WO2022206583A1 - Indazole compound, preparation method therefor and application thereof - Google Patents

Indazole compound, preparation method therefor and application thereof Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
group
alkyl
Prior art date
Application number
PCT/CN2022/082962
Other languages
French (fr)
Chinese (zh)
Inventor
崔孙良
汤用美
赵华军
楼胜颖
楼斯悦
Original Assignee
浙江大学
浙江中医药大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江大学, 浙江中医药大学 filed Critical 浙江大学
Publication of WO2022206583A1 publication Critical patent/WO2022206583A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention 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.

Abstract

A compound of formula (1) and/or pharmaceutically acceptable salts thereof, and/or racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers and tautomers thereof. A pharmaceutical composition containing the compound of formula (1), and an application thereof in preparation of a PI3 kinase inhibitor, a medicament for treating a disease responsive to inhibition of PI3K.

Description

吲唑类化合物及其制备方法和应用Indazole compound and its preparation method and application 技术领域technical field
本发明涉及药物化学领域，具体涉及一类吲唑类化合物及其制备方法和应用。The invention relates to the field of medicinal chemistry, in particular to a class of indazole compounds and a preparation method and application thereof.
背景技术Background technique
一直以来，恶性肿瘤严重威胁着人类健康，特别是B细胞恶性肿瘤，包括慢性淋巴细胞白血病、急性淋巴细胞白血病、非霍奇金淋巴瘤、滤泡性淋巴瘤等。早期的治疗手段主要是通过传统的细胞毒药物来缓解患者的症状随着生物学家们对肿瘤形成机制的深入研究，肿瘤细胞内各种生理过程如信号通路的转导、细胞周期的调控、细胞调亡、血管生成等逐渐被人们所认识。其中PI3K/Akt信号传导通路是哺乳动物中重要的信号通路，其信号传导的异常激活被认为与肿瘤的发生和发展密切相关。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. With the in-depth study of tumor formation mechanism by biologists, various physiological processes in tumor cells such as signal pathway transduction, cell cycle regulation, Apoptosis and angiogenesis are gradually recognized by people. Among them, 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.
在PI3K/Akt信号通路中，PI3K是重要的节点蛋白，它是一类脂激酶，具有丝氨酸/苏氨酸(ser/Thr)激酶活性和磷脂酰肌醇激酶的活性，其功能主要是磷酸化磷脂酰肌醇的3′羟基。PI3Ks主要通过两种方式激活，一种是通过RTKs或GPCRs激活，另一种方式是通过催化亚基p110与Ras结合促使PI3K活化。被激活的PI3Ks磷酸化PIP2形成PIP3，PIP3作为第二信使，募集和激活蛋白激酶PDK1和Akt，从而激活下游效应器，调控细胞的增殖、分化、存活和迁移。有研究报道，PI3Kα抑制剂可以降低其他亚型抑制剂带来的血小板降低、贫血、转氨酶增高等副作用(Brana&Siu,BMC Medicine,Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment,2012,10-161)。In the PI3K/Akt signaling pathway, 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. Activated 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 PI3Kα 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) .
公开号为CN 110156785 A的专利说明书公开了一种吲唑类化合物，以吲唑作为结构母核，设计并合成了一系列小分子PI3Kδ抑制剂，并对该类化合物进行了PI3Kδ激酶抑制活性测试和MV-4-11细胞活性测试，表现出良好的激酶亚型选择性，并且对肿瘤细胞株表现出了更好的体外增殖抑制活性。The patent specification with publication number CN 110156785 A discloses an indazole compound. Using indazole as the structural core, a series of small-molecule PI3Kδ inhibitors have been designed and synthesized, and the PI3Kδ kinase inhibitory activity test has been carried out on these compounds. And MV-4-11 cell activity test, showed good kinase isoform selectivity, and showed better in vitro proliferation inhibitory activity against tumor cell lines.
PI3Kδ作为PI3Ks家族中的重要一员，特异性存在于造血细胞和免疫细胞中，在B细胞表面受体信号转导中发挥着重要作用，调控B细胞的增殖、分化与存活。PI3Kδ被认为是治疗B细胞恶性肿瘤和自身免疫疾病的重要靶点。目前已有三个PI3Kδ被FDA批准上市，分别是2014年Gliade公司上市的用于治疗B细胞非霍奇金淋巴瘤(NHL)以及和利妥昔单抗联用治疗慢性淋巴细胞白血病的Idelalisib、2017年Bayer公司上市的用于治疗至少2种系统性疗法治疗后病情复发的滤泡性淋巴瘤(FL)成人患者的静脉注射类药物Copanlisib以及2018年Intellikine公司上市的首个单药疗法治疗复发性、难治性慢性淋巴白血病、小淋巴细胞淋巴瘤患者及双重耐药的滤泡性淋巴瘤患者的口服药物Duvelisib。尽管上市药物对治疗B细胞恶性肿瘤有显著地治疗效果，但也具有一些严重的临床副作用和药物相互作用。因此急需开发一种新型更安全的PI3Kδ选择性抑制剂。目前认为，提高药物对于PI3Kδ亚型的选择性可以改善其安全性，为此我们合成了一系列PI3Kδ抑制剂，其中大部分化合物对于PI3K其他亚型都表现出了优异的选择性，并且部分化合物在人的正常淋巴细胞CAM191中表现出了比Idelalisib更好的安全性。As an important member of the PI3Ks family, PI3Kδ 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. PI3Kδ is considered an important target for the treatment of B-cell malignancies and autoimmune diseases. At present, three PI3Kδ 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. In 2018, 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, and in 2018, 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. Although 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 PI3Kδ selective inhibitor. At present, it is believed that improving the selectivity of drugs for PI3Kδ isoforms can improve its safety. For this reason, we have synthesized a series of PI3Kδ inhibitors, most of which show excellent selectivity for other PI3K isoforms, and some compounds A better safety profile than Idelalisib was shown in human normal lymphocytes CAM191.
发明内容SUMMARY OF THE INVENTION
本发明提供了一种与现有技术完全不同的，吲唑类化合物、其制备方法、药物组合物和用途。本发明的吲唑类化合物是一种选择性的PI3Kδ抑制剂，可用于制备治疗炎症性疾病、自身免疫性疾病、癌症、感染性疾病或心脑血管疾病的药物。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 PI3Kδ inhibitor, which can be used to prepare medicines for the treatment of inflammatory diseases, autoimmune diseases, cancer, infectious diseases or cardiovascular and cerebrovascular diseases.
本发明提供了式(1)的化合物The present invention provides compounds of formula (1)
Figure PCTCN2022082962-appb-000001
Figure PCTCN2022082962-appb-000001
和/或其药学上可接受的盐，和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体；and/or pharmaceutically acceptable salts thereof, and/or racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers and tautomers thereof;
其中R 1、R 2、R 3、R 4相同或不同，各自独立地选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基中的一个或多个，或者R 1和R 2通过偶联形成取代或非取代的C 4-10芳基的环结构、或形成取代或未取代的C 2-10杂芳基的环结构，或者R 2和R 3通过偶联形成取代或非取代的C 4-10芳基的环结构、或形成取代或未取代的C 2-10杂芳基的环结构，或者R 3和R 4通过偶联形成取代或非取代的C 4-10芳基的环结构、或形成取代或未取代的C 2-10杂芳基的环结构； wherein 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, heteroaryloxycarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, heteroarylcarbonyl Amine group, aminocarbonyl group, alkoxycarboxamido group, alkyl mercapto group, hydroxyalkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group One or more of the radicals, or R 1 and R 2 are coupled to form a substituted or unsubstituted C 4-10 aryl ring structure, or a substituted or unsubstituted C 2-10 heteroaryl ring structure , or R 2 and R 3 are coupled to form a substituted or unsubstituted C 4-10 aryl ring structure, or a substituted or unsubstituted C 2-10 heteroaryl ring structure, or R 3 and R 4 Formation of a substituted or unsubstituted C 4-10 aryl ring structure by coupling, or a substituted or unsubstituted C 2-10 heteroaryl ring structure;
R 5选自氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基； 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, cycloalkylcarbonylamino, heteroarylcarbonylamino, aminocarbonyl, alkoxycarboxamido, alkylmercapto, hydroxyl Alkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group;
X和Y相同或不同，各自独立地选自C或N；X and Y are the same or different, each independently selected from C or N;
R 6选自氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、胺基羰基； 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选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂 芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基； 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, heteroarylcarbonylamino, aminocarbonyl, alkoxycarboxamido, alkylmercapto, hydroxyl Alkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group;
R 8选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基； 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, heteroarylcarbonylamino, aminocarbonyl, alkoxycarboxamido, alkylmercapto, hydroxyl Alkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group;
R 9选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基。 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, heteroarylcarbonylamino, aminocarbonyl, alkoxycarboxamido, alkylmercapto, hydroxyl Alkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group.
在优选方案中，R 1、R 2、R 3、R 4相同或不同，选自氢、卤素、C 1-6烷基、氰基、烷氧基，例如氢、氟、氯、甲基、氰基、甲氧基等。 In a preferred embodiment, 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.
优选地，R 5为甲基、乙基、异丙基、环丙基等。 Preferably, R 5 is methyl, ethyl, isopropyl, cyclopropyl and the like.
又优选地，R 6选自苯基、萘基、吡啶基、吡唑基、喹啉基、噻吩基、吲哚基、2,3-二氢-1,4-苯并二氧杂芑基，其任选地被零个、一个或多个选自以下的取代基取代：卤素、羟基、-CN、C 1-6烷基、C 1-6卤代烷基、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-SO 2(C 1-6烷基)、甲氧基、-NHSO 2(C 1-6烷基)。 Also preferably, 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).
另外优选地，R 7选自H、甲基、乙基、任选地被零个、一个或多个取代基取代的如下所示的苯基或杂芳基： Also preferably, R7 is selected from H, methyl, ethyl, phenyl or heteroaryl optionally substituted with zero, one or more substituents as shown below:
Figure PCTCN2022082962-appb-000002
Figure PCTCN2022082962-appb-000002
以上所示的苯基或杂芳基上的取代基选自：F、OCH 3，OCH 2CH 3、OCH(CH 3) 2、CH 3、OCF 3、CN、CONH 2、CONHCH 3。 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 .
又优选地，R 8选自氨基、羟基； Also preferably, R 8 is selected from amino, hydroxyl;
还优选地，R 9选自氢、甲基、氨基。 Also preferably, R 9 is selected from hydrogen, methyl, amino.
在一优选例中，式(1)的化合物为下式(2)的化合物：In a preferred example, the compound of formula (1) is the compound of following formula (2):
Figure PCTCN2022082962-appb-000003
Figure PCTCN2022082962-appb-000003
其中R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9与式(1)中的定义相同。 wherein 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).
式(2)的化合物中，还可进行以下优选：In the compound of formula (2), the following optimization can also be carried out:
R 1、R 2各自独立地选自氢、卤素、硝基、氰基、氨基、羟基、酯基、酰胺、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、氟、氯、溴、碘、硝基、氰基、酰胺、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、氟、氯、溴、碘、硝基、氰基、酰胺、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、甲基、乙基、丙基、丁基、戊基、环丙基、环丁基、环戊基，取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、胺基羰基； 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选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基。 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.
式(2)的化合物具体可选自：Specifically, the compound of formula (2) can be selected from:
Figure PCTCN2022082962-appb-000004
Figure PCTCN2022082962-appb-000004
Figure PCTCN2022082962-appb-000005
Figure PCTCN2022082962-appb-000005
Figure PCTCN2022082962-appb-000006
Figure PCTCN2022082962-appb-000006
Figure PCTCN2022082962-appb-000007
Figure PCTCN2022082962-appb-000007
Figure PCTCN2022082962-appb-000008
Figure PCTCN2022082962-appb-000008
所述的式(2)的化合物的制备方法，可采用反应路线I合成化合物11-56，利用化合物6a采用反应路线II合成化合物57-85；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;
反应路线I包括以下过程：Reaction scheme I includes following process:
Figure PCTCN2022082962-appb-000009
Figure PCTCN2022082962-appb-000009
化合物1与亚硝酸钠、盐酸在DMF(N,N-二甲基甲酰胺)和水的溶液中反应生成取代吲唑-3-甲醛即化合物2，然后在格式试剂作用下形成化合物3，接着被二氧化锰氧化为化合物4，再与溴代物发生Ullman偶联生成化合物5，化合物5在硼氢化钠的作用下还原生成化合物6a，化合物6a和N-(叔丁氧羰基氨基)邻苯二甲酰亚胺在DIAD(偶氮二甲酸二异丙酯)和PPh 3(三苯基膦)存在的条件下发生Mitsunobu反应生成化合物7，接着经过肼解得到化合物8，化合物8在HCl/EA(乙酸乙酯)溶液中脱除Boc(叔丁氧羰基)生成化合物9，化合物9和不同取代的乙氧基丙二腈反应生成化合物10，最后再关环生成目标化合物11-56； 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. The Mitsunobu reaction of carboximide in the presence of DIAD (diisopropyl azodicarboxylate) and PPh 3 (triphenylphosphine) generates compound 7, which is then subjected to hydrazinolysis to obtain compound 8. Compound 8 is dissolved in HCl/EA (Ethyl acetate) solution removes Boc (tert-butoxycarbonyl) to generate compound 9, compound 9 reacts with different substituted ethoxymalononitrile to generate compound 10, and finally closes the ring to generate target compound 11-56;
反应路线II包括以下过程：Reaction scheme II includes the following process:
Figure PCTCN2022082962-appb-000010
Figure PCTCN2022082962-appb-000010
化合物6a在无水二氯甲烷中和氯化亚砜反应，醇被亲核取代生成相应的氯代物，即化合物6b，接着化合物6b和不同取代的吡唑并氨基嘧啶反应生成目标化合物57-85。Compound 6a was reacted with thionyl chloride in anhydrous dichloromethane, and the alcohol was nucleophilically substituted to generate the corresponding chloride, namely compound 6b, and then compound 6b reacted with different substituted pyrazoloaminopyrimidines to generate target compounds 57-85 .
按照上述方法制备得到的至少一种吲唑类化合物、其药学上可接受的盐、水合物、溶剂合物、多晶型物或前药可以通过柱色谱、高效液相色谱、结晶或其他适当的方法进行纯化。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.
本发明提供的上述化合物可以表现出互变异构、结构异构和立体异构的现象。本发明包括其任意互变或结构或立体异构形式及其混合物，它们具有调节激酶活性的能力，并且此能力并不限于任何一种异构或其混合物的形式。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.
本发明还提供了一种药物组合物，包含所述的式(1)的化合物和/或其药学上可接受的盐、和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体，以及一种或多种可药用载体、稀释剂、赋形剂。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.
药学上可接受的载体(即可药用载体)是指能与组合物中的活性成分相容(在一些实施方案中，能稳定活性成分)并且对所治疗的个体无害的载体。药用载剂和/或赋形剂可选自稀释剂、填充剂、盐、崩解剂、黏合剂、润滑剂、助流剂、润湿剂、控制释放基质、着色剂、调味剂、缓冲剂、稳定剂、增溶剂及其组合。A pharmaceutically acceptable carrier (ie, 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.
包含本文所述的式(1)化合物和/或其药学上可接受的盐的药物组合物可以以各种已知的方式、例如口服、局部、直肠、肠胃外、吸入或植入等方式施用。Pharmaceutical 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 .
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体制剂、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等。According to the purpose of treatment, 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.
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。In order to shape the pharmaceutical composition in tablet form, any of the excipients known and widely used in the art can be used. For example, 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 quaternary amine bases and sodium lauryl sulfate, etc.; wetting agents, such as glycerol, starch, etc.; adsorbents, such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, etc.; and lubricants, Such as pure talc, stearate, boric acid powder and polyethylene glycol. The usual coating materials can also be used to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered film tablets and multi-layered tablets as required.
为了使丸剂形式的药物组合物成形，可使用本领域任何己知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。In order to shape the pharmaceutical composition in pill form, 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.
为了使栓剂形式的药物组合物成形，可使用本领域任何己知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。To shape the pharmaceutical composition in the form of a suppository, 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 .
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体，例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。In order to prepare a pharmaceutical composition in the form of an injection, 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. In the preparation of injections, 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. In addition, usual solubilizers, buffers, pain relievers and the like may be added.
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。In the present invention, 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.
另一方面，本发明还提供了一种体内或体外抑制PI3K活性的方法，其包括使用有效量的一种式(1)的化合物和/或其药学上可接受的盐与PI3K接触。In another aspect, 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.
另一方面，本发明还提供了一种体内或体外抑制PI3K活性的方法，其包括使能有效抑制PI3K活性的量的一种药物组合物与PI3K接触，所述药物组合物包含一种式(1)的化合物(例如，本文中的任何化合物)和/或一种其药学上可接受的盐，以及 至少一种药学上可接受的赋形剂。In another aspect, 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.
另一方面，本发明还提供了一种治疗个体中对抑制Pl3K有响应的疾病的方法，其包括给需要其的个体施用能有效抑制所述个体中PI3K的量的一种式(1)的化合物和/或一种其药学上可接受的盐。In another aspect, 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.
另一方面，本发明还提供了一种治疗个体中对抑制Pl3K有响应的疾病的方法，其包括给需要其的个体施用能有效抑制所述个体中PI3K的量的一种药物组合物，所述药物组合物包含一种式(1)的化合物和/或一种其药学上可接受的盐，以及至少一种药学上可接受的赋形剂。In another aspect, 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.
本发明还提供了所述的式(1)的化合物和/或其药学上可接受的盐、和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体，和/或，所述的药物组合物，在制备PI3激酶抑制剂中的应用。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.
本发明中激酶优选为PI3激酶(PI3K)，进一步优选PI3激酶(PI3K)的p110δ亚型。In the present invention, the kinase is preferably PI3 kinase (PI3K), more preferably the p110δ isoform of PI3 kinase (PI3K).
本发明还提供了所述的式(1)的化合物和/或其药学上可接受的盐、和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体，和/或，所述的药物组合物，在制备用于治疗对抑制PI3K有响应的疾病的药剂中的应用。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.
所述对抑制PI3K有响应的疾病包括但不限于：炎症性疾病、自身免疫性疾病、癌症、感染性疾病、心脑血管疾病、代谢和/或内分泌功能障碍、神经疾病。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.
炎症性疾病指的是导致炎症反应的病理状态，尤其是由于嗜中性粒细胞趋化引起的。这种疾病的例子包括炎性皮肤疾病(包括银屑病和特应性皮炎)；系统性硬皮病和硬化症；与炎性肠病(例如克罗恩病和溃疡性结肠炎)有关的反应；缺血再灌注损伤，包括手术引起组织再灌注损伤、心肌缺血如心肌梗死、心脏骤停、心脏术后再灌注和经皮冠状动脉成形术后冠脉血管的异常收缩反应、中风和腹主动脉瘤手术组织再灌注损伤；中风继发脑水肿；颅外伤；失血性休克；室息；成人呼吸窘迫综合征；急性肺损伤；白塞氏病；皮肌炎；多发性肌炎；多发性硬化症；皮炎；脑膜炎；脑炎；葡萄膜炎；骨关节炎；狼疮性肾炎；自身免疫性疾病如类风湿性关节炎；舍格林氏综合征；脉管炎；涉及白细胞渗出的疾病；败血症或创伤继发中枢神经系统炎症性疾病、多器官损伤综合征：酒精性肝炎；细菌性肺炎；抗原-抗体复合物介导的疾病，包括肾小球肾炎：脓血症：结节病；组织/器官移植引起的免疫病理反应；肺部炎症，包括胸膜炎、肺泡炎、脉管炎、肺炎、慢性支气管炎、支气管扩张、弥漫性泛细支气管炎、过敏性肺炎、特发性肺纤维化以及囊性纤维化等。Inflammatory diseases refer to pathological conditions that lead to an inflammatory response, especially due to neutrophil chemotaxis. Examples of such 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; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis; Sjogren's syndrome; vasculitis; involving leukocyte extravasation inflammatory diseases of the central nervous system, multiple organ injury syndromes secondary to sepsis or trauma; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases, including glomerulonephritis: sepsis: Sarcoidosis; immunopathological response to tissue/organ transplantation; pulmonary inflammation, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic Pulmonary fibrosis and cystic fibrosis.
自身免疫性疾病是指机体对自身抗原发生免疫反应而导致自身组织或器官损害所引起的疾病或病症。自身免疫性疾病的例子包括但不限于：慢性阻塞性肺病、变应性鼻炎、红斑狼疮、重症肌无力、多发性硬化(MS)、类风湿性关节炎、银屑病、炎性肠病、哮喘和特发性血小板减少性紫瘢以及骨髓增生性疾病，例如骨髓纤维化、真性红细胞增多症/原发性血小板增多症性骨髓纤维化。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. Examples of 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.
所述的炎症性疾病、自身免疫性疾病包括类风湿性关节炎、慢性阻塞性肺病(COPD)、变应性鼻炎、哮喘、红斑狼疮、银屑病和多发性硬化。The inflammatory and autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis.
所述的癌症包括但不限于实体瘤或血液系统恶性肿瘤，包括皮肤、组织、器官、骨骼、软骨、血液和血管的癌症，其既包括原发性癌症，也包括转移性癌症。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.
实体瘤的非限制性例子包括胰腺癌；膀胱癌：结肠直肠癌：乳腺癌，包括转移性乳腺癌；前列腺癌，包括雄性激素依赖性和非雄性激素依赖性前列腺癌；肾癌，包括例如转移性肾细胞癌；肝细胞癌；肺癌，包括例如非小细胞肺癌(NSCLC)、细支气管肺泡癌(BAC)和肺腺癌；卵巢癌，包括例如进行性上皮癌或原发性腹膜癌；宫颈癌；胃癌；食道癌；头颈癌，包括例如头颈部鳞状细胞癌；皮肤癌，包括例如恶性黑素瘤：神经内分泌癌，包括转移性神经内分泌瘤：脑瘤，包括例如神经胶质瘤、间变性少突神经胶质瘤、成人多形性成胶质细胞瘤和成人间变型星形细胞瘤；骨癌；软组织肉瘤：和甲状腺癌。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; bone cancer; soft tissue sarcoma: and thyroid cancer.
血液系统恶性肿瘤的非限制性例子包括急性髓性白血病(AML)；慢性髓性白血病(CML)，包括加速期CML和CML急变期(CML-BP)：急性淋巴细胞白血病(ALL)；慢性淋巴细胞白血病(CLL)；霍奇金淋巴瘤；非霍奇金淋巴瘤(NHL)，包括滤泡型淋巴瘤和套细胞淋巴瘤；B细胞淋巴瘤；T细胞淋巴瘤；多发性骨髓瘤(MM)；瓦尔登斯特伦巨球蛋白血症；骨髓增生异常综合征，包括顽固性贫血、环状铁粒幼细胞顽固性贫血、过量芽细胞顽固性贫血和过量芽细胞顽固性贫血合并急性转化；以及骨髓增生综合征。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.
一些实施方案中，典型的，所述的癌症可选自白血病、多发性骨髓瘤(MM)、淋巴瘤；所述的白血病为急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)和慢性髓性白血病(CML)；所述的淋巴瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、套细胞淋巴瘤(MCL)、滤泡型淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、弥散性大B细胞淋巴瘤(DLBCL)；In some embodiments, typically, 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);
所述的感染性疾病包括但不限于细菌性感染、真菌性感染、病毒性感染、寄生虫感染。The infectious diseases include, but are not limited to, bacterial infections, fungal infections, viral infections, and parasitic infections.
所述的心脑血管疾病包括但不限于急性心力衰竭、低血压、高血压、心绞痛、心肌梗塞、心肌病、充血性心力衰竭、动脉粥样硬化、冠心病、再狭窄和血管狭窄，以及外伤性脑损伤、中风、缺血再灌注损伤和动脉The 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
此外，本文所述的式(1)的化合物和/或其药学上可接受的盐可与其它的活性成分联合用药，用于治疗炎症性疾病、自身免疫性疾病、癌症、感染性疾病或心脑血管疾病。式(1)的化合物和/或其药学上可接受的盐可与其它的活性成分分开用药或制成复方制剂。其它的活性成分是指那些已知的对治疗PI3K介导的疾病的有效的成分。In addition, 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.
定义definition
本申请中所用的下列单词、短语和符号具有如下所述的含义，其所处的上下文中另有说明的除外。The following words, phrases and symbols used in this application have the meanings set forth below unless the context in which they are used dictates otherwise.
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，-O(C 1-4烷基)是指通过氧原子与分子的其余部分连接的C 1-4烷基。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如，卤素取代基，“-”可以被省略。 A dash ("-") not between two letters or symbols indicates the site of attachment of the substituent. For example, -O(C 1-4 alkyl) refers to a C 1-4 alkyl group attached to the rest of the molecule through an oxygen atom. However, "-" may be omitted when the point of attachment of the substituent will be apparent to those skilled in the art, eg, halogen substituents.
本文所用的术语“烷基”是指含有1-18个碳原子、例如1-12个碳原子、再例如1-6个碳原子、再例如1-4个碳原子的直链或支链的饱和烷基。例如，“C 1-6烷基”在“烷基”的范围内，表示所述的具有1-6个碳原子的烷基。烷基的例子包括但不限于甲基(“Me”)、乙基(“Et”)、正丙基(“n-Pr”)、异丙基(“i-Pr”)、正丁基(“n-Bu”)、异丁基(“i-Bu”)、仲丁基(“s-Bu”)和叔丁基(“t-Bu”)。 The term "alkyl" as used herein 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. For example, "C 1-6 alkyl" within the scope of "alkyl" refers to the described alkyl group having 1-6 carbon atoms. Examples of 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").
本文所用的术语“卤代”是指氟代、氯代、溴代和碘代，“卤素”是指氟、氯、溴和碘。The term "halo" as used herein refers to fluoro, chloro, bromo and iodo, and "halogen" refers to fluoro, chloro, bromo and iodo.
本文所用的术语“卤代烷基”是指其中一个或多个氢原子、例如1、2、3、4或5个氢原子被卤素原子替代的本文所定义的烷基，并且当超过一个氢原子被卤素原子替代时，所述卤素原子可以彼此相同或不同。在一个实施方案中，本文所用的术语“卤代烷基”是指其中两个或更多个氢原子、例如2、3、4或5个氢原子被卤素原子替代的本文所定义的烷基，其中所述卤素原子彼此相同。在另一个实施方案中，本文所用的术语“卤代烷基”是指其中两个或更多个氢原子、例如2、3、4或5个氢原子被卤素原子替代的本文所定义的烷基，其中所述卤素原子彼此不同。卤代烷基的例子包括但不限于-CF 3、-CHF 2、-CH 2CF 3等。 The term "haloalkyl" as used herein 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. In one embodiment, 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. In another embodiment, 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 different from each other. Examples of haloalkyl groups include, but are not limited to, -CF3 , -CHF2 , -CH2CF3 , and the like.
本文所用的术语＂烷氧基”是指基团-O-烷基，其中烷基如上文所定义。烷氧基的例子包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基和已氧基，包括它们的异构体。The term "alkoxy" as used herein refers to the group -O-alkyl, wherein alkyl is as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexyloxy, including their isomers.
本文所用的术语“芳基”是指由一个环或多个环稠合组成的含有6-14个环碳原子，例如6-12个环碳原子的碳环烃基，其中至少一个环是芳族环并且其它环不是如下文所定义的杂芳基，其连接点可以在芳族环上或在其它环上。芳基的例子包括但不限于苯基、萘基、1,2,3,4-四氢萘基、茚基、茚满基、薁基，优选苯基。The term "aryl" as used herein 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. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl.
如本文所用，“芳基”或“芳族的”遵循休克尔规则，其中π电子数等于4n+2，n为零或任何最多为6的正整数。As used herein, "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.
本文所用的术语“杂芳基”或“杂芳的”是指选自4至12元单环的、双环的和三环的、饱和的和部分不饱和的环，其除了包含至少一个、例如1-4个、再例如1-3个或再例如1或2个选自O、S和N的杂原子外，还包含至少一个碳原子。杂芳基的连接点可以在杂原子上或在碳上。”杂芳基”或“杂芳的”也指单环，其包含至少一个选自O、S和N的杂原子；或者是稠环，其中至少一个环包含至少一个选自O、S和N的杂原子并且其它环不是杂芳基或芳基，其连接点可以在杂芳上或在其它环上。The term "heteroaryl" or "heteroaryl" as used herein 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.
本文所用的术语“杂芳基”是指：The term "heteroaryl" as used herein refers to:
具有5、6或7个环原子、例如具有6个环原子的单环芳族烃基，其在环中包含一个或多个、例如1、2或3个、例如1或2个独立地选自N、O和S的环杂原子，其余环原子是碳原子：和A monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, such as 6 ring atoms, which contains one or more, such as 1, 2 or 3, such as 1 or 2, in the ring independently selected from the group consisting of Ring heteroatoms of N, O and S, the remaining ring atoms are carbon atoms: and
有8-12个环原子、例如具有9或10个环原子的二环芳族烃基，其在环中包含一个或多个、例如1、2、3或4个、例如1或2个独立地选自N、O和S的环杂原子，其余环原子是碳原子，其中至少一个环是芳族环。例如，二环杂芳基包括与5-6元环烃基环、杂芳基环或芳基环稠合的5-6元杂芳基环，其中连接点可以在杂芳基环上或在环烷基环/杂芳基环/芳基环上。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. For example, 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.
杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基，例如N-氧化嘧啶基。Heteroaryl also includes those in which the N-ring heteroatom is in the N-oxide form, eg, N-oxypyrimidinyl.
在一些实施方案中，上述杂芳基中的环杂原子是N原子，这类杂芳基称为“含氮杂芳基”。含氮杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基，例如N-氧化吡啶基。In some embodiments, 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.
杂芳基的例子包括但不限于：吡啶基、N-氧化吡啶基；吡嗪基；嘧啶基；吡唑基； 咪唑基；恶唑基；异恶唑基；噻唑基；异噻唑基；噻二唑基；四唑基；三唑基；噻吩基；呋喃基；吡喃基；吡咯基；哒嗪基；苯并[d]噻唑基；苯并间二氧杂芳戊烯基，例如苯并[d][1,3]间二氧杂芳戊烯基；苯并恶唑基，例如苯并[d]恶唑基；咪唑并吡啶基，例如咪唑并[1,2-a]吡啶基；三唑并吡啶基，例如[l,2,4]三唑并[4,3-a]吡啶基和[1,2,4]三唑并[1,5-a]吡啶基；吲唑基；2H-吲唑基；吡咯并嘧啶基，例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基；吡唑并嘧啶基，例如吡唑并[1,5-a]嘧啶基；四唑并吡啶基，例如四唑并[1,5-a]吡啶基；苯并噻吩基；苯并呋喃基；苯并咪唑啉基；吲哚基；吲哚啉基；嘌呤基，例如9H-嘌呤基和7H-嘌呤基；喹啉基；异喹啉基；1,2,3,4-四氢喹啉基和1,2,3,4-四氢异喹啉基。Examples of 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-a]pyridyl; indium azolyl; 2H-indazolyl; pyrrolopyrimidinyl, eg, pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; pyrazolopyrimidinyl, eg, pyrazole zo[1,5-a]pyrimidinyl; tetrazolopyridyl, eg tetrazolo[1,5-a]pyridyl; benzothienyl; benzofuranyl; benzimidazolinyl; indolyl ; indolinyl; purinyl, such as 9H-purinyl and 7H-purinyl; quinolinyl; isoquinolinyl; 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4 - Tetrahydroisoquinolinyl.
含氮杂芳基的实例包括但不限于：吡咯基；吡唑基；咪唑基；吡啶基；吡嗪基；嘧啶基、N-氧化嘧啶基；哒嗪基；吡咯并嘧啶基，例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基；嘌呤基，例如9H-嘌呤基和7H-嘌呤基；喹啉基；吲哚基；以及吲唑基。Examples of 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 .
本文所述的术语“羟基”是指-OH基团。The term "hydroxyl" as used herein refers to the -OH group.
本文所用的术语“巯基”是指-SH基团。The term "thiol" as used herein refers to the -SH group.
本文所用的术语“羧基”是指-C(O)-OH基团。The term "carboxy" as used herein refers to a -C(O)-OH group.
