WO2013107326A1 - Composés d'imidazo[1,2-a]pyridine de nouveau type, leur procédé de préparation, composition pharmaceutique les contenant et leur utilisation - Google Patents

Composés d'imidazo[1,2-a]pyridine de nouveau type, leur procédé de préparation, composition pharmaceutique les contenant et leur utilisation Download PDF

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WO2013107326A1
WO2013107326A1 PCT/CN2013/070386 CN2013070386W WO2013107326A1 WO 2013107326 A1 WO2013107326 A1 WO 2013107326A1 CN 2013070386 W CN2013070386 W CN 2013070386W WO 2013107326 A1 WO2013107326 A1 WO 2013107326A1
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group
substituted
branched
fluorenyl
compound
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PCT/CN2013/070386
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Chinese (zh)
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柳红
耿美玉
张登友
艾菁
罗成
李淳朴
陈曦
梁中洁
彭霞
季寅淳
蒋华良
丁健
陈凯先
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中国科学院上海药物研究所
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Publication of WO2013107326A1 publication Critical patent/WO2013107326A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • Novel imidazo[l,2-a]pyridine compound preparation method thereof, pharmaceutical composition containing the same, and use thereof
  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to imidazo[l,2-a]pyridine compounds as receptor tyrosine kinase MET inhibitors, preparation methods thereof, pharmaceutical compositions containing the same, and Its use.
  • Targeted therapy has undoubtedly had a major impact on cancer treatment.
  • the occurrence, evolution, spread and tumor angiogenesis of tumors depend on various signal transduction pathways. Significant progress has been made in targeting these signaling pathways to achieve tumorigenesis, and many drugs have been successfully marketed.
  • imatinib an anticancer drug based on ABL tyrosine kinase
  • CML chronic myeloid leukemia
  • members of the Met proto-oncogene family have received widespread attention.
  • the Met family includes Met (also known as c-Met) and Ron receptors.
  • the tyrosine protein kinase c-Met is a cell surface receptor, the hepatocyte growth factor receptor (HGFR), encoded by the Met proto-oncogene. Unlike most other receptor tyrosine kinases, mature Met consists of an extracellular alpha chain (50 kDa) and a transmembrane beta chain (140 kDa, which anchors the intracellular domain of the kinase domain to the cell membrane). The structure of the polymer functions. HGF is a ligand for Met and acts as a multifunctional cytokine that promotes migration, anti-apoptosis, and mitogenic effects.
  • HGFR hepatocyte growth factor receptor
  • c-Met is highly expressed in most cancers and some sarcomas and is closely related to poor prognosis, such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, neutrophil. Tumor, melanoma, etc. c-Met induces cell proliferation, invasion, migration, inhibition of apoptosis, and promotes angiogenesis by interacting with its ligand HGF/SF or by other pathways to activate tyrosine kinases in the intracellular segment, during tumor development. Play an important role.
  • the aberrant activation mechanisms of c-Met kinase are mainly Met gene amplification, Met gene mutation, c-Met transcriptional level upregulation, ligand-dependent autocrine and paracrine loops.
  • Met gene amplification and consequent protein overexpression and constitutive activation are present in numerous human primary cancers, including gastric and esophageal cancer, non-small cell lung cancer and medulloblastoma with acquired resistance to EGFR inhibitors. in.
  • the Met gene can also carry an activating mutation.
  • Various Met germline and somatic mutations are associated with a lower incidence of tumors.
  • the most common Met constitutive activation in human tumors is the upregulation of non-gene amplified Met transcription, resulting in increased protein expression.
  • HGF itself can activate the transcription of Met, and can also promote the dispersion of cancer cells by positive feedback in a paracrine manner. HGF can also be autocrine Abnormal activation of Met, more common in glioblastoma, breast cancer, rhabdomyosarcoma and osteosarcoma.
  • c-Met interacts with other tumor-associated molecules on the cell surface, such as the integrin family, death-related receptors, and other receptor tyrosine kinases, thereby cross-linking activation to amplify tumor-related effects, greatly It promotes the development of tumors, in which c-Met plays a pivotal role, inhibiting it can inhibit the effects of multiple tumor targets.
  • EGFR-TKIs EGFR receptor tyrosine kinase inhibitors
  • blocking HGF-c-Met signaling can be one of the strategies for anti-tumor therapy. Selective blocking of this pathway not only inhibits tumor growth, but also inhibits tumor metastasis.
  • c-Met inhibitors targeting the HGF-c-Met signaling pathway bio-antagonists of HGF and c-Met, small molecule inhibitors that inhibit PTK catalytic activity, and targeting HGF and c- Specific antibodies for Met. Most of them are in the preclinical research stage, and a few enter the clinical research stage.
  • Amgen's injectable human monoclonal antibody Rilotumumab is in the second phase of clinical trials, including non-small cell lung cancer, colorectal cancer, prostate cancer, and digestive tract cancer.
  • the PF-02341066 small molecule inhibitor developed by Pfizer has been in the third phase of clinical practice.
