CN113214247A - Azaindole derivative marrow cell proliferation inhibitor, preparation method and application thereof in pharmacy - Google Patents

Azaindole derivative marrow cell proliferation inhibitor, preparation method and application thereof in pharmacy Download PDF

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CN113214247A
CN113214247A CN202110048904.1A CN202110048904A CN113214247A CN 113214247 A CN113214247 A CN 113214247A CN 202110048904 A CN202110048904 A CN 202110048904A CN 113214247 A CN113214247 A CN 113214247A
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azaindole
pyridin
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周亚明
凌云
杨永泰
贾瑜
刘小锋
陈珍霞
邓名莉
杨成斌
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Fudan University
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Abstract

The present invention provides azaindole derivatives of formula (I) wherein R is1,R2,R33All have the meanings defined in the description of the invention. The compound of the formula I can remarkably inhibitMarrow cell proliferation and related diseases represented by MOLM-16, HL-60, and MV-4-11 can be prepared. The formula I or the salt thereof or the related medicine composition provided by the invention has excellent in-vivo and in-vitro inhibitory activity, good drug property, high bioavailability and no obvious damage to visceral organs. Therefore, the formula I or the salt thereof and the related medicine composition have great clinical application prospect.

Description

Azaindole derivative marrow cell proliferation inhibitor, preparation method and application thereof in pharmacy
Technical Field
The invention relates to the technical field of chemical drugs, in particular to an azaindole derivative inhibitor applied to marrow cell proliferation and related diseases, a preparation method thereof and application thereof in pharmacy.
Background
The myeloid cells are produced from myeloid progenitor cells, and typically include: granulocytes, monocytes, macrophages, myeloid dendritic cells, etc., which together constitute an important branch of the immune system. Studies have shown that myeloid cells are key to the regulation of cancer cell-related activities, including: immunity escapes and affects the treatment of almost all types of cancer. Therefore, the development of relevant inhibitors around myeloid cell proliferation would be useful in overcoming the limitations of current Cancer therapies (Nature reviews Cancer,2016,16, 447-462). Calistoga developed a candidate drug CAL-101(Idelalisib) around the targeted PI3K kinase, and studies showed that: CAL-101 can inhibit proliferation of acute myeloid cells without affecting normal hematopoietic cells, and exhibits good in vitro and in vivo therapeutic effects against acute leukemia (Kong D et al, J Acta Pharmacolsin, 2010,31 (9): 1189-1197). This drug was purchased by gillide corporation and marketed in 2014 under the trade name: zyderig, has wider value in treating hematologic malignancies. This work motivated an alternative research approach to the development of related myeloid inhibitors from PIM kinases. PIM kinases belong to the group of calmodulin kinases and are considered as important targets for the treatment of human lymphomas and myeloid cell tumors (Amson R., PNAS,1989, 86: 8857-8861). Although there is a phenomenon in which the expression level of PIM kinase is significantly upregulated in myeloid cell proliferation and is directly involved in STAT3/5 activation, a variety of cancers downstream of the action, clinical studies on myeloid tumor inhibitors surrounding PIM kinase have been slow. The clinical outcome of CAL-101 undoubtedly points to another avenue worth exploring the development of inhibitors of myeloid neoplasms.
Azaindoles are isosteres of indoles and have good biological activity, and the development of related derivatives is receiving wide attention in the medical field. Such as: the natural alkaloid Variolin B has a strong inhibitory effect on myeloid leukemia (Anderson R.J., et al, Tetrahedron Letters,2001,42,8697-8699), and contains a 7-azaindole structure. Chinese patent CN200980131983.X discloses an azaindole inhibitor of IAP kinase, which is characterized in that the azaindole inhibitor acts on IAP kinase, and the compound is derivatized and functionalized around the 2-position of azaindole; chinese patents CN201280007145.3 and CN201610048667.8 disclose a 7-azaindole derivative which mainly has the inhibiting effect on PDK1 and cell proliferation/cell activity; chinese patent CN201580007276.5 discloses a derivative with selective JAK3 inhibition and excellent oral absorbability and with the function modification at the 4-position of 7-azaindole; chinese patent CN201580058210.9 discloses a 4-azaindole derivative having AMPK activation; chinese patent CN201780019641.3 discloses a halogenated allylamine indole and azaindole derivative inhibitor for inhibiting lysyl oxidase; chinese patent CN201910797733.5 discloses a 3-amide azaindole compound as a mast cell regulator; chinese patent CN201880017923.4 discloses a 7-azaindole inhibitor with an inhibiting effect on HPK1, which is characterized in that the inhibitor is a five-membered ring substituted or non-heterocyclic functional derivative; chinese patent CN201880050882.9 discloses an azaindole inhibitor of histone methyltransferase G9a and/or GLP, the molecular structure of which is characterized in that the azaindole inhibitor is a heterocyclic azaindole compound derivative; chinese patent CN201910107786.X discloses an agonist with high selectivity, high affinity and high activity on cannabinoid 2-type receptor (CB2), which is azaindole functionally modified by amantadine; chinese patent CN202010265070.5 discloses an azaindole compound capable of effectively inhibiting SMAD 3-phosphorylation, which is characterized in that the azaindole five-membered ring is a functionally modified derivative; chinese patent CN201380043657.X discloses a 4-azaindole derivative for treating immune diseases and cardiovascular diseases and a pharmaceutical composition thereof. However, azaindole-related derivatives disclosed in the prior art are not applicable for the treatment of myeloid cells and related diseases.