本文所用的术语“氨基”是指-NH 2基团。 The term "amino" as used herein refers to the -NH2 group.
本文所用的术语“氰基”是指-CN基团。The term "cyano" as used herein refers to the -CN group.
如果本文的某个结构式包含星号“*”，则该结构式所表示的化合物为消旋体。If a structural formula herein contains an asterisk "*", the compound represented by the structural formula is a racemate.
本文所用的术语“被取代的”或“被·····取代”意指给定原子或基团上的一个或多个氢原子被一个或多个选自给定取代基替换，条件是不超过该给定原子的正常化合价。The term "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.
本文所用的术语“被一个或多个取代基取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个选自给定基团的取代基替换。在一些实施方案中，“被一个或多个取代基取代”意指给定的原子或基团被l、2、3或4个独立地选自给定基团的取代基取代。The term "substituted with one or more substituents" as used herein 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. In some embodiments, "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.
本领域技术人员应当理解的是，一些式(1)的化合物可以包含一个或多个手性中心，因此存在两个或更多个立体异构体。这些异构体的外消旋混合物、单个异构体和一种对映异构体富集的混合物，以及当有两个手性中心时的非对映异构体和特定的非对映异构体部分富集的混合物均在本发明的范围内。本领域技术人员还应当理解的是，本发明包括式(1)的化合物的所有单个立体异构体(例如对映异构体)、外消旋混合物或部分拆分的混合物，以及在适当的情况下，包括其单个互变异构体。It will be understood by those skilled in the art that 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.
本发明也提供了式(1)化合物的一种药学上可接受的盐，，“药学上可接受的盐”是指所公开化合物的衍生物，其中母体化合物通过使现有酸或碱部分转化成其盐形式而得到改性。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.
药学上可接受的盐包括但不限于：式(1)化合物与无机酸或有机酸形成的酸加成盐，药学上可接受的盐也包括带有酸性基团的式(1)化合物与药学上可接受的阳离子形成的碱加成盐。本发明的药学上可接受的盐可通过常规化学方法自含有碱性或酸性部分的母体化合物合成。一般来说，这些盐可通过使这些化合物的游离酸或碱形式与化学计算量的适当碱或酸在水或有机溶剂或两者的混合物中反应来制备。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. Base addition salts formed with acceptable cations. 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.
术语“溶剂合物”意指包含化学计量的或非化学计量的溶剂的溶剂加成形式。如果溶剂是水，则形成的溶剂合物是水合物，当溶剂是乙醇时，则形成的溶剂合物是乙醇合物。The term "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.
如本文所用，术语“接触”是指使指定部分在体外系统或体内系统中集合在一起。举例来说，使PI3K与本文所述的化合物“接触”包括向具有PI3K的个体或患者(如人类)施用本发明化合物以及例如将本文所述的化合物引入含有包含PI3K的细胞或纯化制剂的样品中。As used herein, the term "contacting" refers to bringing the specified moieties together in an in vitro system or an in vivo system. For example, "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.
术语“前药”指为化合物的非活性前体，在体内通过正常代谢途径转化为其活性形式的化合物。为了说明，可通过水解(例如)酯或酰胺键将前药转化为药理学活性形式，从而引入或暴露所生成的产物上的官能团。可将前药设计为与内源化合物反应以形成进一步增强化合物的药理学性质，例如增加循环半衰期的水溶性轭合物。或者，可将前药设计为官能团受(例如)葡糖醛酸、硫酸盐、谷胱甘肽、氨基酸或醋酸盐共价修饰。所生成的轭合物可被钝化且排于尿中，或致使其比母体化合物更有效。高分子量轭合物也可排于胆汁中，受酶裂解并释放回循环中，从而有效增加原先施用化合物的生物半衰期。The term "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. To illustrate, 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. Alternatively, 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.
本文所用的属于“个体”是指任何动物，包括哺乳动物和非哺乳动物，其中优选为大鼠、小鼠、其他啮齿动物，、其他啮齿动物、兔、狗、猫、猪、牛、绵羊、马或灵长类动物，且最优选为人类。As used herein, 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.
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。Technical and scientific terms that are not specifically defined herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.
具体实施方式Detailed ways
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的操作方法，通常按照常规条件，或按照制造厂商所建议的条件。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The operation method without specifying the specific conditions in the following examples is usually in accordance with the conventional conditions, or in accordance with the conditions suggested by the manufacturer.
制备实施例1Preparation Example 1
Figure PCTCN2022082962-appb-000011
Figure PCTCN2022082962-appb-000011
将亚硝酸钠(16.6g,0.24mol)置于三口瓶中，抽真空通氩气，置换三次，加入水(60mL)和DMF(45mL)，0℃下缓慢滴加27mL 2N盐酸，反应10min。将6-氯吲哚(4.5g,0.03mol)溶于36mL的DMF中，缓慢滴加进反应体系中，加完后室温反应5h。加入乙酸乙酯分层，收集有机层，水层用乙酸乙酯萃取三次，合并有机层，饱和碳酸氢钠洗，饱和氯化钠洗，无水硫酸钠干燥，浓缩得粗品，粗品用PE/EA重结晶，抽滤得黄色固体2(4g,75％)。Sodium nitrite (16.6g, 0.24mol) was placed in a three-necked flask, evacuated and vented with argon, replaced three times, water (60mL) and DMF (45mL) were added, and 27mL of 2N hydrochloric acid was slowly added dropwise at 0°C, and the reaction was performed for 10min. 6-Chloroindole (4.5 g, 0.03 mol) was dissolved in 36 mL of DMF, slowly added dropwise into the reaction system, and reacted at room temperature for 5 h after the addition. Ethyl acetate was added to separate layers, the organic layer was collected, the aqueous layer was extracted three times with ethyl acetate, the organic layers were combined, washed with saturated sodium bicarbonate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was washed with PE/ EA was recrystallized and suction filtered to obtain yellow solid 2 (4 g, 75%).
制备实施例2Preparation Example 2
Figure PCTCN2022082962-appb-000012
Figure PCTCN2022082962-appb-000012
将原料2(3.5g,19.4mmol)加入到两口瓶中，抽真空通氩气，置换三次，加入无水THF,将反应液冷却至-10℃，缓慢滴加甲基氯化镁(20mL,3.0M in THF)，滴加完成后移至室温反应，反应完成后在低温下加入饱和氯化铵溶液淬灭反应，收集有机层，饱和食盐水洗，硫酸钠干燥，浓缩，用EA/PE(v/v,1:3)的淋洗剂柱层析分离得淡黄色固体3(3.15g,83％)。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%).
制备实施例3Preparation Example 3
Figure PCTCN2022082962-appb-000013
Figure PCTCN2022082962-appb-000013
将原料3(3g,15.3mmol)加入单口瓶中，加入20mL二氯甲烷溶解，分批加入二氧化锰(6.7g,76.5mmol)，45℃回流反应。反应结束后趁热用硅藻土过滤，滤渣用四氢呋喃洗涤至滤出液无荧光，收集滤液，旋蒸除去溶剂，得黄色固体4(2.7g,91％)。Raw material 3 (3 g, 15.3 mmol) was added to a single-necked flask, 20 mL of dichloromethane was added to dissolve, manganese dioxide (6.7 g, 76.5 mmol) was added in batches, and the reaction was carried out at 45°C under reflux. After the reaction was completed, it was filtered through celite while it was still hot, and the filter residue was washed with tetrahydrofuran until the filtrate had no fluorescence. The filtrate was collected, and the solvent was removed by rotary evaporation to obtain yellow solid 4 (2.7 g, 91%).
注意：化合物19在此步，采用氯铬酸吡啶盐作氧化剂。Note: Compound 19 used pyridinium chlorochromate as the oxidant in this step.
制备实施例4Preparation Example 4
Figure PCTCN2022082962-appb-000014
Figure PCTCN2022082962-appb-000014
称取4(2.6g,13.4mmol)，碘化亚铜(514mg,2.7mmol)，L-脯氨酸(622mg,5.4mmol)，碳酸钾(3.7g,26.8mmol)加入到两口瓶中，氩气保护加入30mL DMSO,室温下加入3-溴吡啶(4.12g,20.1mmol)升温至120℃反应。反应完成后，冷却至室温，加入50mL乙酸乙酯搅拌20min，抽滤除去不溶物，滤液加入水，收集有机层，饱和食盐水洗，硫酸钠干燥，浓缩，粗品用PE/EA重结晶，抽滤得黄色固体5(2.88g,79％)。Weigh 4 (2.6g, 13.4mmol), cuprous iodide (514mg, 2.7mmol), L-proline (622mg, 5.4mmol), potassium carbonate (3.7g, 26.8mmol) into a two-necked flask, argon Under gas protection, 30 mL of DMSO was added, 3-bromopyridine (4.12 g, 20.1 mmol) was added at room temperature, and the temperature was raised to 120 °C for reaction. After the reaction was completed, it was cooled to room temperature, 50 mL of ethyl acetate was added and stirred for 20 min, the insolubles were removed by suction filtration, water was added to the filtrate, the organic layer was collected, washed with saturated brine, dried over sodium sulfate, concentrated, and the crude product was recrystallized with PE/EA and filtered with suction. 5 was obtained as a yellow solid (2.88 g, 79%).
制备实施例5Preparation Example 5
Figure PCTCN2022082962-appb-000015
Figure PCTCN2022082962-appb-000015
单口瓶中加入原料5(2.8g,10.3mmol)，加入甲醇，0℃下缓慢分批加入硼氢化钠(1.17g,30.9mmol)，搅拌半小时后移至室温搅拌。反应完成后，0℃下缓慢滴加饱和氯化铵溶液，搅拌半小时后加入水/乙酸乙酯分层，收集有机层，饱和食盐水洗，无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v,50:1)的淋洗剂经柱层析分离得淡黄色固体(2.35g,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. After the completion of the reaction, saturated ammonium chloride solution was slowly added dropwise at 0°C, and after stirring for half an hour, water/ethyl acetate was added to separate the layers, the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and washed with DCM/MeOH ( The eluent of v/v, 50:1) was separated by column chromatography to give a pale yellow solid (2.35 g, 83%).
注意：S构型的制备在此步使用(+)-DIP-Cl做手性催化剂。Note: The preparation of the S configuration uses (+)-DIP-Cl as the chiral catalyst in this step.
制备实施例6Preparation Example 6
Figure PCTCN2022082962-appb-000016
Figure PCTCN2022082962-appb-000016
两口瓶中加入6(2.2g,8mmol)，N’-BOC-N,N-氨基邻苯二甲胺(2.5g,9.6mmol)，三苯基膦(4.2g,16mmol)，抽真空通氩气，置换三次，加入无水THF，0℃下缓慢滴加DIAD(3.2g,16mmol)，加完后移至室温反应过夜。反应完成后加入水/乙酸乙酯分层，收集有机层，饱和食盐水洗，无水硫酸钠干燥，浓缩，用PE/EA(v/v,5:1)的淋洗剂经柱层析分离得淡黄色固体7(3.12g,75％)。Add 6 (2.2g, 8mmol), N'-BOC-N,N-amino-o-xylylenediamine (2.5g, 9.6mmol), triphenylphosphine (4.2g, 16mmol) to the two-necked flask, and vacuumize and pass argon The gas was replaced three times, anhydrous THF was added, and DIAD (3.2 g, 16 mmol) was slowly added dropwise at 0° C. After the addition, it was moved to room temperature to react overnight. After the reaction was completed, water/ethyl acetate was added to separate layers, the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with PE/EA (v/v, 5:1) eluent. 7 was obtained as a pale yellow solid (3.12 g, 75%).
制备实施例7Preparation Example 7
Figure PCTCN2022082962-appb-000017
Figure PCTCN2022082962-appb-000017
单口瓶中加入原料7(3g,5.8mmol),加入THF，加入水合肼(6mL),70℃回流反应3h。反应结束后，加入水/乙酸乙酯分层，收集有机层，水洗三次，饱和食盐水洗两次，无水硫酸钠干燥，浓缩，用PE/EA/(v/v,2:1)的淋洗剂经柱层析分离得淡黄色固体7(1.9g,85％)。Raw material 7 (3 g, 5.8 mmol) was added to the single-necked flask, THF was added, hydrazine hydrate (6 mL) was added, and the reaction was carried out under reflux at 70° C. for 3 h. After the reaction, water/ethyl acetate was added to separate layers, the organic layer was collected, washed three times with water, twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and rinsed with PE/EA/(v/v, 2:1) The lotion was separated by column chromatography to give 7 (1.9 g, 85%) as a pale yellow solid.
制备实施例8Preparation Example 8
Figure PCTCN2022082962-appb-000018
Figure PCTCN2022082962-appb-000018
单口瓶中加入原料8(1.8g，4.6mmol)，加入氯化氢的乙酸乙酯溶液(3N,6mL),45℃反应2h,有白色固体析出，直接旋干得到产物9(1.27g，95％)。Raw material 8 (1.8 g, 4.6 mmol) was added to the single-necked flask, ethyl acetate solution of hydrogen chloride (3N, 6 mL) was added, and the reaction was carried out at 45° C. for 2 h. A white solid was precipitated, and the product was directly spin-dried to obtain product 9 (1.27 g, 95%) .
制备实施例9Preparation Example 9
Figure PCTCN2022082962-appb-000019
Figure PCTCN2022082962-appb-000019
单口瓶中加入原料9(1.2g,4.2mmol),乙醇溶解，加入1-氧基马来腈(571mg,4.2mmol)，0℃下缓慢加入三乙胺，搅拌1h后室温反应过夜。反应结束后，直接旋干，用PE/EA(v/v,2:1)的淋洗剂经柱层析分离得淡黄色固体7(680mg,43％)。Raw material 9 (1.2 g, 4.2 mmol) was added to a single-necked flask, dissolved in ethanol, 1-oxymaleonitrile (571 mg, 4.2 mmol) was added, triethylamine was slowly added at 0° C., stirred for 1 h, and reacted at room temperature overnight. After the reaction, it was directly spin-dried, and was separated by column chromatography with the eluent of PE/EA (v/v, 2:1) to obtain pale yellow solid 7 (680 mg, 43%).
制备实施例10Preparation Example 10
Figure PCTCN2022082962-appb-000020
Figure PCTCN2022082962-appb-000020
将原料10(600mg,1.6mmol)置于耐压管中，加入甲酰胺(3mL)，190℃反应4h。反应结束后，加入水/乙酸乙酯分层，收集有机层，水相用乙酸乙酯萃取三次，合并有机相，水洗三次，饱和食盐水洗两次，无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v,30:1)的淋洗剂经柱层析分离得淡黄色固体11(465mg,72％)。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%).
1H NMR(500MHz,Chloroform-d)δ9.04(d,J＝2.5Hz,1H),8.62(dd,J＝5.0,1.5Hz,1H),8.40(s,1H),8.06(ddd,J＝8.5,2.5,1.5Hz,1H),7.66(d,J＝1.5Hz,1H),7.49(dd,J＝8.5,5.0Hz,1H),7.43(d,J＝8.5Hz,1H),7.07(dd,J＝8.5,1.5Hz,1H),6.58(q,J＝7.0Hz,1H),5.68(brs,3H),2.60(s,3H),2.16(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.27,156.04,154.26,147.78,147.58,143.77,141.00,140.49,136.41,134.27,129.95,124.05,122.95,122.33,121.98,109.85,99.87,49.56,18.51,14.88. 1 H NMR (500MHz, Chloroform-d) δ9.04 (d, J=2.5Hz, 1H), 8.62 (dd, J=5.0, 1.5Hz, 1H), 8.40 (s, 1H), 8.06 (ddd, J =8.5,2.5,1.5Hz,1H),7.66(d,J=1.5Hz,1H),7.49(dd,J=8.5,5.0Hz,1H),7.43(d,J=8.5Hz,1H),7.07 (dd,J=8.5,1.5Hz,1H),6.58(q,J=7.0Hz,1H),5.68(brs,3H),2.60(s,3H),2.16(d,J=7.0Hz,3H) . 13 C NMR(126MHz,CDCl 3 )δ158.27,156.04,154.26,147.78,147.58,143.77,141.00,140.49,136.41,134.27,129.95,124.05,122.95,122.33,121.98,109.85,99.87,49.56,18.51,14.88.
制备实施例11 3-甲基-1-(1-(6-甲基-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-1H-吡唑并[3,4-d]嘧啶-4-胺12Preparation Example 11 3-Methyl-1-(1-(6-methyl-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3 ,4-d]pyrimidin-4-amine 12
Figure PCTCN2022082962-appb-000021
Figure PCTCN2022082962-appb-000021
制备方法同制备实施案例1-10类似，更换反应物即可，下同，柱层析得白色固体12，收率73％。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%.
1H NMR(500MHz,CDCl 3)δ9.07(d,J＝2.5Hz,1H),8.57(dd,J＝5.0,1.5Hz,1H),8.40(s,1H),8.09(ddd,J＝8.5,2.5,1.5Hz,1H),7.49-7.44(m,2H),7.37(d,J＝8.0Hz,1H),6.92(d,J＝8.5Hz,1H),6.58(q,J＝7.0Hz,1H),5.85(brs,2H),2.58(s,3H),2.44(s,3H),2.16(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.26,155.94,154.25,147.35,147.15,143.66,140.77,140.67,138.22,136.99,129.87,123.98,123.95,121.59,120.83,109.55,99.87,49.71,22.05,18.54,14.88. 1 H NMR (500MHz, CDCl 3 ) δ 9.07 (d, J=2.5Hz, 1H), 8.57 (dd, J=5.0, 1.5Hz, 1H), 8.40 (s, 1H), 8.09 (ddd, J= 8.5,2.5,1.5Hz,1H),7.49-7.44(m,2H),7.37(d,J=8.0Hz,1H),6.92(d,J=8.5Hz,1H),6.58(q,J=7.0 Hz, 1H), 5.85(brs, 2H), 2.58(s, 3H), 2.44(s, 3H), 2.16(d, J=7.0Hz, 3H). 13 C NMR(126MHz, CDCl 3 )δ158.26,155.94 ,154.25,147.35,147.15,143.66,140.77,140.67,138.22,136.99,129.87,123.98,123.95,121.59,120.83,109.55,99.87,49.71,22.05,18.54,14
制备实施例12 3-甲基-1-(1-(1-(1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-1H-吡唑并[3,4-d]嘧啶-4-胺13Preparation Example 12 3-methyl-1-(1-(1-(1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4 -d]pyrimidin-4-amine 13
Figure PCTCN2022082962-appb-000022
Figure PCTCN2022082962-appb-000022
制备方法同制备实施案例1-10，柱层析得白色固体13，收率75％。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%.
1H NMR(500MHz,CDCl 3)δ9.08(d,J＝2.5Hz,1H),8.58(dd,J＝4.5,1.5Hz,1H),8.41(s,1H),8.10(ddd,J＝8.5,2.5,1.5Hz,1H),7.68(d,J＝8.5Hz,1H),7.52(d,J＝8.0Hz,1H),7.46(dd,J＝8.5,4.5Hz,1H),7.39(t,J＝8.5,Hz,1H),7.10(t,J＝8.0Hz,1H), 6.62(q,J＝7.0Hz,1H),5.86(brs,2H),2.59(s,3H),2.18(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.27,155.97,154.27,147.45,147.30,143.64,140.85,140.05,136.91,129.84,127.69,123.97,123.47,121.87,121.33,110.00,99.88,49.65,18.55,14.89. 1 H NMR (500MHz, CDCl 3 ) δ 9.08 (d, J=2.5Hz, 1H), 8.58 (dd, J=4.5, 1.5Hz, 1H), 8.41 (s, 1H), 8.10 (ddd, J= 8.5, 2.5, 1.5Hz, 1H), 7.68 (d, J=8.5Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.46 (dd, J=8.5, 4.5Hz, 1H), 7.39 ( t,J＝8.5,Hz,1H),7.10(t,J＝8.0Hz,1H), 6.62(q,J＝7.0Hz,1H),5.86(brs,2H),2.59(s,3H),2.18 (d, J=7.0 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 158.27, 155.97, 154.27, 147.45, 147.30, 143.64, 140.85, 140.05, 136.91, 129.84, 127.69, 123.97, 123.47, 121.8 110.00, 99.88, 49.65, 18.55, 14.89.
制备实施例13 1-(1-(6-氟-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺14Preparation Example 13 1-(1-(6-Fluoro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine 14
Figure PCTCN2022082962-appb-000023
Figure PCTCN2022082962-appb-000023
制备方法同制备实施案例1-10，柱层析得白色固体14，收率78％。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%.
1H NMR(500MHz,DMSO-d 6)δ9.05(d,J＝2.5Hz,1H),8.63(dd,J＝4.5,1.5Hz,1H),8.25(s,1H),8.25-8.22(m,1H),7.72-7.68(m,1H),7.64(dd,J＝8.0,4.5Hz,1H),7.41(dd,J＝9.0,5.5Hz,1H),7.07(td,J＝9.0,2.0Hz,1H),6.50(q,J＝7.0Hz,1H),2.51(s,3H),2.03(d,J＝7.0Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ163.66and 163.37,161.72,158.95,156.48,154.32,148.05,143.46,141.72,140.30and 140.20,136.30,129.83,124.92,122.92and 122.83,120.29,112.13and 111.93,99.23,97.57and 97.35,49.11,18.73,14.97. 1 H NMR (500MHz, DMSO-d 6 ) δ 9.05 (d, J=2.5Hz, 1H), 8.63 (dd, J=4.5, 1.5Hz, 1H), 8.25 (s, 1H), 8.25-8.22 ( m, 1H), 7.72-7.68 (m, 1H), 7.64 (dd, J=8.0, 4.5Hz, 1H), 7.41 (dd, J=9.0, 5.5Hz, 1H), 7.07 (td, J=9.0, 2.0Hz, 1H), 6.50 (q, J=7.0Hz, 1H), 2.51 (s, 3H), 2.03 (d, J=7.0Hz, 3H). 13 C NMR (126MHz, DMSO-d 6 )δ163. 66and 163.37,161.72,158.95,156.48,154.32,148.05,143.46,141.72,140.30and 140.20,136.30,129.83,124.92,122.92and 122.83,120.29,112.13and 111.93,99.23,97.57and 97.35,49.11,18.73,14.97.
制备实施例14 1-(1-(5-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺15Preparation Example 14 1-(1-(5-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine 15
Figure PCTCN2022082962-appb-000024
Figure PCTCN2022082962-appb-000024
制备方法同制备实施案例1-10，柱层析得淡黄色固体15，收率76％。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%.
1H NMR(500MHz,CDCl 3)δ9.04(d,J＝2.0Hz,1H),8.61(d,J＝4.5Hz,1H),8.41(s,1H),8.07(ddd,J＝8.5,2.5,1.5Hz,1H),7.62-7.58(m,2H),7.48(dd,J＝8.0,4.5Hz,1H),7.34(dd,J＝9.0,2.0Hz,1H),6.56(q,J＝7.0Hz,1H),5.81(brs,2H),2.61(s,3H),2.15(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.16,155.94,154.28,147.74,146.89,143.61,141.04,138.58,136.51,129.94,128.32,127.47,124.34,124.04,120.85,111.10,99.92,49.61,18.59,14.89. 1 H NMR (500MHz, CDCl 3 ) δ 9.04 (d, J=2.0Hz, 1H), 8.61 (d, J=4.5Hz, 1H), 8.41 (s, 1H), 8.07 (ddd, J=8.5, 2.5,1.5Hz,1H),7.62-7.58(m,2H),7.48(dd,J=8.0,4.5Hz,1H),7.34(dd,J=9.0,2.0Hz,1H),6.56(q,J =7.0Hz, 1H), 5.81(brs, 2H), 2.61(s, 3H), 2.15(d, J=7.0Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ158.16, 155.94, 154.28, 147.74, 146.89,143.61,141.04,138.58,136.51,129.94,128.32,127.47,124.34,124.04,120.85,111.10,99.92,49.61,18.59,14.89.
制备实施例15 1-(1-(6-甲氧基-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺16Preparation Example 15 1-(1-(6-Methoxy-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[ 3,4-d]pyrimidin-4-amine 16
Figure PCTCN2022082962-appb-000025
Figure PCTCN2022082962-appb-000025
制备方法同制备实施案例1-10，柱层析得黄色固体16，收率80％。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%.
1H NMR(500MHz,CDCl 3)δ9.05(d,J＝2.5Hz,1H),8.59-8.57(m,1H),8.40(s,1H),8.09(dt,J＝8.0,2.0Hz,1H),7.47(dd,J＝8.0,4.5Hz,1H),7.35(d,J＝9.0Hz,1H),7.01(d,J＝2.0Hz,1H),6.74(dd,J＝9.0,2.5Hz,1H),6.56(q,J＝7.0Hz,1H),5.79(brs,2H),3.81(s,3H),2.59(s,3H),2.15(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ160.36,158.16,155.91,154.23,147.50,147.28,143.57,141.43,140.79,137.01,130.11,124.08, 122.07,117.96,113.41,99.86,91.49,55.61,49.69,18.57,14.89. 1 H NMR (500MHz, CDCl 3 ) δ 9.05 (d, J=2.5Hz, 1H), 8.59-8.57 (m, 1H), 8.40 (s, 1H), 8.09 (dt, J=8.0, 2.0Hz, 1H), 7.47(dd, J＝8.0, 4.5Hz, 1H), 7.35(d, J＝9.0Hz, 1H), 7.01(d, J＝2.0Hz, 1H), 6.74(dd, J＝9.0, 2.5 Hz, 1H), 6.56(q, J=7.0Hz, 1H), 5.79(brs, 2H), 3.81(s, 3H), 2.59(s, 3H), 2.15(d, J=7.0Hz, 3H). 13 C NMR(126MHz,CDCl 3 )δ160.36,158.16,155.91,154.23,147.50,147.28,143.57,141.43,140.79,137.01,130.11,124.08, 122.07,117.96,113.41,99.86,91.49,55.61,49.69,18.57,14.89 .
制备实施例16 3-(1-(4-氨基-3-甲基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-1-(吡啶-3-基)-1H-吲唑-6-腈17Preparation Example 16 3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-(pyridin-3-yl) -1H-Indazole-6-carbonitrile 17
Figure PCTCN2022082962-appb-000026
Figure PCTCN2022082962-appb-000026
制备方法同制备实施案例1-10，柱层析得白色固体17，收率77％。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%.
1H NMR(500MHz,DMSO-d 6)δ9.01(d,J＝2.5Hz,1H),8.60(d,J＝4.5Hz,1H),8.41(s,1H),8.26-8.19(m,1H),8.17(s,1H),7.59(dd,J＝8.5,4.5Hz,1H),7.50-7.43(m,2H),6.47(q,J＝7.0Hz,1H),2.42(s,3H),1.96(d,J＝7.0Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ158.95,156.55,154.35,148.62,148.19,143.96,141.88,138.77,135.88,130.49,125.24,124.99,124.74,122.42,119.34,117.19,110.53,99.24,49.06,18.74,14.97. 1 H NMR (500MHz, DMSO-d 6 )δ9.01(d, J=2.5Hz, 1H), 8.60(d, J=4.5Hz, 1H), 8.41(s, 1H), 8.26-8.19(m, 1H), 8.17(s, 1H), 7.59(dd, J=8.5, 4.5Hz, 1H), 7.50-7.43(m, 2H), 6.47(q, J=7.0Hz, 1H), 2.42(s, 3H) The _ ,122.42,119.34,117.19,110.53,99.24,49.06,18.74,14.97.
制备实施例17 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)丙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺18Preparation Example 17 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)propyl)-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine 18
Figure PCTCN2022082962-appb-000027
Figure PCTCN2022082962-appb-000027
制备方法同制备实施案例1-10，柱层析得白色固体18，收率75％。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%.
1H NMR(500MHz,CDCl 3)δ9.03(d,J＝2.5Hz,1H),8.61(dd,J＝4.5,1.5Hz,1H),8.40(s,1H),8.05(ddd,J＝8.0,2.5,1.5Hz,1H),7.66(d,J＝1.5Hz,1H),7.61(d,J＝8.5Hz,1H),7.48(dd,J＝8.0,4.5Hz,1H),7.09(dd,J＝8.5,1.5Hz,1H),6.31(dd,J＝9.5,6.0Hz,1H),5.84(brs,2H),2.80-2.64(m,2H),2.60(s,3H),0.94(t,J＝7.5Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.23,156.03,155.08,147.78,147.01,143.79,141.04,140.42,136.40,134.25,129.95,124.03,122.92,122.59,122.19,109.81,99.68,55.56,25.73,14.92,10.91. 1 H NMR (500MHz, CDCl 3 ) δ 9.03 (d, J=2.5Hz, 1H), 8.61 (dd, J=4.5, 1.5Hz, 1H), 8.40 (s, 1H), 8.05 (ddd, J= 8.0,2.5,1.5Hz,1H),7.66(d,J=1.5Hz,1H),7.61(d,J=8.5Hz,1H),7.48(dd,J=8.0,4.5Hz,1H),7.09( dd,J＝8.5,1.5Hz,1H),6.31(dd,J＝9.5,6.0Hz,1H),5.84(brs,2H),2.80-2.64(m,2H),2.60(s,3H),0.94 (t, J=7.5Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ) δ 158.23, 156.03, 155.08, 147.78, 147.01, 143.79, 141.04, 140.42, 136.40, 134.25, 129.95, 124.03, 122.192, 122. 109.81, 99.68, 55.56, 25.73, 14.92, 10.91.
制备实施例18 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)-2-甲基丙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺19Preparation Example 18 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)-2-methylpropyl)-3-methyl-1H-pyridine Azolo[3,4-d]pyrimidin-4-amine 19
Figure PCTCN2022082962-appb-000028
Figure PCTCN2022082962-appb-000028
制备方法同制备实施案例1-10，柱层析得白色固体19，收率82％。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%.
1H NMR(500MHz,CDCl 3)δ9.02(d,J＝2.5Hz,1H),8.61(dd,J＝5.0,1.5Hz,1H),8.39(s,1H),8.09(d,J＝8.5Hz,1H),8.04(ddd,J＝8.5,2.5,1.5Hz,1H),7.67(d,J＝1.5Hz,1H),7.47(dd,J＝8.5,5.0Hz,1H),7.18(dd,J＝8.5,1.5Hz,1H),6.01(d,J＝11.0Hz,1H),5.71(brs,2H),3.42-3.25(m,1H),2.60(s,3H),1.07(d,J＝6.5Hz,3H),0.86(d,J＝6.5Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.14,156.05,155.03,147.77,146.41,143.78,140.83,140.40,136.37,134.29,130.05,124.02,123.32,122.88,122.43,109.74,99.53,60.32,31.01,20.32,19.71,14.94. 1 H NMR (500MHz, CDCl 3 ) δ 9.02 (d, J=2.5Hz, 1H), 8.61 (dd, J=5.0, 1.5Hz, 1H), 8.39 (s, 1H), 8.09 (d, J= 8.5Hz,1H),8.04(ddd,J=8.5,2.5,1.5Hz,1H),7.67(d,J=1.5Hz,1H),7.47(dd,J=8.5,5.0Hz,1H),7.18( dd,J=8.5,1.5Hz,1H),6.01(d,J=11.0Hz,1H),5.71(brs,2H),3.42-3.25(m,1H),2.60(s,3H),1.07(d , J=6.5Hz, 3H), 0.86 (d, J=6.5Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ158.14, 156.05, 155.03, 147.77, 146.41, 143.78, 140.83, 140.40, 136.37, 134.29, 130.05,124.02,123.32,122.88,122.43,109.74,99.53,60.32,31.01,20.32,19.71,14.94.
制备实施例19 1-((6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)(环丙基)甲基)-3-甲基-1H-吡 唑并[3,4-d]嘧啶-4-胺20Preparation Example 19 1-((6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)(cyclopropyl)methyl)-3-methyl-1H-pyrazolo [3,4-d]pyrimidin-4-amine 20
Figure PCTCN2022082962-appb-000029
Figure PCTCN2022082962-appb-000029
制备方法同制备实施案例1-10，柱层析得白色固体20，收率80％。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%.
1H NMR(500MHz,Chloroform-d)δ9.04(dd,J＝2.7,0.7Hz,1H),8.61(dd,J＝4.8,1.5Hz,1H),8.39(s,1H),8.06(ddd,J＝8.2,2.6,1.5Hz,1H),7.66(dd,J＝1.7,0.6Hz,1H),7.49(ddd,J＝8.2,4.8,0.8Hz,1H),7.44(dd,J＝8.6,0.7Hz,1H),7.06(dd,J＝8.6,1.7Hz,1H),6.58(q,J＝7.1Hz,1H),5.84(s,2H),2.59(s,3H),2.16(d,J＝7.1Hz,3H)； 13C NMR(126MHz,CDCl3)δ158.27,156.05,154.26,147.78,147.58,143.77,140.99,140.49,136.41,134.27,129.95,124.05,122.95,122.33,121.98,109.85,99.87,49.56,18.51,14.88. 1 H NMR (500MHz, Chloroform-d) δ 9.04 (dd, J=2.7, 0.7 Hz, 1H), 8.61 (dd, J=4.8, 1.5 Hz, 1H), 8.39 (s, 1H), 8.06 (ddd , J=8.2, 2.6, 1.5Hz, 1H), 7.66 (dd, J=1.7, 0.6Hz, 1H), 7.49 (ddd, J=8.2, 4.8, 0.8Hz, 1H), 7.44 (dd, J=8.6 ,0.7Hz,1H),7.06(dd,J=8.6,1.7Hz,1H),6.58(q,J=7.1Hz,1H),5.84(s,2H),2.59(s,3H),2.16(d , J=7.1Hz, 3H); 13 C NMR (126MHz, CDCl3)δ158.27,156.05,154.26,147.78,147.58,143.77,140.99,140.49,136.41,134.27,129.95,124.05,122.9,5. ,49.56,18.51,14.88.
制备实施例20 1-(1-(6-氯-1-(吡啶-4-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺21Preparation Example 20 1-(1-(6-Chloro-1-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine 21
Figure PCTCN2022082962-appb-000030
Figure PCTCN2022082962-appb-000030
制备方法同制备实施案例1-10，柱层析得白色固体21，收率82％。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%.
1H NMR(500MHz,CDCl 3)δ8.76-8.71(m,2H),8.40(s,1H),7.81(d,J＝1.5Hz,1H),7.77-7.72(m,2H),7.41(d,J＝8.5Hz,1H),7.09(d,J＝8.5Hz,1H),6.56(q,J＝7.0Hz,1H),5.77(brs,2H),2.59(s,3H),2.16(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.21,156.09,154.32,151.16,148.28,146.50,141.06,140.11,134.62,123.43,122.84,122.46,115.24,110.73,99.87,49.52,18.39,14.88. 1 H NMR (500MHz, CDCl 3 ) δ 8.76-8.71(m, 2H), 8.40(s, 1H), 7.81(d, J=1.5Hz, 1H), 7.77-7.72(m, 2H), 7.41( d, J＝8.5Hz, 1H), 7.09(d, J＝8.5Hz, 1H), 6.56(q, J＝7.0Hz, 1H), 5.77(brs, 2H), 2.59(s, 3H), 2.16( d, J=7.0Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ158.21, 156.09, 154.32, 151.16, 148.28, 146.50, 141.06, 140.11, 134.62, 123.43, 122.84, 122.46, 115.24, 495.46, 115.24, 495.7. ,18.39,14.88.
制备实施例21 1-(1-(6-氯-1-(吡啶-2-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺22Preparation Example 21 1-(1-(6-Chloro-1-(pyridin-2-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine 22
Figure PCTCN2022082962-appb-000031
Figure PCTCN2022082962-appb-000031
制备方法同制备实施案例1-10，柱层析得灰白色固体22，收率77％。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%.
