WO2018208132A1 - Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif - Google Patents

Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif Download PDF

Info

Publication number
WO2018208132A1
WO2018208132A1 PCT/KR2018/005478 KR2018005478W WO2018208132A1 WO 2018208132 A1 WO2018208132 A1 WO 2018208132A1 KR 2018005478 W KR2018005478 W KR 2018005478W WO 2018208132 A1 WO2018208132 A1 WO 2018208132A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
pyrimidine
pyrazolo
dimethylphenyl
tetrahydroisoquinoline
Prior art date
Application number
PCT/KR2018/005478
Other languages
English (en)
Inventor
Pilho KIM
Sung Yun Cho
Jae Du Ha
Hyoung Rae Kim
Jong Yeon Hwang
Chang Soo Yun
Hee Jung Jung
Chi Hoon Park
Chong Ock Lee
Chang Hoon Lee
Sunjoo Ahn
Original Assignee
Korea Research Institute Of Chemical Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020180051686A external-priority patent/KR102128018B1/ko
Application filed by Korea Research Institute Of Chemical Technology filed Critical Korea Research Institute Of Chemical Technology
Priority to US16/612,592 priority Critical patent/US11084824B2/en
Publication of WO2018208132A1 publication Critical patent/WO2018208132A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A23L33/155—Vitamins A or D
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/56—Flavouring or bittering agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/68—Acidifying substances
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a pyrazolopyrimidine derivative, a preparation method thereof and a pharmaceutical composition comprising the same as an active ingredient for the prevention or treatment of cancer, autoimmune disease and brain disease.
  • Cancer is defined by the abnormal state of cells, wherein cell death is not controlled normally because of various changes in gene expression, and abnormal cell growth is induced. Cancer cells penetrate into neighboring tissues and destroy thereof, and migrate to other regions, which can result in human death.
  • the cause of cancer that is, the mechanism by which normal cells are transfected into cancer cells, has not been clearly identified. It is known that the causes of cancer include environmental factors, external factors such as chemicals, radiation, and viruses, and internal factors such as genetic factors and immunological factors, and those factors interact complicate to cause cancer.
  • Cancer is largely divided into blood cancer characterized by abnormal blood cell number and solid cancer in the form of cell mass that has a certain degree of hardness and shape in the body. Cancer can be developed in blood and almost all parts of the body, which can be exemplified by lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer and skin cancer.
  • Major treatment methods for cancer are surgery, radio-therapy, and chemo-therapy using a chemotherapeutic agent inhibiting cell proliferation.
  • a chemotherapeutic agent is not a target-specific agent that directly acts on the target of each cancer. Therefore, repeated chemotherapy treatments result in side effects due to cytotoxicity and resistance to the drugs, indicating that, despite the initial successful response to the anticancer drug, if the cancer treatment duration is prolonged or the cancer recurs, the treatment will fail because of such side effects and drug resistance.
  • molecular biological factors are widely used to predict the prognosis of cancer or to determine the treatment method, either chemo-therapy or radio-therapy.
  • the conventional cancer drugs have been constructed by targeting the rapid cell division characteristics of tumor cells, indicating they are targeting not only tumor cells but also normal cells showing relatively fast cell division (for example, hair follicle cells, gastrointestinal cells, bone marrow cells, reproductive cells), which causes serious side effects. Therefore, it is required to develop a novel anticancer agent that is specifically expressed only in tumor cells and not expressed in normal cells or has no effect on normal cells.
  • Bruton's tyrosine kinase is a nonreceptor tyrosine kinase located on chromosome Xq22, which belongs to Tec family kinase.
  • Bruton's tyrosine kinase plays an important role in the downstream signaling of growth factors, B-cell antigens, chemokine receptors and innate immune receptors. That is, BTK is an important protein that plays an important role in various cell activities such as cell growth, survival, differentiation, pathogenesis, angiogenesis, signaling molecule production, and antigen presentation, and thus it is known to play a crucial role in signal transduction of B-cell immunity, inflammation, and anticancer.
  • BTK Bruton's tyrosine kinase
  • BTK Bruton's tyrosine kinase
  • the present inventors have tried to overcome the problems of resistance and side effects according to the co-treatment with immuno-therapy of the conventional BTK inhibitors and to develop a compound with significantly excellent anticancer effect by reversibly inhibiting BTK.
  • the present inventors confirmed that the compound of the present invention exhibited significantly excellent Bruton's tyrosine kinase inhibitory effect in animal tests, so that the compound could be used effectively in the treatment of cancer, autoimmune disease and Parkinson's disease, leading to the completion of the present invention.
  • It is also an object of the present invention to provide a pharmaceutical composition comprising the pyrazolopyrimidine compound above as an active ingredient for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease.
  • the present invention provides a compound represented by formula 1 below or a pharmaceutically acceptable salt of the same:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in this specification).
  • the present invention also provides a preparation method of the compound represented by formula 1 comprising the step of preparing the compound represented by formula 1 by reacting the compound represented by formula 2 with the compound represented by formula 3 (step 1), as shown in reaction formula 1 below:
  • R 1 , R 2 , R 3 , R 4 , R 5 , and X are as defined in this specification).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease.
  • the present invention also provides a health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or improvement of cancer, autoimmune disease or Parkinson's disease.
  • the present invention also provides a method for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease comprising the step of administering the pharmaceutical composition or the health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient to a subject in need.
  • the present invention provides a use of the pharmaceutical composition or the health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease.
  • the present invention also provides a method of treating a subject having a cancer comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of treating a subject having an autoimmune disease comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of treating a subject having a Parkinson's disease comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a cancer.
  • the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease.
  • the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a Parkinson's disease.
  • the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a cancer.
  • the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease.
  • the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a Parkinson's disease.
  • the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use as a medicament.
  • the present invention also provides a medicament comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
  • the pyrazolopyrimidine derivative of the present invention demonstrates an excellent Bruton's tyrosine kinase (BTK) inhibitory activity, so that a pharmaceutical composition comprising the compound of the invention as an active ingredient can be effectively used for the prevention or treatment of cancer, autoimmune disease and Parkinson's disease.
