate 5,
(4) 将中间体 5硝化产生化合物 6,  (4) nitrating intermediate 5 to produce compound 6,
(5) 化合物 6与化合物 7通过 Suzuki偶联反应得到 8-芳基取代的化合物 8; (5) Compound 6 and Compound 7 are subjected to Suzuki coupling reaction to obtain 8-aryl-substituted compound 8;
(6) 化合物 8与异氰酸酯或异硫氰酸酯 9反应得到脲类化合物 10, 最后还原化合 物 10中的硝基得到 1-氨基咪唑 [1, 5-a]并吡啶类目标产物 11。 还原反应所用的溶剂为 甲醇、 乙醇、 异丙醇、 正丁醇、 叔丁醇、 乙酸乙酯、 乙醚、 丙醚、 甲苯、 苯、 二甲苯、 四氢呋喃、 乙氰、 1,2-二甲氧基乙垸等, 还原剂为氢气、 四氢铝锂、 硼氢化钠、 二异丁 基铝氢、红铝等。上述反应过程中的起始原料即化合物 1为 R3取代的 3-溴 -2-氰基吡啶 可购买获得。 (6) Compound 8 is reacted with isocyanate or isothiocyanate 9 to obtain urea compound 10, and finally nitro group in compound 10 is reduced to obtain 1-aminoimidazole [1, 5-a] pyridine type target product 11. The solvent used in the reduction reaction is Methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, diethyl ether, propyl ether, toluene, benzene, xylene, tetrahydrofuran, acetonitrile, 1,2-dimethoxyacetamidine, etc. The agent is hydrogen, lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, red aluminum or the like. The starting material in the above reaction, that is, the compound 1 is R3 substituted 3-bromo-2-cyanopyridine, is commercially available.
2、当 R1为氢, R2为氨基, R3为氢时,本发明所述的化合物是 3-氨基咪唑 [1, 5 - a] 并吡啶类化合物, 该化合物的化学合成方法如式 III所示。  2. When R1 is hydrogen, R2 is an amino group, and R3 is hydrogen, the compound of the present invention is a 3-aminoimidazo[1,5-a] pyridine compound, and the chemical synthesis method of the compound is as shown in Formula III. .
NaB(OAc)3H NaB(OAc) 3 H
Figure imgf000020_0001
Figure imgf000020_0001
其中, 化合物 j等同于当式 I中的 R2 =氨基时的化合物。 上述反应过程中的起始原料 a为 R3取代的 2-溴 -6-甲酰基吡啶, 可购买得到; 原 料 a与 b通过金属催化的偶联反应得到化合物 c; c通过还原胺化得到化合物 b或与有 机金属试剂发生加成反应生成二级醇, 再经磺酰化及氨取代得到胺山 化合物 d和对甲 氧基苄基与异硫氰酸酯 e反应得到硫脲 f; f用 Ν, Ν' -二环已基碳酰亚胺(DCC) 处理, 使其关环生成双环咪唑 [l, 5-a]并吡啶中间体 g; 中间体 g经三氟乙酸(TFA)脱保护或 氢化还原产生二胺 h;最后 h与异氰酸酯或异硫氰酸酯 i反应得到目标产物 3-氨基咪唑 [1, 5-a]并吡啶类化合物 j。 本发明所述的化合物及其消旋体或对映异构体对血管内皮生长因子受体 2 (VEGFR2)、 酪氨酸激酶 3 (FLT3)、 人干细胞因子受体 (c-Kit ) 的活性等都有抑制作 用, 可作为 VEGFR2、 FLT3和 c_Kit的抑制剂, ·用于制备治疗由 VEGFR2、 FLT3和 c-Kit 活性异常增高引起的疾病的药物, 如癌症、 银屑病、 肝硬化、 糖尿病、 眼睛疾病例如 AMD, 风湿性关节炎及别的炎症、 免疫系统疾病(例如自免疫疾病)、 心血管疾病(例如 动脉粥样硬化) 和肾脏疾病等。 Wherein compound j is equivalent to a compound when R2 = amino group in formula I. The starting material a in the above reaction is R3 substituted 2-bromo-6-formylpyridine, which is commercially available; the starting materials a and b are subjected to metal-catalyzed coupling reaction to obtain compound c; c is reductively aminated to obtain compound b. Or an addition reaction with an organometallic reagent to form a secondary alcohol, followed by sulfonylation and ammonia substitution to obtain an amine mountain compound d and a p-methoxybenzyl group and an isothiocyanate e to obtain a thiourea f; , Ν'-bicyclohexylcarbimide (DCC) treatment, which is closed to form a bicyclic imidazole [l, 5-a] pyridine intermediate g; intermediate g is deprotected by trifluoroacetic acid (TFA) or Hydrogenation reduction produces diamine h; finally, h is reacted with isocyanate or isothiocyanate i to give the desired product 3-aminoimidazole [1, 5-a] pyridine compound j. Activity of the compounds of the present invention and their racemates or enantiomers against vascular endothelial growth factor receptor 2 (VEGFR2), tyrosine kinase 3 (FLT3), human stem cell factor receptor (c-Kit) And other inhibitory effects, can be used as inhibitors of VEGFR2, FLT3 and c_Kit, · for the preparation of drugs for the treatment of diseases caused by abnormal increase in VEGFR2, FLT3 and c-Kit activity, such as cancer, psoriasis, cirrhosis, diabetes Eye diseases such as AMD, rheumatoid arthritis and other inflammations, immune system diseases (such as autoimmune diseases), cardiovascular diseases (such as atherosclerosis) and kidney diseases.
本发明所述的化合物用于治疗由 VEGFR2、 FLT3和 c- Kit活性异常引起的疾病, 其 有效剂量是每日每千克体重 0. 1〜100毫克, 优化的剂量为每日每千克体重使用 1〜70 毫克; 给药频率依据不同的疾病而定, 一般是每日 1〜4次, 优选 2〜3次。 本发明所述的治疗由 VEGFR2、 FLT3和 c- Kit活性异常引起的疾病的药物主要由本 发明所述的化合物与药学上可接受的辅料组成,还可以含有其他的辅助药物,如抗细菌 剂、 抗真菌剂、 抗微生物剂、 维生素、 抗肿瘤药物等中的一种或多种, 本发明所述的化 合物在所述药物中可通过以下方式存在: The compounds of the present invention are useful for treating diseases caused by abnormalities in the activity of VEGFR2, FLT3 and c-kit, The effective dose is 0.1 to 100 mg per kilogram of body weight per day, and the optimized dose is 1 to 70 mg per kilogram of body weight per day; the frequency of administration depends on different diseases, usually 1 to 4 times per day, preferably 2 to 3 times. The medicament for treating diseases caused by abnormal activity of VEGFR2, FLT3 and c-kit of the present invention mainly consists of the compound of the present invention and a pharmaceutically acceptable adjuvant, and may also contain other auxiliary drugs, such as antibacterial agents, One or more of an antifungal agent, an antimicrobial agent, a vitamin, an antitumor drug, and the like, the compound of the present invention may be present in the drug by the following means:
( 1 )药学上可接受的盐, 即本发明所述的化合物与医学上可接受的酸或碱反应形 成的盐, 所述的酸可以是无机酸或有机酸, 如盐酸、 氢溴酸、 氢碘酸、 硫酸、 硝酸、 碳 酸、 磷酸、 高氯酸、 醋酸、 柠檬酸、 草酸、 乳酸、 苹果酸、 水杨酸、 酒石酸、 甲磺酸、 乙磺酸、 苯磺酸、 取代的苯磺酸 (例如, 对甲基苯磺酸)、 异烟酸、 油酸、 鞣酸、 泛酸、 - 抗坏血酸、 丁二酸、 马来酸、 龙胆酸、 富马酸、 葡萄糖酸、 糖醛酸、 葡萄糖二酸或蔗糖 酸、 甲酸、 苯甲酸、 谷氨酸、 双羟萘酸、 山梨酸等; 所述的碱可以是无机碱或有机碱, 如氢氧化钠、 氢氧化钾、 氢氧化锂、 氢氧化铁、 氢氧化钙、 氢氧化钡、 氢氧化铝、 氢氧 化镁、 氢氧化锌、 氨水、 氢氧化有机季铵盐、 碳酸钠、 碳酸钾、 碳酸锂、 碳酸钙、 碳酸 钡、 碳酸镁、 碳酸化有机季铵盐、 碳酸氢钠、 碳酸氢钾、 碳酸氢锂、 碳酸氢钙、 碳酸氢 钡、 碳酸氢镁、 碳酸氢化有机季铵盐等; (1) A pharmaceutically acceptable salt, that is, a salt formed by reacting a compound of the present invention with a medically acceptable acid or base, and the acid may be an inorganic acid or an organic acid such as hydrochloric acid or hydrobromic acid. Hydroiodic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, malic acid, salicylic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, substituted benzenesulfonate Acid (eg, p-toluenesulfonic acid), isonicotinic acid, oleic acid, citric acid, pantothenic acid, - ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, uronic acid, Gluconic acid or sucrose acid, formic acid, benzoic acid, glutamic acid, pamoic acid, sorbic acid, etc.; the base may be an inorganic base or an organic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, Iron hydroxide, calcium hydroxide, barium hydroxide, aluminum hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water, organic quaternary ammonium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, barium carbonate, magnesium carbonate Carbonated organic a quaternary ammonium salt, sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate, calcium hydrogencarbonate, cesium hydrogencarbonate, magnesium hydrogencarbonate, hydrogenated organic quaternary ammonium salt, etc.;
(2) 溶剂合物, 即本发明所述的化合物与药学上常用的溶剂以共价键、 离子键、 氢键、范德华力、络合、包和等形成的稳定物质, 所述的溶剂可以是甲醇、 乙醇、丙醇、 丁醇、 乙二醇、 丙二醇、 聚乙二醇、 丙酮等; (2) a solvate, that is, a stable substance formed by covalent bond, ionic bond, hydrogen bond, van der Waals force, complexation, inclusion, and the like of the compound of the present invention and a pharmaceutically-usual solvent, and the solvent may be Is methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, etc.;
( 3)前药, 即通过化学合成或物理的方法将本发明所述的化合物转化为另一种化 合物, 当该化合物给予哺乳动物后, 在其体内被转化成本发明所述的化合物。 利用 "前 药"方法通常是为了克服药物化合物本身不良或欠佳的物理化学性质或成药性。 本发明中的化合物还可能存在互变异构体 (tautomers)、 旋转异构体 (rotamers)、 顺反异构体等, 这些概念都可在 J. March 的 "Advanced Organic Chemistry, " 4th edition中找到并得到理解。 只要这些异构体具有与本发明中的化合物相同的抑制蛋白 质激酶活性的作用, 这些异构体也涵盖于本发明中。 本发明中的化合物被给予例如人一样的哺乳动物后, 据本领域中公知, 很有可能 在动物体内被不同的酶代谢成各种代谢产物,只要这些代谢产物具有与本发明中的化合 物相同的抑制蛋白质激酶活性的作用, 这些代谢产物也涵盖于本发明中。 本发明所述的药物可通过口服给药, 如制备成片剂、 胶囊、 糖桨、 凝胶、 丸剂、 口服液等; 也可通过注射给药, 如制备成无菌溶液、 悬浮液、 乳剂等; 也可通过肛塞给 药, 如制备成栓剂、 凝胶剂等; 还可通过鼻孔吸入给药, 如制备成喷雾剂、 气雾剂等。 本发明所述药物的包装和保存和一般西药类似, 例如固体剂型的药物可直接装入 玻璃、 塑料、 纸质或金属瓶中, 瓶内最好放入干燥剂等以保持药物的质量; 液体剂型的 药物一般装入玻璃、塑料或金属瓶或软管中; 气雾剂型的药物一般装入耐压的附有减压 阀等装置的金属或塑料容器中。 术语解释 (3) A prodrug, that is, a compound of the present invention is converted into another compound by chemical synthesis or physical means, and when the compound is administered to a mammal, it is converted into a compound of the invention in its body. The "prodrug" method is usually used to overcome the poor or poor physicochemical properties or drug-forming properties of the drug compound itself. The compounds of the present invention may also exist in their tautomeric form (Tautomers), rotamers (rotamers), cis and trans isomers and the like, these concepts can be in J. March in "Advanced Organic Chemistry," 4 th edition Found and understood. As long as these isomers have the same effect of inhibiting protein kinase activity as the compounds of the present invention, these isomers are also encompassed by the present invention. After the compound of the present invention is administered to a mammal such as a human, it is highly known in the art that it is metabolized into various metabolites by different enzymes in the animal as long as these metabolites have the same properties as the compounds of the present invention. The effect of inhibiting protein kinase activity, these metabolites are also encompassed by the present invention. The medicament of the present invention can be administered orally, for example, into tablets, capsules, syrups, gels, pills, oral liquids, etc.; and can also be administered by injection, such as preparation into sterile solutions, suspensions, emulsions. Etc.; can also be administered by anal plug, such as preparation of a suppository, gel, etc.; can also be administered by inhalation through the nostrils, such as preparation into a spray, an aerosol, and the like. The packaging and preservation of the medicament of the invention are similar to those of a general western medicine. For example, the solid dosage form of the medicine can be directly loaded into a glass, a plastic, a paper or a metal bottle, and a desiccant or the like is preferably placed in the bottle to maintain the quality of the drug; The dosage form of the drug is generally contained in a glass, plastic or metal bottle or hose; the aerosol type drug is generally contained in a metal or plastic container with a pressure-resistant device such as a pressure reducing valve. Explanation of terms
"垸基 "指具有指定数目碳原子的直链、支链及环状的碳氢化合物基团,例如 c1-12 垸基指含最少 1个, 最多 12个碳原子的直链、 支链及环状基团。 C。代表一个共价化学 键。 本发明中的垸基包括但不限于甲基、 乙基、 丙基、 丁基、 环戊基、 环己基、 异丙基、 新戊基、 2-甲基 -1-己基等。 垸基中的一个或全部氢原子可被下列基团取代: 卤素、 氨 基、 羟基、 氰基、 硝基、 羧基、 巯基、 氧基 (OXO)等。 "Mercapto" refers to a straight chain, branched chain, and cyclic hydrocarbon group having the specified number of carbon atoms. For example, c 1-12 fluorenyl refers to a straight chain, branched chain having a minimum of 1 and a maximum of 12 carbon atoms. And a cyclic group. C. Represents a covalent chemical bond. The fluorenyl group in the present invention includes, but is not limited to, methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, isopropyl, neopentyl, 2-methyl-1-hexyl and the like. One or all of the hydrogen atoms in the fluorenyl group may be substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, decyl, oxy (OXO) and the like.
"垸氧基"指具有指定数目碳原子的垸基通过氧原子与其他基团相连。 本发明中 的垸氧基包括但不限于甲氧基、 乙氧基、 丙氧基、 丁氧基、 环戊氧基、 环己氧基、 异丙 氧基、 新戊氧基、 2-甲基 -1-己氧基等。 烷氧基中的一个或全部氢原子可被下列基团取 代: 卤素、 氨基、 羟基、 氰基、 硝基、 羧基、 巯基、 氧基 (0X0)等。 "Mercaptooxy" means that a fluorenyl group having the indicated number of carbon atoms is attached to the other group through an oxygen atom. The oxiranyloxy group in the present invention includes, but is not limited to, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a cyclopentyloxy group, a cyclohexyloxy group, an isopropoxy group, a neopentyloxy group, a 2-methyl group. Ke-1-hexyloxy and the like. One or all of the hydrogen atoms in the alkoxy group may be substituted by the following groups: halogen, amino, hydroxy, cyano, nitro, carboxy, decyl, oxy (0X0) and the like.
"卤素"指氟、 氯、 溴、 碘。 "Halogen" means fluoro, chloro, bromo, iodo.
"3-12元饱和或部分饱和杂环基"指由 3至 12个原子组成的单环或多环垸基, 其 中至少一个原子为 0、 N、 S、 S0、 S02、 P或 Si。 除单键外, 这些单环或多环垸基可含有 双键或叁键, 但不构成全部共轭的芳香结构。 这些单环或多环垸基可以以稠环、 桥环或 螺环的形式存在。 本发明中的 3-12元饱和或部分饱和杂环基包括但不限于哌啶、 吗啉、 哌嗪、 吡咯烷、 吲哚啉、 四氢吡啶、 四氢呋喃、 托品醇等, 如表 2所示; 杂环基中的一 个或全部氢原子可被下列基团取代: 卤素、 氨基、 羟基、 氰基、 硝基、 羧基、 巯基、 氧 基(0X0)等。 表 2 The "3-12 membered saturated or partially saturated heterocyclic group" means a monocyclic or polycyclic fluorenyl group composed of 3 to 12 atoms, wherein at least one of the atoms is 0, N, S, S0, S0 2 , P or Si. In addition to a single bond, these monocyclic or polycyclic fluorenyl groups may contain double or triple bonds, but do not constitute all conjugated aromatic structures. These monocyclic or polycyclic fluorenyl groups may exist in the form of fused rings, bridged rings or spiro rings. The 3-12 membered saturated or partially saturated heterocyclic group in the present invention includes, but is not limited to, piperidine, morpholine, piperazine, pyrrolidine, porphyrin, tetrahydropyridine, tetrahydrofuran, tropinol, etc., as shown in Table 2. One or all of the hydrogen atoms in the heterocyclic group may be substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, decyl, oxy (0X0) and the like. Table 2
Figure imgf000023_0001
Figure imgf000023_0001
"芳基"指由 5-12个碳原子组成的单环或多环结构, 其中至少有一个环具有共轭 的芳香结构(即符合 N+2规则), 但整个结构不必全部共轭。 芳基也可以以亚基的形式出 现, 即共轭芳香结构中与其他基团有两个连接点。 本发明中的芳基包括但不限于苯基、 萘基、茚基、二氢化茚基、 四氢化萘等。芳基中的一个或全部氢原子可被下列基团取代: 卤素、 氨基、 羟基、 氰基、 硝基、 羧基、 巯基、 氧基 (OXO)等。  "Aryl" means a monocyclic or polycyclic structure consisting of 5 to 12 carbon atoms, at least one of which has a conjugated aromatic structure (i.e., conforms to the N+2 rule), but the entire structure does not have to be fully conjugated. The aryl group may also be present in the form of a subunit, i.e., two points of attachment to other groups in the conjugated aromatic structure. The aryl group in the present invention includes, but is not limited to, a phenyl group, a naphthyl group, an anthracenyl group, an indanyl group, a tetrahydronaphthalene or the like. One or all of the hydrogen atoms in the aryl group may be substituted with a halogen, an amino group, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a decyl group, an oxy group (OXO) or the like.
"杂芳基"指由 5-12个原子组成的单环或多环结构, 其中至少一个原子为 0、 N、 S、 S0、 S02、 P或 Si , 并且, 至少有一个环具有共轭的芳香结构(即符合 N+2规则), 但 整个结构不必全部共轭。 杂芳基也可以以亚基的形式出现, 即共轭芳香结构中与其他基 团有两个连接点。 本发明中的杂芳基包括但不限于吡啶、 吡啶酮、 四氢吡啶酮、 咪啶、 吡嗪、 哒嗪、 咪唑、 噻唑、 噻吩、 呋喃、 吲哚、 氮杂吲哚、 苯并咪唑、 吲哚啉、 吲哚酮、 喹咛等, 如表 3所示; 芳基中的一个或全部氢原子可被下列基团取代: 卤素、 氨基、 羟 基、 氰基、 硝基、 羧基、 巯基、 氧基 (OXO)等。 "Heteroaryl" means a monocyclic or polycyclic structure consisting of 5-12 atoms, wherein at least one atom is 0, N, S, S0, S0 2 , P or Si, and at least one ring has a conjugation The aromatic structure (ie conforms to the N+2 rule), but the entire structure does not have to be fully conjugated. Heteroaryl groups can also occur in the form of subunits, that is, two points of attachment to other groups in the conjugated aromatic structure. Heteroaryl groups in the present invention include, but are not limited to, pyridine, pyridone, tetrahydropyridone, imidazine, pyrazine, pyridazine, imidazole, thiazole, thiophene, furan, anthraquinone, azaindole, benzimidazole, Porphyrin, anthrone, quinone, etc., as shown in Table 3; one or all of the hydrogen atoms in the aryl group may be substituted by the following groups: halogen, amino, hydroxy, cyano, nitro, carboxy, fluorenyl, Oxyl (OXO) and the like.
表 3  table 3
Figure imgf000023_0002
具体实施方式 以下提供的是本发明的实施例,这些实施例的目的是帮助进一步理解本发明, 但对 本发明的具体实施方式不具有限制作用。
Figure imgf000023_0002
The embodiments of the present invention are provided below, and the embodiments are intended to further understand the present invention, but do not limit the specific embodiments of the present invention.
下面是将在实施例中出现的英文缩写及相应的中文含义。 如果实施例中出现没有 列于此的缩写, 则代表普遍接受的含义。  The following are the English abbreviations and corresponding Chinese meanings that will appear in the examples. If an abbreviation not listed herein is present in the examples, it represents a generally accepted meaning.
DMS0: 二甲基亚砜  DMS0: dimethyl sulfoxide
TMS: 四甲基硅垸  TMS: Tetramethylsilane
DCM: 二氯甲垸  DCM: Dichloromethane
EtOAc: 乙酸乙酯  EtOAc: ethyl acetate
TLC: 薄层色谱  TLC: thin layer chromatography
g: 克  g: g
mg: 毫克  Mg: mg
mmol : 毫摩尔 Mmmol : millimol
: 摩尔浓度  : molar concentration
m/z: 质荷比  m/z: mass to charge ratio
EDC. HC1 : 1-乙基 -3- (3-二甲基氨基丙基)碳二亚胺盐酸盐 制备例 例 1  EDC. HC1 : 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Preparation Example 1
1、 一般实验条件: 核磁共振氢谱及碳谱于 Varian INOVA 500NB仪器上获得(氘代 DMS0、 氘代氯仿、 氘代甲醇等为溶剂, TMS为内标)。 质谱由液相色谱质谱联用仪获得 (采用 ESI或 APCI 离子源 ZQ4000,美国 Waters公司)。紫外光谱由日本日立公司的 UV-3010紫外分光光度 计测得。 红外光谱使用 NICOLET6700 红外光谱分析仪 (KBr 压片)。 高效液相色谱使用 Waters 2695 Z0RBAX 高效液相色谱仪 (Bx_C8 5 μ 150x4. 6 mm色谱柱)。 熔点的测定使 用 Electrothermal数字式熔点仪 IA9100, 并且未校正。 1. General experimental conditions: Nuclear magnetic resonance spectroscopy and carbon spectra were obtained on a Varian INOVA 500NB instrument (deuterated DMS0, deuterated chloroform, deuterated methanol, etc. as solvent, TMS as internal standard). Mass spectra were obtained by liquid chromatography mass spectrometry (using ESI or APCI ion source ZQ4000, Waters, USA). The ultraviolet spectrum was measured by a UV-3010 ultraviolet spectrophotometer from Hitachi, Japan. Infrared spectroscopy was performed using a NICOLET 6700 infrared spectroscopy analyzer (KBr tablet). High performance liquid chromatography was performed using a Waters 2695 Z0RBAX high performance liquid chromatograph (Bx_C 8 5 μ 150 x 4. 6 mm column). The melting point was determined using an Electrothermal digital melting point apparatus IA9100 and was uncorrected.