Disclosure of Invention
The invention aims to provide 5- (substituted six-membered azaheterocyclyl) -azaindole derivatives and related compounds and pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide pharmaceutical combinations of the azaindole derivatives or pharmaceutically acceptable salts thereof, and to provide their effects of inhibiting proliferation of myeloid cells including MOLM-16, HL-60 or MV-4-11, and their therapeutic use in mammals.
It is also an object of the present invention to provide a process for the preparation of said azaindole derivatives.
In order to achieve the purpose, the 5- (substituted hexa-nitrogen heterocyclic group) -azaindole derivative and related compounds provided by the invention have the structures shown in formula I:
Figure BDA0002898256410000021
it should be noted that formula I shall include stereoisomers, tautomers or cis-trans isomers resulting from the change in substitution.
The invention provides an azaindole compound with a general formula I, wherein one of key factors of substituent combination is as follows:
R1is H, -CH (OH) CH2OH、C1-4Alkyl, (C)1-4Alkyl) OH, isopropyl, cyclopropyl, phenyl or pyridyl;
R2is H, C1-6Alkyl radical, C1-6Branched alkyl, -CH2＝CRaRb、R21-phenyl, R22-pyridyl, methylpyrazole, piperidine, pyrrole, morpholine, pyrimidine orPyridazine;
R33in particular to one of the structures shown in the following formula:
Figure BDA0002898256410000022
R3is H, F, Cl, ORa、NRaRcOr CHRaR31；
R4Is H, Cl OR ORa；
RaIs H or C1-4An alkyl group;
Rbis H, C1-4Alkyl, cyclopropyl or cyclohexyl;
Rcis H, C1-4Alkyl radical, C1-4Alkylsulfonyl radical, R21-phenylsulfonyl or R22-a pyridine sulfonyl group;
R21is H, F, Cl, 2, 4-difluoro, 3, 5-difluoro, 3-fluoro-4-amine, -CONH2Morpholine or piperidine;
R22h, F, Cl, 2-fluoro-5-chloro, 2-fluoro-4-amine, morpholine or piperidine;
R31is H, C1-4Alkyl or-NH-hetCycle.
The azaindole compound provided by the invention has the general formula I, and has excellent activity of inhibiting marrow cells when the substituent group has the following characteristics:
R1is H, -CH (OH) CH2OH, cyclopropyl or pyridyl;
R2is H, -CH2＝CRaRb、R21-phenyl, R22-pyridyl, methylpyrazole, pyrrole, morpholine or pyrimidine;
R3is H, F, NRaRcOr CHRaR31；
R4Is H, Cl, OCH3Or OCH2CH3。
The present invention provides azaindole derivatives as inhibitors of myeloid cell proliferation based onThe azaindole structure is derived from novel compounds different from the patents, which are characterized in that the 5-position of the azaindole is connected with a functionalized substituted six-membered heterocycle, and the azaindole structure is characterized in that the position of nitrogen in the six-membered heterocycle and R3/R4The substituent groups or the combination mode thereof are different from the previous reports.
Moreover, the azaindole derivatives provided by the invention are also obviously different from the application direction reported in the literature or the patents in the application field, and are used for the inhibition of the proliferation of myeloid cells represented mainly by MOLM-16, HL-60 or MV-4-11 or the treatment of inflammation, immune system diseases, liquid tumors and solid tumors related to the myeloid cells. More importantly, compared with the CAL-101(Idelalisib) of Gilidide, the azaindole derivative myelocyte proliferation inhibitor provided by the invention not only has obviously different structural general formulas, but also has obvious advantages in vitro and in vivo inhibitory activity.
The azaindole compound with the general formula I, -NH-hetCycle provided by the invention is specifically one of the following structural formulas.
Figure BDA0002898256410000031
In another aspect, the present invention provides azaindole compounds having the general formula I, R33The structural formula shown should satisfy R3≠R4。
In another aspect, the present invention provides azaindole compounds having the general formula I, R33The structural formula should satisfy the following condition that R33In R4Either Cl or-OCH3When then R is3＝NRaRcOr CHRaR31Wherein:
if R is3＝NRaRcThen R is2Is R21-phenyl, R22-pyridyl, methylpyrazole, pyrrole or morpholine;
if R is3＝NRaRcAnd R iscIs R21-benzenesulfonyl, then R22Is F, 2-fluoro-5-chloro, 2-fluoro-4-amineMorpholine or piperidine;
if R is3＝CHRaR31Then R is2is-CH2＝CRaRb、R21-phenyl, methylpyrazole, piperidine, pyrrole, morpholine, pyrimidine or pyridazine.
