WO2022206583A1 - Composé d'indazole, son procédé de préparation et son application - Google Patents
Composé d'indazole, son procédé de préparation et son application Download PDFInfo
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- WO2022206583A1 WO2022206583A1 PCT/CN2022/082962 CN2022082962W WO2022206583A1 WO 2022206583 A1 WO2022206583 A1 WO 2022206583A1 CN 2022082962 W CN2022082962 W CN 2022082962W WO 2022206583 A1 WO2022206583 A1 WO 2022206583A1
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- Prior art keywords
- substituted
- unsubstituted
- compound
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- alkyl
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 6
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- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
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- 230000011242 neutrophil chemotaxis Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 235000011009 potassium phosphates Nutrition 0.000 description 1
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- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
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- 125000005493 quinolyl group Chemical group 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention relates to the field of medicinal chemistry, in particular to a class of indazole compounds and a preparation method and application thereof.
- Malignant tumors have been a serious threat to human health, especially B-cell malignancies, including chronic lymphocytic leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, follicular lymphoma, etc.
- the early treatment methods are mainly to relieve the symptoms of patients through traditional cytotoxic drugs.
- various physiological processes in tumor cells such as signal pathway transduction, cell cycle regulation, Apoptosis and angiogenesis are gradually recognized by people.
- the PI3K/Akt signaling pathway is an important signaling pathway in mammals, and the abnormal activation of its signaling is considered to be closely related to the occurrence and development of tumors.
- PI3K is an important node protein. It is a class of lipid kinases with serine/threonine (ser/Thr) kinase activity and phosphatidylinositol kinase activity. Its function is mainly phosphorylation The 3' hydroxyl of phosphatidylinositol. PI3Ks are mainly activated in two ways, one is activation by RTKs or GPCRs, and the other is through the binding of catalytic subunit p110 to Ras to promote PI3K activation.
- PI3Ks phosphorylate PIP2 to form PIP3, which acts as a second messenger to recruit and activate the protein kinases PDK1 and Akt, thereby activating downstream effectors to regulate cell proliferation, differentiation, survival, and migration.
- Some studies have reported that PI3K ⁇ inhibitors can reduce the side effects of thrombocytopenia, anemia, and increased transaminase caused by other subtype inhibitors (Brana & Siu, BMC Medicine, Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment, 2012, 10-161) .
- PI3K ⁇ exists specifically in hematopoietic cells and immune cells, plays an important role in the signal transduction of receptors on the surface of B cells, and regulates the proliferation, differentiation and survival of B cells.
- PI3K ⁇ is considered an important target for the treatment of B-cell malignancies and autoimmune diseases.
- three PI3K ⁇ have been approved for marketing by the FDA, namely Idelalisib, 2017, which was launched by Gliade in 2014 for the treatment of B-cell non-Hodgkin's lymphoma (NHL) and in combination with rituximab for the treatment of chronic lymphocytic leukemia.
- Bayer launched the intravenous drug Copanlisib for the treatment of adult patients with follicular lymphoma (FL) that has relapsed after at least 2 systemic therapies
- Intellikine launched the first monotherapy for the treatment of recurrent disease.
- the oral drug Duvelisib in patients with refractory chronic lymphocytic leukemia, small lymphocytic lymphoma, and patients with dual drug-resistant follicular lymphoma.
- marketed drugs have significant therapeutic effects in the treatment of B-cell malignancies, they also have some serious clinical side effects and drug interactions. Therefore, there is an urgent need to develop a new and safer PI3K ⁇ selective inhibitor.
- the present invention provides an indazole compound, its preparation method, pharmaceutical composition and use which are completely different from the prior art.
- the indazole compound of the present invention is a selective PI3K ⁇ inhibitor, which can be used to prepare medicines for the treatment of inflammatory diseases, autoimmune diseases, cancer, infectious diseases or cardiovascular and cerebrovascular diseases.