2、 制备过程: 2. Preparation process:
( 1 ) (3-溴吡啶 -2-基)甲胺盐酸盐的制备 在氮气保护下, 将 3-溴 -2-氰基吡啶(1. 83 g, 10 醒 ol)溶解于 50毫升干 THF中, 于该溶液中缓慢滴加 1M BH3 · THF (50 mL, 50 mmol), 加完后, 此混合物在室温下搅拌 24小时, 过量的 3小心用 30毫升 MeOH淬灭。 用旋转蒸发仪除去溶剂, 剩余物溶解于 DCM (lO mL)中, 并加入 4M HC1的二噁烷溶液(10 mL), 生成的固体产物经过滤收集, 烘 干得目标化合物 1. 85 g (得率: 83%)。所得产物的鉴定结果: 1H- MR (DMSO-rf6) δ 8.36 (d, 1H), 7.83 (d, 1H), 7.45-7.50 (m, 1H), 4.53 (s, 2H)。 质谱 m/z: 187.04 [M+H, 79Br], 189.06 [M+H, 81Br]。 Preparation of (1) (3-bromopyridin-2-yl)methylamine hydrochloride 3-bromo-2-cyanopyridine (1.83 g, 10 awake ol) was dissolved in 50 ml of dry THF under a nitrogen atmosphere, and 1 M BH 3 · THF (50 mL, 50) was slowly added dropwise to the solution. After the addition, the mixture was stirred at room temperature for 24 hours and excess 3 was carefully quenched with 30 mL MeOH. The solvent was removed by a rotary evaporator, and the residue was dissolved in EtOAc (EtOAc) (EtOAc). Yield: 83%). Identification of the obtained product: 1H-MR (DMSO-rf 6 ) δ 8.36 (d, 1H), 7.83 (d, 1H), 7.45-7.50 (m, 1H), 4.53 (s, 2H). Mass spectrum m / z: 187.04 [M + H, 79 Br], 189.06 [M + H, 81 Br].
(2 ) Λ 3-溴吡啶 -2-基)甲基甲酰胺的制备: 将甲酸 (368 mg, 8 mmol)及 EDC.HC1 (1.917 g, 10 mmol)悬浮于 DCM (20 mL)中, 在 搅拌下,滴加二异丙基乙基胺 (2.585 g, 20 mmol)o加完后于室温搅拌半小时,加入 C_ (3 - 溴吡啶 -2-基)甲胺盐酸盐 (0. 894 g, 4 mmol) , 继续搅拌 2小时。 旋转蒸发除去溶剂, 剩余物用硅胶柱层析纯化 (EtOAc)得目标产物 0. 817 g (得率: 95%)。 所得产物的鉴定 结果: 1H- M (DMSO-rfe) δ 8.30 (d, 1H), 8.00(s, 1H), 7.86 (d, 1H), 7.40-7.45 (m, 1H), 4.18 (s, 2H)。 质谱 w/ζ·· 215.12 [M+H, 79Br], 217.10 [M+H, 81Br]。 (3 ) 8-溴咪唑 [1, 5- a]并吡啶的制备: 在搅拌下, 于 N-(3-溴吡啶 -2-基)甲基甲酰胺 (0.645 g, 3 mmol)的甲苯溶液 (4 mL)中 加入三氯氧磷 (l mL)。 将此混合物回流 7小时。 旋转蒸发除去过量的三氯氧磷及溶剂, 得到的粘稠液体用 0° C的冰水水解, 并用浓氨水碱化。 水相用 DCM萃取 (3x10 mL), 有机相合并、 干燥、 硅胶柱层析纯化 (EtOAc)得目标产物 0.461 g (得率: 78%)。 所得产 物的鉴定结果: 1H-NMR (DMS0- ) δ 8.65(d, 1H), 7.86 (s, 1H), 7.10-7.25 (m, 3H)。 质谱 m/z: 197.05 [M+H, 79Br], 198.95 [M+H, 81Br]。 (2) Preparation of Λ 3-bromopyridin-2-yl)methylformamide: Formic acid (368 mg, 8 mmol) and EDC.HC1 (1.917 g, 10 mmol) were suspended in DCM (20 mL) Under stirring, diisopropylethylamine (2.585 g, 20 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for half an hour, and C_(3-bromopyridin-2-yl)methylamine hydrochloride (0. 894) was added. g, 4 mmol), stirring was continued for 2 hours. The solvent was removed by EtOAc (EtOAc)EtOAc. Identification of the obtained product: 1H-M (DMSO-rfe) δ 8.30 (d, 1H), 8.00 (s, 1H), 7.86 (d, 1H), 7.40-7.45 (m, 1H), 4.18 (s, 2H ). Mass spectrum w/ζ·· 215.12 [M+H, 79Br], 217.10 [M+H, 81Br]. (3) Preparation of 8-bromoimidazole [1, 5- a] pyridine: a toluene solution of N-(3-bromopyridin-2-yl)methylformamide (0.645 g, 3 mmol) with stirring Phosphorus oxychloride (1 mL) was added to (4 mL). The mixture was refluxed for 7 hours. Excess phosphorus oxychloride and solvent were removed by rotary evaporation, and the resulting viscous liquid was hydrolyzed with ice water at 0 ° C and basified with concentrated aqueous ammonia. The aqueous phase was extracted with EtOAc (EtOAc)EtOAc. The results of the identification of the obtained product: 1H-NMR (DMS0-) δ 8.65 (d, 1H), 7.86 (s, 1H), 7.10-7.25 (m, 3H). Mass spectrum m / z: 197.05 [M + H, 79 Br], 198.95 [M + H, 81 Br].
( 4 ) 8-溴 -1-硝基咪唑 [1, 5-a]并吡啶的制备: 往 8-溴咪唑 [l, 5-a]并吡啶的硫酸氢盐 (0. 295 g, 1 mmol , 按照下列文献制备: Glover, E. E.; Peck, L. W. J. Chem. Soc, Perkin Trans. I 1980, 959-962)的醋酸溶液(2 mL) 加入硝酸 (70% w/w, 130 mg)。 所得混合物于 100。C加热搅拌约 1分钟, 生成的红色溶 液立即用冰水冷却。 该反应混合物用饱和碳酸氢纳水溶液中和至 pH « 8-9, 用 DCM萃 取(3x10 mL),有机相合并、干燥、硅胶柱层析纯化 (EtOAc/hexane: 1/4)得目标产物 0. 087 g (得率: 36%)。 所得产物的鉴定结果: 1H-NMR (DMSO-i/6) δ 8.68(d, 1H), 7.77 (s, 1H), 7.00-7.10 (m, 2H).质谱 m/z: 242.05 [M+H, 79Br], 244.13 [M+H, 81Br]。 ( 5) 4- (1-硝基咪唑 [l,5-a]并吡啶 -8-基)苯胺的制备: 将 8-溴 -1 硝基咪唑 [1, 5-a]并吡啶(0. 242 g, 1 mmol), 4-氨基苯基硼酸 (0. 178 g, 1. 3 mmol)及 K2C03 (276 mg, 2瞧 ol)悬浮于 DME (16 mL)及水(4 mL)中, 并加入 Pd (PPh3) 4 (57. 8 mg, 0. 05 mmol)。 往所得混合物中鼓入氮气 5分钟, 然后在氮气下加热到 90 ° C 搅拌 18小时。 冷至室温后, 加入乙酸乙酯(15 mL)及水(10 mL)。 分离有机相, 水相用 乙酸乙酯 (3x15 mL)提取。 有机相合并、 干燥、 硅胶柱层析纯化 (MeOH/DCM: 4/96)得目 标产物 0. 193 g (得率: 76%)。 所得产物的鉴定结果: 1H- MR (DMSO-4) 5 8.37(d, 1H), 7.73 (s, 1H), 7.32 (d, 2H), 7.03 (d, 2H), 6.83 (d, 2H), 6.50 (d, 2H)。 质谱 w/z, 255.35 [M+H]。 (6) 终产物 l-[4-(l-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-苯基脲的制备: (4) Preparation of 8-bromo-1-nitroimidazo[1,5-]pyridinium: Hydrogen sulfate to 8-bromoimidazole [l, 5-a] pyridine (0. 295 g, 1 mmol Prepared according to the following literature: Glover, EE; Peck, LWJ Chem. Soc, Perkin Trans. I 1980, 959-962) Acetic acid solution (2 mL) Nitric acid (70% w/w, 130 mg) was added. The resulting mixture was at 100. C was heated and stirred for about 1 minute, and the resulting red solution was immediately cooled with ice water. The reaction mixture was neutralized with aq. EtOAc (aq. . 087 g (Year: 36%). Identification of the product obtained: 1H-NMR (DMSO-i/ 6 ) δ 8.68 (d, 1H), 7.77 (s, 1H), 7.00-7.10 (m, 2H). Mass m/z: 242.05 [M+H , 79Br], 244.13 [M+H, 81Br]. (5) Preparation of 4-(1-nitroimidazo[l,5-a]pyridin-8-yl)aniline: 8-Bromo-1 nitroimidazo[1, 5-a]pyridine (0. 242 g, 1 mmol), 4-aminophenylboronic acid (0.18 g, 1. 3 mmol) and K 2 C0 3 (276 mg, 2 瞧ol) suspended in DME (16 mL) and water (4 mL) , and added Pd (PPh 3 ) 4 (57. 8 mg, 0.05 mmol). Nitrogen gas was bubbled through the resulting mixture for 5 minutes, and then heated to 90 ° C under nitrogen for 18 hours. After cooling to room temperature, ethyl acetate (15 mL) and water (10 mL) were added. The organic phase was separated and aqueous was extracted with ethyl acetate (3×15 mL). The organic phase was combined, dried, and purified by silica gel column chromatography (MeOH/D. Identification of the obtained product: 1H-MR (DMSO-4) 5 8.37 (d, 1H), 7.73 (s, 1H), 7.32 (d, 2H), 7.03 (d, 2H), 6.83 (d, 2H), 6.50 (d, 2H). Mass spectrum w/z, 255.35 [M+H]. (6) Preparation of the final product l-[4-(l-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-phenylurea:
4 -(1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入苯基异氰酸酯 (238mg,2mmol),所得溶液于室温搅拌 0.5-5小时,反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶于甲醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5小时。 过滤除去 催化剂,滤液蒸干,粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→ 10/90)得目标产物 1-[4-(1- 氨基咪 1,5-&]并吡啶 -8-基)苯基] -3-苯基脲 583mg (得率: 85%)。其磁核共振和质谱的鉴 定结果为: 1H-NMR (DMSO-i/6) δ 8.39(d, 1H), 7.79(s, 1H), 7.54 (d, 2H), 7.43 (d, 2H), 7.23(d, 2H), 6.90(d, 2H), 6.51 (m, 3H)。 质谱 m/z: 344.42 [M+l]。 例 2 4-(1-Nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then phenyl isocyanate (238 mg, 2 mmol). -5 hours, the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAcjjjjjjjjj 8-yl)phenyl]-3-phenylurea 583 mg (yield: 85%). The results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 ) δ 8.39 (d, 1H), 7.79 (s, 1H), 7.54 (d, 2H), 7.43 (d, 2H), 7.23(d, 2H), 6.90(d, 2H), 6.51 (m, 3H). Mass spectrum m/z: 344.42 [M+l]. Example 2
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程: 步骤 (1 ) 〜 (5 ) 均与例 1相同。 2. Preparation process: Steps (1) to (5) are the same as in Example 1.
(6)终产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(2-氟 -5-甲基苯基)脲的制备: 4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM2 5mL), 然后 加入 2-氟 -5-甲基苯基异氰酸酯 (302mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应 用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶 于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5 小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98-^10/90) 得目标产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-氟 -5-甲基苯基)脲 608mg (得 率: 81%)。其磁核共振和质谱的鉴定结果为: 1H-NMR (DMS0- ) δ 8.39(d, 1H), 7.74(s, IH), 7.54 (d, 2H), 7.43 (d, 2H), 7.37 (s, IH), 6.55-6.71(m, 4H), 2.32(s, 3H)。 质谱 m/z.' 376. 32 [M+l] o 例 3 (6) Preparation of the final product 1-[4-(1-aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea 4-(1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM2 5 mL), then 2-fluoro-5-methylphenylisocyanate (302 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen. hour. The catalyst was removed by filtration, and the filtrate was evaporated to dryness (mjjjjjjjjjjjj Pyridine-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea 608 mg (yield: 81%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMS0-) δ 8.39 (d, 1H), 7.74 (s, IH), 7.54 (d, 2H), 7.43 (d, 2H), 7.37 (s , IH), 6.55-6.71 (m, 4H), 2.32 (s, 3H). Mass spectrum m/z.' 376. 32 [M+l] o Example 3
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 )均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6 )终产物 1-[4-(1-氨基咪 [l,5-a]并吡啶 -8-基)苯基] -3-(4-氟 -3-甲基苯基)脲的制备 (6) Preparation of the final product 1-[4-(1-aminomi[l,5-a]pyridin-8-yl)phenyl]-3-(4-fluoro-3-methylphenyl)urea
4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM2 5mL), 然后 加入 4-氟 -3-甲基苯基异氰酸酯 (302mg,2mmOl), 所得溶液于室温搅拌 0.5-5小时, 反应 用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶 于甲醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5 小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98- 10/90) 得目标产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(4-氟 -3-甲基苯基)脲 638mg (得 率: 85%)。 其磁核共振和质谱的鉴定结果为- 1H-NMR(DMSO-i/6) 8.39(d,lH),7.74(s,lH),7.54(d,2H),7.43(d,2H), 4- (1-nitro-imidazo [1, 5-a] pyridine-8-yl) aniline (508mg, 2mmol dissolved in DCM2 5mL), then 4-fluoro-3-methylphenyl isocyanate (302m g, 2 mm O l), the resulting solution was stirred at room temperature for 0.5-5 hours, and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -8-yl)phenyl]-3-(4-fluoro-3-methylphenyl)urea 638 mg (yield: 85%). The results of the magnetic resonance and mass spectrometry were -1H-NMR (DMSO-i/ 6 ) 8.39 (d, lH), 7.74 (s, lH), 7.54 (d, 2H), 7.43 (d, 2H),
7.20-7.35(m,3H),6.60-6.73(m,2H), 2.30(s, 3H)。 质谱 Λ: 376. 43 [M+l]。 7.20-7.35 (m, 3H), 6.60-6.73 (m, 2H), 2.30 (s, 3H). Mass spectrometry Λ: 376. 43 [M+l].
例 4 Example 4
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6)终产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-氟 -4-甲基苯基)脲的制备 (6) Preparation of the final product 1-[4-(1-aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(3-fluoro-4-methylphenyl)urea
4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 3-氟 -4-甲基苯基异氰酸酯 (302mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应 用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶 于甲醇(25 mL), 并在氮气下加入 10% Pd/C (50 rag) , 所得混合物于室温常压氢化 2-5 小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90) 得目标产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-氟 -4-甲基苯基)脲 631mg (得 率: 84%)。其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i 6) δ 8.39(d, IH), 7.74(s, IH), 7.54 (d, 2H), 7.43 (d, 2H), 7.27-7.40(m,3H),6.60-6.72(m, 2H), 2.32(s, 3H)。 质谱 4-(1-Nitroimidazo[1,5-]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 3-fluoro-4-methylphenylisocyanate (302 mg, 2 mmol) The resulting solution was stirred at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 rag) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. The target product 1-[4-(1-aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(3-fluoro-4-methylphenyl)urea 631mg (yield : 84%). The results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) δ 8.39 (d, IH), 7.74 (s, IH), 7.54 (d, 2H), 7.43 (d, 2H), 7.27 - 7.40 (m, 3H), 6.60-6.72 (m, 2H), 2.32 (s, 3H). Mass spectrometry
376. 28 [M+l]。 376. 28 [M+l].
例 5 Example 5
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6)终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-三氟甲基 -5-氟苯基)脲的制 备:  (6) The final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-trifluoromethyl-5-fluorophenyl)urea Preparation:
4- (1-硝基咪唑[1, 5-a]并吡啶 - 8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 3-氟 -4-甲基苯基异氰酸酯 (410mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应 用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶 于甲醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5 小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90) 得目标产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-三氟甲基 -5-氟苯基)脲 644mg (得率: 75%)。,其磁核共振和质谱的鉴定结果为: 1H-NMR (DMS0- ) δ 8.39(d, IH), 7.74(s, IH), 7.55 (d, 2H), 7.46 (d, 2H),7.37-7.49(m,2H),6.60-6.78(m,3H), 2.32(s, 3H)。 质谱 m/z: 430. 41 [M+l]。 例 6  4-(1-Nitroimidazo[1,5-a]pyridin-3-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 3-fluoro-4-methylphenylisocyanate (410 mg, 2 mmol) The resulting solution was stirred at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -8-yl)phenyl]-3-(2-trifluoromethyl-5-fluorophenyl)urea 644 mg (yield: 75%). The results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMS0-) δ 8.39 (d, IH), 7.74 (s, IH), 7.55 (d, 2H), 7.46 (d, 2H), 7.37- 7.49 (m, 2H), 6.60-6.78 (m, 3H), 2.32 (s, 3H). Mass spectrum m/z: 430. 41 [M+l]. Example 6
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6 ) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-氟苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluorophenyl)urea:
4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 2-氟苯基异氰酸酯 (274mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(2-氟苯基)脲 549mg (得率: 76%)。 其磁核共 振和质谱的鉴定结果为: 1H-NMR(DMSO-i/6)S 8.39(d,lH),7.68-7.79(m, 2H), 7.54 (d, 2H), 7.43 (d,2H),6.98-7.15(m,3H),6.55-6.71(m,2H)。 质谱/ ζ/Λ: 362. 33 [M+l]。 4-(1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 2-fluorophenylisocyanate (274 mg, 2mmol). Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. Filter The catalyst was removed, and the filtrate was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjj 8-yl)phenyl]-3-(2-fluorophenyl)urea 549 mg (yield: 76%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 )S 8.39 (d, lH), 7.68-7.79 (m, 2H), 7.54 (d, 2H), 7.43 (d, 2H) ), 6.98-7.15 (m, 3H), 6.55-6.71 (m, 2H). Mass Spectrum / ζ/Λ: 362. 33 [M+l].
例 7 Example 7
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6) 终产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-氟苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazole [l,5-a]pyridin-8-yl)phenyl]-3-(3-fluorophenyl)urea:
4- (1-硝基咪唑 [1 , 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 3-氟苯基异氰酸酯 (27.4mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物4-(1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 3-fluorophenylisocyanate (27.4mg, 2mmol) Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAcjjjjjj
1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-氟苯基)脲 549mg (得率: 76%)。 其磁核共 振和质谱的鉴定结果为: 1H-NMR (DMSO-de) δ 8.41(d, 1H), 7.75(d, H), 7.54 (d, 2H), 7.431-[4-(1-Aminoimidazole [l,5-a]pyridin-8-yl)phenyl]-3-(3-fluorophenyl)urea 549 mg (yield: 76%). The results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-de) δ 8.41 (d, 1H), 7.75 (d, H), 7.54 (d, 2H), 7.43
(d, 2H),7.12-7.25(m,3H),6.58-6.72(m,3H)。 质谱 m/z 362. 37 [M+l]。 例 8 (d, 2H), 7.12-7.25 (m, 3H), 6.58-6.72 (m, 3H). Mass spectrum m/z 362. 37 [M+l]. Example 8
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(4-氟苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-fluorophenyl)urea:
4-(1-硝基咪唑[ 1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 4-氟苯基异氰酸酯 (274mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物4-(1-nitroimidazo[1, 5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 4-fluorophenylisocyanate (274 mg, 2mmol) Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAcjjjjjj
1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(4-氟苯基)脲 578mg (得率: 80%)。 其磁核共 振和质谱的鉴定结果为: 1H-NMR(DMSO-i 6)58.41(d,lH), 7.75(d, H), 7.54 (d, 2H), 7.38 (d, 2H), 7.17(d,2H),7.01(d,2H),6.59-6.73(m,2H)。 质谱 m/z'. 362. 28 [M+l]。 例 9 1、 一般实验条件: 与例 1相同。 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-fluorophenyl)urea 578 mg (yield: 80%). Its magnetic core The results of the vibration and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) 58.41 (d, lH), 7.75 (d, H), 7.54 (d, 2H), 7.38 (d, 2H), 7.17 (d, 2H) ), 7.01 (d, 2H), 6.59-6.73 (m, 2H). Mass spectrum m/z'. 362. 28 [M+l]. Example 9 1. General experimental conditions: The same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-甲基苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-methylphenyl)urea:
4 -(1-硝基咪唑 [1, 5- a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 2-甲基苯基异氰酸酯 (266mg, 2mmol),所得溶液于室温搅拌 0.5-5小时,反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2- 5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物4-(1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 2-methylphenylisocyanate (266 mg, 2mmol) Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAcjjjjjj
1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-甲基苯基)脲 521mg (得率: 73%)。 其磁核 共振和质谱的鉴定结果为: 1H-NMR(DMSO- 6) 68.41(d,lH), 7.75(d,H),7.54(d,2H),1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-methylphenyl)urea 521 mg (yield: 73%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO- 6 ) 68.41 (d, lH), 7.75 (d, H), 7.54 (d, 2H),
7.43(d,2H), 6.98-7.21(m,4H),6.55-6.68(m,2H),2.19(s,3H)。 质谱 m/z 358. 46 [M+l ]。 例 10 7.43 (d, 2H), 6.98-7.21 (m, 4H), 6.55-6.68 (m, 2H), 2.19 (s, 3H). Mass spectrum m/z 358. 46 [M+l]. Example 10
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6 ) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(3-甲基苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-methylphenyl)urea:
4 -(1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 3-甲基苯基异氰酸酯 (266mg, 2mmol),所得溶液于室温搅拌 0.5-5小时,反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 rag) , 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→ 10/90)得目标产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-甲基苯基)脲 557mg (得率: 78%)。 其磁核 共振和质谱的鉴定结果为: 1H-NMR (DMSO-c?6) δ 8.41(d, 1H), 7.75(d, H), 7.54 (d, 2H), 7.43 (d, 2H),7.22-7.35(m,3H),6.59-6.75(m,3H) , 2.32(s, 3H)。 质谱 m/z 358. 30 [M+l]。 例 11 4-(1-Nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 3-methylphenylisocyanate (266 mg, 2mmol) Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 rag) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -8-yl)phenyl]-3-(3-methylphenyl)urea 557 mg (yield: 78%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-c? 6 ) δ 8.41 (d, 1H), 7.75 (d, H), 7.54 (d, 2H), 7.43 (d, 2H), 7.22-7.35 (m, 3H), 6.59-6.75 (m, 3H), 2.32 (s, 3H). Mass spectrum m/z 358. 30 [M+l]. Example 11
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6 ) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(4-甲基苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-methylphenyl)urea:
4- (1-硝基咪唑[1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 4-甲基苯基异氰酸酯 (266mg, 2mmol),所得溶液于室温搅拌 0.5-5小时,反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物4-(1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 4-methylphenylisocyanate (266 mg, 2mmol) Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAcjjjjjj
1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(4-甲基苯基)脲 578mg (得率: 81%)。, 其磁 核共振和质谱的鉴定结果为: 1H-NMR(DMSO-i/6)S 8.4 l(d, 1H), 7.75(d, H), 7.54 (d, 2H),1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-methylphenyl)urea 578 mg (yield: 81%). , the results of magnetic resonance and mass spectrometry were: 1H-NMR (DMSO-i/ 6 )S 8.4 l(d, 1H), 7.75(d, H), 7.54 (d, 2H),
7.43 (d, 2H),7.26-7.40(m,4H),6.66-6.78(m,2H),2.32(s, 3H)。 质谱 m/z'. 358. 44 [M+l]。 例 12 7.43 (d, 2H), 7.26-7.40 (m, 4H), 6.66-6.78 (m, 2H), 2.32 (s, 3H). Mass spectrum m/z'. 358. 44 [M+l]. Example 12
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6 ) 终产物 1-[4-(1-氨基咪挫 [1,5-a]并吡啶 -8-基)苯基] -3-( 2-氯苯基)脲的制备: 4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 2-氯苯基异氰酸酯 (306mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物 脲 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(2-氯苯基)脲 528mg (得率: 70%)。其磁核 共振和质谱的鉴定结果为: 1H-NMR(DMSO-i 6)58.39(d,lH), 7.72-7.82(m, 2H), 7.54 (d, 2H); 7.43 (d,2H),6.99-7.20(m,3H),6.56-6.72(m,2H) 。 质 谱 m/z 377.08[M+1,35C1], 379.04[M+1,37C1]。 例 13 (6) Preparation of the final product 1-[4-(1-aminomidcon [1,5-a]pyridin-8-yl)phenyl]-3-(2-chlorophenyl)urea: 4- ( 1-Nitroimidazole [1, 5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 2-chlorophenylisocyanate (306 mg, 2 mmol). -5 hours, the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjj Pyridine-8-yl)phenyl]-3-(2-chlorophenyl)urea 528 mg (yield: 70%). The results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) 58.39 (d, lH), 7.72-7.82 (m, 2H), 7.54 (d, 2H) ; 7.43 (d, 2H), 6.99-7.20 (m, 3H), 6.56-6.72 (m, 2H). Mass spectrum m/z 377.08 [M+1, 35 C1], 379.04 [M+1, 37 C1]. Example 13
1、 一般实验条件: 与例 1相同。 2、 制备过程: 1. General experimental conditions: The same as in Example 1. 2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6 ) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(3-氯苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-chlorophenyl)urea:
4- (1-硝基咪唑 [1, 5- a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 3-氯苯基异氰酸酯 (306mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物4-(1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 3-chlorophenylisocyanate (306 mg, 2mmol) Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAcjjjjjj
1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(3-氯苯基)脲 550mg (得率: 73%)。 其磁核共 振和质谱的鉴定结果为: 1H-NMR(DMSO-i/6)S8.41(;d,lH),7.72-7.83(m, 2H), 7.55 (d, 2H),1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-chlorophenyl)urea 550 mg (yield: 73%). The results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 )S8.41 (;d,lH), 7.72-7.83 (m, 2H), 7.55 (d, 2H),
7.44 (d, 2H),7.15-7.28(m,3H),6.58-6.72(m,2H) 。 质 谱 m/z : 377.11 [M+1,35C1],7.44 (d, 2H), 7.15-7.28 (m, 3H), 6.58-6.72 (m, 2H). Mass spectrum m/z : 377.11 [M+1, 35 C1],
379.18[M+l,37Cl 例 14 1、 一般实验条件: 与例 1相同。 379.18 [M+l, 37 Cl Example 14 1. General experimental conditions: same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6 ) 终产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(4-氯苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(4-chlorophenyl)urea:
4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 4-氯苯基异氰酸酯 (306mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2- 5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98 10/90)得目标产物4-(1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 4-chlorophenylisocyanate (306 mg, 2mmol) Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAc m.
