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CN118373824A - Substituted quinazoline-4-ketone compound and preparation method and application thereof - Google Patents

Substituted quinazoline-4-ketone compound and preparation method and application thereof Download PDF

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CN118373824A
CN118373824A CN202410448714.2A CN202410448714A CN118373824A CN 118373824 A CN118373824 A CN 118373824A CN 202410448714 A CN202410448714 A CN 202410448714A CN 118373824 A CN118373824 A CN 118373824A
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陈俐娟
夏文
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Chengdu Zeiling Biomedical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

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Abstract

The invention relates to a substituted quinazoline-4-ketone compound, a preparation method and application thereof, belonging to the field of chemical medicine. The present invention provides substituted quinazolin-4-ones, pharmaceutically acceptable salts thereof, stereoisomers thereof, or solvates thereof. The invention also provides a preparation method and application of the compound. Biological experiments show that the compound has better inhibition activity on PI 3K; meanwhile, the compounds have better inhibitory activity on proliferation of various tumor cells, wherein certain compounds show better antiproliferative activity than CAL-101 and IPI-145; the compound of the invention also has better anti-inflammatory effect.

Description

Substituted quinazoline-4-ketone compound and preparation method and application thereof
Technical Field
The invention relates to a substituted quinazoline-4-ketone compound, a preparation method and application thereof, belonging to the field of chemical medicine.
Background
Phosphatidylinositol 3-kinase (phosphoinositide-kinase, PI 3K) belongs to a lipid kinase family member, is an important signal transduction molecule in cells, plays a key role in PI3K/AKT/mTOR signal transduction pathway, and can mediate in vivo phosphorylation process to influence the processes of growth, proliferation, differentiation, migration, apoptosis and the like of cells. Studies have found that deregulation of the PI3K pathway is involved in a variety of diseases such as cancer, diabetes, thrombosis, rheumatoid arthritis, PI3K delta overactivation syndrome and asthma, PI3K has become a potential therapeutic target for drugs.
Currently known PI3K inhibitors are largely divided into types I, II and III, with the most studied type I PI3 ks being activated by cell surface receptors. Type I is further subdivided into IA (pi3kα, β and δ) and IB (pi3kγ) depending on the type of regulatory subunit to which the catalytic domain (p 110) binds in the form of an active heterodimer. Class IA PI3 ks mediate signal transduction of Receptor Tyrosine Kinases (RTKs), whereas PI3kγ is predominantly activated by G-protein coupled receptors (GPCRs). PI3kα and β are ubiquitous in whole body tissues, while PI3kδ and γ are predominantly present in the hematopoietic system, epithelial cells and Central Nervous System (CNS) 1-3. Deregulation (e.g. overexpression) of the PI3K pathway is associated with all type I PI3 ks. Wherein the mutation of PI3kα is associated with the development and progression of a tumor; pi3kβ is capable of activating platelets, associated with the development of thrombotic disease, and in PTEN-deficient tumors, pi3kβ contributes to malignant changes in the tumor; pi3kγ and pi3kδ are mainly involved in the immune and hematopoietic systems, and are closely related to the occurrence of immune, hematological tumors, and inflammation. Type ii PI3 ks primarily affect membrane trafficking, type iii PI3K member Vps34 can affect endocytosis and vesicle trafficking of cells, regulate autophagy, and can also mediate cell signaling through mTOR.
Disclosure of Invention
The invention aims to provide substituted quinazoline-4-ketone compounds, pharmaceutically acceptable salts or stereoisomers thereof.
Wherein, the structural formula of the compound, the pharmaceutically acceptable salt or the stereoisomer thereof is as follows:
wherein, the structural formula of the compound, the pharmaceutically acceptable salt or the stereoisomer thereof is as follows:
the invention also provides a pharmaceutical composition which is prepared from the compound, pharmaceutically acceptable salt or stereoisomer thereof serving as an active ingredient and pharmaceutically acceptable auxiliary ingredients.
The invention also provides application of the compound, pharmaceutically acceptable salt or stereoisomer thereof in preparing PI3K inhibitor; preferably, the PI3K inhibitor is a PI3K delta inhibitor, a PI3K gamma inhibitor, a PI3K alpha inhibitor, or a PI3K beta inhibitor.
The invention also provides application of the compound, pharmaceutically acceptable salt or stereoisomer thereof in preparing medicines for preventing and/or treating diseases related to PI 3K; the disease related to PI3K is tumor; the tumor is leukemia, hodgkin's lymphoma or non-Hodgkin's lymphoma.
Definition of terms:
The compounds and derivatives provided by the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
The term "alkyl" is a radical of a straight or branched saturated hydrocarbon radical. Examples of C 1～C6 alkyl include, but are not limited to, methyl (C 1), ethyl (C 2), n-propyl (C 3), isopropyl (C 3), n-butyl (C 4), tert-butyl (C 4), sec-butyl (C 4), isobutyl (C 4), n-pentyl (C 5), 3-pentyl (C 5), pentyl (C 5), neopentyl (C 5), 3-methyl-2-butyl (C 5), tert-pentyl (C 5) and n-hexyl (C 6).
The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group containing no heteroatoms, which may be of a single ring structure or of a multiple ring structure, for example: cyclopropane group (3-membered) and cyclohexane group (6-membered).
The term "heterocycloalkyl" means that a carbon atom in "cycloalkyl" is substituted with a heteroatom selected from phosphorus, sulfur, oxygen and/or nitrogen, and monocyclic heterocyclyl comprises pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, tetrahydrofuranyl, and the like; polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
The term "alkenyl" refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms containing at least one double bond, such as: ethenyl, propenyl, butenyl, pentenyl, pentadienyl, hexenyl.
The term "cycloalkenyl" refers to a cyclic hydrocarbon group consisting of carbon and hydrogen atoms containing at least one double bond, such as cyclopropene, cyclopentene, cyclohexene.
The term "heterocycloalkenyl" means that a carbon atom in the "cycloalkenyl" is substituted with a heteroatom selected from phosphorus, sulfur, oxygen, and/or nitrogen, e.g., thiazolinyl.
The term "aryl" refers to an all-carbon monocyclic or fused ring group having a conjugated pi-electron system, and the aryl group may be a fully aromatic group such as phenyl, naphthyl, anthryl, phenanthryl, and the like.
The term "heteroaryl" means that a carbon atom in the "aryl" is substituted with a heteroatom selected from phosphorus, sulfur, oxygen and/or nitrogen, such as pyridine, pyrazole, pyrimidine, benzopyrazole, pyridopyrazole, pyrimidopyrazole, and the like.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I).