- the present invention provides compounds of formula (1)
- R 1 , R 2 , R 3 and R 4 are the same or different, and are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, Substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 4-10 aryl , substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 alkynyl, alkyl mono-substituted amino, alkyl di-substituted amino, alkoxy, alkyl carbonyloxy group, cycloalkylcarbonyloxy, heteroarylcarbonyloxy, alkoxycarbonyl, cycloalkoxycarbonyl, heteroaryloxycarbony
- R 5 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 1-6 cycloalkyl C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 alkynyl, halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, Hydroxyethyl, mercapto, carboxyl, ester, alkyl mono-substituted amine, alkyl di-substituted amine, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heteroarylcarbonyloxy, alkane Oxycarbonyl, cycloalkoxycarbonyl, heteroaryloxycarbonyl, alkylcarbonylamino, cycl
- X and Y are the same or different, each independently selected from C or N;
- R 6 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 1-6 cycloalkyl C 4-10 aryl, substituted or unsubstituted C 1-10 heteroaryl, C 2-10 alkenyl, C 2-10 alkynyl, alkoxycarbonyl, cycloalkoxycarbonyl, heteroaryloxycarbonyl , aminocarbonyl;
- R 7 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-10 heteroaryl, C 2- 10 alkenyl, C 2-10 alkynyl, alkyl mono-substituted amino, alkyl di-substituted amino, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heteroarylcarbonyloxy, alkane Oxycarbonyl, cycloalkoxycarbonyl, heteroaryloxycarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, hetero
- R 8 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-10 heteroaryl, C 2- 10 alkenyl, C 2-10 alkynyl, alkyl mono-substituted amino, alkyl di-substituted amino, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heteroarylcarbonyloxy, alkane Oxycarbonyl, cycloalkoxycarbonyl, heteroaryloxycarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, heteroary
- R 9 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-10 heteroaryl, C 2- 10 alkenyl, C 2-10 alkynyl, alkyl mono-substituted amino, alkyl di-substituted amino, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heteroarylcarbonyloxy, alkane Oxycarbonyl, cycloalkoxycarbonyl, heteroaryloxycarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, hetero
- R 1 , R 2 , R 3 , R 4 are the same or different, and are selected from hydrogen, halogen, C 1-6 alkyl, cyano, alkoxy, such as hydrogen, fluorine, chlorine, methyl, cyano, methoxy, etc.
- R 5 is methyl, ethyl, isopropyl, cyclopropyl and the like.
- R 6 is selected from phenyl, naphthyl, pyridyl, pyrazolyl, quinolyl, thienyl, indolyl, 2,3-dihydro-1,4-benzodioxinyl , which is optionally substituted with zero, one or more substituents selected from halogen, hydroxy, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl), -SO 2 (C 1-6 alkyl), methoxy, -NHSO 2 (C 1-6 alkyl).
- R7 is selected from H, methyl, ethyl, phenyl or heteroaryl optionally substituted with zero, one or more substituents as shown below:
- the substituents on the phenyl or heteroaryl groups shown above are selected from: F, OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , CH 3 , OCF 3 , CN, CONH 2 , CONHCH 3 .
- R 8 is selected from amino, hydroxyl
- R 9 is selected from hydrogen, methyl, amino.
- the compound of formula (1) is the compound of following formula (2):
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 have the same definitions as in formula (1).
- R 1 , R 2 are each independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, ester, amide, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 Cycloalkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 alkynyl;
- R 3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, amide, ester, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 cycloalkyl, Substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 alkynyl;
- R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, amide, ester, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 cycloalkyl, Substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 alkynyl;
- R 5 is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2- 10 alkenyl, C 2-10 alkynyl;
- R 6 is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 1-6 cycloalkyl C 4-10 aryl, substituted or unsubstituted C 1-10 heteroaryl, C 2-10 alkenyl, C 2-10 alkynyl, alkoxycarbonyl, cycloalkoxycarbonyl, heteroaryloxycarbonyl , aminocarbonyl;
- R 7 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-10 heteroaryl, C 2- 10 alkenyl, C 2-10 alkynyl;
- R 8 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-10 heteroaryl, C 2- 10 alkenyl, C 2-10 alkynyl;
- R 9 is selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heterocycloalkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-10 heteroaryl, C 2- 10 alkenyl, C 2-10 alkynyl.
- the compound of formula (2) can be selected from:
- the described preparation method of the compound of formula (2) can adopt reaction scheme I to synthesize compounds 11-56, and use compound 6a to synthesize compounds 57-85 through reaction scheme II;
- Reaction scheme I includes following process:
- Compound 1 reacts with sodium nitrite and hydrochloric acid in a solution of DMF (N,N-dimethylformamide) and water to form substituted indazole-3-carbaldehyde, which is compound 2, and then forms compound 3 under the action of Grignard reagent, followed by It is oxidized to compound 4 by manganese dioxide, and then undergoes Ullman coupling with bromide to generate compound 5.
- Compound 5 is reduced under the action of sodium borohydride to generate compound 6a, compound 6a and N-(tert-butoxycarbonylamino)phthalate.
- Reaction scheme II includes the following process:
- the at least one indazole compound, its pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrug prepared according to the above method can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods. method for purification.
- the above-mentioned compounds provided by the present invention can exhibit the phenomena of tautomerism, structural isomerism and stereoisomerism.
- the present invention includes any tautomeric or structural or stereoisomeric forms and mixtures thereof that possess the ability to modulate kinase activity, and this ability is not limited to any one isomeric or mixture of forms.
- the present invention also provides a pharmaceutical composition, comprising the compound of formula (1) and/or a pharmaceutically acceptable salt thereof, and/or a racemic mixture, hydrate, solvate, and prodrug thereof , enantiomers, diastereomers and tautomers, and one or more pharmaceutically acceptable carriers, diluents, excipients.