1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(4-氯苯基)脲 565mg (得率: 75%)。 其磁核共 振和质谱的鉴定结果为: 1H-NMR(DMSO-i/6)S8.41(d, 1H), 7.75(d, H), 7.55 (d, 2H), 7.45(d,1-[4-(1-Aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(4-chlorophenyl)urea 565 mg (yield: 75%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 )S8.41 (d, 1H), 7.75 (d, H), 7.55 (d, 2H), 7.45 (d,
2H), 7.32(d,2H),6.98(d,2H),6.57-6.70(m,2H) 。 质 谱 m/z 377.03[M+1,35C1],2H), 7.32 (d, 2H), 6.98 (d, 2H), 6.57-6.70 (m, 2H). Mass spectrum m/z 377.03 [M+1, 35 C1],
379.08[M+l,37Cl 例 15 379.08[M+l, 37 Cl Example 15
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
、 制备过程:  , Preparation Process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。 ( 6 ) 终产物 l-[4-(l-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-( 2-溴苯基)脲的制备: 4 -(1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 2-溴苯基异氰酸酯 (386mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-( 2-溴苯基)脲 574mg (得率: 68%)。其磁核共 振和质谱的鉴定结果为: 1H-NMR (DMSO- ) δ 8.39(d, 1H), 7.75(m, 2H), 7.55 (d, 2H), 7.44 (d, 2H),6.98-7.16(m,3H),6.55-6.70(m,2H) 。 质 谱 m/z : 422.33[M+l,79Br], 424.28[M+l,81Br]。 例 16 Steps (1) to (5) are the same as in Example 1. (6) Preparation of the final product l-[4-(l-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-bromophenyl)urea: 4 -(1 -Nitroimidazole [1, 5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 2-bromophenylisocyanate (386 mg, 2 mmol). After 5 hours, the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -8-yl)phenyl]-3-(2-bromophenyl)urea 574 mg (yield: 68%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO- ) δ 8.39 (d, 1H), 7.75 (m, 2H), 7.55 (d, 2H), 7.44 (d, 2H), 6.98-7.16 (m, 3H), 6.55-6.70 (m, 2H). Mass spectrum m / z: 422.33 [M + l, 79 Br], 424.28 [M + l, 81 Br]. Example 16
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6 ) 终产物 1-[4-(1-氨基咪 ¾l,5-a]并吡啶 -8-基)苯基] -3-(3-溴苯基)脲的制备- (6) Preparation of the final product 1-[4-(1-aminomethane, 5-a]pyridin-8-yl)phenyl]-3-(3-bromophenyl)urea-
4 -(1-硝基咪唑 [1, 5- a]并吡啶 - 8-基)苯胺(508mg, 2mmol溶解于 DCM 25raL), 然后 加入 3-溴苯基异氰酸酯 (386mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。反应完成后,旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(3-溴苯基)脲 600mg (得率: 71%)。 其磁核共 振和质谱的鉴定结果为: 1H-NMR(DMSO-i/6)58.41(d,lH),7.67-7.77(m, 2H), 7.55 (d, 2H), 7.44 (d, 2H),7.18-7.30(m,3H),6.60-6.75(m,2H) 。 质 谱 m/z : 422.10[M+l,7¾r], 424.16[M+l,81Br]。 例 17 4-(1-Nitroimidazo[1,5-a]pyridine-3-yl)aniline (508 mg, 2 mmol dissolved in DCM 25raL), then 3-bromophenylisocyanate (386 mg, 2mmol). Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -8-yl)phenyl]-3-(3-bromophenyl)urea 600 mg (yield: 71%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 ) 58.41 (d, lH), 7.67-7.77 (m, 2H), 7.55 (d, 2H), 7.44 (d, 2H) , 7.18-7.30 (m, 3H), 6.60-6.75 (m, 2H). Mass spectrum m/z: 422.10 [M+l, 7 3⁄4r], 424.16 [M+l, 81 Br]. Example 17
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6) 终产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(4-溴苯基)脲的制备: 4 -(1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后 加入 4-溴苯基异氰酸酯 (386mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2_5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物(6) Preparation of the final product 1-[4-(1-aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(4-bromophenyl)urea: 4-(1-Nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then 4-bromophenylisocyanate (386 mg, 2 mmol). Stir at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAcjjjjjj
1- [4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(4-溴苯基)脲 633mg (得率: 75%)。 其磁核共 振和质谱的鉴定结果为: 1H-NMR(DMSO-i 6) 58.41(d,lH), 7.75(d,H), 7.54(d,2H), 7.40(d,2H), 7.20(d,2H),7.01(d,2H),6.59-6.73(m,2H) 。 质谱 m/z: 422.28[M+l,79Br], 424.31 [M+l,81Br]。 例 18 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-bromophenyl)urea 633 mg (yield: 75%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) 58.41 (d, lH), 7.75 (d, H), 7.54 (d, 2H), 7.40 (d, 2H), 7.20 ( d, 2H), 7.01 (d, 2H), 6.59-6.73 (m, 2H). Mass spectrum m / z: 422.28 [M + l, 79 Br], 424.31 [M + l, 81 Br]. Example 18
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
( 6 )终产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-( 2-三氟甲基苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(2-trifluoromethylphenyl)urea:
4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后加入4-(1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then added
2-三氟甲基苯基异氰酸酯 (374mg, 2mmol),所得溶液于室温搅拌 0.5-5小时,反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-三氟甲基苯基)脲 534mg (得率: 65%)。 其 磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i 6) δ 8.41(d, 1H), 7.75(d, H), 7.54 (d, 2H), 7.43 (d, 2H),7.30-7.45(m,4H),6.66-6.78 2-Trifluoromethylphenylisocyanate (374 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 h and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -8-yl)phenyl]-3-(2-trifluoromethylphenyl)urea 534 mg (yield: 65%). The results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) δ 8.41 (d, 1H), 7.75 (d, H), 7.54 (d, 2H), 7.43 (d, 2H), 7.30 -7.45 (m, 4H), 6.66-6.78
(m,2H)。 质谱 412.47[M+1]。 例 19 (m, 2H). Mass spectrum 412.47 [M + 1]. Example 19
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6 ) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(3-三氟甲基苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-trifluoromethylphenyl)urea:
4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后加入 3-三氟甲基苯基异氰酸酯 (374mg, 2mmol),所得溶液于室温搅拌 0.5-5小时,反应用 TLC 跟踪。反应完成后,旋转蒸发除去溶剂,得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2- 5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90)得目标产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-三氟甲基苯基)脲 534mg (得率: 65%)。 其 磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i e) δ 8.41(d, 1H), 7.75-7.85(m, 2H), 7.54 (d, 2H), 7.43 (d, 2H),7.33-7.46(m,3H), 4-(1-nitroimidazo[1, 5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL) 3-Trifluoromethylphenylisocyanate (374 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 h and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -8-yl)phenyl]-3-(3-trifluoromethylphenyl)urea 534 mg (yield: 65%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i e) δ 8.41 (d, 1H), 7.75-7.85 (m, 2H), 7.54 (d, 2H), 7.43 (d, 2H) ,7.33-7.46(m,3H),
6.66-6.78(m,2H)。 质谱 ζ?Λ: 412.37[M+1]。 例 20 6.66-6.78 (m, 2H). Mass Spectrum ζ?Λ: 412.37 [M+1]. Example 20
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(4-三氟甲基苯基)脲的制备: 4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后加入 (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-trifluoromethylphenyl)urea: 4 - (1-nitroimidazo[1, 5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then added
4-三氟甲基苯基异氰酸酯 (374mg, 2mmol),所得溶液于室温搅拌 0.5-5小时,反应用 TLC 跟踪。反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5小时。 过滤 除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90)得目标产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(4-三氟甲基苯基)脲 559mg (得率: 69%)。 其 磁核共振和质谱的鉴定结果为:1 H-NMR (DMS0- ) δ 8.40(d, 1H), 7.74(d, H), 7.53(d, 2H), 7.41 (d, 2H), 7.20-7.33(m,4H),6.59-6.73 4-Trifluoromethylphenylisocyanate (374 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 h and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -8-yl)phenyl]-3-(4-trifluoromethylphenyl)urea 559 mg (yield: 69%). The results of magnetic resonance and mass spectrometry were as follows: 1 H-NMR (DMS0- ) δ 8.40 (d, 1H), 7.74 (d, H), 7.53 (d, 2H), 7.41 (d, 2H), 7.20- 7.33 (m, 4H), 6.59-6.73
(m,2H)。 质谱 Λ/Λ: 412.40[M+1]。 例 21 (m, 2H). Mass Spectrum Λ/Λ: 412.40 [M+1]. Example 21
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-三氟甲氧基苯基)脲的制 备:  (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-trifluoromethoxyphenyl)urea:
4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后加入 2-三氟甲氧基苯基异氰酸酯 (406mg,0.2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶于甲 醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90)得目标 产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-三氟甲氧基苯基)脲 538mg (得率: 63%)。 其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i/6) δ 8.40(d, 1H), 7.74(d, H), 7.48-7.53(m, 3H), 7.41 (d,2H),6.89-7.00(m,3H),6.59-6.73(m,2H)。 质谱 n/z: 428.40[M+1]。 例 22 1、 一般实验条件: 与例 1相同。 4-(1-nitroimidazo[1, 5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL) 2-Trifluoromethoxyphenyl isocyanate (406 mg, 0.2 mmol), the resulting solution was stirred at room temperature for 0.5-5 h. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness (mjjjjjjjjjjjjj -8-yl)phenyl]-3-(2-trifluoromethoxyphenyl)urea 538 mg (yield: 63%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 ) δ 8.40 (d, 1H), 7.74 (d, H), 7.48-7.53 (m, 3H), 7.41 (d, 2H) ), 6.89-7.00 (m, 3H), 6.59-6.73 (m, 2H). Mass spectrum n/z: 428.40 [M + 1]. Example 22 1. General experimental conditions: The same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6) 终产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-三氟甲氧基苯基)脲的制 备- 4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺 (508mg, 2mmol溶解于 DCM 25mL), 然后加入 (6) Preparation of the final product 1-[4-(1-aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(3-trifluoromethoxyphenyl)urea- 4-(1-nitroimidazo[1, 5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL)
3-三氟甲氧基苯基异氰酸酯 (406mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶于甲 醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90)得目标 产物 1-[4-(1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-三氟甲氧基苯基)脲 555mg (得率: 65%)。 其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO- 6) δ 8.40(d, 1H), 7.74(d, H), 7.53(d,3H),7.41(d,2H), 7.11-7.23(m,3H), 6.58-6.70(m,3H)。 质谱 m/z'. 428.28[M+1]。 例 23 1、 一般实验条件: 与例 1相同。 3-Trifluoromethoxyphenyl isocyanate (406 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 h. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd / C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -8-yl)phenyl]-3-(3-trifluoromethoxyphenyl)urea 555 mg (yield: 65%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO- 6 ) δ 8.40 (d, 1H), 7.74 (d, H), 7.53 (d, 3H), 7.41 (d, 2H), 7.11- 7.23 (m, 3H), 6.58-6.70 (m, 3H). Mass spectrum m/z'. 428.28 [M+1]. Example 23 1. General experimental conditions: The same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 1相同。  Steps (1) to (5) are the same as in Example 1.
(6) 终产物 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(4-三氟甲氧基苯基)脲的制 备:  (6) Preparation of the final product 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-trifluoromethoxyphenyl)urea:
4- (1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺(508mg, 2mmol溶解于 DCM 25mL), 然后加入4-(1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (508 mg, 2 mmol dissolved in DCM 25 mL), then added
4-三氟甲氧基苯基异氰酸酯 (406mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶于甲 醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得目标 产物脲 1-[4-(1-氨基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(4-三氟甲氧基苯基)脲 564mg (得率: 66%)。 其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-de) δ 8.41(d, 1H), 7.75(d, H), 7.54 (d, 2H), 7.40 (d, 2H), 7.15(d,2H),6.79(d,2H),6.59-6.73(m,2H)。质谱 m/z 428.31 [M+1]。 例 24 4-Trifluoromethoxyphenyl isocyanate (406 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 hours, for reaction TLC tracking. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness (mjjjjjjjjjjjjj Pyridine-8-yl)phenyl]-3-(4-trifluoromethoxyphenyl)urea 564 mg (yield: 66%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-de) δ 8.41 (d, 1H), 7.75 (d, H), 7.54 (d, 2H), 7.40 (d, 2H), 7.15 ( d, 2H), 6.79 (d, 2H), 6.59-6.73 (m, 2H). Mass spectrum m/z 428.31 [M+1]. Example 24
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
( 1 ) (3-溴吡啶 -2-基)甲胺盐酸盐的制备  (1) Preparation of (3-bromopyridin-2-yl)methylamine hydrochloride
在氮气保护下, 将 3-溴 -2-氰基吡啶(1. 83 g, 10 mmol)溶解于 50毫升干 THF中, 于该溶液中缓慢滴加 1M BH3 · THF (50 mL, 50 mmol) , 加完后, 此混合物在室温下搅拌 24小时, 过量的 BH3小心用 30毫升 MeOH淬灭。 用旋转蒸发仪除去溶剂, 剩余物溶解于 DCM (lO mL)中, 并加入 4M HC1的二噁垸溶液(10 mL) , 生成的固体产物经过滤收集, 烘 干得目标化合物 1. 85 g (得率: 83%)。所得产物的鉴定结果: 1H-NMR (DMSO-c/6) S 8.36 (d, 1H), 7.83 (d, 1H), 7.45-7.50 (m, 1H), 4.53 (s, 2H).质谱 m/z: 187.04 [M+H, 79Br], 189.06 [M+H, 81Br]。 (2 ) (3_溴吡啶 -2-基)甲基乙酰胺的制备: Under nitrogen atmosphere, 3-bromo-2-cyanopyridine (1. 83 g, 10 mmol) was dissolved in 50 ml of dry THF, was slowly added dropwise to this solution 1M BH 3 · THF (50 mL , 50 mmol ) of the addition, the mixture was stirred at room temperature for 24 hours, an excess of BH 3 carefully quenched with 30 mL of MeOH. The solvent was removed by a rotary evaporator, the residue was dissolved in DCM (10 mL), and 4M HCl solution (10 mL) was added. The solid product was collected by filtration and dried to give the title compound 1.85 g ( Yield: 83%). Identification of the obtained product: 1H-NMR (DMSO-c/ 6 ) S 8.36 (d, 1H), 7.83 (d, 1H), 7.45-7.50 (m, 1H), 4.53 (s, 2H). z: 187.04 [M+H, 79 Br], 189.06 [M+H, 81 Br]. (2) Preparation of (3_bromopyridin-2-yl)methylacetamide:
将乙酸 (480 mg, 8 mmol)及 EDC.HC1 (1.917 g, 10 mmol)悬浮于 DCM (20 mL)中, 在 搅拌下,滴加二异丙基乙基胺 (2.585 g, 20 mmol)„加完后于室温搅拌半小时,加入 (3 - 溴吡啶 -2-基)甲胺盐酸盐 (0. 894 g, 4 mmol) , 继续搅拌 2小时。 旋转蒸发除去溶剂, 剩余物用硅胶柱层析纯化 (EtOAc)得目标产物, 得率: 90%。 所得产物的鉴定结果- 1H-NMR (DMSO-J6) δ 8.75(b, 1H), 8.43(d, 1H), 7.80 (d, 1H), 7.40-7.45 (m, 1H), 4.27 (s, 2H), 1.80 (s, 3H) o 质谱 229. 23 [M+H, 79Br] , 231. 14 [M+H, 81Br]。 Acetic acid (480 mg, 8 mmol) and EDC.HC1 (1.917 g, 10 mmol) were suspended in DCM (20 mL) and diisopropylethylamine (2.585 g, 20 mmol) was added dropwise with stirring After the addition was completed, the mixture was stirred at room temperature for half an hour, (3 - bromopyridin-2-yl)methylamine hydrochloride (0. 894 g, 4 mmol) was added and stirring was continued for 2 hr. The solvent was removed by rotary evaporation and the residue was applied to silica gel column . purified by chromatography (EtOAc) to give the desired product, yield: 90% of the resulting product identification results - 1H-NMR (DMSO-J 6) δ 8.75 (b, 1H), 8.43 (d, 1H), 7.80 (d, 1H), 7.40-7.45 (m, 1H ), 4.27 (s, 2H), 1.80 (s, 3H) o mass 229. 23 [m + H, 79 Br], 231. 14 [m + H, 81 Br] .
( 3 ) 8-溴- 3-甲基咪唑 [1, 5-a]并吡啶的制备:  (3) Preparation of 8-bromo-3-methylimidazo[1,5-]pyridinium:
在搅拌下, 于 (3-溴吡啶 - 2-基)甲基乙酰胺 (0. 687g, 3 mmol)的甲苯溶液 (4 mL) 中加入三氯氧磷 (1 mL)。将此混合物回流 7小时。旋转蒸发除去过量的三氯氧磷及溶剂, 得到的粘稠液体用 0° C的冰水水解, 并用浓氨水碱化。 水相用 DCM萃取 (3x10 mL) , 有 机相合并、 干燥、 硅胶柱层析纯化 (EtOAc)得目标产物, 得率: 72%。 所得产物的鉴定结 果: ^-NMR (DMSO- 6) δ 8.7 l(d, 1H), 7.82(s, 1H), 7.15-7.30 (m, 3H), 2.59 (s, 3H).质谱 m/z-. 211. 11 [M+H, 79Br], 213. 13 [M+H, 81Br]。 (4) 8-溴 -3-甲基 -1-硝基咪唑 [1, 5- a]并吡啶的制备: Phosphorus oxychloride (1 mL) was added to a solution of (3-bromopyridin-2-yl)methylacetamide (0. 687 g, 3 mmol) in toluene (4 mL). The mixture was refluxed for 7 hours. Excess phosphorus oxychloride and solvent were removed by rotary evaporation, and the resulting viscous liquid was hydrolyzed with ice water at 0 ° C and basified with concentrated aqueous ammonia. The aqueous phase was extracted with EtOAc (EtOAc)EtOAc. Identification of the obtained product: ^-NMR (DMSO- 6 ) δ 8.7 l (d, 1H), 7.82 (s, 1H), 7.15-7.30 (m, 3H), 2.59 (s, 3H). - 211. 11 [M+H, 79 Br], 213. 13 [M+H, 81 Br]. (4) Preparation of 8-bromo-3-methyl-1-nitroimidazo[1,5-a]pyridine:
8-溴— 3—甲基咪唑 5-a]并吡啶的硫酸氢盐 (0. 307g, 1 mmol , 按照下列文献制 备: Glover, E. E.; Peck, L. W. J. Chem. Soc., Perkin Trans. I 1980, 959—962) 的醋酸溶液 (2 mL)加入硝酸 (70% w/w, 130 rag) 所得混合物于 100°C加热搅拌约 1分 钟,生成的红色溶液立即用冰水冷却。该反应混合物用饱和碳酸氢纳水溶液中和至 pH 8-9, 用 DCM萃取(3xl0 mL), 有机相合并、 干燥、 硅胶柱层析纯化 (EtOAc/hexane: 1/4) 得目标产物, 得率: 28%。 所得产物的鉴定结果: 1H-NMR (DMSO-i/6) S 8.70(d, 1H), 7.81 (s, 1H), 7.00-7.10 (m, 2H), 2.49 (s, 3H).质谱 256. 02 [ +H, 79Br] , 258. 04 [M+H, 81Br]。 Hydrogen sulfate to 8 -bromo- 3 -methylimidazolium 5-a]pyridine (0. 307 g, 1 mmol, prepared according to the following literature: Glover, EE; Peck, LWJ Chem. Soc., Perkin Trans. I 1980 , 959-962) Acetic acid solution (2 mL) was added with nitric acid (70% w/w, 130 rag). The resulting mixture was heated and stirred at 100 ° C for about 1 minute, and the resulting red solution was immediately cooled with ice water. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate to pH 8-9, and extracted with DCM (3×10 mL), and the organic phase was combined, dried and purified by silica gel column chromatography (EtOAc/hexane: 1/4) Rate: 28%. Identification of the obtained product: 1H-NMR (DMSO-i/ 6 ) S 8.70 (d, 1H), 7.81 (s, 1H), 7.00-7.10 (m, 2H), 2.49 (s, 3H). 02 [ +H, 79 Br] , 258. 04 [M+H, 81 Br].