1H NMR(500MHz,CDCl 3)δ8.86-8.86(m,1H),8.48(ddd,J＝5.0,2.0,1.0Hz,1H),8.39(s,1H),8.10(dt,J＝8.5,1.0Hz,1H),7.83-7.78(m,1H),7.33(d,J＝9.0Hz,1H),7.13(ddd,J＝7.5,5.0,1.0Hz,1H),7.06(dd,J＝9.0,2.0Hz,1H),6.56(q,J＝7.0Hz,1H),5.84(brs,2H),2.57(s,3H),2.17(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.25,155.96,154.25,153.95,147.57,147.27,140.95,140.33,138.19,134.12,123.27,122.43,121.19,120.04,115.29,113.62,99.86,49.66,18.38,14.86. 1 H NMR (500 MHz, CDCl 3 ) δ 8.86-8.86 (m, 1H), 8.48 (ddd, J=5.0, 2.0, 1.0 Hz, 1H), 8.39 (s, 1H), 8.10 (dt, J=8.5 ,1.0Hz,1H),7.83-7.78(m,1H),7.33(d,J＝9.0Hz,1H),7.13(ddd,J＝7.5,5.0,1.0Hz,1H),7.06(dd,J＝ 9.0,2.0Hz,1H),6.56(q,J=7.0Hz,1H),5.84(brs,2H),2.57(s,3H),2.17(d,J=7.0Hz,3H). 13C NMR( 126MHz,CDCl 3 )δ158.25,155.96,154.25,153.95,147.57,147.27,140.95,140.33,138.19,134.12,123.27,122.43,121.19,120.04,115.29,113.62,99.86,49.66,18.38,14.86.
制备实施例22 3-(3-(1-(4-氨基-3-甲基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氯-1H-吲唑-1-基)苯甲腈23Preparation Example 22 3-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-1H- Indazol-1-yl)benzonitrile 23
Figure PCTCN2022082962-appb-000032
Figure PCTCN2022082962-appb-000032
制备方法同制备实施案例1-10，柱层析得灰白色固体23，收率81％。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%.
1H NMR(500MHz,CDCl 3)δ8.40(s,1H),8.07-8.06(m,1H),7.99(dt,J＝7.5,2.0Hz,1H),7.69-7.62(m,3H),7.44(d,J＝8.5Hz,1H),7.08(dd,J＝8.5,2.0Hz,1H),6.57(q,J＝7.0Hz,1H),5.68(brs,2H),2.60(s,3H),2.15(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.15,156.08,154.31,147.70,140.99,140.51,140.15,134.47,130.44,129.86,126.23,125.70,123.16,122.45,122.23,118.05,113.77,109.87,99.88,49.49,18.47,14.89. 1 H NMR (500 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.07-8.06 (m, 1H), 7.99 (dt, J=7.5, 2.0 Hz, 1H), 7.69-7.62 (m, 3H), 7.44(d,J=8.5Hz,1H),7.08(dd,J=8.5,2.0Hz,1H),6.57(q,J=7.0Hz,1H),5.68(brs,2H),2.60(s,3H The _ ,122.23,118.05,113.77,109.87,99.88,49.49,18.47,14.89.
制备实施例23 1-(1-(6-氯-1-(3-(甲磺酰基)苯基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺24Preparation Example 23 1-(1-(6-Chloro-1-(3-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazole Do[3,4-d]pyrimidin-4-amine 24
Figure PCTCN2022082962-appb-000033
Figure PCTCN2022082962-appb-000033
制备方法同制备实施案例1-10，柱层析得淡黄色固体24，收率75％。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%.
1H NMR(500MHz,CDCl 3)δ8.40(s,1H),8.34(t,J＝2.0Hz,1H),8.02(ddd,J＝8.0,2.5,1.5Hz,1H),7.93(ddd,J＝8.0,2.0,1.0Hz,1H),7.75(t,J＝8.0Hz,1H),7.69-7.65(m,1H),7.45(d,J＝8.5Hz,1H),7.08(dd,J＝8.5,1.5Hz,1H),6.57(q,J＝7.0Hz,1H),5.61(brs,2H),3.15(s,3H),2.60(s,3H),2.16(d,J＝7.0Hz,3H). 1 H NMR (500MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.34 (t, J=2.0Hz, 1H), 8.02 (ddd, J=8.0, 2.5, 1.5Hz, 1H), 7.93 (ddd, J=8.0,2.0,1.0Hz,1H),7.75(t,J=8.0Hz,1H),7.69-7.65(m,1H),7.45(d,J=8.5Hz,1H),7.08(dd,J =8.5,1.5Hz,1H),6.57(q,J=7.0Hz,1H),5.61(brs,2H),3.15(s,3H),2.60(s,3H),2.16(d,J=7.0Hz , 3H).
13C NMR(126MHz,DMSO-d 6)δ158.94,156.50,154.32,148.09,142.77,141.78,140.12,140.00,133.73,131.69,127.15,125.53,123.39,122.66,122.20,120.87,110.89,99.25,49.13,43.89,18.78,14.97. 13 C NMR(126MHz,DMSO-d 6 )δ158.94,156.50,154.32,148.09,142.77,141.78,140.12,140.00,133.73,131.69,127.15,125.53,123.39,122.66,122.20,120.87,110.89,99.25,49.13,43.89 ,18.78,14.97.
制备实施例24 1-(1-(6-氟-1-(3-(甲磺酰基)苯基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺25Preparation Example 24 1-(1-(6-Fluoro-1-(3-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazole Do[3,4-d]pyrimidin-4-amine 25
Figure PCTCN2022082962-appb-000034
Figure PCTCN2022082962-appb-000034
制备方法同制备实施案例1-10，柱层析得白色固体25，收率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%.
1H NMR(500MHz,CDCl 3)δ8.40(s,1H),8.33(t,J＝2.0Hz,1H),8.05-8.01(m,1H),7.93-7.89(m,1H),7.74(t,J＝8.0Hz,1H),7.48(dd,J＝9.0,5.5Hz,1H),7.34(dd,J＝9.0,2.5Hz,1H),6.88(td,J＝8.5,2.0Hz,1H),6.58(q,J＝7.0Hz,1H),5.69(brs,2H),3.15(s,3H),2.60(s,3H),2.16(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ163.95and 161.99,158.17,156.09,154.30,147.77,142.10,140.97,140.86,140.29and 140.19,130.64,126.84,124.92,123.05and 122.96,121.05,120.44,111.89and 111.69,99.89,96.46and 96.24,49.55,44.53,18.52,14.89. 1 H NMR (500MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.33 (t, J=2.0 Hz, 1H), 8.05-8.01 (m, 1H), 7.93-7.89 (m, 1H), 7.74 ( t, J=8.0Hz, 1H), 7.48 (dd, J=9.0, 5.5Hz, 1H), 7.34 (dd, J=9.0, 2.5Hz, 1H), 6.88 (td, J=8.5, 2.0Hz, 1H) ), 6.58(q, J=7.0Hz, 1H), 5.69(brs, 2H), 3.15(s, 3H), 2.60(s, 3H), 2.16(d, J=7.0Hz, 3H). 13 C NMR (126MHz,CDCl 3 )δ163.95and 161.99,158.17,156.09,154.30,147.77,142.10,140.97,140.86,140.29and 140.19,130.64,126.84,124.92,123.05and 122.96,121.05,120.44,111.89and 111.69,99.89,96.46 and 96.24,49.55,44.53,18.52,14.89.
制备实施例25 1-(1-(6-氯-1-(3-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-乙基-1H-吡唑并[3,4-d]嘧啶-4-胺26Preparation Example 25 1-(1-(6-Chloro-1-(3-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-ethyl-1H-pyrazolo [3,4-d]pyrimidin-4-amine 26
Figure PCTCN2022082962-appb-000035
Figure PCTCN2022082962-appb-000035
制备方法同制备实施案例1-10，柱层析得灰白色固体26，收率83％。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%.
1H NMR(500MHz,CDCl 3)δ9.03(d,J＝2.5Hz,1H),8.62(dd,J＝5.0,1.5Hz,1H),8.40(s,1H),8.06(ddd,J＝8.5,2.5,1.5Hz,1H),7.66(d,J＝1.0Hz,1H),7.52-7.44(m,2H),7.07(dd,J＝8.5,1.5Hz,1H),6.58(q,J＝7.0Hz,1H),5.60(brs,2H),2.94(qd,J＝7.5,1.5Hz,2H),2.16(d,J＝7.0Hz,3H),1.36(t,J＝7.5Hz,3H). 13C NMR(126MHz,CDCl 3)δ157.95,155.91,154.37,147.79,147.77,146.45,143.80,140.52,136.40,134.21,129.95,124.04,122.83,122.60,121.94,109.81,99.12,49.89,22.66,18.70,13.53. 1 H NMR (500MHz, CDCl 3 ) δ 9.03 (d, J=2.5Hz, 1H), 8.62 (dd, J=5.0, 1.5Hz, 1H), 8.40 (s, 1H), 8.06 (ddd, J= 8.5,2.5,1.5Hz,1H),7.66(d,J=1.0Hz,1H),7.52-7.44(m,2H),7.07(dd,J=8.5,1.5Hz,1H),6.58(q,J ＝7.0Hz,1H),5.60(brs,2H),2.94(qd,J＝7.5,1.5Hz,2H),2.16(d,J＝7.0Hz,3H),1.36(t,J＝7.5Hz,3H) ). 13 C NMR(126MHz,CDCl 3 )δ157.95,155.91,154.37,147.79,147.77,146.45,143.80,140.52,136.40,134.21,129.95,124.04,122.83,122.60,121.94,109.81,99.12,49.89,22.66,18.70 , 13.53.
制备实施例26 1-(1-(6-氯-1-(3-(吡啶-3-基)-1H-吲唑-3-基)乙基)-1H-吡唑并[3,4-d]嘧啶-4-胺27Preparation Example 26 1-(1-(6-Chloro-1-(3-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[3,4- d] Pyrimidine-4-amine 27
Figure PCTCN2022082962-appb-000036
Figure PCTCN2022082962-appb-000036
制备方法同制备实施案例1-10，柱层析得黄色固体27，收率81％。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%.
1H NMR(500MHz,CDCl 3)δ9.03(d,J＝2.0Hz,1H),8.62(dd,J＝5.0,1.5Hz,1H),8.46(s,1H),8.07-8.04(m,1H),7.94(s,1H),7.66(d,J＝1.5Hz,1H),7.49(dd,J＝8.5,5.0Hz,1H),7.44(d,J＝8.5Hz,1H),7.07(dd,J＝8.5,1.5Hz,1H),6.66(q,J＝7.0Hz,1H),5.88(brs,2H),2.19(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ157.56,156.01,153.33,147.84,147.36,143.77,140.49,136.37,134.37,131.21,129.98,124.08,123.08,122.15,121.86,109.92,100.63,50.10,18.63. 1 H NMR (500 MHz, CDCl 3 ) δ 9.03 (d, J=2.0 Hz, 1H), 8.62 (dd, J=5.0, 1.5 Hz, 1H), 8.46 (s, 1H), 8.07-8.04 (m, 1H), 7.94(s, 1H), 7.66(d, J=1.5Hz, 1H), 7.49(dd, J=8.5, 5.0Hz, 1H), 7.44(d, J=8.5Hz, 1H), 7.07( dd, J=8.5, 1.5Hz, 1H), 6.66 (q, J=7.0Hz, 1H), 5.88 (brs, 2H), 2.19 (d, J=7.0Hz, 3H). 13 C NMR (126MHz, CDCl) 3 ) δ157.56,156.01,153.33,147.84,147.36,143.77,140.49,136.37,134.37,131.21,129.98,124.08,123.08,122.15,121.86,109.100.63,50
制备实施例27 1-(1-(6-氯-1-(3-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺28Preparation Example 27 1-(1-(6-Chloro-1-(3-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine 28
Figure PCTCN2022082962-appb-000037
Figure PCTCN2022082962-appb-000037
制备方法同制备实施案例1-9，最后一步的操作如下：The preparation method is the same as the preparation and implementation cases 1-9, and the operation of the last step is as follows:
将原料10(150mg,0.4mmol)置于耐压管中，加入盐酸胍(38mg,0.4mmol)，乙醇钠(54mg,0.8mmol)，加入无水乙醇(2mL)溶解，130℃反应5h。反应结束后，旋干乙醇，加入水/乙酸乙酯分层，收集有机层，水洗三次，饱和食盐水洗两次，无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v,30:1)的淋洗剂经柱层析分离得淡黄色固体28(75mg,45％)。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. After the reaction, ethanol was spin-dried, water/ethyl acetate was added to separate layers, the organic layer was collected, washed three times with water, twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and washed with DCM/MeOH (v/v, 30:1) ) of the eluent was separated by column chromatography to give 28 (75 mg, 45%) as a pale yellow solid.
1H NMR(500MHz,CDCl 3)δ9.04(d,J＝2.5Hz,1H),8.60(dd,J＝5.0,1.5Hz,1H),8.06-8.03(m,1H),7.63(d,J＝2.0Hz,1H),7.49-7.44(m,2H),7.06(dd,J＝8.5,2.0Hz,1H),6.32(q,J＝7.0Hz,1H),5.51(brs,2H),5.27(brs,2H),2.44(s,3H),2.09(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ162.02,158.81,156.92,148.14,147.70,143.83,141.25,140.52,136.43,134.20,129.93,124.05,122.88,122.75,122.03,109.72,95.23,49.09,18.61,14.79. 1 H NMR (500MHz, CDCl 3 ) δ 9.04 (d, J=2.5Hz, 1H), 8.60 (dd, J=5.0, 1.5Hz, 1H), 8.06-8.03 (m, 1H), 7.63 (d, J=2.0Hz,1H),7.49-7.44(m,2H),7.06(dd,J=8.5,2.0Hz,1H),6.32(q,J=7.0Hz,1H),5.51(brs,2H), 5.27(brs, 2H), 2.44(s, 3H), 2.09(d, J=7.0Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ 162.02, 158.81, 156.92, 148.14, 147.70, 143.83, 141.25, 140.52 ,136.43,134.20,129.93,124.05,122.88,122.75,122.03,109.72,95.23,49.09,18.61,14.79.
制备实施例28 1-(1-(6-氯-1-(6-甲氧基-5-(三氟甲基)吡啶-3-基)-1H-吲唑-3-基)乙 基)-3-甲基-1H-吡唑[3,4-d]嘧啶-4-胺29Preparation Example 28 1-(1-(6-Chloro-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-1H-indazol-3-yl)ethyl) -3-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 29
Figure PCTCN2022082962-appb-000038
Figure PCTCN2022082962-appb-000038
制备方法同制备实施案例1-10，柱层析得白色固体29，收率75％。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%.
1H NMR(500MHz,CDCl 3)δ8.64(d,J＝2.5Hz,1H),8.40(s,1H),8.22(d,J＝2.5Hz,1H),7.51(d,J＝1.5Hz,1H),7.43(d,J＝8.5Hz,1H),7.06(dd,J＝8.5,1.5Hz,1H),6.57(q,J＝7.0Hz,1H),5.56(brs,2H),4.12(s,3H),2.60(s,3H),2.14(d,J＝7.0Hz,3H). 1 H NMR (500MHz, CDCl 3 ) δ 8.64 (d, J=2.5Hz, 1H), 8.40 (s, 1H), 8.22 (d, J=2.5Hz, 1H), 7.51 (d, J=1.5Hz) ,1H),7.43(d,J＝8.5Hz,1H),7.06(dd,J＝8.5,1.5Hz,1H),6.57(q,J＝7.0Hz,1H),5.56(brs,2H),4.12 (s, 3H), 2.60(s, 3H), 2.14(d, J=7.0Hz, 3H).
制备实施例29 1-(1-(6-氯-1-(6-甲氧基-5-(三氟甲基)吡啶-3-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑[3,4-d]嘧啶-4-胺30Preparation Example 29 1-(1-(6-Chloro-1-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-1H-indazol-3-yl)ethyl) -3-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 30
Figure PCTCN2022082962-appb-000039
Figure PCTCN2022082962-appb-000039
制备方法同制备实施案例1-10，柱层析得黄色固体30，收率78％。The preparation method is the same as the preparation example 1-10, and column chromatography obtains yellow solid 30 with a yield of 78%.
1H NMR(400MHz,CDCl3)δ8.49(d,J＝2.4Hz,1H),8.41(s,1H),7.92(dd,J＝8.8,2.8Hz,1H),7.57-7.52(m,1H),7.44(d,J＝8.8Hz,1H),7.10-6.99(m,1H),6.93(d,J＝8.8Hz,1H),6.59(q,J＝7.2Hz,1H),5.97(brs,2H),4.03(s,3H),2.61(s,3H),2.17(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ162.92,158.35,156.00,154.21,146.66,141.33,140.99,140.95,134.70,133.88,130.49,122.54,122.19,121.40,111.67,109.71,99.87,53.98,49.63,18.64,14.93. 1 H NMR (400MHz, CDCl3) δ 8.49 (d, J=2.4Hz, 1H), 8.41 (s, 1H), 7.92 (dd, J=8.8, 2.8Hz, 1H), 7.57-7.52 (m, 1H) ),7.44(d,J＝8.8Hz,1H),7.10-6.99(m,1H),6.93(d,J＝8.8Hz,1H),6.59(q,J＝7.2Hz,1H),5.97(brs , 2H), 4.03(s, 3H), 2.61(s, 3H), 2.17(d, J=7.2Hz, 3H). 13 C NMR(101MHz, CDCl 3 )δ162.92,158.35,156.00,154.21,146.66,141.33 ,140.99,140.95,134.70,133.88,130.49,122.54,122.19,121.40,111.67,109.71,99.87,53.98,49.63,18.64,14.93.
制备实施例30 1-(1-(6-氯-1-(6-甲氧基吡啶-3-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑[3,4-d]嘧啶-4-胺31Preparation Example 30 1-(1-(6-Chloro-1-(6-methoxypyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyridine Azole[3,4-d]pyrimidin-4-amine 31
Figure PCTCN2022082962-appb-000040
Figure PCTCN2022082962-appb-000040
制备方法同制备实施案例1-10，最后一步的操作如下：The preparation method is the same as the preparation implementation case 1-10, and the operation of the last step is as follows:
取化合物23(130mg,0.3mmol)置于单口瓶中，用DMSO(2mL)溶解，0℃加入碳酸钾(21mg,0.15mmol)30％过氧化氢溶液(30L)，室温反应1h，反应结束后，加入水/乙酸乙酯分层，收集有机层，水洗三次，饱和食盐水洗两次，无水硫酸钠干燥，用DCM/MeOH(v/v,20:1)的淋洗剂经柱层析分离得淡黄色固体31(105mg,78％)。Take compound 23 (130 mg, 0.3 mmol) and put it in a single-necked bottle, dissolve it with DMSO (2 mL), add potassium carbonate (21 mg, 0.15 mmol) 30% hydrogen peroxide solution (30 L) at 0 °C, and react at room temperature for 1 h. , water/ethyl acetate was added to separate layers, the organic layer was collected, washed three times with water, twice with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography with an eluent of DCM/MeOH (v/v, 20:1) 31 was isolated as a pale yellow solid (105 mg, 78%).
1H NMR(400MHz,CDCl3)δ8.40(s,1H),8.20(s,1H),7.88-7.79(m,2H),7.66(s,1H),7.63-7.57(m,1H),7.51(d,J＝8.8Hz,1H),7.10-7.04(m,1H),6.79(brs,1H),6.59(q,J＝6.8Hz,1H),6.31(brs,1H),5.84(brs,2H),2.61(s,3H),2.17(d,J＝6.8Hz,3H). 13C NMR(126MHz,CDCl 3)δ168.71,158.33,156.01,154.16,146.89,141.06,140.35,139.80,135.14,134.07,129.72,125.77,125.55,122.80,122.27,121.85,121.78,110.07,99.86,49.64,18.65,14.84. 1 H NMR(400MHz, CDCl3)δ8.40(s,1H),8.20(s,1H),7.88-7.79(m,2H),7.66(s,1H),7.63-7.57(m,1H),7.51 (d, J=8.8Hz, 1H), 7.10-7.04(m, 1H), 6.79(brs, 1H), 6.59(q, J=6.8Hz, 1H), 6.31(brs, 1H), 5.84(brs, 2H), 2.61(s, 3H), 2.17(d, J=6.8Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ168.71, 158.33, 156.01, 154.16, 146.89, 141.06, 140.35, 139.80, 135.14, 134.07 ,129.72,125.77,125.55,122.80,122.27,121.85,121.78,110.07,99.86,49.64,18.65,14.84.
制备实施例31 1-(1-(6-氯-1-(3-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮32Preparation Example 31 1-(1-(6-Chloro-1-(3-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1,5-di Hydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 32
Figure PCTCN2022082962-appb-000041
Figure PCTCN2022082962-appb-000041
制备方法同制备实施案例1-9，最后一步的操作如下：The preparation method is the same as the preparation and implementation cases 1-9, and the operation of the last step is as follows:
将原料10(150mg,0.4mmol)置于耐压管中，加入甲酸(1.5mL)，125℃反应4h。反应结束后旋掉甲酸，加入水，用碳酸氢钠调至碱性，乙酸乙酯萃取，有机层水洗两次，饱和食盐水洗两次，无水硫酸钠干燥。浓缩，用DCM/MeOH(v/v,20:1)的淋洗剂经柱层析分离得白色固体32(135mg,83％)。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%).
1H NMR(500MHz,CDCl3)δ12.07(brs,1H),9.03(d,J＝2.0Hz,1H),8.63(dd,J＝4.5,1.5Hz,1H),8.08-8.04(m,1H),8.03(s,1H),7.69-7.66(m,1H),7.52-7.47(m,2H),7.14-7.09(m,1H),6.50(q,J＝7.0Hz,1H),2.61(s,3H),2.18(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ160.46,152.34,147.90,147.13,146.44,146.34,143.85,140.57,136.32,134.39,130.05,124.09,123.10,122.25,121.78,109.95,104.39,50.59,18.76,13.89. 1 H NMR (500MHz, CDCl3) δ 12.07 (brs, 1H), 9.03 (d, J=2.0Hz, 1H), 8.63 (dd, J=4.5, 1.5Hz, 1H), 8.08-8.04 (m, 1H) ), 8.03(s, 1H), 7.69-7.66(m, 1H), 7.52-7.47(m, 2H), 7.14-7.09(m, 1H), 6.50(q, J=7.0Hz, 1H), 2.61( s, 3H), 2.18 (d, J=7.0Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ 160.46, 152.34, 147.90, 147.13, 146.44, 146.34, 143.85, 140.57, 136.32, 134.39, 130.05, 124.09 123.10, 122.25, 121.78, 109.95, 104.39, 50.59, 18.76, 13.89.
制备实施例32 9-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-9H-嘌呤-6-胺33Preparation Example 32 9-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-9H-purin-6-amine 33
Figure PCTCN2022082962-appb-000042
Figure PCTCN2022082962-appb-000042
制备方法前六步同制备实施案例1-6，后续步骤如下：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:
Figure PCTCN2022082962-appb-000043
Figure PCTCN2022082962-appb-000043
两口瓶中加入原料6(1.2g,4.4mmol)，6-氯嘌呤(1g,6.6mmol)，三苯基膦(2.3g,8.8mmol)，抽真空通氩气，置换三次，加入无水THF，0℃下缓慢滴加DIAD(1.8g,8.8mmol)，加完后移至室温反应过夜。反应完成后加入水/乙酸乙酯分层，收集有机层，饱和食盐水洗，无水硫酸钠干燥，浓缩，用PE/EA(v/v,3:1)的淋洗剂经柱层析分离得淡黄色固体(1.3g,72％)。In the two-necked flask, add raw material 6 (1.2g, 4.4mmol), 6-chloropurine (1g, 6.6mmol), triphenylphosphine (2.3g, 8.8mmol), evacuate argon, replace three times, add anhydrous THF , DIAD (1.8 g, 8.8 mmol) was slowly added dropwise at 0 °C, and after the addition was completed, it was moved to room temperature to react overnight. After the reaction was completed, water/ethyl acetate was added to separate layers, the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with PE/EA (v/v, 3:1) eluent. A pale yellow solid (1.3 g, 72%) was obtained.
将上述固体(325mg，0.8mmol)加入耐压管中，加入氨的乙醇溶液(2N，1mL)，125℃反应3h。反应结束后，旋干，乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v,30:1)的淋洗剂经柱层析分离得黄色固体33(256mg,82％)。The above solid (325 mg, 0.8 mmol) was added to a pressure-resistant tube, and an ethanol solution of ammonia (2N, 1 mL) was added, and the reaction was carried out at 125° 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) to obtain a yellow color Solid 33 (256 mg, 82%).
1H NMR(500MHz,CDCl 3)δ9.05(d,J＝2.5Hz,1H),8.68-8.66(m,1H),8.45(s,1H),8.06-8.02(m,1H),8.00(s,1H),7.70(d,J＝1.5Hz,1H),7.55(d,J＝8.5Hz,1H),7.54-7.51(m,1H),7.15(dd,J＝8.5,1.5Hz,1H),6.47(q,J＝7.0Hz,1H),6.03(brs,2H),2.17(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ155.64,153.20,149.60,148.25,146.70,143.85, 140.40,138.99,136.14,134.93,129.89,124.17,123.63,121.59,121.49,119.29,110.10,46.43,20.15. 1 H NMR (500MHz, CDCl 3 ) δ 9.05(d, J=2.5Hz, 1H), 8.68-8.66(m, 1H), 8.45(s, 1H), 8.06-8.02(m, 1H), 8.00( s,1H),7.70(d,J=1.5Hz,1H),7.55(d,J=8.5Hz,1H),7.54-7.51(m,1H),7.15(dd,J=8.5,1.5Hz,1H) ), 6.47(q, J=7.0Hz, 1H), 6.03(brs, 2H), 2.17(d, J=7.0Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ155.64, 153.20, 149.60, 148.25, 146.70, 143.85, 140.40, 138.99, 136.14, 134.93, 129.89, 124.17, 123.63, 121.59, 121.49, 119.29, 110.10, 46.43, 20.15.
制备实施例33 1-(1-(6-氯-1-(3-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3,6-二甲基-1H-吡唑并[3,4-d]嘧啶-4-胺34Preparation Example 33 1-(1-(6-Chloro-1-(3-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3,6-dimethyl-1H- Pyrazolo[3,4-d]pyrimidin-4-amine 34
Figure PCTCN2022082962-appb-000044
Figure PCTCN2022082962-appb-000044
制备方法前几步同制备实施案例1-9，后续步骤如下：The first steps of the preparation method are the same as the preparation implementation cases 1-9, and the subsequent steps are as follows:
Figure PCTCN2022082962-appb-000045
Figure PCTCN2022082962-appb-000045
单口瓶中加入原料10(300mg,0.8mmol)，原乙酸三乙酯(292mg,1.8mmol)，醋酸酐(3mL)，130℃反应3h。反应结束后，加入水/乙酸乙酯分层，收集有机层，水洗，饱和食盐水洗，无水硫酸钠干燥。浓缩，用PE/EA(v/v,1:1)的淋洗剂经柱层析分离得淡黄色固体(265g,74％)。Raw material 10 (300 mg, 0.8 mmol), triethyl orthoacetate (292 mg, 1.8 mmol), and acetic anhydride (3 mL) were added to the single-necked flask, and the reaction was carried out at 130° C. for 3 h. After the reaction was completed, water/ethyl acetate was added to separate the layers, the organic layer was collected, washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration and column chromatography with an eluent of PE/EA (v/v, 1:1) gave a pale yellow solid (265 g, 74%).
将所得淡黄色固体(225mg,0.5mmol)置于耐压管中，加入氨的乙醇溶液(2N,1.5mL)，130℃反应3h。反应结束后，旋干，乙酸乙酯稀释，水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v,30:1)的淋洗剂经柱层析分离得淡黄色固体34(165mg,79％)。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%).
1H NMR(500MHz,CDCl 3)δ9.04(d,J＝2.5Hz,1H),8.62(dd,J＝4.5,1.5Hz,1H),8.06(ddd,J＝8.5,2.5,1.5Hz,1H),7.68-7.64(m,1H),7.49(dd,J＝8.5,4.5Hz,1H),7.38(d,J＝8.5Hz,1H),7.06(dd,J＝8.5,1.5Hz,1H),6.57(q,J＝7.0Hz,1H),5.59(brs,2H),2.63(s,3H),2.56(s,3H),2.13(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ165.83,157.81,155.47,147.76,143.77,140.86,140.48,136.45,134.20,129.90,124.05,122.88,122.45,122.09,109.80,97.88,49.10,26.03,18.57,14.90. 1 H NMR (500MHz, CDCl 3 ) δ 9.04 (d, J=2.5Hz, 1H), 8.62 (dd, J=4.5, 1.5Hz, 1H), 8.06 (ddd, J=8.5, 2.5, 1.5Hz, 1H),7.68-7.64(m,1H),7.49(dd,J=8.5,4.5Hz,1H),7.38(d,J=8.5Hz,1H),7.06(dd,J=8.5,1.5Hz,1H) ), 6.57(q, J=7.0Hz, 1H), 5.59(brs, 2H), 2.63(s, 3H), 2.56(s, 3H), 2.13(d, J=7.0Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ165.83,157.81,155.47,147.76,143.77,140.86,140.48,136.45,134.20,129.90,124.05,122.80,122.45,122.09,109.80,91.8018,49.
制备实施例34 1-(1-(6-氯-1-(3-(吡啶-4-基)-1H-吲唑-3-基)乙基)-3-乙基-1H-吡唑并[3,4-d]嘧啶-4-胺35Preparation Example 34 1-(1-(6-Chloro-1-(3-(pyridin-4-yl)-1H-indazol-3-yl)ethyl)-3-ethyl-1H-pyrazolo [3,4-d]pyrimidin-4-amine 35
Figure PCTCN2022082962-appb-000046
Figure PCTCN2022082962-appb-000046
制备方法同制备实施案例1-10，柱层析得淡黄色固体35，收率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 81%.
1H NMR(500MHz,CDCl 3)δ8.75-8.71(m,2H),8.40(s,1H),7.81(d,J＝1.5Hz,1H),7.75-7.72(m,2H),7.44(d,J＝9.0Hz,1H),7.09(dd,J＝9.0,1.5Hz,1H),6.56(q,J＝7.0Hz,1H),5.88(brs,2H),2.93(qd,J＝7.5,1.5Hz,2H),2.16(d,J＝7.0Hz,3H),1.35(t,J＝7.5Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.02,155.93,154.40,151.17,148.47,146.57, 146.48,140.12,134.56,123.31,122.80,122.72,115.23,110.70,99.12,49.85,22.65,18.58,13.53. 1 H NMR (500MHz, CDCl 3 ) δ 8.75-8.71(m, 2H), 8.40(s, 1H), 7.81(d, J=1.5Hz, 1H), 7.75-7.72(m, 2H), 7.44( d, J=9.0Hz, 1H), 7.09 (dd, J=9.0, 1.5Hz, 1H), 6.56 (q, J=7.0Hz, 1H), 5.88 (brs, 2H), 2.93 (qd, J=7.5 , 1.5Hz, 2H), 2.16 (d, J=7.0Hz, 3H), 1.35 (t, J=7.5Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ158.02, 155.93, 154.40, 151.17, 148.47, 146.57, 146.48, 140.12, 134.56, 123.31, 122.80, 122.72, 115.23, 110.70, 99.12, 49.85, 22.65, 18.58, 13.53.
制备实施例35 1-(1-(6-氯-1-(4-(甲磺酰基)苯基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺36Preparation Example 35 1-(1-(6-Chloro-1-(4-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazole Do[3,4-d]pyrimidin-4-amine 36
Figure PCTCN2022082962-appb-000047
Figure PCTCN2022082962-appb-000047
制备方法同制备实施案例1-10，柱层析得淡黄色固体35，收率76％。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%.
1H NMR(500MHz,DMSO-d 6)δ8.25(s,1H),8.16-8.09(m,4H),8.03(d,J＝1.5Hz,1H),7.40(d,J＝9.0Hz,1H),7.24(dd,J＝8.5,2.0Hz,1H),6.51(q,J＝7.0Hz,1H),3.31(s,3H),2.50(s,3H),2.03(d,J＝7.0Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ158.94,156.51,154.33,148.50,143.32,141.83,140.02,138.55,133.92,129.44,123.60,122.61,122.51,122.46,111.32,99.25,49.09,44.16,18.67,14.97. 1 H NMR (500MHz, DMSO-d 6 )δ8.25(s, 1H), 8.16-8.09(m, 4H), 8.03(d, J=1.5Hz, 1H), 7.40(d, J=9.0Hz, 1H), 7.24(dd, J=8.5, 2.0Hz, 1H), 6.51(q, J=7.0Hz, 1H), 3.31(s, 3H), 2.50(s, 3H), 2.03(d, J=7.0 Hz, 3H). 13 C NMR (126MHz, DMSO-d 6 )δ158.94,156.51,154.33,148.50,143.32,141.83,140.02,138.55,133.92,129.44,123.60,122.61,122.51,129.32,46,111 44.16, 18.67, 14.97.
制备实施例36 1-(1-(6-氯-1-(4-(甲磺酰基)苯基)-1H-吲唑-3-基)乙基)-3-乙基-1H-吡唑并[3,4-d]嘧啶-4-胺37Preparation Example 36 1-(1-(6-Chloro-1-(4-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-3-ethyl-1H-pyrazole Do[3,4-d]pyrimidin-4-amine 37
Figure PCTCN2022082962-appb-000048
Figure PCTCN2022082962-appb-000048
制备方法同制备实施案例1-10，柱层析得淡黄色固体37，收率78％。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%.
1H NMR(500MHz,DMSO-d 6)δ8.24(s,1H),8.16-8.09(m,4H),8.03(d,J＝1.5Hz,1H),7.42(d,J＝8.5Hz,1H),7.25(dd,J＝8.5,1.5Hz,1H),6.51(q,J＝7.0Hz,1H),3.31(s,3H),2.95(qd,J＝7.5,4.5Hz,2H),2.04(d,J＝7.0Hz,3H),1.18(t,J＝7.5Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ158.70,156.37,154.47,148.62,147.25,143.31,140.05,138.56,133.90,129.43,123.51,122.83,122.46,111.31,98.49,49.49,44.16,21.82,18.82,14.13. 1 H NMR (500MHz, DMSO-d 6 )δ8.24(s, 1H), 8.16-8.09(m, 4H), 8.03(d, J=1.5Hz, 1H), 7.42(d, J=8.5Hz, 1H), 7.25(dd, J=8.5, 1.5Hz, 1H), 6.51(q, J=7.0Hz, 1H), 3.31(s, 3H), 2.95(qd, J=7.5, 4.5Hz, 2H), 2.04 (d, J=7.0Hz, 3H), 1.18 (t, J=7.5Hz, 3H). 13 C NMR (126MHz, DMSO-d 6 )δ158.70, 156.37, 154.47, 148.62, 147.25, 143.31, 140.05, 138.56 ,133.90,129.43,123.51,122.83,122.46,111.31,98.49,49.49,44.16,21.82,18.82,14.13.
制备实施例37 1-(1-(6-氯-1-(3-(甲磺酰基)苯基)-1H-吲唑-3-基)乙基)-3-乙基-1H-吡唑并[3,4-d]嘧啶-4-胺38Preparation Example 37 1-(1-(6-Chloro-1-(3-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-3-ethyl-1H-pyrazole Do[3,4-d]pyrimidin-4-amine 38
Figure PCTCN2022082962-appb-000049
Figure PCTCN2022082962-appb-000049
制备方法同制备实施案例1-10，柱层析得白色固体38，收率75％。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%.
1H NMR(400MHz,DMSO-d 6)δ8.26(t,J＝1.6Hz,1H),8.23(s,1H),8.22-8.18(m,1H),7.99(dt,J＝8.0,1.6Hz,1H),7.93(d,J＝1.6Hz,1H),7.89(t,J＝8.0Hz,1H),7.47(d,J＝8.8Hz,1H),7.24(dd,J＝8.8,1.6Hz,1H),6.51(q,J＝6.8Hz,1H),2.95(qd,J＝7.6,2.4Hz,2H),2.05(d,J＝6.8Hz,3H),1.19(t,J＝7.6Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ158.69,156.36,154.45,148.22,147.20,142.78,140.15,139.99,133.71,131.68,127.15,125.53,123.30,122.89,122.12,120.90,110.89,98.48,49.53,43.88,21.82,18.97,14.12. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.26 (t, J=1.6Hz, 1H), 8.23 (s, 1H), 8.22-8.18 (m, 1H), 7.99 (dt, J=8.0, 1.6 Hz,1H),7.93(d,J=1.6Hz,1H),7.89(t,J=8.0Hz,1H),7.47(d,J=8.8Hz,1H),7.24(dd,J=8.8,1.6 Hz, 1H), 6.51(q, J＝6.8Hz, 1H), 2.95(qd, J＝7.6, 2.4Hz, 2H), 2.05(d, J＝6.8Hz, 3H), 1.19(t, J＝7.6 Hz, 3H). 13 C NMR (126MHz, DMSO-d 6 )δ158.69,156.36,154.45,148.22,147.20,142.78,140.15,139.99,133.71,131.68,127.15,125.53,123.30,122.9,122.9 98.48, 49.53, 43.88, 21.82, 18.97, 14.12.
制备实施例38 1-(1-(6-氯-1-(3-氟苯基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并 [3,4-d]嘧啶-4-胺39Preparation Example 38 1-(1-(6-Chloro-1-(3-fluorophenyl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine 39
Figure PCTCN2022082962-appb-000050
Figure PCTCN2022082962-appb-000050
制备方法同制备实施案例1-10，柱层析得白色固体39，收率81％。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%.
1H NMR(500MHz,CDCl 3)δ8.38(s,1H),7.67(d,J＝1.5Hz,1H),7.53-7.45(m,3H),7.41(d,J＝8.5Hz,1H),7.09-7.02(m,2H),6.57(q,J＝7.0Hz,1H),6.03(brs,2H),2.59(s,3H),2.15(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ164.12and 162.15,158.00,155.41,154.08,146.79,141.11and 141.06,140.98,140.28,133.99,130.71and 130.64,122.75,122.18,121.90,117.85and 117.82,113.73and 113.56,110.36,110.17,99.76,49.65,18.54,14.86. 1 H NMR (500MHz, CDCl 3 ) δ 8.38 (s, 1H), 7.67 (d, J=1.5Hz, 1H), 7.53-7.45 (m, 3H), 7.41 (d, J=8.5Hz, 1H) ,7.09-7.02(m,2H),6.57(q,J=7.0Hz,1H),6.03(brs,2H),2.59(s,3H),2.15(d,J=7.0Hz,3H) .13C NMR(126MHz,CDCl 3 )δ164.12and 162.15,158.00,155.41,154.08,146.79,141.11and 141.06,140.98,140.28,133.99,130.71and 130.64,122.75,122.18,121.90,117.85and 117.82,113.73and 113.56,110.36, 110.17, 99.76, 49.65, 18.54, 14.86.