  • BTK Bruton's tyrosine kinase
  • the pyrazolopyrimidine derivative of the present invention can be used for immunotherapy because it does not inhibit ITK (Interlukin-2 receptor inducible T-cell kinase) and can be used as an autoimmune disease therapeutic agent for long-term administration because it is a reversible inhibitor.
  • ITK Interlukin-2 receptor inducible T-cell kinase
  • the derivative of the invention also shows an excellent pharmaceutical effect on Abl and Abl mutants along with excellent BBB permeability, so that it can be effectively used for the treatment of Parkinson's disease.
  • Figure 1 is a schematic diagram illustrating the enzyme liked immuosrobent assay performed for measuring the concentration of TNFa.
  • Heterocyclic ring means a saturated or partially unsaturated heterocyclic ring of 3 to 8 ring atoms (refers to a carbocyclic radical having one or more double or triple bonds in the ring without directionality) which contains at least one of hetero atoms selected from the group consisting of N, O and S and the remaining ring atoms are carbon. In a preferred embodiment of the present invention, it refers to monoheterocyclic consisting of one ring, wherein the hetero atom means a nitrogen atom or an oxygen atom.
  • it can be pyrrolidine, dihydrofuran, tetrahydrothiophene, tetrahydropyrane, dihydropyrane, tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, thioxane, piperazine, azetidine, oxetane, thietane, oxepan, oxazepine, diazepine, thiazepine, 2-pyrroline, or 3-pyrroline.
  • “Cycloalkane” is a saturated or partly unsaturated (i.e., nonaromatic) group containing all carbon ring atoms.
  • it can be cyclohexene, cyclohexane, cyclopentene, cyclopentane, cyclobutene, cyclobutane, or cyclopropane.
  • Alkyl is a branched or straight-chain saturated aliphatic hydrocarbon group.
  • the alkyl contains 1 ⁇ 5 carbon atoms or 1 ⁇ 3 carbon atoms.
  • it can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, t-pentyl, or neopentyl.
  • Alkenyl is a branched or straight-chain aliphatic hydrocarbon group having at least one carbon-carbon double bond that can occur along the chain at a stable point.
  • the alkenyl contains 2 ⁇ 5 carbon atoms.
  • it can be ethenyl or propenyl.
  • Alkynyl is a branched or straight-chain aliphatic hydrocarbon group having at least one carbon-carbon triple bond that can occur along the chain at any stable point.
  • the alkynyl contains 2 ⁇ 5 carbon atoms.
  • it can be ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, or 4-pentynyl.
  • Dialkyl indicates an alkyl substituted group as defined above wherein two same or different alkyls are substituted.
  • Alkoxy is an alkyl group as defined above covalently bonded through an oxygen bridge (-O-).
  • Hydroalkyl is an alkyl group as described above substituted with one or more hydroxy substituents.
  • Haloalkyl indicates a branched or straight alkyl group substituted with one or more halogen atoms and up to a maximum number of halogen atoms. For example, it can be trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, or penta-fluoroethyl.
  • Cycloalkyl is a saturated or partly unsaturated (i.e., nonaromatic) group containing all carbon ring atoms.
  • it can be cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, or cyclopropyl.
  • Alkyloxyalkyl is an alkyl group as defined above wherein additional alkyl is covalently bonded through an oxygen bridge (-O-).
  • Aryl indicates an aromatic group containing only carbon in the aromatic ring. In a preferred embodiment of the present invention, it may be phenyl or naphthalenyl.
  • Heteroaryl indicates a stable 5 ⁇ 12 membered monocyclic aromatic ring, bicyclic or tricyclic system containing one or more hetero atoms selected from the group consisting of N, O and S and the remaining ring atoms are carbon. In a preferred embodiment of the present invention, the only hetero atom is nitrogen.
  • the monocyclic heteroaryl group typically has 5 ⁇ 7 ring atoms.
  • the bicyclic heteroaryl group is a 9 or 10 membered heteroaryl group wherein a 5 ⁇ 7 membered aromatic ring is fused with the second aromatic or non-aromatic ring and 9 ⁇ 10 ring atoms are contained.
  • the heteroaryl group is exemplified by pyridinyl (including 2-hydroxypyridinyl), imidazolyl, imidazolopyridinyl, pyrimidinyl (including 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazoly
  • Halo or "halogen” independently represents any fluoro, chloro, bromo, and iodo.
  • the present invention provides a compound represented by formula 1 below or a pharmaceutically acceptable salt of the same:
  • A is 3 ⁇ 8 membered heterocyclic ring containing one or more hetero atoms selected from the group consisting of N, O and S or C 3-10 cycloalkane;
  • R 3 , R 4 , and R 5 are independently hydrogen, straight or branched C 1-5 alkyl or C 3-8 cycloalkyl. At this time, the alkyl or cycloalkyl can be substituted with hydroxy; and
  • A is 3 ⁇ 6 membered heterocyclic ring containing one or more hetero atoms selected from the group consisting of N, O and S or C 5-7 cycloalkane;
  • R 3 , R 4 , and R 5 are independently hydrogen, straight or branched C 1-3 alkyl or C 3-6 cycloalkyl. At this time, the alkyl or cycloalkyl can be substituted with hydroxy; and
  • R 10 is straight or branched C 1-3 alkyl or C 1-3 alkyloxy C 1-3 alkyl; C 5-10 aryl; or 6 ⁇ 10 membered heteroaryl containing one or more nitrogen atoms; and the aryl or heteroaryl can be substituted with one or more substituents selected from the group consisting of straight or branched C 1-3 alkyl, C 1-3 alkoxy and C 1-3 haloalkyl.
  • A is piperidine, tetrahydropyrane, pyrrolidine, or cyclohexane
  • R 2 is hydrogen or methoxy
  • R 3 is hydrogen
  • R 4 is hydrogen, methyl, isopropyl, cyclopentyl, cyclohexyl, or (4-hydroxy)cyclohexyl;
  • R 5 is hydrogen
  • R 6 is one or more substituents selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, methoxy, chloro, fluoro, methoxyethoxy, phenoxy, , , , and .
  • the compound represented by formula 1 above is any one selected from the group consisting of the following compounds:
  • the compound represented by formula 1 of the present invention can be used as a form of a pharmaceutically acceptable salt, in which the salt is preferably acid addition salt formed by pharmaceutically acceptable free acids.
  • the acid addition salt herein can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid; non-toxic organic acids such as aliphatic mono/dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate, alkandioate, aromatic acids, and aliphatic/aromatic sulfonic acids; or organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid.
  • inorganic acids such as hydrochloric acid, nitric
  • the pharmaceutically non-toxic salts are exemplified by sulfate, pyrosulfate, bisulfate, sulphite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutylate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, cabacate, fumarate, maliate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, tolu
  • the acid addition salt in this invention can be prepared by the conventional method known to those in the art.
  • the derivative represented by formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylenechloride, or acetonitrile, to which organic acid or inorganic acid is added to induce precipitation.
  • the precipitate is filtered and dried to give the salt.
  • the solvent and the excessive acid are distillated under reduced pressure, and dried to give the salt.
  • the precipitate is crystallized in an organic solvent to give the same.
  • a pharmaceutically acceptable metal salt can be prepared by using a base.
  • Alkali metal or alkali earth metal salt is obtained by the following processes: dissolving the compound in excessive alkali metal hydroxide or alkali earth metal hydroxide solution; filtering non-soluble compound salt; evaporating the remaining solution and drying thereof.
