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Definitions

• the present invention relates to a series of novel polyfluoro-substituted pyrazolopyrimidines and processes for their preparation, pharmaceutical compositions containing them as active ingredients and methods for inhibiting Bruton's kinase activity.
• the invention also relates to a series of novel polyfluoro-substituted benzophenones and corresponding boronic esters, polyfluoro-substituted phenoxybenzenes and corresponding boronic esters, and novel processes for their preparation.
• Bruton's tyrosine kinase belongs to the Tec family. It consists of a unique N-terminal domain, namely the PH (pleckstrin homology) domain, the TH (Tec homology) homology region, the SH3 (Src homology 3) domain, the SH2 (Src homology 2) domain, and the catalytic domain.
• the SH 1/TK (Src homologyl/Tyrosine kinase) domain or kinase domain composition is referred to (Akinley et al: Ibrutinib and novel BTK inhibitors in clinical development. Journal of Hematology & Oncology 2013, 6:59).
• B lymphocytes the correct expression of different protein regions of BTK gene plays a key role in the function of B cells and various transduction pathways.
• BTK Downstream of the BTK function, there are a variety of receptors, including growth factors, B cell antigens, chemokines and innate immune receptors, which initiate a diverse range of cellular processes such as cell proliferation, survival, differentiation, exercise, angiogenesis, Cytokine production, antigen expression, etc. Therefore, BTK plays an important role in many hematopoietic signaling pathways, and is also important in B cell activation, development, survival, and signaling (Kurosaki, Molecular mechanisms in B cell antigen receptor signaling. Curr OPImm, 1997, 9 ( 3): 309-18).
• the CD20 antibody rituximab (Rituxan) is a protein-based therapeutic agent that depletes B cells and is used as an inflammatory disease such as rheumatoid arthritis for the treatment of autoimmune diseases such as chronic lymphocytic leukemia and autoantibodies. Therefore, protein kinases that play a key role in inhibiting B cell activation should be helpful for pathology of B cell-associated diseases.
• BTK-deficient mice BTK-deficient mice and BTK-sufficient mouse model tests
• Kil LP et al: Bruton's tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia .Am JBlood Res 2013, 3(1): 71-83.
• CLL chronic lymphocytic leukemia
• BTK-deleted mice completely abolish chronic lymphocytic leukemia, and overexpression of BTK accelerates the onset of leukemia and increases mortality.
• BTK inhibitors are not ideal: in addition to inhibiting BTK, it also inhibits other various kinases (such as ETK, EGF, BLK, FGR, HCK, YES, BRK and JAK3, etc.), thereby producing more side effects. Side effects of better selective inhibitors may be smaller.
• other various kinases such as ETK, EGF, BLK, FGR, HCK, YES, BRK and JAK3, etc.
• BTK inhibitors produce a variety of derivatives in vivo, which also affects the efficacy and side effects.
• the pharmacokinetics of BTK inhibitors are also known to be improved.
• the present invention relates to a BTK inhibitor for use as a method of treating or inhibiting an autoimmune disease or condition, a xenogenic immune disease or condition, an inflammatory disease, and a cancer or condition. This includes administering to the patient an effective amount of a compound expressed by the formula (I) or (II), or a pharmaceutically acceptable salt thereof.