- a pharmaceutically acceptable carrier refers to a carrier that is compatible with (in some embodiments, stabilizes) the active ingredient in the composition and that is not injurious to the individual being treated.
- Pharmaceutical carriers and/or excipients may be selected from diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants, flavors, buffers agents, stabilizers, solubilizers, and combinations thereof.
- compositions comprising a compound of formula (1) described herein and/or a pharmaceutically acceptable salt thereof can be administered in a variety of known ways, such as orally, topically, rectally, parenterally, by inhalation or implanted .
- the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions) Wait.
- administration unit dosage forms such as tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions) Wait.
- any of the excipients known and widely used in the art can be used.
- carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.
- binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
- disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose, etc.
- disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil, and hydrogenated Oils
- adsorption promoters such as lactose, white sugar,
- any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.; binders , such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrating agents, such as agar and kelp powder.
- carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.
- binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.
- disintegrating agents such as agar and kelp powder.
- any excipient known and widely used in the art may be used, for example, polyethylene glycols, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides and the like .
- the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerol, etc.) to prepare an injection of isotonic pressure with blood.
- any carrier commonly used in the art may also be used, for example, fats of water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and polyethylene sorbitan acid esters, etc.
- usual solubilizers, buffers, pain relievers and the like may be added.
- the administration method of the pharmaceutical composition is not particularly limited.
- Various dosage forms can be selected for administration according to the patient's age, sex and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or mixed with injection delivery solutions (such as glucose solutions and amino acid solutions) for intravenous injection; suppositories are administered medicine to the rectum.
- the present invention also provides a method for inhibiting PI3K activity in vivo or in vitro, comprising contacting PI3K with an effective amount of a compound of formula (1) and/or a pharmaceutically acceptable salt thereof.
- the present invention also provides a method for inhibiting PI3K activity in vivo or in vitro, comprising contacting PI3K with a pharmaceutical composition in an amount effective to inhibit PI3K activity, the pharmaceutical composition comprising a formula ( A compound of 1) (eg, any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- a pharmaceutical composition comprising a formula ( A compound of 1) (eg, any compound herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- the present invention also provides a method of treating a disease in an individual responsive to inhibition of PI3K, comprising administering to an individual in need thereof an amount of formula (1) effective to inhibit the amount of PI3K in said individual
- the compound and/or a pharmaceutically acceptable salt thereof are administered to an individual in need thereof.
- the present invention also provides a method of treating a disease in an individual responsive to inhibition of PI3K, comprising administering to an individual in need thereof a pharmaceutical composition in an amount effective to inhibit the amount of PI3K in said individual, wherein
- the pharmaceutical composition comprises a compound of formula (1) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
- the present invention also provides the compound of formula (1) and/or its pharmaceutically acceptable salt, and/or its racemic mixture, hydrate, solvate, prodrug, enantiomer, Use of diastereomers and tautomers, and/or the pharmaceutical composition, in the preparation of PI3 kinase inhibitors.
- the kinase is preferably PI3 kinase (PI3K), more preferably the p110 ⁇ isoform of PI3 kinase (PI3K).
- the present invention also provides the compound of formula (1) and/or its pharmaceutically acceptable salt, and/or its racemic mixture, hydrate, solvate, prodrug, enantiomer, Use of diastereomers and tautomers, and/or said pharmaceutical compositions, in the manufacture of a medicament for the treatment of diseases responsive to inhibition of PI3K.
- the diseases responsive to inhibition of PI3K include, but are not limited to, inflammatory diseases, autoimmune diseases, cancer, infectious diseases, cardiovascular and cerebrovascular diseases, metabolic and/or endocrine dysfunction, and neurological diseases.
- Inflammatory diseases refer to pathological conditions that lead to an inflammatory response, especially due to neutrophil chemotaxis.
- diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; those associated with inflammatory bowel diseases (eg, Crohn's disease and ulcerative colitis) Response; ischemia-reperfusion injury, including surgically induced tissue reperfusion injury, myocardial ischemia such as myocardial infarction, cardiac arrest, post-cardiac reperfusion and abnormal vasoconstriction of coronary vessels after percutaneous coronary angioplasty, stroke and Abdominal aortic aneurysm surgical tissue reperfusion injury; cerebral edema secondary to stroke; cranial trauma; hemorrhagic shock; ventricular asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; polymyositis; Multiple sclerosis; dermatitis; men
- Autoimmune diseases refer to diseases or conditions caused by the body's immune response to self-antigens, resulting in damage to its own tissues or organs.
- autoimmune diseases include, but are not limited to: chronic obstructive pulmonary disease, allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis, psoriasis, inflammatory bowel disease, Asthma and idiopathic thrombocytopenic purpura and myeloproliferative disorders such as myelofibrosis, polycythemia vera/essential thrombocythemia myelofibrosis.
