WO2017198049A1 - Dérivé de pyrazolopyrimidine utilisé en tant qu'inhibiteur de la btk et procédé de préparation et composition pharmaceutique associés - Google Patents

Dérivé de pyrazolopyrimidine utilisé en tant qu'inhibiteur de la btk et procédé de préparation et composition pharmaceutique associés Download PDF

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WO2017198049A1
WO2017198049A1 PCT/CN2017/081905 CN2017081905W WO2017198049A1 WO 2017198049 A1 WO2017198049 A1 WO 2017198049A1 CN 2017081905 W CN2017081905 W CN 2017081905W WO 2017198049 A1 WO2017198049 A1 WO 2017198049A1
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formula
substituted
compound
group
phenyl
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PCT/CN2017/081905
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吴予川
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浙江予川医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the technical field of medicinal chemistry, and in particular to a novel pyrazole pyrimidine derivative as a BTK inhibitor with high efficiency, good selectivity and good pharmacokinetic properties and preparation method thereof And pharmaceutical compositions.
  • Protein kinases are the largest family of biological enzymes in the human body, including over 500 proteins.
  • the phenolic function on the tyrosine residue can be phosphorylated to exert important biosignaling effects.
  • the tyrosine kinase family has members that control cell growth, migration, and differentiation. Abnormal kinase activity has been elucidated in close association with many human diseases, including cancer, autoimmune diseases, and inflammatory diseases.
  • Bruton's tyrosine kinase is a cytoplasmic non-receptor tyrosine kinase belonging to the TEC kinase family (a total of five members BTK, TEC, ITK, TXK, BMX).
  • the BTK gene is located on Xq21.33-Xq22 of the X-chromosome and shares 19 exons spanning 37.5 kb of genomic DNA.
  • BTK expression plays an essential role in almost all hematopoietic cells, especially in the development, differentiation, signaling and survival of B lymphocytes.
  • B cells are activated by the B cell receptor (BCR), and BTK plays a decisive role in the BCR signaling pathway.
  • BCR B cell receptor
  • Activation of BCR on B cells causes activation of BTK, which in turn leads to an increase in downstream phospholipase C (PLC) concentration and activates the IP3 and DAG signaling pathways. This signaling pathway promotes cell proliferation, adhesion and survival.
  • PLC phospholipase C
  • This signaling pathway promotes cell proliferation, adhesion and survival.
  • Mutations in the BTK gene result in a rare hereditary B cell-specific immunodeficiency disease known as X-Iinked agammaglobulinemia (XLA).
  • XLA X-Iinked agammaglobulinemia
  • BTK In this disease, the function of BTK is inhibited, resulting in the production or maturation of B cells. Men with XLA disease have almost no B cells in their bodies, and there are few circulating antibodies, which are prone to serious or even fatal infections. This strongly proves that BTK plays an extremely important role in the growth and differentiation of B cells.
  • BTK inhibitors bind to BTK, inhibit BTK autophosphorylation, and prevent BTK activation. This can block the signal transduction of the BCR pathway, inhibit the proliferation of B lymphoma cells, destroy the adhesion of tumor cells, and promote the apoptosis of tumor cells. And induce apoptosis.
  • B-cell lymphomas and leukemias such as non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and Recurrent or refractory mantle cell lymphoma (MCL) and the like.
  • BTK inhibitors In addition to fighting against B-cell lymphoma and leukemia, BTK inhibitors also inhibit B cell autoantibodies and cytokine production.
  • B cells present autoantigens, promote the activation and secretion of T cells, cause inflammatory factors, cause tissue damage, and activate B cells to produce a large number of antibodies, triggering autoimmune responses.
  • the interaction of T and B cells forms a feedback regulatory chain, leading to uncontrolled autoimmune response and aggravation of histopathological damage. Therefore, BTK can be used as a drug target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and allergic diseases (such as diseases such as esophagitis).
  • BTK inhibitors have been reported to be useful in combination with chemotherapeutic agents or immunological checkpoint inhibitors, and have shown superior therapeutic effects in a variety of solid tumors in clinical trials.
  • Ibrutinib is an irreversible BTK inhibitor developed by Pharmacyclics and Johnson & Johnson, and was approved by the FDA in November 2013 and February 2014 for the treatment of mantle cell lymphocytes.
  • An irreversible inhibitor is a chemical that binds a relatively strong covalent bond to a group in an enzyme protein.
  • An irreversible inhibitor can usually inactivate an enzyme to exert its unique high biological activity.