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
The term "pharmaceutically acceptable salts" refers to organic and inorganic salts, preferably inorganic salts, pharmaceutically acceptable non-toxic acid forming salts of the compounds of the present invention, including, but not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, nitrate, organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, hydrochloride, oleate, stearate, ascorbate, formate, borate, camphorite, mesylate, ethanesulfonate, p-toluenesulfonate, malate, and the like.
The term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The pharmaceutically acceptable auxiliary ingredient of the present invention means a substance contained in a dosage form in addition to an active ingredient, such as cyclodextrin, arginine or meglumine. The cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, (C 1-4 alkyl) -alpha-cyclodextrin, (C 1-4 alkyl) -beta-cyclodextrin, (C 1-4 alkyl) -gamma-cyclodextrin, (hydroxy-C 1-4 alkyl) -alpha-cyclodextrin, (hydroxy-C 1-4 alkyl) -beta-cyclodextrin, (hydroxy-C 1-4 alkyl) -gamma-cyclodextrin, (carboxy-C 1-4 alkyl) -alpha-cyclodextrin, (carboxy-C 1-4 alkyl) -beta-cyclodextrin, (carboxy-C 1-4 alkyl) -gamma-cyclodextrin, a saccharide ether of alpha-cyclodextrin, a saccharide ether of beta-cyclodextrin, a saccharide ether of gamma-cyclodextrin, a sulfobutyl ether of alpha-cyclodextrin, a sulfobutyl ether of beta-cyclodextrin, and a sulfobutyl ether of gamma-cyclodextrin. The adjunct ingredients further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. Can be used for pharmaceutically acceptable pharmaceutical compositions, such as ion exchangers, aluminum oxide, aluminum stearate and egg gel; buffer substances include phosphates, glycine, arginine, sorbic acid, and the like.
The invention discloses a compound of a formula I, and pharmacodynamic experiment results show that the compound of the invention can act on a PI3K target spot, can be used as a single therapeutic agent for tumor or inflammation or can be combined with other anti-tumor or anti-inflammatory drugs, thereby achieving the purposes of improving the curative effect on tumor or inflammation and reducing the dosage and toxicity.
The compounds of the invention are potentially useful in the treatment of a variety of diseases including, but not limited to, inter alia, autoimmune diseases, auto-inflammatory diseases, allergic diseases, pathologic immune diseases, respiratory diseases such as asthma and COPD, transplant rejection, malignant tumors (e.g. of blood origin or solid tumors).
Detailed Description
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
Preparation of CLJ-1
Step a: preparation of intermediate N-Boc-L-octahydroindole-2-carboxylic acid (SM 1)
L-octahydroindole-2-carboxylic acid (2.00 g,1eq,11.80 mmol) was dissolved in dichloromethane, triethylamine (3.30 mL,2eq,23.60 mmol) was added to the solution, stirred at room temperature for 10min, boc anhydride (2.70 mL,1eq,11.80 mmol) was added, the reaction was continued at room temperature for 2-3h, then saturated ammonium chloride solution 20mL was added, the organic layer was collected by extraction, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was used directly in the next step without further purification.
Step b: preparation of SM4
2-Amino-6-chlorobenzoic acid (2.03 g,1eq,11.80 mmol) and N-Boc-L-octahydroindole-2-carboxylic acid (3.18 g,1eq,11.80 mmol) were dissolved in pyridine under nitrogen, triphenyl phosphite (7.75 mL,2.5eq,29.5 mmol) was injected into the mixture, the temperature was raised to 70℃and the reaction was detected by TLC, aniline (1.32 mL,1.2eq,11.8 mmol) was slowly added dropwise to the reaction solution until the reaction was completed, and the reaction was carried out overnight at 70 ℃. The reaction solution is evenly dispersed in ethyl acetate and water in the next day, extraction is carried out, the organic layer is washed for 1 time by water, then the organic layer is collected, the solvent is concentrated under reduced pressure until the solvent is dried, the residue is directly dissolved in ethyl acetate without further purification, and a proper amount of concentrated hydrochloric acid is injected into the mixed solution, after reaction for 2-3 hours at normal temperature, 1M NaOH solution is directly added, the condition PH is weak alkaline, the organic layer is collected by extraction and separation, the concentration is carried out under reduced pressure, and the residue is purified by silica gel column chromatography, thus obtaining pale yellow solid powder SM5, and the yield is 54%.
1H NMR(400MHz,DMSO-d6)δ7.78(t,J＝8.0Hz,1H),7.66(dd,J＝8.2,1.2Hz,1H),7.60–7.51(m,4H),7.49–7.44(m,2H),3.72(dt,J＝9.9,5.5Hz,1H),2.84(q,J＝4.8Hz,1H),1.87–1.74(m,2H),1.71–1.59(m,2H),1.53–1.38(m,4H),1.35(d,J＝5.2Hz,1H),1.27–1.09(m,2H).ESI-MS m/z:379.8[M+H]+.
Step c: obtaining of the end product
SM5 (0.100 g,1eq,0.263 mmol) and 4-chloropyrrolopyrimidine (0.049 g,1.2eq,0.316 mmol) were dissolved in n-butanol, triethylamine (110. Mu.L, 3eq, 0.780 mmol) was added to the reaction solution, the temperature was raised to 80 ℃, the reaction was detected by TLC, after completion of the reaction, the reaction was concentrated under reduced pressure, ethyl acetate was added to the residue, the mixture was washed with water and saturated sodium chloride solution, the organic layer was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give a white solid powder in a yield of 70%.
1H NMR(400MHz,Chloroform-d)δ10.73(s,1H),8.14(s,1H),7.88(d,J＝8.0Hz,1H),7.67–7.34(m,8H),7.03(d,J＝3.5Hz,1H),4.71(dd,J＝9.4,7.4Hz,1H),4.33(q,J＝7.7Hz,1H),2.39–2.23(m,4H),1.99–1.93(m,1H),1.79–1.66(m,3H),1.59(d,J＝13.1Hz,1H),1.50–1.39(m,2H).ESI-MS m/z:496.1[M+H]+.
EXAMPLE 2 preparation of Compound CLJ-2
The preparation process is the same as in example 1, 4-chloropyrrolopyrimidine in step c is replaced by 2-amino-6-chloropurine to give the final product CLJ-2.1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),7.92(d,J＝7.8Hz,1H),7.70(s,1H),7.67–7.55(m,5H),7.51–7.47(m,2H),7.43–7.39(m,1H),4.93(dt,J＝11.6,6.2Hz,1H),4.52(t,J＝8.5Hz,1H),2.39(d,J＝12.2Hz,1H),2.30–2.04(m,4H),1.81(dd,J＝12.6,6.2Hz,1H),1.75–1.58(m,4H),1.45(s,1H),1.27(t,J＝12.7Hz,2H).ESI-MS m/z:512.1[M+H]+.