制备实施例39 3-(3-(1-(4-氨基-3-乙基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氯-1H-吲唑-1-基)苯甲酰胺40Preparation Example 39 3-(3-(1-(4-amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-1H- Indazol-1-yl)benzamide 40
Figure PCTCN2022082962-appb-000051
Figure PCTCN2022082962-appb-000051
制备方法同制备实施案例1-10和实施案例30，柱层析得白色固体40，收率75％。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%.
1H NMR(400MHz,DMSO-d 6)δ8.26(brs,1H),8.25(s,1H),8.22(t,J＝2.0Hz,1H),7.98-7.92(m,2H),7.89(d,J＝1.6Hz,1H),7.71(t,J＝8.0Hz,1H),7.62(brs,1H),7.43(d,J＝8.4Hz,1H),7.21(dd,J＝8.8,2.0Hz,1H),6.51(q,J＝7.2Hz,1H),2.96(qd,J＝7.6,2.8Hz,2H),2.05(d,J＝7.2Hz,3H),1.19(t,J＝7.6Hz,3H). 13C NMR(126MHz,CDCl 3)δ168.52,157.94,155.86,154.31,147.13,146.43,140.41,139.90,135.11,134.04,129.75,125.69,125.62,122.69,122.58,121.83,121.78,110.04,99.14,50.00,22.65,18.82,13.46. 1 H NMR (400MHz, DMSO-d 6 )δ8.26(brs,1H),8.25(s,1H),8.22(t,J=2.0Hz,1H),7.98-7.92(m,2H),7.89( d, J=1.6Hz, 1H), 7.71 (t, J=8.0Hz, 1H), 7.62 (brs, 1H), 7.43 (d, J=8.4Hz, 1H), 7.21 (dd, J=8.8, 2.0 Hz, 1H), 6.51 (q, J=7.2Hz, 1H), 2.96 (qd, J=7.6, 2.8Hz, 2H), 2.05 (d, J=7.2Hz, 3H), 1.19 (t, J=7.6 Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ168.52,157.94,155.86,154.31,147.13,146.43,140.41,139.90,135.11,134.04,129.75,125.69,125.62,122.69,122.58,121.83,121.78,110.04, 99.14, 50.00, 22.65, 18.82, 13.46.
制备实施例40 4-(3-(1-(4-氨基-3-乙基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氯-1H-吲唑-1-基)苯甲酰胺41Preparation Example 40 4-(3-(1-(4-amino-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-1H- Indazol-1-yl)benzamide 41
Figure PCTCN2022082962-appb-000052
Figure PCTCN2022082962-appb-000052
制备方法同制备实施案例1-10和实施案例30，柱层析得白色固体41，收率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 41 with a yield of 76%.
1H NMR(500MHz,DMSO-d 6)δ8.22(s,1H),8.14(brs,1H),8.12-8.08(m,2H),7.93(d,J＝1.5Hz,1H),7.91-7.86(m,2H),7.49(brs,1H),7.40(d,J＝9.0Hz,1H),7.21(dd,J＝9.0,1.5Hz,1H),6.49(q,J＝7.0Hz,1H),2.93(qd,J＝7.5,3.5Hz,2H),2.03(d,J＝7.0Hz,3H),1.17(t,J＝7.5Hz,3H). 13C NMR(126MHz,DMSO-d 6)δ167.54,158.68,156.34,154.42,147.83,147.19,141.61,140.05,133.55,132.64,129.62,123.11,122.74,122.09,121.88,111.09,98.47,49.54,21.82,18.91,14.13. 1 H NMR (500MHz, DMSO-d 6 ) δ 8.22(s, 1H), 8.14(brs, 1H), 8.12-8.08(m, 2H), 7.93(d, J=1.5Hz, 1H), 7.91- 7.86(m, 2H), 7.49(brs, 1H), 7.40(d, J=9.0Hz, 1H), 7.21(dd, J=9.0, 1.5Hz, 1H), 6.49(q, J=7.0Hz, 1H) ), 2.93(qd, J=7.5, 3.5Hz, 2H), 2.03(d, J=7.0Hz, 3H), 1.17(t, J=7.5Hz, 3H). 13 C NMR (126MHz, DMSO-d 6 )δ167.54,158.68,156.34,154.42,147.83,147.19,141.61,140.05,133.55,132.64,129.62,123.11,122.74,112.09,121.88,111.09,98.47,8.19,121.88
制备实施例41 4-(3-(1-(4-氨基-3-甲基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氯-1H-吲唑-1-基)苯甲酰胺42Preparation Example 41 4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-1H- Indazol-1-yl)benzamide 42
Figure PCTCN2022082962-appb-000053
Figure PCTCN2022082962-appb-000053
制备方法同制备实施案例1-10和实施案例30，柱层析得白色固体42，收率80％。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%.
1H NMR(400MHz,CD 3OD)δ8.28(s,1H),8.16-8.05(m,2H),7.93-7.84(m,2H),7.81(d,J＝1.6Hz,1H),7.30(d,J＝8.8Hz,1H),7.08(dd,J＝8.8,2.0Hz,1H),6.54(q,J＝6.8Hz,1H),2.57(s,3H),2.12(d,J＝6.8Hz,3H). 13C NMR(101MHz,CD 3OD)δ169.95,158.91,155.75,153.67,146.91,142.59,142.29,140.14,133.95,131.64,128.91,122.56,121.94,121.57,110.20,99.19,49.46,17.33,13.02. 1 H NMR (400MHz, CD 3 OD) δ 8.28 (s, 1H), 8.16-8.05 (m, 2H), 7.93-7.84 (m, 2H), 7.81 (d, J=1.6Hz, 1H), 7.30 (d, J=8.8Hz, 1H), 7.08 (dd, J=8.8, 2.0Hz, 1H), 6.54 (q, J=6.8Hz, 1H), 2.57 (s, 3H), 2.12 (d, J= 6.8Hz, 3H). 13 C NMR (101MHz, CD 3 OD)δ169.95,158.91,155.75,153.67,146.91,142.59,142.29,140.14,133.95,131.64,128.91,122.56,121.94,121.90,4 17.33, 13.02.
制备实施例42 1-(1-(6-氯-1-(吡啶-2-基甲基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺43Preparation Example 42 1-(1-(6-Chloro-1-(pyridin-2-ylmethyl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[ 3,4-d]pyrimidin-4-amine 43
Figure PCTCN2022082962-appb-000054
Figure PCTCN2022082962-appb-000054
制备方法同制备实施案例1-10,柱层析得白色固体43，收率82％。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%.
1H NMR(600MHz,Chloroform-d)δ8.61-8.54(m,1H),8.37(s,1H),7.55(td,J＝7.8,1.8Hz,1H),7.41(d,J＝8.4Hz,1H),7.30(d,J＝1.2Hz,1H),7.22-7.13(m,1H),6.95(dd,J＝8.4,1.8Hz,1H),6.86(d,J＝7.8Hz,1H),6.53(q,J＝7.2Hz,1H),5.78(brs,2H),5.73-5.63(m,1H),2.59(s,3H),2.13(d,J＝7.2Hz,3H). 13C NMR(151MHz,CDCl 3)δ158.20,156.46,155.92,154.18,149.38,144.88,141.50,140.65,137.01,133.03,122.68,121.91,121.82,121.38,120.75,109.29,99.89,54.87,49.71,18.66,14.88. 1 H NMR (600MHz, Chloroform-d) δ8.61-8.54 (m, 1H), 8.37 (s, 1H), 7.55 (td, J=7.8, 1.8Hz, 1H), 7.41 (d, J=8.4Hz) ,1H),7.30(d,J＝1.2Hz,1H),7.22-7.13(m,1H),6.95(dd,J＝8.4,1.8Hz,1H),6.86(d,J＝7.8Hz,1H) ,6.53(q,J＝7.2Hz,1H),5.78(brs,2H),5.73-5.63(m,1H),2.59(s,3H),2.13(d,J＝7.2Hz,3H) .13C NMR(151MHz,CDCl 3 )δ158.20,156.46,155.92,154.18,149.38,144.88,141.50,140.65,137.01,133.03,122.68,121.91,121.82,121.38,120.75,109.29,99.89,54.87,49.71,18.66,14.88.
制备实施例43 1-(1-(6-氯-1-(嘧啶-5-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺44Preparation Example 43 1-(1-(6-Chloro-1-(pyrimidin-5-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine 44
Figure PCTCN2022082962-appb-000055
Figure PCTCN2022082962-appb-000055
制备方法同制备实施案例1-10,柱层析得白色固体44，收率73％。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%.
1H NMR(500MHz,CDCl 3)δ9.20(s,3H),8.40(s,1H),7.68(d,J＝1.5Hz,1H),7.46(d,J＝8.5,1H),7.11(dd,J＝8.5,1.5Hz,1H),6.58(q,J＝7.0Hz,1H),5.91(brs,2H),2.60(s,3H),2.16(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.29,156.09,156.05,154.31,149.75,148.83,141.11,140.36,135.08,134.89,123.53,122.58,122.35,109.64,99.88,49.45,18.39,14.88. 1 H NMR (500MHz, CDCl 3 ) δ 9.20 (s, 3H), 8.40 (s, 1H), 7.68 (d, J=1.5Hz, 1H), 7.46 (d, J=8.5, 1H), 7.11 ( dd,J=8.5,1.5Hz,1H),6.58(q,J=7.0Hz,1H),5.91(brs,2H),2.60(s,3H),2.16(d,J=7.0Hz,3H). 13 C NMR (126MHz, CDCl 3 )δ158.29,156.09,156.05,154.31,149.75,148.83,141.11,140.36,135.08,134.89,123.53,122.58,122.35,109.64,184.9.88,489.
制备实施例44N-(3-(3-(1-(4-氨基-3-甲基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氯-1H-吲唑-1-基)苯基)甲磺酰胺45Preparation Example 44 N-(3-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro- 1H-Indazol-1-yl)phenyl)methanesulfonamide 45
Figure PCTCN2022082962-appb-000056
Figure PCTCN2022082962-appb-000056
制备方法同制备实施案例1-3，后续步骤如下：The preparation method is the same as the preparation implementation case 1-3, and the subsequent steps are as follows:
Figure PCTCN2022082962-appb-000057
Figure PCTCN2022082962-appb-000057
化合物45-1的制备方法同制备实施案例4。The preparation method of compound 45-1 is the same as that of Preparation Example 4.
步骤1：化合物45-2的合成Step 1: Synthesis of Compound 45-2
两口瓶中加入化合物45-1(6g,19mmol)和Fe粉(5.3g,95mmol)，抽真空通氩气，置换三次，加入乙醇，浓盐酸(57mmol,4.75mL)，80℃回流反应。TLC监测，反应结束后趁热用硅藻土过滤，收集滤液，旋蒸除去乙醇。所得粗产物加水稀释，用0.5N的NaOH溶液调至碱性(PH＝8-9)，加入乙酸乙酯，搅拌一段时间后用硅藻土过滤，收集滤液分层，收集有机层，饱和食盐水洗，无水硫酸钠干燥，浓缩，用EA/PE(v/v,1:3)的淋洗剂柱层析分离得黄色固体45-2(4.2g,77％)。Compound 45-1 (6 g, 19 mmol) and Fe powder (5.3 g, 95 mmol) were added to the two-necked flask, and argon was evacuated and replaced three times. Ethanol, concentrated hydrochloric acid (57 mmol, 4.75 mL) were added, and the reaction was carried out at 80°C under reflux. TLC monitoring, after the reaction is completed, filter through celite while still hot, collect the filtrate, and remove ethanol by rotary evaporation. The obtained crude product was diluted with water, adjusted to alkalinity (PH=8-9) with 0.5N NaOH solution, ethyl acetate was added, and after stirring for a period of time, it was filtered with celite, the filtrate was collected and the layers were collected, and the organic layer was collected. Washed with water, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with EA/PE (v/v, 1:3) eluent to obtain yellow solid 45-2 (4.2 g, 77%).
步骤2：化合物45-3的合成Step 2: Synthesis of Compound 45-3
两口瓶中加入45-2(1.4g,4.9mmol)，抽真空通氩气，置换三次，加入无水二氯甲烷，加入吡啶(0.44mL,5.4mmol)，缓慢滴加甲基磺酰氯(0.42mL,5.4mmol)，回流反应。TLC监测，反应结束后，旋掉二氯甲烷，加入水，用碳酸氢钠溶液调至碱性，水相用乙酸乙酯萃取至无荧光，收集有机相，饱和食盐水洗，无水硫酸钠干燥，旋干得粉红色固体45-3(1.63g,92％)。45-2 (1.4 g, 4.9 mmol) was added to the two-necked flask, evacuated and passed through argon, replaced three times, anhydrous dichloromethane was added, pyridine (0.44 mL, 5.4 mmol) was added, and methylsulfonyl chloride (0.42 mmol) was slowly added dropwise. mL, 5.4 mmol), the reaction was refluxed. TLC monitoring, after the reaction was over, spin off dichloromethane, add water, make alkaline with sodium bicarbonate solution, extract the aqueous phase with ethyl acetate until no fluorescence, collect the organic phase, wash with saturated brine, and dry over anhydrous sodium sulfate , spin-dried to obtain pink solid 45-3 (1.63g, 92%).
步骤3：化合物45-4的合成Step 3: Synthesis of Compound 45-4
单口瓶中加入45-3(1.4g,3.85mmol)，Boc2O(1g,4.62mmol)和DMAP(49mg,0.4mmol)，加入二氯甲烷溶解，缓慢滴加三乙胺(1.6mL,11.55mmol)，室温反应2h。反应液用二氯甲烷稀释，水洗，饱和氯化钠洗，无水硫酸钠干燥，浓缩，用EA/PE(v/v,1:1)的淋洗剂柱层析分离得黄色固体45-4(1.3g,73％)。Add 45-3 (1.4g, 3.85mmol), Boc2O (1g, 4.62mmol) and DMAP (49mg, 0.4mmol) to the single-necked flask, add dichloromethane to dissolve, slowly add triethylamine (1.6mL, 11.55mmol) dropwise , and reacted at room temperature for 2h. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography with an eluent of EA/PE (v/v, 1:1) to obtain a yellow solid 45- 4 (1.3 g, 73%).
后续步骤同制备实施案例5-10。柱层析得白色固体45，收率78％。Subsequent steps are the same as the preparation and implementation cases 5-10. Column chromatography gave 45 as a white solid with a yield of 78%.
1H NMR(500MHz,DMSO-d 6)δ10.06(brs,1H),8.24(s,1H),7.86(d,J＝2.0Hz,1H),7.65-7.60(m,1H),7.59-7.52(m,2H),7.40(d,J＝9.0Hz,1H),7.32-7.25(m,1H),7.22-7.17(m,1H),6.48(q,J＝7.0Hz,1H),3.10(s,3H),2.49(s,3H),2.01(d,J＝7.0Hz, 3H). 13C NMR(126MHz,DMSO-d 6)δ158.94,156.48,154.30,147.28,141.70,140.15,140.07,139.96,133.39,131.22,123.00,122.60,122.01,117.78,117.60,113.29,110.86,99.23,49.13,18.78,14.97. 1 H NMR (500MHz, DMSO-d 6 )δ10.06(brs,1H),8.24(s,1H),7.86(d,J=2.0Hz,1H),7.65-7.60(m,1H),7.59- 7.52(m, 2H), 7.40(d, J=9.0Hz, 1H), 7.32-7.25(m, 1H), 7.22-7.17(m, 1H), 6.48(q, J=7.0Hz, 1H), 3.10 (s, 3H), 2.49 (s, 3H), 2.01 (d, J=7.0Hz, 3H). 13 C NMR (126MHz, DMSO-d 6 )δ158.94, 156.48, 154.30, 147.28, 141.70, 140.15, 140.07, 139.96,133.39,131.22,123.00,122.60,122.01,117.78,117.60,113.29,110.86,99.23,49.13,18.78,14.97.
制备实施例45 3-(3-(1-(4-氨基-3-甲基-1H-吡唑并[3,4-d]嘧啶-1-基)乙基)-6-氯-1H-吲唑-1-基)-N-甲基苯甲酰胺46Preparation Example 45 3-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-1H- Indazol-1-yl)-N-methylbenzamide 46
Figure PCTCN2022082962-appb-000058
Figure PCTCN2022082962-appb-000058
制备方法同制备实施案例1-4，后续步骤如下：The preparation method is the same as the preparation and implementation cases 1-4, and the subsequent steps are as follows:
Figure PCTCN2022082962-appb-000059
Figure PCTCN2022082962-appb-000059
步骤1：化合物46-2的合成Step 1: Synthesis of Compound 46-2
单口瓶中加入46-1(4g,12.17mmol)，氢氧化锂(874mg,36.51mmol)，加入20mL THF和4mL H2O，室温反应，TLC监测。反应结束后，旋蒸除去THF，加水稀释，水相用1M HCl调至PH＝3-4，乙酸乙酯提取，水洗，饱和氯化钠洗，无水硫酸钠干燥，旋干得黄色固体46-2(3.1g,81％)。Add 46-1 (4g, 12.17mmol), lithium hydroxide (874mg, 36.51mmol) to single-necked flask, add 20mL THF and 4mL H O, react at room temperature, and monitor by TLC. After the reaction, the THF was removed by rotary evaporation, diluted with water, the aqueous phase was adjusted to PH=3-4 with 1M HCl, extracted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotated to give a yellow solid 46 -2 (3.1 g, 81%).
步骤2：化合物46-3的合成Step 2: Synthesis of Compound 46-3
两口瓶中加入甲胺盐酸盐(429mg,6.35mmol)，46-2(3g,9.53mmol),HATU(2.9g,7.62mmol)，抽真空通氩气，置换三次，加入无水DMF，0℃下加入缓慢滴加DIPEA(3.15mL,19.05mmol)，室温反应过夜。反应结束后，反应液加水，水相用乙酸乙酯萃取三次，收集有机相，水洗，饱和氯化钠洗，无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v,30:1)的淋洗剂柱层析分离得淡黄色固体46-3(1.7g,82％)。In the two-necked flask, add methylamine hydrochloride (429mg, 6.35mmol), 46-2 (3g, 9.53mmol), HATU (2.9g, 7.62mmol), evacuate argon, replace three times, add anhydrous DMF, 0 DIPEA (3.15 mL, 19.05 mmol) was slowly added dropwise at ℃, and the reaction was carried out at room temperature overnight. After the reaction, water was added to the reaction solution, the aqueous phase was extracted three times with ethyl acetate, the organic phase was collected, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and washed with DCM/MeOH (v/v, 30:1) 46-3 (1.7 g, 82%) was isolated as a pale yellow solid by column chromatography on the eluent.
后续步骤同制备实施案例5-10。柱层析得白色固体46，收率85％。Subsequent steps are the same as the preparation and implementation cases 5-10. Column chromatography gave 46 as a white solid with a yield of 85%.
1H NMR(500MHz,DMSO-d 6)δ8.68(d,J＝4.5Hz,1H),8.25(s,1H),8.17(t,J＝2.0Hz,1H),7.98-7.85(m,3H),7.70(t,J＝8.0Hz,1H),7.41(d,J＝8.5Hz,1H),7.20(dd,J＝8.5,1.5Hz,1H),6.50(q,J＝7.0Hz,1H),2.85(d,J＝4.5Hz,3H),2.51(s,3H),2.03(d,J＝7.0Hz,3H). 13C NMR(151MHz,DMSO)δ166.22,158.94,156.48,154.29,147.39,141.72,140.13,139.47,136.55,133.40,130.37,126.01,125.32,123.04,122.53,121.93,121.38,110.79,99.23,49.14,26.83,18.83,14.98. 1 H NMR (500MHz, DMSO-d 6 )δ8.68(d, J=4.5Hz, 1H), 8.25(s, 1H), 8.17(t, J=2.0Hz, 1H), 7.98-7.85(m, 3H), 7.70(t, J＝8.0Hz, 1H), 7.41(d, J＝8.5Hz, 1H), 7.20(dd, J＝8.5, 1.5Hz, 1H), 6.50(q, J＝7.0Hz, 1H), 2.85(d, J=4.5Hz, 3H), 2.51(s, 3H), 2.03(d, J=7.0Hz, 3H). 13 C NMR(151MHz, DMSO)δ166.22,158.94,156.48,154.29, 147.39,141.72,140.13,139.47,136.55,133.40,130.37,126.01,125.32,123.04,122.53,121.93,121.38,110.79,99.23,49.14,26.83,18.83,14.9
制备实施例46 1-(1-(6-氯-1-苯基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺47Preparation Example 46 1-(1-(6-Chloro-1-phenyl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3,4-d] Pyrimidine-4-amine 47
Figure PCTCN2022082962-appb-000060
Figure PCTCN2022082962-appb-000060
制备方法同制备实施案例1-10,柱层析得白色固体47，收率78％。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%.
1H NMR(400MHz,Chloroform-d)δ8.39(s,1H),7.72-7.66(m,2H),7.64(d,J＝1.6Hz,1H),7.51(t,J＝7.6Hz,2H),7.40(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.01(dd,J＝8.4,1.6Hz,1H),6.58(q,J＝6.8Hz,1H),6.07(brs,2H),2.57(s,3H),2.16(d,J＝6.8Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.45,155.97,154.25,146.37,140.96,140.48,139.60,133.62,129.52,126.99,123.00,122.41,122.14,121.68,110.23,99.88,49.73,18.71,14.92. 1 H NMR (400MHz, Chloroform-d) δ8.39(s, 1H), 7.72-7.66(m, 2H), 7.64(d, J=1.6Hz, 1H), 7.51 (t, J=7.6Hz, 2H) ),7.40(d,J＝8.4Hz,1H),7.35(t,J＝7.6Hz,1H),7.01(dd,J＝8.4,1.6Hz,1H),6.58(q,J＝6.8Hz,1H) ), 6.07(brs, 2H), 2.57(s, 3H), 2.16(d, J=6.8Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ158.45, 155.97, 154.25, 146.37, 140.96, 140.48, 139.60 ,133.62,129.52,126.99,123.00,122.41,122.14,121.68,110.23,99.88,49.73,18.71,14.92.
制备实施例47 1-(1-(6-氯-1-(间甲苯基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺48Preparation Example 47 1-(1-(6-Chloro-1-(m-tolyl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3,4- d] Pyrimidine-4-amine 48
Figure PCTCN2022082962-appb-000061
Figure PCTCN2022082962-appb-000061
制备方法同制备实施案例1-10,柱层析得白色固体48，收率68％。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%.
1H NMR(400MHz,Chloroform-d)δ8.43(s,1H),7.66(d,J＝1.6Hz,1H),7.57-7.53(m,1H),7.52-7.47(m,1H),7.45-7.40(m,2H),7.20(d,J＝7.2Hz,1H),7.04(dd,J＝8.8,1.6Hz,1H),6.61(q,J＝6.8Hz,1H),5.96(brs,2H),2.61(s,3H),2.48(s,3H),2.19(d,J＝6.8Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.35,155.99,154.25,146.17,140.89,140.52,139.70,139.49,133.51,129.24,127.87,123.86,122.32,122.10,121.58,120.04,110.28,99.88,49.74,21.55,18.74,14.93. 1 H NMR (400MHz, Chloroform-d) δ8.43(s, 1H), 7.66(d, J=1.6Hz, 1H), 7.57-7.53(m, 1H), 7.52-7.47(m, 1H), 7.45 -7.40(m, 2H), 7.20(d, J=7.2Hz, 1H), 7.04(dd, J=8.8, 1.6Hz, 1H), 6.61(q, J=6.8Hz, 1H), 5.96(brs, 2H), 2.61(s, 3H), 2.48(s, 3H), 2.19(d, J=6.8Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ158.35, 155.99, 154.25, 146.17, 140.89, 140.52, 139.70,139.49,133.51,129.24,127.87,123.86,122.32,122.10,121.58,120.04,110.28,99.88,49.74,21.55,18.74,14.93.
制备实施例48 1-(1-(6-氯-1-(3,5-二氟苯基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺49Preparation Example 48 1-(1-(6-Chloro-1-(3,5-difluorophenyl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo [3,4-d]pyrimidin-4-amine 49
Figure PCTCN2022082962-appb-000062
Figure PCTCN2022082962-appb-000062
制备方法同制备实施案例1-10,柱层析得白色固体49，收率76％。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%.
1H NMR(600MHz,Chloroform-d)δ8.41(s,1H),7.70(d,J＝1.8Hz,1H),7.40(d,J＝8.4Hz,1H),7.32(dd,J＝7.8,1.8Hz,3H),7.07(dd,J＝8.4,1.8Hz,1H),6.84-6.77(m,1H),6.55(q,J＝7.2Hz,1H),5.48(brs,2H),2.59(s,3H),2.14(d,J＝7.2Hz,3H). 1 H NMR (600MHz, Chloroform-d) δ 8.41 (s, 1H), 7.70 (d, J=1.8Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.32 (dd, J=7.8 ,1.8Hz,3H),7.07(dd,J=8.4,1.8Hz,1H),6.84-6.77(m,1H),6.55(q,J=7.2Hz,1H),5.48(brs,2H),2.59 (s, 3H), 2.14(d, J=7.2Hz, 3H).
制备实施例49 1-(1-(6-氯-1-(噻吩-3-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺50Preparation Example 49 1-(1-(6-Chloro-1-(thiophen-3-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine 50
Figure PCTCN2022082962-appb-000063
Figure PCTCN2022082962-appb-000063
制备方法同制备实施案例1-10,柱层析得白色固体50，收率74％。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%.
1H NMR(400MHz,Chloroform-d)δ8.44(s,1H),7.71-7.62(m,1H),7.56-7.52(m,1H),7.51-7.47(m,2H),7.41(d,J＝8.4Hz,1H),7.05(dd,J＝8.8,1.6Hz,1H),6.60(q,J＝6.8Hz,1H),5.62(brs,2H),2.62(s,3H),2.18(d,J＝6.8Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.22,156.03,154.27,145.97,140.83,140.57,138.37,133.79,126.13,122.93,122.42,122.08,121.26,113.87,110.17,99.87,49.68,18.63,14.90. 1 H NMR (400MHz, Chloroform-d) δ8.44(s, 1H), 7.71-7.62(m, 1H), 7.56-7.52(m, 1H), 7.51-7.47(m, 2H), 7.41(d, J=8.4Hz, 1H), 7.05(dd, J=8.8, 1.6Hz, 1H), 6.60(q, J=6.8Hz, 1H), 5.62(brs, 2H), 2.62(s, 3H), 2.18( d, J=6.8Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ158.22, 156.03, 154.27, 145.97, 140.83, 140.57, 138.37, 133.79, 126.13, 122.93, 122.42, 122.08, 1217.26, 99.87. ,49.68,18.63,14.90.
制备实施例50 1-(1-(6-氯-1-(1-甲基-1H-吡唑-4-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺51Preparation Example 50 1-(1-(6-Chloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)ethyl)-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4-amine 51
Figure PCTCN2022082962-appb-000064
Figure PCTCN2022082962-appb-000064
制备方法同制备实施案例1-10,柱层析得白色固体51，收率80％。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%.
1H NMR(400MHz,Chloroform-d)δ8.42(s,1H),7.84(s,1H),7.80(s,1H),7.45(d,J＝1.6Hz,1H),7.39(d,J＝8.8Hz,1H),7.02(dd,J＝8.8,1.6Hz,1H),6.57(q,J＝7.2Hz,1H),5.79(brs,2H),4.02(s,3H),2.61(s,3H),2.15(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.24,156.04,154.27,145.94,141.31,140.85,133.68,133.24,124.43,123.48,122.25,122.05,120.84,109.66,99.88,49.65,39.69,18.67,14.92. 1 H NMR(400MHz, Chloroform-d)δ8.42(s,1H),7.84(s,1H),7.80(s,1H),7.45(d,J=1.6Hz,1H),7.39(d,1H) =8.8Hz,1H),7.02(dd,J=8.8,1.6Hz,1H),6.57(q,J=7.2Hz,1H),5.79(brs,2H),4.02(s,3H),2.61(s , 3H), 2.15(d, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ158.24, 156.04, 154.27, 145.94, 141.31, 140.85, 133.68, 133.24, 124.43, 123.48, 122.25, 122.845, ,109.66,99.88,49.65,39.69,18.67,14.92.
制备实施例51 3-(3-(1-(4-氨基-3-甲基-1H-吡唑[3,4-d]嘧啶-1-基)乙基)-6-氯-1H-吲唑-1-基)苯酚52Preparation Example 51 3-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-1H-indium oxazol-1-yl)phenol 52
Figure PCTCN2022082962-appb-000065
Figure PCTCN2022082962-appb-000065
制备方法同制备实施案例1-10,柱层析得白色固体52，收率82％。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%.
1H NMR(600MHz,Chloroform-d)δ8.44(s,1H),7.43(d,J＝8.4Hz,1H),7.27(s,1H),7.24(t,J＝5.2Hz,1H),7.18-7.14(m,1H),7.12(d,J＝1.2Hz,1H),6.85(dd,J＝8.4,1.2Hz,1H),6.76-6.67(m,2H),6.59(q,J＝6.6Hz,1H),5.61(brs,2H),2.59(s,3H),2.19(d,J＝6.6Hz,3H). 1 H NMR (600MHz, Chloroform-d) δ8.44(s, 1H), 7.43(d, J=8.4Hz, 1H), 7.27(s, 1H), 7.24(t, J=5.2Hz, 1H), 7.18-7.14(m, 1H), 7.12(d, J=1.2Hz, 1H), 6.85(dd, J=8.4, 1.2Hz, 1H), 6.76-6.67(m, 2H), 6.59(q, J= 6.6Hz, 1H), 5.61(brs, 2H), 2.59(s, 3H), 2.19(d, J=6.6Hz, 3H).
制备实施例52 1-(1-(萘-2-基)-1H-吲唑-3-基)甲基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺53Preparation Example 52 1-(1-(Naphthalen-2-yl)-1H-indazol-3-yl)methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4 - Amine 53
Figure PCTCN2022082962-appb-000066
Figure PCTCN2022082962-appb-000066
制备方法同制备实施案例1-10,柱层析得白色固体53，收率78％。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%.
1H NMR(600MHz,Chloroform-d)δ8.43(s,1H),8.11(d,J＝2.4Hz,1H),8.01(d,J＝8.4Hz,1H),7.96-7.89(m,3H),7.77-7.74(m,1H),7.60-7.52(m,2H),7.45(dd,J＝9.0,1.2Hz,1H),7.06(dd,J＝9.0,1.8Hz,1H),6.63(q,J＝7.2Hz,1H),5.59(brs,2H),2.61(s,3H),2.20(d,J＝7.2Hz,4H). 13C NMR(101MHz,CDCl 3)δ158.20,156.06,154.32,146.59,140.84,140.68,137.11,133.72,133.53,132.06,129.59,128.00,127.88,126.97,126.26,122.52,122.20,122.00,121.79,120.33,110.30,99.91,49.77,18.70,14.92. 1 H NMR(600MHz, Chloroform-d)δ8.43(s,1H),8.11(d,J=2.4Hz,1H),8.01(d,J=8.4Hz,1H),7.96-7.89(m,3H) ),7.77-7.74(m,1H),7.60-7.52(m,2H),7.45(dd,J=9.0,1.2Hz,1H),7.06(dd,J=9.0,1.8Hz,1H),6.63( q, J=7.2Hz, 1H), 5.59 (brs, 2H), 2.61 (s, 3H), 2.20 (d, J=7.2Hz, 4H). 13 C NMR (101MHz, CDCl 3 )δ158.20, 156.06, 154.32 146.59,140.80.68,137.11,133.72,132.06,129.59, 127.88,126.26.22.52.02.00, 12.7.7.79.7.7.7
制备实施例53 1-(1-(6-氯-1-(喹啉-7-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺54Preparation Example 53 1-(1-(6-Chloro-1-(quinolin-7-yl)-1H-indazol-3-yl)ethyl)-3-methyl-1H-pyrazolo[3 ,4-d]pyrimidin-4-amine 54
Figure PCTCN2022082962-appb-000067
Figure PCTCN2022082962-appb-000067
制备方法同制备实施案例1-10,柱层析得白色固体54，收率83％。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%.
1H NMR(600MHz,Chloroform-d)δ8.99(dd,J＝4.2,1.8Hz,1H),8.42(s,1H),8.39(d,J＝1.8Hz,1H),8.25-8.20(m,1H),8.13-8.10(m,1H),8.00(d,J＝8.4Hz,1H),7.95-7.91(m,1H),7.47-7.43(m,2H),7.08(dd,J＝8.4,1.8Hz,1H),6.62(q,J＝6.6Hz,1H),5.56(brs,2H),2.60(s,3H),2.20(d,J＝6.6Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.25,156.13,154.37,151.50,148.56,147.28,140.97,140.54,136.01,134.26,129.43,126.71,123.00,122.75,122.25,121.24,120.12,110.70,99.96,49.74,18.63,14.97. 1 H NMR(600MHz, Chloroform-d)δ8.99(dd,J=4.2,1.8Hz,1H),8.42(s,1H),8.39(d,J=1.8Hz,1H),8.25-8.20(m ,1H),8.13-8.10(m,1H),8.00(d,J=8.4Hz,1H),7.95-7.91(m,1H),7.47-7.43(m,2H),7.08(dd,J=8.4 , 1.8Hz, 1H), 6.62(q, J=6.6Hz, 1H), 5.56(brs, 2H), 2.60(s, 3H), 2.20(d, J=6.6Hz, 3H). 13 C NMR(101MHz) ,CDCl 3 )δ158.25,156.13,154.37,151.50,148.56,147.28,140.97,140.54,136.01,134.26,129.43,126.71,123.00,122.75,122.25,121.24,120.12,110.70,99.96,49.74,18.63,14.97.
制备实施例54 1-(1-(6-氯-1-(1-甲基-1H-吲哚-6-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶-4-胺55Preparation Example 54 1-(1-(6-Chloro-1-(1-methyl-1H-indol-6-yl)-1H-indazol-3-yl)ethyl)-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4-amine 55
Figure PCTCN2022082962-appb-000068
Figure PCTCN2022082962-appb-000068
制备方法同制备实施案例1-10,柱层析得白色固体55，收率79％。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%.
1H NMR(600MHz,Chloroform-d)δ8.42(s,1H),7.73(d,J＝8.4Hz,1H),7.65-7.63(m,1H),7.63-7.60(m,1H),7.43-7.37(m,2H),7.16(d,J＝3.6Hz,1H),7.01(dd,J＝9.0,1.8Hz,1H),6.62(q,J＝7.2Hz,1H),6.58-6.54(m,1H),5.56(brs,2H),3.86(s,3H),2.61(s,3H),2.19(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.26,156.03,154.29,145.70,141.11,140.81,136.86,133.95,133.28,130.36,127.83,122.10,122.04,121.42,121.28,115.75,110.31,105.26,101.29,99.91,49.91,33.20,18.86,14.93. 1 H NMR (600MHz, Chloroform-d) δ8.42(s, 1H), 7.73(d, J=8.4Hz, 1H), 7.65-7.63(m, 1H), 7.63-7.60(m, 1H), 7.43 -7.37(m, 2H), 7.16(d, J=3.6Hz, 1H), 7.01(dd, J=9.0, 1.8Hz, 1H), 6.62(q, J=7.2Hz, 1H), 6.58-6.54( m, 1H), 5.56(brs, 2H), 3.86(s, 3H), 2.61(s, 3H), 2.19(d, J=7.2Hz, 3H). 13 C NMR(101MHz, CDCl 3 )δ158.26,156.03 ,154.29,145.70,141.11,140.81,136.86,133.95,133.28,130.36,127.83,122.10,122.04,121.42,121.28,115.75,110.31,105.26,101.29,99.91,49.91,33.20,18.86,14.93.
制备实施例55 1-(1-(6-氯-1-(2,3-二氢苯并[b][1,4]二恶英-6-基)-1H-吲唑-3-基)乙基)-3-甲基-1H-吡唑并[3,4-d]嘧啶56Preparation Example 55 1-(1-(6-Chloro-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indazol-3-yl )ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine 56
Figure PCTCN2022082962-appb-000069
Figure PCTCN2022082962-appb-000069
制备方法同制备实施案例1-10,柱层析得白色固体56，收率83％。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%.
1H NMR(600MHz,Chloroform-d)δ8.40(s,1H),7.57(d,J＝1.8Hz,1H),7.36(d,J＝8.4Hz,1H),7.20(d,J＝2.4Hz,1H),7.14(dd,J＝9.0,2.4Hz,1H),7.03-6.94(m,2H),6.56(q,J＝7.2Hz,1H),5.50(brs,2H),4.32(s,4H),2.59(s,3H),2.14(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.23,156.01,154.27,145.82,143.93,142.78,140.79,140.61,133.43,133.19,122.19,122.02,121.32,117.79,116.54,112.76,110.11,99.87,64.47,49.73,18.68,14.90. 1 H NMR (600MHz, Chloroform-d)δ8.40(s,1H),7.57(d,J=1.8Hz,1H),7.36(d,J=8.4Hz,1H),7.20(d,J=2.4 Hz,1H),7.14(dd,J=9.0,2.4Hz,1H),7.03-6.94(m,2H),6.56(q,J=7.2Hz,1H),5.50(brs,2H),4.32(s , 4H), 2.59(s, 3H), 2.14(d, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ158.23, 156.01, 154.27, 145.82, 143.93, 142.78, 140.79, 140.61, 133.43, 133.19,122.19,122.02,121.32,117.79,116.54,112.76,110.11,99.87,64.47,49.73,18.68,14.90.