  • Ibrutinib has been designated by the FDA as a "breakthrough" new drug that works by reacting with the thiol group of cysteine in BTK and forming a covalent bond that inactivates the BTK enzyme.
  • ibrutinib is easily metabolized during metabolism (digested by metabolic enzymes to be dihydroxylated or inactivated by other thiol-containing enzymes, cysteine, glutathione, etc.) Affect the efficacy.
  • the clinically administered dose reached 560 mg per day, which increased the burden on the patient.
  • Ibrutinib also has a certain inhibitory effect on some kinases other than BTK, especially the inhibition of EGFR can lead to more serious rash, diarrhea and other adverse reactions. Therefore, there is still a need in the art to develop a new class of BTK inhibitors that are more efficient, selective, and have good pharmacokinetic properties for the treatment of related diseases.
  • the present inventors have developed a novel pyrazolopyrimidine derivative which is an effective, safe and highly selective inhibitor of protein kinase BTK.
  • Embodiments of the invention provide a novel pyrazolopyrimidine derivative. It is a new covalent bond inhibitor that improves its affinity with the target by altering its reactivity with cysteine to improve efficacy, selectivity and safety.
  • Embodiments of the invention also provide methods of preparing the above derivatives.
  • Embodiments of the invention also provide pharmaceutical compositions containing the above derivatives.
  • Embodiments of the invention also provide the use of the above derivatives.
  • an embodiment of the present invention provides a novel pyrazolopyrimidine compound, as shown in formula (I), a stereoisomer thereof, a tautomer thereof , or a pharmaceutically acceptable salt, or solvate, or prodrug:
  • n, m are independently taken from 0, 1 or 2;
  • L is O, -C(O)-, -C(O)NH-, -CH 2 -, S, S(O), NH or S(O) 2 ;
  • A is derived from a substituted or unsubstituted benzene ring, or a substituted or unsubstituted heteroaryl ring, and a linking site to the parent nucleus and L may be optional;
  • B is independently taken from a substituted or unsubstituted aliphatic ring, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted benzene ring, or a substituted or unsubstituted heteroaryl ring, and the linking site with L may be optionally selected ;
  • R 1 and R 2 are each independently selected from hydrogen, unsubstituted C1-C4 alkyl, halogen, cyano, or R 1 and R 2 together with the carbon atom to which they are attached form a ternary carbocyclic or quaternary carbocyclic ring, Or R 1 and R 2 are combined into an oxo group;
  • Y is selected from cyano, or
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, unsubstituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, C1-C4 alkoxy C1-4 alkyl, halogen, a cyano group, or -(CH 2 ) q N(R a R b ), wherein q is 1, 2, 3, or 4, and R a and R b are each independently selected from hydrogen, unsubstituted C1-C4 alkane base;
  • R 1 and R 2 are hydrogen, A is a phenyl group, L is O, and B is 4-chlorophenyl, 3-chloropyridin-6-yl, 2,4-difluorophenyl; Y Is 4-hydroxybut-2-enoyl, but-2-ynyl, or cyano;
  • R 1 and R 2 are hydrogen, A is phenyl, L is C(O)-, or -CH 2 -, B is morpholin-4-yl; Y is cyano;
  • R 1 and R 2 are hydrogen
  • A is pyrazolyl
  • L is S(O) 2 , or -CH 2 -
  • B is phenyl or cyclopropyl
  • Y is cyano
  • R 1 and R 2 are hydrogen
  • A is a pyridyl group
  • L is NH or O
  • B is pyran-4-yl or cyclohexyl
  • Y is a cyano group
  • an embodiment of the present invention provides a pyrazolopyrimidine compound of the formula (I), wherein n, m are independently taken from 0, 1 or 2; , -C(O)-, -C(O)NH-, -CH 2 -, NH or S, more preferably O, -C(O)NH-, NH.
  • an embodiment of the present invention provides a pyrazolopyrimidine compound of the formula (I), wherein A is derived from a substituted or unsubstituted benzene or heteroaryl ring, and The attachment site to the parent nucleus and L may be optionally selected; B is independently derived from a substituted or unsubstituted aliphatic ring, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted benzene ring, or a substituted or unsubstituted hetero An aromatic ring, and a linking site with L can be optionally selected; wherein:
  • the substituted benzene ring means that any position on the benzene ring is substituted with an optional substituent selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethyl.
  • an optional substituent selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethyl.