- the inflammatory and autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis.
- COPD chronic obstructive pulmonary disease
- the cancers include, but are not limited to, solid tumors or hematological malignancies, including cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels, including both primary and metastatic cancers.
- Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer: colorectal cancer: breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastases renal cell carcinoma; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial cancer or primary peritoneal cancer; cervical cancer Cancer; gastric cancer; esophagus cancer; head and neck cancer, including eg head and neck squamous cell carcinoma; skin cancer, including eg malignant melanoma: neuroendocrine carcinoma, including metastatic neuroendocrine tumor: brain tumor, including eg glioma , anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma;
- Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast phase (CML-BP): acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (ALL); cell leukemia (CLL); Hodgkin lymphoma; non-Hodgkin lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM ); Waldenström macroglobulinemia; myelodysplastic syndromes including refractory anemia, ring sideroblast refractory anemia, excess blastocyst refractory anemia, and excess blastocyst refractory anemia with acute transformation ; and myelodysplastic syndrome.
- AML acute myeloid leukemia
- CML chronic myeloid leukemia
- the cancer can be selected from leukemia, multiple myeloma (MM), lymphoma;
- the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic Lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML);
- the lymphomas are Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma , B-cell lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL);
- infectious diseases include, but are not limited to, bacterial infections, fungal infections, viral infections, and parasitic infections.
- cardiovascular and cerebrovascular diseases include but are not limited to acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, and trauma brain injury, stroke, ischemia-reperfusion injury, and arterial
- the compounds of formula (1) and/or pharmaceutically acceptable salts thereof described herein may be administered in combination with other active ingredients for the treatment of inflammatory diseases, autoimmune diseases, cancer, infectious diseases or cardiac Cerebrovascular disease.
- the compound of formula (1) and/or a pharmaceutically acceptable salt thereof can be administered separately from other active ingredients or formulated into a combined preparation.
- Other active ingredients are those known to be effective in the treatment of PI3K mediated diseases.
- a dash (“-") not between two letters or symbols indicates the site of attachment of the substituent.
- -O(C 1-4 alkyl) refers to a C 1-4 alkyl group attached to the rest of the molecule through an oxygen atom.
- "-" may be omitted when the point of attachment of the substituent will be apparent to those skilled in the art, eg, halogen substituents.
- alkyl refers to a straight or branched chain containing 1-18 carbon atoms, such as 1-12 carbon atoms, another example, 1-6 carbon atoms, still another example, 1-4 carbon atoms. Saturated alkyl.
- C 1-6 alkyl within the scope of “alkyl” refers to the described alkyl group having 1-6 carbon atoms.
- alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”), isopropyl (“i-Pr”), n-butyl ( “n-Bu”), isobutyl (“i-Bu”), sec-butyl (“s-Bu”) and tert-butyl (“t-Bu”).
- halo refers to fluoro, chloro, bromo and iodo
- halogen refers to fluoro, chloro, bromo and iodo
- haloalkyl refers to an alkyl group as defined herein wherein one or more hydrogen atoms, eg, 1, 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom When halogen atoms are substituted, the halogen atoms may be the same or different from each other.
- the term "haloalkyl” as used herein refers to an alkyl group as defined herein wherein two or more hydrogen atoms, eg 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, wherein The halogen atoms are the same as each other.
- haloalkyl refers to an alkyl group as defined herein wherein two or more hydrogen atoms, eg 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, wherein the halogen atoms are different from each other.
- haloalkyl groups include, but are not limited to, -CF3 , -CHF2 , -CH2CF3 , and the like.
- alkoxy refers to the group -O-alkyl, wherein alkyl is as defined above.
- alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexyloxy, including their isomers.
- aryl refers to a carbocyclic hydrocarbon group consisting of one or more rings fused together containing 6-14 ring carbon atoms, eg, 6-12 ring carbon atoms, wherein at least one ring is aromatic Ring and other rings are not heteroaryl groups as defined below, the point of attachment may be on the aromatic ring or on the other ring.
- aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl.
- aryl or “aromatic” follows Huckel's rule, where the number of pi electrons is equal to 4n+2, and n is zero or any positive integer up to 6.
- heteroaryl refers to a ring selected from the group consisting of 4 to 12 membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated, except containing at least one, such as In addition to 1-4, another example 1-3 or another example 1 or 2 heteroatoms selected from O, S and N, it also contains at least one carbon atom.
- the point of attachment of a heteroaryl group can be on a heteroatom or on a carbon.
- Heteroaryl or “heteroaryl” also refers to a monocyclic ring, which contains at least one heteroatom selected from O, S, and N; or a fused ring, where at least one ring contains at least one heteroatom selected from O, S, and N and the other ring is not a heteroaryl or aryl, the point of attachment may be on the heteroaryl or on the other ring.