  • Another object of the present invention is to provide a process for producing a compound of the above formula (I).
  • a further object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of the above formula (I) or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide a compound of the above formula (I) for the preparation of a cell proliferative disorder associated with the treatment of a tyrosine kinase c-Met signal transduction pathway, such as cancer, hyperplasia, restenosis, immune disorders And the use of inflammatory drugs.
  • a tyrosine kinase c-Met signal transduction pathway such as cancer, hyperplasia, restenosis, immune disorders And the use of inflammatory drugs.
  • the compounds of the invention are useful for inhibiting tyrosine kinases, particularly the receptor tyrosine kinase Met.
  • the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof,
  • X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched fluorenyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched decyloxy group, C3-C12 cyclic hydrocarbon group, C1-C6 linear or branched decanoyl group, or C1-C6 linear chain Or branched guanidinium;
  • ⁇ ⁇ is a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group, or a substituted or unsubstituted C6-C12 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 ⁇ 5 substituents, the heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituents are halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoro Methyl, trifluoromethoxy, carboxy, fluorenyl, oxo, C1-C6 straight or branched fluorenyl, C2-C6 straight or branched unsaturated hydrocarbon;
  • R 1 is hydrogen, halogen, C1-C12 linear or branched fluorenyl group, C2-C12 linear or branched unsaturated hydrocarbon group, C3-C12 cyclic hydrocarbon group, C3-C12 heterocyclic group, cyano group, nitro group , amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, -SOR 2 , -SO 2 R 2 , -COR 2 , -COOR 2 , -SO 3 R 2 , -CONR 2 R 3 , -CON(R 2 )R 8 NR 4 R 5 , -SO 2 NR 2 R 3 , -OCONR 2 R 3 , -O 3 CON 3 4 , -N( 2 ) 8 CO ⁇ N 2 3 CON ( 4 )-, -N(R 2 )R 8 SO 2 R 4 , N 2 3 SO 2 N( 4 )-, -NR 2 R 3
  • substituted heterocyclic group or substituted aryl group includes 1 to 5 a substituent having 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen; the substituent is a halogen, a C1-C12 linear or branched fluorenyl group, a C2-C12 linear or branched unsaturated hydrocarbon group, a C3-C12 cycloalkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, Trifluoromethoxy, carboxy, fluorenyl;
  • R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, C1-C12 linear or branched fluorenyl group, C2-C12 linear or branched unsaturated hydrocarbon group, C3-C12 cyclic hydrocarbon group, a C1-C6 decyloxy group, a C1-C6 acyl group, a C6-C12 aryl group, or a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group; said substituted or unsubstituted saturated or unsaturated C3-
  • the C12 heterocyclic group contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, and the substituted C3-C12 heterocyclic group contains one or more fluorenyl groups selected from halogen, C1-C12 straight or branched chain, C2-C12 linear or branched unsaturated hydrocarbon group, C1-C6 decyloxy group, C3-C12
  • R 6 and R 7 are each independently hydrogen or a C1 to C6 fluorenyl group; and R 8 is a C1 to C6 fluorenylene group.
  • W is -CH 2 -, -CF 2 -, -CFH -, -CO-, -CH 2 -O-, -CH 2 -NH- or further;
  • X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C6 straight or branched fluorene a C2-C6 straight or branched chain and a hydrocarbyl group; a substituted or unsubstituted saturated or unsaturated C3-C12 heterocyclic group, or a substituted or unsubstituted C6-C12 aryl group, wherein the substituted
  • the heterocyclic group or substituted aryl group includes 1 to 3 substituents; the heterocyclic group contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent is halogen, cyano, nitro , amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, oxo, C1-C6 straight or branched fluoreny
  • R 1 is hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C10 straight or branched fluorenyl, C2- C10 linear or branched unsaturated hydrocarbon
  • M each independently being a C2-C3 fluorene group
  • Z is a C1-C4 fluorene group
  • r is 0 or 1;
  • T is a hydroxy group, an ester group, a carboxyl group, a C1-C6 linear or branched fluorenyl group, a C1-C6 linear or branched fluorenyloxy group, a C2-C6 linear or branched unsaturated hydrocarbon group, with one or a C1-C6 fluorenyl or decyloxy substituted amine group, an unsubstituted or substituted C3-C10 cycloalkyl group, an unsubstituted or substituted C6-C10 aryl group, an unsubstituted or substituted C3-C10 heterocyclic group;
  • the substituent is halogen, cyano, hydroxy, nitro, amino, trifluoromethyl, benzhydryl, an amine group substituted with one or two C1-C6 fluorenyl groups, a C1-C6 fluorenyl group;
  • R 9 and R 1Q are each independently halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C6 straight or branched fluorene a C2-C6 linear or branched unsaturated hydrocarbon group, a C1-C6 linear or branched decyloxy group, a C3-C10 cyclic hydrocarbon group, a C3-C10 heterocyclic group, a C1-C6 straight or branched chain a decanoyl group, a spiro-C3-C10 cycloalkyl group, a spiro-C3-C10 heterocyclic group, or an amine group substituted with one or two C1-C6 fluorenyl groups;
  • R 11 is hydrogen or a C1-C4 fluorenyl group
  • R 12 and R 13 are each independently hydrogen, halogen, C1 to C6 linear or branched fluorenyl group, C2 to C6 linear or branched unsaturated hydrocarbon group, cyano group, nitro group, amino group, hydroxy group, trifluoro group Methyl, trifluoromethoxy, carboxyl, fluorenyl
  • substituted or unsubstituted saturated or unsaturated C3-C10 heterocyclic group or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 to 3 a substituent, the heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;
  • the substituent in the ⁇ is halogen, C1-C10 linear or branched fluorenyl group, C2-C10 linear or branched unsaturated hydrocarbon group, C3-C10 cycloalkyl group, cyano group, nitro group, amino group, hydroxyl group , hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl.