  • the unsubstituted heteroaryl ring means furan, pyrrole, thiophene, oxazole, isoxazole, pyrazole, imidazole, thiazole, isothiazole, oxadiazole, triazole, thiadiazole, tetrazolium, pyridine , pyrimidine, pyrazine, pyridazine, triazine; said substituted heteroaryl ring means that any position on the above group is substituted by an optional substituent selected from the group consisting of hydrogen, methyl, methoxy a radical, a fluorine, a chlorine, a trifluoromethyl group, a trifluoromethoxy group or a cyano group; more preferably, the substituted pyridine is a chloropyridine, particularly preferably a 4-chloro-pyridin-2-yl group;
  • the unsubstituted aliphatic ring means cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane; the substituted aliphatic ring means any position on the above group is optionally selected Substituted by a substituent selected from hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy or cyano;
  • the unsubstituted heterocyclic ring means tetrahydrofuran, tetrahydropyran, tetrahydropyrrole, piperidine, Wherein w is taken from 0, 1 or 2; the substituted heterocyclic ring means that any position on the above group is substituted by an optional substituent selected from the group consisting of hydrogen, methyl, methoxy, and fluorine. , chlorine, trifluoromethyl, trifluoromethoxy or cyano.
  • an embodiment of the present invention provides a pyrazolopyrimidine compound of the formula (I), wherein preferably, one of R 1 and R 2 is hydrogen and the other is Unsubstituted C1-C4 alkyl (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl), or R 1 and R 2 together with the carbon atom to which they are attached
  • the cyclopropyl group is formed; more preferably, both R 1 and R 2 are hydrogen, or one of them is hydrogen and the other is methyl, or R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl group.
  • an embodiment of the invention provides a pyrazolopyrimidine compound of formula (II), a stereoisomer, tautomer thereof, or pharmaceutically acceptable Salt, or solvate, or prodrug:
  • L, A, B and Y are as defined above for formula (I);
  • A is a phenyl group, L is O, B is 4-chlorophenyl, 3-chloropyridin-6-yl, 2,4-difluorophenyl; Y is 4-hydroxybut-2-enoyl, But-2-ynyl, or cyano;
  • A is phenyl, L is C(O)-, or -CH 2 -, B is morpholin-4-yl; Y is cyano;
  • A is pyrazolyl
  • L is S(O) 2 or -CH 2 -
  • B is phenyl or cyclopropyl
  • Y is cyano
  • A is a pyridyl group
  • L is NH or O
  • B is pyran-4-yl or cyclohexyl
  • Y is a cyano group.
  • a pyrazolopyrimidine compound of the formula (II) according to an embodiment of the present invention is one of the following compounds:
  • L, B and Y in the formula (II-1) or (II-2) are as defined in the above formula (I);
  • L is O
  • B is 4-chlorophenyl, 3-chloropyridin-6-yl, 2,4-difluorophenyl
  • Y is 4-hydroxybut-2-enoyl, but-2-yne An acyl group or a cyano group
  • L is C(O)-, or -CH 2 -
  • B is morpholin-4-yl
  • Y is cyano
  • an embodiment of the invention provides a pyrazolopyrimidine compound of formula (III), a stereoisomer, tautomer thereof, or pharmaceutically acceptable Salt, or solvate, or prodrug:
  • L, A, B and Y are as defined in the above formula (I).
  • a pyrazolopyrimidine compound of the formula (III) is one of the following compounds:
  • L, B and Y in the formulae (III-1), (III-2), (III-3) and (III-4) are as defined in the above formula (I).
  • an embodiment of the invention provides a pyrazolopyrimidine compound of formula (IV), a stereoisomer, tautomer thereof, or pharmaceutically acceptable Salt, or solvate, or prodrug:
  • L, A, B and Y are as defined in the above formula (I).
  • a pyrazolopyrimidine compound of the formula (IV) provided by an embodiment of the present invention is one of the following compounds:
  • L, B and Y in the formula (IV-1) or (IV-2) are as defined in the above formula (I).
  • Y is selected from cyano, or
  • R 3 , R 4 , R 5 and R 6 are each independently selected from unsubstituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, C1-C4 alkoxy C1-4 alkyl, halogen, cyano, Or -(CH 2 ) q N(R a R b ), wherein q is 1, 2, 3, or 4, and R a and R b are each independently selected from hydrogen, unsubstituted C1-C4 alkyl.
  • an embodiment of the present invention provides a pyrazolopyrimidine compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or one of the following compounds medicine:
  • the "pharmaceutically acceptable salt” refers to a pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable base addition salt:
  • the "pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid capable of retaining the bioavailability of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, propionate, glycolate, gluconate , lactate, oxalate, maleate, succinate, fumarate, tartrate, citrate, glutamate, aspartate, benzoate, methanesulfonate , p-toluenesulfonate and salicylate. These salts can be prepared by methods known in the art.
