WO2019091441A1 - Composé 5-amino pyrazole carboxamide en tant qu'inhibiteur de btk et son procédé de préparation - Google Patents

Composé 5-amino pyrazole carboxamide en tant qu'inhibiteur de btk et son procédé de préparation Download PDF

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WO2019091441A1
WO2019091441A1 PCT/CN2018/114669 CN2018114669W WO2019091441A1 WO 2019091441 A1 WO2019091441 A1 WO 2019091441A1 CN 2018114669 W CN2018114669 W CN 2018114669W WO 2019091441 A1 WO2019091441 A1 WO 2019091441A1
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compound
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substituted
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吴予川
黄少强
陈曦
胡永韩
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苏州信诺维医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 invention belongs to the technical field of medicinal chemistry, in particular to a novel high-efficiency, selective and good pharmacokinetic property, 5-aminopyrazolecarboxamide compound as a BTK inhibitor and preparation method thereof .
  • 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.
  • 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 5-aminopyrazole carboxamide derivative which is an effective, safe and highly selective inhibitor of protein kinase BTK.
  • a second object of the present invention is to provide a process for the preparation of the above derivatives.
  • a third object of the present invention is to provide a pharmaceutical composition containing the above derivative.
  • a fourth object of the invention is to provide the use of the above derivatives.
  • the present invention provides a novel 5-aminopyrazolecarboxamide compound or a pharmaceutically acceptable salt of the formula (I):
  • n, m are independently taken from 0, 1 or 2;
  • L is O, -C(O)NH-, -CH 2 -, S, S(O), NH or S(O) 2 ;
  • A is derived from a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted benzene ring, or a substituted or unsubstituted heteroaryl ring, and a linking site to the mother nucleus and L may be optionally selected;
  • 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, 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 group
  • 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 ), where 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 and the other is methyl, and Y is a cyano group
  • A is a benzene ring, L is O, m is 1 and n is 2
  • B is not substituted or unsubstituted a benzene ring
  • R 1 and R 2 are hydrogen, and A is a benzene ring, m is 1 and n is 2
  • B is not a substituted or unsubstituted benzene ring, and a substituted or unsubstituted pyridine
  • R 1 And R 2 is hydrogen, and A is a pyridine ring, m is 1 and n is 2, B is not a substituted or unsubstituted benzene ring;
  • R 1 and R 2 are both hydrogen, and A is a benzene ring, L is When O, m is 1 and n is 1, B is not a substituted or unsubstituted benzene ring.
  • the present invention provides a 5-aminopyrazolecarboxamide compound of the formula (I), wherein n, m are independently taken from 0, 1 or 2; Is O, -C(O)NH-, -CH 2 -, NH or S, more preferably O, -C(O)NH-, NH.
  • the substituted benzene ring means that any position on the phenyl group is substituted with an optional substituent selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethyl.
  • An oxy or cyano group preferably, the substituted benzene ring is a fluoro substituted phenyl group, or a chloro substituted phenyl group, more preferably a 2,4-difluorophenyl group, or a 4-chlorophenyl group;
  • 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.
  • the present invention provides a 5-aminopyrazolecarboxamide compound of the formula (I), wherein, preferably, both R 1 and R 2 are hydrogen, or one of them Is hydrogen and the other is C1-C4 alkyl (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl), or R 1 and R 2 are attached to them
  • the present invention provides a 5-aminopyrazolecarboxamide compound represented by formula (II) or a pharmaceutically acceptable salt thereof:
  • L, A, B and Y are as defined above for the formula (I);
  • the 5-aminopyrazolecarboxamide compound of the formula (II) provided by the present invention is one of the following compounds:
  • B is not a substituted or unsubstituted benzene ring, and a substituted or unsubstituted pyridine.
  • the present invention provides a 5-aminopyrazolecarboxamide compound represented by formula (III) or a pharmaceutically acceptable salt thereof:
  • L, A, B and Y are as defined above for the formula (I);
  • the 5-aminopyrazolecarboxamide compound of the formula (III) provided by the present invention is one of the following compounds:
  • the present invention provides a 5-aminopyrazolecarboxamide compound represented by formula (IV) or a pharmaceutically acceptable salt thereof:
  • L, A, B, and Y are as defined in the above formula (I).
  • the 5-aminopyrazolecarboxamide compound of the formula (IV) provided by the present invention is the following compound:
  • L, B and Y in the formula (IV-1) are as defined in the above formula (I).
  • the invention provides formula (I), (II), (II-1), (III), (III-1), (III-2), (IV) Or (IV-1), wherein L is O;
  • Y is -CN
  • 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, cyano, or -(CH 2 ) q N(R a R b ), where q is 1, 2, 3, or 4, and R a and R b are each independently selected from hydrogen, unsubstituted C1- C4 alkyl.
  • the 5-aminopyrazole carboxamide compound provided by the invention is selected from one of the following compounds:
  • 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 present invention provides a process for the preparation of the 5-aminopyrazolecarboxamide compound represented by the above formula (I), comprising the steps of:
  • PG is an amino protecting group (suitable amino protecting groups include acyl (eg acetyl), carbamate (eg 2', 2', 2'- Trichloroethoxycarbonyl, Cbzbenzyloxycarbonyl or BOC-tert-butoxycarbonyl) and arylalkyl (for example Bnbenzyl) which may be hydrolyzed, if appropriate (for example using diacids such as hydrogen chloride) Solution or trifluoroacetic acid in dichloromethane) or by reduction (eg hydrogenolysis of benzyl or benzyloxycarbonyl, or reduction of 2', 2', 2'-trichloroethoxy by zinc in acetic acid