  • W is selected from -CH 2 -, -CF 2 -, -CFH -, -CH 2 -O-, -CH 2 -NH- or further;
  • X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched fluorenyl;
  • substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent;
  • the heterocyclic group contains 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;
  • the substituent is halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl Base, trifluoromethoxy, carboxyl, oxo group,
  • R 1 is hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, fluorenyl, C1-C6 straight or branched fluorenyl, C2- C6 linear or branched unsaturated hydrocarbon group, N(R)—(Z) r — T
  • M each independently being a C2-C3 fluorene group
  • Z is a C1-C4 fluorene group
  • r is 0 or 1;
  • T is a C1-C6 linear or branched fluorenyl group, a C2-C6 linear or branched unsaturated hydrocarbon group, an amine group substituted with one or two C1-C6 fluorenyl groups, an unsubstituted or substituted C3-C8 group.
  • a cycloalkyl group an unsubstituted or substituted C6-C8 aryl group, an unsubstituted or substituted C3-C8 heterocyclic group; wherein the substituent is halogen, hydroxy, nitro, amino, trifluoromethyl, diphenyl a group, an amine group substituted with one or two C1-C6 thiol groups, a C1-C6 fluorenyl group;
  • R 9 and R 1Q are each independently halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched fluorenyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched decyloxy group, C3-C8 cyclic hydrocarbon group, C3-C8 heterocyclic group, C1-C6 linear or branched decanoyl group , a spiro-C3-C8 cycloalkyl group, a spiro-C3-C8 heterocyclic group, or an amine group substituted with one or two C1-C6 thiol groups;
  • R 11 is hydrogen or a C1-C4 fluorenyl group;
  • R 12 and R 13 are each independently hydrogen, halogen, C1 to C6 linear or branched fluorenyl group, C2 to C6 linear or branched unsaturated hydrocarbon group, cyano group, nitro group, amino group, hydroxy group, trifluoro group Methyl, trifluoromethoxy, carboxy;
  • substituted or unsubstituted saturated or unsaturated C3-C8 heterocyclic group or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or a substituent having 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; the substituent in the group being a halogen, a C1-C6 linear or branched fluorenyl group, Cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy.
  • W is -CH 2 -, -CF 2 -, -CFH -, -CH 2 -O-, -CH 2 -NH- or further;
  • X and Y are each independently hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C4 straight or branched fluorenyl;
  • substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent;
  • the heterocyclic group contains 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;
  • the substituent is halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl a fluorenyl group, a trifluoromethoxy group, a carboxyl group, an oxo group, a C1-C4 straight or branched chain;
  • R 1 is hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, carboxy, fluorenyl, C1-C4 straight or branched fluorenyl, C3-C8 heterocyclic,
  • M each independently being a C2-C3 fluorene group
  • Z is a C1-C4 fluorene group
  • r is 0 or 1;
  • T is a C1-C4 linear or branched fluorenyl group, an amine group substituted with one or two C1-C4 thiol groups, Unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C8 heterocyclic group; wherein the substituent is halogen, hydroxy, nitro, amino, trifluoromethyl, diphenylmethyl, One or two C1-C4 fluorenyl substituted amine groups, C1-C4 fluorenyl groups;
  • R 9 and R 1Q are each independently halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C4 straight or branched fluorenyl, a C3-C6 heterocyclic group, a spiro-C3-C6 heterocyclic group, or an amine group substituted with one or two C1-C4 fluorenyl groups;
  • R 11 is hydrogen or a C1-C4 fluorenyl group
  • R 12 and R 13 are each independently hydrogen, halogen, C1 to C4 linear or branched fluorenyl, cyano, nitro, amino, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy;
  • ® is a substituted or unsubstituted saturated or unsaturated C3-C8 heterocyclic group, or a substituted or unsubstituted C6-C10 aryl group, wherein the substituted heterocyclic group or substituted aryl group includes 1 or 2 a substituent, the heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;
  • the substituent in the Y is a halogen, a C1-C4 linear or branched fluorenyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, or a carboxyl group.