制备实施例56 1-(1-(6-氯-1-(3-(甲基磺酰基)苯基)-1H-吲唑-3-基)乙基)-3-(3-氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺57Preparation Example 56 1-(1-(6-Chloro-1-(3-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-3-(3-fluoro-4 -Methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 57
Figure PCTCN2022082962-appb-000070
Figure PCTCN2022082962-appb-000070
制备方法同制备实施案例1-5，后续步骤如下：The preparation method is the same as the preparation and implementation cases 1-5, and the subsequent steps are as follows:
Figure PCTCN2022082962-appb-000071
Figure PCTCN2022082962-appb-000071
步骤1：化合物57-3的合成Step 1: Synthesis of Compound 57-3
两口瓶中加入57-1(700mg,2.68mmol)，59-2(1.37g,8.04mmol)，四三苯基膦钯(312mg,0.27mmol)，碳酸钾(741mg,5.36mmol)，抽真空通氩气，置换三次，加入30mL二氧六环和10mL水，再次抽真空通氩气，置换完后135℃反应14h，旋掉二氧六环，加水有大量固体析出，过滤，所得固体用二氯甲烷洗涤，干燥，得黄色固体(1.1g,59％)。In the two-necked flask, add 57-1 (700mg, 2.68mmol), 59-2 (1.37g, 8.04mmol), tetrakistriphenylphosphine palladium (312mg, 0.27mmol), potassium carbonate (741mg, 5.36mmol), vacuumize through Argon, replaced three times, added 30 mL of dioxane and 10 mL of water, evacuated and passed argon again, and reacted at 135 °C for 14 h after the replacement. Washed with methyl chloride and dried to give a yellow solid (1.1 g, 59%).
步骤2：化合物6b的合成Step 2: Synthesis of Compound 6b
两口瓶中加入化合物6(500mg,1.83mmol)，抽真空通氩气，置换三次，加入无水二氯甲烷，0℃下缓慢滴加二氯亚砜(0.4mL,5.49mmol)，室温反应过夜。反应结束后，旋掉二氯亚砜，反应液加乙酸乙酯，有机相用饱和碳酸氢钠萃取三次，水洗，饱和氯化钠洗，无水硫酸钠干燥，浓缩，用PE/EA(v/v,1:1)的淋洗剂柱层析分离得淡黄色固体6b(491mg,92％)。Compound 6 (500 mg, 1.83 mmol) was added to the two-necked flask, evacuated and passed through argon, replaced three times, anhydrous dichloromethane was added, thionyl chloride (0.4 mL, 5.49 mmol) was slowly added dropwise at 0°C, and the reaction was performed at room temperature overnight. . After the reaction, spin off thionyl chloride, add ethyl acetate to the reaction solution, extract the organic phase three times with saturated sodium bicarbonate, wash with water, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and use PE/EA (v /v, 1:1) eluent column chromatography to obtain pale yellow solid 6b (491 mg, 92%).
步骤3：化合物57的合成Step 3: Synthesis of Compound 57
两口瓶中加入化合物6b(300mg,1.03mmol)，57-3(399mg,1.54mmol)，无水碳酸钾(427mg,3.09mmol)，抽真空通氩气，置换三次，加入无水DMF，65℃反应过夜。反应结束后，加水稀释，乙酸乙酯萃取三次，合并有机相，有机相用饱和氯化钠洗，无水硫酸钠干燥，浓缩，用DCM/MeOH(v/v,50:1)的淋洗剂柱层析分离得淡黄色固体57(365mg,60％)。Compound 6b (300mg, 1.03mmol), 57-3 (399mg, 1.54mmol), anhydrous potassium carbonate (427mg, 3.09mmol) were added to the two-necked flask, argon was evacuated, replaced three times, anhydrous DMF was added, 65° C. React overnight. After the reaction, diluted with water, extracted three times with ethyl acetate, combined the organic phases, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, rinsed with DCM/MeOH (v/v, 50:1) 57 (365 mg, 60%) was isolated as a pale yellow solid by column chromatography.
1H NMR(500MHz,Chloroform-d)δ8.45(s,1H),8.33(t,J＝2.0Hz,1H),8.04-7.99(m,1H),7.96-7.90(m,1H),7.75(t,J＝8.0Hz,1H),7.67(d,J＝1.0Hz,1H),7.60(d,J＝8.5Hz,1H),7.43-7.36(m,2H),7.13-7.06(m,2H),6.69(q,J＝7.0Hz,1H),5.76(brs,2H),3.94(s,3H),3.15(s,3H),2.22(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ157.86, 156.11,154.40,153.57and 151.59,148.59and 148.51,147.55,143.53and 143.51,142.20,140.66,140.33,134.49,130.67,127.01,126.04and 125.99,125.14,124.54and 124.51,123.20,122.59,122.15,121.43,116.54and 116.39,113.95and 113.93,109.95,98.45,56.38,50.23,44.52,18.74. 1 H NMR (500MHz, Chloroform-d) δ8.45(s, 1H), 8.33(t, J=2.0Hz, 1H), 8.04-7.99(m, 1H), 7.96-7.90(m, 1H), 7.75 (t, J=8.0Hz, 1H), 7.67(d, J=1.0Hz, 1H), 7.60(d, J=8.5Hz, 1H), 7.43-7.36(m, 2H), 7.13-7.06(m, 2H), 6.69(q, J=7.0Hz, 1H), 5.76(brs, 2H), 3.94(s, 3H), 3.15(s, 3H), 2.22(d, J=7.0Hz, 3H). 13 C NMR(126MHz,CDCl 3 )δ157.86, 156.11,154.40,153.57and 151.59,148.59and 148.51,147.55,143.53and 143.51,142.20,140.66,140.33,134.49,130.67,127.01,126.04and 125.99,125.14,124.54and 124.51 ,123.20,122.59,122.15,121.43,116.54and 116.39,113.95and 113.93,109.95,98.45,56.38,50.23,44.52,18.74.
制备实施例57 1-(1-(6-氯-1-(3-(甲基磺酰基)苯基)-1H-吲唑-3-基)乙基)-3-(3-氟-4-异丙氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺58Preparation Example 57 1-(1-(6-Chloro-1-(3-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-3-(3-fluoro-4 -Isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 58
Figure PCTCN2022082962-appb-000072
Figure PCTCN2022082962-appb-000072
制备方法同制备实施案例56，柱层析得白色固体58，收率65％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 58 with a yield of 65%.
1H NMR(500MHz,Chloroform-d)δ8.46(s,1H),8.36-8.30(m,1H),8.03-8.00(m,1H),7.94-7.92(m,1H),7.76(t,J＝8.0Hz,1H),7.67(d,J＝1.5Hz,1H),7.59(d,J＝9.0Hz,1H),7.43-7.36(m,1H),7.36-7.32(m,1H),7.14-7.07(m,2H),6.69(q,J＝7.0Hz,1H),4.61(p,J＝6.0Hz,1H),3.15(s,3H),2.22(d,J＝7.0Hz,3H),1.40(d,J＝6.0Hz,6H). 1 H NMR (500MHz, Chloroform-d)δ8.46(s,1H), 8.36-8.30(m,1H), 8.03-8.00(m,1H), 7.94-7.92(m,1H), 7.76(t, J=8.0Hz, 1H), 7.67(d, J=1.5Hz, 1H), 7.59(d, J=9.0Hz, 1H), 7.43-7.36(m, 1H), 7.36-7.32(m, 1H), 7.14-7.07(m, 2H), 6.69(q, J=7.0Hz, 1H), 4.61(p, J=6.0Hz, 1H), 3.15(s, 3H), 2.22(d, J=7.0Hz, 3H) ),1.40(d,J＝6.0Hz,6H).
制备实施例58 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(3-氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺59Preparation Example 58 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(3-fluoro-4-methoxybenzene yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 59
Figure PCTCN2022082962-appb-000073
Figure PCTCN2022082962-appb-000073
制备方法同制备实施案例56，柱层析得白色固体59，收率62％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 59 with a yield of 62%.
1H NMR(500MHz,Chloroform-d)δ9.11-8.96(m,1H),8.62(dd,J＝5.0,1.5Hz,1H),8.46(s,1H),8.06(ddd,J＝8.0,2.5,1.5Hz,1H),7.70-7.65(m,1H),7.63-7.57(m,1H),7.53-7.46(m,1H),7.44-7.39(m,1H),7.39-7.35(m,1H),7.13-7.05(m,2H),6.70(q,J＝7.0Hz,1H),5.65(brs,2H),3.94(s,3H),2.23(d,J＝7.0Hz,3H). 1 H NMR (500MHz, Chloroform-d) δ9.11-8.96 (m, 1H), 8.62 (dd, J=5.0, 1.5Hz, 1H), 8.46 (s, 1H), 8.06 (ddd, J=8.0, 2.5,1.5Hz,1H),7.70-7.65(m,1H),7.63-7.57(m,1H),7.53-7.46(m,1H),7.44-7.39(m,1H),7.39-7.35(m, 1H), 7.13-7.05(m, 2H), 6.70(q, J=7.0Hz, 1H), 5.65(brs, 2H), 3.94(s, 3H), 2.23(d, J=7.0Hz, 3H).
13C NMR(126MHz,CDCl 3)δ157.89,156.05,154.38,153.56and 151.59,148.58and 148.49,147.87,147.41,143.81,143.50and 143.48,140.56,136.35,134.28,129.98,126.07and 126.01,124.52and 124.49,124.05,122.96,122.51,121.93,116.55and 116.40,113.91and 113.90,109.89,98.43,56.37,50.26,18.74. 13 C NMR(126MHz,CDCl 3 )δ157.89,156.05,154.38,153.56and 151.59,148.58and 148.49,147.87,147.41,143.81,143.50and 143.48,140.56,136.35,134.28,129.98,126.07and 126.01,124.52and 124.49,124.05 ,122.96,122.51,121.93,116.55and 116.40,113.91and 113.90,109.89,98.43,56.37,50.26,18.74.
制备实施例59 1-(1-(6-氯-1-(3-(甲基磺酰基)苯基)-1H-吲唑-3-基)乙基)-3-(3,4-二甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺60Preparation Example 59 1-(1-(6-Chloro-1-(3-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-3-(3,4-di Methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 60
Figure PCTCN2022082962-appb-000074
Figure PCTCN2022082962-appb-000074
制备方法同制备实施案例56，柱层析得白色固体60，收率65％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 60 with a yield of 65%.
1H NMR(500MHz,Chloroform-d)δ8.45(s,1H),8.34-8.32(m,1H),8.06-7.98(m,1H),7.95-7.89(m,1H),7.75(t,J＝8.0Hz,1H),7.67(d,J＝1.5Hz,1H),7.62(d,J＝8.5Hz,1H),7.19(dd,J＝8.5,2.0Hz,1H),7.15(d,J＝2.0Hz,1H),7.12-7.08(m,1H),6.99(d,J＝8.0Hz,1H),6.70(q,J＝7.0Hz,1H),5.72(brs,2H),3.93(s,3H),3.92(s,3H),3.15(s,3H),2.24(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ157.96,156.07,154.31,149.91,149.59,147.69,144.79,142.20,140.67,140.35,134.44,130.66,126.97,125.71,125.13,123.08,122.77,122.23,121.44,120.97,111.66,111.62,109.93,98.58,56.06,50.26,44.53,18.80. 1 H NMR (500MHz, Chloroform-d) δ8.45(s, 1H), 8.34-8.32(m, 1H), 8.06-7.98(m, 1H), 7.95-7.89(m, 1H), 7.75(t, J=8.0Hz, 1H), 7.67(d, J=1.5Hz, 1H), 7.62(d, J=8.5Hz, 1H), 7.19(dd, J=8.5, 2.0Hz, 1H), 7.15(d, J=2.0Hz,1H),7.12-7.08(m,1H),6.99(d,J=8.0Hz,1H),6.70(q,J=7.0Hz,1H),5.72(brs,2H),3.93( s, 3H), 3.92(s, 3H), 3.15(s, 3H), 2.24(d, J=7.0Hz, 3H). 13 C NMR(126MHz, CDCl 3 )δ157.96,156.07,154.31,149.91,149.59, 147.69,144.79,142.20,140.67,140.35,134.44,130.66,126.97,125.71,125.13,123.08,122.77,122.23,121.44,120.97,111.66,111.62,109.93,98.58,56.06,50.26,44.53,18.80.
制备实施例60 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(3,4-二甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺61Preparation Example 60 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl )-1H-pyrazolo[3,4-d]pyrimidin-4-amine 61
Figure PCTCN2022082962-appb-000075
Figure PCTCN2022082962-appb-000075
制备方法同制备实施案例56，柱层析得白色固体61，收率66％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 61 with a yield of 66%.
1H NMR(500MHz,Chloroform-d)δ9.04(d,J＝2.5Hz,1H),8.62(dd,J＝5.0,1.5Hz,1H),8.44(s,1H),8.13-8.01(m,1H),7.67(d,J＝1.5Hz,1H),7.61(d,J＝8.5Hz,1H),7.51-7.47(m,1H),7.19(dd,J＝8.0,2.0Hz,1H),7.15(d,J＝2.0Hz,1H),7.12-7.07(m,1H),6.99(d,J＝8.0Hz,1H),6.70(q,J＝7.0Hz,1H),5.88(brs,2H),3.93(s,3H),3.92(s,3H),2.24(d,J＝7.0Hz,3H). 13C NMR(126MHz,CDCl 3)δ158.03,155.98,154.28,149.87,149.56,147.83,147.54,144.75,143.79,140.56,136.34,134.21,129.92,125.73,124.03,122.82,122.67,121.99,120.94,111.65,111.59,109.86,98.55,56.03,50.27,18.79. 1 H NMR (500MHz, Chloroform-d) δ9.04 (d, J=2.5Hz, 1H), 8.62 (dd, J=5.0, 1.5Hz, 1H), 8.44 (s, 1H), 8.13-8.01 (m ,1H),7.67(d,J＝1.5Hz,1H),7.61(d,J＝8.5Hz,1H),7.51-7.47(m,1H),7.19(dd,J＝8.0,2.0Hz,1H) ,7.15(d,J＝2.0Hz,1H),7.12-7.07(m,1H),6.99(d,J＝8.0Hz,1H),6.70(q,J＝7.0Hz,1H),5.88(brs, 2H), 3.93(s, 3H), 3.92(s, 3H), 2.24(d, J=7.0Hz, 3H). 13 C NMR (126MHz, CDCl 3 )δ158.03, 155.98, 154.28, 149.87, 149.56, 147.83, 147.54,144.75,143.79,140.56,136.34,134.21,129.92,125.73,124.03,122.82,122.67,121.99,120.94,111.65,111.59,109.86,98.55,1.79.03,5
制备实施例61 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(6-甲氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺62Preparation Example 61 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(6-methoxypyridin-3-yl )-1H-pyrazolo[3,4-d]pyrimidin-4-amine 62
Figure PCTCN2022082962-appb-000076
Figure PCTCN2022082962-appb-000076
制备方法同制备实施案例56，柱层析得白色固体62，收率58％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 62 with a yield of 58%.
1H NMR(400MHz,Chloroform-d)δ9.06(d,J＝2.4Hz,1H),8.65(dd,J＝4.8,1.6Hz,1H),8.49(s,1H),8.49-8.46(m,1H),8.13-8.04(m,1H),7.89(dd,J＝8.4,2.4Hz,1H),7.70(d,J＝1.6Hz,1H),7.65(d,J＝8.4Hz,1H),7.52(dd,J＝8.4,4.8Hz,1H),7.14(dd,J ＝8.8,1.6Hz,1H),6.91(d,J＝8.4Hz,1H),6.74(q,J＝7.2Hz,1H),5.75(brs,2H),4.02(s,3H),2.26(d,J＝7.2Hz,3H). 13C NMR(151MHz,CDCl 3)δ164.58,157.85,156.13,154.45,147.88,147.38,146.54,143.82,141.63,140.57,138.80,136.34,134.31,130.00,124.05,123.00,122.52,122.49,121.91,111.65,109.90,98.67,53.79,50.31,18.76. 1 H NMR (400MHz, Chloroform-d) δ9.06 (d, J=2.4Hz, 1H), 8.65 (dd, J=4.8, 1.6Hz, 1H), 8.49 (s, 1H), 8.49-8.46 (m ,1H),8.13-8.04(m,1H),7.89(dd,J＝8.4,2.4Hz,1H),7.70(d,J＝1.6Hz,1H),7.65(d,J＝8.4Hz,1H) ,7.52(dd,J＝8.4,4.8Hz,1H),7.14(dd,J＝8.8,1.6Hz,1H),6.91(d,J＝8.4Hz,1H),6.74(q,J＝7.2Hz, 1H), 5.75(brs, 2H), 4.02(s, 3H), 2.26(d, J=7.2Hz, 3H). 13 C NMR(151MHz, CDCl 3 )δ164.58,157.85,156.13,154.45,147.88,147.38, 146.54,143.82,141.63,140.57,138.80,136.34,134.31,130.00,124.05,123.00,122.52,122.49,121.91,111.65,109.90,98.67,53.79,50.31,18.79
制备实施例62 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(1-甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺63Preparation Example 62 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(1-methyl-1H-pyrazole- 4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 63
Figure PCTCN2022082962-appb-000077
Figure PCTCN2022082962-appb-000077
制备方法同制备实施案例56，柱层析得白色固体63，收率54％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 63 with a yield of 54%.
1H NMR(400MHz,Chloroform-d)δ9.06(d,J＝2.8Hz,1H),8.64(dd,J＝4.8,1.6Hz,1H),8.47(s,1H),8.15-8.01(m,1H),7.80(s,1H),7.73(s,1H),7.69(d,J＝1.6Hz,1H),7.56(d,J＝8.8Hz,1H),7.51(dd,J＝8.0,4.8Hz,1H),7.19-7.05(m,1H),6.70(q,J＝7.2Hz,1H),5.83(brs,2H),4.00(s,3H),2.23(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.09,156.14,154.14,147.87,147.47,143.83,140.57,138.41,136.95,136.41,134.30,129.97,129.76,124.08,122.99,122.48,122.02,114.72,109.90,99.02,50.11,39.31,18.69. 1 H NMR (400MHz, Chloroform-d) δ9.06 (d, J=2.8Hz, 1H), 8.64 (dd, J=4.8, 1.6Hz, 1H), 8.47 (s, 1H), 8.15-8.01 (m ,1H),7.80(s,1H),7.73(s,1H),7.69(d,J＝1.6Hz,1H),7.56(d,J＝8.8Hz,1H),7.51(dd,J＝8.0, 4.8Hz, 1H), 7.19-7.05(m, 1H), 6.70(q, J=7.2Hz, 1H), 5.83(brs, 2H), 4.00(s, 3H), 2.23(d, J=7.2Hz, 3H). 13 C NMR(101MHz,CDCl 3 )δ158.09,156.14,154.14,147.87,147.47,143.83,140.57,138.41,136.95,136.41,134.30,129.97,129.76,124.08,122.99,122.48,122.02,114.72,109.90, 99.02, 50.11, 39.31, 18.69.
制备实施例63 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(2-甲氧基嘧啶-5-基)-1H-吡唑并[3,4-d]嘧啶-4-胺64Preparation Example 63 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(2-methoxypyrimidin-5-yl )-1H-pyrazolo[3,4-d]pyrimidin-4-amine 64
Figure PCTCN2022082962-appb-000078
Figure PCTCN2022082962-appb-000078
制备方法同制备实施案例56，柱层析得白色固体64，收率67％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 64 with a yield of 67%.
1H NMR(400MHz,Chloroform-d)δ9.05(s,1H),8.84(s,2H),8.72-8.59(m,1H),8.53(s,1H),8.08(d,J＝8.0Hz,1H),7.76-7.63(m,2H),7.58-7.46(m,1H),7.16(d,J＝8.8Hz,1H),6.77(q,J＝7.2Hz,1H),5.60(brs,2H),4.11(s,3H),2.27(d,J＝7.2Hz,3H). 13C NMR(151MHz,CDCl 3)δ165.69,158.77,157.67,156.16,154.57,147.95,147.07,143.83,140.59,138.30,134.42,130.05,124.08,123.10,122.36,121.84,121.28,109.98,98.81,55.38,50.40,29.70,18.72. 1 H NMR (400MHz, Chloroform-d) δ9.05(s, 1H), 8.84(s, 2H), 8.72-8.59(m, 1H), 8.53(s, 1H), 8.08(d, J=8.0Hz ,1H),7.76-7.63(m,2H),7.58-7.46(m,1H),7.16(d,J=8.8Hz,1H),6.77(q,J=7.2Hz,1H),5.60(brs, 2H), 4.11(s, 3H), 2.27(d, J=7.2Hz, 3H). 13 C NMR (151MHz, CDCl 3 )δ165.69, 158.77, 157.67, 156.16, 154.57, 147.95, 147.07, 143.83, 140.59, 138.30 ,134.42,130.05,124.08,123.10,122.36,121.84,121.28,109.98,98.81,55.38,50.40,29.70,18.72.
制备实施例64 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-1H-吡唑并[3,4-d]嘧啶-4-胺65Preparation Example 64 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(2,3-dihydrobenzo[b ][1,4]dioxin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 65
Figure PCTCN2022082962-appb-000079
Figure PCTCN2022082962-appb-000079
制备方法同制备实施案例56，柱层析得白色固体65，收率69％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 65 with a yield of 69%.
1H NMR(400MHz,Chloroform-d)δ9.06(d,J＝2.8Hz,1H),8.64(dd,J＝4.8,1.6Hz,1H),8.46(s,1H),8.13-8.04(m,1H),7.69(d,J＝1.6Hz,1H),7.60(d,J＝8.4Hz,1H), 7.51(dd,J＝8.0,4.8Hz,1H),7.19(d,J＝2.0Hz,1H),7.16-7.10(m,2H),7.01(d,J＝8.4Hz,1H),6.71(q,J＝7.2Hz,1H),5.87(brs,2H),4.32(s,4H),2.25(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.01,156.05,154.35,147.86,147.64,144.61,144.43,144.21,143.85,140.61,136.44,134.29,130.04,126.49,124.10,122.98,122.68,122.01,121.61,118.24,117.56,109.90,98.50,64.51,64.43,50.35,18.84. 1 H NMR (400MHz, Chloroform-d) δ9.06(d, J=2.8Hz, 1H), 8.64(dd, J=4.8, 1.6Hz, 1H), 8.46(s, 1H), 8.13-8.04(m ,1H),7.69(d,J＝1.6Hz,1H),7.60(d,J＝8.4Hz,1H), 7.51(dd,J＝8.0,4.8Hz,1H),7.19(d,J＝2.0Hz ,1H),7.16-7.10(m,2H),7.01(d,J=8.4Hz,1H),6.71(q,J=7.2Hz,1H),5.87(brs,2H),4.32(s,4H) , 2.25(d, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ158.01,156.05,154.35,147.86,147.64,144.61,144.43,144.21,143.85,140.61,136.44,126.29,130. 124.10,122.98,122.68,122.01,121.61,118.24,117.56,109.90,98.50,64.51,64.43,50.35,18.84.
制备实施例65 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(1H-吲哚-5-基)-1H-吡唑并[3,4-d]嘧啶-4-胺66Preparation Example 65 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(1H-indol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine 66
Figure PCTCN2022082962-appb-000080
Figure PCTCN2022082962-appb-000080
制备方法同制备实施案例56，柱层析得白色固体66，收率72％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 66 with a yield of 72%.
1H NMR(400MHz,Chloroform-d)δ9.01(dd,J＝2.8,0.8Hz,1H),8.92(s,1H),8.61(dd,J＝4.8,1.6Hz,1H),8.47(s,1H),8.09-7.98(m,1H),7.94-7.87(m,1H),7.69-7.65(m,1H),7.62(dd,J＝8.8,0.8Hz,1H),7.51-7.45(m,1H),7.43(d,J＝0.8Hz,3H),7.28-7.22(m,1H),7.12(dd,J＝8.8,1.6Hz,1H),6.74(q,J＝7.2Hz,1H),6.63-6.55(m,1H),5.96(brs,2H),2.29(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.27,155.99,154.29,147.78,147.72,146.40,143.76,140.59,136.41,136.14,134.26,130.01,128.42,125.68,124.53,124.09,122.98,122.71,122.36,122.06,121.01,112.03,109.86,102.99,98.77,50.35,18.87. 1 H NMR (400MHz, Chloroform-d) δ 9.01 (dd, J=2.8, 0.8 Hz, 1H), 8.92 (s, 1H), 8.61 (dd, J=4.8, 1.6 Hz, 1H), 8.47 (s ,1H),8.09-7.98(m,1H),7.94-7.87(m,1H),7.69-7.65(m,1H),7.62(dd,J=8.8,0.8Hz,1H),7.51-7.45(m ,1H),7.43(d,J＝0.8Hz,3H),7.28-7.22(m,1H),7.12(dd,J＝8.8,1.6Hz,1H),6.74(q,J＝7.2Hz,1H) , 6.63-6.55(m, 1H), 5.96(brs, 2H), 2.29(d, J=7.2Hz, 3H). 13 C NMR(101MHz, CDCl 3 )δ158.27,155.99,154.29,147.78,147.72,146.40, 88
制备实施例66 1-(1-(6-氯-1-(3-(甲基)苯基)-1H-吲唑-3-基)乙基)-3-(6-甲氧基吡啶-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺67Preparation Example 66 1-(1-(6-Chloro-1-(3-(methyl)phenyl)-1H-indazol-3-yl)ethyl)-3-(6-methoxypyridine- 3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 67
Figure PCTCN2022082962-appb-000081
Figure PCTCN2022082962-appb-000081
制备方法同制备实施案例56，柱层析得白色固体67，收率59％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 67 with a yield of 59%.
1H NMR(600MHz,Chloroform-d)δ8.45(s,1H),8.44(d,J＝2.4Hz,1H),8.34-8.31(m,1H),8.04-7.98(m,1H),7.95-7.90(m,1H),7.89-7.84(m,1H),7.75(t,J＝7.8Hz,1H),7.67(d,J＝1.8Hz,1H),7.64(d,J＝8.4Hz,1H),7.17-7.06(m,1H),6.88(d,J＝8.4Hz,1H),6.71(q,J＝7.2Hz,1H),5.76(brs,2H),3.98(s,3H),3.15(s,3H),2.23(d,J＝7.2Hz,3H). 13C NMR(151MHz,CDCl 3)δ164.59,157.89,156.13,154.43,147.51,146.53,142.21,141.70,140.63,140.34,138.82,134.52,130.67,127.03,125.17,123.23,122.61,122.46,122.12,121.46,111.66,109.95,98.67,53.80,50.28,44.51,18.77. 1 H NMR (600MHz, Chloroform-d) δ8.45(s, 1H), 8.44(d, J=2.4Hz, 1H), 8.34-8.31(m, 1H), 8.04-7.98(m, 1H), 7.95 -7.90(m,1H),7.89-7.84(m,1H),7.75(t,J=7.8Hz,1H),7.67(d,J=1.8Hz,1H),7.64(d,J=8.4Hz, 1H), 7.17-7.06(m, 1H), 6.88(d, J=8.4Hz, 1H), 6.71(q, J=7.2Hz, 1H), 5.76(brs, 2H), 3.98(s, 3H), 3.15(s, 3H), 2.23(d, J=7.2Hz, 3H). 13 C NMR (151MHz, CDCl 3 )δ164.59, 157.89, 156.13, 154.43, 147.51, 146.53, 142.21, 141.70, 140.63, 140.34, 138.82, 134.52,130.67,127.03,125.17,123.23,122.61,122.46,122.12,121.46,111.66,109.95,98.67,53.80,50.28,44.51,18.77.
制备实施例67 1-(1-(6-氯-1-(3-(甲基磺酰基)苯基)-1H-吲唑-3-基)乙基)-3-(1-甲基-1H-吡唑4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺68Preparation Example 67 1-(1-(6-Chloro-1-(3-(methylsulfonyl)phenyl)-1H-indazol-3-yl)ethyl)-3-(1-methyl- 1H-pyrazol 4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 68
Figure PCTCN2022082962-appb-000082
Figure PCTCN2022082962-appb-000082
制备方法同制备实施案例56，柱层析得白色固体68，收率68％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 68 with a yield of 68%.
1H NMR(600MHz,Chloroform-d)δ8.43(s,1H),8.33(t,J＝1.8Hz,1H),8.01(dd,J＝7.8,2.4Hz,1H),7.92(d,J＝7.8Hz,1H),7.80-7.71(m,3H),7.66(s,1H),7.56(d,J＝8.4Hz,1H),7.14-7.04(m,1H),6.66(q,J＝7.2Hz,1H),5.89(brs,2H),3.97(s,3H),3.15(s,3H),2.20(d,J＝7.2Hz,3H). 13C NMR(151MHz,CDCl 3)δ158.12,156.09,154.09,147.58,142.20,140.68,140.30,138.34,136.99,134.47,130.65,129.79,126.90,125.10,123.18,122.52,122.19,121.45,114.63,109.92,98.98,50.00,44.52,39.27,18.67. 1 H NMR (600MHz, Chloroform-d) δ 8.43 (s, 1H), 8.33 (t, J=1.8Hz, 1H), 8.01 (dd, J=7.8, 2.4Hz, 1H), 7.92 (d, J =7.8Hz,1H),7.80-7.71(m,3H),7.66(s,1H),7.56(d,J=8.4Hz,1H),7.14-7.04(m,1H),6.66(q,J= 7.2Hz, 1H), 5.89(brs, 2H), 3.97(s, 3H), 3.15(s, 3H), 2.20(d, J=7.2Hz, 3H). 13 C NMR (151MHz, CDCl 3 )δ158. 12,156.09,154.09,147.58,142.20,140.68,140.30,138.34,136.99,134.47,130.65,129.79,126.90,125.10,123.18,122.52,122.19,121.45,114.63,109.92,98.98,50.00,44.52,39.27,18.67.
制备实施例68 1-(1-(6-氯-1-(3-(甲基)苯基)-1H-吲唑-3-基)乙基)-3-(2-甲氧基吡啶-5-基)-1H-吡唑并[3,4-d]嘧啶-4-胺69Preparation Example 68 1-(1-(6-Chloro-1-(3-(methyl)phenyl)-1H-indazol-3-yl)ethyl)-3-(2-methoxypyridine- 5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 69
Figure PCTCN2022082962-appb-000083
Figure PCTCN2022082962-appb-000083
制备方法同制备实施案例56，柱层析得白色固体69，收率45％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 69 with a yield of 45%.
1H NMR(500MHz,Chloroform-d)δ8.81(s,1H),8.50(s,1H),8.32(t,J＝2.0Hz,1H),8.06-7.99(m,1H),7.97-7.88(m,1H),7.76(t,J＝8.0Hz,1H),7.71-7.64(m,1H),7.19-7.09(m,1H),6.73(q,J＝7.0Hz,1H),5.55(brs,2H),4.08(s,3H),3.15(s,3H),2.23(d,J＝7.0Hz,3H). 13C NMR(151MHz,CDCl 3)δ165.69,158.78,157.67,156.33,154.61,147.22,142.24,140.57,140.36,138.31,134.62,130.71,127.08,125.27,123.33,122.46,122.05,121.50,121.28,110.02,98.83,55.38,50.37,44.51,18.73. 1 H NMR (500MHz, Chloroform-d) δ 8.81(s, 1H), 8.50(s, 1H), 8.32(t, J=2.0Hz, 1H), 8.06-7.99(m, 1H), 7.97-7.88 (m,1H),7.76(t,J=8.0Hz,1H),7.71-7.64(m,1H),7.19-7.09(m,1H),6.73(q,J=7.0Hz,1H),5.55( brs, 2H), 4.08(s, 3H), 3.15(s, 3H), 2.23(d, J=7.0Hz, 3H). 13 C NMR (151MHz, CDCl 3 )δ165.69,158.78,157.67,156.33,154.61, 147.22,142.24,140.57,140.36,138.31,134.62,130.71,127.08,125.27,123.33,122.46,122.05,121.50,121.28,110.02,98.83,55.38,50.37,44
制备实施例69 1-(1-(6-氯-1-(3-(甲基)苯基)-1H-吲唑-3-基)乙基)-3-(4-乙氧基-3-氟苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺70Preparation Example 69 1-(1-(6-Chloro-1-(3-(methyl)phenyl)-1H-indazol-3-yl)ethyl)-3-(4-ethoxy-3 -Fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 70
Figure PCTCN2022082962-appb-000084
Figure PCTCN2022082962-appb-000084
制备方法同制备实施案例56，柱层析得白色固体70，收率64％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 70 with a yield of 64%.
1H NMR(600MHz,Chloroform-d)δ8.45(s,1H),8.33(t,J＝1.8Hz,1H),8.09-7.98(m,1H),7.97-7.89(m,1H),7.75(t,J＝8.4Hz,1H),7.67(d,J＝1.8Hz,1H),7.59(d,J＝9.0Hz,1H),7.44-7.38(m,1H),7.37-7.32(m,1H),7.11(dd,J＝9.0,1.8Hz,1H),7.07(t,J＝8.4Hz,1H),6.69(q,J＝7.2Hz,1H),5.67(brs,2H),4.16(q,J＝7.2Hz,2H),3.15(s,3H),2.22(d,J＝7.2Hz,3H),1.48(t,J＝7.2Hz,3H). 13C NMR(151MHz,CDCl 3)δ157.83,156.13,154.41,153.59and 151.95,147.92and 147.85,147.57,143.57,142.21,140.68,140.34,134.49,130.66,127.01,125.92and 125.87,125.14,124.49and 124.47,123.20,122.59,122.16,121.43,116.58and 116.45,115.14and 115.13,109.94,98.45,65.07,50.23, 44.53,18.73,14.74. 1 H NMR (600MHz, Chloroform-d) δ8.45(s, 1H), 8.33(t, J=1.8Hz, 1H), 8.09-7.98(m, 1H), 7.97-7.89(m, 1H), 7.75 (t, J=8.4Hz, 1H), 7.67(d, J=1.8Hz, 1H), 7.59(d, J=9.0Hz, 1H), 7.44-7.38(m, 1H), 7.37-7.32(m, 1H), 7.11(dd, J=9.0, 1.8Hz, 1H), 7.07(t, J=8.4Hz, 1H), 6.69(q, J=7.2Hz, 1H), 5.67(brs, 2H), 4.16( q, J=7.2Hz, 2H), 3.15 (s, 3H), 2.22 (d, J=7.2Hz, 3H), 1.48 (t, J=7.2Hz, 3H). 13 C NMR (151MHz, CDCl 3 ) δ157.83,156.13,154.41,153.59and 151.95,147.92and 147.85,147.57,143.57,142.21,140.68,140.34,134.49,130.66,127.01,125.92and 125.87,125.14,124.49and 124.47,123.20,122.59,122.16,121.43,116.58and 116.45,115.14and 115.13,109.94,98.45,65.07,50.23, 44.53,18.73,14.74.
制备实施例70 1-(1-(6-氯-1-(3-(甲基磺酰基)苯基)-1H-吲唑-3-基)丙基)-3-(3-氟-4-甲氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺71Preparation Example 70 1-(1-(6-Chloro-1-(3-(methylsulfonyl)phenyl)-1H-indazol-3-yl)propyl)-3-(3-fluoro-4 -Methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 71
Figure PCTCN2022082962-appb-000085
Figure PCTCN2022082962-appb-000085
制备方法同制备实施案例56，柱层析得白色固体71，收率61％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 71 with a yield of 61%.
1H NMR(600MHz,Chloroform-d)δ8.45(s,1H),8.32(t,J＝1.8Hz,1H),8.04-7.98(m,1H),7.96-7.88(m,1H),7.85-7.79(m,1H),7.74(t,J＝7.8Hz,1H),7.70-7.64(m,1H),7.44-7.40(m,1H),7.40-7.37(m,1H),7.15(dd,J＝8.4,1.8Hz,1H),7.09(t,J＝8.4Hz,1H),6.55-6.31(m,1H),5.70(brs,2H),3.95(s,3H),3.14(s,3H),2.86-2.67(m,2H),0.99(t,J＝7.2Hz,3H). 13C NMR(151MHz,CDCl 3)δ157.84,156.17,155.18,153.42and 151.78,148.58and 148.51,146.97,143.58,142.20,140.66,140.30,134.49,130.65,127.03,126.13and 126.08,125.13,124.53and 124.50,123.17,122.97,122.32,121.42,116.53and 116.41,113.97,109.90,98.26,56.39,56.26,44.52,26.04,10.99. 1 H NMR (600MHz, Chloroform-d) δ8.45(s, 1H), 8.32(t, J=1.8Hz, 1H), 8.04-7.98(m, 1H), 7.96-7.88(m, 1H), 7.85 -7.79(m,1H),7.74(t,J=7.8Hz,1H),7.70-7.64(m,1H),7.44-7.40(m,1H),7.40-7.37(m,1H),7.15(dd , J=8.4, 1.8Hz, 1H), 7.09(t, J=8.4Hz, 1H), 6.55-6.31(m, 1H), 5.70(brs, 2H), 3.95(s, 3H), 3.14(s, 3H), 2.86-2.67(m, 2H), 0.99(t, J=7.2Hz, 3H). 13 C NMR (151MHz, CDCl 3 )δ157.84, 156.17, 155.18, 153.42and 151.78, 148.58and 148.51, 146.97, 143.58 ,142.20,140.66,140.30,134.49,130.65,127.03,126.13and 126.08,125.13,124.53and 124.50,123.17,122.97,122.32,121.42,116.53and 116.41,113.97,109.90,98.26,56.39,56.26,44.52,26.04,10.99 .
制备实施例71 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)丙基)-3-(1-甲基-1H-吡唑-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺72Preparation Example 71 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)propyl)-3-(1-methyl-1H-pyrazole- 4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 72
Figure PCTCN2022082962-appb-000086