  • suitable amino protecting groups include acyl (eg acetyl), carbamate (eg 2', 2', 2'- Trichloroethoxycarbonyl, Cbzbenzyloxycarbonyl or BOC-tert-butoxycarbonyl) and aryl
  • the reaction is preferably carried out under basic conditions, wherein the base is selected from the group consisting of organic bases and inorganic bases which are common in the art;
  • the organic base may be selected, for example, from DIPEA, triethylamine, pyridine, DBN, DBU. , piperidine, 4-dimethylaminopiperidine, etc.
  • the inorganic base may be selected, for example, from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, carbonic acid Potassium, cesium carbonate, sodium hydrogencarbonate, and the like.
  • the reaction is preferably carried out under acidic conditions, wherein the acid may be selected, for example, from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, formic acid, acetic acid, trifluoroacetic acid, benzene.
  • the reaction temperature may be in the range of 0-100 ° C, preferably in the range of 0-50 ° C, more preferably in the range of 20-30 ° C.
  • the reaction can be carried out under the conditions of deprotection groups which are common in the art.
  • the reaction is carried out under basic conditions, wherein the base is selected from the group consisting of organic bases and inorganic bases which are common in the art.
  • the organic base may be selected, for example, from DIPEA, triethylamine, pyridine, DBN, DBU, piperidine, 4-dimethylaminopiperidine, N-methylmorpholine or the like;
  • the inorganic base may be selected, for example, from lithium hydroxide or sodium hydroxide. , potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate, and the like.
  • the present invention provides a process for producing a 5-aminopyrazolecarboxamide compound represented by the above formula (I), wherein the compound of the formula (VI) can be obtained by:
  • R 4 in the above compound is a C 1 -C 4 alkyl group (preferably a methyl group);
  • X is chlorine or bromine, preferably chlorine; and
  • R 3 is a C 1 -C 4 alkyl group ( Preferably ethyl);
  • L, A and B are as defined for the compound of formula (I);
  • the compound (VI-1) is subjected to hydrolysis reaction under basic conditions to obtain a compound (VI-2), which is then reacted with an acid halide reagent to obtain a compound (VI-3) wherein the acid halide reagent includes a chloride Sulfone, oxalyl chloride, triphosgene, phosphorus oxychloride, phosphorus pentachloride, and the like.
  • the acid halide reagent includes a chloride Sulfone, oxalyl chloride, triphosgene, phosphorus oxychloride, phosphorus pentachloride, and the like.
  • compound (VI-3) is then reacted with malononitrile under basic conditions to obtain compound (VI-4) wherein the base is selected from the group consisting of n-butyl lithium, methyl lithium, hexamethyldisilazide sodium, and six Methyldisilazide potassium, sodium amide, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, carbonic acid Hydrazine, sodium hydrogencarbonate, triethylamine, trimethylamine, pyridine, DBN, DBU, piperidine, 4-dimethylaminopiperidine, N-methylmorpholine and the like.
  • the base is selected from the group consisting of n-butyl lithium, methyl lithium, hexamethyldisilazide sodium, and six Methyldisilazide potassium, sodium amide, sodium hydr
  • the compound VI-4 is reacted with (R 3 O) 3 CH in the presence of acetic anhydride to obtain the compound (VI), and the reaction temperature is in the range of room temperature to 150 ° C, preferably in the range of 50 to 150 ° C, It is preferably in the range of 100 to 150 °C.
  • the above 5-aminopyrazolecarboxamide compound provided by the present invention is a production method represented by the formula (I), wherein the compound of the formula (V) can be produced by referring to the following method:
  • PG 1 and PG 3 are defined as PG.
  • PG 2 is a hydroxy protecting group including, but not limited to, an ether protecting group (eg, benzyl, methoxymethyl, methoxyethyl), a silyl ether protecting group (eg, TBS, TES, TBDMS, etc.), an ester-forming protecting group (benzoyl, p-nitrobenzoyl, trifluoroacetyl) and the like.
  • ether protecting group eg, benzyl, methoxymethyl, methoxyethyl
  • silyl ether protecting group eg, TBS, TES, TBDMS, etc.
  • an ester-forming protecting group benzoyl, p-nitrobenzoyl, trifluoroacetyl
  • a common hydroxy protecting group can be referred to TW Greene 'Protective Groups in Organic Synthesis' (4th edition, J. Wiley and Sons, 2006).
  • the compound of the formula (V) can be produced by referring to the following methods:
  • the oxidizing agent used in the oxidation reaction includes RuCl 3 H 2 O/NaIO 4 , diacetoxyiodobenzene/t-butane hydroperoxide, potassium permanganate, iodine/sodium hydrogencarbonate, potassium dichromate, etc.
  • the reagents used in the hydrogenation reaction include lithium aluminum hydride, aluminum hydride, platinum dioxide, diisobutylaluminum hydride, sodium borohydride, copper chrome oxide, Raney nickel, and the like.
  • the compound of the formula (V) can be produced by referring to the following methods:
  • the present invention provides a pharmaceutical composition comprising an effective amount of one or more of the above 5-aminopyrazolecarboxamide compounds of the present invention or a pharmaceutically acceptable salt thereof, the pharmaceutical composition further comprising A pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and Aerosol.
  • compositions 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).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compound of the formula (I) of the present invention contained in these preparations 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 or the like.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • 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 present invention may be presented in unit dosage forms 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 hereinbefore described, or an appropriate fraction thereof.
  • compositions of this invention are formulated, quantified, and administered in a manner consistent with medical practice.