( 5 ) 4- (3-甲基 -1-硝基咪唑 [1, 5-a]并吡啶 -8-基)苯胺的制备:  (5) Preparation of 4-(3-methyl-1-nitroimidazo[1,5-]pyridin-8-yl)aniline:
将 8-溴 -3-甲基 -1-硝基咪唑 [1, 5- a]并吡啶(0. 256g, 1 mmol) , 4-氨基苯基硼酸 (0. 178 g, 1. 3 画 ol)及 K2C03 (276 mg, 2 mmol)悬浮于 DME (16 mL)及水(4 mL)中, 并 加入 Pd (PPh3) 4 (57. 8 mg, 0. 05 mmol)。 往所得混合物中鼓入氮气 5分钟, 然后在氮气 下加热到 90。(:搅拌 18小时。 冷至室温后, 加入乙酸乙酯(15 mL)及水(10 mL)。 分离 有机相,水相用乙酸乙酯(3x15 mL)提取。有机相合并、干燥、硅胶柱层析纯化 (MeOH/DCM : 4/96)得目标产物,得率: 82%。所得产物的鉴定结果: 1H-NMR (DMSO-i/6) δ 8.40(d, 1H), 7.74 (s, 1H), 7.36 (d, 2H), 7.00(d, 2H), 6.8 l(d, 2H), 6.51 (d, 2H), 2.71 (d, 2H)。 质谱 m/z 269. 33 [M+H] 0 8-Bromo-3-methyl-1-nitroimidazo[1,5-a] pyridine (0. 256 g, 1 mmol), 4-aminophenylboronic acid (0. 178 g, 1. 3 ol And K 2 C0 3 (276 mg, 2 mmol) was suspended in DME (16 mL) and water (4 mL), and Pd (PPh 3 ) 4 (57. 8 mg, 0.05 mmol). Nitrogen gas was bubbled through the resulting mixture for 5 minutes and then heated to 90 under nitrogen. (: stirring for 18 hours. After cooling to room temperature, ethyl acetate (15 mL) and water (10 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×15 mL). purified by chromatography (MeOH / DCM: 4/96) to give the desired product, yield: 82% of the resulting product identification results:. 1H-NMR (DMSO- i / 6) δ 8.40 (d, 1H), 7.74 (s, (H)H. ] 0
(6) 终产物 l-[4-(l-氨基 -3-甲基咪唑 [1,5-a]并吡啶 -8-基)苯基] -3-(2-氟 -5-甲基苯基) 脲的制备- (6) The final product l-[4-(l-amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylbenzene Base) Preparation of urea -
4- (3-甲基 -1-硝基咪唑 [1, 5- a]并吡啶 -8-基)苯胺(536mg, 2mmol)溶解于 DCM (25 mL) , 然后加入 2-氟 -5-甲基苯基异氰酸酯 (302mg, 2mmol), 所得溶液于室温搅拌 0.5-5 小时, 反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶于甲醇(25 mL), 并在氮气下加入 10% Pd/C (50 rag) , 所得混合物于室温常 压氢化 2-5 小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90)得目标产物 1-[4-(1-氨基 -3-甲基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(2-氟 -5-甲 基苯基) 脲 630mg (得率: 81%)。其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i/6) δ 8.42(d, 1H), 7.54 (d, 2H), 7.43 (d, 2H), 7.36(s, 1H), 6.52-6.68(m, 4H), 2.46(s, 3H) ,2.32(s, 3H)。 质谱 ζ/Λ: 390.27[M+1]。 例 25 4-(3-Methyl-1-nitroimidazo[1,5-a]pyridin-8-yl)aniline (536 mg, 2 mmol) was dissolved in DCM (25 mL) then 2-fluoro-5- Phenyl phenyl isocyanate (302 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 h. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 rag) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness (mjjjjjjjjj -a] pyridine-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea 630 mg (yield: 81%). The results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 ) δ 8.42 (d, 1H), 7.54 (d, 2H), 7.43 (d, 2H), 7.36 (s, 1H), 6.52-6.68 (m, 4H), 2.46 (s, 3H), 2.32 (s, 3H). Mass spectrum ζ/Λ: 390.27 [M+1]. Example 25
1、 一般实验条件: 与例 1相同。  1. General experimental conditions: Same as in Example 1.
1、 制备过程:  1, the preparation process:
步骤 (1 ) 〜 (5 ) 均与例 24相同。  Steps (1) to (5) are the same as in Example 24.
(6)终产物 1-[4-(1-氨基 -3-甲基咪 ¾l,5-a]并吡啶 -8-基)苯基] -3-(4-氟 -3-甲基苯基)脲 的制备- (6) The final product 1-[4-(1-amino-3-methylmethane, 5-a]pyridin-8-yl)phenyl]-3-(4-fluoro-3-methylphenyl) ) Preparation of urea -
4- (3-甲基-1 硝基咪唑[1, 5-&]并吡啶-8-基)苯胺(53611^, 2mmol)溶解于 DCM (25 mL) , 然后加入 4-氟 -3-甲基苯基异氰酸酯 ((302mg, 2mmol), 所得溶液于室温搅拌 0.5-5 小时, 反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常 压氢化 2-5 小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90)得目标产物 1-[4-(1-氨基 -3-甲基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(4-氟 -3-甲 基苯基) 脲 607mg (得率: 78%)。其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO- ) δ 8.42(d, 1H), 7.54(d, 2H), 7.43(d,2H),7.22-7.37(m,3H),6.62-6.75(m,2H), 2.46(s, 3H) ,2.32(s, 3H)。 质谱 ¾/ 390.20[M+1]。 例 26 4-(3-Methyl-1 nitroimidazo[1,5-]pyridin-8-yl)phenylamine (53611^, 2mmol) was dissolved in DCM (25 mL) then 4-fluoro-3-methyl Phenyl phenyl isocyanate ((302 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 hours, and the reaction was followed by TLC. After completion of the reaction, solvent was removed by rotary evaporation to give crude nitro-formed product. (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2-5 hours at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. DCM: 2/98→10/90) gave the target product 1-[4-(1-amino-3-methylimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(4) -fluoro-3-methylphenyl)urea 607 mg (yield: 78%). The results of magnetic resonance and mass spectrometry were: 1H-NMR (DMSO-) δ 8.42 (d, 1H), 7.54 (d, 2H), 7.43(d,2H), 7.22-7.37(m,3H), 6.62-6.75(m,2H), 2.46(s, 3H), 2.32(s, 3H). Mass Spectrum 3⁄4/ 390.20[M+1 Example 26
1、 一般实验条件: 与例 1相同。  1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5) 均与例 24相同。  Steps (1) to (5) are the same as in Example 24.
(6) 终产物 1-[4-(1-氨基 -3-甲基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-甲基苯基)脲的制 备:  (6) The final product 1-[4-(1-amino-3-methylimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(3-methylphenyl)urea Preparation:
4 - (3-甲基- 1-硝基咪唑 [l,5-a]并吡啶 - 8-基)苯胺(536mg, 2mmol)溶解于 DCM (25 mL) , 然后加入 3-甲基苯基异氰酸酯 (266mg,2mmol), 所得溶液于室温搅泮 0.5-5小时, 反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产 物溶于甲醇 (25 mL), 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5小时。过滤除去催化剂,滤液蒸干,粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90) 得目标产物 1-[4-(1-氨基 -3-甲基咪 ¾l,5-a]并吡啶 -8-基)苯基] -3- (3-甲基苯基)脲 557mg (得率: 75%) 。 其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i 6) δ 8.42(d,lH),7.54(d,2H),7.43(d,2H),7.22-7.35 (m,3H),6.60-6.75(m,3H),2.46(s,3H),2.32(s, 3H)。 质谱 372.44[M+1]。 例 27 4-(3-Methyl-1-nitroimidazo[l,5-a]pyridin-3-yl)aniline (536 mg, 2 mmol) was dissolved in DCM (25 mL) then 3-methylphenylisocyanate (266 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature under normal pressure for 2-5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. EtOAcjjjjjjjjjjj a] pyridine-8-yl)phenyl]-3-(3-methylphenyl)urea 557 mg (yield: 75%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) δ 8.42 (d, lH), 7.54 (d, 2H), 7.43 (d, 2H), 7.22-7.35 (m, 3H) , 6.60-6.75 (m, 3H), 2.46 (s, 3H), 2.32 (s, 3H). Mass spectrum 372.44 [M + 1]. Example 27
1、 一般实验条件: 与例 1相同。  1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 24相同。  Steps (1) to (5) are the same as in Example 24.
(6 ) 终产物 1-[4-(1-氨基 -3-甲基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(4-甲基苯基)脲的制 备:  (6) The final product 1-[4-(1-amino-3-methylimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(4-methylphenyl)urea Preparation:
4- (3-甲基- 1 -硝基咪唑 [ 1, 5- a]并吡啶 - 8-基)苯胺(536mg,2mmol)溶解于 DCM (25 mL) , 然后加入 4-甲基苯基异氰酸酯 (266mg, 2mmo0, 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产 物溶于甲醇 (25 mL) , 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室温常压氢化 2-5小时。过滤除去催化剂,滤液蒸干,粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90) 得目标产物 1-[4-(1-氨基 -3-甲基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3- ( 4-甲基苯基) 脲 603mg (得率: 81%)。其磁核共振和质谱的鉴定结果为: 1H-NMR (DMS0- ) δ 8.42(d, 1H), 7.54 (d, 2H), 7.43(d,2H),7.25-7.40(m,4H),6.63-6.78(m,2H), 2.46(s,3H),2.32(s, 3H)。 质谱 m/z: 372.38[M+1]。 例 28  4-(3-Methyl- 1 -nitroimidazo[1,5-a]pyridinyl 8-yl)aniline (536 mg, 2 mmol) was dissolved in DCM (25 mL) then 4-methylphenylisocyanate (266 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 hours, and the reaction was followed by TLC. After the reaction was completed, the solvent was removed by rotary evaporation to give the crude product of the crude nitro. The crude product was dissolved in methanol (25 mL). 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2-5 hours at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. 10/90) The desired product 1-[4-(1-amino-3-methylimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(4-methylphenyl) Urea 603mg (yield: 81%). The results of magnetic resonance and mass spectrometry were: 1H-NMR (DMS0-) δ 8.42 (d, 1H), 7.54 (d, 2H), 7.43 (d, 2H), 7.25-7.40 (m, 4H), 6.63-6.78 (m, 2H), 2.46 (s, 3H), 2.32 (s, 3H). Mass m/z: 372.38 [M+1].
1、 一般实验条件: 与例 1相同。  1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 24相同。  Steps (1) to (5) are the same as in Example 24.
( 6 )终产物 1-[4-(1-氨基 -3-甲基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3-(3-氟苯基)脲的制备: (6) Preparation of the final product 1-[4-(1-amino-3-methylimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(3-fluorophenyl)urea :
4- (3-甲基-1-硝基咪唑[ 1, 5-&]并吡啶-8-基)苯胺(536呵, 2mmol)溶解于 DCM (25 mL) , 然后加入 3-氟苯基异氰酸酯 (306mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反 应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产物。 此粗产物 溶于甲醇(25 mL), 并在氮气下加入 10% Pd/C (50 mg), 所得混合物于室温常压氢化 2-5 小时。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM : 2/98- 10/90) 得目标产物 1-[4-(1-氨基 -3-甲基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3- ( 3-氟苯基) 脲 547mg (得率: 70%)。其磁核共振和质谱的鉴定结果为: 1H-NMR (DMS0- ) δ 8.41 (d, 1H), 7.70 (s, H), 7.55 (d, 2H), 7.44 (d, 2H),7.15-7.28(m,3H),6.58-6.72(m,2H) ,2.46(s,3H)。 质谱 m/z: 391.34[M+1,35C1],393.21 [M+1,37C1]。 例 29 4-(3-Methyl-1-nitroimidazo[1,5-]-pyridin-8-yl)aniline (536 °, 2 mmol) was dissolved in DCM (25 mL) then 3-fluorophenylisocyanate (306 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 h. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours. The catalyst was removed by filtration, and the filtrate was evaporated to dryness (mjjjjjjjjjjjj -a] pyridine-8-yl)phenyl]-3-(3-fluorophenyl)urea 547 mg (yield: 70%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMS0-) δ 8.41 (d, 1H), 7.70 (s, H), 7.55 (d, 2H), 7.44 (d, 2H), 7.15-7.28 (m, 3H), 6.58-6.72 (m, 2H), 2.46 (s, 3H). Mass spectrum m/z: 391.34 [M+1, 35 C1], 393.21. [M+1, 37 C1]. Example 29
1、 一般实验条件: 与例 1相同。  1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (5 ) 均与例 24相同。  Steps (1) to (5) are the same as in Example 24.
(6) 终产物 1-[4-(1-氨基 -3-甲基咪 ¾l,5-a]并吡啶 -8-基)苯基] -3-(3-三氟甲基苯基)脲 的制备:  (6) The final product 1-[4-(1-amino-3-methylmethane,5-a]pyridin-8-yl)phenyl]-3-(3-trifluoromethylphenyl)urea Preparation:
4- (3-甲基-1-硝基咪唑[1,5-&]并吡啶-8-基)苯胺(536!¾, 0. 2mmol)溶解于 DCM (25 mL) , 然后加入 3-三氟甲基苯基异氰酸酯 (374mg, 0.2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗含硝基的脲产 物。 此粗产物溶于甲醇(25 mL) , 并在氮气下加入 10% Pd/C (50 mg) , 所得混合物于室 温常压氢化 2-5小吋。 过滤除去催化剂, 滤液蒸干, 粗产物硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90)得目标产物 1-[4-(1-氨基 -3-甲基咪挫 [1,5-a]并吡啶 -8-基)苯基] -3-G-三氟甲 基苯基) 脲 528mg (得率: 62%)。,其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i/6) δ 8.42(d,lH),7.75-7.87 (m, 2H), 7.54 (d, 2H), 7.43(d,2H),7.35-7.48 (m,3H),6.66-6.78(m,2H), 2.46(s,3H)。 质谱 426.32[M+1]。 例 30 4-(3-Methyl-1-nitroimidazo[1,5-&]pyridin-8-yl)aniline (536!3⁄4, 0.2 mmol) was dissolved in DCM (25 mL) then 3-3- The fluoromethylphenylisocyanate (374 mg, 0.2 mmol) was stirred at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude nitro-containing product. This crude product was dissolved in methanol (25 mL), and then 10% Pd/C (50 mg) was added under nitrogen, and the mixture was hydrogenated at room temperature for 2 to 5 hours under normal pressure. The catalyst was removed by filtration, and the filtrate was evaporated to dryness. m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5-a]pyridin-8-yl)phenyl]-3-G-trifluoromethylphenyl)urea 528 mg (yield: 62%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 ) δ 8.42 (d, lH), 7.75-7.87 (m, 2H), 7.54 (d, 2H), 7.43 (d, 2H), 7.35-7.48 (m, 3H), 6.66-6.78 (m, 2H), 2.46 (s, 3H). Mass spectrum 426.32 [M + 1]. Example 30
1、 一般实验条件: 与例 1相同。  1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
( 1 ) 叔丁基 -4-[6- (氨基甲基)吡啶 -2-基]苯氨基甲酸酯的制备  (1) Preparation of tert-butyl-4-[6-(aminomethyl)pyridin-2-yl]phenylcarbamate
将叔丁基 -4- (6-甲酰吡啶 -2-基)苯氨基甲酸酯 0.500克 (1.68mmol)溶于 3ml甲 醇中, 加 3ml氨水,室温下搅拌 2小时, 加入硼氢化钠(2eq),室温搅拌 5小时后, 低温 下加水除去多余的硼氢化钠, 加入乙醚萃取, 有机层用无水 Na2S04干燥后浓缩, 用硅 胶柱层析纯化 (EtOAc)得目标产物 0.36g (得率: 72%)。其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i 6) δ 8.16 (d, 2H), 7.83 (d, 2H), 6.93-7.15(m, 3H), 4.52 (s, 2H), 1.52 (s, 9H). 质谱 m/z: 300.15 [M+H]。 0.500 g (1.68 mmol) of tert-butyl-4-(6-formylpyridin-2-yl)phenylcarbamate was dissolved in 3 ml of methanol, and 3 ml of aqueous ammonia was added thereto, and the mixture was stirred at room temperature for 2 hours, and sodium borohydride was added thereto. 2eq), was stirred at room temperature for 5 hours and at a low temperature water was added to remove excess sodium borohydride was added and extracted with ether, the organic layer was dried over anhydrous Na 2 S0 4 dried and concentrated to give the desired product 0.36g was purified by silica gel column (EtOAc) with (Yield: 72%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) δ 8.16 (d, 2H), 7.83 (d, 2H), 6.93-7.15 (m, 3H), 4.52 (s, 2H) , 1.52 (s, 9H). Mass m/z: 300.15 [M+H].
( 2 ) 叔丁基 -4-[6-[(3-(4-甲氧苯基)硫脲基)甲基]吡啶 -2-基]苯氨基甲酸酯  (2) tert-Butyl-4-[6-[(3-(4-methoxyphenyl)thioureido)methyl]pyridin-2-yl]phenylcarbamate
将 4- (甲氧苯基)甲胺 1.38克 (lmmol) 和硫光气 1.15克 (lmmol) 加入 15ml的二 氯甲垸中, 加入 4.2ml三乙胺, 于室温下搅拌 3小时后加入 2.54克 (0.85mmol) 叔丁 基 -4-[6- (氨基甲基) B比啶 -2-基]苯氨基甲酸酯和 2.8ml三乙胺, 反应进行 8小时, 减压除 去溶剂后用硅胶柱层析纯化 (MeOH/DCM)得目标产物 2.6克 (得率: 65%)。其磁核共振和质 谱的鉴定结果为: 1H-NMR (DMSO-i/6) δ 8.16 (d, 2H), 7.83 (d, 2H), 6.93-7.15(m, 5H) ,6.80 (d, 2H), 4.52 (m, 4H), 3.52 (s, 3H),1.52 (s, 9H).质谱 miz'. 479.48 [M+H]。 1.38 g (1 mmol) of 4-(methoxyphenyl)methanamine and 1.15 g (1 mmol) of thiophosgene were added to 15 ml of dichloromethane, and 4.2 ml of triethylamine was added thereto, and the mixture was stirred at room temperature for 3 hours and then added to 2.54.克(0.85 mmol) tert-butyl-4-[6-(aminomethyl) B-pyridin-2-yl]phenylcarbamate and 2.8 ml of triethylamine, the reaction was carried out for 8 hours, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (MeOH/DMeOH) Magnetic resonance and quality The results of the spectrum identification are: 1H-NMR (DMSO-i/ 6 ) δ 8.16 (d, 2H), 7.83 (d, 2H), 6.93-7.15 (m, 5H), 6.80 (d, 2H), 4.52 (m , 4H), 3.52 (s, 3H), 1.52 (s, 9H). Mass spectrum miz'. 479.48 [M+H].
(3 ) 叔丁基 -4-(3-(4-甲氧苯基氨基)咪唑 [1,5-a]并吡啶 -5-基)苯氨基甲酸酯 取叔丁基 -4-[6-[(3-(4-甲氧苯基)硫脲基)甲基]吡啶 -2-基]苯氨基甲酸酯 0.48 克 ( lmmol) , Ν,Ν'-二环己基碳二亚胺 (DCC) 0.31 克(1.5mmol )溶于 5ml的无水甲苯中, 氮气保护下加热回流 2小时, 减压浓缩, 剩余物加入 4%的稀盐酸 15ml、 氯仿 10ml萃 取, 酸层用碳酸钾溶液中和析出目标化合物 0.27 克 (得率: 61%)。 其磁核共振和质谱的 鉴定结果为: 1H-NMR (DMSO-i 6) δ 8.16 (d, 2H), 7.83 (d, 2H), 6.95-7.15(m, 5H) ,6.80-6.95 (m, 3H), 4.33 (s, 2H), 3.52 (s, 3H),1.52 (s, 9Η)·质谱 m/z 445.38 [M+H]。 (3) tert-Butyl-4-(3-(4-methoxyphenylamino)imidazo[1,5-a]pyridin-5-yl)phenylcarbamate as tert-butyl-4-[6 -[(3-(4-methoxyphenyl)thioureido)methyl]pyridin-2-yl]phenylcarbamate 0.48 g (1 mmol) , hydrazine, Ν'-dicyclohexylcarbodiimide ( DCC) 0.31 g (1.5 mmol) was dissolved in 5 ml of anhydrous toluene, heated under reflux for 2 hours under nitrogen atmosphere, concentrated under reduced pressure, and the residue was added to 4% diluted hydrochloric acid 15 ml, chloroform 10 ml, and the acid layer was used in potassium carbonate solution. And the target compound was 0.27 g (yield: 61%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) δ 8.16 (d, 2H), 7.83 (d, 2H), 6.95-7.15 (m, 5H), 6.80-6.95 (m, (H, H).
(4) 5-(4-氨基苯基)咪唑 [l,5--a]并吡啶 -3-胺  (4) 5-(4-Aminophenyl)imidazole [l,5--]pyridin-3-amine
叔丁基 -4-(3-(4-甲氧苯基氨基)咪唑 [1,5-a]并吡啶 -5-基)苯氨基甲酸酯 1.33 克 (3 mmol), 溶于 10ml三氟乙酸和 0.5ml水中, 室温搅拌 2小时, 将反应产物倒入 50ml水 中, 用氯仿 15ml萃取, 水层加碳酸钠溶液中和后析出固体过滤干燥的目标化合物 0.61 克 (得率: 91%)。 其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i 6) δ 7.96 (d, 2H), 7.15-7.30 (m, 3H), 6.95 (m, 1H) ,6.66 (d, 2H). 质谱 m/z: 225.11 [M+H]。 Tert-butyl-4-(3-(4-methoxyphenylamino)imidazo[1,5-a]pyridin-5-yl)phenylcarbamate 1.33 g (3 mmol), dissolved in 10 ml of trifluoro Acetic acid and 0.5 ml of water were stirred at room temperature for 2 hours, and the reaction product was poured into 50 ml of water, and extracted with chloroform (15 ml). The aqueous layer was neutralized with sodium carbonate solution to precipitate a solid filtered product (0.61 g, yield: 91%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) δ 7.96 (d, 2H), 7.15-7.30 (m, 3H), 6.95 (m, 1H), 6.66 (d, 2H) Mass spectrum m/z: 225.11 [M+H].
( 5 ) 终产物 1- [4- (3-氨基咪唑 [1, 5- a]并吡啶 -5-基)苯基] -3- (4-三氟甲基苯基) 脲的制备:  (5) Preparation of the final product 1-[4-(3-aminoimidazo[1,5-a]pyridine-5-yl)phenyl]-3-(4-trifluoromethylphenyl)urea:
5- (4-氨基苯基)咪唑 [1, 5- a]并吡啶 -3-胺 0. 448克(2mmol)溶解于 DCM (25 mL), 然 后加入 4-三氟甲基苯基异氰酸酯 (374mg, 2mmol) , 所得溶液于室温搅拌 0. 5_5小时, 反 应用 TLC 跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗产物采用硅胶柱层析纯化 (MeOH/DCM : 2/98 10/90)得 1- [4- (3-氨基咪唑 [1, 5_a]并吡啶 -5-基)苯基] -3- (4-三氟 甲基苯基)脲 559mg (得率: 68%)。其磁核共振和质谱的鉴定结果为: 1H-NMR (DMSO-i¾) δ 8.16 (d, 2H), 7.83 (d, 2H), 7.58-7.65(m,4H),7.10-7.30 (m, 3H), 6.75 (m, 1H)。 质谱 m/z 412.17[M+1]。 例 31  5-(4-Aminophenyl)imidazo[1,5-a]pyridin-3-amine 0. 448 g (2 mmol) was dissolved in DCM (25 mL) then 4-trifluoromethylphenylisocyanate ( 374 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5_5 hours, and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to afford crude crystals eluted eluted eluted eluted elut elut elut elut -Phenyl]-3-(4-trifluoromethylphenyl)urea 559 mg (yield: 68%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i3⁄4) δ 8.16 (d, 2H), 7.83 (d, 2H), 7.58-7.65 (m, 4H), 7.10-7.30 (m, 3H) ), 6.75 (m, 1H). Mass spectrum m/z 412.17 [M + 1]. Example 31
1、 一般实验条件: 与例 1相同。  1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (4 ) 与例 30相同;  Steps (1) to (4) are the same as in Example 30;
( 5 ) 终产物 1-[4-(3-氨基咪唑 [l,5-a]并吡啶 -5-基)苯基] -3-(3-氟苯基)脲的制备: (5) Preparation of the final product 1-[4-(3-aminoimidazo[l,5-a]pyridine-5-yl)phenyl]-3-(3-fluorophenyl)urea:
5-(4-氨基苯基)咪唑 [1,5-a]并吡啶 -3-胺 0.448克 (2mmol)溶解于 DCM (25 mL) , 然后 加入 3-氟苯基异氰酸酯 (274mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗产物采用硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得 1-[4-(3-氨基咪唑 [l,5-a]并吡啶 -5-基)苯基] -3-(3-氟苯基)脲 556mg (得率: 77%)。, 其磁核共振和质谱的鉴定结果为: 1H- MR(DMSO-i/6) δ 8.16 (d, 2H), 7.83 (d, 2H), 7.72(s,lH),7.45-7.58(m, 3H),7.10-7.30 (m, 3H), 6.75 (m, 1H)。质谱 m/z: 362.02[M+1]。 5-(4-Aminophenyl)imidazo[1,5-a]pyridin-3-amine 0.448 g (2 mmol) dissolved in DCM (25 mL), then 3-Fluorophenyl isocyanate (274 mg, 2 mmol) was added and the resulting solution was stirred at room temperature for 0.5-5 h. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude material (yield: MeOH/DCM: 2/98→10/90) to give 1-[4-(3-aminoimidazole[l,5-a] Pyridine-5-yl)phenyl]-3-(3-fluorophenyl)urea 556 mg (yield: 77%). , the results of magnetic resonance and mass spectrometry are: 1H- MR (DMSO-i/ 6 ) δ 8.16 (d, 2H), 7.83 (d, 2H), 7.72 (s, lH), 7.45-7.58 (m, 3H), 7.10-7.30 (m, 3H), 6.75 (m, 1H). Mass spectrum m/z: 362.02 [M + 1].
