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WO2019007293A1 - Composé utilisé comme inhibiteur de la kinase alk et son utilisation - Google Patents

Composé utilisé comme inhibiteur de la kinase alk et son utilisation Download PDF

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WO2019007293A1
WO2019007293A1 PCT/CN2018/093906 CN2018093906W WO2019007293A1 WO 2019007293 A1 WO2019007293 A1 WO 2019007293A1 CN 2018093906 W CN2018093906 W CN 2018093906W WO 2019007293 A1 WO2019007293 A1 WO 2019007293A1
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group
compound
alkyl
halogen
cycloalkyl
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吴豫生
职五斌
李敬亚
郑茂林
梁阿朋
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Deuracor Therapeutic Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention relates to the field of medical technology, and in particular to a compound for use as an ALK kinase inhibitor and its use in the preparation of a medicament for modulating ALK kinase activity or treating ALK-related diseases, particularly non-small cell lung cancer.
  • Malignant tumors are one of the main killers of human health. For example, according to the statistics of the International Health Organization, at present, 12 million new lung cancer patients are diagnosed every year, and 8 million people die of lung cancer every year. At present, humans have made remarkable progress in the level of understanding of tumors and treatment methods, and some tumors can be effectively controlled. However, due to the complexity of the formation mechanism of tumors, most malignant tumor cells have multiple pathways for growth, which leads to strong vitality of cancer cells. Inhibition of one or part of the pathways does not completely eliminate cancer cells. On the contrary, in addition to the usual lesion metastasis, chemotherapy often leads to mutations in cancer cell genes, resulting in drug resistance.
  • Non-small cell lung cancer is the most common type of lung cancer, accounting for 80% to 85% of all lung cancer patients, some of which are accompanied by genetic mutations.
  • Two to five percent of NSCLC cases are anaplastic lymphoma kinase (ALK) rearrangements, and anaplastic lymphoma kinase is a receptor-type protein tyrosine phosphokinase of the insulin receptor superfamily.
  • ALK was first discovered in the form of an activated fusion oncogene in anaplastic large cell lymphoma, and subsequent studies have found a fusion of ALK in a variety of cancers, including systemic tissue dysplasia, inflammation. Myofibroblastic carcinoma, non-small cell lung cancer, etc.
  • the mutation and abnormal activity of ALK in various cancers has made it a drug target for the treatment of ALK-positive cancers.
  • Crizotinib developed by Pfizer Pharmaceuticals, Inc., has been clinically validated to reduce the size of malignant tumors in patients with advanced genetically modified non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • crizotinib has the following side effects: visual impairment, gastrointestinal side effects, elevated levels of grade 3-4 liver transaminases in 16% of patients, and ALK-positive patients undergoing crizozolidine treatment at the beginning Acquired resistance is inevitable after the sensitive period.
  • the second generation of ALK inhibitors such as LDK378, alexinib and AP26113, have found that treatment improves the efficacy, but there are problems with large side effects.