EXAMPLE 3 preparation of Compound CLJ-3
The preparation process is the same as in example 1, the 4-chloropyrrolopyrimidine in step c is replaced by 4-amino-2-chloropyrimidine to give the final product CLJ-3.1H NMR(400MHz,DMSO-d6)δ7.80–7.35(m,10H),6.22(d,J＝53.2Hz,2H),4.26(dd,J＝9.1,7.0Hz,1H),4.19–4.03(m,1H),2.12(s,3H),2.02–1.91(m,1H),1.84(s,1H),1.63(q,J＝17.0,13.9Hz,3H),1.44(d,J＝12.5Hz,1H),1.23(d,J＝4.0Hz,2H).ESI-MS m/z:472.2[M+H]+.
EXAMPLE 4 preparation of Compound CLJ-4
The preparation is carried out in the same way as in example 1, 4-chloropyrrolopyrimidine in step c being replaced by 2-chloro-3-cyanopyridine to give the final product CLJ-4.1H NMR(400MHz,DMSO-d6)δ8.71(dd,J＝4.9,1.9Hz,1H),8.48(dd,J＝7.7,1.9Hz,1H),8.31(dd,J＝4.7,1.9Hz,1H),7.85(dd,J＝7.7,1.9Hz,1H),7.68–7.63(m,3H),7.60(dd,J＝8.5,6.8Hz,2H),7.48(ddd,J＝7.9,6.5,1.6Hz,2H),4.46(ddd,J＝17.3,10.7,6.8Hz,2H),2.32–2.10(m,4H),1.90–1.81(m,1H),1.75(d,J＝12.7Hz,1H),1.69–1.55(m,2H),1.46(d,J＝
13.0Hz,1H),1.40–1.26(m,1H),1.22–1.14(m,1H).ESI-MS m/z:482.1[M+H]+.
Implementation of preparation of Compound CLJ-5
The preparation is carried out in the same way as in example 1, the substitution of 4-chloropyrrolopyrimidine in step c for 2-chloro-4-methylpyridine giving the end product CLJ-5.1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝53.1Hz,1H),7.76(s,1H),7.59–7.47(m,5H),7.39(dd,J＝6.8,2.2Hz,1H),7.22(d,J＝7.6Hz,1H),6.25(d,J＝5.0Hz,1H),4.49(s,1H),4.33–4.18(m,1H),2.36–2.17(m,6H),1.92(dd,J＝7.3,5.1Hz,1H),1.81–1.66(m,3H),1.60–1.48(m,3H),1.41(t,J＝7.4Hz,1H).ESI-MS m/z:472[M+H]+.
EXAMPLE 6 preparation of Compound CLJ-6
The preparation process is the same as in example 1, 4-chloropyrrolopyrimidine in step c being replaced by 6-chloropurine to give the final product CLJ-6.1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.13(d,J＝13.7Hz,2H),7.80–7.75(m,1H),7.65–7.58(m,3H),7.57–7.48(m,3H),7.39(dd,J＝8.2,1.2Hz,1H),4.88(dt,J＝11.3,6.2Hz,1H),4.49(dd,J＝9.3,7.4Hz,1H),2.29(q,J＝10.6,9.8Hz,2H),2.23–2.12(m,2H),1.78–1.60(m,4H),1.48(s,1H),1.43–1.33(m,2H).ESI-MS m/z:498[M+H]+.
Implementation of preparation of Compound CLJ-7, example 7
The procedure is as in example 1, substituting 4-chloropyrrolopyrimidine in step c with 4-chloro-1H-pyrazolo [3,4-d ] pyrimidine to give the final product CLJ-7.1H NMR(400MHz,Chloroform-d)δ12.20(s,1H),8.26(s,1H),7.95(s,1H),7.84–7.80(m,1H),7.66–7.45(m,5H),7.39(dd,J＝8.0,0.9Hz,2H),4.72(dd,J＝9.5,7.5Hz,1H),4.23(dd,J＝10.2,6.6Hz,1H),2.44–2.26(m,4H),2.01(dt,J＝11.7,6.8Hz,1H),1.91(d,J＝12.1Hz,1H),1.49–1.32(m,3H).ESI-MS m/z:498.0[M+H]+.
Example 8 preparation of Compound CLJ-8
The preparation process is the same as in example 1, 4-chloropyrrolopyrimidine in step C being replaced by 4-chloroimidazo [4,5-C ] pyridine to give the final product CLJ-8.1H NMR(500MHz,Chloroform-d)δ8.10–8.03(m,2H),7.61–7.53(m,2H),7.51–7.43(m,4H),7.35–7.29(m,2H),7.03(d,J＝7.5Hz,1H),3.63(d,J＝5.8Hz,1H),2.73(ddd,J＝16.7,7.0,2.7Hz,1H),2.29(ddd,J＝16.8,3.7,1.4Hz,1H),2.07(ddd,J＝9.8,6.6,3.4Hz,1H),1.54–1.41(m,2H),1.29–1.22(m,1H),1.20–1.10(m,2H),1.09–0.98(m,1H),0.90–0.72(m,2H),0.54–0.42(m,1H).ESI-MS m/z:497.1[M+H]+.
EXAMPLE 9 preparation of Compound CLJ-9
The procedure is as in example 1, substituting 2-chloro-7H-pyrrolo [2,3-d ] pyrimidine for 4-chloropyrrolo pyrimidine in step c to give the final product CLJ-9.1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),8.91(s,1H),7.81(t,J＝8.0Hz,1H),7.70(dd,J＝8.2,1.2Hz,1H),7.66–7.59(m,2H),7.44(ddd,J＝14.5,10.7,7.8Hz,5H),6.64(d,J＝3.6Hz,1H),3.63(d,J＝5.8Hz,1H),3.17(d,J＝5.2Hz,1H),2.73(ddd,J＝16.8,7.0,2.6Hz,1H),2.34–2.27(m,1H),2.08(dt,J＝9.7,3.5Hz,1H),1.47(dq,J＝15.8,5.5Hz,2H),1.31–1.23(m,1H),1.14(d,J＝13.1Hz,2H),1.08–0.98(m,1H),0.80–0.71(m,1H),0.48(qd,J＝10.8,10.4,5.3Hz,1H).ESI-MS m/z:497.2[M+H]+.