- heteroaryl refers to:
- Bicyclic aromatic hydrocarbon radicals having 8-12 ring atoms, eg 9 or 10 ring atoms, which contain one or more, eg 1, 2, 3 or 4, eg 1 or 2 independently in the ring Ring heteroatoms selected from N, O and S, the remaining ring atoms are carbon atoms, at least one of which is an aromatic ring.
- a bicyclic heteroaryl group includes a 5-6 membered heteroaryl ring fused to a 5-6 membered cyclic hydrocarbyl ring, heteroaryl ring, or aryl ring, where the point of attachment can be on the heteroaryl ring or on the ring On an alkyl ring/heteroaryl ring/aryl ring.
- Heteroaryl also includes those in which the N-ring heteroatom is in the N-oxide form, eg, N-oxypyrimidinyl.
- the ring heteroatom in the above-described heteroaryl groups is an N atom, and such heteroaryl groups are referred to as "nitrogen-containing heteroaryl groups.”
- Nitrogen-containing heteroaryl groups also include those in which the N-ring heteroatom is in the N-oxide form, eg, N-oxide pyridyl.
- heteroaryl groups include, but are not limited to: pyridyl, N-oxypyridyl; pyrazinyl; pyrimidinyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiazolyl oxadiazolyl; tetrazolyl; triazolyl; thienyl; furyl; pyranyl; pyrrolyl; pyridazinyl; benzo[d]thiazolyl; zo[d][1,3]dioxolyl; benzoxazolyl, eg, benzo[d]oxazolyl; imidazopyridyl, eg, imidazo[1,2-a]pyridine triazolopyridyl, such as [1,2,4]triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-
- nitrogen-containing heteroaryl groups include, but are not limited to: pyrrolyl; pyrazolyl; imidazolyl; pyridyl; pyrazinyl; pyrimidinyl, N-oxypyrimidinyl; pyridazinyl; [3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; purinyl groups such as 9H-purinyl and 7H-purinyl; quinolinyl; indolyl; and indazolyl .
- hydroxyl refers to the -OH group.
- thiol refers to the -SH group.
- amino refers to the -NH2 group.
- cyano refers to the -CN group.
- substituted or “substituted by” as used herein means that one or more hydrogen atoms on a given atom or group are replaced with one or more substituents selected from the given substituent, provided that does not exceed the normal valence for that given atom.
- substituted with one or more substituents means that one or more hydrogen atoms on a given atom or group are independently replaced with one or more substituents selected from the given group.
- substituted with one or more substituents means that a given atom or group is substituted with 1, 2, 3, or 4 substituents independently selected from the given group.
- some compounds of formula (1) may contain one or more chiral centers and thus exist as two or more stereoisomers. Racemic mixtures of these isomers, single isomers and one enantiomerically enriched mixture, as well as diastereomers and specific diastereomers when there are two chiral centers Constructed moiety enriched mixtures are within the scope of the present invention. It will also be understood by those skilled in the art that the present invention includes all individual stereoisomers (eg enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (1), as well as in appropriate case, including its individual tautomers.
- the present invention also provides a pharmaceutically acceptable salt of a compound of formula (1).
- “Pharmaceutically acceptable salt” refers to a derivative of the disclosed compound, wherein the parent compound is obtained by converting an existing acid or base moiety Modified into its salt form.
- Pharmaceutically acceptable salts include but are not limited to: acid addition salts formed by compounds of formula (1) with inorganic or organic acids, and pharmaceutically acceptable salts also include compounds of formula (1) with acidic groups and pharmaceutically acceptable salts.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, these salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
- solvate means a solvent addition form comprising stoichiometric or non-stoichiometric amounts of solvent. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate.
- contacting refers to bringing the specified moieties together in an in vitro system or an in vivo system.
- "contacting" a PI3K with a compound described herein includes administering a compound of the invention to an individual or patient (eg, a human) having a PI3K and, eg, introducing a compound described herein into a sample containing cells or purified preparations comprising PI3K middle.
- prodrug refers to a compound that is an inactive precursor of a compound that is converted to its active form in vivo by normal metabolic pathways.
- a prodrug can be converted to a pharmacologically active form by hydrolysis of, for example, an ester or amide bond, thereby introducing or exposing functional groups on the resulting product.
- Prodrugs can be designed to react with endogenous compounds to form water-soluble conjugates that further enhance the pharmacological properties of the compound, such as increased circulating half-life.
- prodrugs can be designed with functional groups covalently modified with, for example, glucuronic acid, sulfate, glutathione, amino acid, or acetate.
- the resulting conjugate can be inactivated and excreted in the urine, or rendered more potent than the parent compound.
- High molecular weight conjugates can also be excreted in bile, cleaved by enzymes and released back into the circulation, effectively increasing the biological half-life of the originally administered compound.