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • n 0 or 1
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C or N, and when N is selected, n is 0;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, anthracene, halogen, cyano, nitro, ester, C 1-6 alkyl , C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1 ⁇ 6 Alkylthio, C 1-6 acyl, C 1-6 alkylamino or C 3-6 cycloalkylamino;
  • Y 1 and Y 2 are each independently selected from O, S, sulfoxide, sulfone, NR 9 or R 11 -C-R 10 , and R 9 , R 10 and R 11 are each independently selected from H, hydrazine, halogen, C. a 1 to 6 alkyl group, a C 3-6 cycloalkyl group or a C 1 to 6 haloalkyl group;
  • R a is H, ⁇ , Methoxy, Cyano group, Halogen, acetyl, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently selected from the group consisting of H, hydrazine, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 a haloalkyl group, R 18 and R 19 are each independently selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group;
  • R b is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 acyl, C 1-6 alkylamino or C 3-6 Cycloalkylamino;
  • R c is selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, difluoromethoxy or C 1-6 alkylthio;
  • R d is selected from any of the following structures:
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof is as shown in Formula II or Formula III:
  • R 1 is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C a 1 to 6 haloalkoxy group, a C 3-6 cycloalkoxy group, a C 1 to 6 haloalkyl group, a C 1 to 6 alkylthio group, a C 1 to 6 acyl group, a C 1 to 6 alkylamino group or a C 3-6 cycloalkylamino group;
  • n 0 or 1
  • X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C or N, and when N is selected, n is 0;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3 -6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1-6 alkyl sulfide a C 1 - 6 acyl group, a C 1 - 6 alkylamino group or a C 3-6 cycloalkylamino group;
  • Y 1 and Y 2 are each independently selected from O, S, sulfoxide, sulfone, NR 9 or R 11 -C-R 10 , and R 9 , R 10 and R 11 are each independently selected from H, hydrazine, halogen, C. a 1 to 6 alkyl group, a C 3-6 cycloalkyl group or a C 1 to 6 haloalkyl group;
  • R a is H, ⁇ , Methoxy, Cyano group, Halogen, acetyl, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently selected from the group consisting of H, hydrazine, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 a haloalkyl group, R 18 and R 19 are each independently selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group;
  • R c is selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy or C 1-6 alkylthio;
  • R d is selected from any of the following structures:
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof is as shown in Formula IV or Formula V:
  • R 1 is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C a 1 to 6 haloalkoxy group, a C 3-6 cycloalkoxy group, a C 1 to 6 haloalkyl group, a C 1 to 6 alkylthio group, a C 1 to 6 acyl group, a C 1 to 6 alkylamino group or a C 3-6 cycloalkylamino group;
  • n 0 or 1
  • X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C or N, and when N is selected, n is 0;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3 -6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1-6 alkyl sulfide a C 1 - 6 acyl group, a C 1 - 6 alkylamino group or a C 3-6 cycloalkylamino group;
  • Y 2 is selected from O, S, sulfoxide, sulfone, NR 9 or R 11 -C-R 10 , and R 9 , R 10 and R 11 are each independently selected from the group consisting of H, hydrazine, halogen, C 1 - 6 alkyl a C 3-6 cycloalkyl or a C 1-6 haloalkyl group;
  • R a is H, ⁇ , Methoxy, Cyano group, Halogen, acetyl, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently selected from the group consisting of H, hydrazine, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 a haloalkyl group, R 18 and R 19 are each independently selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group;
  • R c is selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy or C 1-6 alkylthio;
  • R d is selected from any of the following:
  • the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof is as shown in Formula VI or Formula VII:
  • R 1 is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy , C 1 - 6 haloalkoxy, C 3-6 cycloalkoxy, C 1 - 6 haloalkyl, C 1-6 alkylthio, C 1-6 acyl, C 1-6 alkane An amino group or a C 3-6 cycloalkylamino group;
  • R a is H, ⁇ , Methoxy, Cyano group, Halogen, acetyl, R 12 , R 13 , R 14 , R 15 , R 16 , R 17 are each independently selected from the group consisting of H, hydrazine, halogen, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 a haloalkyl group, R 18 and R 19 are each independently selected from a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group;
  • R d is selected from any of the following structures:
  • R 4 is selected from the group consisting of H, hydrazine, halogen, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 acyl, C 1-6 alkylamino or C 3-6 Cycloalkylamino;
  • R c is selected from the group consisting of H, hydrazine, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy or C 1-6 alkylthio group.
  • formula VII ⁇ , R 1 is halo ⁇ .
  • R a is H, hydrazine, methoxy, cyano, halogen, acetyl
  • R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are each independently selected from the group consisting of H, anthracene, halogen, and C 1-6 alkyl.
  • R d is selected from any of the following structures:
  • R c is selected from the group consisting of H, isopropoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy.
  • R 4 is selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy.
  • the compound is selected from the compounds represented by the following structural formula:
  • the pharmaceutically acceptable salt is a mineral or organic acid salt of the compound selected from the group consisting of a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, and a hydrogen sulfate.
  • the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalic acid Salt, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylic acid Salt, picrate, glutamate, ascorbate, camphorate, camphorsulfonate.