EXAMPLE 10 preparation of Compound CLJ-10
The preparation process is the same as in example 1, 4-chloropyrrolopyrimidine in step c being replaced by 2, 6-dichloropurine to give the final product CLJ-10.1H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.15(s,1H),7.86(d,J＝8.4Hz,1H),7.68–7.62(m,2H),7.62–7.56(m,2H),7.51(dd,J＝7.9,1.5Hz,2H),7.40(dd,J＝8.2,1.2Hz,1H),4.86(dt,J＝11.7,6.1Hz,1H),4.50–4.44(m,1H),2.35(d,J＝20.0Hz,2H),2.19(dd,J＝20.8,8.2Hz,2H),1.92(dt,J＝12.9,6.9Hz,1H),1.77–1.68(m,2H),1.28(dd,J＝24.8,13.1Hz,3H).ESI-MS m/z:532.4[M+H]+.
EXAMPLE 11 preparation of Compound CLJ-11
The preparation process is the same as in example 1, 4-chloropyrrolopyrimidine in step c being replaced by 2, 4-dichloropyrimidine to give the final product CLJ-11.1H NMR(400MHz,Chloroform-d)δ8.99–8.95(m,2H),8.02(d,J＝6.0Hz,1H),7.62–7.56(m,2H),7.32(t,J＝7.9Hz,2H),7.10(t,J＝7.4Hz,1H),6.32(d,J＝6.1Hz,1H),4.65(d,J＝8.9Hz,1H),3.84(s,1H),2.85–2.71(m,1H),2.14(dt,J＝14.3,7.7Hz,1H),1.96–1.84(m,2H),1.81–1.68(m,2H),1.63–1.48(m,4H),1.28–1.18(m,1H).ESI-MS m/z:492.4[M+H]+.
EXAMPLE 12 preparation of Compound CLJ-12
The preparation is carried out in the same way as in example 1, the substitution of 4-chloropyrrolopyrimidine in step c with 4-amino-5-cyano-6-chloropyrimidine giving the end product CLJ-12.1H NMR(400MHz,Chloroform-d)δ7.96(s,1H),7.64(d,J＝7.9Hz,1H),7.60–7.47(m,5H),7.42(dd,J＝7.6,1.4Hz,1H),7.22(dt,J＝7.2,1.9Hz,1H),5.37(s,2H),4.65(t,J＝8.5Hz,1H),4.51(dt,J＝11.7,6.1Hz,1H),2.36(s,1H),2.31–2.12(m,3H),1.86(d,J＝18.4Hz,2H),1.76–1.64(m,2H),1.54(s,1H),1.34(dt,J＝14.4,8.1Hz,2H).ESI-MS m/z:498[M+H]+.
EXAMPLE 13 preparation of Compound CLJ-13
Preparation method As in example 1, SM1 was replaced with (S) -5- (t-butoxycarbonyl) -5-azaspiro [2.4] heptane-6-carboxylic acid, which was directly available, and 4-chloropyrrolopyrimidine in step c was replaced with 2-amino-6-chloropurine to give the final product CLJ-13.1H NMR(400MHz,DMSO-d6)δ8.05–7.86(m,1H),7.80–7.37(m,8H),5.62(d,J＝48.6Hz,2H),4.78(dd,J＝8.6,3.9Hz,1H),4.18(dd,J＝57.1,10.8Hz,1H),3.81(t,J＝10.1Hz,1H),2.08–1.83(m,2H),0.76–0.29(m,4H).ESI-MS m/z:484.9[M+H]+.
EXAMPLE 14 preparation of Compound CLJ-14
The preparation method is the same as in example 1.
CLJ-14,1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.09(s,1H),7.77(dt,J＝8.2,1.4Hz,
1H),7.69–7.52(m,5H),7.50–7.46(m,2H),7.41(dd,J＝8.2,1.2Hz,1H),7.12(dd,J＝3.5,2.2Hz,1H),4.78(dd,J＝8.1,4.5Hz,1H),4.03(dd,J＝8.3,6.1Hz,1H),3.92(d,J＝9.4Hz,1H),2.10–2.00(m,2H),0.87–0.74(m,2H),0.64(pd,J＝5.7,3.4Hz,2H).ESI-MS m/z:468.9[M+H]+.
EXAMPLE 15 preparation of Compound CLJ-15
The preparation method is the same as in example 1, and 4-chloropyrrolopyrimidine is replaced by 6-chloropurine to obtain the final product.
CLJ-15,1H NMR(400MHz,Chloroform-d)δ8.28(s,1H),7.92(s,1H),7.84(d,J＝7.9Hz,
1H),7.67–7.58(m,2H),7.53(dd,J＝6.5,2.9Hz,3H),7.44–7.39(m,2H),7.21(d,J＝6.5Hz,1H),5.05(dd,J＝8.2,5.3Hz,1H),4.44–4.34(m,2H),4.03–3.90(m,2H),0.75–0.59(m,4H).ESI-MS m/z:469.9[M+H]+.
EXAMPLE 16 preparation of Compound CLJ-16
The preparation method is the same as in example 1, 4-chloro-pyrrolopyrimidine is replaced by 4-amino-5-cyano-6-chloro-pyrimidine to obtain the final product .CLJ-16,1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.63–7.43(m,7H),7.19(s,1H),6.55(s,2H),5.04(s,1H),4.27–4.15(m,1H),3.91(d,J＝39.4Hz,3H),0.82(s,1H),0.64(d,J＝25.4Hz,2H),0.51(s,1H).ESI-MS m/z:469.9[M+H]+.
EXAMPLE 17 preparation of Compound CLJ-17
The preparation method is the same as in example 1, and 4-chloropyrrolopyrimidine is replaced by 2, 4-diamino-6-chloropyrimidine to obtain the final product.
CLJ-17,1H NMR(400MHz,Chloroform-d)δ7.73(dd,J＝8.2,1.3Hz,1H),7.65(t,J＝8.0
Hz,1H),7.54(dd,J＝7.8,1.3Hz,1H),7.46(pd,J＝7.8,6.8,2.4Hz,4H),7.33–7.30(m,2H),3.72(t,J＝2.2Hz,2H),2.48(t,J＝2.2Hz,2H),1.25(s,1H),0.47–0.42(m,4H).ESI-MS m/z:459.9[M+H]+.