Figure PCTCN2022082962-appb-000086
制备方法同制备实施案例56，柱层析得白色固体72，收率72％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 72 with a yield of 72%.
1H NMR(400MHz,DMSO-d 6)δ9.03(d,J＝2.8Hz,1H),8.65(dd,J＝4.8,1.2Hz,1H),8.32(s,1H),8.28-8.21(m,1H),8.07(s,1H),7.93(d,J＝1.6Hz,1H),7.75-7.69(m,2H),7.65(dd,J＝8.4,4.8Hz,1H),7.29(dd,J＝8.8,1.6Hz,1H),6.47-6.26(m,1H),3.90(s,3H),2.76-2.55(m,2H),0.87(t,J＝7.2Hz,3H). 13C NMR(101MHz,DMSO)δ158.84,156.51,155.11,148.35,147.18,143.91,140.38,138.14,137.76,136.12,133.69,130.86,130.34,125.00,123.36,123.00,122.11,113.99,110.91,97.79,55.62,25.77,11.24. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.03 (d, J=2.8Hz, 1H), 8.65 (dd, J=4.8, 1.2Hz, 1H), 8.32 (s, 1H), 8.28-8.21 ( m,1H),8.07(s,1H),7.93(d,J=1.6Hz,1H),7.75-7.69(m,2H),7.65(dd,J=8.4,4.8Hz,1H),7.29(dd , J=8.8, 1.6Hz, 1H), 6.47-6.26(m, 1H), 3.90(s, 3H), 2.76-2.55(m, 2H), 0.87(t, J=7.2Hz, 3H). 13 C NMR(101MHz,DMSO)δ158.84,156.51,155.11,148.35,147.18,143.91,140.38,138.14,137.76,136.12,133.69,130.86,130.34,125.00,123.36,123.00,122.11,113.99,110.91,97.79,55.62,25.77, 11.24.
制备实施例72 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(4-甲氧基-1苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺73Preparation Example 72 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(4-methoxy-1phenyl) -1H-Pyrazolo[3,4-d]pyrimidin-4-amine 73
Figure PCTCN2022082962-appb-000087
Figure PCTCN2022082962-appb-000087
制备方法同制备实施案例56，柱层析得白色固体73，收率68％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 73 with a yield of 68%.
1H NMR(400MHz,Chloroform-d)δ9.05(d,J＝2.4Hz,1H),8.62(d,J＝4.4Hz,1H),8.44(s,1H),8.15-7.99(m,1H),7.71-7.65(m,1H),7.63-7.55(m,3H),7.49(dd,J＝8.0,4.8Hz,1H),7.10(dd,J＝8.8,1.6Hz,1H),7.03(d,J＝8.4Hz,2H),6.70(q,J＝6.8Hz,1H),3.86(s,3H),2.24(d,J＝6.8Hz,3H). 13C NMR(101MHz,CDCl 3)δ160.37,158.14, 155.97,154.31,147.83,147.63,144.70,143.81,140.57,136.40,134.25,129.98,129.86,125.49,124.07,122.93,122.66,122.00,114.76,109.87,98.57,55.45,50.27,18.82. 1 H NMR(400MHz, Chloroform-d)δ9.05(d,J=2.4Hz,1H),8.62(d,J=4.4Hz,1H),8.44(s,1H),8.15-7.99(m,1H) ),7.71-7.65(m,1H),7.63-7.55(m,3H),7.49(dd,J=8.0,4.8Hz,1H),7.10(dd,J=8.8,1.6Hz,1H),7.03( d, J=8.4Hz, 2H), 6.70 (q, J=6.8Hz, 1H), 3.86 (s, 3H), 2.24 (d, J=6.8Hz, 3H). 13 C NMR (101MHz, CDCl 3 ) δ160.37,158.14, 155.97,154.31,147.83,147.63,144.70,143.81,140.57,136.40,134.25,129.98,129.86,125.49,124.07,122.93,122.66,122.00,114.76,109.87,98.57,55.45,50.27,18.82.
制备实施例73 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(噻吩-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺74Preparation Example 73 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(thiophen-3-yl)-1H-pyridine Azolo[3,4-d]pyrimidin-4-amine 74
Figure PCTCN2022082962-appb-000088
Figure PCTCN2022082962-appb-000088
制备方法同制备实施案例56，柱层析得白色固体74，收率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%.
1H NMR(400MHz,Chloroform-d)δ9.06(d,J＝2.4Hz,1H),8.71-8.60(m,1H),8.48(s,1H),8.15-8.02(m,1H),7.70(d,J＝1.6Hz,1H),7.66-7.60(m,2H),7.56-7.48(m,2H),7.46-7.40(m,1H),7.18-7.08(m,1H),6.72(q,J＝7.2Hz,1H),5.81(brs,2H),2.25(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ157.97,156.15,154.21,147.90,147.49,143.86,140.60,140.19,136.40,134.30,134.15,130.01,127.74,127.69,124.53,124.09,122.98,122.61,122.00,109.91,98.80,50.32,18.79. 1 H NMR(400MHz, Chloroform-d)δ9.06(d,J=2.4Hz,1H),8.71-8.60(m,1H),8.48(s,1H),8.15-8.02(m,1H),7.70 (d, J＝1.6Hz, 1H), 7.66-7.60(m, 2H), 7.56-7.48(m, 2H), 7.46-7.40(m, 1H), 7.18-7.08(m, 1H), 6.72(q , J=7.2Hz, 1H), 5.81 (brs, 2H), 2.25 (d, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ157.97, 156.15, 154.21, 147.90, 147.49, 143.86, 140.60 ,140.19,136.40,134.30,134.15,130.01,127.74,127.69,124.53,124.09,122.98,122.61,122.00,109.91,98.80,50.32,18.79.
制备实施例74 3-(苯并[1,3]二氧戊环-5-基)-1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-1H-吡唑并[3,4-d]嘧啶-4-胺75Preparation Example 74 3-(Benzo[1,3]dioxolan-5-yl)-1-(1-(6-chloro-1-(pyridin-3-yl)-1H-indazole-3 -yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 75
Figure PCTCN2022082962-appb-000089
Figure PCTCN2022082962-appb-000089
制备方法同制备实施案例56，柱层析得白色固体75，收率58％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 75 with a yield of 58%.
1H NMR(400MHz,Chloroform-d)δ9.05(d,J＝2.0Hz,1H),8.63(d,J＝4.0Hz,1H),8.45(s,1H),8.13-8.03(m,1H),7.69(d,J＝1.6Hz,1H),7.59(d,J＝8.8Hz,1H),7.50(dd,J＝8.4,4.8Hz,1H),7.17-7.08(m,3H),6.99-6.91(m,1H),6.71(q,J＝7.2Hz,1H),6.04(s,2H),2.24(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.01,156.04,154.32,148.54,148.52,147.86,147.54,144.54,143.82,140.58,136.40,134.28,130.00,127.05,124.08,122.97,122.59,122.31,121.98,109.90,109.04,109.03,101.56,98.45,50.28,18.80. 1 H NMR(400MHz, Chloroform-d)δ9.05(d,J=2.0Hz,1H),8.63(d,J=4.0Hz,1H),8.45(s,1H),8.13-8.03(m,1H) ),7.69(d,J＝1.6Hz,1H),7.59(d,J＝8.8Hz,1H),7.50(dd,J＝8.4,4.8Hz,1H),7.17-7.08(m,3H),6.99 -6.91(m, 1H), 6.71(q, J=7.2Hz, 1H), 6.04(s, 2H), 2.24(d, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ158. 01,156.04,154.32,148.54,148.52,147.86,147.54,144.54,143.82,140.58,136.40,134.28,130.00,127.05,124.08,122.97,122.59,122.31,121.98,109.90,109.04,109.03,101.56,98.45,50.28,18.80.
制备实施例75 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(喹啉-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺76Preparation Example 75 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(quinolin-3-yl)-1H- Pyrazolo[3,4-d]pyrimidin-4-amine 76
Figure PCTCN2022082962-appb-000090
Figure PCTCN2022082962-appb-000090
制备方法同制备实施案例56，柱层析得白色固体76，收率74％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 76 with a yield of 74%.
1H NMR(600MHz,DMSO-d 6)δ9.12(d,J＝2.4Hz,1H),9.04(d,J＝2.4Hz,1H),8.64(d,J＝4.2Hz,1H),8.56(d,J＝1.8Hz,1H),8.40(s,1H),8.28-8.19(m,1H),8.09(t,J＝7.8Hz,2H),7.92(d,J＝1.8Hz,1H),7.88-7.77(m,1H),7.71-7.58(m,3H),7.33-7.24(m, 1H),6.72(q,J＝7.2Hz,1H),2.16(d,J＝7.2Hz,3H). 13C NMR(151MHz,DMSO)δ158.92,156.68,154.87,150.26,148.34,147.70,147.68,143.90,142.18,140.47,136.11,135.78,133.71,130.45,130.32,129.21,127.93,127.50,126.36,124.95,123.38,122.74,121.94,110.93,98.32,50.17,18.97. 1 H NMR (600MHz, DMSO-d 6 ) δ 9.12 (d, J=2.4Hz, 1H), 9.04 (d, J=2.4Hz, 1H), 8.64 (d, J=4.2Hz, 1H), 8.56 (d, J＝1.8Hz, 1H), 8.40(s, 1H), 8.28-8.19(m, 1H), 8.09(t, J＝7.8Hz, 2H), 7.92(d, J＝1.8Hz, 1H) ,7.88-7.77(m,1H),7.71-7.58(m,3H),7.33-7.24(m,1H),6.72(q,J=7.2Hz,1H),2.16(d,J=7.2Hz,3H ). 13 C NMR(151MHz,DMSO)δ158.92,156.68,154.87,150.26,148.34,147.70,147.68,143.90,142.18,140.47,136.11,135.78,133.71,130.45,130.32,129.21,127.93,127.50,126.36,124.95, 123.38, 122.74, 121.94, 110.93, 98.32, 50.17, 18.97.
制备实施例76 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(3-三氟甲氧基)-苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺77Preparation Example 76 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(3-trifluoromethoxy)-benzene yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 77
Figure PCTCN2022082962-appb-000091
Figure PCTCN2022082962-appb-000091
制备方法同制备实施案例56，柱层析得白色固体77，收率58％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 77 with a yield of 58%.
1H NMR(400MHz,Chloroform-d)δ9.06(d,J＝2.4Hz,1H),8.65(dd,J＝4.8,1.6Hz,1H),8.50(s,1H),8.13-8.04(m,1H),7.73-7.62(m,3H),7.61-7.55(m,2H),7.51(dd,J＝8.2,4.7Hz,1H),7.39-7.30(m,1H),7.14(dd,J＝8.8,1.6Hz,1H),6.76(q,J＝7.2Hz,1H),5.83(brs,2H),2.27(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ157.81,156.18,154.56,149.81,147.94,147.32,143.86,143.16,140.62,136.36,135.26,134.37,130.89,130.04,126.84,124.10,123.04,122.54,121.93,121.45,121.09,109.96,98.50,50.42,18.81. 1 H NMR(400MHz, Chloroform-d)δ9.06(d,J=2.4Hz,1H),8.65(dd,J=4.8,1.6Hz,1H),8.50(s,1H),8.13-8.04(m ,1H),7.73-7.62(m,3H),7.61-7.55(m,2H),7.51(dd,J=8.2,4.7Hz,1H),7.39-7.30(m,1H),7.14(dd,J =8.8, 1.6Hz, 1H), 6.76 (q, J=7.2Hz, 1H), 5.83 (brs, 2H), 2.27 (d, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ157 .81,156.18,154.56,149.81,147.94,147.32,143.86,143.16,140.62,136.36,135.26,134.37,130.89,130.04,126.84,124.10,123.04,122.54,121.93,121.45,121.09,109.96,98.50,50.42,18.81.
制备实施例77 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(呋喃-3-基)-1H-吡唑并[3,4-d]嘧啶-4-胺78Preparation Example 77 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(furan-3-yl)-1H-pyridine Azolo[3,4-d]pyrimidin-4-amine 78
Figure PCTCN2022082962-appb-000092
Figure PCTCN2022082962-appb-000092
制备方法同制备实施案例56，柱层析得白色固体78，收率59％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 78 with a yield of 59%.
1H NMR(400MHz,DMSO-d 6)δ9.04(d,J＝2.4Hz,1H),8.65(dd,J＝4.8,1.6Hz,1H),8.35(s,1H),8.29-8.21(m,1H),8.13-8.07(m,1H),7.92(d,J＝1.6Hz,1H),7.85(t,J＝1.6Hz,1H),7.69-7.62(m,1H),7.57(d,J＝8.8Hz,1H),7.26(dd,J＝8.8,1.6Hz,1H),6.87-6.78(m,1H),6.64(q,J＝7.2Hz,1H),2.11(d,J＝7.2Hz,3H). 13C NMR(101MHz,DMSO)δ158.79,156.55,154.39,148.35,147.76,144.84,143.89,142.21,140.45,137.11,136.14,133.71,130.30,124.99,123.36,122.72,121.96,118.63,110.92,98.21,49.90,18.91. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.04 (d, J=2.4Hz, 1H), 8.65 (dd, J=4.8, 1.6Hz, 1H), 8.35 (s, 1H), 8.29-8.21 ( m,1H),8.13-8.07(m,1H),7.92(d,J=1.6Hz,1H),7.85(t,J=1.6Hz,1H),7.69-7.62(m,1H),7.57(d , J=8.8Hz, 1H), 7.26(dd, J=8.8, 1.6Hz, 1H), 6.87-6.78(m, 1H), 6.64(q, J=7.2Hz, 1H), 2.11(d, J= 7.2Hz,3H). 13 C NMR(101MHz,DMSO)δ158.79,156.55,154.39,148.35,147.76,144.84,143.89,142.21,140.45,137.11,136.14,133.71,130.30,124.99,123.36,122.72,121.96,118.63, 110.92, 98.21, 49.90, 18.91.
制备实施例78 3-(4-氨基-1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯甲腈79Preparation Example 78 3-(4-Amino-1-(1-(6-chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[ 3,4-d]pyrimidin-3-yl)benzonitrile 79
Figure PCTCN2022082962-appb-000093
Figure PCTCN2022082962-appb-000093
制备方法同制备实施案例56，柱层析得白色固体79，收率52％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 79 with a yield of 52%.
1H NMR(400MHz,Chloroform-d)δ9.06(d,J＝2.4Hz,1H),8.66(dd,J＝4.8,1.6Hz,1H),8.54(s,1H),8.14-8.05(m,1H),8.02(t,J＝1.6Hz,1H),7.98-7.91(m,1H),7.81-7.75(m,1H),7.71(d,J＝1.6Hz,1H),7.70-7.62(m,2H),7.53(dd,J＝8.4,4.8Hz, 1H),7.15(dd,J＝8.4,1.6Hz,1H),6.78(q,J＝7.2Hz,1H),5.64(brs,2H),2.27(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ157.62,156.35,154.69,148.01,147.13,143.89,142.35,140.61,136.34,134.68,134.43,132.67,132.45,132.05,130.17,130.05,124.12,123.13,122.31,121.91,118.13,113.70,110.03,98.49,50.37,18.71. 1 H NMR (400MHz, Chloroform-d) δ9.06 (d, J=2.4Hz, 1H), 8.66 (dd, J=4.8, 1.6Hz, 1H), 8.54 (s, 1H), 8.14-8.05 (m ,1H),8.02(t,J＝1.6Hz,1H),7.98-7.91(m,1H),7.81-7.75(m,1H),7.71(d,J＝1.6Hz,1H),7.70-7.62( m, 2H), 7.53 (dd, J=8.4, 4.8Hz, 1H), 7.15 (dd, J=8.4, 1.6Hz, 1H), 6.78 (q, J=7.2Hz, 1H), 5.64 (brs, 2H) The _ ,130.17,130.05,124.12,123.13,122.31,121.91,118.13,113.70,110.03,98.49,50.37,18.71.
制备实施例79 4-(4-氨基-1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)-N-甲基苯甲酰胺80Preparation Example 79 4-(4-Amino-1-(1-(6-chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[ 3,4-d]pyrimidin-3-yl)-N-methylbenzamide 80
Figure PCTCN2022082962-appb-000094
Figure PCTCN2022082962-appb-000094
制备方法同制备实施案例56，柱层析得白色固体80，收率64％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 80 with a yield of 64%.
1H NMR(600MHz,DMSO-d 6)δ9.03(d,J＝2.4Hz,1H),8.64(dd,J＝4.8,1.2Hz,1H),8.59-8.50(m,1H),8.37(s,1H),8.28-8.19(m,1H),8.03-7.95(m,1H),7.94-7.88(m,1H),7.77-7.69(m,2H),7.67-7.61(m,1H),7.57(d,J＝9.0Hz,1H),7.30-7.19(m,1H),6.68(q,J＝6.6Hz,1H),2.81(d,J＝4.8Hz,3H),2.12(d,J＝6.6Hz,3H). 13C NMR(151MHz,DMSO)δ166.56,158.72,156.54,154.73,148.33,147.68,144.12,143.89,140.45,136.11,135.54,134.82,133.69,130.30,128.59,128.30,124.95,123.33,122.67,121.92,110.93,97.92,50.01,26.77,18.93. 1 H NMR (600MHz, DMSO-d 6 ) δ 9.03 (d, J=2.4Hz, 1H), 8.64 (dd, J=4.8, 1.2Hz, 1H), 8.59-8.50 (m, 1H), 8.37 ( s,1H),8.28-8.19(m,1H),8.03-7.95(m,1H),7.94-7.88(m,1H),7.77-7.69(m,2H),7.67-7.61(m,1H), 7.57(d,J＝9.0Hz,1H),7.30-7.19(m,1H),6.68(q,J＝6.6Hz,1H),2.81(d,J＝4.8Hz,3H),2.12(d,J ＝6.6Hz,3H). 13 C NMR(151MHz,DMSO)δ166.56,158.72,156.54,154.73,148.33,147.68,144.12,143.89,140.45,136.11,135.54,134.82,133.69,130.30,128.59,128.30,124.95,123.33 ,122.67,121.92,110.93,97.92,50.01,26.77,18.93.
制备实施例80 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-苯基-1H-吡唑并[3,4-d]嘧啶-4-胺81Preparation Example 80 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-phenyl-1H-pyrazolo[3, 4-d]pyrimidin-4-amine 81
Figure PCTCN2022082962-appb-000095
Figure PCTCN2022082962-appb-000095
制备方法同制备实施案例56，柱层析得白色固体81，收率71％。The preparation method was the same as that of Preparation Example 56, and column chromatography gave white solid 81 with a yield of 71%.
1H NMR(600MHz,Chloroform-d)δ8.95(s,1H),8.53(d,J＝4.8Hz,1H),8.36(s,1H),7.97(d,J＝8.4Hz,1H),7.63-7.55(m,3H),7.51(d,J＝8.4Hz,1H),7.46-7.35(m,4H),7.01(d,J＝8.4Hz,1H),6.63(q,J＝7.2Hz,1H),2.16(d,J＝7.2Hz,3H). 13C NMR(151MHz,CDCl 3)δ158.02,156.00,154.41,147.83,147.54,144.81,143.81,140.57,136.38,134.24,133.21,129.95,129.32,129.13,128.53,124.04,122.93,122.60,121.97,109.87,98.55,50.35,18.79. 1 H NMR (600MHz, Chloroform-d) δ8.95(s, 1H), 8.53(d, J=4.8Hz, 1H), 8.36(s, 1H), 7.97(d, J=8.4Hz, 1H), 7.63-7.55(m,3H),7.51(d,J=8.4Hz,1H),7.46-7.35(m,4H),7.01(d,J=8.4Hz,1H),6.63(q,J=7.2Hz , 1H), 2.16 (d, J=7.2Hz, 3H). 13 C NMR (151MHz, CDCl 3 )δ158.02, 156.00, 154.41, 147.83, 147.54, 144.81, 143.81, 140.57, 136.38, 134.24, 133.21, 129.95, ,129.13,128.53,124.04,122.93,122.60,121.97,109.87,98.55,50.35,18.79.
制备实施例81 3-(4-氨基-1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯甲酰胺82Preparation Example 81 3-(4-Amino-1-(1-(6-chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-1H-pyrazolo[ 3,4-d]pyrimidin-3-yl)benzamide 82
Figure PCTCN2022082962-appb-000096
Figure PCTCN2022082962-appb-000096
制备方法同制备实施案例56，柱层析得白色固体82，收率52％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 82 with a yield of 52%.
1H NMR(600MHz,DMSO-d 6)δ9.08(d,J＝2.4Hz,1H),8.78-8.62(m,1H),8.42(s, 1H),8.33-8.26(m,1H),8.18(t,J＝1.8Hz,1H),8.12(brs,1H),8.04-7.98(m,1H),7.96(d,J＝1.2Hz,1H),7.85-7.77(m,1H),7.69(dd,J＝8.4,4.8Hz,1H),7.64(t,J＝7.8Hz,1H),7.59(d,J＝8.4Hz,1H),7.50(brs,1H),7.32-7.27(m,1H),6.73(q,J＝7.2Hz,1H),2.18(d,J＝7.2Hz,3H). 13C NMR(151MHz,DMSO)δ167.97,158.72,156.55,154.69,148.33,147.73,144.39,143.88,140.45,136.12,135.47,133.69,133.17,131.40,130.32,129.54,128.07,127.92,124.96,123.33,122.64,121.93,110.93,97.87,49.96,18.92. 1 H NMR (600MHz, DMSO-d 6 )δ9.08(d, J=2.4Hz, 1H), 8.78-8.62(m, 1H), 8.42(s, 1H), 8.33-8.26(m, 1H), 8.18(t,J＝1.8Hz,1H),8.12(brs,1H),8.04-7.98(m,1H),7.96(d,J＝1.2Hz,1H),7.85-7.77(m,1H),7.69 (dd,J=8.4,4.8Hz,1H),7.64(t,J=7.8Hz,1H),7.59(d,J=8.4Hz,1H),7.50(brs,1H),7.32-7.27(m, 1H), 6.73 (q, J=7.2Hz, 1H), 2.18 (d, J=7.2Hz, 3H). 13 C NMR (151MHz, DMSO) δ 167.97, 158.72, 156.55, 154.69, 148.33, 147.73, 144.39, 143.88 ,140.45,136.12,135.47,133.69,133.17,131.40,130.32,129.54,128.07,127.92,124.96,123.33,122.64,121.93,110.93,97.87,49.96,18.92.
制备实施例82 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(1H-吡咯并[2,3-b]吡啶-5-基)-1H-吡唑并[3,4-d]嘧啶-4-胺83Preparation Example 82 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(1H-pyrrolo[2,3-b ]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 83
Figure PCTCN2022082962-appb-000097
Figure PCTCN2022082962-appb-000097
制备方法同制备实施案例56，柱层析得白色固体83，收率61％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 83 with a yield of 61%.
1H NMR(400MHz,DMSO-d 6)δ11.85(brs,1H),9.04(d,J＝2.4Hz,1H),8.64(dd,J＝4.8,1.2Hz,1H),8.44(d,J＝2.0Hz,1H),8.37(s,1H),8.29-8.21(m,1H),8.16(d,J＝2.0Hz,1H),7.92(d,J＝1.6Hz,1H),7.64(dd,J＝8.4,4.8Hz,1H),7.62-7.53(m,2H),7.27(dd,J＝8.8,1.6Hz,2H),6.68(q,J＝7.2Hz,1H),6.59-6.53(m,1H),2.14(d,J＝7.2Hz,3H). 13C NMR(101MHz,DMSO)δ158.93,156.52,154.63,148.92,148.34,147.88,143.91,143.79,142.83,140.47,136.15,133.70,130.34,128.39,127.68,124.98,123.36,122.76,121.98,121.15,120.00,110.93,101.01,98.15,49.97,19.00. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.85 (brs, 1H), 9.04 (d, J=2.4Hz, 1H), 8.64 (dd, J=4.8, 1.2Hz, 1H), 8.44 (d, J=2.0Hz, 1H), 8.37(s, 1H), 8.29-8.21(m, 1H), 8.16(d, J=2.0Hz, 1H), 7.92(d, J=1.6Hz, 1H), 7.64( dd,J＝8.4,4.8Hz,1H),7.62-7.53(m,2H),7.27(dd,J＝8.8,1.6Hz,2H),6.68(q,J＝7.2Hz,1H),6.59-6.53 (m, 1H), 2.14 (d, J=7.2Hz, 3H). 13 C NMR (101MHz, DMSO) δ 158.93, 156.52, 154.63, 148.92, 148.34, 147.88, 143.91, 143.79, 142.83, 140.47, 136.15, 133.70, 130.34,128.39,127.68,124.98,123.36,122.76,121.98,121.15,120.00,110.93,101.01,98.15,49.97,19.00.
制备实施例83 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(1H-吲唑-5-基)-1H-吡唑并[3,4-d]嘧啶-4-胺84Preparation Example 83 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(1H-indazol-5-yl)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine 84
Figure PCTCN2022082962-appb-000098
Figure PCTCN2022082962-appb-000098
制备方法同制备实施案例56，柱层析得白色固体84，收率54％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 84 with a yield of 54%.
1H NMR(400MHz,Chloroform-d)δ9.03(d,J＝2.8Hz,1H),8.63(dd,J＝4.8,1.6Hz,1H),8.52(s,1H),8.16(s,1H),8.09-8.05(m,2H),7.71-7.67(m,2H),7.66-7.59(m,2H),7.50(dd,J＝8.0,4.8Hz,1H),7.14(dd,J＝8.8,1.6Hz,1H),6.77(q,J＝7.2Hz,1H),5.85(brs,2H),2.29(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.04,156.09,154.40,147.80,147.55,145.13,143.79,140.59,140.08,136.39,135.23,134.33,130.01,127.41,126.03,124.11,123.66,123.04,122.56,122.02,121.23,110.91,109.93,98.74,50.31,18.82. 1 H NMR (400MHz, Chloroform-d) δ9.03 (d, J=2.8Hz, 1H), 8.63 (dd, J=4.8, 1.6Hz, 1H), 8.52 (s, 1H), 8.16 (s, 1H) ),8.09-8.05(m,2H),7.71-7.67(m,2H),7.66-7.59(m,2H),7.50(dd,J=8.0,4.8Hz,1H),7.14(dd,J=8.8 , 1.6Hz, 1H), 6.77 (q, J=7.2Hz, 1H), 5.85 (brs, 2H), 2.29 (d, J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ158.04, 156.09 ,154.40,147.80,147.55,145.13,143.79,140.59,140.08,136.39,135.23,134.33,130.01,127.41,126.03,124.11,123.66,123.04,122.56,122.02,121.23,110.91,109.93,98.74,50.31,18.82.
制备实施例84 1-(1-(6-氯-1-(吡啶-3-基)-1H-吲唑-3-基)乙基)-3-(4-甲氧基-3-甲基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺85Preparation Example 84 1-(1-(6-Chloro-1-(pyridin-3-yl)-1H-indazol-3-yl)ethyl)-3-(4-methoxy-3-methyl) Phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 85
Figure PCTCN2022082962-appb-000099
Figure PCTCN2022082962-appb-000099
制备方法同制备实施案例56，柱层析得白色固体85，收率43％。The preparation method is the same as the preparation example 56, and column chromatography obtains a white solid 85 with a yield of 43%.
1H NMR(400MHz,Chloroform-d)δ9.05(d,J＝2.8Hz,1H),8.63(dd,J＝4.8,1.6Hz,1H),8.45(s,1H),8.14-8.03(m,1H),7.68(d,J＝1.6Hz,1H),7.60-7.56(m,1H),7.53-7.48(m,1H),7.47-7.43(m,2H),7.15-7.07(m,1H),6.95(d,J＝8.4Hz,1H),6.70(q,J＝7.2Hz,1H),5.73(brs,2H),3.89(s,3H),2.29(s,3H),2.25(d,J＝7.2Hz,3H). 13C NMR(101MHz,CDCl 3)δ158.61,158.03,156.04,154.31,147.83,147.67,144.94,143.83,140.58,136.42,134.23,130.82,129.99,127.92,127.11,125.00,124.07,122.90,122.67,122.03,110.40,109.86,98.58,55.50,50.28,18.79,16.37. 1 H NMR (400MHz, Chloroform-d) δ9.05(d, J=2.8Hz, 1H), 8.63(dd, J=4.8, 1.6Hz, 1H), 8.45(s, 1H), 8.14-8.03(m ,1H),7.68(d,J＝1.6Hz,1H),7.60-7.56(m,1H),7.53-7.48(m,1H),7.47-7.43(m,2H),7.15-7.07(m,1H) ), 6.95(d, J=8.4Hz, 1H), 6.70(q, J=7.2Hz, 1H), 5.73(brs, 2H), 3.89(s, 3H), 2.29(s, 3H), 2.25(d , J=7.2Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ158.61, 158.03, 156.04, 154.31, 147.83, 147.67, 144.94, 143.83, 140.58, 116.42, 1304.23, 130.82, 129.99, 127. 124.07, 122.90, 122.67, 122.03, 110.40, 109.86, 98.58, 55.50, 50.28, 18.79, 16.37.
生物实验实施例1：PI3Kα、PI3Kβ、PI3Kδ和PI3Kγ酶活性抑制IC 50评价试验 Biological experiment Example 1: PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ enzyme activity inhibition IC 50 evaluation test
采用ADP-Glo TM Kinase实验来测定。将受试化合物稀释成测试所需的一系列浓度，各取50nL转移到384孔板上，阴性对照孔和阳性对照孔中分别加50nL的DMSO，用激酶缓冲溶液将将PI3Kα，β，γ和δ分别稀释至1.25nM，1.25nM，10nM，1.25nM，然后以每孔2μL加到384孔板上，在阴性和阳性对照孔中加入2.5μL,离心30秒，振荡混匀后室温孵育10分钟，加入2.5μL ATP和PIP2的混合溶液，离心30秒，振荡混匀后室温孵育2小时，加入5μL ADP-Glo Reagent振荡混匀后室温孵育3小时后加入10μL Kinase Detection Reagent，振荡混匀后室温孵育1小时，样品经离心等处理后，用Enspire酶标仪读取RLU值，并根据公式计算抑制率。 Measured using the ADP-Glo ™ Kinase assay. The 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 PI3Kα, β, γ and PI3Kα, β, γ and δ was diluted to 1.25nM, 1.25nM, 10nM, and 1.25nM respectively, then added 2μL per well to 384-well plate, added 2.5μL to negative and positive control wells, centrifuged for 30 seconds, shaken and mixed and incubated at room temperature for 10 minutes , add 2.5 μL of the mixed solution of ATP and PIP2, centrifuge for 30 seconds, shake and mix, incubate at room temperature for 2 hours, add 5 μL ADP-Glo Reagent, shake and mix, incubate at room temperature for 3 hours, add 10 μL 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.
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。 Taking the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the log(inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism 5 was used to fit the dose-response curve to obtain the IC 50 of each compound on the enzyme activity value.
表1显示了本发明的化合物对PI3Kδ活性的IC 50值，表2显示了部分化合物的PI3Kα与PI3Kδ的IC 50值之比(记为α/δ),PI3Kβ与PI3Kδ的IC 50值之比(记为β/δ)和PI3Kγ与PI3Kδ的IC 50值之比(记为γ/δ)。 Table 1 shows the IC 50 values of the compounds of the present invention for PI3Kδ activity, Table 2 shows the ratio of the IC 50 values of PI3Kα and PI3Kδ (denoted as α/δ) for some compounds, and the ratio of the IC 50 values of PI3Kβ and PI3Kδ ( Denoted β/δ) and the ratio of IC50 values of PI3Kγ to PI3Kδ (denoted γ/δ).
表1吲唑类衍生物的PI3Kδ抑制活性Table 1 PI3Kδ inhibitory activity of indazole derivatives
化合物编号Compound number PI3Kδ IC 50(nM) PI3Kδ IC50 (nM) 化合物编号Compound number PI3Kδ IC 50(nM) PI3Kδ IC50 (nM)
1111 1111 1212 4141
1313 3131 1414 4545
1515 8080 1616 13831383
1717 243243 1818 1010
1919 108108 2020 8484
21twenty one 6.46.4 22twenty two 273273
23twenty three 21twenty one 24twenty four 4.74.7
2525 1919 2626 8.18.1
2727 212212 2828 147147
2929 248248 3030 3636
3131 99 3232 547547
3333 2525 3434 64146414
3535 9.69.6 3636 6.46.4
3737 1414 3838 1313
3939 179179 4040 1616
4141 1414 4242 6.86.8
4343 3232 4444 9.39.3
4545 3838 4646 9.79.7
4747 405405 4848 343343
4949 214214 5050 342342
5151 6.16.1 5252 285285
5353 12561256 5454 5050
5555 176176 5656 124124
5757 7.17.1 5858 1111
5959 8.88.8 6060 1.21.2
6161 1.81.8 6262 7.67.6
6363 0.780.78 6464 2.32.3
6565 1010 6666 2.32.3
6767 4.14.1 6868 0.850.85
6969 1.31.3 7070 2.12.1
7171 6.26.2 7272 1.341.34
7373 11.211.2 7474 10.210.2
7575 8.28.2 7676 7.87.8
7777 14.214.2 7878 13.213.2
7979 3.43.4 8080 1.31.3
8181 1818 8282 1.41.4
8383 2.22.2 8484 1.31.3
8585 8.68.6      
表2吲唑类衍生物对PI3K的亚型选择性Table 2 Subtype selectivity of indazole derivatives for PI3K
化合物编号Compound number α/δα/δ β/δβ/δ γ/δγ/δ
1111 ＞909＞909 8181 ＞909＞909
1414 ＞222>222 131131 ＞222>222
1818 ＞1000>1000 156156 ＞1000>1000
21twenty one ＞1563>1563 7777 13251325
24twenty four 16191619 272272 346346
2626 ＞1234>1234 347347 ＞1234>1234
3131 930930 133133 994994
3535 ＞1041>1041 223223 ＞1041>1041
3636 14831483 9292 ＞1562>1562
4242 10051005 7676 11491149
4646 644644 6161 303303
5757 ＞1408>1408 ＞1408>1408 ＞1408>1408
5959 980980 531531 405405
6060 16301630 918918 782782
6161 609609 135135 289289
6262 560560 5959 618618
6363 985985 202202 696696
6464 957957 236236 ＞4347>4347
6767 425425 19801980 ＞2439>2439
6868 328328 416416 483483
6969 519519 736736 ＞7692>7692
由表1可知，本发明全新结构的化合物均可表现出较好的PI3Kδ抑制活性。而且，本发明全新结构的化合物对其他的PI3K亚型也都具有良好的选择性，部分化合物选择性列于表2。这为制备癌症治疗药物的研究提供了新的依据。It can be seen from Table 1 that the compounds of the new structure of the present invention can all show good PI3Kδ 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.
生物实验实施例2：细胞增殖实验Biological Experiment Example 2: Cell Proliferation Experiment
采用MTT法检测一系列PI3Kδ抑制剂对细胞活力的影响。将Mino、Raji、OCI-LY7细胞用培养基重悬成单细胞悬液，将10μL细胞悬液与10μL 0.4％台盼蓝溶液混合，5min后用血细胞计数板计数活细胞数。接下来，将细胞以10000个细胞/孔的密度接种到96孔板中，用不同浓度的化合物作用72小时。随后每孔中加入20μL MTT溶液(5mg/ml)，再孵育4小时。用100μL DMSO将形成的甲瓒晶体溶解，随后在酶标仪(Bio-Tek，CA，USA)上在570nm波长下测定吸光度。抑制率计算公式如下：(OD对照细胞-OD处理细胞-ODDay0)/(OD对照细胞-ODDay0)×100％，其中ODDay0表示处理前对照细胞的OD值。半抑制浓度值采用GraphPadPrism5.0软件(GraphPad软件，CA，USA)计算。The effects of a series of PI3Kδ 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 μL of cell suspension was mixed with 10 μL of 0.4% trypan blue solution, and the number of viable cells was counted with a hemocytometer after 5 minutes. Next, 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 μL 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 μL 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).
表3吲唑类衍生物对淋巴瘤细胞的抑制结果Table 3 Inhibitory results of indazole derivatives on lymphoma cells
Figure PCTCN2022082962-appb-000100
Figure PCTCN2022082962-appb-000100
表4吲唑类衍生物对人正常淋巴细胞的抑制结果Table 4 Inhibitory results of indazole derivatives on human normal lymphocytes
Figure PCTCN2022082962-appb-000101
Figure PCTCN2022082962-appb-000101
Figure PCTCN2022082962-appb-000102
Figure PCTCN2022082962-appb-000102
本发明全新结构的化合物在淋巴瘤细胞上均可表现出优异的抗增殖活性，且优于阳性对照化合物Idelalisib，部分化合物在淋巴瘤细胞上的抗增殖活性列于表3。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.
此外，本发明全新结构的化合物对于人的正常淋巴细胞CAM-191的抑制作用弱于Idelalisib，显示出了更好的安全性，部分化合物对人的正常淋巴细胞CAM-191的抑制作用列于表4。In addition, 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.
此外应理解，在阅读了本发明的上述描述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。In addition, it should be understood that after reading the above description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (9)