• Ar 1 and Ar 2 are each independently of the formula (III) or (IV):
• a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 and A 10 are each independently C or N, and when N, there is no substituent thereon. connection;
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 may be independently represented by hydrogen, hydrazine, amino, halogen, hydroxy, carboxy, nitro, cyano, amide.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 are preferably hydrogen, deuterium, halogen, more preferably hydrogen, fluorine;
• R 6 , R 7 , R 8 or R 9 may form a 6-8 membered saturated or unsaturated heteroaryl ring or heterocyclic ring with NH 2 on the pyrimidine ring;
• Ar 1 may also be selected from substituted or unsubstituted benzoaryl, benzoheteroaryl, wherein the substituent is preferably anthracene, amino, halogen, hydroxy, carboxy, nitro, cyano, amide, lower alkyl sulfonamide , (C2-C6)alkenyl, (C2-C6)alkynyl, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C10 a cycloalkyl group wherein the alkyl group, alkoxy group or cycloalkyl group may be further optionally oxime, halogen, amino, hydroxy, carboxy, nitro, cyano, (C1-C6)alkyl, (C1- C6) substituted by alkoxy
• M 1 is a saturated or unsaturated C1-C8 carbon chain, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, cycloalkyl, ring Alkylalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheterocycloalkyl; these carbon chains, aryl, heteroaryl, cycloalkyl and heterocycloalkyl
• the hydrogen atom on the carbon or nitrogen atom may optionally be oxime, amino, halogen, hydroxy, carboxy, nitro, cyano, amide, (C2-C6)alkenyl, (C2-C6)alkynyl, trifluoromethyl Substituted with a trifluoromethoxy group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an amino group,
• R 10 , R 11 may be independently represented as amino, cycloamino, aryl, heteroaryl ring, heterocycloalkyl, oxoheterocyclyl, trifluoromethyl, trifluoromethoxy, trifluoroacetyl, Amido, acyl, decyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl, (C3-C10)cycloalkyl, (C1-C6)alkoxy, (C1-C6) oxoalkyl group, wherein amino group, amide group, acyl group, (C2-C6) alkenyl group, alkyl group, alkoxy group or cycloalkyl group may further be oxime, halogen, amino group, hydroxyl group, hydroxyl group Alkyl, carboxyl, ester, amide, nitro, cyano, trifluoroacetyl, trifluoromethyl, triflu
• the carbon of the aromatic ring or heterocyclic ring or the hydrogen of the nitrogen atom may be optionally substituted by an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an amino group, a cyano group, an amide group or a halogen;
• Ar 1 is optimally selected from the following formula:
• Q is preferably O, thereby constituting (X) and (XI):
• Ar 2 , M 1 , Y and R 10 are as defined above.
• Ar 2 is preferably a substituted phenyl or heteroaryl group, preferably a substituted phenyl group, further preferably More preferably
• M 1 is a saturated or unsaturated C1-C8 carbon chain, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, cycloalkyl , cycloalkylalkyl, alkylcycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheterocycloalkyl.
• the hydrogen atoms on the carbon or nitrogen atom of these carbon chains, aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups may be optionally alkyl, cycloalkyl, alkoxy, cycloalkoxy, amino, Substituted by CN, amido or halogen.
• M 1 is preferably piperidinyl or pyrrolidinyl
• R 10 is selected from the group consisting of amino, cycloamino, aryl, heteroaryl ring, heterocycloalkyl, oxoheterocyclyl, trifluoromethyl, trifluoromethoxy, trifluoroacetyl, amide, acyl , mercapto, (C2-C6) alkenyl, (C2-C6)alkynyl, (C1-C6)alkyl, (C3-C10)cycloalkyl, (C1-C6)alkoxy, (C1-C6 An oxoalkyl group, wherein the amino group, the amide group, the acyl group, the (C2-C6) alkenyl group, the alkyl group, the alkoxy group or the cycloalkyl group may be further optionally selected from the group consisting of hydrazine, halogen, amino, hydroxy, hydroxyalkane.
• Base carboxyl group, ester group, amide group, nitro group, cyano group, trifluoroacetyl group, trifluoromethyl group, trifluoromethoxy group, (C1-C6) alkyl group, (C1-C6) alkoxy group, C1-C6) alkylene oxide, substituted by (C3-C10)cycloalkyl.
• R 10 is most preferably a vinyl group.
• alkyl alkenyl and “alkynyl” are, unless otherwise stated, preferably a straight or branched alkyl group of one to six carbon atoms or a straight chain of two to six carbon atoms or Branched alkenyl and alkynyl groups, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl, vinyl, propenyl, butenyl, pentenyl or hexenyl and their derivatives Structure.