EXAMPLE 18 preparation of Compound CLJ-18
Step a: preparation of HM1
Boc-L-hydroxyproline (1 g,1 eq) was dissolved in tetrahydrofuran, the reaction flask was placed in an ice bath, after the temperature had fallen to about 0deg.C, 60% NaH (0.52 g,3 eq) was added, stirred in the ice bath for 10min, bromocarbonitrile (0.63 mL,2 eq) was slowly added dropwise, the ice bath was removed after the addition was completed, the reaction was carried out at room temperature overnight, the reaction solution was slowly added dropwise with ice water the next day for quenching, and ethyl acetate was added for extraction, the organic layer was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was used in the next step without further purification. The remaining steps were carried out in the same manner as in example 1, except that 4-chloropyrrolopyrimidine was replaced with 2-amino-6-chloropurine to give the final product CLJ-18.1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.20(s,1H),7.80–7.48(m,3H),7.28(t,J＝7.7Hz,2H),7.02(t,J＝7.4Hz,1H),5.87(ddd,J＝16.1,10.7,5.2Hz,1H),5.65(s,1H),5.24(d,J＝17.2Hz,1H),5.12(d,J＝10.4Hz,1H),4.71(d,J＝99.0Hz,1H),4.31(s,1H),3.99(q,J＝7.8,6.3Hz,2H),3.53–3.35(m,2H),2.26(s,1H).ESI-MS m/z:513.1[M+H]+.
Example 19, example 20 and example 21 were prepared by the same procedure as in example 18, respectively, CLJ-19, CLJ-20 and CLJ-21 to obtain the final products by substituting 4-chloropyrrolopyrimidine with 2-amino-6-chloropurine, and 4-amino-5-cyano-6-chloropyrimidine with CLJ-19, CLJ-20 and CLJ-21.
CLJ-19,1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.17(s,1H),8.06(s,1H),7.59(d,J＝8.0Hz,2H),7.32–7.24(m,2H),7.16(t,J＝2.8Hz,1H),7.05–6.99(m,1H),6.62(s,1H),5.89(ddt,J＝17.3,10.5,5.3Hz,1H),5.26(dq,J＝17.2,1.8Hz,1H),5.13(dq,J＝10.4,1.6Hz,1H),4.89(s,1H),4.36(d,J＝5.6Hz,1H),4.15(s,1H),4.04(ddt,J＝5.7,2.9,1.6Hz,2H),4.00–3.95(m,1H),2.42(s,1H),2.18(s,1H).ESI-MS m/z:497.1[M+H]+.
CLJ-20,1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),10.19(s,1H),8.15(s,2H),7.60(d,J＝8.1Hz,2H),7.28(t,J＝7.7Hz,2H),7.02(t,J＝7.4Hz,1H),5.88(ddt,J＝16.2,10.5,5.3Hz,1H),5.24(dd,J＝17.2,2.1Hz,1H),5.12(d,J＝10.3Hz,1H),4.87(s,1H),4.65(d,J＝11.3Hz,1H),4.35(s,1H),4.15(d,J＝11.9Hz,1H),4.01(t,J＝4.9Hz,2H),2.45(s,1H),2.14(s,1H).ESI-MS m/z:498.1[M+H]+.
CLJ-21,1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),7.94(s,1H),7.58–7.54(m,2H),7.28(t,J＝7.9Hz,3H),7.07–7.00(m,1H),5.90(ddt,J＝17.3,10.6,5.3Hz,1H),5.26(dq,J＝17.2,1.8Hz,1H),5.15(dq,J＝10.4,1.5Hz,1H),4.84(s,1H),4.30(s,1H),4.08–3.97(m,3H),3.87(d,J＝11.3Hz,1H),2.39(s,1H),2.05(s,1H).ESI-MS m/z:498.1[M+H]+.
EXAMPLE 22 preparation of Compound CLJ-22
Preparation method As in example 1, SM1 was replaced with N-BOC-4-methylene-L-proline, which was purchased directly, and 4-chloropyrrolopyrimidine in step c was replaced with 2-amino-6-chloropurine to give the final product CLJ-22.1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),7.96–7.24(m,9H),5.22–4.78(m,4H),4.56–4.35(m,1H),2.88(dd,J＝26.3,16.2Hz,1H),2.75–2.59(m,1H).ESI-MS m/z:470.9[M+H]+.
Example 23, example 24, example 25, example 26, CLJ-23, CLJ-24, CLJ-25, CLJ-26, respectively, were prepared in the same manner as in example 1, CLJ-24, CLJ-25, CLJ-26, substituting 4-chloropyrrolopyrimidine with 6-chloropurine, 4-amino-5-cyano-6-chloropyrimidine, 2, 4-diamino-6-chloropyrimidine, respectively, to give the final product.
CLJ-23，1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.12(s,1H),7.77(dt,J＝8.1,1.5Hz,
1H),7.70–7.64(m,1H),7.63–7.54(m,4H),7.46(dd,J＝7.8,1.2Hz,1H),7.33(dd,J＝8.2,1.2Hz,1H),7.18(dd,J＝3.6,2.2Hz,1H),6.70(dd,J＝3.6,1.7Hz,1H),5.19(s,1H),5.05(s,1H),4.88(dd,J＝9.3,2.5Hz,1H),4.80(d,J＝14.1Hz,1H),4.69(d,J＝14.1Hz,1H),2.91(d,J＝16.2Hz,1H),2.79–2.69(m,1H).ESI-MS m/z:454.9[M+H]+.
CLJ-24，1H NMR(400MHz,DMSO-d6)δ12.98(d,J＝18.8Hz,1H),8.29–8.14(m,2H),
7.83–7.26(m,8H),5.64(d,J＝9.4Hz,1H),5.15(d,J＝15.4Hz,1H),5.01(d,J＝13.0Hz,1H),4.96–4.87(m,1H),4.53(q,J＝16.0Hz,1H),2.95(t,J＝16.1Hz,1H),2.75(s,1H).ESI-MS m/z:455.9[M+H]+.
CLJ-25,1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.70–7.46(m,8H),7.29(s,2H),5.14(d,J＝2.9Hz,1H),5.04–4.99(m,1H),4.84(d,J＝9.3Hz,1H),4.68(s,2H),2.89–2.80(m,1H),2.64(dd,J＝16.0,9.6Hz,1H).ESI-MS m/z:455.9[M+H]+.
CLJ-26，1H NMR(400MHz,DMSO-d6)δ7.77(t,J＝8.0Hz,1H),7.64(dd,J＝8.2,1.2Hz,
1H),7.62–7.46(m,6H),4.83(dt,J＝5.3,2.3Hz,2H),3.79–3.68(m,2H),3.26–3.20(m,1H),2.60–2.52(m,1H),2.26(dd,J＝16.4,7.6Hz,1H).ESI-MS m/z:445.9[M+H]+.