  • a "therapeutically effective amount" of a compound 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/day
  • the dose for oral administration may be 1-1000 mg/kg/day.
  • the present invention provides the above 5-aminopyrazolecarboxamide compound or a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof for use in the prevention or treatment of BTK Use in drugs that cause disease.
  • the present invention provides a method for inhibiting BTK activity comprising administering to a biological system the above 5-aminopyrazolecarboxamide compound of the present invention or a stereoisomer, tautomer, solvate thereof or pharmaceutically acceptable salt thereof Or a pharmaceutical composition comprising the above 5-aminopyrazolecarboxamide 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.
  • the present invention also provides a method for preventing or treating a disease mediated by BTK, comprising administering a therapeutically effective amount of one or more of the above 5-aminopyrazolecarboxamide compounds of the present invention or a combination thereof to a patient in need thereof a stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof and one or more drugs selected from the group consisting of an immunomodulator, an immunological checkpoint inhibitor, a glucocorticoid, a non-purine Anti-inflammatory drugs, Cox-2 specific inhibitors, TNF- ⁇ binding proteins, interferons, interleukins and chemotherapeutic drugs.
  • 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.
  • Figure 1 shows that the compound of the present invention significantly inhibited the growth of the diffuse large B-cell lymphoma cell line TMD-8 in vivo and showed the same antitumor effect as the control compound Ibrutinib.
  • the unit of temperature is Celsius (°C); the definition of room temperature is 18-25 ° C;
  • 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).
  • the intermediate compound 3 can be obtained by oxidizing the intermediate compound 2 using water/ethyl acetate as a reaction solvent and KMnO 4 as an oxidizing agent.
  • Compound 4 was prepared in a similar manner to Compound 1 starting from the corresponding starting material.
  • Compound 5 was prepared in a similar manner to Compound 1 starting from the corresponding starting material.
  • the compounds of the present invention exhibit strong kinase inhibitory activity (IC50 ⁇ 1000 nM), and some of the preferred compounds have strong kinase inhibitory activity (IC50 ⁇ 100 nM).
  • IC50 ⁇ 1000 nM strong kinase inhibitory activity
  • IC50 ⁇ 100 nM strong kinase inhibitory activity
  • the kinase inhibitory activity levels are classified as A, B, C, specifically A (IC 50 ⁇ 100 nM), B (100 nM ⁇ 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 inhibitory effects of the compounds disclosed herein on different kinase activities were tested separately. Each compound activity data were determined at 11 concentrations of the compound IC 50 value calculated using Graphpad Prism software.
  • the compound of the present invention exhibited a strong kinase selectivity, which was significantly superior to the control compound ibrutinib. See the table below for the results.
  • 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).
  • 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.
  • the compounds of the examples of the present invention have strong inhibitory activity against B cells, and their IC50 values are less than 10 nM.
  • 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 compounds of the examples of the present invention have a weak inhibitory activity or no inhibition on T cells, and have an IC50 value of more than 4000 nM, as determined by the above method.
  • 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. IC50 values were calculated using XLfit v3, Equation 201.
  • the compound of the present invention has strong inhibitory activity against B cells in human whole blood, and its IC50 value is less than 200 nM.
  • a compound of the present invention was dissolved in acetonitrile to prepare a stock solution having a concentration of 0.5 mM.
  • liver microsome protein concentration 20 mg/ml suspension [BD Gentest], liver microsomes.
  • the genus was human, dog, rat, and mouse; the control group was added with 158 ⁇ L of phosphate buffer (100 mM, pH 7.4).
  • 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
  • the compounds of the examples of the present invention exhibited 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 minutes, 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 minutes, 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 final result of this experiment is to calculate the IC50 value of the half inhibitory concentration.
  • IC50 ((50% - low inhibition rate %) / (high inhibition rate % - low inhibition rate %)) x (high concentration - low concentration) + low concentration.
  • the compounds of the examples of the present invention have only strong inhibition or no inhibition on various CYP enzymes, indicating that they have less influence on the metabolism of other drugs.
  • 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 as follows:
  • the compounds of the examples of the present invention exhibited better bioavailability (>40%).
  • the IC50 value of the compound for hERG inhibition can be determined according to the method described in the patent US20050214870 A1.
  • the compounds of the present invention have only a weak or no inhibitory effect on hERG and have an IC50 value greater than 1000 nM.
  • the immunodeficiency serious defect NOD.SCID mouse was purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. and was raised in the SPF animal room. After the TMD-8 cells were cultured to a sufficient amount, the cells were collected by centrifugation and washed twice with PBS. Finally, the cells were resuspended in serum-free RPMI 1640 medium and Matrigel (1:1 v/v). Using a 1 ml syringe and a 25G syringe needle, 0.2 ml of the cell suspension was injected into the right flank area of each mouse.
  • the compound of the present invention can significantly inhibit the growth of the diffuse large B-cell lymphoma cell line TMD-8 in vivo and exhibit the same antitumor effect as the control compound ibrutinib (see Fig. 1 for experimental results).