• hydroxy refers to a group having the formula -OH.
• halogen or halo means fluoro, chloro, bromo or iodo.
• cycloalkyl refers to a mono- or polycyclic carbocyclic ring wherein each ring contains from 3 to 10 carbon atoms, and any of the rings may contain one or more double or triple bonds. Examples include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl.
• cycloalkyl additionally includes spiro ring systems in which the cycloalkyl ring has a common carbon ring atom.
• heterocycloalkyl is a five- to six-membered non-aromatic heterocyclic ring which may have one or more of the same selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom (which may be oxidized). Or different heteroatoms.
• the heterocycloalkyl group can be unsaturated or can be fused to a benzene ring. However, nitrogen-bridged hydrocarbons are not included.
• the heterocycloalkyl group may include, for example, azacyclopropyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, Tetrahydrofuranyl, tetrahydrothiophenyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, indanyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, and benzoxazinyl Preferred are dihydrooxazolyl, oxadiazolyl, oxadiazolanyl and furyl.
• cyclic amino group is a 3- to 8-membered non-aromatic cyclic amine in the group defined by “heterocycloalkyl” which has at least one nitrogen atom and may have a nitrogen atom, an oxygen atom and sulfur. One or more of the same or different heteroatoms in the atom (which may be oxidized), wherein at least one of the nitrogen atoms is bonded. However, nitrogen bridged hydrocarbons are not included.
• the "cyclic amino group” may include, for example, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholino, thiomorpholino, and piperazinyl.
• aryl is an aromatic hydrocarbon group, preferably an aryl group having 6 to 10 carbon atoms, more preferably a phenyl group, a naphthyl group and an anthracenyl group, and most preferably a phenyl group.
• heteroaryl is a monovalent five- or six-membered aromatic heterocyclic group having one or more of the same or different heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and is compatible with benzene.
• the ring is fused.
• Heteroaryl may include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furyl, oxadiazole , thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indolyl, oxazolyl, quinoxalinyl and quinazolinyl, preferably pyridazine Base, pyridyl, pyrazinyl, thiazolyl, pyrazolyl and thiooxazolyl.
• bridged ring group means “bridged cyclic hydrocarbon group” and “aza bridged hydrocarbon group”
• bridged cyclic hydrocarbon group is a saturated or unsaturated bicyclic or polycyclic bridged hydrocarbon group having two or three cycloalkyl rings having 3 to 10 carbon atoms. Non-bridged cycloalkyl groups are not included. Particularly preferred are bicyclic or polycyclic bridged hydrocarbon groups having 4 to 16 carbon atoms.
• the bridged cyclic hydrocarbon group may include, for example, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [4.3.1] fluorenyl, bicyclo [3.3.1 Sulfhydryl, borneol, borneol, norbornyl, norbornene, 6,6-dimethylbicyclo[3.1.1]heptyl, tricyclobutyl, and adamantyl, preferably adamantyl Or bicyclo [2.2.1] heptyl.
• nitro refers to a group having -NO 2 .
• amino refers to a group having the structure -NH 2 .
• the amino group may have one, two or three groups such as an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and the like.
• cyano refers to a group of the formula -CN.
• alkoxy refers to a moiety in which a group containing an alkyl group is bonded to an oxygen atom, such as a methoxy group.
• the oxygen atom of the alkoxy group of the alkoxy moiety is bonded to the other part of the molecule. Examples of such groups include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy.
• alkyl "cycloalkyl", “heterocycloalkyl", “aryl” and “heteroaryl” are as defined above.
• carboxy refers to a carboxyl group, -CO 2 H, or a salt thereof.
• trifluoromethyl refers to a group having the formula -CF 3.
• trifluoromethoxy means a group having the structure of formula -OCF 3.
• pharmaceutically acceptable salt refers to a salt which is present in acid or base form, non-limiting examples of which are (a) acidic addition salts, inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid) , nitric acid, etc.), organic acid salts, organic acids such as vinegar Acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, Alginic acid, poly glutamic acid, and salicylic acid; (b) base addition salts, formed with metal cations such as zinc, calcium, sodium, potassium, and the like.