The invention provides an azaindole compound with a formula I, which is characterized in that when the pyridyl or substituted pyridyl is connected with the formula I, the specific connection form is that N is one of ortho, meta and para:
Figure BDA0002898256410000032
the invention provides an azaindole compound with a formula I, which is characterized in that when R is2＝(R21-phenyl), (R)22-pyridyl), methylpyrazole, pyrimidine or pyridazine, the specific linkage is any one of the following formulae:
Figure BDA0002898256410000033
the invention provides an azaindole compound with a formula I, which is characterized in that R3Is H, F, Cl, (OR)a)、(NRaRc) Or (CHR)aR31) In any case, the inhibitory activity is preferably when R is4Either Cl or-OCH3When R is3＝(NRaRc) Or (CHR)aR31) Wherein: the molecular activity of sulfonamide or chiral structure is excellent.
The invention provides an azaindole compound with a formula I, which is characterized in that R3＝(NRaRc) When R isc＝R22-the pyridine sulfonyl group is attached in any of the following formulae:
Figure BDA0002898256410000034
the invention provides an azaindole compound with a formula I, which is characterized in that a substituent group R4Is H, Cl OR ORaOne of them, with Cl OR ORaWhen the inhibitory activity is significantly dependent on R1And R2Combinations of (a) and (b).
It should be noted that the azaindole compound of formula I provided by the present invention is not only significantly different from GSK2126458 and its related derivatives in structural formula (as shown in the following formula, Knight, s. etc., ACS med. chem. lett.2010,1(1),39-43.), but also different from Amgen (as shown in the following formula, Nishimura, n. etc., j.med. chem.2011,54(13),4735-4751.), and also different in application field.
Figure BDA0002898256410000041
Wherein: r1，R2The specific chemical meaning of the group is defined by the literature.
It should be noted that ACS Med. chem. Lett.2017,8,875-880 reported azaindole compounds with PI3K kinase inhibition, and the structure of IC50<3.0nM is shown below. The invention provides a general formula I, wherein the structure combination can contain three structures, but the invention does not relate to the claims of the three compounds. Moreover, the research work described above is directed to PI3K kinase, and the compounds provided by the present invention are also directed to inhibition of myeloid cell proliferation, and their application is also different.
Figure BDA0002898256410000042
The azaindole compound provided by the invention is different from a drug CAL-101 on the market in girlidide 2014, and the molecular formula of the azaindole compound is shown as follows:
Figure BDA0002898256410000043
in order to achieve the above object, the present invention provides a pilot production method for the azaindole derivative.
Scheme (a) shows the key steps for the preparation of formula I: dissolving equivalent amounts of formula II and formula III in a proper amount of organic solvent, adding a catalyst amount of noble metal catalyst, adding an organic ligand and alkali, heating and refluxing for 8-10 hours to perform a coupling reaction to obtain formula I with protecting groups, and then separating and purifying, removing one or more protecting groups, and separating and purifying to obtain the formula I.
Flow (a)
Figure BDA0002898256410000044
Scheme (b) shows the key steps for the preparation of formula I: dissolving equivalent amounts of the formula IV and the formula V in a proper amount of organic solvent, adding a catalyst amount of noble metal catalyst, matching with an organic ligand and alkali, heating and refluxing for 8-10 hours to perform a coupling reaction to obtain the formula I with protecting groups, and then separating and purifying, removing one or more protecting groups, and separating and purifying to obtain the formula I.
Flow (b)
Figure BDA0002898256410000051
The noble metal catalyst and the organic ligand are catalyst equivalent of a reaction substrate, preferably 0.02-0.1 equivalent, and the weight ratio of the catalyst to the organic ligand is 1: 0-1: 2.
The base is an inorganic base or an organic base, and includes: potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, ammonia or triethylamine, preferably potassium carbonate.
The organic solvent is one of 1, 4-dioxane, ethylene glycol dimethyl ether and tetrahydrofuran.
The noble metal catalyst is any one of palladium chloride, palladium acetate, [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, zero-valent palladium, rhodium chloride, rhodium acetate, palladium acetylacetonate, rhodium acetylacetonate, palladium carbon and rhodium carbon, and is preferably a palladium acetate complex or a zero-valent palladium complex. The organic ligand comprises: any one or combination of two of triphenylphosphine, triphenylphosphine oxide, (S) - (-) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, (R) - (+) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, if chiral structure of formula I is prepared, chiral organophosphine ligands are preferred.