  • the compound of the formula (I) of the invention is preferably a specific compound as follows:
  • the compounds of the invention may have asymmetric centers, chiral axes and chiral planes and may exist in the form of enantiomers, diastereomers, racemates, and mixtures thereof.
  • the present invention provides a pharmaceutically acceptable salt of the compound of the formula (I), in particular a compound of the formula (I) which is reacted with an inorganic or organic acid to form a conventional non-toxic salt.
  • a conventional non-toxic salt can be obtained by reacting a compound of the formula (I) with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc.
  • Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, and acrylic acid.
  • the present invention provides a process for the preparation of a compound represented by the formula (I), which comprises the following steps, comprising:
  • Step b The compound 1 is dissolved in chloroform, N-chlorosuccinimide is added at room temperature, and the reaction is stirred at room temperature to obtain a compound I b;
  • Step c 2-aminopyridine derivative is dissolved in a solvent, was added N- bromosuccinimide in an ice bath, an ice bath was stirred to give compound I e, the solvent is acetonitrile;
  • Step d Dissolving I b in a solvent, adding I e , protecting with argon gas, stirring the reaction in an oil bath at 80 ° C to obtain a compound I d , the solvent is anhydrous ethanol;
  • Step e catalytically coupling the compound I d with a substituted boronic acid ester or boric acid under a palladium catalyst to obtain a final product;
  • Step f bromination of o with a brominating agent to obtain compound I e , the brominating reagent is bromine; Step g: reacting compound I e with DMA to obtain compound I f;
  • Step h The compound I e and If are dissolved in a solvent, and stirred under an oil bath at 80 ° C to obtain a compound 3 ⁇ 4, the solvent is anhydrous ethanol;
  • Step i catalytically coupling the compound I g with a substituted boronic acid ester or boric acid under a palladium catalyst to obtain a compound I h;
  • Step j fluorinating the compound I h using a fluorinating agent to obtain a final product, the fluorinating agent is DAST;
  • Step k dissolving compound I e in a solvent and reacting with chloroacetaldehyde to obtain compound I m , wherein the solvent is anhydrous ethanol;
  • Step 1 Hydroxymethylation of compound i m to give compound i ⁇ ; Step m: nucleophilic substitution reaction of compound ⁇ with ⁇ ) to obtain compound I. ; Step will be compound I. Catalytic coupling with a substituted boronic acid ester or boric acid under a palladium catalyst to obtain a product;
  • Step p Compound I. Azide to give compound I p ;
  • Step q reductive amination of compound Ip to give compound I q; step r: performing the same reaction as step m to obtain compound ⁇ step s: performing the same reaction as step n to obtain the final product;
  • Step t Dissolving W in DMF solvent and reacting with (trimethylsilyl) acetonitrile, post-treatment and then reacting with 1-bromo-2-chloroacetamidine to obtain compound I s;
  • Step u Compound 1 8 is dissolved in toluene and reacted with diisobutylaluminum hydride to obtain a compound
  • Step w the compound I t and chloro(methoxymethyl)triphenylphosphorus by Witting reaction to obtain a compound I u;
  • Step X Hydrolysis of the compound I u with hydrochloric acid, followed by chlorosuccinimide chloroation to obtain the compound I w ;
  • Step y dissolving in a solvent, adding I e , protecting with argon, stirring the reaction in an oil bath at 80 ° C to obtain a compound I x , the solvent is anhydrous ethanol;
  • Step z The same reaction as in the step n is carried out to obtain a final product.
  • the pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the above formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition may further comprise an odorant, a flavoring agent or the like.
  • the pharmaceutical composition provided by the present invention preferably contains an active ingredient in a weight ratio of 1 to 99%, preferably in a ratio of 65 wt% to 99 wt% of the total weight of the compound of the formula (I) as an active ingredient, the remainder being pharmaceutically An acceptable carrier, diluent or solution or salt solution.
  • the compounds and pharmaceutical compositions provided herein may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be presented in suitable solid or liquid carriers or diluents. Neutralizes a suitable sterilizing device for injection or drip.
  • the unit dosage of the preparation formulation contains 0.05 to 200 mg of the compound of the formula (I), and preferably, the unit dosage of the formulation contains 0.1 mg to 100 mg of the compound of the formula (I).
  • the compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, by route of administration to the mouth, nose, skin, lungs, or gastrointestinal tract. Most preferably oral. Most preferably, the daily dose is 0.01 to 200 mg/kg body weight, taken once, or 0.01 to 100 mg/kg body weight. Regardless of the method of administration, the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found.
  • the compound of the general formula (I) can be used to regulate receptor tyrosine kinase activity, particularly members of the receptor tyrosine kinase Met subfamily.
  • the regulation described herein is to increase or decrease the activity of Met kinase.
  • the compounds of the invention inhibit the activity of Met kinase.