  • the "pharmaceutically acceptable base addition salt” refers to a salt capable of maintaining the bioavailability of the free acid without other side effects. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, calcium and magnesium salts and the like. Salts derived from organic bases include, but are not limited to, ammonium salts, triethylamine salts, lysine salts, arginine salts, and the like. These salts can be prepared by methods known in the art.
  • the "solvate” refers to a complex of a compound of an embodiment of the invention with a solvent. They either react in a solvent or precipitate out of a solvent or Crystallize out.
  • a complex formed with water is referred to as a "hydrate.”
  • the compounds of the embodiments of the invention may contain one or more chiral centers and exist in different optically active forms.
  • the compound contains a chiral center, the compound contains the enantiomer.
  • Embodiments of the invention include 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 the compound of formula (I) contains more than one chiral center, diastereomers may be present.
  • Embodiments 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.
  • the prodrug refers to a known amino protecting group and a carboxy protecting group which are hydrolyzed under physiological conditions or released via an enzymatic reaction to give the parent compound.
  • Specific prodrug preparation methods can be referred to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990. Greenwald, RB; Choe, YH Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • an embodiment of the present invention provides a method for preparing the pyrazolopyrimidine compound represented by the above formula (I), comprising the steps of:
  • Suitable amino protecting groups include trifluoroacetyl (-COCF3) which can be removed by base catalyzed hydrolysis to remove benzyloxy, carbonyl or tert-butoxycarbonyl.
  • -COCF3 trifluoroacetyl
  • X is chlorine, bromine or hydroxyl.
  • the present invention provides a method for producing a pyrazolopyrimidine compound represented by the above formula (I), wherein the compound of the formula (V) can be produced by referring to the following method:
  • embodiments of the invention also provide intermediate compounds for use in the synthesis of the above pyrazolopyrimidine compounds, including but not limited to:
  • Bn is a benzyl group and Boc is a tert-butoxycarbonyl group.
  • the present invention provides an excipient, a stereoisomer, a solvate or a pharmaceutically thereof thereof, comprising an effective amount of one or more of the pyrazolopyrimidine compounds of the present invention or a stereoisomer thereof A pharmaceutical composition of an acceptable salt, the pharmaceutical composition further comprising a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition of the embodiment of the present invention may be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet, a capsule, a powder, a granule, a plaster, a solution, a suppository, an injection, an inhalant, a gel, and a micro Balls and aerosols.
  • a solid, semi-solid, liquid or gaseous preparation such as a tablet, a capsule, a powder, a granule, a plaster, a solution, a suppository, an injection, an inhalant, a gel, and a micro Balls and aerosols.
  • compositions of the embodiments of the present invention can be prepared by methods well known in the pharmaceutical art.
  • practical methods for preparing pharmaceutical compositions are known to those skilled in the art, for example, see The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000).
  • Routes of administration of the pharmaceutical compositions of the embodiments of the invention include, but are not limited to, oral, topical, transdermal, intramuscular, intravenous, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal.
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compound of formula (I) of the embodiments of the invention included in these formulations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion, and the like.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • the above carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include, but are not limited to, water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or suspension with the above carriers. The particular mode of administration and dosage form will depend on the physicochemical properties of the compound itself, as well as the severity of the disease being applied.
  • compositions of the embodiments of the invention may be presented in unit dosage form containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage compositions are those containing a daily or sub-dose, or an appropriate fraction thereof, of the active ingredient. Thus, such unit doses can be administered more than once a day.
  • Preferred unit dosage compositions are those containing a daily or sub-dose (more than one administration per day) as described above, or an appropriate fraction thereof, of the active ingredient.
  • compositions of the embodiments of the invention are formulated, quantified, and administered in a manner consistent with medical practice.
  • a "therapeutically effective amount" of a compound of an embodiment of the invention is determined by the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • the dose for parenteral administration may be 1-200 mg/kg
  • the dose for oral administration may be 1-1000 mg/kg.
  • the present invention provides the above pyrazolopyrimidine compound or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof for use in the prevention or treatment of BTK-mediated Use in medicines for diseases.
  • Embodiments of the present invention provide a method of inhibiting BTK activity, comprising administering to a biological system, the pyrazolopyrimidine compound of the present invention, or a stereoisomer, tautomer, solvate thereof, or a pharmaceutically acceptable thereof thereof.
  • a salt or a pharmaceutical composition comprising the above pyrazolopyrimidine compound of the present invention or a stereoisomer, tautomer, solvate thereof or a pharmaceutically acceptable salt thereof.