It should be noted that scheme (a) or scheme (b) provided herein is a pilot production process for preparing formula I, which is limited to experimental amounts (milligram to gram). The starting materials for schemes (a) and (b) can be obtained by standard conventional organic synthesis methods, notably when R is3When the substituent contains a chiral structure (e.g. CHR)aR31) Chiral catalysis, separation or resolution can be used in the formula II or IV or in the raw material stage, or preparation-grade chiral column resolution can be adopted after the formula I is obtained by synthesis.
It is another object of the present invention to provide pharmaceutically acceptable salts of said azaindole derivatives. Salts of physiologically compatible organic and/or inorganic acids, selected from, but not limited to: acetic, oxalic, citric, salicylic, benzoic, maleic, lauric, malic, fumaric, succinic, tartaric, methanesulfonic, lactic, nicotinic, cinnamic, p-toluenesulfonic, benzenesulfonic, glutamic and mandelic, hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids with a pKa under standard conditions1<4.5, the biological compatibility is good and does not seriously affect the pharmacodynamic activity of the formula I; the salt may be a salt with an organic base and/or an inorganic base, and may be selected from readily soluble hydroxides of alkali metals and alkaline earth metals, triethylamine, L-arginine, L-lysine, sarcosine, serine, N-ethylpiperidine, dibenzylamine, and the like, and among them, an inorganic base is preferable.
It is to be noted that the above pharmaceutically acceptable salts can be prepared by various methods satisfying the pharmaceutical requirements, including: the formula I reacts with the appropriate acid or base to obtain the required salt, or the protecting group of the formula I precursor is removed under the corresponding acid or base condition to obtain the formula I which is directly salified.
It is noted that formula I or the above pharmaceutically acceptable salts, when used in pharmaceutical formulations, may exist in amorphous or crystalline form.
When used in pharmaceutical preparations, the pharmaceutically acceptable salt of formula I or formula I may be present in the form of solvent-containing molecules or solvent-free molecules. If the solvent molecules are contained, the solvent molecules and the content of the solvent molecules must meet the biological or pharmaceutical related safety regulations.
It is another object of the present invention to provide the azaindole derivatives or pharmaceutically acceptable salt forms in dosage forms including solid, semi-solid or liquid forms. Such as: tablet, chewable agent, dispersant, spray, mixing agent, syrup, etc. Fillers useful in the formulation include: gelatin, hydroxypropylmethyl cellulose, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, an antioxidant, starch, sucrose, mannitol, dibasic calcium phosphate dihydrate, or the like. The Active Pharmaceutical Ingredient (API) can account for 0.1-88% of the dosage form by mass, and the preferred dosage form API accounts for 1-20% by mass.
It is noted that solid, semi-solid or liquid formulations may contain surfactants, lubricants, binders or disintegrants which meet pharmacopoeial requirements.
It is another object of the present invention to provide the effect of said azaindole derivatives or pharmaceutically acceptable salts on inhibition of myeloid cell proliferation at the cellular level in vitro.
Typically any of HL-60, MOLM-16 or MV-4-11 myeloid cells. After the cells are recovered, inoculating the cells into a prepared culture medium, placing the cells in an incubator, carrying out subculture and liquid change once every 2 to 3 days, and taking the cells in a logarithmic growth cycle for activity evaluation. The proliferation inhibitory effect of formula I or salts on the cells was measured using CCK8 or MTT method and co-incubation was performed according to standard cell experimental procedures. 0.1% DMSO solvent was used as a negative control, and CAL-101 was used as a positive control. Cells were treated for 48h under standard culture conditions. Calculation of the inhibition of cell proliferation IC50 by GraphPad Prism software analysis, four parameter fit inhibition survival curves, showed that the compounds of formula I had IC50 values of less than 100nM and had myeloid selective inhibition (as in figure 2), superior to the positive CAL-101 control (>100 nM).
Morphological observation of cell survival. Relevant marrow cells are treated for 24h by using different concentrations of the formula I or salts thereof, DMSO is used as a negative control, and the morphology of plasma membranes of cells and cell nuclei is recorded by photographing and observing through a confocal microscope, so that the cells have morphological characteristics of early apoptosis and cell damage along with the increase of the treatment concentration (see figure 3). Detecting apoptotic cells with formula I or salt effect and influence on cell cycle by adopting flow cytometry instrument annexin V-FITC + PI staining method (cell number detected by flow cytometry is 3 multiplied by 10)4And (b) the relevant myeloid cells treated with formula I or its salt showed concentration-dependent early and late withering phenomena compared to the untreated control, with the total amount of early and late withering being 4-20 times that of the control, indicating that formula I has significant concentration-dependent in vitro drug activity.