  • Alkyl refers to a monovalent straight or branched chain saturated hydrocarbon group containing from 1 to 12 carbon atoms consisting solely of carbon and hydrogen atoms.
  • the "alkyl group” is preferably an alkyl group of 1 to 6 carbon atoms, that is, a C 1 -C 6 alkyl group, more preferably a C 1 -C 4 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
  • Alkoxy refers to a radical of the formula -OR wherein R is alkyl as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, t-butoxy, and the like.
  • Halogen (halo) means a fluorine, chlorine, bromine or iodine substituent.
  • Haloalkyl refers to an alkyl group, as defined herein, wherein one or more hydrogens are replaced by the same or different halogens.
  • haloalkyl groups include -CH 2 Cl, -CH 2 CF 3 , -CH 2 CCl 3 , perfluoroalkyl groups (e.g., -CF 3 ), and the like.
  • Haloalkoxy refers to a radical of the formula -OR wherein R is haloalkyl as defined herein.
  • haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.
  • Cycloalkyl refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having from 3 to 12, preferably from 3 to 10, more preferably from 3 to 6 ring atoms.
  • the cycloalkyl group may be optionally substituted by one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino.
  • substituents include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Cycloalkoxy refers to a radical of the formula -OR wherein R is cycloalkyl as defined herein.
  • exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • acyl means a radical of the formula -C(O)R wherein R is alkyl as defined herein.
  • exemplary acyl groups include acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl and the like.
  • ester group refers to a group of the formula -C(O)OR wherein R is alkyl as defined herein.
  • exemplary ester groups include -C(O)OMe, -C(O)OEt, and the like.
  • Alkylthio refers to a radical of the formula -SRa wherein Ra is H or alkyl as defined herein.
  • Alkylamino refers to a radical of the formula -NRaRb wherein Ra is H or alkyl as defined herein and Rb is alkyl as defined herein.
  • Cycloalkylamino refers to a radical of the formula -NRaRb wherein Ra is H, alkyl as defined herein or cycloalkyl as defined herein, and Rb is cycloalkyl as defined herein.
  • Heteroaryl refers to a monocyclic, bicyclic or tricyclic group of 5 to 12 ring atoms containing at least one ring heteroatom comprising 1, 2 or 3 selected from N, O or S, The remaining ring atom is the aromatic ring of C, and it should be clear that the point of attachment of the heteroaryl group should be on the aromatic ring.
  • the heteroaryl group is preferably specifically 5-8 ring atoms, more preferably 5-6 ring atoms.
  • heteroaryl groups include, but are not limited to, imidazolyl, Azolyl, different Azyl, thiazolyl, isothiazolyl, Diazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolinyl, benzofuranyl, Benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzo Azolyl, benzo Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, decyl, isodecyl, triazolyl, triazinyl, quinoxalinyl, fluorenyl, quinazoline Base, quinolizinyl, naphthyridinyl, pteridinyl, ox
  • the solvate referred to in the present invention means a complex of the compound of the present invention and a solvent. They either react in a solvent or precipitate out of the solvent or crystallize out.
  • a complex formed with water is referred to as a hydrate; others include an alcoholate, a ketone compound, and the like.
  • the solvates of the present invention include the compounds of the formula I of the present invention and salts thereof, and solvates of stereoisomers.
  • a stereoisomer as referred to in the present invention means that the compound of formula I in the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains a chiral center, the compound contains the enantiomer.
  • the invention includes mixtures of the two isomers and isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula I contains more than one chiral center, diastereomers may be present.
  • Stereoisomers of the invention include resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • a prodrug as referred to in the present invention refers to a parent compound which includes a known amino protecting group and a carboxy protecting group, which are hydrolyzed under physiological conditions or released by an enzymatic reaction.
  • Specific prodrug preparation methods can be referred to the prior art (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. ChemLett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • a compound of formula I of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which is effective for inhibiting ALK kinase activity, and ALK resistance mutants.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising:
  • a compound of formula I provided by the present invention or a pharmaceutical composition comprising the compound of formula I for the preparation of a medicament for modulating ALK kinase activity or for treating a disease associated with abnormal ALK kinase activity, particularly for cancer treatment, such as Small Cell Lung Cancer.