例 32 Example 32
1、 一般实验条件: 与例 1相同。  1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (4) 与例 30相同;  Steps (1) to (4) are the same as in Example 30;
( 5 )终产物 1-[4-(3-氨基咪唾 [1,5-a]并吡啶 -5-基)苯基] -3-(3-三氟甲基苯基)脲的制备: (5) Preparation of the final product 1-[4-(3-aminoimipa[1,5-a]pyridine-5-yl)phenyl]-3-(3-trifluoromethylphenyl)urea:
5-(4-氨基苯基)咪唑 [1,5-a]并吡啶 -3-胺 0.448克 (2ramol)溶解于 DCM (25 mL) , 然后 加入 3-三氟甲基苯基异氰酸酯 (2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC 跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗产物采用硅胶柱层析纯化 (MeOH/DCM : 2/98- 10/90)得 1-[4-(3-氨基咪唑 [1,5-a]并吡啶 -5-基)苯基] -3-(3-三氟甲基苯基)脲 56.4mg (得率: 66%)。,其磁核共振和质谱的鉴定结果为: 1H-NMR(DMSO-i/6) S 8.16 (d, 2H), 7.93 (s, lH),7.83(d,2H),7.35-7.48(m,3H),7.10-7.30 (m, 3H), 6.75 (m, 1H)。 质谱 m/z: 412.14[M+1]。 例 33 5-(4-Aminophenyl)imidazo[1,5-a]pyridin-3-amine 0.448 g (2ramol) was dissolved in DCM (25 mL) then 3-trifluoromethylphenylisocyanate (2mmol) The resulting solution was stirred at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude material (yield: MeOH/DCM: 2/98 - 10/90) to give 1-[4-(3-aminoimidazole[1,5-a] Pyridine-5-yl)phenyl]-3-(3-trifluoromethylphenyl)urea 56.4 mg (yield: 66%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 ) S 8.16 (d, 2H), 7.93 (s, lH), 7.83 (d, 2H), 7.35-7.48 (m, 3H), 7.10-7.30 (m, 3H), 6.75 (m, 1H). Mass spectrum m/z: 412.14 [M + 1]. Example 33
1、 一般实验条件: 与例 1相同。  1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (4) 与例 30相同;  Steps (1) to (4) are the same as in Example 30;
( 5 ) 终产物 1-[4-(3-氨基咪唑 [1,5-a]并吡啶 -5-基)苯基] -3-(4-氟苯基)脲的制备: (5) Preparation of the final product 1-[4-(3-aminoimidazo[1,5-a]pyridine-5-yl)phenyl]-3-(4-fluorophenyl)urea:
5-(4-氨基苯基)咪唑 [1 ,5-a]并吡啶 -3-胺 0.448克(2mmol)溶解于 DCM (25 mL), 然后加 入 4-氟苯基异氰酸酯 (374mg,2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC跟 踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗产物采用硅胶柱层析纯化 (MeOH/DCM :5-(4-Aminophenyl)imidazo[1,5-a]pyridin-3-amine 0.448 g (2 mmol) was dissolved in DCM (25 mL), then 4-fluorophenylisocyanate (374mg, 2mmol) The resulting solution was stirred at room temperature for 0.5-5 hours and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude material.
2/98→10/90)得 1-[4-(3-氨基咪唑 [l,5-a]并吡啶 -5-基)苯基] -3-(4-氟苯基)脲 433mg (得率: 60%) 。 , 其 磁 核 共振和 质谱 的 鉴 定 结 果 为 : 1H-NMR(DMSO-i/6) δ2/98→10/90) 1-[4-(3-Aminoimidazo[l,5-a]pyridin-5-yl)phenyl]-3-(4-fluorophenyl)urea 433mg Rate: 60%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i/ 6 ) δ
8.16(d,2H),7.83(d,2H),7.60(d,2H),7.10-7.30 (m, 5H), 6.75 (m, 1H)。质谱 m/z'. 362· 16[Μ+1]。 例 34 8.16 (d, 2H), 7.83 (d, 2H), 7.60 (d, 2H), 7.10-7.30 (m, 5H), 6.75 (m, 1H). Mass spectrum m/z'. 362· 16 [Μ +1]. Example 34
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 )〜(4) 与例 30相同;  Steps (1) to (4) are the same as in Example 30;
(5 ) 终产物 1-[4-(3-氨基咪唑 [1,5-a]并吡啶 -5-基)苯基] -3-(4-三氟甲氧基苯基)脲的制 备:  (5) Preparation of the final product 1-[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(4-trifluoromethoxyphenyl)urea:
5-(4-氨基苯基)咪唑 [1,5-a]并吡啶 -3-胺 0.448克 (2mmol)溶解于 DCM (25 mL), 然后加 入 4-三氟甲氧基苯基异氰酸酯 (406mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应 用 TLC 跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗产物采用硅胶柱层析纯化 (MeOH/DCM: 2/98- 10/90)得 1-[4-(3-氨基咪唑 [1,5-a]并吡啶 -5-基)苯基] -3-(4-三氟甲氧基 苯基)脲 548mg (得率: 64%)。, 其磁核共振和质谱的鉴定结果为: 1H-NMR(DMSO-i 6) δ 8.16(d,2H),7.83(d,2H),7.49(d,2H),7.15-7.29 (m, 3H), 6.89(d,2H), 6.75 (m, 1H)。 质谱 429.36[M+l 例 35 5-(4-Aminophenyl)imidazo[1,5-a]pyridin-3-amine 0.448 g (2 mmol) was dissolved in DCM (25 mL), then 4-trifluoromethoxyphenylisocyanate (406 mg) , 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 hours, and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude material (yield: MeOH/DCM: 2/98 - 10/90) to give 1-[4-(3-aminoimidazole[1,5-a] Pyridyl-5-yl)phenyl]-3-(4-trifluoromethoxyphenyl)urea 548 mg (yield: 64%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) δ 8.16 (d, 2H), 7.83 (d, 2H), 7.49 (d, 2H), 7.15-7.29 (m, 3H ), 6.89 (d, 2H), 6.75 (m, 1H). Mass spectrometry 429.36 [M+l example 35
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程- 步骤 (1 )〜(4) 与例 30相同;  2. Preparation process - Steps (1) to (4) are the same as in Example 30;
(5 )终产物 1-[4-(3-氨基咪唑 [1,5-a]并吡啶 -5-基)苯基] -3-(3-氟 -4-甲基苯基)脲的制备: (5) Preparation of the final product 1-[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-fluoro-4-methylphenyl)urea :
5-(4-氨基苯基)咪唑 [1,5-a]并吡啶 -3-胺 0.448克 (2mmol)溶解于 DCM (25 mL), 然后加 入 3-氟 -4-甲基苯基异氰酸酯 (303mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用5-(4-Aminophenyl)imidazo[1,5-a]pyridin-3-amine 0.448 g (2 mmol) was dissolved in DCM (25 mL) then 3-fluoro-4-methylphenylisocyanate ( 303 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 hours, for reaction
TLC跟踪。反应完成后,旋转蒸发除去溶剂,得到粗产物采用硅胶柱层析纯化 (MeOH/DCM:TLC tracking. After completion of the reaction, the solvent was removed by rotary evaporation to afford crude crystals.
2/98→10/90)得 1-[4-(3-氨基咪唑 [1,5-a]并吡啶 -5-基)苯基] -3-(3-氟 -4-甲基苯基)脲 495mg (得率: 66%)。, 其磁核共振和质谱的鉴定结果为: 1H-NMR(DMSO-rf6) δ2/98→10/90) 1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-fluoro-4-methylphenyl) Urea 495 mg (yield: 66%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-rf 6 ) δ
8.16(d,2H),7.83(d,2H),7.58(s,H),7.13-7.30 (m, 5H), 6.75 (m, 1H), 3.30(s,3H)。 质谱 ζΛ:8.16 (d, 2H), 7.83 (d, 2H), 7.58 (s, H), 7.13-7.30 (m, 5H), 6.75 (m, 1H), 3.30 (s, 3H). Mass spectrometry ζΛ:
376.12[M+l 例 36 1、 一般实验条件: 与例 1相同。 376.12 [M+l Example 36 1. General experimental conditions: Same as Example 1.
2、 制备过程: 步骤 (1:) 〜 (4) 与例 30相同; 2. Preparation process: Step (1:) ~ (4) is the same as in Example 30;
( 5 ) 终产物 1-[4-(3-氨基咪唑 [1,5-a]并吡啶 -5-基)苯基] -3-(3-甲基 -4-三氟甲基苯基)脲 的制备- (5) The final product 1-[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-methyl-4-trifluoromethylphenyl) Preparation of urea -
5-(4-氨基苯基)咪唑 [1 ,5-a]并吡啶 -3-胺 0.448克 (2睡 ol)溶解于 DCM (25 mL), 然后加 入 3-甲基 -4-三氟甲基苯基异氰酸酯 (402mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗产物采用硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得 1-[4-(3-氨基咪唑 [1,5-a]并吡啶 -5-基)苯基] -3-(3-甲基 -4-三氟 甲基苯基)脲 519mg (得率: 61%)。,其磁核共振和质谱的鉴定结果为: 1H-NMR(DMSO-i 6) δ 8.16(d,2H),7.83(d,2H),7.45-7.55(m,3H),7.13-7.30 (m, 3H), 6.75 (m, 1H), 3.30(s,3H)。 质谱 m/z: 426.03 [M+l] o 例 37 5-(4-Aminophenyl)imidazo[1,5-a]pyridin-3-amine 0.448 g (2 oz) dissolved in DCM (25 mL), then 3-methyl-4-trifluoromethyl Phenyl phenyl isocyanate (402 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 h and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude material (yield: MeOH/DCM: 2/98→10/90) to give 1-[4-(3-aminoimidazole[1,5-a] Pyridine-5-yl)phenyl]-3-(3-methyl-4-trifluoromethylphenyl)urea 519 mg (yield: 61%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i 6 ) δ 8.16 (d, 2H), 7.83 (d, 2H), 7.45-7.55 (m, 3H), 7.13-7.30 (m , 3H), 6.75 (m, 1H), 3.30 (s, 3H). Mass spectrum m/z: 426.03 [M+l] o Example 37
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1:) 〜 (4) 与例 30相同;  Step (1:) ~ (4) Same as Example 30;
( 5 ) 终产物 1-[4-(3-氨基咪唑 [l,5-a]并吡啶 -5-基)苯基] -3-(3-氯 -4-三氟甲基苯基)脲的 制备- (5) The final product 1-[4-(3-aminoimidazo[l,5-a]pyridin-5-yl)phenyl]-3-(3-chloro-4-trifluoromethylphenyl)urea Preparation -
5-(4-氨基苯基)咪唑 [l,5-a]并吡啶 -3-胺 0.448克(2mmol)溶解于 DCM (25 mL), 然后加 入 3-氯 -4-三氟甲基苯基异氰酸酯 (443mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反 应用 TLC 跟踪。 反应完成后, 旋转蒸发除去溶剂, 得到粗产物采用硅胶柱层析纯化 (MeOH/DCM : 2/98→10/90)得 1-[4-(3-氨基咪唑 [l,5-a]并吡啶 -5-基)苯基] -3-(3-氯 -4-三氟甲 基苯基)脲 535mg (得率: 60%)。,其磁核共振和质谱的鉴定结果为: 1H-NMR(DMSO-d6) δ 8.16(d,2H),7.90(s,lH),7.83(d,2H),7.43-7.54(m,2H),7.13-7.30 (m, 3H), 6.75 (m, 1H)。 质谱 m/z: 446.01 [M+1,35C1], 447.98[M+1,37C1]。 例 38 5-(4-Aminophenyl)imidazole [l,5-a]pyridin-3-amine 0.448 g (2 mmol) was dissolved in DCM (25 mL) then 3-chloro-4-trifluoromethylphenyl Isocyanate (443 mg, 2 mmol), the resulting solution was stirred at room temperature for 0.5-5 h and the reaction was followed by TLC. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude material (yield: MeOH/DCM: 2/98→10/90) to give 1-[4-(3-aminoimidazole[l,5-a] Pyridine-5-yl)phenyl]-3-(3-chloro-4-trifluoromethylphenyl)urea 535 mg (yield: 60%). The results of magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-d 6 ) δ 8.16 (d, 2H), 7.90 (s, lH), 7.83 (d, 2H), 7.43-7.54 (m, 2H) ), 7.13-7.30 (m, 3H), 6.75 (m, 1H). Mass spectrum m/z: 446.01 [M+1, 35 C1], 447.98 [M+1, 37 C1]. Example 38
1、 一般实验条件: 与例 1相同。 1. General experimental conditions: Same as in Example 1.
2、 制备过程:  2. Preparation process:
步骤 (1 ) 〜 (4 ) 与例 30相同;  Steps (1) to (4) are the same as in Example 30;
( 5 )终产物 1-[4-(3-氨基咪唑 [1,5-a]并吡啶 -5-基)苯基] -3-(2-氟 -5-甲基苯基)脲的制备: (5) Preparation of the final product 1-[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea :
5-(4-氨基苯基)咪唑 [1,5-a]并吡啶 -3-胺 0.448克 (2mmol)溶解于 DCM (25 mL), 然后加 入 2-氟 -5-甲基苯基异氰酸酯 (302mg, 2mmol), 所得溶液于室温搅拌 0.5-5小时, 反应用 TLC跟踪。反应完成后,旋转蒸发除去溶剂,得到粗产物采用硅胶柱层析纯化 (MeOH/DCM: 2/98→10/90)得 1-[4-(3-氨基咪唑 [l,5-a]并吡啶 -5-基)苯基] -3-(2-氟 -5-甲基苯基)脲 510mg (得率: 68%)。,其磁核共振和质谱的鉴定结果为: 1H-NMR(DMSO-i¾ δ 8.16(d,2H): 7.83(d,2H), 7.68(s,lH),7.16-7.35 (m, 5H), 6.75 (m, 1H)。 质谱 m/z: 376.06[M+1]。 5-(4-Aminophenyl)imidazo[1,5-a]pyridin-3-amine 0.448 g (2 mmol) dissolved in DCM (25 mL) 2-Fluoro-5-methylphenylisocyanate (302 mg, 2 mmol) was added, and the resulting solution was stirred at room temperature for 0.5-5 hr. After completion of the reaction, the solvent was removed by rotary evaporation to give a crude material (yield: MeOH/DCM: 2/98→10/90) to give 1-[4-(3-aminoimidazole[l,5-a] Pyridyl-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea 510 mg (yield: 68%). The results of the magnetic resonance and mass spectrometry were as follows: 1H-NMR (DMSO-i3⁄4 δ 8.16 (d, 2H) : 7.83 (d, 2H), 7.68 (s, lH), 7.16-7.35 (m, 5H), 6.75 (m, 1H). Mass m/z: 376.06 [M+1].
效果例 Effect example
1、本发明化合物对 VEGFR、 FLT3、 c- KIT的生化半抑制浓度(IC5。)测试方法和条件: 本发明化合物针对三种酪氨酸激酶 (VEGFR、 FLT3、 c- KIT)的半抑制浓度(IC5。)按照 文献提供的 HTRF方法测试(Kolb, A. J.; Kapl ita, P. V.; Hayes, D. J.; Park, Y. - W.;1. Biochemical half-inhibitory concentration (IC 5 ) of the compounds of the present invention against VEGFR, FLT3, c-KIT. Test methods and conditions: Semi-inhibition of the compounds of the present invention against three tyrosine kinases (VEGFR, FLT3, c-KIT) Concentration (IC 5 .) was tested according to the HTRF method provided by the literature (Kolb, AJ; Kapl ita, PV; Hayes, DJ; Park, Y. - W.;
Pernell, C.; Major, J. S.; Mathis, G. Drug Discovery Today 1998, 3, 333-342): 肽底物 (Biotin-Ahx-AEEEYFFLFA-amide)的浓度为 4 μΜ、 三磷酸腺苷 (ATP)的浓度为 1 mM、 相应的激酶及脲类化合物抑制剂于如下溶液中室温反应 1小时: 50 mM Hepes/NaOH H 7. 5, 10 mM MgCl2, 2 mM MnCl2, 2. 5 mM DTT, 0. 1 mM orthovanadate, and 0. 01% bovine serium albumin0 本发明化合物抑制剂按 3. 2 nM to 50 μΜ的最终浓度用 5% DMS0作为 共溶剂加入 96孔板的孔中。 反应用下面方法停止: 10 μΜ每孔的 0. 5 M EDTA, 然后用 含 streptavidin-allophycocyanin (prozyme; 1. 1 g/mL 及 PT66 antibody europium cryptate (Ci s-Bio ; 0. 1 g/mL)。 读板方法: 加入检测试剂 1-4小时后, 用 Packard Discovery仪器测试荧光 (665到 615的比例)。 检测的信噪比介于 10-15之间。 半抑制 浓度为至少两次测试的平均值。 实施例 1〜38所得的化合物的 VEGFR、 FLT3、 c- KIT的 生化半抑制浓度 (IC5。)结果如表 4所示。 Pernell, C.; Major, JS; Mathis, G. Drug Discovery Today 1998, 3, 333-342): The concentration of the peptide substrate (Biotin-Ahx-AEEEYFFLFA-amide) is 4 μΜ, and the concentration of adenosine triphosphate (ATP) is 1 mM, the corresponding kinase and urea compound inhibitor was reacted in the following solution for 1 hour at room temperature: 50 mM Hepes/NaOH H 7. 5, 10 mM MgCl 2 , 2 mM MnCl 2 , 2. 5 mM DTT, 0.1 mM orthovanadate, and 0. 01% bovine serium albumin 0 The inhibitor of the present invention was added to the wells of a 96-well plate at a final concentration of 3.2 nM to 50 μM with 5% DMS0 as a co-solvent. The reaction was stopped by the following method: 10 μM per well of 0.5 M EDTA, followed by containing streptavidin-allophycocyanin (prozyme; 1. 1 g/mL and PT66 antibody europium cryptate (Ci s-Bio; 0.1 g/mL) Plate reading method: After adding the detection reagent for 1-4 hours, the fluorescence was measured with a Packard Discovery instrument (the ratio of 665 to 615). The detected signal-to-noise ratio is between 10 and 15. The semi-inhibitory concentration is at least two tests. The average value of the biochemical semi-inhibitory concentrations (IC 5 ) of VEGFR, FLT3, and c-KIT of the compounds obtained in Examples 1 to 38 are shown in Table 4.
表 4  Table 4
序号 VEGFR2 IC50, nM FLT3 IC50> nM c- IT ICso, nM Serial number VEGFR2 IC 50 , nM FLT3 IC 50> nM c- IT ICso, nM
例 1化合物 71 53 47  Example 1 Compound 71 53 47
例 2化合物 9 21 13  Example 2 Compound 9 21 13
例 3化合物 13 17 24  Example 3 Compound 13 17 24
例 4化合物 71 59 156  Example 4 Compound 71 59 156
例 5化合物 65 170 210  Example 5 Compound 65 170 210
例 6化合物 80 152 48  Example 6 Compound 80 152 48
例 7化合物 23 19 25  Example 7 Compound 23 19 25
例 8化合物 69 50 84  Example 8 Compound 69 50 84
例 9化合物 82 44 73  Example 9 Compound 82 44 73
例 10化合物 17 20 9  Example 10 Compound 17 20 9
例 11化合物 8 23 15 例 12化合物 370 43 79 Example 11 Compound 8 23 15 Example 12 Compound 370 43 79
例 13化合物 41 27 15  Example 13 Compound 41 27 15
例 14化合物 74 17 68  Example 14 Compound 74 17 68
例 15化合物 34 11 63  Example 15 Compound 34 11 63
例 16化合物 13 124 53  Example 16 Compound 13 124 53
例 17化合物 157 73 126  Example 17 Compound 157 73 126
例 18化合物 122 37 102  Example 18 Compound 122 37 102
例 19化合物 11 18 8  Example 19 Compound 11 18 8
例 20化合物 138 69 123  Example 20 Compound 138 69 123
例 21化合物 231 44 35  Example 21 Compound 231 44 35
例 22化合物 109 54 178  Example 22 Compound 109 54 178
例 23化合物 12 202 75  Example 23 Compound 12 202 75
例 24化合物 8 9 21  Example 24 Compound 8 9 21
例 25化合物 8 28 31  Example 25 Compound 8 28 31
例 26化合物 28 37 42  Example 26 Compound 28 37 42
例 27化合物 72 42 35  Example 27 Compound 72 42 35
例 28化合物 13 27 32  Example 28 Compound 13 27 32
例 29化合物 67 73 92  Example 29 Compound 67 73 92
例 30化合物 12 21 17  Example 30 Compound 12 21 17
例 31化合物 35 125 79  Example 31 Compound 35 125 79
例 32化合物 8 31 25  Example 32 Compound 8 31 25
例 33化合物 63 92 87  Example 33 Compound 63 92 87
例 34化合物 17 28 34  Example 34 Compound 17 28 34
例 35化合物 15 20 29  Example 35 Compound 15 20 29
例 36化合物 27 143 58  Example 36 Compound 27 143 58
例 37化合物 14 41 27  Example 37 Compound 14 41 27
例 38化合物 19 32 32  Example 38 Compound 19 32 32
从表 4可以看出, 本发明化合物对 VEGFR、 FLT3、 c-KIT有很好的抑制作用, 生化 半抑制浓度(IC5。)大部分都小于 100πΜ, 其中 1- [4- (1-氨基咪唑 [l,5-a]并吡啶 - 8-基) 苯基] -3- (2-氟 -5-甲基苯基)脲、 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (4 - 氟 -3-甲基苯基)脲、 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-氟苯基)脲、 1-[4- (1-氨基咪唑 [1, 5- a]并吡啶 -8-基)苯基] -3- (3-甲基苯基)脲、 1- [4-(1-氨基咪唑 [1, 5- a]并吡啶 -8-基)苯基] -3- (4-甲基苯基)脲、 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 _8_ 基)苯基] -3- (3-氯苯基)脲、 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-三氟 甲基苯基)脲、 1- [4- (1-氨基- 3-甲基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2 -氟 -5-甲基 苯基)脲、 1- [4- (1-氨基 -3-甲基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (4-氟 -3-甲基苯基) 脲、 1- [4- (1-氨基- 3-甲基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3- (3-甲基苯基)脲、 1 - [4- (1-氨基 -3-甲基咪唑 [1, 5- a]并吡啶 -8-基)苯基] - 3- (3-氯苯基)脲、 1_ [4- (3_氨基 咪唑 [1, 5-a]并吡啶 -5-基)苯基] - 3- (4-三氟甲基苯基)脲、 1- [4- (3-氨基咪唑 [1, 5 - a] 并吡啶 -5-基)苯基] -3- (3-三氟甲基苯基)脲、 1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5 -基) 苯基] -3- (4-三氟甲氧基苯基)脲、 1- [4- (3-氨基咪唑 [1, 5- a]并吡啶 -5-基)苯基] -3- (3- 氟 -4-甲基苯基)脲、 1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (3-氯 -4-三氟甲 基苯基)脲和 1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (2-氟 -5-甲基苯基)脲对 对 VEGFR、 FLT3、 c- KIT的 IC5。都小于 50nM。 As can be seen from Table 4, the compounds of the present invention have a good inhibitory effect on VEGFR, FLT3, c-KIT, and the biochemical half-inhibitory concentration (IC 5 ) is mostly less than 100πΜ, wherein 1- [4- (1-amino) Imidazole [l,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea, 1-[4-(1-aminoimidazole[1, 5- a]pyridin-8-yl)phenyl]-3-(4-fluoro-3-methylphenyl)urea, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8 -yl)phenyl]-3-(3-fluorophenyl)urea, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3 -Methylphenyl)urea, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-methylphenyl)urea, 1- [4-(1-Aminoimidazo[1,5-a]pyridinyl-8-yl)phenyl]-3-(3-chlorophenyl)urea, 1-[4-(1-aminoimidazole[1, 5 -a]pyridin-8-yl)phenyl]-3-(3-trifluoromethylphenyl)urea, 1-[4-(1-amino-3-methylimidazo[1, 5-a] And pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea, 1-[4-(1-amino-3-methylimidazo[1, 5-a] Pyridine-8-yl)phenyl]-3-(4-fluoro-3-methylphenyl)urea, 1-[4-(1-amino-3-methylimidazo[l,5-a]pyridine -8-yl)phenyl]-3-(3-methylphenyl)urea, 1-[4-(1-amino-3-methylimidazo[1,5-a]pyridin-8-yl) Phenyl]-3-(3-chlorophenyl)urea, 1_[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(4-trifluoromethyl) Phenyl)urea, 1-[4-(3-aminoimidazole[1, 5 - a] And pyridin-5-yl)phenyl]-3-(3-trifluoromethylphenyl)urea, 1-[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)benzene 3-(4-trifluoromethoxyphenyl)urea, 1-[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3 - Fluoro-4-methylphenyl)urea, 1-[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-chloro-4-tri Fluoromethylphenyl)urea and 1-[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl) urea pairs VEGFR, FLT3, c- KIT the IC 5. Both are less than 50nM.