And (5) detecting cell cycle distribution. Cell seeding density 1X 105Treating the cells for 24h, fixing the cells by 70% of glacial ethanol, dyeing the PI nucleic acid dye at room temperature in a dark place for 15min, detecting by a flow cytometer, and detecting the number of the cells to be 3 multiplied by 104In addition, the Modifit TL software carries out cell cycle fitting to respectively count the distribution percentages of the G0/G1, S and G2/M phases of cells. With increasing concentrations of formula I treatment, cell division progression is inhibited and cell cycle G1, G2 arrest is induced, respectively. And (3) detecting the expression of the related protein of the formula I or the salt thereof after the formula I or the salt thereof acts on the cells by a Western-blot method. The detection result shows that the protein level is obviously reduced and even superior to that of CAL101 in a control group, which shows that the activation of corresponding key protein is inhibited and controlled and has a concentration dependence trend and a good target inhibition effect.
It is another object of the present invention to provide the therapeutic effect and related basic pharmaceutical evaluation of said azaindole derivatives or pharmaceutically acceptable salts or pharmaceutical combinations thereof on the vaccination of mammals against myeloid cell tumors.
Orally, the formula I or the salt thereof is suspended in 0.1 percent PEG-400/0.5 percent cmcNA solution, the administration dose is 20mg/kg of positive group (CAL-101), the experimental group is 20mg/kg and 40mg/kg respectively, the administration is carried out once a day, the administration is continuously carried out for 14 days, the weight and the subcutaneous tumor size are recorded once 2 to 3 days, the state is observed and recorded, and the tumor is removed after 14 days of sacrifice. The tumor picture and the tumor mass can be intuitively seen that the tumor mass of the experimental group is obviously smaller than that of the control group, which shows that the formula I or the salt thereof has good effect of inhibiting tumor proliferation. The organ tissue section shows that the related organ tissues have no obvious phenomena such as necrosis, mutation and the like, and shows that the formula I or the salt thereof has good biological safety. The drug metabolism research shows that the oral availability of the drug combination of the formula I or the salt thereof is 15-30%.
The transcriptome of the mammal with the action of the formula I or the salt or the medicine combination thereof proves the inhibition effect of the related medicine signal pathway, has no influence on other pathways, and shows that the mammal has good targeting property of the marrow cells.
The present invention also provides the use of formula I or a salt thereof or a corresponding pharmaceutical combination thereof as indicated above for the treatment of said myeloid cell proliferation or a related clinical disease comprising: immune system diseases, liquid tumors, solid tumors, or cancerous diseases that result in beneficial therapeutic effects, such as: myeloid leukemia, multiple myeloma, autoimmune diseases, and metastasis-associated cancers of the lung, pancreas, bladder, prostate, breast, glioma, stomach, and esophagus.
The corresponding pharmaceutical combination, for example, formula I or a salt thereof, may be combined with one or more clinically used cytotoxic agents, such as: alkylating agents, plant-derived agents and topoisomerase inhibitors, molecular targeted inhibitors, immunological agents.
Representative alkylating agents include: platinum compounds (carboplatin, cisplatin, olsalazine), atypical alkylating agents (dacarbazine).
Representative plant-derived preparations include: vincristine, vindesine, vinzolidine, paclitaxel, docetaxel, otaxel, testasite.
Representative topoisomerase inhibitors include: camptothecin, including irinotecan, topotecan.
Representative molecularly targeted inhibitors include: granulocyte colony factor inhibitor filgrastim, granulocyte macrophage inhibitor sargrastim, colony stimulating factor 1 receptor (CSF1R) inhibitor pexidartinib, broad-spectrum anticancer drug cabozantinib, other specific molecular targeting drugs such as imatinib, dasatinib, gefitinib, trastuzumab, cetuximab, agents inducing apoptosis such as bortezomib, agents blocking angiogenesis such as bevacizumab, solifenanib, monoclonal antibodies delivering toxic molecules to cancer cells such as tositumomab, tiitumomab, trastuzumab ozogamicin.
The azaindole derivative marrow cell proliferation inhibitor provided by the invention has the beneficial effects or has the main advantages compared with the existing clinical test inhibitor:
(1) the azaindole derivative provided by the invention is R1、R2、R33A functional modified 7-azaindole, and the 5-position is connected with R3、R4The substituted six-membered heterocyclic derivative has the meaning and combination mode defined by the invention, and the general formula is different from the published Chinese patent of azaindole compounds.
(2) The azaindole derivative or the salt thereof or the possible medicine combination thereof provided by the invention has obvious inhibition on proliferation of myeloid cells represented by HL-60, MOLM-16 and MV-4-11, and the intrinsic mechanism and the cellular object are different from the mechanism or the cells of IAP, PDK1, JAK3, AMPK, SMAD-3, histone methyltransferase and cannabinoid 2 type receptor related to the azaindole patent.