EXAMPLE 27 preparation of Compound CLJ-27
Preparation method As in example 1, SM1 was replaced with N-Boc-4-oxo-L-proline, which was purchased directly, and 4-chloropyrrolopyrimidine in step c was replaced with 4-amino-5-cyano-6-chloropyrimidine to give the final product CLJ-22.1H NMR(500MHz,Chloroform-d)δ8.80(s,1H),7.65(dd,J＝6.9,2.7Hz,1H),7.59–7.47(m,3H),7.35–7.30(m,2H),7.26–7.20(m,2H),6.96(t,J＝7.0Hz,1H),5.80(s,2H),4.56(d,J＝9.5Hz,1H),4.39(d,J＝9.5Hz,1H),2.72(dd,J＝18.8,7.0Hz,1H),2.45(dd,J＝18.7,6.9Hz,1H).ESI-MS m/z:457.9[M+H]+.
The preparation method of example 28, example 29 and example 30 is the same as that of example 18, bromoacetonitrile is replaced by bromopropene, and 4-chloropyrrolopyrimidine, 6-chloropurine and 4-amino-5-cyano-6-chloropyrimidine are respectively used for CLJ-28, CLJ-29 and CLJ-30 to replace 2-amino-6-chloropurine, so that the final product is obtained.
CLJ-28，1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.09(s,1H),7.79(dd,J＝7.8,2.0Hz,
1H),7.67–7.59(m,3H),7.57–7.50(m,2H),7.50–7.46(m,1H),7.42–7.38(m,1H),7.16(dd,J＝3.6,2.4Hz,1H),5.83–5.72(m,1H),5.14(dq,J＝17.3,1.8Hz,1H),5.06(dq,J＝10.4,1.5Hz,1H),4.62(t,J＝7.4Hz,1H),4.48(s,1H),4.28(dd,J＝10.8,4.9Hz,1H),3.98–3.87(m,3H),2.40–2.33(m,1H),2.15–2.08(m,1H).ESI-MS m/z:499.1[M+H]+.
CLJ-29，1H NMR(400MHz,DMSO-d6)δ12.99(s,1H),8.22–8.11(m,2H),7.54(dddd,J＝
46.4,26.4,14.7,7.8Hz,8H),5.74(ddt,J＝15.6,9.9,5.0Hz,1H),5.17–5.00(m,2H),4.73–4.59(m,1H),4.42(s,1H),4.22(dt,J＝18.6,8.8Hz,1H),3.87(q,J＝7.6,6.4Hz,3H),2.40–2.27(m,1H),2.14(t,J＝11.1Hz,1H).ESI-MS m/z:500.1[M+H]+.
CLJ-30,1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.73–7.46(m,8H),7.28(s,2H),5.76(ddt,J＝17.3,10.6,5.4Hz,1H),5.15–5.03(m,2H),4.58(s,1H),4.39(s,1H),4.15(d,J＝9.5Hz,1H),3.93–3.81(m,3H),2.27(ddd,J＝12.7,7.5,4.9Hz,1H),2.07(d,J＝10.1Hz,1H).ESI-MS m/z:500.1[M+H]+.
Examples 31, 32, 33 and 34 were prepared by the same procedure as in example 1 except that SM1 was replaced with N-Boc-4, 4-difluoro-L-proline and the starting materials of the last steps of CLJ-31, CLJ-32, CLJ-33 and CLJ-34 were replaced with 2-amino-6-chloropurine, 4-chloropyrrolopyrimidine, 6-chloropurine and 4-amino-5-cyano-6-chloropyrimidine, respectively, to give the final products.
CLJ-31，1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),7.85–7.37(m,8H),5.83(d,J＝54.6
Hz,2H),4.98(d,J＝77.9Hz,1H),4.57–4.06(m,2H),2.84(d,J＝16.5Hz,1H),2.45(d,J＝4.6Hz,1H).ESI-MS m/z:494.9[M+H]+.
CLJ-32，1H NMR(400MHz,DMSO-d6)δ11.78(s,1H),8.17(s,1H),7.77(dd,J＝8.2,1.8Hz,
1H),7.70–7.55(m,6H),7.50(dd,J＝7.9,1.2Hz,1H),7.40(dd,J＝8.2,1.2Hz,1H),7.23(dd,J＝3.6,2.4Hz,1H),4.88(dd,J＝9.2,5.2Hz,1H),4.56(ddd,J＝23.2,19.5,9.7Hz,2H),2.88(qd,J＝14.6,5.2Hz,1H),2.71–2.57(m,1H).ESI-MS m/z:478.9[M+H]+.
CLJ-33，1H NMR(400MHz,DMSO-d6)δ13.11(d,J＝31.9Hz,1H),8.44–7.30(m,10H),
4.96(d,J＝60.1Hz,1H),4.55(d,J＝58.6Hz,1H),4.22(d,J＝14.1Hz,1H),3.03–2.85(m,1H),2.62(d,J＝37.2Hz,1H).ESI-MS m/z:479.9[M+H]+.
CLJ-34,1H NMR(400MHz,Chloroform-d)δ12.05(s,1H),8.07(s,1H),7.64–7.53(m,5H),7.48(ddd,J＝15.8,7.9,1.4Hz,2H),7.19(dd,J＝6.9,2.7Hz,1H),5.92(s,2H),5.11(s,1H),4.55(dd,J＝16.7,6.4Hz,2H),2.60–2.44(m,2H).ESI-MS m/z:479.9[M+H]+.
Examples 35, 36, 37 and 38 were prepared by the same procedure as in example 1 except that SM1 was replaced with (2S, 5S) -N-Boc-5-methylpyrrolidine-2-carboxylic acid, and the starting materials of the last steps of CLJ-35, CLJ-36, CLJ-37 and CLJ-38 were replaced with 2-amino-6-chloropurine, 4-chloropyrrolopyrimidine, 6-chloropurine and 4-amino-5-cyano-6-chloropyrimidine, respectively, to give the final products.
CLJ-35，1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.05(d,J＝106.1Hz,1H),7.76–
7.34(m,8H),5.59(d,J＝59.0Hz,2H),5.17(d,J＝40.6Hz,1H),4.53(s,1H),2.13(s,1H),1.93(dd,J＝14.5,7.3Hz,2H),1.74(s,1H),1.57(d,J＝6.2Hz,3H).ESI-MS m/z:472.9[M+H]+.
CLJ-36，1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.08(s,1H),7.78(dd,J＝8.0,2.2Hz,
1H),7.67–7.44(m,7H),7.38(dd,J＝8.2,1.2Hz,1H),7.18–7.14(m,1H),4.55(dt,J＝36.5,7.1Hz,2H),2.19(q,J＝7.7Hz,1H),2.05(q,J＝8.2Hz,2H),1.85(t,J＝8.4Hz,1H),1.61(d,J＝6.2Hz,3H).ESI-MS m/z:456.9[M+H]+.