  1. 式(1)的化合物Compounds of formula (1)
    Figure PCTCN2022082962-appb-100001
    Figure PCTCN2022082962-appb-100001
    和/或其药学上可接受的盐，和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体；and/or pharmaceutically acceptable salts thereof, and/or racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers and tautomers thereof;
    其中R 1、R 2、R 3、R 4相同或不同，各自独立地选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基中的一个或多个，或者R 1和R 2通过偶联形成取代或非取代的C 4-10芳基的环结构、或形成取代或未取代的C 2-10杂芳基的环结构，或者R 2和R 3通过偶联形成取代或非取代的C 4-10芳基的环结构、或形成取代或未取代的C 2-10杂芳基的环结构，或者R 3和R 4通过偶联形成取代或非取代的C 4-10芳基的环结构、或形成取代或未取代的C 2-10杂芳基的环结构； wherein 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, heteroaryloxycarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, heteroarylcarbonyl Amine group, aminocarbonyl group, alkoxycarboxamido group, alkyl mercapto group, hydroxyalkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group One or more of the radicals, or R 1 and R 2 are coupled to form a substituted or unsubstituted C 4-10 aryl ring structure, or a substituted or unsubstituted C 2-10 heteroaryl ring structure , or R 2 and R 3 are coupled to form a substituted or unsubstituted C 4-10 aryl ring structure, or a substituted or unsubstituted C 2-10 heteroaryl ring structure, or R 3 and R 4 Formation of a substituted or unsubstituted C 4-10 aryl ring structure by coupling, or a substituted or unsubstituted C 2-10 heteroaryl ring structure;
    R 5选自氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基； 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, cycloalkylcarbonylamino, heteroarylcarbonylamino, aminocarbonyl, alkoxycarboxamido, alkylmercapto, hydroxyl Alkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group;
    X和Y相同或不同，各自独立地选自C或N；X and Y are the same or different, each independently selected from C or N;
    R 6选自氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、胺基羰基； 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选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺 基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基； 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, heteroarylcarbonylamino, aminocarbonyl, alkoxycarboxamido, alkylmercapto, hydroxyl Alkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group;
    R 8选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基； 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, heteroarylcarbonylamino, aminocarbonyl, alkoxycarboxamido, alkylmercapto, hydroxyl Alkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group;
    R 9选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷基单取代胺基、烷基双取代胺基、烷氧基、烷基羰氧基、环烷基羰氧基、杂芳基羰氧基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、烷基羰胺基、环烷基羰胺基、杂芳基羰胺基、胺基羰基、烷氧甲酰胺基、烷巯基、羟基烷氧基、糖残基、磺酸基、磷酸基、多羟基烷氧基羰基、羧基烷氧基、羧基烷基甲酰氧基。 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, heteroarylcarbonylamino, aminocarbonyl, alkoxycarboxamido, alkylmercapto, hydroxyl Alkoxy group, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxycarbonyl group, carboxyalkoxy group, carboxyalkylformyloxy group.
  2. 根据权利要求1所述的化合物和/或其药学上可接受的盐，和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体，其特征在于，式(1)的化合物为下式(2)的化合物：The compound according to claim 1 and/or its pharmaceutically acceptable salt, and/or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer and tautomers, characterized in that the compound of formula (1) is a compound of the following formula (2):
    Figure PCTCN2022082962-appb-100002
    Figure PCTCN2022082962-appb-100002
    其中R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9与式(1)中的定义相同。 wherein 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).
  3. 根据权利要求2所述的化合物和/或其药学上可接受的盐，和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体，其特征在于，式(2)的化合物中：The compound according to claim 2 and/or its pharmaceutically acceptable salt, and/or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer and tautomers, characterized in that in the compound of formula (2):
    R 1、R 2各自独立地选自氢、卤素、硝基、氰基、氨基、羟基、酯基、酰胺、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、氟、氯、溴、碘、硝基、氰基、酰胺、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、氟、氯、溴、碘、硝基、氰基、酰胺、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、甲基、乙基、丙基、丁基、戊基、环丙基、环丁基、环戊基，取代或 未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-8杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基、烷氧基羰基、环烷氧基羰基、杂芳氧基羰基、胺基羰基； 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选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基； 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选自氢、卤素、硝基、氰基、氨基、羟基、羟甲基、羟乙基、巯基、羧基、酯基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6杂环烷基、取代或未取代的C 1-6环烷基、取代或未取代的C 4-10芳基、取代或未取代的C 1-10杂芳基、C 2-10烯基、C 2-10炔基。 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.
  4. 根据权利要求2所述的化合物和/或其药学上可接受的盐，和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体，其特征在于，式(2)的化合物选自：The compound according to claim 2 and/or its pharmaceutically acceptable salt, and/or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer and tautomers, characterized in that the compound of formula (2) is selected from:
    Figure PCTCN2022082962-appb-100003
    Figure PCTCN2022082962-appb-100003
    Figure PCTCN2022082962-appb-100004
    Figure PCTCN2022082962-appb-100004
    Figure PCTCN2022082962-appb-100005
    Figure PCTCN2022082962-appb-100005
    Figure PCTCN2022082962-appb-100006
    Figure PCTCN2022082962-appb-100006
    Figure PCTCN2022082962-appb-100007
    Figure PCTCN2022082962-appb-100007
  5. 根据权利要求4所述的式(2)的化合物的制备方法，其特征在于，采用反应路线I合成化合物11-56，利用化合物6a采用反应路线II合成化合物57-85；The preparation method of the compound of formula (2) according to claim 4, wherein the compound 11-56 is synthesized by the reaction scheme I, and the compound 57-85 is synthesized by the reaction scheme II using the compound 6a;
    反应路线I包括以下过程：Reaction scheme I includes following process:
    Figure PCTCN2022082962-appb-100008
    Figure PCTCN2022082962-appb-100008
    化合物1与亚硝酸钠、盐酸在DMF和水的溶液中反应生成取代吲唑-3-甲醛即化合物2，然后在格式试剂作用下形成化合物3，接着被二氧化锰氧化为化合物4，再与溴代物发生Ullman偶联生成化合物5，化合物5在硼氢化钠的作用下还原生成化合物6a，化合物6a和N-(叔丁氧羰基氨基)邻苯二甲酰亚胺在DIAD和PPh 3存在的条件下发生Mitsunobu反应生成化合物7，接着经过肼解得到化合物8，化合物8在HCl/EA溶液中脱除Boc生成化合物9，化合物9和不同取代的乙氧基丙二腈反应生成化合物10，最后再关环生成目标化合物11-56； Compound 1 reacts with sodium nitrite and hydrochloric acid in a solution of DMF and water to form substituted indazole-3-carbaldehyde, which is compound 2, and then forms compound 3 under the action of Grignard reagent, which is then oxidized by manganese dioxide to compound 4, which is then combined with The bromide undergoes Ullman coupling to generate compound 5, which is reduced under the action of sodium borohydride to generate compound 6a. Compound 6a and N-(tert-butoxycarbonylamino)phthalimide are in the presence of DIAD and PPh 3 . The Mitsunobu reaction occurred under the conditions to generate compound 7, followed by hydrazinolysis to obtain compound 8, compound 8 was removed Boc in HCl/EA solution to generate compound 9, compound 9 reacted with different substituted ethoxymalononitriles to generate compound 10, and finally Close the ring again to generate the target compound 11-56;
    反应路线II包括以下过程：Reaction scheme II includes the following process:
    Figure PCTCN2022082962-appb-100009
    Figure PCTCN2022082962-appb-100009
    化合物6a在无水二氯甲烷中和氯化亚砜反应，醇被亲核取代生成相应的氯代物，即化合物6b，接着化合物6b和不同取代的吡唑并氨基嘧啶反应生成目标化合物57-85。Compound 6a was reacted with thionyl chloride in anhydrous dichloromethane, and the alcohol was nucleophilically substituted to generate the corresponding chloride, namely compound 6b, and then compound 6b reacted with different substituted pyrazoloaminopyrimidines to generate target compounds 57-85 .
  6. 一种药物组合物，其特征在于，包含权利要求1～4任意一项所述的式(1)的化合物和/或其药学上可接受的盐、和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体，以及一种或多种可药用载体、稀释剂、赋形剂。A pharmaceutical composition, characterized in that it comprises the compound of formula (1) according to any one of claims 1 to 4 and/or a pharmaceutically acceptable salt thereof, and/or a racemic mixture or hydrate thereof , solvates, prodrugs, enantiomers, diastereomers and tautomers, and one or more pharmaceutically acceptable carriers, diluents, excipients.
  7. 根据权利要求1～4任意一项所述的式(1)的化合物和/或其药学上可接受的盐、和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体，和/或，根据权利要求5所述的药物组合物，在制备PI3激酶抑制剂中的应用。The compound of formula (1) according to any one of claims 1 to 4 and/or its pharmaceutically acceptable salt, and/or its racemic mixture, hydrate, solvate, prodrug, enantiomer Use of isomers, diastereomers and tautomers, and/or, according to claim 5, in the preparation of PI3 kinase inhibitors.
  8. 根据权利要求1～4任意一项所述的式(1)的化合物和/或其药学上可接受的盐、 和/或其外消旋混合物、水合物、溶剂合物、前药、对映异构体、非对映异构体和互变异构体，和/或，根据权利要求5所述的药物组合物，在制备用于治疗对抑制PI3K有响应的疾病的药剂中的应用，其特征在于，所述疾病包括炎症性疾病、自身免疫性疾病、癌症、感染性疾病、心脑血管疾病。The compound of formula (1) according to any one of claims 1 to 4 and/or its pharmaceutically acceptable salt, and/or its racemic mixture, hydrate, solvate, prodrug, enantiomer Isomers, diastereomers and tautomers, and/or, the use of a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the treatment of a disease responsive to inhibition of PI3K, It is characterized in that the diseases include inflammatory diseases, autoimmune diseases, cancer, infectious diseases, cardiovascular and cerebrovascular diseases.
  9. 根据权利要求8所述的应用，其特征在于，所述的炎症性疾病、自身免疫性疾病为类风湿性关节炎、慢性阻塞性肺病、变应性鼻炎、哮喘、红斑狼疮、银屑病和多发性硬化；The application according to claim 8, wherein the inflammatory diseases and autoimmune diseases are rheumatoid arthritis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis;
    所述的癌症为实体瘤或血液系统恶性肿瘤，其选自白血病、多发性骨髓瘤、淋巴瘤；所述的白血病为急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病和慢性髓性白血病；所述的淋巴瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤、套细胞淋巴瘤、滤泡型淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、弥散性大B细胞淋巴瘤；Described cancer is solid tumor or hematological malignancy, and it is selected from leukemia, multiple myeloma, lymphoma; Described leukemia is acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia The lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma;
    所述的感染性疾病包括细菌性感染、真菌性感染、病毒性感染、寄生虫感染；Described infectious disease includes bacterial infection, fungal infection, viral infection, parasitic infection;
    所述的心脑血管疾病包括急性心力衰竭、低血压、高血压、心绞痛、心肌梗塞、心肌病、充血性心力衰竭、动脉粥样硬化、冠心病、再狭窄和血管狭窄，以及外伤性脑损伤、中风、缺血再灌注损伤和动脉。The cardiovascular and cerebrovascular diseases include acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, and traumatic brain injury , stroke, ischemia-reperfusion injury, and arteries.
PCT/CN2022/082962 2021-03-29 2022-03-25 Indazole compound, preparation method therefor and application thereof WO2022206583A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110335169 2021-03-29
CN202110335169.2 2021-03-29