(3) The azaindole derivative or the salt or the possible medicine combination thereof provided by the invention has the inhibiting activity obviously superior to that of CAL-101 (trade name: Zydeig), shows good treatment effect, bioavailability and basic biological safety at the level of mammals, has huge clinical research value, and has obvious advantages in the aspects of marrow cell proliferation and related cancer treatment.
Drawings
FIG. 1 is a general formula of the molecular structure diagram of formula I.
FIG. 2 is a graph of the inhibition of cell proliferation by the action of formula I.
FIG. 3 is a myeloid cell morphology of the effect of formula I.
FIG. 4 protein level expression of the effect of formula I.
FIG. 5 is a graph showing the tumor suppressive effect of formula I on mammals.
FIG. 6 is a section of a mammal having the formula I as a post-treatment organ.
Detailed Description
The following examples, which are intended to be illustrative and not limiting, represent specific embodiments of the invention and are not intended to be exhaustive of formula I or a salt thereof in the present specification, but are presented to assist in a clearer understanding of the technical disclosure of the invention.
The specific molecular structures of the compounds of formula I were synthesized according to schemes (a) or (b) described in the present specification, and in order to more clearly show the inventive content, the following are presented as methods for the preparation of two key reactant fragments (M, N). It is to be noted that the fragments M or N presented below are only representative in the description of the present invention, and not all M or N.
Preparation of M1: 3-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
Figure BDA0002898256410000071
N2Under protection, 1, 4-dioxane (10mL), 3-fluoro-5-bromopyridine (0.31g,1.75mmol), pinacol ester bisboronic acid (0.67g,2.63mmol), anhydrous sodium acetate (0.52g,5.25mmol), Pd (PPh) were sequentially added into a 50mL three-necked flask3)4(0.04g,0.035mmol), refluxed with stirring and followed by TLC until the starting material disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M1.
Preparation of M2: 3-hydroxypropyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
Figure BDA0002898256410000081
N2Under protection, 1, 4-dioxane (15mL), 3-fluoro-5-bromopyridine (0.37g,1.7mmol), pinacol ester of bisboronic acid (0.67g,2.63mmol), and anhydrous ethyl acetate were sequentially added into a 50mL three-necked flaskPotassium (0.58g,5.2mmol), Rh (PPh)3)4(0.04g,0.03mmol), refluxed with stirring, and followed by TLC until the starting material disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M2.
Preparation of M3: 3-fluoro-2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
Figure BDA0002898256410000082
N2Under protection, 1, 4-dioxane (10mL), 3-fluoro-2-methoxy-5-bromopyridine (0.31g,1.5 mmol), pinacol ester boronate doublet (0.67g,2.63mmol), anhydrous sodium acetate (0.43g,5.2mmol), Pd [ P (C) were added in sequence to a 50mL three-necked flask6H5)3]4(0.035g,0.03mmol), refluxing with stirring, and TLC follow-up until the starting material has disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M3.
Preparation of M4: 3-chloro-2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
Figure BDA0002898256410000083
N2Under protection, 1, 4-dioxane (15mL), 3-chloro-2-methoxy-5-bromopyridine (0.31g,1.5 mmol), pinacol ester boronate doublet (0.71g,2.65mmol), anhydrous sodium acetate (0.43g,5.2mmol), Rh [ P (C) in a 50mL three-necked flask were added in sequence6H5)3]4(0.042g,0.03mmol), refluxing with stirring, and TLC follow-up until the starting material disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M4.
Preparation of M5: n- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) pyridine-4-sulfonamide
Figure BDA0002898256410000084
Step 1.N2Under protection, pyridine sulfonyl chloride (0.27g,1.5mmol), 2-methoxy-3-amino-5-bromopyridine (0.25g,1.25mmol), potassium carbonate (0.69g,5mmol) and tetrahydrofuran (20mL) are sequentially added into a 100mL three-necked bottle, heating and refluxing are carried out under stirring, TCL (trichloromethyl pyrrolidone) tracks and reacts until a raw material point disappears, cooling is carried out to room temperature, silica gel column chromatography is carried out, and products are decompressed, evaporated and concentrated to obtain the nitrogen- (2-methoxy-5-bromopyridine-3-yl) pyridine-4-sulfonamide.
Step 2.N2Under protection, 1, 4-dioxane (15mL), N- (2-methoxy-5-bromopyridin-3-yl) pyridine-4-sulfonamide (0.52g,1.5mmol), pinacol ester bisboronic acid (0.71g,2.65mmol), anhydrous sodium acetate (0.45g,5.2 mmol), Pd [ P (C) in a 50mL three-necked flask were added in sequence6H5)3]4(0.042g,0.03mmol), refluxing with stirring, and TLC follow-up until the starting material disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M5.