- the term "individual” refers to any animal, including mammals and non-mammals, preferably rats, mice, other rodents, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, Horses or primates, and most preferably humans.
- the raw material 2 (3.5g, 19.4mmol) was added to the two-necked flask, evacuated and passed through argon, replaced three times, anhydrous THF was added, the reaction solution was cooled to -10°C, and methylmagnesium chloride (20mL, 3.0M) was slowly added dropwise. in THF), moved to room temperature after the dropwise addition was completed, after the reaction was completed, saturated ammonium chloride solution was added at low temperature to quench the reaction, the organic layer was collected, washed with saturated brine, dried over sodium sulfate, concentrated, and washed with EA/PE (v/ v, 1:3) eluent column chromatography gave a pale yellow solid 3 (3.15 g, 83%).
- Raw material 5 (2.8 g, 10.3 mmol) was added to the single-necked flask, methanol was added, and sodium borohydride (1.17 g, 30.9 mmol) was slowly added in batches at 0°C, stirred for half an hour, and then moved to room temperature for stirring.
- the raw material 10 (600 mg, 1.6 mmol) was placed in a pressure-resistant tube, formamide (3 mL) was added, and the reaction was carried out at 190° C. for 4 h. After the reaction was completed, water/ethyl acetate was added to separate the layers, the organic layer was collected, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed three times with water, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and washed with DCM/ Column chromatography with an eluent of MeOH (v/v, 30:1) gave 11 as a pale yellow solid (465 mg, 72%).
- the preparation method is similar to the preparation example 1-10, just replace the reactant, the same below, column chromatography obtains white solid 12 with a yield of 73%.
- the preparation method is the same as that of the preparation examples 1-10, and column chromatography obtains a white solid 13 with a yield of 75%.
- the preparation method is the same as the preparation example 1-10, and column chromatography obtains a white solid 14 with a yield of 78%.
- the preparation method is the same as that of the preparation examples 1-10, and column chromatography obtains a pale yellow solid 15 with a yield of 76%.
- the preparation method is the same as the preparation example 1-10, and column chromatography obtains a yellow solid 16 with a yield of 80%.
- the preparation method is the same as that of the preparation examples 1-10, and column chromatography obtains a white solid 17 with a yield of 77%.
- the preparation method is the same as that of the preparation examples 1-10, and column chromatography obtains a white solid 18 with a yield of 75%.
- the preparation method is the same as the preparation example 1-10, and column chromatography obtains a white solid 19 with a yield of 82%.
- the preparation method is the same as the preparation example 1-10, and column chromatography obtains a white solid 20 with a yield of 80%.
- the preparation method was the same as that of the preparation examples 1-10, and column chromatography gave white solid 21 with a yield of 82%.
- the preparation method is the same as that of the preparation examples 1-10, and the column chromatography obtains an off-white solid 22 with a yield of 77%.
- the preparation method is the same as that of the preparation examples 1-10, and the column chromatography obtains an off-white solid 23 with a yield of 81%.
- the preparation method is the same as that of the preparation examples 1-10, and the column chromatography obtains a pale yellow solid 24 with a yield of 75%.
- the preparation method is the same as the preparation example 1-10, and column chromatography obtains a white solid 25 with a yield of 75%.
- the preparation method is the same as the preparation example 1-10, and the column chromatography obtains an off-white solid 26 with a yield of 83%.
- the preparation method is the same as that of the preparation examples 1-10, and column chromatography obtains a yellow solid 27 with a yield of 81%.
- the preparation method is the same as the preparation and implementation cases 1-9, and the operation of the last step is as follows:
- the raw material 10 (150 mg, 0.4 mmol) was placed in a pressure-resistant tube, guanidine hydrochloride (38 mg, 0.4 mmol) and sodium ethoxide (54 mg, 0.8 mmol) were added, and anhydrous ethanol (2 mL) was added to dissolve, and the reaction was carried out at 130 °C for 5 h.
- the preparation method is the same as the preparation example 1-10, and column chromatography obtains a white solid 29 with a yield of 75%.
- the preparation method is the same as the preparation example 1-10, and column chromatography obtains yellow solid 30 with a yield of 78%.
- the preparation method is the same as the preparation implementation case 1-10, and the operation of the last step is as follows:
- the preparation method is the same as the preparation and implementation cases 1-9, and the operation of the last step is as follows:
- the raw material 10 (150 mg, 0.4 mmol) was placed in a pressure-resistant tube, formic acid (1.5 mL) was added, and the reaction was carried out at 125° C. for 4 h. After the reaction, spin off the formic acid, add water, make alkaline with sodium bicarbonate, extract with ethyl acetate, wash the organic layer twice with water, twice with saturated brine, and dry with anhydrous sodium sulfate. Concentration and column chromatography with an eluent of DCM/MeOH (v/v, 20:1) gave 32 as a white solid (135 mg, 83%).