  • the metal salt is preferably prepared in the pharmaceutically suitable form of sodium, potassium, or calcium salt.
  • the corresponding silver salt is prepared by the reaction of alkali metal or alkali earth metal salt with proper silver salt (ex; silver nitrate).
  • the present invention includes not only the compound represented by formula 1 but also a pharmaceutically acceptable salt thereof, and a solvate, an optical isomer, or a hydrate possibly produced from the same.
  • the present invention also provides a preparation method of the compound represented by formula 1 comprising the step of preparing the compound represented by formula 1 by reacting the compound represented by formula 2 with the compound represented by formula 3 (step 1), as shown in reaction formula 1 below:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in formula 1, and
  • X is halogen
  • step 1 is to prepare the compound represented by formula 1 by reacting the compound represented by formula 2 with the compound represented by formula 3.
  • step 1 is a step of condensing an amine group (-NHR 5 ) of the compound represented by formula 2 and a halogen group (X) of the compound represented by formula 3 in the presence of an acid.
  • the acid is not particularly limited as long as it is an acid generally used in the field, but trifluoroacetic acid (TFA), p-toluenesulfonic acid (p-TSA), hydrochloric acid (HCl) and formic acid can be used.
  • TFA trifluoroacetic acid
  • p-TSA p-toluenesulfonic acid
  • HCl hydrochloric acid
  • formic acid formic acid can be used.
  • the reaction temperature is not limited but can be 10 ⁇ 150°C, preferably 30 ⁇ 120°C, and more preferably 50 ⁇ 100°C. Most preferably, the reaction temperature can be the boiling point of the organic solvent used in the reaction.
  • reaction solvent is not particularly limited as long as it is an organic solvent generally used in the field, but isopropanol, butanol, and 1,4-dioxane can be used.
  • step 1 preparing the compound represented by formula 3-3 by reacting the compound represented by formula 3-1 with the compound represented by formula 3-2 via amidation (step 1);
  • step 2 preparing the compound represented by formula 3-5 by reacting the compound represented by formula 3-3 prepared in step 1 with the compound represented by formula 3-4 with the addition of hydrazine (step 2);
  • step 3 cyclizing the compound represented by formula 3-5 prepared in step 2 (step 3).
  • R 3 , R 4, and R 5 are as defined in formula 1, and X is halogen.
  • reaction conditions for step 1 ⁇ step 3 shown in reaction formula 2 above are not particularly limited as long as they are generally used in the art, so that the detailed description is omitted herein.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer.
  • the compound is characterized by being effective in preventing or treating cancer by inhibiting Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • the cancer can be solid cancer or blood cancer.
  • the solid tumor can be selected from the group consisting of brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brain stem tumor, head and neck tumor, laryngeal cancer, uveal cancer, nasal cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary cancer, pancreatic cancer, small bowel cancer, colon cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervix cancer, endometrial cancer
  • composition comprising the compound represented by formula 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer can be administered independently or co-administered with other anticancer agents in use.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of autoimmune disease.
  • the compound is characterized by being effective in preventing or treating autoimmune disease by inhibiting Bruton's tyrosine kinase (BTK).
  • the autoimmune disease can be selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes mellitus, myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guilin Barre syndrome, acute sporadic encephalomyelitis, Addison's disease, ocular hepatocellular seizure-epileptic syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, chronic digestive dysfunction, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary dysplasia cirrhosis, Takay
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of Parkinson's disease.
  • the compound represented by formula 1 or the pharmaceutically acceptable salt thereof included in the pharmaceutical composition of the present invention can be administered orally or parenterally and be used in general forms of pharmaceutical formulation. That is, the composition of the present invention can be prepared for oral or parenteral administration by mixing with generally used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants.
  • the formulations for oral administration are exemplified by tablets, pills, hard/soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, and troches, etc.
  • These formulations can include diluents (for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine) and lubricants (for example, silica, talc, stearate and its magnesium or calcium salt, and/or polyethylene glycol) in addition to the active ingredient.
  • Tablets can include binding agents such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrolidone, and if necessary disintegrating agents such as starch, agarose, alginic acid or its sodium salt or azeotropic mixtures and/or absorbents, coloring agents, flavours, and sweeteners can be additionally included thereto.
  • binding agents such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrolidone
  • disintegrating agents such as starch, agarose, alginic acid or its sodium salt or azeotropic mixtures and/or absorbents, coloring agents, flavours, and sweeteners can be additionally included thereto.
  • the pharmaceutical composition comprising the compound represented by formula 1 as an active ingredient can be administered by parenterally and the parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the compound represented by formula 1 or the pharmaceutically acceptable salt thereof is mixed with a stabilizer or a buffering agent in water to produce a solution or suspension, which is then formulated as ampoules or vials.
  • the composition herein can be sterilized and additionally contains preservatives, stabilizers, wettable powders or emulsifiers, salts and/or buffers for the regulation of osmotic pressure, and other therapeutically useful materials, and the composition can be formulated by the conventional mixing, granulating or coating method.
  • the effective dosage of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof of the present invention can be determined according to age, weight, gender, administration method, health condition, and severity of disease.
  • the dosage is generally 0.1 ⁇ 1000 mg/day, and preferably 1 ⁇ 500 mg/day based on an adult patient weighing 70 kg, which can be administered once or several times a day at intervals of a certain time depending on the judgment of a doctor or a pharmacist.
  • composition comprising the compound represented by formula 1, the optical isomer, or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of cancer can be administered as an individual therapeutic agent or in combination with other anticancer agents in use.
  • the present invention also provides a health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or improvement of cancer.
  • the present invention also provides a health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or improvement of autoimmune disease.
  • the present invention provides a health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or improvement of Parkinson's disease.
  • the compound represented by formula 1 of the present invention can be used as a food additive.
  • the compound represented by formula 1 of the present invention can be added as it is or as mixed with other food components according to the conventional method.