CLJ-37,1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),8.25–8.10(m,2H),7.84–7.45(m,7H),7.38(d,J＝6.0Hz,1H),5.19(d,J＝61.5Hz,1H),4.54(d,J＝32.2Hz,1H),2.22(t,J＝6.6Hz,1H),2.12–1.91(m,2H),1.83(d,J＝8.3Hz,1H),1.67–1.55(m,3H).ESI-MS m/z:457.9[M+H]+.
CLJ-38,1H NMR(400MHz,DMSO-d6)δ8.41(s,2H),8.01(s,1H),7.73–7.61(m,2H),7.56(dd,J＝16.6,7.4Hz,2H),7.53–7.46(m,2H),7.18(s,2H),4.66(dt,J＝7.2,3.6Hz,1H),4.50(t,J＝7.5Hz,1H),2.12(s,1H),2.01(dt,J＝14.7,6.7Hz,2H),1.91(s,1H),1.82(s,1H),1.56(d,J＝6.2Hz,3H).ESI-MS m/z:457.9[M+H]+.
Examples 39, 40, 41, 42, 43 and 44 were prepared as described in examples CLJ-39, CLJ-40, CLJ-41, CLJ-42, CLJ-43 and CLJ-44, respectively, by the same procedure as in example 1 except that SM3 was replaced with directly available m-trifluoromethoxyaniline, and starting materials in the last steps of CLJ-39, CLJ-40, CLJ-41, CLJ-42, CLJ-43 and CLJ-44 were replaced with 4-chloro-1H-pyrazolo [3,4-d ] pyrimidine, 2-amino-6-chloropurine, 4-chloropyrrolopyrimidine, 6-chloropurine, 4-amino-5-cyano-6-chloropyrimidine and 2, 6-dichloropurine, respectively, to give the final product.
CLJ-39,1H NMR(400MHz,Chloroform-d)δ8.97(s,1H),8.18(s,1H),7.51–7.46(m,2H),7.30(t,J＝7.9Hz,2H),7.12–7.07(m,1H),5.73(s,2H),4.94(dd,J＝7.8,5.0Hz,1H),4.79(td,J＝6.7,4.7Hz,1H),2.54(dt,J＝12.5,6.2Hz,1H),2.24(dt,J＝12.2,7.3Hz,1H),2.14–2.07(m,1H),1.97(ddd,J＝12.0,7.0,4.7Hz,1H),1.46(d,J＝6.3Hz,3H).ESI-MS m/z:322.2[M+H]+.
CLJ-40,1H NMR(400MHz,Chloroform-d)δ7.73–7.65(m,1H),7.64–7.55(m,2H),7.49(dt,J＝14.2,8.0Hz,2H),7.42–7.34(m,4H),7.25–7.14(m,1H),4.60(dt,J＝18.3,9.0Hz,2H),2.47–2.28(m,2H),2.24–2.12(m,2H),1.77(dt,J＝47.0,17.2Hz,6H),1.40–1.34(m,1H).ESI-MS m/z:597[M+H]+.
CLJ-41，1H NMR(400MHz,Chloroform-d)δ11.97(s,1H),8.16(d,J＝2.4Hz,1H),7.86(d,
J＝7.2Hz,1H),7.62(dt,J＝28.1,8.2Hz,1H),7.49–7.34(m,4H),7.23–7.16(m,1H),7.06(d,J＝3.5Hz,1H),6.47(d,J＝3.6Hz,1H),4.71–4.60(m,1H),4.36(q,J＝7.9Hz,1H),2.44–2.26(m,4H),2.00–1.69(m,4H),1.67–1.56(m,1H),1.47–1.30(m,2H).ESI-MS m/z:581[M+
H]+.
CLJ-42，1H NMR(400MHz,Chloroform-d)δ8.21(s,1H),7.92(s,1H),7.80(d,J＝8.2Hz,
1H),7.61(dt,J＝16.7,8.2Hz,1H),7.52–7.33(m,5H),7.20(d,J＝17.9Hz,1H),5.02(dt,J＝
11.6,6.3Hz,1H),4.72–4.59(m,1H),2.50(s,1H),2.46–2.36(m,1H),2.33–2.20(m,2H),1.96(dt,J＝12.5,6.7Hz,1H),1.77(ddd,J＝36.4,18.7,8.4Hz,5H),1.62–1.53(m,1H).ESI-MS m/z:582[M+H]+.
CLJ-43,1H NMR(400MHz,Chloroform-d)δ7.95(s,1H),7.63–7.48(m,4H),7.47–7.36(m,2H),7.22–7.12(m,1H),5.70(s,2H),4.65–4.48(m,2H),2.44–2.15(m,4H),1.92–1.52(m,6H),1.28(d,J＝9.0Hz,1H).ESI-MS m/z:582[M+H]+.
CLJ-44，1H NMR(400MHz,Chloroform-d)δ8.06–8.03(m,1H),7.88(d,J＝2.7Hz,1H),
7.71–7.64(m,1H),7.59(dd,J＝9.4,6.9Hz,1H),7.51(ddd,J＝8.5,7.5,1.2Hz,1H),7.45–7.36(m,4H),5.04–4.94(m,1H),4.59(ddd,J＝9.4,7.5,5.4Hz,1H),2.51–2.35(m,3H),2.33–2.27(m,1H),2.00–1.93(m,1H),1.77(dt,J＝34.5,17.7Hz,5H),1.57(d,J＝11.1Hz,1H).ESI-MS m/z:616.4[M+H]+.