  • the biological system is an enzyme, a cell, or a mammal.
  • Embodiments of the present invention also provide a method of preventing or treating a disease mediated by BTK comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the above pyrazolopyrimidine compounds of the present invention.
  • the BTK mediated diseases include autoimmune diseases, inflammatory diseases, xenogeneic immune conditions or diseases, thromboembolic diseases, and cancer.
  • the cancer comprises B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute myeloid leukemia, diffuse large B-cell lymphoma , multiple myeloma, mantle cell lymphoma, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, solid tumor.
  • the autoimmune disease and inflammatory disease are selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile arthritis, chronic obstructive pulmonary disease, multiple sclerosis, systemic lupus erythematosus, psoriasis , psoriatic arthritis, Crohn's disease, ulcerative colitis, and irritable bowel syndrome.
  • the xenogeneic immune condition or disease comprises graft versus host disease, transplantation, blood transfusion, allergic reaction, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis or atopy dermatitis.
  • the unit of temperature is Celsius (°C); the definition of room temperature is 18-25 ° C;
  • 200-300 mesh silica gel is used as a carrier for rapid column chromatography, and thin layer chromatography is used for thin layer chromatography;
  • the progress of the reaction is monitored by thin layer chromatography or LC-MS;
  • the identification of the final product was performed by nuclear magnetic resonance (Bruker AVANCE 300, 300 MHz) and LC-MS (Bruker esquine 6000, Agilent 1200 series).
  • Example 2 Taking the product of the third step reaction of Example 1 as a starting material, Example 2 was prepared by the following steps:
  • Example 3 was prepared in a similar manner to Example 1 starting from the corresponding starting material.
  • Example 4 was prepared in a similar manner to Example 2 starting from the corresponding starting material.
  • Example 5 was prepared in a similar manner to Example 1 starting from the corresponding starting material.
  • Example 6 was prepared in a similar manner to Example 2 starting from the corresponding starting material.
  • the third step is the preparation of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester:
  • the fifth step is 3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(6-methylpiperidin-3-yl)-1H-pyrazolo[3,4 -d]Preparation of pyrimidine-4-amine hydrochloride:
  • Example 8 was prepared by the following steps:
  • Example 9 was prepared in a similar manner to Example 7 starting from the corresponding starting material.
  • Example 10 was prepared by chiral resolution of the product of Example 7.
  • the resolution conditions were: Supercritical fluid chromatography (ChiralPak AD 5 ⁇ , 21 x 250 mm col, 27% methanol, 70 mL/min).
  • Example 11 was prepared by chiral resolution of the product of Example 8.
  • the resolution conditions were: Supercritical fluid chromatography (ChiralPak AD 5 ⁇ , 21 x 250 mm col, 27% methanol, 70 mL/min).
  • Example 12 was prepared by chiral resolution of the product of Example 9. The resolution conditions were: Supercritical fluid chromatography (ChiralPak AD 5 ⁇ , 21 x 250 mm col, 27% methanol, 70 mL/min).
  • the second step is the preparation of methyl 4-oxobutanoate:
  • the third step is the preparation of methyl 4-hydroxy-5-nitropentanoate:
  • the fourth step is the preparation of 5-hydroxypiperidin-2-one:
  • 6-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-azaspiro[2.5]octane-4-carboxylic acid tert-butyl ester 500 mg, 1.1 mmol
  • 5-chloro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine 500 mg, 1.5 mmol was dissolved in 95% ethanol (20 mL).
  • Example 14 was obtained by chiral resolution of the product of the twelfth step of Example 13.
  • the resolution conditions were: Supercritical fluid chromatography (ChiralPak AD 5 ⁇ , 21 x 250 mm col, 27% methanol, 70 mL/min).
  • Example 15 Starting from the product of the eleventh step of Example 13, the preparation of Example 15 was carried out by the following procedure:
  • the compound of Example 15 was obtained after chiral resolution of the compound of Example 15.
  • the resolution conditions were: Supercritical fluid chromatography (ChiralPak AD 5 ⁇ , 21 x 250 mm col, 27% methanol, 70 mL/min).
  • Example 17 was prepared in a similar manner to Example 13 starting from the corresponding starting material.
  • Example 18 was prepared in a similar manner to Example 15 starting from the corresponding starting material.
  • Example 19 Starting from the corresponding starting material, 5-(4-amino-3-(4-(4-chlorophenoxy)phenyl)-1H-pyrazole was prepared in the same manner as in Example 7. [3,4-d]Pyridine-1-yl)-2-methylpiperidine-1-carbonitrile, which was obtained by chiral resolution to give compounds WS-323 and WS-324.