  • the mixing ratio of active ingredients can be regulated according to the purpose of use (prevention or improvement).
  • the compound of the present invention is preferably added to food or beverages by 0.1 ⁇ 90 weight part for the total weight of the food or beverages.
  • the content can be lower than the above but higher content can be accepted as well since the compound of the present invention has been proved to be very safe.
  • the health beverage composition of the present invention can additionally include various flavors or natural carbohydrates, etc, like other beverages.
  • the natural carbohydrates above can be one of monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xilytole, sorbitol and erythritol.
  • natural sweetening agents thaumatin, stevia extract, for example rebaudioside A, glycyrrhizin, etc.
  • synthetic sweetening agents sacharin, aspartame, etc.
  • the content of the natural carbohydrate is preferably 1 ⁇ 20 g and more preferably 5 ⁇ 12 g in 100 g of the composition of the invention.
  • the compound represented by formula 1 of the present invention can include in variety of nutrients, vitamins, minerals (electrolytes), flavors including natural flavors and synthetic flavors, coloring agents and extenders (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acid, protective colloidal viscosifiers, pH regulators, stabilizers, antiseptics, glycerin, alcohols, carbonators which used to be added to soda, etc.
  • the compound represented by formula 1 of the present invention can also include natural fruit juice, fruit beverages and fruit flesh addable to vegetable beverages.
  • the present invention also provides a method for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease comprising the step of administering the pharmaceutical composition or the health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient to a subject in need.
  • the present invention provides a use of the pharmaceutical composition or the health functional food comprising the compound represented by formula 1 or the pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease.
  • the present invention also provides a method of treating a subject having a cancer comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of treating a subject having an autoimmune disease comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of treating a subject having a Parkinson's disease comprising administering an effective amount of the compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a cancer.
  • the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease.
  • the present invention also provides a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a Parkinson's disease.
  • the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a cancer.
  • the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease.
  • the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use in the treatment of a Parkinson's disease.
  • the present invention also provides a composition comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof for use as a medicament.
  • the present invention also provides a medicament comprising a compound represented by formula 1 or the pharmaceutically acceptable salt thereof.
  • novel pyrazolopyrimidine compound of the present invention demonstrates an excellent BTK inhibitory activity at a low concentration, and therefore it can be used as a pharmaceutical composition for the prevention or treatment of cancer, autoimmune disease or Parkinson's disease, which is supported by the results of the following experiments.
  • Trifluoro acetic anhydride (0.43 mL, 2.99 mmol) was added to 2-(4-bromophenyl)ethane-1-amine (500 mg, 2.50 mmol) solution in DCM (25 mL), to which TEA (0.87 mL, 6.25 mmol) was added.
  • the reaction mixture was stirred at room temperature for 1 hour.
  • water 50 mL was added to the reaction mixture, followed by extraction with DCM (2 X 50 mL).
  • the combined organic layer was washed with saturated brine solution, which was dried over Na 2 SO 4 .
  • the solvent was eliminated in vacuum.
  • the crude mixture was purified by re-crystallization. As a result, N-(4-bromophenetyl)-2,2,2-trifluoroacetamide (700 mg, 2.36 mmol, 94%) was obtained as a white solid.
  • Step 2 Preparation of 1-(7-bromo-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
  • step 1 Compound of step 1 (250 mg, 0.844 mmol) was dissolved in HOAc (1.41 mL) and sulfuric acid (0.94 mL), to which paraformaldehyde (40 mg, 1.35 mmol) was added at room temperature, followed by stirring for 12 hours.
  • the reaction mixture was poured carefully into approximately 10 mL of ice.
  • the generated white sludge suspension was extracted with EtOAc.
  • the organic material was washed with saturated aqueous NaHCO 3 and brine, followed by drying over MgSO 4 .
  • the crude mixture was purified by column chromatography using EtOAc/Hx (1:4) as an eluent.
  • Step 3 Preparation of 1-(7-bromo-6-nitro-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
  • Step 4 Preparation of 1-(6-amino-3,4-dihydroisoquinoline-2(1 H )-yl)-2,2,2-trifluoroethane-1-one
  • Trifluoro acetic anhydride (6.22 g, 29.61 mmol) was added to 2-(4-nitrophenyl)ethane-1-amine (5.0 g, 24.67 mmol) solution in DCM (100 mL), to which TEA (8.6 mL, 61.67 mmol) was added.
  • the reaction mixture was stirred at room temperature for 2 hours.
  • water 50 mL was added to the reaction mixture, followed by extraction with DCM (2 X 50 mL).
  • the combined organic layer was washed with saturated brine solution, which was dried over Na 2 SO 4 .
  • the solvent was eliminated in vacuum.
  • the crude mixture was purified by re-crystallization. As a result, 2,2,2-trifluoro-N-(4-nitrophenetyl)acetamide (5.8 g, 22.1 mmol, 90%) was obtained as a grey-white solid.
  • step 1 Compound of step 1 (750 mg, 2.86 mmol) was dissolved in HOAc (4 mL), to which sulfuric acid (7.5 mL) and paraformaldehyde (137 mg, 4.57 mmol) were added at room temperature, followed by stirring at 50°C for 12 hours.
  • the reaction mixture was poured carefully into approximately 100 mL of ice.
  • the generated white sludge suspension was extracted with EtOAc.
  • the organic material was washed with saturated aqueous NaHCO 3 and brine, followed by drying over MgSO 4 .
  • the crude mixture was purified by column chromatography using hexane/EA (1:4) as an eluent.
  • Step 3 Preparation of 1-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
  • step 1 Compound of step 1 (4.0 g, 12.3 mmol) was dissolved in 30 mL of methanol, to which 30 mL of sodium hydroxide solution (2.7 g, 67.6 mmol) was added at room temperature, followed by stirring at room temperature for 5 hours. Most of methane was concentrated under reduced pressure, and pH of the residue was adjusted to 2 with conc. HCl. The solid was precipitated and filtered. The filtered cake was washed with water and dried. As a result, 2-(carboxymethyl)-5-nitrobenzoic acid (2.2 g, 9.77 mmol, 79%) was obtained as a cream type solid.
  • BH 3 THF (1.0 M) (21 mL, 21.03 mmol) was added to cold compound of step 1 (1.0 g, 5.25 mmol) THF (25 mL) solution at 0°C.
  • the reaction mixture was stirred at 70°C for 2 hours.
  • the reaction was terminated with methanol, followed by concentration and drying.
  • 1.5 N HCl (15.00 mL) was added to the residue, followed by extraction with EtOAc.
  • the aqueous layer was basified with NaOH solution and extracted with EtOAc (2 X 50 mL).
  • the combined organic layer was washed with sodium sulfate and the remaining mixture was subjected to the following steps without any purification process.
  • Step 3 Preparation of 1-(4,4-dimethyl-7-nitro-3,4-dihydroisoquinoline-2(1 H )-yl)-2,2,2-trifluoroethane-1-one
  • Step 4 Preparation of 1-(7-amino-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
  • Step 4 Preparation of 2,2,2-trifluoro-1-(1-isopropyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