  • the compounds and compositions of the invention are useful in the treatment and prevention of cancer, hyperplasia, restenosis, immune disorders and inflammation, including, but not limited to, histiocytic lymphoma, ovarian cancer, head and neck squamous cell carcinoma, Gastric cancer, breast cancer, childhood hepatocellular carcinoma, colorectal cancer, cervical cancer, lung cancer, sarcoma, nasopharyngeal carcinoma, pancreatic cancer, glioblastoma, prostate cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma , thyroid cancer, testicular cancer, cervical cancer, lung adenocarcinoma, colon cancer, papillary renal cell carcinoma, glioblastoma, endometrial cancer, esophageal cancer, leukemia, renal cell carcinoma, bladder cancer, liver cancer and star Cell tumors and the like; more preferably used for the treatment of cancers such as head and neck squamous cell carcinoma, histiocytic lymph
  • the compounds and compositions of the present invention are useful for treating, preventing or regulating metastatic tumors of cancer cells and cancer, in particular for preventing or regulating ovarian cancer, childhood hepatocellular carcinoma, metastatic head and neck squamous cell carcinoma, Metastatic tumors of gastric cancer, breast cancer, colorectal cancer, cervical cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, glioblastoma and sarcoma.
  • Figure 1 shows the effect of the compounds of the present invention on TPR-Met phosphorylation in BaF3/TPR-Met cells
  • Figure 2 shows the growth inhibitory effect of the compounds on EBC-1 nude mice xenografts.
  • Step 1 Preparation of 3-(quinolin-6-yl)propanal Pd 2 (dba) 3 (32.66 mg, 34.95 ⁇ 1) and triphenylphosphorus tetrafluoride (20.92 mg, 9.93 ⁇ 1) were placed in a 25 mL two-necked flask and protected with argon. 6-bromoquinoline (500 mg, 2.33 mmol), allyl alcohol (0.32 mL, 4.66 mmol), N-methyldicyclohexylamine dissolved in 2 mL of 1,4-dioxane, and injected into the neck The reaction was stirred at 30 ° C in a bottle.
  • 6-bromoquinoline 500 mg, 2.33 mmol
  • allyl alcohol (0.32 mL, 4.66 mmol
  • N-methyldicyclohexylamine dissolved in 2 mL of 1,4-dioxane
  • Compound DC381104 was prepared in the same manner as in Example 4 except that the 1-methylimidazole-4-boronic acid pinacol ester was replaced with 3,5-difluorophenylboronic acid in a yield of 86.90%.
  • Step 2 Preparation of 6-( ⁇ 6-bromo-8-trifluoromethylimidazo[l,2-a]pyridin-3-yl ⁇ methyl)quinoline except 3-trifluoromethyl-2-amino
  • the reaction was carried out in the same manner as in Example 3 except that -5-bromopyridine was replaced with 2-amino-5-bromo-3-fluoropyridine, and the column was separated by rapid separation (dichloromethane/methanol 20/1, v /v) Separation and purification, yield 28.84% o MS (ESI, m/z): 406 (M + H)" o
  • Step 3 Preparation of 6- ⁇ [6-(l-methyl-1H-pyrazol-4-yl)-8-trifluoromethylimidazo[l,2-a]pyridin-3-yl]methyl ⁇ Quinoline (DC381105)
  • Step 3 Preparation of 6- ⁇ [7-chloro-6-(l-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]methyl ⁇ quinoline ( DC381108)
  • 6-( ⁇ 6-bromo-7-chloroimidazo[l,2-a]pyridin-3-yl ⁇ methyl)quinoline 6-( ⁇ 6-bromo-8-fluoroimidazo[1, Compound DC381108 was obtained in the same manner as in Example 4 except for 2-a]pyridin-3-yl ⁇ methyl)quinoline, yield 49.84%.
  • 6-( ⁇ 6-bromo-8-cyanoimidazo[l,2-a]pyridin-3-yl ⁇ methyl)quinoline 6-( ⁇ 6-bromo-8-fluoroimidazo[1] Compound DC381109 was obtained in the same manner as in Example 4 except for 2-a]pyridin-3-yl ⁇ methyl)quinoline. Yield: 21.93%.
  • Step 3 Preparation of 6- ⁇ [7-cyano-6-(l-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]methyl ⁇ quinoline (DC381110)
  • Step 1 Preparation of 3-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid methyl ester except 3-methoxycarbonylbenzene
  • the reaction was carried out in the same manner as in Example 4 except that the boronic acid was replaced with 1-methylimidazole-4-boronic acid pinacol ester, and the yield was 90.90%.
  • Step 2 Preparation of 3-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid 3-[8-fluoro-3- (Quinoline-6-ylmethyl) imidazo[l,2-a]pyridin-6-yl]benzoic acid methyl ester (100 mg, 243.06 ⁇ 1) was dispersed in 12 ml of tetrahydrofuran/methanol/water (1/2/1, To ⁇ / ⁇ / ⁇ ), lithium hydroxide monohydrate (51 mg, 1.22 mmol) was added and stirred at room temperature. No raw materials were detected by TLC. EA and a small amount of water were added to the reaction solution for extraction. The aqueous layer was taken, and potassium hydrogen sulfate was added to adjust the pH to precipitate a gray solid. MS (ESI, m/z): 397 (M+H) + .