• acidic addition salts eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid
• organic acid salts organic acids such as vinegar Acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid,
• the invention is exemplified by the examples and the compounds disclosed herein.
• Particular compounds of the invention are selected from the group consisting of the compounds of the disclosed examples and their pharmaceutically acceptable salts and their individual diastereomeric compounds or salts.
• the present invention actively explores the synthetic route, and eliminates various preparation schemes (see Schemes 1-3), and successfully designs a new method for synthesizing pyrazolopyrimidines (see Schemes 4-11 and specific reaction examples).
• the resulting borate ester is subjected to a Suzuki reaction with a substituted 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine under the action of a suitable catalyst (e.g., Pd-118) to give the title compound.
• a suitable catalyst e.g., Pd-118
• the literature is known to synthesize a method to try 2: 3-fluoro-4-bromo-phenol (or 3-fluoro-4-chloro-phenol) and 3-fluorobenzeneboronic acid to form 1-bromo-2-fluoro-4-(3-fluorophenoxy Benzo)benzene (or 1-chloro-2-fluoro-4-(3-fluorophenoxy)benzene) is then converted to the corresponding boronic ester to give the target compound.
• 1-bromo-2-fluoro-4-(3-fluorophenoxy)benzene (or 1-chloro-2-fluoro-) was synthesized according to literature methods.
• the fluorine-substituted starting material A1 may form the intermediate C1 with the substituted phenol B1 in the presence of a base such as potassium carbonate and in a suitable solvent such as DMF.
• a suitable base such as potassium acetate
• a suitable solvent such as 1,4-dioxane
• intermediate C1 can be combined with a bis-pinacol borate in a suitable catalyst (eg [1]
• the reaction is carried out by the action of 1'-bis(diphenylphosphino)ferrocene]palladium dichloride to provide intermediate D1.
• the starting material 1H-pyrazolo[3,4-d]pyrimidin-4-amine can be reacted with NIS in a suitable solvent such as DMF to give intermediate F1.
• Intermediate F1 and alcohol G1 are subjected to Mitsunobu reaction with a catalyst under appropriate conditions to form intermediate H1.
• a suitable base such as potassium phosphate
• intermediate H1 can be reacted with borate D1 in a suitable catalyst such as Pd-118.
• the reaction was carried out to provide intermediate I1.
• the Boc group of I1 can be removed to give the amine compound J1.
• the amine compound J1 can be reacted with an electrophile to give the product K1.
• Intermediate F1 can be reacted with Boc protected bromo (or mesylate) A2 in the presence of a suitable base such as potassium carbonate or cesium carbonate in a suitable solvent such as (DMF) to afford intermediate B2.
• a suitable solvent such as 1,4-dioxane and water
• a suitable base such as sodium carbonate
• a suitable catalyst such as palladium (triphenylphosphine) 4
• the Suzuki cross-coupling reaction of the bulk B2 and the heterocyclic boronic ester D1 can give the intermediate C2.
• the Boc group of C2 can be removed to give the amine compound D2.
• the amine compound D2 can be reacted with an electrophile to give the product E2.
• a suitable solvent such as 1,4-dioxane and water
• a suitable base such as sodium carbonate
• a suitable catalyst such as palladium (triphenylphosphine) 4
• the Suzuki cross-coupling reaction can be carried out on the F1 and the heterocyclic boronic ester D1 to give the intermediate A3.
• Intermediate F1 can be reacted with Boc protected bromo (or mesylate) A2 in the presence of a suitable base such as potassium carbonate or cesium carbonate in a suitable solvent such as (DMF) to afford intermediate C2.
• a suitable base such as potassium carbonate or cesium carbonate
• a suitable solvent such as (DMF)
• the Boc group of C2 can be removed to give the amine compound D2.