  • the resolution conditions were: Supercritical fluid chromatography (ChiralPak AD 5 ⁇ , 21 x 250 mm col, 27% methanol, 70 mL/min).
  • Example 20 was prepared starting from the corresponding starting material in a similar manner to Example 9 to give 5-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4- d]pyrimidin-1-yl)-2-methylpiperidine-1-carbonitrile, which was chirally resolved to give compounds WS-325 and WS-326.
  • the resolution conditions were: Supercritical fluid chromatography (ChiralPak AD 5 ⁇ , 21 x 250 mm col, 27% methanol, 70 mL/min).
  • Example 21 was prepared by the following procedure:
  • Example 22 was prepared by the following procedure:
  • Example 23 was prepared in a similar manner to Example 21 starting from the corresponding starting material.
  • Example 24 was prepared in a similar manner to Example 22 starting from the corresponding starting material.
  • Example 25 Starting from the product of the eleventh step of Example 13, the preparation of Example 25 was carried out by the following procedure:
  • Example 26 was prepared in a similar manner to Example 22 starting from the corresponding starting material.
  • Example 27 was prepared in a similar manner to Example 21 starting from the corresponding starting material.
  • Example 28 was prepared in a similar manner to Example 1 starting from the corresponding starting material.
  • Example 29 was prepared in a similar manner to Example 7 starting from the corresponding starting material.
  • Example 30 was prepared in a similar manner to Example 7 starting from the corresponding starting material.
  • Example 31 was prepared in a similar manner to Example 7 starting from the corresponding starting material.
  • Example 32 was prepared in a similar manner to Example 7 starting from the corresponding starting material.
  • Example 33 was prepared in a similar manner to Example 21 starting from the corresponding starting material.
  • Example 34 was prepared in a similar manner to Example 26 starting from the corresponding starting material.
  • Example 35 was prepared in a similar manner to Example 21 starting from the corresponding starting material.
  • Example 36 was prepared in a similar manner to Example 1 starting from the corresponding starting material.
  • Example 36 Compounds of Example 36 were resolved by chirality to afford compounds WS-353 and WS-354 of Example 37.
  • the resolution conditions were: Supercritical fluid chromatography (ChiralPak AD 5 ⁇ , 21 x 250 mm col, 27% methanol, 70 mL/min).
  • Examples 38 to 47 can be produced by a method similar to that of Examples 1 to 37 of the present patents.
  • BTK kinase activity was tested in a test based on a time resolved fluorescence resonance energy transfer method.
  • Recombinant Btk and the compounds disclosed herein are tested at room temperature in a test buffer containing 50 mM Tris pH 7.4, 10 mM MgCl 2 , 2 mM MnCl 2 , 0.1 mM EDTA, 1 mM DTT, 20 nM SEB, 0.1% BSA, 0.005% tween-20
  • the solution was incubated for 1 hour in advance. The reaction was initiated by the addition of ATP (at ATP Km concentration) and the peptide substrate (Biotin-AVLESEEELYSSARQ-NH2).
  • the kinase inhibitory activity levels are classified into A, B, C, specifically A (IC 50 ⁇ 100 nM), B (100 nM ⁇ IC 50 ⁇ 1000 nM), C (IC 50 >1000 nM)
  • the detection platform of EGFR and ITK kinase activity was established by time-resolved fluorescence resonance energy transfer method.
  • the detection platform of LCK, SRC and LYN kinase activity was established by Z'-Lyte method.
  • the detection platform of TEC and JAK3 kinase activity was established by Lance Ultra method.
  • the compounds disclosed herein were tested for inhibition of different kinase activities, respectively. Each compound activity data were determined at 11 concentrations of the compound IC 50 value calculated using Graphpad Prism software.
  • the kinase inhibitory activity levels are classified into A, B, C, specifically A (IC 50 ⁇ 100 nM), B (100 nM ⁇ IC 50 ⁇ 1000 nM), C (IC 50 >1000 nM)
  • CD B cells were purified from healthy donor blood by negative selection using the RosetteSep Human B Cell Enrichment Mix. Cells were plated in growth medium (10% RPMI + 10% fetal bovine serum) and inhibitors of the indicated concentrations were added. After incubating for 1 hour at 37 ° C, the cells were washed three times, and each wash was used for 8-fold dilution in growth medium. The cells were then stimulated with 10 ⁇ g/mL IgM F(ab') 2 for 18 hours at 37 °C. Cells were subsequently stained with anti-CD69-PE antibody and analyzed by flow cytometry using standard conditions. According to the above method, the preferred compound of the present application has a strong inhibitory activity against B cells and has an IC 50 value of less than 1 nM.