  • Step 5 Preparation of 1-(7-amino-1-isopropyl-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
  • Step 3 Preparation of 2,2,2-trifluoro-1-(1,3,3-trimethyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
  • Step 4 Preparation of 1-(7-amino-1,3,3-trimethyl-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
  • Trifluoroacetic anhydride (1.64 mL, 11.7 mmol) was added dropwise to cold isoindolin (400 mg, 3.35 mmol) acetonitrile (15 mL) solution at -10°C.
  • Potassium nitrate (366 mg, 3.62 mmol) was added to the stirred mixture at once. The mixture was stirred at -10°C for 1 hour. Saturated sodium bicarbonate aqueous solution (10 mL) was slowly added to the mixture. Active gas generation was observed. The mixture was stirred for 1 hour and then the temperature of the mixture was raised to room temperature. The mixture was basified with saturated sodium carbonate (10 mL). The sticky turbid solution was filtered.
  • a target compound was prepared by the same manner as described in step 4 of Preparative Example A-7 except that 2,2,2-trifluoro-1-(5-nitroisoindolin-2-yl)ethane-1-one prepared in step 1 was used instead of 2,2,2-TRIFLUORO-1-(1,3,3-TRIMETHYL-7-NITRO-3,4-DIHYDROISOQUINOLINE-2(1H)-YL)ETHANE-1-ONE.
  • Step 5 Preparation of 2,2,2-trifluoro-1-(6-methoxy-1,1-dimethyl-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
  • Step 6 Preparation of 2,2,2-trifluoro-1-(6-methoxy-1,1-dimethyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
  • Step 7 Preparation of 2,2,2-trifluoro-1-(6-hydroxy-1,1-dimethyl-7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-one
  • Step 8 Preparation of 1,1-dimethyl-7-nitro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl trifluoromethanesulfonate
  • Step 9 Preparation of 1-(7-amino-1,1-dimethyl-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
  • N -(4-nitrophenyl)acrylamide 200 mg, 1.04 mmol was suspended in ethanol/water (5:1) mixture, to which Fe powder (116 mg, 2.08 mmol) and ammonium chloride solution (1 mL) were added. The mixture was heated to 80°C for 4 hours. The reaction mixture was cooled at room temperature and filtered with a celite pad. The celite above was washed with ethanol (10 mL) and ethyl acetate (50 mL). The solution above was concentrated under vacuum. The reaction residue was fractionated with DCM (50 mL) and water (20 mL). The combined organic layer was concentrated under reduced pressure. The obtained crude mixture was purified by column chromatography (EtOAc/Hexane (1:5)). As a result, N -(4-aminophenyl)acrylamide (100 mg, 0.616 mmol, 60%) was obtained as a yellow solid.
  • Fuming nitric acid (128 mg, 2.04 mmol) was added dropwise to -5°C conc. sulfuric acid (2.0 mL) containing 3,4-dihydroisoquinolin-1(2H)-one (400 mg, 2.31 mmol) at 0°C. The temperature of the mixture was raised to room temperature for 2 hours. The reaction mixture was placed in ice-water (10 mL) and basified with potassium hydroxide pellet (pH 9). The mixture was extracted with dichloromethane, followed by drying. The solvent was eliminated under reduced pressure. The crude product was purified by column chromatography (MeOH/DCM (1:9)). As a result, 7-nitro-3,4-dihydroisoquinoline-1(2H)-one (300 mg, 1.56 mmol, 76%) was obtained as brown oil.
  • a target compound was prepared by the same manner as described in step 4 of Preparative Example A-7 except that 7-nitro-3,4-dihydroisoquinoline-1(2H)-one prepared in step 1 was used instead of 2,2,2-TRIFLUORO-1-(1,3,3-TRIMETHYL-7-NITRO-3,4-DIHYDROISOQUINOLINE-2(1H)-YL)ETHANE-1-ONE.
  • 2,6-Dimethylaniline (5.81 g, 48 mmol) was added to 2,4-dichloropyrimidine-5-carbonyl chloride (10.2 g, 48 mmol) in EtOAc (400 mL) at room temperature, to which amberlyst 21 resin (2.0 g) was added. The mixture was stirred at room temperature for 12 hours, followed by filtering. The filtrate was washed serially with water, 1.5 N HCl (15 mL), NaOH, and brine in that order. The combined organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was recrystallized by using DCM.
  • Methyl hydrazine (205 mg, 4.45 mmol) was added to 2,4-DICHLORO-N-(2,6-DIMETHYLPHENYL)PYRIMIDINE-5-CARBOXAMIDE(1.2 g, 4.05 mmol) in THF (30 mL) at room temperature, to which Et 3 N (1.42 mL, 10.1 mmol) was added. The mixture was stirred at room temperature for 24 hours, which was concentrated to eliminate THF. The reaction mixture was washed with water, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
  • PCl 5 (681 mg, 3.27 mmol) was added to 2-CHLORO-N-(2,6-DIMETHYLPHENYL)-4-(1-METHYLHYDRAZINYL)PYRIMIDINE-5-CARBOXAMIDE(1.0 g, 3.27 mmol) in toluene (40 mL) at room temperature. The mixture was stirred at room temperature for 24 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
  • 6-CHLORO-N-(2,6-DIMETHYLPHENYL)-1-METHYL-1H-PYRAZOLO[3,4-D]PYRIMIDINE-3-AMINE 800 mg, 2.78 mmol, 85 %) was obtained as a yellow solid.
  • PCl 5 (150 mg, 0.720 mmol) was added to 2-chloro-4-(1-methylhydrazinyl)-N-phenylpyrimidine-5-carboxamide (200 mg, 0.720 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 100°C for 18 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4). As a result, 6-chloro-1-methyl-N-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine (150 mg, 0.577 mmol, 80%) was obtained as a yellow solid.
  • 2,6-Dichloroaniline (383 mg, 2.36 mmol) was added to 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.36 mmol) in EtOAc (40 mL) at room temperature, to which amberlyst 21 resin (100 mg) was added. The mixture was stirred for 12 hours, followed by filtering. The filtrate was washed with water, 1.5 N HCl (15 mL), NaOH, and brine in that order. The combined organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was recrystallized by using DCM. As a result, 2,4-dichloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide (650 mg, 1.93 mmol, 81%) was obtained as a grey-white solid.
  • PCl 5 120 mg, 0.577 mmol was added to 2-chloro-N-(2,6-dichlorophenyl)-4-(1-methylhydrazinyl)pyrimidine-5-carboxamide (200 mg, 0.577 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 100°C for 18 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
  • 6-chloro-N-(2,6-dichlorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine 130 mg, 0.395 mmol, 68%) was obtained as a yellow solid.
  • Step 1 Preparation of tert-butyl-2-(2-chloro-5-((2,6-dimethylphenyl)carbamoyl)pyrimidine-4-yl)hydrazine-1-carboxylate
  • tert-butyl-2-(2-chloro-5-((2,6-dimethylphenyl)carbamoyl)pyrimidine-4-yl)hydrazine-1-carboxylate 560 mg, 1.429 mmol, 84%) was obtained as a white solid.
  • PCl 5 (297 mg, 1.429 mmol) was added to tert-butyl-2-(2-chloro-5-((2,6-dimethylphenyl)carbamoyl)pyrimidine-4-yl)hydrazine-1-carboxylate (560 mg, 1.429 mmol) in toluene (50 mL) at room temperature. The mixture was stirred at 100°C for 18 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4). As a result, 6-chloro-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-amine (65 mg, 0.237 mmol, 16%) was obtained as a yellow solid.
  • Step 1 Preparation of 2-chloro-4-(1-cyclopentylhydrazinyl)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide
  • Step 2 Preparation of 6-chloro-1-cyclopentyl-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-amine
  • PCl 5 (104 mg, 0.500 mmol) was added to 2-chloro-4-(1-cyclopentylhydrazinyl)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide (180 mg, 0.500 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 100°C for 18 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by column chromatography using EtOAc/Hx (1/4).
  • 6-chloro-1-cyclopentyl-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-amine 120 mg, 0.351 mmol, 70% was obtained as a yellow solid.
  • Step 1 Preparation of 2-chloro-4-(1-cyclohexylhydrazinyl)- N -(2,6-dimethylphenyl)pyrimidine-5-carboxamide
  • Step 2 Preparation of 6-chloro-1-cyclohexyl- N -(2,6-dimethylphenyl)-1 H -pyrazolo[3,4-d]pyrimidine-3-amine