  • Step 3 Preparation of N-methyl-3-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzamide (DC381111)
  • Step 1 Preparation of 2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzoic acid methyl ester
  • Compound DC381 1 13 was obtained in the same manner as in Example 16 except that N-(2-aminoethyl)piperidine was used instead of 2M methylamine in tetrahydrofuran, yield of 90.10%.
  • Compound DC381117 was prepared in the same manner as in Example 16 except that the morpholine was used to replace the 2M methylamine in tetrahydrofuran, yield 56.59%.
  • Compound DC381127 was obtained in the same manner as in Example 16 except that (5-fluoropyridin-3-yl)methylamine was used to replace 2M methylamine in tetrahydrofuran. MS (ESI, m/z): 524 (M + H) + .
  • Compound DC381128 was prepared in the same manner as in Example 16 except that a solution of 2M-methylamine in tetrahydrofuran was replaced with 3-aminotetrahydrofuran, yield 75.64%. MS (ESI, m/z): 495 (M + H) + .
  • Compound DC381129 was prepared in the same manner as in Example 16 except that a solution of 2M methylamine in tetrahydrofuran was replaced by 3-aminomethyl oxetane. The yield was 63.47%. MS (ESI, m/z): 495 (M + H) + .
  • Step 1 N-(N-tert-Butoxycarbonylpiperidin-2-ylmethylene)-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethyl)imidazo[l ,2-a]pyridin-6-yl]benzamide
  • step a The resultant product of step a was dissolved in 2ml CH 2 C1 2, was added dropwise TFA 0.5 mL was stirred at room temperature 1 h, the reaction mixture was evaporated to dryness, the residue was taken up with CH 2 Cl 2 / MeOH (10 / l, v / v), washed with saturated sodium bicarbonate solution, the aqueous phase was re-extracted, the organic layer was combined CH 2 C1 2, dried over anhydrous Na 2 SO 4 dried, filtered, and the solvent was distilled off under reduced pressure, to give compound DC381130, 80% yield.
  • step a The resultant product of step a was dissolved in 2ml CH 2 C1 2, was added dropwise TFA 0.5 mL was stirred at room temperature 1 h, the reaction mixture was evaporated to dryness, the residue was taken up with CH 2 Cl 2 / MeOH (10 / l, v / v), washed with saturated sodium bicarbonate solution, the aqueous phase was re-extracted, the organic layer was combined CH 2 C1 2, dried over anhydrous Na 2 SO 4 dried, filtered, and the solvent was distilled off under reduced pressure, to give compound DC381131, 80% yield.
  • Step 2 Preparation of 6-( ⁇ 6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl ⁇ methyl)-1,3-benzothiazole except 2-chloro-3-( The 1,3-benzothiazol-6-yl)propanal was replaced with 2-chloro-3-(quinolin-6-yl)propanal, and the reaction was carried out in the same manner as in Example 3 in a yield of 21.80%. MS (ESI, m/z): 362 (M + H) + .
  • Step 3 Preparation of 2-fluoro-4-[8-fluoro-3-(l,3-benzothiazol-6-ylmethyl)imidazo[l,2-a]pyridine-6-yl]benzoic acid
  • Step 4 Preparation of N-methyl-2-fluoro-4-[3-(1,3-benzothiazol-6-ylmethyl)imidazo[l,2-a]pyridin-6-yl]benzamide Amide (DC381133)
  • Step 1 Preparation of 6-( ⁇ 8-fluoro-6-[1-(indolyl-tert-butoxycarbonylpiperidin-4-yl)-1H-pyrazol-4-yl]imidazo[1,2-a] Pyridin-3-yl ⁇ methyl)quinoline
  • Step 2 Preparation of 6-( ⁇ 8-fluoro-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]imidazo[l,2-a]pyridin-3-yl ⁇ Methyl)quinoline (DC381134)
  • Compound DC381136 was prepared in the same manner as in Example 4 except that the 1-methyl-4-pyrazoleboronic acid pinacol ester was replaced with indole-2-one-5-boronic acid pinacol ester. The yield was 54.74. %. MS (ESI, m/z): 409 (M+H).
  • Step 1 Preparation of 4-( ⁇ 6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl ⁇ methoxy)quinoline
  • Step 2 Preparation of N-methyl-2-fluoro-4- ⁇ 8-fluoro-3-[(quinolin-4-oxy)methyl]imidazo[l,2-a]pyridin-6-yl] Benzoylamide (DC381137)
  • the product obtained in the above step is dissolved in an ethanol-water mixed solvent, NH 4 C1 is added, and zinc powder is added under stirring at room temperature, and the reaction is carried out at 80 ° C.
  • the reaction is completely detected by TLC, and dichloromethane is added to the reaction flask. After filtration, the filtrate was evaporated to dryness. Water was added to the reaction mixture, and the mixture was washed with methylene chloride, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered and evaporated.