  • CD T cells were purified from healthy donor blood by negative selection using the RosetteSep Human T Cell Enrichment Mix. Cells were plated in growth medium (10% RPMI + 10% fetal bovine serum) and inhibitors of the indicated concentrations were added. After incubating for 1 hour at 37 ° C, the cells were washed three times, and each wash was used for 10-fold dilution in growth medium. The cells were then challenged with anti-CD3/CD28 coated beads (bead/cell ratio of 1:1) for 18 hours at 37 °C. Cells were subsequently stained with anti-CD69-PE antibody and analyzed by flow cytometry using standard conditions.
  • the preferred compound in the present application has a weak inhibitory activity or no inhibition on T cells, and its IC 50 value is greater than 4000 nM.
  • Human whole blood was obtained from healthy volunteers and blood was collected by venipuncture into a Vacutainer tube that was anticoagulated with sodium heparin. Test compounds were diluted to 10 times the required initial drug concentration in PBS), followed by three-fold serial dilutions in 10% DMSO in PBS to give a 9 point dose response curve. 5.5 ⁇ L of each compound dilution was added to the aiil 96-well V-bottom plate in duplicate; 5.5 ⁇ L of 10% DMSO in PBS was added to the control and non-stimulated wells. Human whole blood (100 ⁇ L) was added to each well, and after mixing, the plates were incubated for 30 minutes at 37 C, 5% CO 2 , 100% humidity.
  • the sample was then lysed with 1 ml of IX Pharmingen Lyse Buffer (BD Pharmingen) and the plate was centrifuged at 1500 rpm for 5 minutes. The supernatant was removed by aspiration, and the remaining pellet was again lysed with an additional 1 ml of IX Pharmingen Lyse Buffer, and the plate was centrifuged as before. The supernatant was aspirated and the remaining pellet was washed in FACs buffer (PBS + 1% FBQ. After centrifugation and the supernatant was removed, the pellet was resuspended in 150 ⁇ L of FACs buffer. Transfer the sample to a suitable one.
  • IX Pharmingen Lyse Buffer BD Pharmingen
  • 96-well plates run on the HTS 96-well system of the BD LSR II flow cytometer. Data were acquired using excitation and emission wavelengths appropriate for the fluorophore used and percent positive cells were obtained using Cell Quest Software. Results were initially analyzed using FACS analysis (Flow Jo) Analysis. IC 50 values were calculated using XLfit v3, Equation 201.
  • the preferred compound of the present application has a strong inhibitory activity against B cells in human whole blood, and its IC 50 value is less than 200 nM.
  • test compound was dissolved in acetonitrile to prepare a stock solution having a concentration of 0.5 mM.
  • step 3 Prepare the mixed system in step 2, pre-incubated for 3 minutes in a 37 ° C water bath, then add 40 ⁇ L of NADPH production system (containing NADP +: 6.5 mM, glucose 6-phosphate: 16.5 mM, MgCl 2 : 16.5 mM, glucose 6 - Phosphate dehydrogenase: 2 U/ml) The reaction was initiated and incubated for 1 hour in a 37 ° C water bath.
  • NADPH production system containing NADP +: 6.5 mM, glucose 6-phosphate: 16.5 mM, MgCl 2 : 16.5 mM, glucose 6 - Phosphate dehydrogenase: 2 U/ml
  • Preparation method of parallel preparation 0 minute reaction sample The prepared mixed system in step 2 was taken out in a 37 ° C water bath for 3 minutes, and then taken out, 400 ⁇ L of acetonitrile was added, and then 40 ⁇ L of NADPH generation system was added. After vortexing for 3 minutes, centrifugation (13,000 rpm, 4 ° C) for 5 minutes, and the supernatant was taken to detect the drug concentration C0 by HPLC.
  • the preferred compounds of the present application exhibit better microsomal stability with a residual percentage > 30% in liver microsomes of various genera.
  • CYP enzyme metabolism is the main pathway for drug biotransformation, and its quantity and activity directly affect the activation and metabolism of drugs in the body.
  • cytochrome CYP is an important drug phase I metabolizing enzyme that catalyzes the oxidation and reductive metabolism of various exogenous compounds.
  • the CYP enzyme plays a very important role in the elimination of the drug, and is also the main factor in the drug interaction caused by the combination.