• the amine compound D2 can be reacted with an electrophile to give the product E2.
• a suitable solvent in e.g., in the presence of a suitable base (such as potassium or cesium carbonate), intermediates, and F 1 may be Boc protected bromide (or mesylate) reaction of Intermediate A4 B4 .
• a suitable solvent such as 1,4-dioxane and water
• a suitable base such as sodium carbonate
• a suitable catalyst such as palladium (triphenylphosphine) 4
• the Suzuki cross-coupling reaction can be carried out on the A4 and heterocyclic boronate D1 to give the product E2.
• the starting material Grinard Reagent A5 can form intermediate alcohol C5 with bromo (or chloro) aryl aldehyde B5.
• Intermediate C5 can be oxidized to ketone D5 by the action of a suitable oxidizing agent such as tetrapropylammonium perruthenate and N-methyloxymorpholine in a suitable solvent such as dichloromethane.
• intermediate D5 can be combined with a bis-pinacol borate in a suitable catalyst (eg The reaction is carried out under the action of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) to provide intermediate E5.
• a suitable base such as potassium acetate
• a suitable solvent such as 1,4-dioxane
• a suitable solvent such as 1,4-dioxane and water
• a suitable base such as sodium carbonate
• a suitable catalyst such as palladium (triphenylphosphine) 4
• a Suzuki cross-coupling reaction can be carried out on the A4 and heterocyclic boronate E5 to give the product F5.
• Compound D2 can react with maleic anhydride to form intermediate A6 in the presence of a suitable base such as triethylamine in a suitable solvent such as dichloromethane.
• Intermediate A6 is cleaved in polyphosphoric acid at the appropriate temperature (e.g., 100 ° C - 110 ° C) to afford product B6.
• the fluorine-substituted starting material A7 can form the intermediate B7 with the substituted phenol B1 in the presence of a base such as potassium carbonate and in a suitable solvent such as DMF.
• the nitro compound B7 can be reduced to the amine C7 in a suitable reducing agent such as iron powder and ammonium chloride in a suitable solvent such as ethanol and water.
• Intermediate C7 produces a fluorine-substituted intermediate D7 under the action of sodium nitrite and pyridine hydrogen fluoride.
• intermediate D7 can be combined with a bis-pinacol borate in a suitable catalyst (eg [1] The reaction is carried out by the action of 1'-bis(diphenylphosphino)ferrocene]palladium dichloride to provide intermediate E7.
• a suitable base such as potassium phosphate
• a suitable solvent such as 1,4-dioxane and water
• intermediate G1 can interact with the boronate E7 in a suitable catalyst (eg, Pd-118).
• the reaction was carried out to provide intermediate F7. Under acidic conditions, the Boc group of F7 can be removed to give the amine compound G7.
• the amine compound G7 can be reacted with an electrophile to give the product H7.
• a Suzuki cross-coupling reaction can be carried out on the A4 and heterocyclic boronate E7 to give the product A8.
• the present invention provides compounds of the formulae (I) to (XIII), and enantiomers and diastereomers thereof, or pharmaceutically acceptable salts thereof.
• the compounds of the present invention comprising the formulae (I) to (IX) include one or more stable isotopes or radioisotopes including, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O and so on.
• the present invention introduces the 1 H isotope 2 H into a BTK inhibitor for the first time.
• the present invention provides a process for the preparation of the compounds of the formulae (I) to (XIII), and their enantiomers and diastereomers.