- the first six steps of the preparation method are the same as the preparation implementation cases 1-6, and the subsequent steps are as follows:
- the first steps of the preparation method are the same as the preparation implementation cases 1-9, and the subsequent steps are as follows:
- the obtained pale yellow solid (225 mg, 0.5 mmol) was placed in a pressure-resistant tube, an ethanol solution of ammonia (2N, 1.5 mL) was added, and the reaction was carried out at 130° C. for 3 h. After the reaction, it was spin-dried, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with the eluent of DCM/MeOH (v/v, 30:1). 34 as a yellow solid (165 mg, 79%).
- the preparation method is the same as that of the preparation examples 1-10, and the column chromatography obtains a pale yellow solid 35 with a yield of 81%.
- the preparation method is the same as that of the preparation examples 1-10, and the column chromatography obtains a pale yellow solid 35 with a yield of 76%.
- the preparation method is the same as that of the preparation examples 1-10, and column chromatography obtains a pale yellow solid 37 with a yield of 78%.
- the preparation method is the same as the preparation example 1-10, and column chromatography obtains a white solid 38 with a yield of 75%.
- the preparation method is the same as the preparation example 1-10, and column chromatography obtains a white solid 39 with a yield of 81%.
- the preparation method is the same as that of Preparation Example 1-10 and Example 30, and column chromatography obtains white solid 40 with a yield of 75%.
- the preparation method is the same as the preparation implementation cases 1-10 and implementation case 30, and column chromatography obtains a white solid 41 with a yield of 76%.
- the preparation method is the same as the preparation implementation cases 1-10 and implementation case 30, and column chromatography obtains a white solid 42 with a yield of 80%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 43 with a yield of 82%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 44 with a yield of 73%.
- the preparation method is the same as the preparation implementation case 1-3, and the subsequent steps are as follows:
- the preparation method is the same as the preparation and implementation cases 1-4, and the subsequent steps are as follows:
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 47 with a yield of 78%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 48 with a yield of 68%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 49 with a yield of 76%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 50 with a yield of 74%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 51 with a yield of 80%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 52 with a yield of 82%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 53 with a yield of 78%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 54 with a yield of 83%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 55 with a yield of 79%.
- the preparation method is the same as the preparation implementation case 1-10, and column chromatography obtains a white solid 56 with a yield of 83%.
- the preparation method is the same as the preparation and implementation cases 1-5, and the subsequent steps are as follows:
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 58 with a yield of 65%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 59 with a yield of 62%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 60 with a yield of 65%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 61 with a yield of 66%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 62 with a yield of 58%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 63 with a yield of 54%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 64 with a yield of 67%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 65 with a yield of 69%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 66 with a yield of 72%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 67 with a yield of 59%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 68 with a yield of 68%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 69 with a yield of 45%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 70 with a yield of 64%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 71 with a yield of 61%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 72 with a yield of 72%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 73 with a yield of 68%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 74 with a yield of 68%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 75 with a yield of 58%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 76 with a yield of 74%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 77 with a yield of 58%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 78 with a yield of 59%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 79 with a yield of 52%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 80 with a yield of 64%.
- the preparation method was the same as that of Preparation Example 56, and column chromatography gave white solid 81 with a yield of 71%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 82 with a yield of 52%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 83 with a yield of 61%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 84 with a yield of 54%.
- the preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 85 with a yield of 43%.
- test compound was diluted to a series of concentrations required for the test, and 50nL of each was transferred to a 384-well plate. 50nL of DMSO was added to the negative control well and the positive control well, respectively.
- the PI3K ⁇ , ⁇ , ⁇ and PI3K ⁇ , ⁇ , ⁇ and ⁇ was diluted to 1.25nM, 1.25nM, 10nM, and 1.25nM respectively, then added 2 ⁇ L per well to 384-well plate, added 2.5 ⁇ L to negative and positive control wells, centrifuged for 30 seconds, shaken and mixed and incubated at room temperature for 10 minutes , add 2.5 ⁇ L of the mixed solution of ATP and PIP2, centrifuge for 30 seconds, shake and mix, incubate at room temperature for 2 hours, add 5 ⁇ L ADP-Glo Reagent, shake and mix, incubate at room temperature for 3 hours, add 10 ⁇ L Kinase Detection Reagent, shake and mix at room temperature After incubation for 1 hour, the samples were centrifuged, and the RLU value was read with an Enspire microplate reader, and the inhibition rate was calculated according to the formula.
- Table 1 shows the IC 50 values of the compounds of the present invention for PI3K ⁇ activity
- Table 2 shows the ratio of the IC 50 values of PI3K ⁇ and PI3K ⁇ (denoted as ⁇ / ⁇ ) for some compounds, and the ratio of the IC 50 values of PI3K ⁇ and PI3K ⁇ ( Denoted ⁇ / ⁇ ) and the ratio of IC50 values of PI3K ⁇ to PI3K ⁇ (denoted ⁇ / ⁇ ).