  • METHODS This experiment used the cocktail probe drug method to simultaneously determine the inhibitory effect of compounds on five CYP450 enzymes in human liver microsomes.
  • the human microsomes were from BD Gentest.
  • the reaction was carried out in 100 mM phosphate buffer in a total volume of 200 ⁇ L.
  • the concentration of the microsomes in the reaction system was 0.25 mg/mL, and the concentration of the test compound was 20 ⁇ M, 6.67 ⁇ M, 2.22 ⁇ M, 0.74 ⁇ M, 0.25 ⁇ M.
  • the specific probe substrate and concentration were phenacetin (CYP1A2) 40 ⁇ M, respectively.
  • the incubation system was pre-incubated for 5 minutes in a 37-degree constant temperature shaker, and the reaction was started by adding a NADPH-producing system (containing 1.3 mM NADP+, 3.3 mM glucose 6-phosphate, 0.4 U/L glucose 6-phosphate dehydrogenase, 3.3 mM MgCL2). After incubation for 45 min, the reaction was stopped by adding an equal volume of acetonitrile, vortexed, centrifuged at 13,000 rpm, and the supernatant was subjected to LC-MS-MS injection to determine the amount of metabolite production.
  • a NADPH-producing system containing 1.3 mM NADP+, 3.3 mM glucose 6-phosphate, 0.4 U/L glucose 6-phosphate dehydrogenase, 3.3 mM MgCL2. After incubation for 45 min, the reaction was stopped by adding an equal volume of acetonitrile, vortexed, centrifuged at 13,000 rpm, and
  • the specific metabolites were acetaminophen (CYP1A2), dextrorphan (CYP2D6), 4-hydroxydiclofenac (CYP2C9), 4-hydroxyfenfenin (CYP2C19), and 6 ⁇ -hydroxytestosterone (CYP3A4).
  • the specific inhibitors were furaphylline (CYP1A2), quinidine (CYP2D6), sulfaphenazole (CYP2C9), tranylcypromine (CYP2C19), ketoconazole (CYP3A4).
  • the end result of this experiment the concentration IC 50 values of inhibition calculated half.
  • IC 50 ((50% - low inhibition rate %) / (high inhibition rate % - low inhibition rate %)) x (high concentration - low concentration) + low concentration.
  • the collected blood samples were centrifuged at 12000 rpm for 5 minutes at 4 ° C, then the upper plasma samples were collected and stored in a refrigerator at -20 ° C for testing.
  • LC-MS/MS liquid phase Waters Acquity UPLC (USA) and mass spectrometry 5500Q Trap (Applied Biosystem/MDS SCIEX) or HPLC-MS ⁇ MS: liquid phase Agilent 1200 series (USA) and mass spectrometry API 4000 (Applied Biosystem/MDS SCIEX) detects the concentration of compounds in plasma. Typical test conditions are shown in the table below.
  • the compounds which have been determined in the present application exhibit a good bioavailability (>40%).
  • IC 50 values may be determined for a compound hERG inhibition. Only weak inhibition present in preferred compounds of the application or no hERG inhibition, an IC 50 value greater than 1000nM.
  • a novel pyrazolopyrimidine derivative provided by an embodiment of the present invention is a protein kinase BTK An effective, safe, and highly selective inhibitor that can be used as a drug for the treatment of BTK-mediated diseases.

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Abstract

L'invention concerne un nouveau composé de pyrazolopyrimidine tel que présenté dans la formule (I), et un stéréoisomère, ou un sel pharmaceutiquement acceptable, ou un solvate, ou un promédicament de celui-ci. L'invention concerne également un procédé de préparation du composé, une composition pharmaceutique et une utilisation associées.
PCT/CN2017/081905 2016-05-16 2017-04-25 Dérivé de pyrazolopyrimidine utilisé en tant qu'inhibiteur de la btk et procédé de préparation et composition pharmaceutique associés WO2017198049A1 (fr)

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US11352339B2 (en) 2016-03-24 2022-06-07 Mission Therapeutics Limited 1-cyano-pyrrolidine derivatives as DUB inhibitors

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CN111153906B (zh) * 2016-05-16 2020-09-11 苏州信诺维医药科技有限公司 作为btk抑制剂的吡唑并嘧啶衍生物及其制备方法和药物组合物
AU2018364183B2 (en) 2017-11-10 2020-10-15 Sinomab Bioscience Limited Crystal form I of a 5-aminopyrazole carboxamide compound as BTK inhibitor
CN115417827B (zh) * 2022-09-30 2023-05-26 中国药科大学 6-氨基-1,3,5-三嗪类化合物及其合成方法和应用

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