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Abstract

La présente invention concerne un nouveau composé de 5-amino pyrazole carboxamide tel que représenté dans la formule (I), un procédé de préparation de celui-ci, une composition pharmaceutique comprenant le composé, et une utilisation de celui-ci. (I)
PCT/CN2018/114669 2017-11-10 2018-11-08 Composé 5-amino pyrazole carboxamide en tant qu'inhibiteur de btk et son procédé de préparation WO2019091441A1 (fr)

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US11180475B2 (en) 2017-11-10 2021-11-23 Sinomab Bioscience Limited Crystal form I of a 5-aminopyrazole carboxamide compound as BTK inhibitor
WO2023110970A1 (fr) 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs macrocycliques de btk
WO2023110936A1 (fr) 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs de kinase réversibles macrocycliques

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WO2017198050A1 (fr) * 2016-05-16 2017-11-23 浙江予川医药科技有限公司 Dérivé de 5-aminopyrazole carboxamide en tant qu'inhibiteur de la btk, son procédé de préparation et composition pharmaceutique associée

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11180475B2 (en) 2017-11-10 2021-11-23 Sinomab Bioscience Limited Crystal form I of a 5-aminopyrazole carboxamide compound as BTK inhibitor
WO2023110970A1 (fr) 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs macrocycliques de btk
WO2023110936A1 (fr) 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Inhibiteurs de kinase réversibles macrocycliques

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