Preparation of M6: n- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -4-fluoropyridine-3-sulfonamide
Figure BDA0002898256410000091
Step 1.N2Under protection, 4-fluoropyridine-3-sulfonyl chloride (0.29g,1.5mmol), 2-chloro-3-amino-5-bromopyridine (0.26g,1.25mmol), potassium carbonate (0.71g,5mmol) and tetrahydrofuran (20mL) are sequentially added into a 100mL three-necked flask, heated and refluxed under stirring, TCL (thermal conductive liquid chromatography) tracks reaction until a raw material point disappears, cooled to room temperature, passed through a silica gel column, and a product is subjected to reduced pressure rotary evaporation and concentration to obtain nitrogen- (2-chloro-5-bromopyridine-3-yl) -4-fluoropyridine-3-sulfonamide.
Step 2.N2Under protection, 1, 4-dioxane (10mL), N- (2-chloro-5-bromopyridin-3-yl) -4-fluoropyridine-3-sulfonamide (0.55g,1.5mmol), pinacol ester bis (boronate) (0.69g,2.65mmol), and anhydrous sodium acetate (0.46g,5.2 mmol) were sequentially added to a 50mL three-necked flaskmmol)，Pd[P(C6H5)3]4(0.038g,0.03mmol), refluxing with stirring, and TLC follow-up until the starting material disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M6.
Preparation of M7: n- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -N-propylmethanesulfonamide
Figure BDA0002898256410000092
Step 1.N2Under protection, methanesulfonyl chloride (0.17g,1.5mmol), 2-methoxy-3-amino-5-bromopyridine (0.27g,1.25mmol), potassium carbonate (0.71g,5mmol) and tetrahydrofuran (20mL) are sequentially added into a 100mL three-necked flask, heated and refluxed under stirring, TCL tracks reaction until a raw material point disappears, cooled to room temperature, passed through a silica gel column, and the product is subjected to reduced pressure rotary evaporation and concentration to obtain the nitrogen- (2-methoxy-5-bromopyridine-3-yl) methanesulfonamide.
Step 2.N2Acetonitrile (10mL), N- (2-methoxy-5-bromopyridin-3-yl) methanesulfonamide (0.42g,1.5mmol), bromopropane (0.185g,1.5mmol), potassium carbonate (0.71g,5mmol) were added sequentially in a 50mL three-necked flask with protection, refluxed with stirring, and TLC followed until the starting material disappeared. Cooling the reaction system to room temperature, purifying by a column, collecting, and concentrating in vacuum to obtain a solid product of N- (2-methoxy-5-bromopyridine-3-yl) -N-propyl methanesulfonate.
Step 3.N2Under protection, 1, 4-dioxane (10mL), N- (2-methoxy-5-bromopyridin-3-yl) -N-propylmethanesulfonate (0.49g,1.5mmol), pinacol bisboronic acid ester (0.69g,2.65mmol), anhydrous sodium acetate (0.46g,5.2 mmol), Rh [ P (C) in a 50mL three-necked flask were added in sequence6H5)3]4(0.038g,0.03mmol), refluxing with stirring, and TLC follow-up until the starting material disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M7.
Preparation of M8: n- (1- (3-methoxy-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) propyl) -9H-purin-6-amine
Figure BDA0002898256410000093
Step 1.N2Under protection, 6-bromo-2- (1-chloropropyl) -3-hydroxymethylpyridine (0.37g,1.5mmol), 2-methoxy-3-amino-5-bromopyridine with a protective group (0.47g,1.75mmol), potassium carbonate (0.71g,5mmol) and acetonitrile (20mL) are sequentially added into a 100mL three-necked flask, heated and refluxed under stirring, TCL tracks the reaction until the raw material point disappears, cooled to room temperature, passed through a silica gel column, and the product is subjected to reduced pressure rotary evaporation and concentration to obtain nitrogen- (1- (6-bromo-3-hydroxymethylpyridine-2-yl) propyl) -9H (protective group) -purin-6-amine.
Step 2.N2Under protection, 1, 4-dioxane (10mL), N- (1- (6-bromo-3-hydroxymethylpyridin-2-yl) propyl) -9H (protecting group) -purin-6-amine (0.75g,1.5mmol), pinacol ester bis (boronic acid) (0.69g,2.65mmol), anhydrous potassium acetate (0.58g,5.2mmol), Pt [ P (C) were added sequentially in a 50mL three-necked flask6H5)3]4(0.035g,0.03mmol), refluxing with stirring, and TLC follow-up until the starting material has disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M8.
Preparation of M9: 5-chloro-N- (1- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) ethyl) -2, 6-dimethylpyrimidin-4-amine
Figure BDA0002898256410000101
Step 1.N2Under protection, 5-bromo-2-chloro-3- (1-chloroethyl) pyridine (0.38g,1.5mmol), 5-chloro-2, 6-dimethylpyridine-4-amine (0.27g,1.75mmol), potassium carbonate (0.71g,5mmol) and acetonitrile (20mL) are sequentially added into a 100mL three-necked flask, heated and refluxed under stirring, TCL tracks the reaction until the raw material point disappears, cooled to room temperature, passed through a silica gel column, and the product is subjected to reduced pressure rotary evaporation and concentration to obtain nitrogen- (1- (5-bromo-2-chloropyridine-3-yl) ethyl) -5-chloro-2, 6-dimethylpyridine-4-amine.