2、 本发明化合物对结肠癌肿瘤生长的抑制作用  2. Inhibition of colon cancer growth by the compounds of the invention
( 1 ) 实验用药:  (1) Experimental medication:
实施例 2 目标化合物 1- [4- (1-氨基咪唑 [1, 5- a]并吡啶 - 8-基)苯基] -3- (2-氟 -5 -甲基苯基)脲  Example 2 Target compound 1-[4-(1-Aminoimidazo[1,5-a]pyridine-3-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea
实施例 24 目标化合物 1_[4- (1-氨基咪唑 [1, 5- a]并吡啶 -8-基)苯基] -3- (2 -氟 Example 24 Target compound 1_[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro
- 5-甲基苯基)脲 - 5-methylphenyl)urea
实施例 32 目标化合物 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 - 8-基)苯基] -3_ (2-氟 -5-甲基苯基)脲  EXAMPLE 32 Target compound 1-[4-(1-Aminoimidazo[1,5-a]pyridin-3-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea
(2)实验方法:常规复苏人结肠癌细胞株 Colo205,用含 10%新鲜小牛血清的 DMEM 培养基, 37°C、 5% C02培养, 至对数生长期后收集细胞, 用预热至 37Ό的生理盐水调 整细胞数至 1 X 107/ml , 立即接种至 32只准备好的 6~8周龄的 BALB/c裸鼠左腋皮下, 每只小鼠皮下注射 0. 2ml (约 2. 0 X 106细胞 /只)。 继续饲养 15天至皮下可见明显的肿 瘤块形成, 用游标尺测量肿瘤体积长径和短径, 计算肿瘤体积为给药前肿瘤体积。 按 肿瘤体积大小随机分为模型组、 高 (20mg/kg)、 中 (10mg/kg)、 低剂量组 (5mg/kg), 每组 8只,雌雄各半。 并按剂量灌胃给药, 连续 12天。 分别在给药后第 4、 7、 12天测 量肿瘤长径和短径, 计算瘤体积和抑瘤率。 肿瘤体积= 11 /6 (长径 短径 2)。 肿瘤抑 瘤率 = (模型组平均体积 - 给药组平均体积) /模型组平均体积 X 100%。 (2) Experimental method: conventional resuscitation of human colon cancer cell line Colo205, cultured in DMEM medium containing 10% fresh calf serum, 37 ° C, 5% CO 2 , and collected in logarithmic growth phase, preheated to The sputum was adjusted to 1 x 107/ml, and immediately inoculated to 32 left-beats of 6-8 weeks old BALB/c nude mice. Each mouse was injected subcutaneously with 0.2 ml (about 2. 0 X 106 cells / only). Continue to raise for 15 days until the formation of obvious tumor mass was observed under the skin. The long diameter and short diameter of the tumor volume were measured with a vernier scale, and the tumor volume was calculated as the tumor volume before administration. According to the tumor volume, they were randomly divided into model group, high (20 mg/kg), medium (10 mg/kg), and low dose group (5 mg/kg), with 8 rats in each group, half male and half female. It was administered by intragastric administration for 12 consecutive days. Tumor long diameter and short diameter were measured on the 4th, 7th and 12th day after administration, and the tumor volume and tumor inhibition rate were calculated. Tumor volume = 1 1 /6 (long diameter and short diameter 2). Tumor inhibition rate = (average volume of model group - mean volume of administration group) / average volume of model group X 100%.
(3) 实验结果:  (3) Experimental results:
表 5 实施例 2目标化合物灌胃给药对人结肠癌 Colo205细胞裸鼠皮下移植瘤体积 和抑瘤率的影响  Table 5 Example 2 Effect of intragastric administration of target compound on the volume and tumor inhibition rate of human colon cancer Colo205 cells in nude mice
组别 剂量 例 给药前 给药 4天后 给药 7天后 给药 12天后 Group doses before administration 4 days after administration 7 days after administration 12 days after administration
(mg kg) 数 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 (mg kg) number tumor volume tumor inhibition rate tumor volume tumor inhibition rate tumor volume tumor inhibition rate tumor volume tumor inhibition rate
(mm3) (%) (mm3) (%) (mm3) (%) (mm3) (%) 模型组 - 8 175±23 ― 225士 29 ― 408±57 712±53 (mm 3 ) (%) (mm 3 ) (%) (mm 3 ) (%) (mm 3 ) (%) Model group - 8 175 ± 23 ― 225 ± 29 ― 408 ± 57 712 ± 53
低剂量组 5 8 183±18 ― 222±21 1.3 362±62 1 1.3 561±55* 21 2 中剂量组 10 8 172±16 ― 182±20* 19.1 251 ±22" 38.5 368±26** 48.3 高剂量组 20 δ 178±20 - 180±17* 20.0 188±13** 53.9 263±31** 63.1 Low dose group 5 8 183±18 ― 222±21 1.3 362±62 1 1.3 561±55* 21 2 medium dose group 10 8 172±16 ― 182±20* 19.1 251 ±22" 38.5 368±26** 48.3 high Dosage group 20 δ 178 ± 20 - 180 ± 17 * 20.0 188 ± 13 ** 53.9 263 ± 31 ** 63.1
与模型组比较, *P<0. 05, **P<0. 01. 从表 5可以看出, 与模型组比较, 实施例 2目标化合物 1- [4- (1-氨基咪唑 [l,5-a] 并吡啶 -8-基)苯基] -3- (2-氟 -5-甲基苯基)脲给药后 4天, 中、 高剂量口服对人结肠癌 Colo205细胞 BALB/c裸鼠皮下移植瘤有明显的抑制作用,抑瘤率分别为 19. 1%和 20. 0% (P<0. 05); 给药 7天中、 高剂量组的抑制率分别为 38. 5%和 53. 9% (P<0. 01) ; 给药 12 天后、 高剂量组的抑制率分别达 46. 9%和 63. 1% (P<0. 01)。 低剂量组的抑制率虽然相对 较低, 但也有明显的抑制作用, 抑制率为 21. 2% (P<0. 05), 充分表明该化合物具有明 显的抑制结肠癌生长的作用。 Compared with the model group, *P<0.05, **P<0. 01. As can be seen from Table 5, the target compound of Example 2, 1-[4-(1-aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(2-), was compared with the model group. 4% after the administration of fluoro-5-methylphenyl) urea, medium and high dose oral administration of human colon cancer Colo205 cells BALB / c nude mice subcutaneously transplanted tumors have a significant inhibitory effect, the tumor inhibition rate was 19.1% And 0. 0% (P<0.05); the inhibition rate of the medium-dose and high-dose groups in the 7-day administration was 38.5% and 53.9% (P<0.01); 12 days after administration, high The inhibition rate of the dose group was 46.9% and 63.1%, respectively (P<0.01). Although the inhibition rate of the low-dose group was relatively low, it also showed significant inhibition. The inhibition rate was 21. 2% (P < 0.05), which fully indicated that the compound had a significant inhibitory effect on colon cancer growth.
表 6 实施例 24目标化合物灌胃给药对人结肠癌 Colo205细胞裸鼠皮下移植瘤体 积和抑瘤率的影响  Table 6 Example 24 Effect of intragastric administration of target compound on human colon cancer Colo205 cell subcutaneous transplantation tumor volume and tumor inhibition rate in nude mice
组别 剂量 例 给药前 给药 4天后 给药 7天后 给药 12天后 Group doses before administration 4 days after administration 7 days after administration 12 days after administration
(mg kg) 数 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 (mg kg) number tumor volume tumor inhibition rate tumor volume tumor inhibition rate tumor volume tumor inhibition rate tumor volume tumor inhibition rate
(mm3) (%) (mm3) (%) (mm3) (%) (mm3) (%) 模型组 ― 8 197±39 - 247+40 ― 430±58 - 761±62 - 低剂量组 5 8 188+23 ― 228+35 7.7 351±39 18.4 574±53* 24.6 中剂量组 10 8 190+37 - 207+29* 16.2 282±31" 34.4 381±34** 49.9 高剂量组 20 8 201±41 - 203±35* 17.8 221 ±29" 48.6 282±27** 62..9 (mm 3 ) (%) (mm 3 ) (%) (mm 3 ) (%) (mm 3 ) (%) Model group - 8 197 ± 39 - 247 + 40 ― 430 ± 58 - 761 ± 62 - low dose Group 5 8 188+23 ― 228+35 7.7 351±39 18.4 574±53* 24.6 Medium dose group 10 8 190+37 - 207+29* 16.2 282±31" 34.4 381±34** 49.9 High dose group 20 8 201±41 - 203±35* 17.8 221 ±29" 48.6 282±27** 62..9
与模型组比较, *P〈0. 05, MP<0. 01. 从表 6可以看出,与模型组比较,实施例 24目标化合物 1- [4- (1-氨基咪唑 [1, 5-a] 并吡啶 -8-基)苯基] -3- (2-氟 -5-甲基苯基)脲给药后 4天, 中、 高剂量口服对人结肠癌 Colo205细胞 BALB/c裸鼠皮下移植瘤有明显的抑制作用,抑瘤率分别为 16. 2%和 17. 8% (P<0. 05); 给药 7天中、 高剂量组的抑制率分别为 34. 4%和 48. 6% (P<0. 01) ; 给药 12 天后、 高剂量组的抑制率分别达 49. 9%和 62. 9% (P<0. 01)。 低剂量组的抑制率虽然相对 较低, 但也有明显的抑制作用, 抑制率为 24. 6% (P<0. 05), 充分表明该化合物具有明 显的抑制结肠癌生长的作用。 表 7 实施例 32目标化合物灌胃给药对人结肠癌 Colo205细胞裸鼠皮下移植瘤体 积和抑瘤率的影响 Compared with the model group, *P<0.05, M P<0. 01. As can be seen from Table 6, the target compound of Example 24 1- [4-(1-aminoimidazole [1, 5] was compared with the model group. -a] pyridine-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea 4 days after administration, medium and high dose oral administration of BALB/c to human colon cancer Colo205 cells The inhibitory rate of the subcutaneous transplantation of the mice was significantly inhibited, and the inhibition rate was 16.2% and 17.8% (P<0.05). 9%和62.9% (P<0.01), and the inhibition rate of the high-dose group was 49.9% and 62.9%, respectively (P<0.01). Although the inhibition rate of the low-dose group was relatively low, it also showed significant inhibition. The inhibition rate was 24.6% (P<0.05), which fully indicated that the compound had obvious inhibitory effect on colon cancer growth. Table 7 Example 32 Effect of target compound intragastric administration on the volume and tumor inhibition rate of human colon cancer Colo205 cells transplanted subcutaneously in nude mice
组别 剂量 例 给药前 给药 4天后 给药 7天后 给药 12天后 Group doses before administration 4 days after administration 7 days after administration 12 days after administration
(mg kg) 数 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 (mg kg) number tumor volume tumor inhibition rate tumor volume tumor inhibition rate tumor volume tumor inhibition rate tumor volume tumor inhibition rate
(mm3) (%) (mm3) (%) (mm3) (%) (mm3) (%) 模型组 ― 8 187+21 - 238+27 ― 420±34 - 737161 - 低剂量组 5 8 201+27 - 231+30 2.9 359±36 14.5 558±57· 24.3 中剂量组 10 8 197+17 - 210+20* 11.8 297±28** 29.3 307±26" 58.3 高剂量组 20 8 190 22 - 199+17* 16.4 217±22" 48.3 290+21" 60.7 (mm 3 ) (%) (mm 3 ) (%) (mm 3 ) (%) (mm 3 ) (%) Model group - 8 187+21 - 238+27 ― 420±34 - 737161 - Low dose group 5 8 201+27 - 231+30 2.9 359±36 14.5 558±57· 24.3 medium dose group 10 8 197+17 - 210+20* 11.8 297±28** 29.3 307±26" 58.3 high dose group 20 8 190 22 - 199+17* 16.4 217±22" 48.3 290+21" 60.7
与模型组比较, *Ρ〈0. 05, "Ρ<0. 01. 从表 7可以看出,与模型组比较,实施例 32目标化合物 1_ [4- (1-氨基咪唑 [1, 5-a] 并吡啶 -8-基)苯基] -3- (2-氟- 5-甲基苯基)脲给药后 4天, 中、 高剂量口服对人结肠癌 Colo205细胞 BALB/c裸鼠皮下移植瘤有明显的抑制作用,抑瘤率分别为 11. 8%和 16. 4% (P<0. 05); 给药 7天中、 高剂量组的抑制率分别为 29. 3%和 48. 3% (P<0. 01) ; 给药 12 天后、 高剂量组的抑制率分别达 58. 3%和 60. 7%(P<0. 01)。 低剂量组的抑制率虽然相对 较低, 但也有明显的抑制作用, 抑制率为 24. 3% (P<0. 05), 充分表明该化合物具有明 显的抑制结肠癌生长的作用。 Compared with the model group, *Ρ<0. 05, "Ρ<0. 01. As can be seen from Table 7, the target compound 1_[4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl]-3-(2-fluoride) of Example 32 was compared with the model group. After the administration of 5-methylphenyl)urea, the medium- and high-dose oral administration had a significant inhibitory effect on the subcutaneous transplantation of human colon cancer Colo205 cells in BALB/c nude mice, and the tumor inhibition rate was 11.8% and 16. 4% (P<0.05); The inhibition rates of the 7-day and high-dose groups were 29.3% and 48.3% (P<0.01); 12 days after administration, high dose The inhibition rate of the group was 58.3% and 60.7% (P<0.01). Although the inhibition rate of the low-dose group was relatively low, it also showed significant inhibition. The inhibition rate was 24.3% (P<0.05), which fully indicated that the compound had obvious inhibitory effect on colon cancer growth.
3、 本发明化合物对胃癌肿瘤生长的抑制作用 3. Inhibition of the growth of gastric cancer tumors by the compounds of the invention
( 1 ) 实验用药- 实施例 2 目标化合物 1- [4- (1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] - 3- (2-氟 (1) Experimental use - Example 2 Target compound 1- [4-(1-Aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro
-5-甲基苯基)脲 -5-methylphenyl)urea
(2) 实验方法: 常规复苏人胃癌细胞株 HS-746T, 用含 10%新鲜小牛血清的 DMEM 培养基, 37Ό、 5% C02培养, 至对数生长期后收集细胞, 用预热至 37Ό的生理盐水调 整细胞数至 I X 107/ml, 立即接种至 32只准备好的 6〜8周龄的 BALB/c裸鼠左腋皮下, 每只小鼠皮下注射 0. 2ml (约 2. 0 X 106细胞 /只)。 继续饲养 15天至皮下可见明显的肿 瘤块形成, 用游标尺测量肿瘤体积长径和短径, 计算肿瘤体积为给药前肿瘤体积。 按 肿瘤体积大小随机分为模型组、 高 (20mg/kg)、 中 (10mg/kg) , 低剂量组 (5mg/kg), 每组 8只,雌雄各半。 并按剂量灌胃给药, 连续 12天。 分别在给药后第 4、 7、 12天测 量肿瘤长径和短径, 计算瘤体积和抑瘤率。 肿瘤体积= /6 (长径 短径 2)。 肿瘤抑 瘤率 = (模型组平均体积 一 给药组平均体积) /模型组平均体积 X 100%。  (2) Experimental method: Conventional resuscitation of human gastric cancer cell line HS-746T was carried out in DMEM medium containing 10% fresh calf serum, 37Ό, 5% C02, and collected in logarithmic growth phase, preheated to 37Ό. The amount of the saline was adjusted to IX 107 / ml, and immediately inoculated to 32 left-beats of 6-8 weeks old BALB / c nude mice, each mouse was subcutaneously injected 0. 2ml (about 2. 0 X 106 cells / only). Continue to raise for 15 days until the formation of obvious tumor mass was observed under the skin. The long and short diameters of the tumor volume were measured with a vernier scale, and the tumor volume was calculated as the tumor volume before administration. According to the tumor volume, they were randomly divided into model group, high (20 mg/kg), medium (10 mg/kg), and low dose group (5 mg/kg), with 8 rats in each group, half male and half female. It was administered by intragastric administration for 12 consecutive days. The long and short diameters of the tumor were measured on the 4th, 7th, and 12th day after administration, and the tumor volume and tumor inhibition rate were calculated. Tumor volume = /6 (long diameter short diameter 2). Tumor inhibition rate = (average volume of the model group - average volume of the administration group) / average volume of the model group X 100%.
(3) 实验结果: (3) Experimental results:
表 8 实施例 2目标化合物灌胃给药对人胃癌 HS-746T细胞裸鼠皮下移植瘤体积 和抑瘤率的影响  Table 8 Example 2 Effect of intragastric administration of target compound on the volume and tumor inhibition rate of human gastric cancer HS-746T cells in nude mice
组别 剂量 例 给药前 给药 4天后 给药 7天后 给药 12天后 Group doses before administration 4 days after administration 7 days after administration 12 days after administration
(mg kg) 数 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 肿瘤体积 抑瘤率 (mg kg) number tumor volume tumor inhibition rate tumor volume tumor inhibition rate tumor volume tumor inhibition rate tumor volume tumor inhibition rate
(mm3) (%) (mm3) (%) (mm3) (%) (mm3) (%) 模型组 8 189±25 235±31 - 432±63 - 733±63 (mm 3 ) (%) (mm 3 ) (%) (mm 3 ) (%) (mm 3 ) (%) Model group 8 189±25 235±31 - 432±63 - 733±63
低剂量组 8 173118 227±23 3.4 385±62 10.9 576±58* 22.6 中剂量组 10 8 182±20 208+30* 11.5 289±23** 33.1 389+36** 46.9 Low dose group 8 173118 227±23 3.4 385±62 10.9 576±58* 22.6 medium dose group 10 8 182±20 208+30* 11.5 289±23** 33.1 389+36** 46.9
20 8 178±2 198±2 15.7 209±15* 51.9 279±31* 61.9  20 8 178±2 198±2 15.7 209±15* 51.9 279±31* 61.9
9 8*  9 8*
与模型组比较, *P<0. 05, "Ρ<0. 01. 从表 8可以看出, 与模型组比较, 实施例 2目标化合物 1- [4- (1-氨基咪唑 [1, 5 - a] 并吡啶 -8-基)苯基] -3- (2-氟 -5-甲基苯基)脲给药后 4 天, 中、 高剂量口服对人胃癌 HS-746T细胞 BALB/c裸鼠皮下移植瘤有明显的抑制作用,抑瘤率分别为 11. 5%和 15. 7% (P<0. 05); 给药 7天中、 高剂量组的抑制率分别为 33. 1%和 51. 9% (P〈0. 01) ; 给药 12 天后、 高剂量组的抑制率分别达 46. 9%和 61. 9%(P<0. 01)。 低剂量组的抑制率虽然相对 较低, 但也有明显的抑制作用, 抑制率为 22. 3% (P<0. 05), 充分表明该化合物具有明 显的抑制胃癌生长的作用。 应用例 例 1 : 滴丸 (剂量: 25mg/粒) 【制剂处方】 实施例 2目标化合物 1-[4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] 3- (2-氟 -5-甲 基苯基)脲 2. 5g Compared with the model group, *P<0.05, "Ρ<0. 01. As can be seen from Table 8, the target compound of Example 2, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-), was compared with the model group. 4 days after the administration of fluoro-5-methylphenyl) urea, medium and high doses of oral administration of human gastric cancer HS-746T cells BALB/c nude mice subcutaneously transplanted tumors have a significant inhibitory effect, the tumor inhibition rate was 11. 5 % and 15.7% (P<0.05); The inhibition rates of the 7-day and high-dose groups were 33.1% and 51.9% (P<0.01), 12 days after administration, The inhibition rate of the high-dose group was 46.9% and 61.9% (P<0.01), respectively. Although the inhibition rate of the low-dose group was relatively low, it also showed significant inhibition. The inhibition rate was 22.3% (P<0.05), which fully indicated that the compound had obvious inhibitory effect on gastric cancer growth. Application Example 1: Dropping pills (dosage: 25 mg/granule) [Formulation prescription] Example 2 target compound 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl] 3-(2-Fluoro-5-methylphenyl)urea 2. 5g
聚乙二醇 6000 (PEG6000) 6g  Polyethylene glycol 6000 (PEG6000) 6g
聚乙二醇 400 (PEG400) lg  Polyethylene glycol 400 (PEG400) lg
甘油 0. 5 g  Glycerin 0. 5 g
共制 100粒, 每粒含该化合物 25 rag。 【制备方法】 称取该化合物 2. 5g, 5ml无水乙醇溶解(37°C ), 备用。 另取 PGE6000于 80°C水浴 溶解后混入 PEG400, 接搅匀。 保温, 缓慢加入备好的化合物乙醇溶液, 边加边搅, 使 其充分混匀并无醇味, 加入甘油, 趁热采用纱布过滤, 置贮液瓶中, 80°C保温下, 用管 口内、 外径分别为 9. 0mm、 9. 8mm的滴管滴制, 滴速 80滴 /mi n, 滴入液体石蜡(外层为 冰水浴) 冷却液中, 冷凝成丸, 用毛边纸吸去粘附的液体石蜡, 即得 (每粒 0. 1 g), 质检、 包装, 即得。  A total of 100 capsules were prepared, each containing 25 rag of the compound. [Preparation method] Weigh the compound 2. 5 g, 5 ml of absolute ethanol (37 ° C), and set aside. Another PGE6000 was dissolved in a water bath at 80 ° C, mixed with PEG400, and stirred. Insulation, slowly add the prepared compound ethanol solution, stir while stirring, make it fully mixed and have no alcohol flavor, add glycerin, filter with gauze while hot, place in a storage bottle, keep warm at 80 °C, use the inside of the tube , the outer diameter of 9. 0mm, 9. 8mm dropper drop, drop speed 80 drops / mi n, drip into the liquid paraffin (outer is ice water bath) in the coolant, condense into pellets, suck with a burr paper Attached liquid paraffin, that is, (0.1 g per capsule), quality inspection, packaging, that is.