The preparation of CLJ-45 to CLJ-91 was the same as in example 1, CLJ-45 to CLJ-49 substituting SM3 for m-fluoroaniline, CLJ-50 substituting SM3 for 2-amino-2-thiazoline, CLJ-51 for 4-aminotetrahydropyran, CLJ-52 to CLJ-56 substituting SM3 for m-aminopyridine, CLJ-57-CLJ-61 substituting SM3 for N-aminomorpholine, CLJ-62 to CLJ-66 substituting SM3 for 3, 5-difluoroaniline, CLJ-66 to CLJ-71 substituting SM2 for 2-amino-6-fluorobenzoic acid, SM3 for 3, 5-difluoroaniline, CLJ-72 to CLJ-76 substituting SM1 for commercially available (2S, 5S) -N-Boc-5-methylpyrrolidine-2-carboxylic acid, replacement of SM3 with m-fluoroaniline, replacement of SM1 with commercially available (2S, 5S) -N-Boc-5-methylpyrrolidine-2-carboxylic acid, replacement of SM3 with 3, 5-difluoroaniline, replacement of SM1 with commercially available (2S, 5S) -N-Boc-5-methylpyrrolidine-2-carboxylic acid by CLJ-82 to CLJ-86, replacement of SM3 with m-aminopyridine by CLJ-77 to CLJ-91, replacement of SM1 with commercially available (2S, 5S) -N-Boc-5-methylpyrrolidine-2-carboxylic acid by CLJ-91, replacement of SM3 with N-aminomorpholine to obtain the key intermediate, the intermediate and 2-amino-6-chloropurine, respectively, 4-chloropyrrolopyrimidine, 6-chloropurine, 4-amino-5-cyano-6-chloropyrimidine and 2, 4-diamino-6-chloro-5-cyanopyrimidine react to obtain a final product. The results are characterized as follows:
Pharmacodynamic test section
The following representative experiments (without limitation) were used to analyze the biological activity of the compounds of the present invention (1) to test the inhibitory activity of the compounds on four subtypes of pi3kα, β, γ, δ at the enzyme level
Experimental method
The kinase activity test methods used in this experiment were essentially identical, except that different concentrations were used to achieve the optimal detection range based on different kinases and corresponding different substrates.
PI3K inhibitory activity assay: 40mMTris,pH7.4, 10mMMgC12,0.1mg/ml BSA,1mM DTT,10 μMATP, PI3K kinase, kinase substrate; meanwhile, compounds to be screened with different concentrations are added to form a 50uL reaction system, the reaction is carried out for 40 minutes at 30 ℃, then ADP content in the system is detected by a luciferase method, after the reaction is carried out for 5 minutes, chemiluminescent signals are detected on an MD-SpectralMax M multifunctional enzyme-labeled instrument, and the intensity of the chemiluminescent signals is in direct proportion to the inhibition of enzyme activity. The detected chemiluminescent signal value is substituted into the following formula:
percent enzyme activity (%) = (0D dosing well-0D background)/(OD control well-OD background) ×100%
The drug concentration was diluted in a three-fold concentration gradient, and each concentration was measured in two duplicate wells. The IC50 values of each test compound were calculated using GRAPHPAD PRISM as nonlinear regression with drug concentrations as abscissa and the percentage of enzyme activity corresponding to each concentration as ordinate.
The results of some examples are shown in tables 1 and 2.
Table 1 inhibitory Activity of some of the Compounds against four isoforms of PI3K at different concentrations
"In" means that the inhibition ratio is greater than 50% at the set concentration, and "in" means that the inhibition ratio is less than 50% at the set concentration.
Table 2 IC50 values of some compounds for the four PI3K subtypes
Numbering device PI3Kδ PI3Kγ PI3Kα PI3Kβ Numbering device PI3Kδ PI3Kγ PI3Kα PI3Kβ
CLJ-1 --- ND ND ND CLJ-60 +++ +++ --- ---
CLJ-7 --- ND ND ND CLJ-61 +++ - --- ---
CLJ-10 --- ND ND ND CLJ-65 +++ - --- ---
CLJ-12 ++ -- -- -- CLJ-70 +++ - --- ---
CLJ-16 +++ -- -- --- CLJ-74 +++ - --- -
CLJ-25 +++ + -- -- CLJ-75 +++ - --- ---
CLJ-30 +++ ND ND ND CLJ-76 +++ +++ - -
CLJ-34 +++ -- ND ND CLJ-80 +++ +++ --- ---
CLJ-35 +++ +++ ND ND CLJ-81 ++ ++ -- ---
CLJ-38 +++ - -- -- CLJ-85 +++ -- -- ---
CLJ-48 +++ - --- --- CLJ-86 +++ ++ --- ---
CLJ-49 +++ - --- --- CLJ-90 +++ - -- --
CLJ-55 +++ - --- --- CLJJ-91 +++ +++ -- --
CLJ-56 +++ - --- ---
"+++" Means IC50 in the range of 0-50nM, "++" means that the IC50 is in the range of 50-100nM, "+" means that the IC50 is in the range of 100-200nM, "-" means that the IC50 is in the range of 200-500nM, "-" means that the IC50 is in the range of 500-1000nM, "-" means that the IC50 is > 1000nM.
The results show that the tested compound has better inhibition activity on PI 3K.
(2) Detecting proliferation inhibitory activity of compounds on tumor and inflammation-associated cells
Experimental method
Cells in the logarithmic growth phase (including but not limited to cell lines OCI-AML2, daudi, raji, jurkat) were seeded in a number of 96-well plates (200 uL/well), cultured for 24 hours to allow adherence, and then dosed. 3 compound holes are arranged on each drug concentration, and corresponding zeroing holes and blank control are arranged. After 72 hours of drug action, adherent cells were added with 50% TCA (50 uL/well), fixed at 4℃for 1 hour, the fixed liquid was poured off, washed 5 times with distilled water, and dried naturally. mu.L of 4mg/mL SRB was added to each well, stained at room temperature for 15 minutes, discarded, washed with 1% glacial acetic acid 5 times, and dried naturally. Finally 150uL of 10mM Tris solution was added to each well, shaken well and the 0D value was determined with a microplate reader (VERSAmaxTM, molecular Device) of adjustable wavelength at 565 nm. Results statistical analysis gave inhibition or IC50 values, results are shown in table 3.
The experimental results are as follows:
Table 3 results of in vitro cell experiments on some of the compounds
The symbol "represents IC 50. Ltoreq.10. Mu.M; the symbol "represents an IC50 range of 10-20. Mu.M; the symbol "corresponds to an IC50 of 20-50. Mu.M; "" in the subject means IC 50.gtoreq.50. Mu.M.
The results show that the tested compounds have better inhibitory activity on cell proliferation of OCI-AML2 and Daudi, jurKat, raji, wherein certain compounds have better antiproliferative activity than CAL-101 and IPI-145, and are novel, potential and potential inhibitors for treating PI3K related diseases.

Claims (6)

1. A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized by the following structural formula:
2. A compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized by the following structural formula:
3. a pharmaceutical composition comprising the compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof as an active ingredient, and a pharmaceutically acceptable auxiliary ingredient.
4. Use of a compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a PI3K inhibitor.
5. Use according to claim 4, characterized in that: the PI3K inhibitor is a PI3K delta inhibitor, a PI3K gamma inhibitor, a PI3K alpha inhibitor, or a PI3K beta inhibitor.
6. Use of a compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the manufacture of a medicament for the prevention and/or treatment of a PI 3K-related disease; the disease related to PI3K is tumor; the tumor is leukemia, hodgkin's lymphoma or non-Hodgkin's lymphoma.
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