  • PCl 5 (72 mg, 0.347 mmol) was added to 2-chloro-4-(1-cyclohexylhydrazinyl)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide (130 mg, 0.347 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 110°C for 3 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by column chromatography using EtOAc/Hx (1/4).
  • 6-chloro-1-cyclohexyl-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-amine 90 mg, 0.253 mmol, 73%) was obtained as a yellow solid.
  • Step 1 Preparation of 2-chloro- N -(2,6-dimethylphenyl)-4-(1-isopropylhydrazinyl)pyrimidine-5-carboxamide
  • Et 3 N (0.18 mL, 1.26 mmol) was added to 2,4-dichloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide (150 mg, 0.506 mmol) in THF (10 mL), to which isopropyl hydrazine (41 mg, 0.577 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, which was concentrated to eliminate THF. The reaction mixture was washed with water, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
  • Step 2 Preparation of 6-chloro- N -(2,6-dimethylphenyl)-1-isopropyl-1 H -pyrazolo[3,4-d]pyrimidine-3-amine
  • PCl 5 (68.6 mg, 0.329 mmol) was added to 2-chloro-N-(2,6-dimethylphenyl)-4-(1-isopropylhydrazinyl)pyrimidine-5-carboxamide (110 mg, 0.329 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 110°C for 3 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4).
  • 6-chloro-N-(2,6-dimethylphenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine 75 mg, 0.237 mmol, 72%) was obtained as a yellow solid.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide prepared in step 4 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • Step 5 Preparation of N-(3-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)amino)-2,4-dimethylphenyl)-3-(trifluoromethyl)benzamide
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that N-(3-amino-2,4-dimethylphenyl)-3-(trifluoromethyl)benzamide prepared in step 4 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • Step 2 Preparation of 6-chloro-N-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 4-(2-methoxyethoxy)-2,6-dimethylaniline prepared in step 1 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,6-dimethyl-4-phenoxybenzamine was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • T3P (2.30 mL, 10.2 mmol) and TEA (1.42 mL, 10.2 mmol) were added to DCM (20 mL) solution containing 3,5-dimethyl-4-nitrobenzoic acid (1.00 g, 5.12 mmol) and 2-aminopyridine (482 mg, 5.12 mmol) at room temperature, followed by stirring at room temperature overnight.
  • the reaction was terminated with NaHCO 3 (aq), followed by extraction with DCM (2 X 25 mL).
  • the combined organic layer was dried over Na 2 SO 4 and the solvent was eliminated under reduced pressure.
  • the residue mixture was purified by silica gel column chromatography using EtOAc/Hex (3/7). As a result, the target compound (290 mg, 1.07 mmol, 21%) was obtained as a white solid.
  • Step 3 Preparation of 4-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)amino)-3,5-dimethyl-N-(pyridine-2-yl)benzamide
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 4-amino-3,5-dimethyl-N-(pyridine-2-yl)benzamide prepared in step 2 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • Step 2 Preparation of 6-chloro-N-(4-methoxy-2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 4-methoxy-2,6-dimethylaniline prepared in step 1 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,4-diethylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,4-diisopropylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • Step 1 Preparation of 2,4-dichloro- N -(3,5-dimethylphenyl)pyrimidine-5-carboxamide
  • Step 2 Preparation of 2-chloro- N -(3,5-dimethylphenyl)-4-(1-methylhydrazinyl)pyrimidine-5-carboxamide
  • Step 3 Preparation of 6-chloro- N -(2-chloro-3,5-dimethylphenyl)-1-methyl-1 H -pyrazolo[3,4-d]pyrimidine-3-amine
  • PCl 5 (82 mg, 0.392 mmol) was added to 2-chloro-N-(3,5-dimethylphenyl)-4-(1-methylhydrazinyl)pyrimidine-5-carboxamide (120 mg, 0.392 mmol) in toluene (20 mL) at room temperature. The mixture was stirred at 110°C for 2 hours, which was concentrated to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The obtained crude product was purified by silica gel column chromatography using EtOAc/Hx (1/4) as an eluent.
  • 6-chloro-N-(2-chloro-3,5-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-amine 40 mg, 0.124 mmol, 32%) was obtained as a yellow solid.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,4-dimethylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2-methylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 3,5-dimethylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,6-difluoroaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,6-dimethoxyaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,5-dimethyl-4-fluoroaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2,5-dimethylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2-chloro-6-methylaniline was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 5-(2-methoxyethoxy)-2-methylaniline prepared in step 2 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that 2-methyl-5-nitroanilyl was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • Step 3 Preparation of N-(3-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)amino)-4-methylphenyl)picolineamide
  • Step 2 Preparation of 3-((6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)amino)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide
  • a target compound was prepared by the same manner as described in steps 2, 3, and 4 of Preparative Example B-1 except that N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide prepared in step 1 above was used instead of 2,6-dimethylaniline in step 2 of Preparative Example B-1.
  • Step 1 Preparation of N 1 -(6-chloro-1-methyl-1 H -pyrazolo[3,4-d]pyrimidine-3-yl)-6-methylbenzene-1,3-diamine
  • N 1 -(6-chloro-1-methyl-1 H -pyrazolo[3,4-d]pyrimidine-3-yl)-6-methylbenzene-1,3-diamine 60 mg, 0.207 mmol, 66%) was obtained as a yellow solid.
  • Step 2 Preparation of 1-(3-((6-chloro-1-methyl-1 H -pyrazolo[3,4-d]pyrimidine-3-yl)amino)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea
  • N3-(2,6-dimethylphenyl)-1-methyl-N6-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (20 mg, 0.050 mmol, 50%) was obtained as a grey-white solid.
  • Lithium hydroxide monohydrate (2.5 mg, 0.057 mmol) was added to THF (1.0 mL), MeOH (0.5 mL), and H 2 O (0.5 mL) containing the compound of Example 3 (1-(6-(3-(2,6-dimethylphenylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino)-7-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethaneone, 15 mg, 0.028 mmol) at room temperature, followed by stirring at room temperature for 1 hour. TLC analysis indicated the complete consumption of the starting material. The reaction mixture was concentrated to eliminate THF and methanol.
  • a target compound was prepared by the same manner as described in Example 3 except that the compound prepared in Preparative Example A-2 was used instead of 1-(6-amino-7-methoxy-3,4 dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one in Example 3.
  • a target compound was prepared by the same manner as described in Example 4 except that the compound of Example 6 was used instead of the compound of Example 3 in Example 4.
  • a target compound was prepared by the same manner as described in Example 5 except that the compound of Example 7 was used instead of the compound of Example 4 in Example 5.
  • a target compound was prepared by the same manner as described in Example 3 except that the compound prepared in Preparative Example A-3 was used instead of 1-(6-amino-7-methoxy-3,4 dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one and the compound prepared in Preparative Example B-2 was used instead of the compound prepared in Preparative Example B-1 in Example 3
  • a target compound was prepared by the same manner as described in Example 4 except that the compound of Example 9 was used instead of the compound of Example 3 in Example 4.
  • a target compound was prepared by the same manner as described in Example 9 except that the compound of Preparative Example B-3 was used instead of the compound of Preparative Example B-2 in Example 9.