【用法用量】 每次 1片, 每日 3次。 【适用人群】 适用各种肿瘤患者。 例 2: 滴丸 (剂量: 50mg/粒) 【制剂处方】 实施例 2目标化合物 1 - [4- (1-氨基咪唑 [ 1, 5-a]并吡啶 -8-基)苯基] -3- (2-氟 -5-甲 基苯基)脲 5g [Usage and Dosage] 1 tablet each time, 3 times a day. 【For people】 Applicable to a variety of cancer patients. Example 2: Dropping pills (dosage: 50 mg/granule) [Formulation prescription] Example 2 target compound 1 - [4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl] -3 - (2-Fluoro-5-methylphenyl)urea 5g
聚乙二醇 6000 (PEG6000) 12g  Polyethylene glycol 6000 (PEG6000) 12g
聚乙二醇 400 (PEG400) 2g  Polyethylene glycol 400 (PEG400) 2g
甘油 lg  Glycerin lg
共制 100粒, 每粒含该化合物 50mg。  A total of 100 capsules were prepared, each containing 50 mg of the compound.
【制备方法】 称取该化合物 5g, 10ml无水乙醇溶解 (37°C ), 备用。 另取 PGE6000于 80Ό水浴 溶解后混入 PEG400, 接搅匀。 保温, 缓慢加入备好的化合物乙醇液, 边加边搅, 使其 充分混匀并无醇味, 加入甘油, 趁热采用纱布过滤, 置贮液瓶中, 80°C保温下, 用管口 内、 外径分别为 18. 0mm、 19. 6麵的滴管滴制, 滴速 40滴 /min, 滴入液体石蜡(外层为 冰水浴)冷却液中, 冷凝成丸, 用毛边纸吸去粘附的液体石蜡, 即得(每 0. 2g), 质检、 包装, 即得。 [Preparation method] 5 g of the compound was weighed and dissolved in 10 ml of absolute ethanol (37 ° C), and used. In addition, PGE6000 was dissolved in a 80-inch water bath and mixed with PEG400. Stir well. Insulation, slowly add the prepared compound ethanol solution, stir while stirring, make it fully mixed and have no alcohol flavor, add glycerin, filter with gauze while hot, place in a storage bottle, keep warm at 80 °C, use the inside of the tube The outer diameter of the dropper is 18. 0mm, 19. 6 sides, the dropping speed is 40 drops / min, dripping into the liquid paraffin (the outer layer is ice water bath) in the cooling liquid, condensing into pellets, sucking off the paper with burrs Attached liquid paraffin, that is, (every 0. 2g), quality inspection, packaging, that is.
【用法用量】 每次 1片, 每日 3次。 【适用人群】 适用各种肿瘤患者。 例 3: 片剂 (剂量: 25mg/片) 【制剂处方】 实施例 2目标化合物 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-氟- 5_甲 基苯基)脲 2. 5 g [Usage and Dosage] 1 tablet each time, 3 times a day. [Applicable people] Applicable to a variety of cancer patients. Example 3: Tablet (dosage: 25 mg/tablet) [Formulation Formulation] Example 2 target compound 1- [4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl] -3 - (2-Fluoro-5-methylphenyl)urea 2. 5 g
聚维酮 (polyvinylpyrrolidine, PVP) 7. 5g 微晶纤维素 10g Polyvinylpyrrolidine (PVP) 7. 5g Microcrystalline cellulose 10g
麦子淀粉 13g  Wheat Starch 13g
滑石粉 lg  Talc powder lg
共制 100片, 每片含该化合物 25 mg。 【制备方法】 称取该化合物 2. 5g, 球磨成极细粉, 备用。 取 PVP水浴加热 (80Γ ) 溶解, 加入 备好的化合物细粉, 搅勾, 再加入微晶纤维素、 麦子淀粉, 加入适量无水乙醇制软材, 用 14目筛制粒后, 置 70-80°C干燥后于 12目筛整粒, 加入滑石粉, 压片 (0. 25g/片), 质检, 即得。  A total of 100 tablets were prepared, each containing 25 mg of the compound. [Preparation method] Weigh the compound 2. 5g, ball milled into a very fine powder, and set aside. Take PVP water bath heating (80 Γ) to dissolve, add the prepared compound fine powder, stir the hook, then add microcrystalline cellulose, wheat starch, add appropriate amount of anhydrous ethanol to soft material, use 14 mesh sieve to make granules, set 70- After drying at 80 ° C, the granules were sieved on a 12-mesh sieve, and talc powder was added thereto, and the tablets were granulated (0.25 g/tablet), and quality inspection was obtained.
【用法用量】 每次 1片, 每日 3次。 【适用人群】 适用各种肿瘤患者。 例 4: 片剂 (剂量: 50mg/片) 【制剂处方】 实施例 2目标化合物 1- [4- (1-氨基咪唑 [1, 5- a]并吡啶 -8-基)苯基] -3- (2-氟 -5-甲 基苯基)脲 5g [Usage and Dosage] 1 tablet each time, 3 times a day. [Applicable people] Applicable to a variety of cancer patients. Example 4: Tablet (dosage: 50 mg/tablet) [Formulation Formulation] Example 2 target compound 1- [4-(1-aminoimidazo[1, 5-a]pyridin-8-yl)phenyl] -3 - (2-Fluoro-5-methylphenyl)urea 5g
聚维酮 (polyvinylpyrrolidine, PVP) 10g  Polyvinylpyrrolidine (PVP) 10g
微晶纤维素 lg  Microcrystalline cellulose lg
麦子淀粉 13g  Wheat Starch 13g
滑石粉 lg  Talc powder lg
共制 100片, 每片含该化合物 50n)g。 【制备方法】 称取该化合物 5g, 球磨成极细粉, 备用。 取 PVP水浴加热 (80°C ) 溶解, 加入备 好的化合物细粉, 搅匀, 再加入微晶纤维素、 麦子淀粉, 加入适量无水乙醇制软材, 用 14目筛制粒后, 置 70-80°C干燥后于 12目筛整粒, 加入滑石粉, 压片 (0. 3g/片), 质 检, 即得。 A total of 100 tablets were prepared, each containing 50 n) g of the compound. [Preparation method] 5 g of the compound was weighed and ball-milled into a very fine powder for use. Take PVP water bath heating (80 ° C) to dissolve, add the prepared compound fine powder, stir well, then add microcrystalline cellulose, wheat starch, add appropriate amount of anhydrous ethanol to soft material, use 14 mesh sieve to make the grain, set After drying at 70-80 ° C, the granules were sieved on a 12-mesh sieve, and talc powder was added, and the tablets were compressed (0.3 g/tablet). Check, that is.
【用法用量】 每次 1片, 每日 3次 【Usage and Dosage】 1 tablet each time, 3 times a day
【适用人群】 【For people】
适用各种肿瘤患者。 例 5: 胶囊剂  Applicable to a variety of cancer patients. Example 5: Capsules
【制剂处方】 实施例 2目标化合物 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-氟 -5-甲 基苯基)脲 2.5 g [Formulation Formulation] Example 2 target compound 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl) Urea 2.5 g
麦子淀粉 12g  Wheat Starch 12g
10%淀粉浆 适量  10% starch slurry
食用色素 适量  Food coloring
共制成硬胶囊剂 100粒, 每粒含该化合物 25 mg。 【制备方法】 取该化合物研成细粉, 过 80目筛, 备用; 取 10%淀粉浆加入少量食用橘黄 (最大用 量为万分之一)制成黄糊; 将备好的化合物细粉与麦子淀粉混匀后加入黄糊, 制软材后, 过 14目尼龙筛制粒,于 70°C干燥至水分 3%以下,整粒后填入空胶囊中即得(5号胶囊, 每粒 0.1 g), 质检、 包装, 即得。  A total of 100 capsules of hard capsules were prepared, each containing 25 mg of the compound. [Preparation method] Take the compound into a fine powder, pass through a 80 mesh sieve, and set aside; take a 10% starch slurry and add a small amount of edible orange (maximum dosage is one ten thousandth) to make a yellow paste; After mixing the wheat starch, add yellow paste, make soft material, granulate through 14 mesh nylon sieve, dry at 70 °C to below 3% of water, fill it into empty capsule after whole grain, get (5 capsules, each capsule 0.1 g), quality inspection, packaging, that is.
【用法用量】 每次 1粒, 每日 3次。 【适用人群】 适用各种肿瘤患者。 [Usage and Dosage] 1 capsule each time, 3 times a day. [Applicable people] Applicable to a variety of cancer patients.
例 6: 胶囊剂 【制剂处方】 实施例 2目标化合物 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3_ (2-氟 -5-甲 基苯基)脲 5 g 麦子淀粉 19g Example 6: Capsule [prescription] Example 2 target compound 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea 5 g wheat Starch 19g
10%淀粉浆适量 食用色素 适量 共制成硬胶囊剂 100粒, 每粒含该化合物 50 mg。 【制备方法】 Appropriate amount of 10% starch slurry Food colorion A total of 100 capsules of hard capsules were prepared, each containing 50 mg of the compound. 【Preparation】
取该化合物研成细粉, 过 80目筛, 备用; 取 10%淀粉桨加入少量食用橘黄 (最大用 量为万分之一)制成黄糊; 将备好的化合物细粉与麦子淀粉混匀后加入黄糊, 制软材后, 过 14目尼龙筛制粒,于 70°C千燥至水分 3%以下,整粒后填入空胶囊中即得(4号胶囊, 每粒 0.25 g), 质检、 包装, 即得。  Take the compound into a fine powder, pass through a 80 mesh sieve, and set aside; take a 10% starch paddle and add a small amount of edible orange (maximum dosage is one ten thousandth) to make a yellow paste; mix the prepared compound powder with wheat starch. After adding the yellow paste, after making the soft material, the granules are passed through a 14-mesh nylon sieve, dried at 70 ° C to a moisture content of 3% or less, and then filled into empty capsules after the whole granules (the capsule No. 4, 0.25 g per capsule) , quality inspection, packaging, that is.
【用法用量】 每次 1粒, 每日 3次。 【适用人群】 适用各种肿瘤患者。 [Usage and Dosage] 1 capsule each time, 3 times a day. [Applicable people] Applicable to a variety of cancer patients.

Claims

权利 要 求 Rights request
1、 一种咪唑并吡啶类化合物, 该化合物的分子结构如式 I所示; 1. An imidazopyridine compound having a molecular structure as shown in Formula I;
Figure imgf000056_0001
Figure imgf000056_0001
其中,  among them,
R1和 R2分别独立地表示:  R1 and R2 are respectively represented independently:
(1) 氢; 或者  (1) hydrogen; or
(2) 氨基或 烷基取代的氨基; 或者  (2) an amino group or an alkyl group substituted amino group; or
(3) CL12烷基, 羟基取代的 CM2烷基, 垸氧基取代的 d.12烷基, 氨基取代的(3) CL 12 alkyl, hydroxy substituted C M2 alkyl, decyl substituted d. 12 alkyl, amino substituted
C1-12院基, C1-12垸基取代的氨基取代的 d_12烷基, 或 3- 12元饱和 /部分饱和杂环取代的C 1-12 , C 1-12 fluorenyl substituted amino substituted d 12 alkyl, or 3- 12 saturated/partial saturated heterocyclic substituted
G1-12院基; G 1-12 yard base;
R3表示:  R3 means:
(1) 氢, 氨基, 羟基, 氰基, 素, 硝基, 羧基, 巯基, 或 12垸基; 或者(1) hydrogen, amino, hydroxy, cyano, nitro, carboxy, fluorenyl, or 12 fluorenyl;
(2) 氨基、 羟基、 氰基、 卤素、 硝基、 羧基或巯基取代的 CW2烷基, d_12浣氧基 取代的 CW2垸基, CW2垸基取代的氨基取代的 d.12烷基, 3-12元饱和或部分饱和杂环 取代的垸基, Cw2垸基取代的巯基取代的 d.12烷基, 12垸基取代的亚砜基取代的 d.12 烷基, CL12垸基取代的砜基取代的 CL12垸基, Co.12烷基取代的氨基羰基取代的 d.12垸基, C。.12烷基取代的氨基亚磺酰基取代的 烷基, CQ.12烷基取代的氨基磺酰基取代的 d.12 烷基, Q).12垸基取代的脲基取代的 垸基, Q)_12垸基取代的羰基氨基取代的 烷基, Co.12垸基取代的亚磺酰基氨基取代的 CW2烷基, CQ_12垸基取代的磺酰基氨基取代的 C1-12 垸基, CW2垸氧基取代的 12垸基, CW2垸基取代的氨基取代的 C1-12垸基, 3-12元饱 和或部分饱和杂环取代的垸基, Cw2垸基取代的巯基取代的 C1-12垸基, CM2垸基取代的 亚砜基取代的 Cw2垸基, 或 Cw2垸基取代的砜基取代的 Cw2烷基; 或者 (2) Alkyl, hydroxy, cyano, halogen, nitro, carboxy or decyl substituted C W2 alkyl, d 12 12 methoxy substituted C W 2 fluorenyl, C W 2 fluorenyl substituted amino substituted d. 12 alkane a 3-12 membered saturated or partially saturated heterocyclic substituted fluorenyl group, a Cw 2 fluorenyl substituted fluorenyl substituted d. 12 alkyl group, a 12 fluorenyl substituted sulfoxide group substituted d. 12 alkyl group, CL 12 A mercapto substituted sulfone group substituted CL 12 fluorenyl group, a Co. 12 alkyl substituted aminocarbonyl group substituted d. 12 fluorenyl group, C. . 12 alkyl substituted aminosulfinyl substituted alkyl, C Q . 12 alkyl substituted aminosulfonyl substituted d. 12 alkyl, Q). 12 fluorenyl substituted ureido substituted fluorenyl, Q ) 12 fluorenyl substituted carbonylamino substituted alkyl, Co. 12 fluorenyl substituted sulfinylamino substituted C W2 alkyl, C Q -12 alkyl substituted sulfonylamino substituted C 1-12 fluorene , C W 2 methoxy substituted 12 fluorenyl, C W 2 fluorenyl substituted amino substituted C 1-12 fluorenyl, 3-12 membered saturated or partially saturated heterocyclic substituted fluorenyl, Cw 2 fluorenyl substituted a mercapto-substituted C 1-12 fluorenyl group, a C M 2 fluorenyl substituted sulfoxide group-substituted Cw 2 fluorenyl group, or a Cw 2 fluorenyl substituted sulfone group-substituted Cw 2 alkyl group;
(3) 乙烯基, 或 CW2烷基取代的乙烯基; 或者 (3) a vinyl group, or a C W2 alkyl substituted vinyl group; or
(4) 乙炔基, 或 Cw2垸基取代的乙炔基; 或者 (4) an ethynyl group, or a Cw 2 fluorenyl substituted ethynyl group;
(5)氨基、 羟基、 氰基、 卤素、 硝基、 羧基或巯基取代的 C1-12烷氧基, C1-12烷氧 基取代的 C1-12垸氧基, C1-12垸基取代的氨基取代的 Cw2垸氧基, 3-12元饱和或部分饱 和杂环取代的垸氧基, Cw2垸基取代的巯基取代的 d_12垸氧基, _12烷基取代的亚砜 基取代的 Cw2垸氧基, Cw2烷基取代的砜基取代的 d_12垸氧基, 3-12元饱和或部分饱 和杂环取代的 Cw2垸氧基, Q 2垸基取代的氨基羰基取代的 CW2垸氧基, Q)_12垸基取 代的氨基亚磺酰基取代的 Cm垸氧基, C( 2烷基取代的氨基磺酰基取代的 Cw2垸氧基, QM2烷基取代的脲基取代的 Cw2垸氧基, C(M2垸基取代的羰基氨基取代的 _12烷氧基, QM2垸基取代的亚磺酰基氨基取代的 Cw2垸氧基, 或 C(M2垸基取代的磺酰基氨基取代 的 .12垸氧基; 或者 (5) Amino, hydroxy, cyano, halogen, nitro, carboxy or fluorenyl substituted C 1-12 alkoxy, C 1-12 alkoxy a substituted C 1-12 decyloxy group, a C 1-12 fluorenyl substituted amino substituted Cw 2 decyloxy group, a 3-12 membered saturated or partially saturated heterocyclic substituted fluorenyloxy group, Cw 2 fluorenyl substituted Mercapto-substituted d- 12 oxirane, -12 alkyl-substituted sulfoxide-substituted Cw 2 decyloxy, Cw 2 alkyl-substituted sulfone-substituted d- 12 oxirane, 3-12-membered saturated or partially saturated Heterocyclic substituted Cw 2 decyloxy, Q 2 fluorenyl substituted aminocarbonyl substituted C W2 decyloxy, Q) -12 fluorenyl substituted aminosulfinyl substituted Cm decyloxy, C ( 2 alkyl Substituted aminosulfonyl substituted Cw 2 decyloxy, QM 2 alkyl substituted ureido substituted Cw 2 decyloxy, C (M 2 fluorenyl substituted carbonylamino substituted -12 alkoxy, QM 2 thiol substituted Sulfonylamino substituted Cw 2 decyloxy, or C (M 2 fluorenyl substituted sulfonylamino substituted . 12 fluorenyloxy; or
(6 ) C1-12烷基取代的氨基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基或巯基取代的 CW2烷基取代的氨基, Cw2垸氧基取代的氨基, d.12烷基取代的氨基取代的 d.12垸基 取代的氨基, 3-12元饱和或部分饱和杂环取代的氨基, 3-12元饱和或部分饱和杂环取代 的 Cw2垸基取代的氨基, d_12垸基取代的巯基取代的氨基, Q.l2垸基取代的亚砜基取 代的氨基, .12烷基取代的砜基取代的氨基, CQ.12垸基取代的氨基羰基取代的 —12烷 基取代的氨基, QM2垸基取代的氨基亚磺酰基取代的 d.12垸基取代的氨基, C(M2垸基 取代的氨基磺酰基取代的 Cw2垸基取代的氨基, C(M2垸基取代的脲基取代的 d.12垸基 取代的氨基, Q 2烷基取代的羰基氨基取代的 d.12垸基取代的氨基, Q)_12烷基取代的 亚磺酰基氨基取代的 12垸基取代的氨基, 或 C(M2垸基取代的磺酰基氨基取代的 d.12 垸基取代的氨基; 或者 (6) C 1-12 alkyl-substituted amino group, amino group, hydroxy group, cyano group, halogen, nitro group, carboxy group or fluorenyl group substituted C W2 alkyl group substituted amino group, Cw 2 methoxy group substituted amino group, d. 12 An alkyl-substituted amino-substituted d. 12- mercapto-substituted amino group, a 3-12-membered saturated or partially saturated heterocyclic-substituted amino group, a 3-12-membered saturated or partially saturated heterocyclic substituted Cw 2 fluorenyl-substituted amino group, D_ 12 alkyl with a substituted mercapto group substituted with an amino, Q. l2 alkyl with a substituted sulfoxide group substituted with an amino, C12 alkyl substituted sulfone group substituted with an amino, C Q 12 alkyl with a substituted aminocarbonyl substituted. - 12 alkyl-substituted amino group, QM 2 fluorenyl substituted aminosulfinyl substituted d. 12 fluorenyl substituted amino group, C (M 2 fluorenyl substituted aminosulfonyl substituted Cw 2 fluorenyl substituted amino group, C (M 2 fluorenyl substituted ureido substituted d. 12 fluorenyl substituted amino group, Q 2 alkyl substituted carbonylamino substituted d. 12 fluorenyl substituted amino group, Q) -12 alkyl substituted sulfinyl group 12 is a substituted amino group substituted with an amino embankment, or C (M 2 embankment substituted sulfonyl group substituted with an amino group d. 12-substituted embankment Group; or
( 7 ) d.12垸基取代的巯基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基、 巯基取代的 12垸基取代的巯基, 12垸氧基取代的巯基, CW2垸基取代的氨基取代的 Cw2垸基取 代的巯基, 3-12元饱和或部分饱和杂环取代的巯基, 3-12元饱和或部分饱和杂环取代 的 12烷基取代的巯基, Cw2烷基取代的巯基取代的巯基, Cw2垸基取代的亚砜基取代 的巯基, CL12垸基取代的砜基取代的巯基, CQ.12垸基取代的氨基羰基取代的 C 12垸基取 代的巯基, 0>_12垸基取代的氨基亚磺酰基取代的 d_12烷基取代的巯基, C().12烷基取代的 氨基磺酰基取代的 C,.12烷基取代的巯基, C 2垸基取代的脲基取代的 C 12垸基取代的 巯基, Q 2烷基取代的羰基氨基取代的 C 12垸基取代的巯基, C( 2垸基取代的亚磺酰基 氨基取代的 12烷基取代的巯基, 或 C( 2垸基取代的磺酰基氨基取代的 C1-12垸基取代 的巯基; 或者 (7) d. 12 -mercapto-substituted fluorenyl, amino, hydroxy, cyano, halogen, nitro, carboxy, fluorenyl substituted 1 2 fluorenyl substituted fluorenyl, 12 methoxy substituted fluorenyl, C W2 thiol substituted Amino substituted Cw 2 fluorenyl substituted fluorenyl, 3-12 membered saturated or partially saturated heterocyclic substituted fluorenyl, 3-12 membered saturated or partially saturated heterocyclic substituted 12 alkyl substituted fluorenyl, Cw 2 alkyl substituted Thiol-substituted fluorenyl, Cw 2 fluorenyl substituted sulfoxide substituted fluorenyl, CL 12 fluorenyl substituted sulfone substituted fluorenyl, C Q . 12 fluorenyl substituted aminocarbonyl substituted C 12 fluorenyl substituted fluorenyl , 0> _ 12 mercapto substituted aminosulfinyl substituted d- 12 alkyl substituted fluorenyl, C(). 12 alkyl substituted aminosulfonyl substituted C,. 12 alkyl substituted fluorenyl, C 2垸Substituted ureido-substituted C 12 fluorenyl substituted fluorenyl, Q 2 alkyl substituted carbonylamino substituted C 12 fluorenyl substituted fluorenyl, C( 2 fluorenyl substituted sulfinylamino substituted 12 alkyl substituted mercapto, or C (2 embankment amino substituted sulfonyl group substituted with C 1-12 alkyl with a substituted thiol group; By
( 8 ) 垸基取代的亚砜基, Cw2垸基取代的砜基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基、 巯基取代的 Cw2垸基取代的亚砜基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基、巯基取代的 ^.12垸基取代的砜基, C 12垸氧基取代的亚砜基, Cw2垸氧基取代的 砜基, c 12浣基取代的氨基取代的 C1-12垸基取代的亚砜基, _12垸基取代的氨基取代的 C1-12烷基取代的砜基, 3-12元饱和或部分饱和杂环取代的亚砜基, 3- 12元饱和或部分 饱和杂环取代的砜基, 3-12元饱和或部分饱和杂环取代的 Cw2垸基取代的 砜基, 3-12 元饱和或部分饱和杂环取代的 C142垸基取代的砜基, CW2垸基取代的巯基取代的亚砜 基, CW2垸基取代的巯基取代的砜基, CL12垸基取代的砜基取代的亚砜基, d.12烷基取 代的砜基取代的砜基, C(M2烷基取代的氨基羰基取代的 烷基取代的亚砜基, Co_12 烷基取代的氨基羰基取代的 CL12垸基取代的砜基, C( 2垸基取代的氨基磺酰基取代的 CL12烷基取代的亚砜基, C(M2烷基取代的氨基磺酰基取代的 d.12垸基取代的砜基, C0-12 垸基取代的脲基取代的 Cw2垸基取代的亚砜基, Co.12垸基取代的脲基取代的 d_12垸基 取代的砜基, C。.12垸基取代的羰基氨基取代的 d.12垸基取代的亚砜基, Q 2烷基取代的 羰基氨基取代的 CL12垸基取代的砜基, CQ_12烷基取代的磺酰基氨基取代的 d.12垸基取 代的亚砜基, 或 CQ.12烷基取代的磺酰基氨基取代的 d_12垸基取代的砜基; 或者 (8) fluorenyl substituted sulfoxide group, Cw 2 fluorenyl substituted sulfone group, amino group, hydroxy group, cyano group, halogen, nitro group, carboxyl group, fluorenyl substituted Cw 2 fluorenyl substituted sulfoxide group, amino group, hydroxyl group , cyano, halogen, nitro, carboxy, fluorenyl substituted ^ 12 alkyl substituted sulfone, C 12 nonyl substituted sulfoxide, Cw 2 decyl substituted Sulfone group, c 12 fluorenyl substituted amino substituted C 1-12 fluorenyl substituted sulfoxide group, -12 fluorenyl substituted amino substituted C 1-12 alkyl substituted sulfone group, 3-12 member saturated or Partially saturated heterocyclic substituted sulfoxide group, 3- 12 member saturated or partially saturated heterocyclic substituted sulfone group, 3-12 membered saturated or partially saturated heterocyclic substituted Cw 2 fluorenyl substituted sulfone group, 3-12 yuan a saturated or partially saturated heterocyclic substituted C 142 fluorenyl substituted sulfone group, a C W2 fluorenyl substituted fluorenyl substituted sulfoxide group, a C W2 fluorenyl substituted fluorenyl substituted sulfone group, a CL 12 fluorenyl substituted sulfone group Substituted sulfoxide group, d. 12 alkyl substituted sulfone group substituted sulfone group, C (M 2 alkyl substituted aminocarbonyl substituted alkyl substituted sulfoxide group, Co 12 alkyl substituted aminocarbonyl substituted CL 12 fluorenyl substituted sulfone group, C ( 2 fluorenyl substituted aminosulfonyl substituted CL 12 alkyl substituted sulfoxide group, C (M 2 alkyl substituted aminosulfonyl substituted d. 12 fluorenyl substituted) the sulfone group, C 0-12 alkyl with the substituent of the substituted ureido group substituted Cw 2 embankment sulfoxide group, Co. 12 alkyl with the substituent of the substituted ureido group substituted d_ 12 embankment Group, C .. 12 alkyl with an amino substituted carbonyl substituted with d. 12 substituted alkyl with the sulfoxide group, Q 2 alkyl substituted amino-substituted carbonyl group substituted CL 12 embankment sulfone group, C Q _ 12 alkyl a substituted sulfonylamino substituted d. 12 fluorenyl substituted sulfoxide group, or a C Q. 12 alkyl substituted sulfonylamino substituted d- 12 12 substituted sulfone group;