  • Step 3 Preparation of N-methyl-2-fluoro-4-(8-fluoro-3- ⁇ [(quinolin-4-yl)amino Methyl ⁇ imidazo[l,2-a]pyridin-6-yl]benzamide (DC381138)
  • Step 1 N'-(3-Fluoro-5-bromo-pyridin-2-yl)-N,N-dimethylformamidine
  • Step 3 6- ⁇ [8-Fluoro-6-(l-methyl-1H-pyrazol-4-yl)imidazo[l,2-a]pyridin-3-yl]carbonyl ⁇ quinoline
  • 6-Bromoquinoline (10 g, 48 mmol), (9,9-dimethyl-9H-oxaindole-4,5-diyl)bis(diphenylphosphine) (558 mg, 1 mmol), Pd 2 (dba) 3 (833 mg, 1 mmol) was dissolved in 100 mL of DMF, and (trimethylsilyl) acetonitrile (8.2 mL, 60 mmol) was added with stirring, followed by the addition of zinc difluoride (3.5 g, 33.3 mmol). After argon gas protection, the reaction was stirred under an oil bath at 105 ° C for 20 h.
  • the 50% aqueous sodium hydroxide solution was added to the product obtained in the above step (4 g, 16.65 mmol) at 50 ° C, and chlorobromo-2-chloroacetone (5.5 mL, 66.25 mmol) and benzyltriethyl chloride. Mixture of ammonium (247.5 mg, 1.08 mmol).
  • the reaction mixture was stirred at 50 ° C for 3 h. After cooling to room temperature, the reaction mixture was poured into 60 mL of dichloromethane, and extracted with dichloromethane, washed with saturated brine, dried over anhydrous Na 2 SO 4 and filtered. The solvent was evaporated under reduced pressure and the residue was purifiedjjjjjjjj Used directly in the next step.
  • Step 1 Preparation of 6-( ⁇ 6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl ⁇ cyclopropylmethyl)quinoline in addition to chloro(1-quinoline-6-
  • the reaction was carried out in the same manner as in Example 3 except that 2-cyclo-3-(quinolin-6-yl)propanal was replaced by acetaldehyde, and subjected to rapid separation column chromatography (dichloromethane/ Methanol 20/1, v/v) isolated and purified, yield 34.45% c MS (ESI, m/z): 383 (M -iH) + 0
  • Step 2 Preparation of 2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethylcyclopropyl)imidazo[l,2-a]pyridine-6-yl: Benzoic acid
  • Step 3 N-Methyl-2-fluoro-4-[8-fluoro-3-(quinolin-6-ylmethylcyclopropyl)imidazo[l,2-a]pyridin-6-yl]benzene Formamide (DC381141)
  • Step 1 Preparation of ⁇ 6-bromo-8-fluoroimidazo[l,2-a]pyridin-3-yl Kquinolin-6-yl)methanol
  • Step 3 Preparation of 2-fluoro-4- ⁇ 8-fluoro-3-[fluoro(quinolin-6-yl)methyl]imidazo[l,2-a]pyridine-6-yl ⁇ benzoic acid
  • Step 4 Preparation of N-methyl-2-fluoro-4- ⁇ 8-fluoro-3-[fluoro(quinolin-6-yl)methyl]imidazo[l,2-a]pyridine-6-yl ⁇ Benzoylamide
  • Enzyme reaction substrate Poly(Glu, Tyr) 4:1 diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 g/ml, 125 ⁇ l/well coated enzyme
  • the target plate was reacted at 37 ° C for 12-16 hours. Discard the liquid in the well. Plates were washed and washed three times with 200 ⁇ l/well of T-PBS (PBS containing 0.1% Tween-20 in potassium free) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours.
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • 50 ⁇ M compound 1% DMSO dissolved in a final concentration of 10 ⁇ M
  • 50 ⁇ l of the c-Met tyrosine kinase protein diluted with the reaction buffer was added.
  • the reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). For each experiment, two wells without ATP control wells and corresponding DMSO solvent control wells (negative control wells) were required. The liquid in the well was discarded and the plate was washed three times with T-PBS.
  • the antibody PY99 ⁇ /well was added (the antibody was diluted with BSA 5 mg/ml in T-PBS at a concentration of 0.4 g/ml), and shaken at 37 ° C for 0.5 hour. The liquid in the well was discarded and the plate was washed three times with T-PBS.
  • the screened compound c-Met inhibitory activity has a clear (compound 10- 5 ⁇ tyrosine kinase inhibition rate of c-Met receptor> 50%) dubbed a concentration gradient, for IC 5. Evaluation.
  • the IC 5 of the inhibitory protein tyrosine kinase at the molecular level of each compound was calculated by a four-parameter method. Values, the results are listed in Table 1.
  • Table 1 shows the results of the biological test of the selected compounds of the invention, expressed as ⁇ (3 5 ( ⁇ ).