  • a target compound was prepared by the same manner as described in Example 10 except that the compound of Example 11 was used instead of the compound of Example 9 in Example 10.
  • Example 14 Preparation of 1-(7-(3-(2,6-dimethylphenylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)prop-2-en -1-one
  • Step 1 Preparation of 1-(6-((3-((2,6-dichlorophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
  • a target compound was prepared by the same manner as described in Example 6 except that the compound prepared in Preparative Example B-3 was used instead of the compound of Preparative Example B-1 in Example 6.
  • Step 2 Preparation of N 3 -(2,6-dichlorophenyl)-1-methyl-N 6 -(1,2,3,4-tetrahydroisoquinoline-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine
  • a target compound was prepared by the same manner as described in Example 7 except that the compound prepared in step 1 above was used instead of the compound of Example 6 in Example 7.
  • a target compound was prepared by the same manner as described in Example 13 except that the compound of Example 15 was used instead of the compound of Example 12 in Example 13.
  • Formalin (35%) (1.5 mg, 0.05 mmol) was added to MeOH (1.0 mL) and acetic acid (0.1 mL) containing the compound of Example 2 (1-(7-(3-(2,6-dimethylphenylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-ylamino)-3,4-dihydroisoquinoline-2(1H)-yl)prop-2-en -1-one, 10 mg, 0.025 mmol) at 0°C, followed by stirring at room temperature for 30 minutes. NaCNBH 3 (2.3 mg, 0.037 mmol) was added to the reaction mixture, which was stirred for 30 minutes.
  • N3-(2,6-dimethylphenyl)-N6-(isochroman-7-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine 50 mg, 0.125 mmol, 75%) was obtained as a grey-white solid.
  • Step 1 Preparation of 1-(7-((3-((2,6-dimethylphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one
  • a target compound was prepared by the same manner as described in Example 9 except that the compound of Preparative Example B-4 was used instead of the compound of Preparative Example B-2 in Example 9.
  • Step 2 Preparation of N3-(2,6-dimethylphenyl)-N6-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine
  • a target compound was prepared by the same manner as described in Example 10 except that the compound prepared in step 1 above was used instead of the compound of Example 9 in Example 10.
  • Step 1 A target compound was prepared by the same manner as described in Example 3 except that 1-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 1-(6-amino-7-methoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one in Example 3.
  • Step 2 A target compound was prepared by the same manner as described in Example 4 except that the compound prepared in step 1 above was used instead of the compound of Example 3 in Example 4.
  • a target compound was prepared by the same manner as described in Example 22 except that cyclopropanecarboxylic acid was used instead of glycolic acid in Example 22.
  • a target compound was prepared by the same manner as described in Example 22 except that iodoethanol was used instead of glycolic acid in Example 22.
  • Example 25 Preparation of 1-cyclopentyl-N 3 -(2,6-dimethylphenyl)-N 6 -(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4- d ]pyrimidine-3,6-diamine
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-5 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-6 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-7 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-8 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-9 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-10 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 22 except that N , N -dimethylglycine was used instead of glycolic acid in Example 22.
  • a target compound was prepared by the same manner as described in Example 22 except that iodoethane was used instead of glycolic acid in Example 22.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-11 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-12 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-13 was used instead of the compound of Preparative Example B-4 in Example 19.
  • Example 36 Preparation of N 3 -(2,6-diethylphenyl)-1-methyl-N 6 -(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4- d ]pyrimidine-3,6-diamine
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-14 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-15 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 10 except that the compound of Preparative Example B-16 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-17 was used instead of the compound of Preparative Example B-4 in Example 19.
  • Example 40 Preparation of 1-methyl-N 6 -(1,2,3,4-tetrahydroisoquinoline-7-yl)-N 3 -o-tolyl-1H-pyrazolo[3,4- d ]pyrimidine-3,6-diamine
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-18 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-19 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-20 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-21 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-22 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-23 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 20 except that the compound of Preparative Example A-5 was used instead of 1-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in Example 20.
  • a target compound was prepared by the same manner as described in Example 20 except that the compound of Preparative Example B-8 was used instead of the compound of Preparative Example B-1 in Example 20.
  • Example 48 Preparation of N 3 -(2-chloro-6-methylphenyl)-1-methyl-N 6 -(1,2,3,4-tetrahydroisoquinoline-7-yl)-1H-pyrazolo[3,4- d ]pyrimidine-3,6-diamine
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-24 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 20 except that the compound of Preparative Example A-6 was used instead of 1-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in Example 20.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-25 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-26 was used instead of the compound of Preparative Example B-4 in Example 19.
  • Example 52 Preparation of 4-methyl-3-(1-methyl-6-(1,2,3,4-tetrahydroisoquinoline-7-ylamino)-1H-pyrazolo[3,4- d ]pyrimidine-3-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide
  • a target compound was prepared by the same manner as described in Example 19 except that the compound of Preparative Example B-27 was used instead of the compound of Preparative Example B-4 in Example 19.
  • a target compound was prepared by the same manner as described in Example 20 except that 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 1-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in Example 20.
  • Example 54 Preparation of 4-(3-((2,6-dimethylphenyl)amino)-6-((1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)cyclohexane-1-ol
  • Step 1 Preparation of tert-butyl2-(1,4-dioxaspiro[4.5]decane-8-yl)hydrazine-1-carboxylate
  • Step 2 Preparation of tert -butyl-2-(2-chloro-5-((2,6-dimethylphenyl)carbamoyl)pyridine-4-yl-2-(1,4-dioxaspiro[4.5]decane-8-yl)hydrazine-1-carboxylate
  • Step 3 Preparation of 6-chloro-N-(2,6-dimethylphenyl)-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole[3,4-d]pyrimidine-3-amine
  • PCl 5 (78 mg, 0.375 mmol) was added to toluene (20 mL) solution containing the compound prepared in step 2 above (200 mg, 0.375 mmol) at room temperature, followed by stirring at 110°C for 3 hours. The mixture was concentrated under reduced pressure to eliminate toluene. The reaction mixture was washed with sodium bicarbonate, and the organic layer was dried over sodium sulfate, followed by concentration under reduced pressure. The crude product was purified by column chromatography (EtOAc/Hx (1/4)). As a result, the target compound (80 mg, 0.193 mmol, 51%) was obtained as a yellow solid.