• the present invention provides a method for modulating the activity of BTK and treating or inhibiting a disease associated with BTK activity. It has been confirmed that the compound of the present invention has an inhibitory effect on BTK activity, and the present invention provides an active ingredient in a medicament for treating and/or preventing diseases caused by the compounds of the formulae (I) to (XIII),
• a disease is a disease caused by unfavorable cytokine signaling, including but not limited to:
• autoimmune diseases such as chronic lymphatic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritis syndrome (goodpasture syndrome), pemphigus vulgaris, pemphigoid, primary biliary cirrhosis, multiple cerebrospinal sclerosing, acute idiopathic polyneuritis, systemic lupus erythematosus, rheumatoid arthritis Systemic vascular Inflammation, scleroderma, pemphigus, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, ulcerative colitis, etc.;
• xenogeneic immune diseases such as serum diseases, asthma, allergic rhinitis and drug allergies
• inflammatory diseases such as keratitis, rhinitis, stomatitis, mumps, pharyngitis, tonsillitis, bronchitis, bronchitis, pneumonia, myocarditis, gastritis, gastroenteritis, cholecystitis, appendicitis, etc.;
• Cancer includes, but is not limited to, various B cell malignancies (including small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma and Mantle cell lymphoma (MCL) and other diseases that inhibit BTK kinase activity in patients;
• SLL small lymphocytic lymphoma
• CLL chronic lymphocytic leukemia
• DLBCL diffuse large B-cell lymphoma
• MCL Mantle cell lymphoma
• diseases that inhibit BTK kinase activity are beneficial to patients including, but not limited to, brain tumors, bladder cancer, stomach cancer, ovarian cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, and renal cancer.
• esophageal cancer pre-existing adenocarcinoma, thyroid cancer, bone cancer, skin cancer, colon cancer, female genital tract tumor, lymphoma, multiple myeloma and testicular cancer.
• the method comprises administering to a patient in need thereof an effective amount of a compound of claims 1-12.
• compositions of the compounds of the invention may be used alone or in combination with one or more additional agents, depending on standard pharmaceutical practice, the pharmaceutical formulation of the BTK inhibitor and the additional agent
• the routes of administration may be the same or different, and the administration times may be the same or different.
• Such additional agents include, but are not limited to, tyrosine kinase inhibitors (eg, axitinib, dasatinib, ectinib, etc.), topoisomerase inhibitors (eg, topotecan, etc.) ), protein kinase C inhibitors (such as AEB-071, etc.), sphingosine-1-phosphate receptor agonists (such as fingolimod, KRP-203, etc.), anti-T cell immunoglobulin (such as AtGam, etc.) Anti-IL-2 receptor antibodies (such as dalizumab), amide (CTX), ifosfamide (IFO), doxorubicin (ADM), daunorubicin (DNR), vincristine (VCR), vinblastine (VBL), etoposide (VP16), virgin (Vumon), carboplatin (CBP) and methotrexate (MTX) cyclosporin A, tacrolimus, sir
• the carrier, the excipient, and other additives conventionally used in pharmaceutical preparations can be used to prepare a compound containing one or two or more compounds of the formula (I)-(IX) or a pharmaceutically acceptable salt thereof as an active ingredient.
• Pharmaceutical composition a compound containing one or two or more compounds of the formula (I)-(IX) or a pharmaceutically acceptable salt thereof as an active ingredient.
• a dosage form for parenteral administration such as a nasal preparation or an inhalation is administered for therapeutic administration.
• the symptoms, age, sex, and the like of each patient to be treated should be considered in order to appropriately determine the dose of the compound.
• an adult patient takes a daily dose of a compound of about 0.001 mg/kg to 100 mg/kg, and the dose is taken once or divided into 2 to 4 times.
• adult patients are administered once or more times per day in a dose range of 0.0001 mg/kg to 10 mg/kg. Further, in the case of administration by inhalation, in general, an adult patient is administered once or more times per day in a dose range of 0.0001 mg/kg to 1 mg/kg.
• the solid composition for oral administration may be in the form of a tablet, a powder, a granule or the like.
• one or more active substances are combined with at least one inert excipient (eg, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, poly Mixing with vinylpyrrolidone, magnesium aluminum silicate, etc.).
• the composition may also contain inert additives such as a lubricant (e.g., magnesium stearate), a disintegrant (e.g., sodium carboxymethyl starch), and a dissolution aid, according to a conventional method.
• Tablets or pills may also be coated with a sugar coating or a gastric or enteric coating as needed.