(9) 3-12元饱和或部分饱和杂环基, d.12垸基取代的 3-12元饱和或部分饱和杂环 基, 氨基、 羟基、 氰基、 卤素、 硝基、 羧基或巯基取代的 Q_I2烷基取代的 3-12元饱和 或部分饱和杂环基, d.12烷氧基取代的 3-12元饱和或部分饱和杂环基, C 12烷基取代 的氨基取代的 _12垸基取代的 3-12元饱和或部分饱和杂环基, 3-12元饱和或部分饱和 杂环取代的 3-12元饱和或部分饱和杂环基, 3-12元饱和或部分饱和杂环取代的 .12烷 基取代的 3-12元饱和或部分饱和杂环基, .12垸基取代的巯基取代的 3-12元饱和或部 分饱和杂环基, Cw2烷基取代的亚砜基取代的 3-12元饱和或部分饱和杂环基, CW2烷 基取代的砜基取代的 3-12元饱和或部分饱和杂环基, Co.12烷基取代的氨基羰基取代的 d.12垸基取代的 3-12元饱和或部分饱和杂环基, Co.12垸基取代的氨基亚磺酰基取代的 d.12垸基取代的 3-12元饱和或部分饱和杂环基, CQ_12垸基取代的氨基磺酰基取代的 CM2 垸基取代的 3-12元饱和或部分饱和杂环基, QM2垸基取代的脲基取代的 Cw2烷基取代 的 3-12元饱和或部分饱和杂环基, QM2烷基取代的羰基氨基取代的 Cw2垸基取代的 3-12 元饱和或部分饱和杂环基, Q).12垸基取代的亚磺酰基氨基取代的 C1-12垸基取代的 3-12 元饱和或部分饱和杂环基, 或 C( 2烷基取代的磺酰基氨基取代的 C 12烷基取代的 3-12 元饱和或部分饱和杂环基; (9) 3-12-membered saturated or partially saturated heterocyclic group, d. 12 -mercapto-substituted 3-12-membered saturated or partially saturated heterocyclic group, substituted by amino group, hydroxy group, cyano group, halogen, nitro group, carboxyl group or thiol group the Q_ I2 alkyl substituted 3-12 membered saturated or partially saturated heterocyclyl, d. 12 alkoxy substituted 3-12 membered saturated or partially saturated heterocyclic group, C 12 alkyl substituted amino-substituted _ 12 A mercapto-substituted 3-12 membered saturated or partially saturated heterocyclic group, a 3-12 membered saturated or partially saturated heterocyclic substituted 3-12 membered saturated or partially saturated heterocyclic group, a 3-12 membered saturated or partially saturated heterocyclic ring. Substituted. 12 alkyl substituted 3-12 membered saturated or partially saturated heterocyclic group, 12 fluorenyl substituted fluorenyl substituted 3-12 membered saturated or partially saturated heterocyclic group, Cw 2 alkyl substituted sulfoxide group Substituted 3-12 membered saturated or partially saturated heterocyclic group, C W 2 alkyl substituted sulfone group substituted 3-12 membered saturated or partially saturated heterocyclic group, Co. 12 alkyl substituted aminocarbonyl substituted d. 12 alkyl with a substituted 3-12-membered saturated or partially saturated heterocyclic group, Co. 12 alkyl with a substituted amino group substituted alkylsulfinyl d. 12 embankment group substituted 3-12 membered saturated Partially saturated heterocyclyl, C Q _ 12 alkyl with an amino substituted sulfonyl group substituted with a C M2 alkyl with a substituted 3-12-membered saturated or partially saturated heterocyclic group, QM2 embankment substituted ureido alkyl group substituted Cw 2 Substituted 3-12 membered saturated or partially saturated heterocyclic group, QM 2 alkyl substituted carbonylamino substituted Cw 2 fluorenyl substituted 3-12 membered saturated or partially saturated heterocyclic group, Q). 12 fluorenyl substituted sub Sulfonylamino substituted C1-12 fluorenyl substituted 3-12 membered saturated or partially saturated heterocyclic group, or C ( 2 alkyl substituted sulfonylamino substituted C 12 alkyl substituted 3-12 member saturated or partially Saturated heterocyclic group;
X表示氧, 硫, N-CN, 或 N-N02; X represents oxygen, sulfur, N-CN, or N-N0 2 ;
Ar和 Ar'分别独立地表示芳基或杂芳基, 或者芳环或杂芳环上的 1〜4个氢被 R3、 芳基或杂芳基取代的芳基或杂芳基。 2、 如权利要求 1所述的化合物, 其特征在于 R1表示氢, R2表示氨基。 Ar and Ar' each independently represent an aryl or heteroaryl group, or an aryl or heteroaryl group in which 1 to 4 hydrogens on the aromatic ring or heteroaryl ring are substituted by R3, aryl or heteroaryl. 2. A compound according to claim 1 wherein R1 represents hydrogen and R2 represents an amino group.
3、 如权利要求 1所述的化合物, 其特征在于 R1表示氪基, R2表示氢。 3. A compound according to claim 1, wherein R1 represents a fluorenyl group and R2 represents a hydrogen.
4、 如权利要求 1所述的化合物, 其特征在于 X表示氧。 4. A compound according to claim 1 wherein X represents oxygen.
5、如权利要求 1所述的化合物, 其特征在于 Ar和 Ar'分别独立地表示苯环, 吡啶, 吡啶酮, 四氢吡啶酮, 咪啶, 吡嗪, 哒嗪, 咪唑, 噻唑, 噻吩, 呋喃, 吲哚, 氮杂吲哚, 苯并咪唑, 吲哚啉, 或吲哚酮中的任何一种, 或者苯环或杂环上的 1〜4个氢被 R3、 芳 基或杂芳基取代的苯环, 吡啶, 吡啶酮, 四氢吡啶酮, 咪啶, 吡嗪, 哒嗪, 咪唑, 噻唑, 噻吩, 呋喃, 吲哚, 氮杂吲哚, 苯并咪唑, 吲哚啉, 或吲哚酮中的任何一种。 The compound according to claim 1, wherein Ar and Ar' each independently represent a benzene ring, a pyridine, a pyridone, a tetrahydropyridone, an pyridine, a pyrazine, a pyridazine, an imidazole, a thiazole, a thiophene, Any of furan, anthracene, azaindene, benzimidazole, porphyrin, or anthrone, or 1 to 4 hydrogens on a benzene or heterocyclic ring by R3, aryl or heteroaryl Substituted benzene ring, pyridine, pyridone, tetrahydropyridone, pyridine, pyrazine, pyridazine, imidazole, thiazole, thiophene, furan, hydrazine, azaindole, benzimidazole, porphyrin, or hydrazine Any of the fluorenone.
6、 如权利要求 1所述的化合物, 其特征在于 R1表示氢或氨基, R2表示氢或氨基, X表示氧, Ar表示苯环, Ar'表示苯环或者被 1〜2个相同或不同基团取代的苯环, 所述 的基团是卤素, 甲基, 甲氧基, 卤素取代的甲基或甲氧基。 6. The compound according to claim 1, wherein R1 represents hydrogen or an amino group, R2 represents hydrogen or an amino group, X represents oxygen, Ar represents a benzene ring, Ar' represents a benzene ring or is 1 or 2 identical or different groups. a group-substituted benzene ring, the group being a halogen, a methyl group, a methoxy group, a halogen-substituted methyl group or a methoxy group.
7、 如权利要求 6所述的化合物, 其特征在于该化合物是: 7. A compound according to claim 6 wherein the compound is:
(1) 1- [4- (1-氨基咪唑 [1, 5- a]并吡啶 -8-基)苯基] - 3-苯基脲,  (1) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-phenylurea,
(2) 1-[4- (1-氨基咪唑 [1, 5- a]并吡啶 -8-基)苯基] -3- (2-氟- 5-甲基苯基)脲, (2) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea,
(3) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (4-氟- 3-甲基苯基)脲,(3) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-fluoro-3-methylphenyl)urea,
(4) 1-[4- (1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] - 3- (3-氟 -4-甲基苯基)脲,(4) 1-[4-(1-Aminoimidazole [l,5-a]pyridin-8-yl)phenyl]-3-(3-fluoro-4-methylphenyl)urea,
(5) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-三氟甲基 -5-氟苯基)脲,(5) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-trifluoromethyl-5-fluorophenyl)urea,
(6) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-氟苯基)脲, (6) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluorophenyl)urea,
(7) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 _8_基)苯基] -3- (3-氟苯基)脲,  (7) 1-[4-(1-Aminoimidazo[1,5-a]pyridinyl-8-yl)phenyl]-3-(3-fluorophenyl)urea,
(8) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (4-氟苯基)脲,  (8) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-fluorophenyl)urea,
(9) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-甲基苯基)脲,  (9) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-methylphenyl)urea,
(10) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-甲基苯基)脲,  (10) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-methylphenyl)urea,
(11) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 _8_基)苯基] -3- (4-甲基苯基)脲,  (11) 1-[4-(1-Aminoimidazo[1,5-a]pyridinyl-8-yl)phenyl]-3-(4-methylphenyl)urea,
(12) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-氯苯基)脲,  (12) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-chlorophenyl)urea,
(13) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-氯苯基)脲,  (13) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-chlorophenyl)urea,
(14) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (4-氯苯基)脲,  (14) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-chlorophenyl)urea,
(15) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 _8_基)苯基] -3- (2-溴苯基)脲,  (15) 1-[4-(1-Aminoimidazo[1,5-a]pyridinyl-8-yl)phenyl]-3-(2-bromophenyl)urea,
(16) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-溴苯基)脲,  (16) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-bromophenyl)urea,
(17) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (4-溴苯基)脲, (17) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-bromophenyl)urea,
(18) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-三氟甲基苯基)脲,(18) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-trifluoromethylphenyl)urea,
(19) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-三氟甲基苯基)脲,(19) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-trifluoromethylphenyl)urea,
(20) 1- [4- (1-氨基咪唑 [1, 5- a]并吡啶 -8-基)苯基] -3- (4-三氟甲基苯基)脲,(20) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-trifluoromethylphenyl)urea,
(21) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-三氟甲氧基苯基)脲,(21) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-trifluoromethoxyphenyl)urea,
(22) 1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-三氟甲氧基苯基)脲,(22) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-trifluoromethoxyphenyl)urea,
(23) 1- [4- (1-氨基咪唑 [1, 5- a]并吡啶 -8-基)苯基] - 3- (4 -三氟甲氧基苯基)脲,(23) 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-trifluoromethoxyphenyl)urea,
(24) 1- [4- (1-氨基- 3-甲基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-氟 -5-甲基苯基) (24) 1-[4-(1-Amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)
(25) 1- [4- (1-氨基- 3-甲基咪唑 [ 1, 5- a]并吡啶 -8-基)苯基] -3- (4 -氟- 3-甲基苯基) (25) 1-[4-(1-Amino-3-methylimidazo[1, 5-a]pyridin-8-yl)phenyl]-3-(4-fluoro-3-methylphenyl)
(26) 1- [4- (1-氨基- 3-甲基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-甲基苯基)脲,(26) 1-[4-(1-Amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-methylphenyl)urea,
(27) 1- [4- (1-氨基 -3-甲基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (4-甲基苯基)脲,(27) 1-[4-(1-Amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-methylphenyl)urea,
(28) 1- [4- (1-氨基 -3-甲基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-氯苯基)脲,(28) 1-[4-(1-Amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-chlorophenyl)urea,
(29) 1- [4- (1-氨基 -3-甲基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-三氟甲基苯基) (29) 1-[4-(1-Amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-trifluoromethylphenyl)
(30) 1- [4- (3-氨基咪唑 [ 1, 5-a]并吡啶 _5 -基)苯基] -3- (4-三氟甲基苯基)脲,(30) 1-[4-(3-Aminoimidazo[1, 5-a]pyridinyl-5-yl)phenyl]-3-(4-trifluoromethylphenyl)urea,
(31) 1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (3-氟苯基)脲, (31) 1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-fluorophenyl)urea,
(32) 1- [4- (3-氨基咪唑 [ 1 ' 5-a]并吡啶 _5_基)苯基] _3_ (3-三氟甲基苯基)脲, (32) 1-[4-(3-Aminoimidazole [ 1 ' 5-a]pyridine _5-yl)phenyl] _3_ (3-trifluoromethylphenyl)urea,
(33) 1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5 -基)苯基] -3- (4-氟苯基)脲, (33) 1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(4-fluorophenyl)urea,
(34) 1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 _5_基)苯基] -3- (4-三氟甲氧基苯基)脲, (34) 1-[4-(3-Aminoimidazo[1,5-a]pyridinyl-5-yl)phenyl]-3-(4-trifluoromethoxyphenyl)urea,
(35) 1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (3-氟 -4-甲基苯基)脲,(35) 1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-fluoro-4-methylphenyl)urea,
(36) 1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (3-甲基 -4-三氟甲基苯基) (36) 1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-methyl-4-trifluoromethylphenyl)
(37) 1- [4- (3-氨基咪唑 [1, 5- a]并吡啶 -5-基)苯基] -3- (3-氯 -4-三氟甲基苯基) 或 (37) 1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-chloro-4-trifluoromethylphenyl) or
(38) 1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (2-氟- 5-甲基苯基)脲。  (38) 1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea.
8、 如权利要求 7所述的化合物, 其特征在于该化合物是: 8. A compound according to claim 7 wherein the compound is:
1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-氟 -5-甲基苯基)脲, 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea,
1 - [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] _3_ (4-氟- 3-甲基苯基)脲, 1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]_3_(4-fluoro-3-methylphenyl)urea,
1 - [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-氟苯基)脲, 1- [4- (1 -氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-甲基苯基)脲,1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-fluorophenyl)urea, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-methylphenyl)urea,
1- [4- (1 -氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (4-甲基苯基)脲, 1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-methylphenyl)urea,
1- [4- (1 -氨基咪唑 [1, 5- a]并吡啶 -8-基)苯基] -3- (3-氯苯基)脲,  1-[4-(1-aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-chlorophenyl)urea,
1- [4- (1-氨基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (2-溴苯基)脲,  1-[4-(1-Aminoimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-bromophenyl)urea,
1- [4- (1-氨基咪唑 [l,5-a]并吡啶 -8-基)苯基] -3- (3-三氟甲基苯基)脲,  1-[4-(1-Aminoimidazo[l,5-a]pyridin-8-yl)phenyl]-3-(3-trifluoromethylphenyl)urea,
1- [4- (1-氨基- 3 -甲基咪唑 [1, 5- a]并吡啶 -8-基)苯基] -3- (2-氟- 5-甲基苯基)脲, 1-[4-(1-Amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea,
1- •[4- (1-氨基 -3-甲基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (4-氟 -3-甲基苯基)脲,1- •[4-(1-Amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(4-fluoro-3-methylphenyl)urea,
1- [4- (1-氨基- 3-甲基咪唑 [1, 5- a]并吡啶 -8-基)苯基] -3- (3-甲基苯基)脲,1-[4-(1-Amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-methylphenyl)urea,
1- [4- (1-氨基 -3-甲基咪唑 [1, 5-a]并吡啶 -8-基)苯基] -3- (3-氯苯基)脲, 1-[4-(1-Amino-3-methylimidazo[1,5-a]pyridin-8-yl)phenyl]-3-(3-chlorophenyl)urea,
1- -[4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (4-三氟甲基苯基)脲,  1--[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(4-trifluoromethylphenyl)urea,
1- [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (3-三氟甲基苯基)脲,  1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-trifluoromethylphenyl)urea,
1- ■[4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (4-三氟甲氧基苯基)脲, 1-■[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(4-trifluoromethoxyphenyl)urea,
1- -[4- (3 -氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (3-氟 -4-甲基苯基)脲,1--[4-(3-aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-fluoro-4-methylphenyl)urea,
1- - [4- (3-氨基咪唑 [1, 5- a]并吡啶 -5-基)苯基] -3- (3-氯 -4-三氟甲基苯基)脲, 或1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(3-chloro-4-trifluoromethylphenyl)urea, or
1- - [4- (3-氨基咪唑 [1, 5-a]并吡啶 -5-基)苯基] -3- (2-氟 -5-甲基苯基)脲。 1-[4-(3-Aminoimidazo[1,5-a]pyridin-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea.
9、一种咪唑并吡啶类化合物, 该化合物为权利要求 1〜8之一所述的化合物的消旋 体或对映异构体。 An imidazopyridine compound which is a racemate or an enantiomer of the compound according to any one of claims 1 to 8.
10、 一种 1-氨基咪唑 [1, 5-a]并吡啶类化合物的合成方法, 该方法由式 II所示的步 骤组成。 A method for synthesizing a 1-aminoimidazole [1,5-a] pyridine compound, which comprises the step of the formula II.
Figure imgf000062_0001
Figure imgf000062_0001
其中, 化合物 11等同于当式 I中的 Rl 为 氨基时的化合物。 Wherein compound 11 is equivalent to a compound when R1 in formula I is an amino group.
11、 一种 3-氨基咪唑 [1, 5-a]并吡啶类化合物的合成方法, 该方法由式 III所示的步 骤组成。 A method for synthesizing a 3-aminoimidazole [1,5-a] pyridine compound, which comprises the step of the formula III.
NaB(OAc)3H NaB(OAc) 3 H
Figure imgf000062_0002
Figure imgf000062_0002
其中, 化合物 j等同于当式 I中的 R2为氨基时的化合物。  Wherein compound j is equivalent to a compound when R2 in formula I is an amino group.
12、 权利要求 1〜9之一所述的化合物在制备因激酶活性异常增高引起的疾病的药 物中的应用, 其中所述的激酶为血管内皮生长因子受体 2、 Flt3或 c- Kit。 The use of a compound according to any one of claims 1 to 9 for the preparation of a medicament for a disease caused by an abnormal increase in kinase activity, wherein the kinase is vascular endothelial growth factor receptor 2, Flt3 or c-kit.
13、 如权利要求 12所述的应用, 其特征在于所述的疾病是癌症。  13. Use according to claim 12, characterized in that the disease is cancer.
14、 如权利要求 13所述的应用, 其特征在于所述的癌症是肺癌、 骨癌、 胰腺癌, 皮肤癌、 头或颈癌、 皮肤或眼内黑素瘤、 子宫癌、 卵巢癌、 直肠癌、 肛门区癌、 胃癌、 结肠癌、 乳腺癌、 输卵管癌、 子宫内膜癌、 宫颈癌、 阴道癌、 阴户癌、 何杰金病、 食道 癌、 小肠癌、 内分泌系统癌、 甲状腺癌、 甲状旁腺癌、 肾上腺癌、 软组织肉瘤、尿道癌、 阴茎癌、 前列腺癌、 慢性或急性白血病、 淋巴细胞性淋巴瘤、 膀胱癌、 肾或输尿管癌、 肾细胞癌、 肾盂癌、 中枢神经中枢系统 (CNS)赘生物、 原发性 CNS淋巴瘤、 脊柱轴肿瘤、 脑干神经胶质瘤、 垂体腺瘤、 胃肠间质肿瘤、 结肠直肠癌、 非小细胞肺癌、 神经内分泌 胶肿瘤、 小细胞肺癌、 肥大细胞增多症、 神经胶质瘤、 肉瘤或淋巴瘤。 14. The use according to claim 13, wherein said cancer is lung cancer, bone cancer, pancreatic cancer, Skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer , vulgar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic Lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, Gastrointestinal stromal tumors, colorectal cancer, non-small cell lung cancer, neuroendocrine collagen tumors, small cell lung cancer, mastocytosis, glioma, sarcoma or lymphoma.
15、 如权利要求 14所述的应用, 其特征在于所述的癌症是胃癌或结肠癌。 15. Use according to claim 14, characterized in that the cancer is gastric cancer or colon cancer.
16、一种治疗由因激酶活性异常增高引起的疾病的药物, 该药物主要由式 I所示的 化合物或其在药学上可接受的盐、 溶剂合物或前药与药学上可接受的辅料组成。 16. A medicament for the treatment of a disease caused by an abnormal increase in kinase activity, which is mainly a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof and a pharmaceutically acceptable excipient. composition.
17、 如权利要求 16所述的药物, 其特征在于该药物还含有抗细菌剂、 抗真菌剂、 抗微生物剂、 维生素和抗肿瘤药物中的一种或多种。 17. The medicament according to claim 16, wherein the medicament further comprises one or more of an antibacterial agent, an antifungal agent, an antimicrobial agent, a vitamin, and an antitumor drug.
18、 如权利要求 16所述的药物, 其特征在于所述的药物是: 18. The medicament of claim 16 wherein said medicament is:
( 1 ) 口服剂: 片剂、 胶囊、 糖浆、 凝胶、 丸剂或口服液;  (1) Oral agents: tablets, capsules, syrups, gels, pills or oral solutions;
(2) 注射剂: 无菌溶液、 悬浮液或乳剂;  (2) Injection: a sterile solution, suspension or emulsion;
(3) 肛塞剂: 栓剂或凝胶剂;  (3) Anal plug: a suppository or gel;
(4) 鼻孔吸入剂: 喷雾剂或气雾剂。  (4) Nostril inhalation: Spray or aerosol.
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