  • the compound of the formula I of the present invention can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • dosage forms include those suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, and the like).
  • compositions of this invention may be formulated, quantified, and administered in a manner consistent with medical practice.
  • the "effective amount" of a compound administered is determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • the pharmaceutical composition may further comprise an additional therapeutic agent, and the additional therapeutic agent is a cancer, a cardiovascular disease, an inflammation, an infection, an immune disease, a cell proliferative disease, a viral disease, a metabolic disease or an organ transplant. .
  • the modulating ALK kinase activity or treating a disease associated with abnormal ALK kinase activity refers to treating cancer, cell proliferative diseases, inflammation, infection, immune disease, organ transplantation, viral disease, cardiovascular disease or Metabolic disease.
  • the cancer includes, but is not limited to, lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma. , kidney cancer, stomach cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
  • the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of non-small cell lung cancer.
  • reaction formula is:
  • the compound c19-2 (945 mg, 1.93 mmol) was dissolved in 20 ml of methanol, and palladium carbon (472 mg, 10%) was added with stirring at room temperature, then hydrogen was replaced three times, and reacted at room temperature overnight at 0.2-0.4 MPa, TLC showed The reaction was completed, filtered, and concentrated to give a crude benzyl benzene (yield: 596 mg). The crude product was then dissolved in 20 ml of methanol. Palladium hydroxide carbon (500 mg) was added with stirring at room temperature, three times with hydrogen, and reacted at room temperature at 0.2-0.4 MPa.
  • the compound c-27 (60 mg, 0.09 mmol) was dissolved in 20 ml of anhydrous ethanol, and then sodium borohydride (14 mg, 0.36 mmol) was added, and the mixture was stirred at room temperature. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the compound c-27 (50 mg) was dissolved in 10 ml of anhydrous methanol, and then ammonia gas was passed to cool in an ice salt bath to be saturated, and then transferred to a humidified tank at 100 ° C overnight, and then concentrated by cooling to obtain 20 mg of a c-29 product.
  • the compounds prepared in Examples 1-9 were screened for activity against anaplastic lymphoma kinase (ALK) using the Caliper Mobility Shift Assay method at ATP Km concentrations.
  • ALK anaplastic lymphoma kinase
  • ALK anaplastic lymphoma kinase
  • Anaplastic lymphoma kinase (ALK) (Carna, Cat. No. 08-105, Lot. No. 08CBS ⁇ 0112);
  • Staurosporine (Sigma, Cat. No. S4400 ⁇ 1 MG, Lot. No. 046K4080).
  • Each sample was separately formulated into a solution having a concentration of 10 mM.
  • the concentration was 50 mM EDTA solution.
  • this assay plate contained a 10% DMSO solution in 5% of the compound at a starting concentration of 50 [mu]M.
  • the maximum value represents DMSO control; the minimum value represents low control;
  • IC 50 (nM) values of the inhibitory activity of the obtained test sample against anaplastic lymphoma kinase (ALK) are shown in the following table:
  • the compounds synthesized by Staurosporine (brassinin) and brigitinib (brutinib) as reference materials have good effects on anaplastic lymphoma kinase (ALK). Inhibition ability.

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Abstract

L'invention concerne un composé tel que présenté dans la formule I, et un sel, stéréoisomère, solvate ou promédicament pharmaceutiquement acceptable de celui-ci, chaque symbole étant tel que défini dans les revendications. Le composé tel que représenté dans la formule I a une bonne activité inhibitrice de la kinase ALK, et peut être utilisé pour préparer un médicament pour réguler l'activité de la kinase ALK ou traiter une maladie associée à l'ALK, en particulier le cancer du poumon non à petites cellules.
PCT/CN2018/093906 2017-07-01 2018-06-30 Composé utilisé comme inhibiteur de la kinase alk et son utilisation Ceased WO2019007293A1 (fr)

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