• the liquid composition for oral administration includes a pharmaceutically acceptable emulsion, solution, suspension, syrup, or elixir, and the like, and contains an inert diluent (e.g., purified water, ethanol) which can be usually used.
• an inert diluent e.g., purified water, ethanol
• the composition may also contain adjuvants such as solubilizers, wetting agents, suspending agents, and sweetening, flavoring, perfuming, and preservatives.
• Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, emulsions.
• the diluent for the aqueous solution may, for example, include distilled water for injection and physiological saline.
• the diluent for the non-aqueous solution may, for example, include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.
• Such compositions may also contain additives such as isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers, solubilizers.
• compositions may be sterilized by filtration through a bacteria-retaining filter, addition of a bactericide, or light irradiation. Further, these compositions may be prepared into a sterile solid composition which is dissolved or suspended by using sterile water or a sterile injectable solvent before use.
• Transmucosal agents such as inhalants and nasal sprays can be used in a solid, liquid, or semi-solid state, and these transmucosal agents can be prepared according to a conventionally known method.
• excipients such as lactose and starch
• pH adjusters such as lactose and starch
• antiseptic agents such as lactose and starch
• surfactants such as surfactants
• lubricating agents such as sodium bicarbonate
• stabilizers such as a metered dose inhalation device or a nebulizer.
• the compound may be combined with a pharmaceutically acceptable carrier and administered as a solution or suspension.
• a dry powder inhaler or the like can be used for single administration or multiple administration, and a dry powder or a capsule containing a powder can be used. Alternatively, it may be administered by a pressurized aerosol spray or the like by using a suitable propellant (for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide).
• a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.
• the reaction was carried out under microwave irradiation and subjected to a nitrogen atmosphere for 30 minutes at 85 °C.
• the reaction solution was diluted with water (10 mL) and then th
• the combined organic phases were dried over anhydrous sodium sulfate (MgSO4).
• the reaction was carried out under microwave irradiation and subjected to a nitrogen atmosphere for 30 minutes at 85 °C.
• the reaction solution was diluted with water (10 mL) and then th
• the combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness.
• the obtained crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water, gradient elution 10% to 100% by volume)
• the volatile component was evaporated under reduced pressure, and then lyophilized to give the title compound (42 mg, yield: 10%).
• the reaction was carried out under microwave irradiation and subjected to a nitrogen atmosphere for 30 minutes at 85 °C.
• the reaction solution was diluted with water (10 mL) and then th
• the combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness.
• the obtained crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water/0.5% HCl, gradient elution 10% to 100%) (volume ratio))
• the volatile component was distilled off under reduced pressure and lyophilized to give the title compound hydrochloride (10 mg, yield: 4%).
• the reaction was stirred under microwave irradiation and under nitrogen for 30 minutes at 85 °C.
• the reaction was diluted with water (50 mL) andEtOAc
• the combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness.
• the obtained crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water/0.5% HCl, gradient elution 10% to 100%) (volume ratio))
• the volatile component was distilled off under reduced pressure and lyophilized to give the title compound hydrochloride (150 mg, yield: 4%).
• reaction solution was poured into ice water (300 mL), and then extracted four times with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness.
• reaction mixture was stirred at 0 ° C for 1 hour, then quenched with water (5mL), then diluted with dichloromethane (50mL), twice with water (30mL) and brine (30mL). The organic phase was dried over anhydrous sodium sulfate (MgSO4). Rate: 64%).
• reaction mixture was stirred at 0 ° C for 1 hour, then diluted with water (5 mL), then diluted with dichloromethane (10 mL), twice with water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate (MgSO4). .
• the crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water/0.7 %NH 4 HCO 3 , gradient elution 10% to 100% by volume), the volatile component was evaporated under reduced pressure and lyophilized to give the title compound (19 g, yield: 23%).