  • BaF3/TP-Met cells (without Met extracellular interference, the TPR-Met fusion protein in cells is expressed in the cytoplasm and can be continuously activated independently of HGF-like stimulation; BaF3 background cells need to be supplemented with IL-3 to proliferate Survival, but after introduction of TPR-Met, it became a Met-dependent sensitive cell line) inoculated in a 12-well plate (500,000/well), and cultured for 18-24 hours, and added to the molecular level to obtain a clear inhibition of c-Met activity. After the action of each compound (final concentration was ⁇ ), the cells were collected 4 hours later.
  • the supernatant was taken for SDS-PAGE electrophoresis (Mini-PROTEAN 3 Cell, Bio-ad, Hercules, CA, USA), and after electrophoresis, the protein was transferred to a nitrocellulose membrane using a semi-dry electrotransfer system (Amersham Life Sciences, Arlington Heights, IL, USA), the nitrocellulose membrane was placed in a blocking solution (5% skimmed milk powder diluted in TBS containing 1 mM sodium vanadate) for 2 hours at room temperature, and then the membrane was placed in anti-pc-Met (Y1234/ 1235, Cell Sinaling Technology) (1:1000) or anti-GAPDH (Kangcheng Bio) (1:6000) antibody overnight at 4 °C.
  • a blocking solution 5% skimmed milk powder diluted in TBS containing 1 mM sodium vanadate
  • Example 3 Effect of compounds on c-Met-mediated cell proliferation
  • MET-dependent tumor cell lines two MET-dependent tumor cell lines were used: BaF3/TPR-Met cells (suspended cells, no Met extracellular interference, TPR-Met fusion protein expression in the cytoplasm, independent of HGF stimulation Continuous activation; BaF3 background cells need to be supplemented with IL-3 to proliferate, but after introduction of TPR-Met, become Met-dependent sensitive cell lines) and EBC-1 cells (adherent cells, non-small cell lung cancer cell lines, ⁇ Gene amplification results in sustained activation of Met, a Met-dependent cell line).
  • the adherent cells were de-cultured, added with 10% (w/v) trichloroacetic acid ( ⁇ well) and fixed at 4 ° C for 1 h, then rinsed with distilled water five times, after drying at room temperature, each Add SRB solution (4 mg/mL, dissolved in 1% glacial acetic acid) 100 L, incubate for 15 min at room temperature, rinse with unwashed SRB five times with 1% glacial acetic acid, and dry at room temperature.
  • the optical density (OD value) at a wavelength of 515 nm was measured by adding a 10 mM Tris solution to a 100 VE SMax plate reader.
  • the level of inhibition of tumor cells by such compounds is on the nanomolar scale, and some of the compounds exhibit a considerable effect on the cellular level with the positive compound PF02341066.
  • EBC-1 was subcutaneously inoculated into the right axilla of nude mice by 5 ⁇ 10 6 / each, and the transplanted tumor was formed and then used in nude mice for three generations.
  • the tumor tissue in the vigorous growth stage was cut into 1.5 mm 3 under aseptic conditions, and inoculated into the right axilla of the nude mice.
  • the diameter of the transplanted tumor was measured with a vernier caliper.
  • the animals were randomly divided into tumor volumes, 12 in the negative control group, 6 in the positive control group, and 6 in the experimental group. only.
  • the experimental group received different concentrations of DC381112 (50mg/kg, 100mg/kg) daily.
  • the positive control group received daily oral JNJ-38877605 (50mg/kg), once daily, for 17 days, negative control group. Give the same amount of normal saline at the same time.
  • RTV relative tumor volume
  • V t V t / V.
  • V t the tumor volume at a given time, V.
  • the resulting tumor volume was measured before the caged administration.
  • the weight of each group of nude mice was weighed twice a week to initially evaluate the toxic side effects of the drug.
  • Compound DC38112 showed significant growth inhibition on non-small cell lung cancer Lung cancer cell line EBC-1 at 50 and 100 mg/kg doses, and each dose group had no significant effect on mouse body weight.
  • Compound JNJ-38877605 showed a very significant anti-tumor effect on the xenograft model at a dose of 50 mg/kg, and the transplanted tumor of 4 mice regressed, and the compound had no significant effect on the body weight of the mice.

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Abstract

Cette invention concerne des composés d'imidazo[l,2-a]pyridine comme représenté dans la formule générale (I), un procédé pour leur préparation, une composition pharmaceutique les contenant et leur utilisation pour préparer des médicaments destinés à traiter des maladies de type hyperplasie cellulaire concernant la voie de transduction du signal de la tyrosine kinase c-Met.
PCT/CN2013/070386 2012-01-21 2013-01-11 Composés d'imidazo[1,2-a]pyridine de nouveau type, leur procédé de préparation, composition pharmaceutique les contenant et leur utilisation WO2013107326A1 (fr)

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CN104402881A (zh) * 2014-11-05 2015-03-11 定陶县友帮化工有限公司 一种3-醛基-6-溴咪唑并[1,2-a]吡啶-8-甲酸乙酯的合成方法
CN104402882A (zh) * 2014-11-05 2015-03-11 定陶县友帮化工有限公司 一种3-醛基-6-氯咪唑并[1,2-a]吡啶-8-甲酸乙酯的合成方法

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