Publications (1)

Publication Number Publication Date
WO2022206583A1 true WO2022206583A1 (en) 2022-10-06

Family

ID=81811267

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/082962 WO2022206583A1 (en) 2021-03-29 2022-03-25 Indazole compound, preparation method therefor and application thereof

Country Status (2)

Country Link
CN (1) CN114591335B (en)
WO (1) WO2022206583A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101448505A (en) * 2006-04-04 2009-06-03 加利福尼亚大学董事会 P13 kinase antagonists
CN104428293A (en) * 2012-06-11 2015-03-18 Ucb生物制药私人有限公司 TNF -alpha modulating benzimidazoles
CN105431437A (en) * 2013-07-02 2016-03-23 理森制药股份公司 PI3K protein kinase inhibitors, particularly delta and/or gamma inhibitors
CN110156785A (en) * 2019-04-15 2019-08-23 浙江大学 Indazole compounds and its preparation method and application

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1621536A1 (en) * 2004-07-27 2006-02-01 Aventis Pharma S.A. Amino cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
US8188109B2 (en) * 2009-07-20 2012-05-29 Naxospharma S.R.L. Benzoquinolizinium salt derivatives as anticancer agents
CN107033145B (en) * 2016-02-04 2019-11-22 浙江大学 Benzothiazine and benzothiadiazines compound and preparation and application
EP3964512A4 (en) * 2019-06-27 2022-08-10 Hangzhou Healzen Therapeutics Co., Ltd. CASEIN KINASE 1epsilon INHIBITOR, PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101448505A (en) * 2006-04-04 2009-06-03 加利福尼亚大学董事会 P13 kinase antagonists
CN104428293A (en) * 2012-06-11 2015-03-18 Ucb生物制药私人有限公司 TNF -alpha modulating benzimidazoles
CN105431437A (en) * 2013-07-02 2016-03-23 理森制药股份公司 PI3K protein kinase inhibitors, particularly delta and/or gamma inhibitors
CN110156785A (en) * 2019-04-15 2019-08-23 浙江大学 Indazole compounds and its preparation method and application

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
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 *

Also Published As

Publication number Publication date
CN114591335B (en) 2023-06-27
CN114591335A (en) 2022-06-07

Similar Documents

Publication Publication Date Title
RU2563644C2 (en) Pyrrolopyrimidine compounds and application thereof
TWI752155B (en) ARYL HYDROCARBON RECEPTOR (AhR) MODULATOR COMPOUNDS
EP3008053B1 (en) Phosphatidylinositol 3-kinase inhibitors
AU2016290820A1 (en) Cot modulators and methods of use thereof
JP6808905B2 (en) A pharmaceutical composition for preventing or treating a heteroaryl derivative or a pharmaceutically acceptable salt thereof, a method for producing the same, and a PI3 kinase-related disease containing the heteroaryl derivative as an active ingredient.
TW201124416A (en) Heterocyclic compounds useful as PDK1 inhibitors
AU2015320142B2 (en) Novel imidazopyridazine compounds and their use
TW200951133A (en) P38 kinase inhibiting agents
CN104768952A (en) PI3Kdelta inhibitor
TW202104223A (en) Phosphatidylinositol 3-kinase inhibitors
AU2018351059B2 (en) Benzimidazole derivatives and their uses
CA3168494A1 (en) Pgdh inhibitors and methods of making and using
KR20220061958A (en) Heterobicyclic amides as inhibitors of CD38
US20230067237A1 (en) Caffeine inhibitors of mthfd2 and uses thereof
WO2014151630A2 (en) Compounds and compositions for the treatment of parasitic diseases
WO2019228404A1 (en) Novel phosphoinositide 3-kinase inhibitor and preparation method and use thereof
WO2018229543A2 (en) Therapeutic inhibitory compounds
CA3158731A1 (en) Adenosine receptor antagonist compounds
AU2014284013A1 (en) Five-membered heterocyclic pyridine compounds and preparation method and use thereof
CN114591335B (en) Indazole compound, preparation method and application thereof
WO2015014283A1 (en) Protein tyrosine kinase inhibitor and application thereof
WO2014154168A1 (en) Bicyclic substituted pyrimidine pde-5 inhibitor prodrug
CN116096718A (en) Aryl amide compound, pharmaceutical composition containing same, preparation method and application thereof
CN116903626A (en) Aryl amide compound, pharmaceutical composition containing same, preparation method and application thereof
TW202406908A (en) Novel prmt5 inhibitor and use thereof

Legal Events

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

Ref document number: 22778766

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22778766

Country of ref document: EP

Kind code of ref document: A1