Abstract

La présente invention concerne un dérivé de pyrazolopyrimidine, son procédé de préparation et une composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau. Le dérivé de pyrazolopyrimidine de la présente invention présente une excellente activité d'inhibition de la tyrosine kinase de Bruton, de sorte qu'il peut être utilisé efficacement en tant que composition pharmaceutique pour la prévention ou le traitement du cancer, d'une maladie auto-immune et de la maladie de Parkinson.
PCT/KR2018/005478 2017-05-12 2018-05-14 Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif WO2018208132A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/612,592 US11084824B2 (en) 2017-05-12 2018-05-14 Pyrazolopyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer, autoimmune disease and brain disease containing the same as an active ingredient

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2017-0059165 2017-05-12
KR20170059165 2017-05-12
KR10-2018-0051686 2018-05-04
KR1020180051686A KR102128018B1 (ko) 2017-05-12 2018-05-04 피라졸로 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암, 자가면역질환 및 뇌질환의 예방 또는 치료용 약학적 조성물

Publications (1)

Publication Number Publication Date
WO2018208132A1 true WO2018208132A1 (fr) 2018-11-15

Family

ID=64104794

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2018/005478 WO2018208132A1 (fr) 2017-05-12 2018-05-14 Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif

Country Status (1)

Country Link
WO (1) WO2018208132A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019212256A1 (fr) * 2018-05-02 2019-11-07 제이더블유중외제약 주식회사 Nouveau dérivé hétérocyclique
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée
WO2022197641A1 (fr) * 2021-03-15 2022-09-22 Rapt Therapeutics, Inc. Dérivés de 1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine servant de modulateurs et/ou d'inhibiteurs de kinase progénitrice hématopoïétique 1 (hpk1) pour traiter le cancer et d'autres maladies
WO2022270994A1 (fr) * 2021-06-25 2022-12-29 한국화학연구원 Nouveau composé hétérocyclique bifonctionnel ayant une fonction de dégradation de btk par l'intermédiaire d'une voie de protéasome d'ubiquitine, et son utilisation
KR20230000983A (ko) * 2021-06-25 2023-01-03 한국화학연구원 유비퀴틴 프로테오좀 경로를 통해 비티케이 분해작용을 가지는 신규한 이작용성 헤테로사이클릭 화합물과 이의 용도

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007024680A1 (fr) * 2005-08-22 2007-03-01 Amgen Inc. Composes de pyrazolopyridine et de pyrazolopyrimidine utilises comme modulateurs d'enzymes kinases
WO2008112695A2 (fr) * 2007-03-12 2008-09-18 Irm Llc Inhibiteurs de protéine kinase et procédés d'utilisation de ceux-ci
WO2015048689A1 (fr) * 2013-09-30 2015-04-02 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007024680A1 (fr) * 2005-08-22 2007-03-01 Amgen Inc. Composes de pyrazolopyridine et de pyrazolopyrimidine utilises comme modulateurs d'enzymes kinases
WO2008112695A2 (fr) * 2007-03-12 2008-09-18 Irm Llc Inhibiteurs de protéine kinase et procédés d'utilisation de ceux-ci
WO2015048689A1 (fr) * 2013-09-30 2015-04-02 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEUNG, C. S. ET AL.: "Methyl Effects on Protein-Ligand Binding", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 9, 2012, pages 4489 - 4500, XP055556365 *
WU, S. ET AL.: "Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 112, no. 50, 2015, pages 15480 - 15485, XP055556362 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019212256A1 (fr) * 2018-05-02 2019-11-07 제이더블유중외제약 주식회사 Nouveau dérivé hétérocyclique
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée
WO2022197641A1 (fr) * 2021-03-15 2022-09-22 Rapt Therapeutics, Inc. Dérivés de 1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine servant de modulateurs et/ou d'inhibiteurs de kinase progénitrice hématopoïétique 1 (hpk1) pour traiter le cancer et d'autres maladies
US11918582B2 (en) 2021-03-15 2024-03-05 Rapt Therapeutics, Inc. Pyrazole pyrimidine compounds and uses thereof
WO2022270994A1 (fr) * 2021-06-25 2022-12-29 한국화학연구원 Nouveau composé hétérocyclique bifonctionnel ayant une fonction de dégradation de btk par l'intermédiaire d'une voie de protéasome d'ubiquitine, et son utilisation
KR20230000983A (ko) * 2021-06-25 2023-01-03 한국화학연구원 유비퀴틴 프로테오좀 경로를 통해 비티케이 분해작용을 가지는 신규한 이작용성 헤테로사이클릭 화합물과 이의 용도
KR102637915B1 (ko) 2021-06-25 2024-02-19 한국화학연구원 유비퀴틴 프로테오좀 경로를 통해 비티케이 분해작용을 가지는 신규한 이작용성 헤테로사이클릭 화합물과 이의 용도

Similar Documents

Publication Publication Date Title
WO2018208132A1 (fr) Dérivés de pyrazolopyrimidine, leur procédé de préparation et composition pharmaceutique pour utilisation dans la prévention ou le traitement du cancer, d'une maladie auto-immune et d'une maladie du cerveau contenant ceux-ci en tant que principe actif
WO2021112538A1 (fr) Agoniste du récepteur glp-1
WO2020149723A1 (fr) Dérivé de pyrrolopyrimidine et composition pharmaceutique pour la prévention ou le traitement d'une maladie liée à la protéine kinase le comprenant en tant que principe actif
WO2014061970A1 (fr) Bloqueurs de canal sodique, leur procédé de préparation et leur utilisation
WO2015160192A1 (fr) Composition pharmaceutique permettant de traiter et de prévenir la leucémie, contenant un dérivé de thiénopyrimidine ou un sel pharmaceutiquement acceptable de celui-ci
WO2020149715A1 (fr) Dérivé de pyrrolopyridine et son utilisation dans la prévention et le traitement d'une maladie liée à la protéine kinase
WO2014109530A1 (fr) Dérivé 2-(phényléthynyl)thiéno[3,4-b]pyrazine, et composition pharmaceutique comprenant ce dérivé et destinée à la prévention ou au traitement du cancer
WO2020096372A1 (fr) Nouveau dérivé de pipéridine-2,6-dione et utilisation associée
WO2018021826A1 (fr) Nouveau dérivé de pyrimidine-2,4-diamine et composition pharmaceutique pour la prévention ou le traitement du cancer contenant celui-ci comme ingrédient actif
WO2016006974A2 (fr) Nouveaux dérivés triazolopyrimidinone ou triazolopyridinone et leur utilisation
WO2016006975A2 (fr) Nouveaux dérivés imidazotriazinone ou imidazopyrazinone et leur utilisation
WO2011049274A1 (fr) Dérivés d'imidazole et compositions pour le traitement d'un mélanome
WO2022139304A1 (fr) Nouveau composé dérivé de quinazoline en tant qu'inhibiteur de sos1, et son utilisation
WO2010032986A2 (fr) Nouveaux dérivés de 5-(4-aminophenyl)-isoquinoline, leurs sels pharmaceutiquement acceptables, procédé de production associé et composition contenant les dérivés comme principe actif pour la prophylaxie et le traitement d'états pathologiques induits par l'hyperactivité de la kinase raf
AU2019344240B2 (en) Novel thiazole derivatives and pharmaceutically acceptable salts thereof
WO2020263058A1 (fr) Dérivé d'aminocyanopyridine et son utilisation
WO2021040422A1 (fr) Nouveau dérivé de pyrimido[4,5-d]pyrimidine-2-one ayant une activité inhibitrice de protéine kinase
EP3166945A2 (fr) Nouveaux dérivés triazolopyrimidinone ou triazolopyridinone et leur utilisation
WO2021086077A1 (fr) Dérivé d'isoquinolinone, son procédé de préparation et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement d'une maladie associée à la poly(adp-ribose) polymérase-1 (parp-1)
WO2019039905A1 (fr) Nouvel inhibiteur de la tryptophane hydroxylase et composition pharmaceutique le comprenant
WO2021201576A1 (fr) Composé dérivé de benzothiazole
WO2020106059A1 (fr) Nouveau composé tricyclique en tant qu'inhibiteur d'irak4
WO2022270977A1 (fr) Nouveau composé dérivé de pyridine en tant qu'inhibiteur de ron
WO2022270980A1 (fr) Nouveau composé dérivé d'urée en tant qu'inhibiteur de ron
WO2019107922A1 (fr) Dérivé d'arylpyrazolylpipérazine ou d'arylpyrazolyldiazépane agissant en tant que régulateur du récepteur 5-ht7 et composition pharmaceutique comprenant celui-ci pour le traitement ou la prévention d'un trouble du système nerveux central

Legal Events

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

Ref document number: 18798751

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18798751

Country of ref document: EP

Kind code of ref document: A1