• reaction solution was stirred under a nitrogen atmosphere and stirred at 80 ° C for 40 minutes under microwave irradiation. After cooling to room temperature, it was extracted three times with ethyl acetate (50 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated to dryness.
• the reaction mixture was stirred at 0 ° C for 1 hour, then diluted with water (5 mL), then diluted with dichloromethane (10 mL), twice with water (5 mL) and brine (5 mL).
• the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness.
• the obtained crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water/0.5% HCl, gradient elution 10% to 100% (volume)
• the title compound hydrochloride (6.3 mg, yield: 10%) was obtained by evaporation of the volatile component under reduced pressure.
• the obtained crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water/0.5% HCl, gradient elution 10% to 100%) (volume ratio)), the volatile component was distilled off under reduced pressure, and then lyophilized to give the hydrochloride salt of Example 16 (11 mg, yield: 5%) and the hydrochloride salt of Example 17 (3.8 mg, yield: 2%).
• the reaction was carried out under microwave irradiation for 40 minutes at 85 ° C under a nitrogen atmosphere.
• the reaction solution was diluted with water (10 mL) and then th
• the combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness.
• the obtained crude product was separated on a C18 reverse phase column by high-performance liquid chromatography (mobile phase: acetonitrile/water/7 ⁇ NH 4 HCl 3 , gradient elution 10%) To 100% (volume ratio), the volatile component was evaporated under reduced pressure and lyophilized to give the title compound (5 mg, yield: 4%).
• the reaction was carried out under microwave irradiation for 40 minutes at 85 ° C under a nitrogen atmosphere.
• the reaction solution was diluted with water (10 mL) and then th
• the combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness.
• the obtained crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water/0.5% HCl, gradient elution 10% to 100%) (volume ratio))
• the volatile component was distilled off under reduced pressure and lyophilized to give the title compound hydrochloride (16 mg, yield: 22%).
• the reaction was stirred at 60 ° C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, it was filtered over Celite, and then filtered and evaporated th The combined organic phase was dried over anhydrous sodium sulfate and evaporated to dryness crystals crystals crystals , yield: 46%).
• the reaction solution was diluted with water (10 mL) and then th The combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness.
• the obtained crude product was separated on a C18 reverse phase column by high performance liquid chromatography (mobile phase: acetonitrile/water/0.5% HCl, gradient elution 10% to 100%) (volume ratio)) The volatile component was distilled off under reduced pressure and lyophilized to give the title compound hydrochloride (2 mg, yield: 2%).
• Example 23 (18 mg, yield: 11%) and Example 24 (3.5 mg, yield: 2%).
• Triethylamine (3.02 g) was added dropwise to a solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate (2.0 g, 10.0 mmol, 1.0 eq.) in dichloromethane (20 mL). , 30.0 mmol, 3.0 eq.) and methanesulfonyl chloride (2.28 g, 20 mmol, 2.0 eq.). The reaction was stirred at 0<0>C for 1 h then quenched with water (20 mL). The combined organic layers were dried with anhydrous sodium
• Triethylamine (1.9 g) was added dropwise to a solution of tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (2.0 g, 9.3 mmol, 1.0 eq.) in dichloromethane (20 mL). , 18.6 mmol, 2.0 eq.) and methanesulfonyl chloride (2.12 g, 18.6 mmol, 2.0 eq.). The reaction was stirred at 0<0>C for 1 h then quenched with water (20 mL). The combined organic layers were dried with anhydrous sodium
• the reaction was carried out under microwave irradiation and subjected to a nitrogen atmosphere for 30 minutes at 85 °C.
• the reaction solution was diluted with water (10 mL) and then th
• the combined organic phase was dried over anhydrous sodium sulfate and evaporated to dryness crystals crystalsssssssssss %).
• the reaction was stirred at 80 ° C for 12 hours under a nitrogen atmosphere.
• the reaction solution was diluted with water (10 mL) and then th
• the combined organic phase was dried over anhydrous sodium sulfate and evaporated to dryness crystals crystalsssssssssssss %).

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