- the compounds of the new structure of the present invention can all show good PI3K ⁇ inhibitory activity. Moreover, the compounds of the novel structure of the present invention also have good selectivity to other PI3K subtypes, and the selectivity of some compounds is listed in Table 2. This provides a new basis for the preparation of cancer therapeutic drugs.
- PI3K ⁇ inhibitors The effects of a series of PI3K ⁇ inhibitors on cell viability were detected by MTT assay.
- Mino, Raji and OCI-LY7 cells were resuspended in medium to form a single cell suspension, 10 ⁇ L of cell suspension was mixed with 10 ⁇ L of 0.4% trypan blue solution, and the number of viable cells was counted with a hemocytometer after 5 minutes.
- cells were seeded into 96-well plates at a density of 10,000 cells/well and treated with various concentrations of compounds for 72 hours. 20 ⁇ L of MTT solution (5 mg/ml) was then added to each well and incubated for an additional 4 hours.
- the formed formazan crystals were dissolved with 100 ⁇ L of DMSO, and then the absorbance was measured on a microplate reader (Bio-Tek, CA, USA) at a wavelength of 570 nm.
- the formula for calculating the inhibition rate is as follows: (OD control cells-OD treated cells-ODDay0)/(OD control cells-ODDay0) ⁇ 100%, where ODDay0 represents the OD value of the control cells before treatment.
- Half-inhibitory concentration values were calculated using GraphPad Prism 5.0 software (GraphPad software, CA, USA).
- the compounds with the new structure of the present invention can all show excellent anti-proliferation activities on lymphoma cells, and are better than the positive control compound Idelalisib.
- the anti-proliferative activities of some compounds on lymphoma cells are listed in Table 3.
- the compound of the present invention has a weaker inhibitory effect on human normal lymphocyte CAM-191 than Idelalisib, showing better safety.
- the inhibitory effect of some compounds on human normal lymphocyte CAM-191 is listed in the table. 4.
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Abstract
L'invention concerne un composé de formule (1) et/ou des sels pharmaceutiquement acceptables de celui-ci, et/ou des mélanges racémiques, des hydrates, des solvates, des promédicaments, des énantiomères, des diastéréomères et des tautomères de ceux-ci. L'invention concerne une composition pharmaceutique contenant le composé de formule (1), ainsi qu'une application de celle-ci dans la préparation d'un inhibiteur de PI3 kinase, un médicament pour le traitement d'une maladie sensible à l'inhibition de PI3K.
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CN101448505A (zh) * | 2006-04-04 | 2009-06-03 | 加利福尼亚大学董事会 | Pi3激酶拮抗剂 |
CN104428293A (zh) * | 2012-06-11 | 2015-03-18 | Ucb生物制药私人有限公司 | 调节TNFα的苯并咪唑类 |
CN105431437A (zh) * | 2013-07-02 | 2016-03-23 | 理森制药股份公司 | PI3K蛋白激酶抑制剂,特别是δ抑制剂和/或γ抑制剂 |
CN110156785A (zh) * | 2019-04-15 | 2019-08-23 | 浙江大学 | 吲唑类化合物及其制备方法和应用 |
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US8188109B2 (en) * | 2009-07-20 | 2012-05-29 | Naxospharma S.R.L. | Benzoquinolizinium salt derivatives as anticancer agents |
CN107033145B (zh) * | 2016-02-04 | 2019-11-22 | 浙江大学 | 苯并噻嗪和苯并噻二嗪类化合物及制备和应用 |
EP3964512A4 (fr) * | 2019-06-27 | 2022-08-10 | Hangzhou Healzen Therapeutics Co., Ltd. | INHIBITEUR DE CASÉINE KINASE 1epsilon, COMPOSITION PHARMACEUTIQUE ET UTILISATION ASSOCIÉE |
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CN101448505A (zh) * | 2006-04-04 | 2009-06-03 | 加利福尼亚大学董事会 | Pi3激酶拮抗剂 |
CN104428293A (zh) * | 2012-06-11 | 2015-03-18 | Ucb生物制药私人有限公司 | 调节TNFα的苯并咪唑类 |
CN105431437A (zh) * | 2013-07-02 | 2016-03-23 | 理森制药股份公司 | PI3K蛋白激酶抑制剂,特别是δ抑制剂和/或γ抑制剂 |
CN110156785A (zh) * | 2019-04-15 | 2019-08-23 | 浙江大学 | 吲唑类化合物及其制备方法和应用 |
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DATABASE REGISTRY 13 December 2013 (2013-12-13), ANONYMOUS : "-9H-Purin-6-amine, 9-[(1-methyl-1H-indazol-3-yl)methyl]- (CA INDEX NAME) ", XP055973223, retrieved from STN Database accession no. 1494310-19-8 * |
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