Step 2.N2Under protection, 1, 4-dioxane (10mL), nitrogen- (1- (5-bromo-2-chloropyridin-3-yl) ethyl) -5-chloro-2, 6-dimethylpyridin-4-amine (0.58g,1.5mmol), pinacol bis-borate (0.69g,2.65mmol), anhydrous sodium acetate (0.58g,5.2mmol), tetrakis (S) - (-) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthylpalladium (0.055g,0.03mmol) were sequentially added to a 50mL three-necked flask, and refluxed with stirring and TLC was followed until the starting material disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M9.
Preparation of M10: 4- ((1- (3-ethoxy-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) ethyl) amine) -5-fluoropyrimidin-2 (1H) -one
Figure BDA0002898256410000102
Step 1.N2Under protection, 6-bromo-2- (1-chloroethyl) -3-ethoxypyridine (0.41g,1.5mmol), 4-amino-5-fluorouracil (0.23g,1.75mmol), sodium carbonate (0.65g,5mmol) and tetrahydrofuran (20mL) are sequentially added into a 100mL three-necked flask, heating and refluxing are carried out under stirring, TCL (thermal conductive liquid chromatography) tracks the reaction until the raw material point disappears, cooling to room temperature, passing through a silica gel column, and carrying out reduced pressure rotary evaporation and concentration on the product to obtain 4- ((1- (6-bromo-3-ethoxypyridine-2-yl) ethyl) amino) -5-fluorouracil.
Step 2.N2Under protection, 1, 4-dioxane (10mL), 4- ((1- (6-bromo-3-ethoxypyridin-2-yl) ethyl) amino) -5-fluorouracil (0.51g,1.5mmol), pinacol ester bis (boronate) (0.68g,2.65mmol), anhydrous sodium acetate (0.58g,5.2mmol), palladium tetrakistriphenylphosphine oxide (0.038g,0.03mmol) were sequentially added into a 50mL three-necked flask, and refluxed with stirring and TLC tracked until the starting material disappeared. The reaction system was cooled to room temperature, purified by column chromatography, collected, concentrated in vacuo to give the solid product, which was recrystallized to afford the title compound M10.
Preparation N1: 5-bromo-2-phenyl-1H-7-azaindoles
Figure BDA0002898256410000111
2, 3-diamino-5-bromopyridine (1.0g,5.3mmol), benzoic acid (0.65g,5.3mmol) and PPA (39.4g,116.6mmol) are sequentially added into a 100mL round-bottom flask, the reaction temperature is raised to 200 ℃, after stirring for 12 hours, the temperature is reduced to 80 ℃, water (40mL) is added for dilution, then ethyl acetate is used for extraction, the organic phase is dried by anhydrous sodium sulfate, filtration and vacuum concentration are carried out, and the precipitated solid is dried in vacuum to obtain the product 5-bromo-2-phenyl-1H-7-azaindole.
Preparation N2: 5-bromo-3-phenyl-1H-7-azaindoles
Figure BDA0002898256410000112
Step 1. in an ice-water bath, dry DMF (8mL), 5-bromo-3-iodo-1H-7-azaindole (1.0g, 3.1mmol) were added sequentially to a 25mL round-bottomed flask, then NaH (0.16g,6.18mmol, 60% mineral oil mixture) was added in portions, stirring was carried out for 10 minutes, 2- (trimethylsilyl) ethoxymethyl chloride (0.93mL,5.25mmol) was added dropwise, and after completion of the addition, stirring was carried out at room temperature for 1 hour. Water was added for trituration, extracted with ethyl acetate (3X 10mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the crude product purified on a silica gel column to give the product 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-7-azaindole.
Step 2. under the protection of N2, 1, 4-dioxane (3.0mL) and 5-bromo-3-iodo-1H-pyrrole [2,3-b ] are sequentially added into a 25mL three-necked bottle]Pyridine (70.8mg,0.22mmol), phenylboronic acid (27.1mg,0.22mmol), Pd (PPh)3)4(10.1mg,0.008mmol)、K2CO3(90.1mg, 0.66mmol), oil bath heating reflux reaction for 3H, cooling to room temperature, adding water (5mL) for dilution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filtering, vacuum concentration to remove solvent, purifying by a silica gel column after passing through to obtain a solid product, and finally removing a protecting group to obtain the 3-phenyl-5-bromo-1H-7-azaindole. If necessary for the subsequent reaction, the protecting group may not be removed here.
Preparation N3: 1- (5-bromo-3-phenyl-1H-7-azaindol-2-yl) -1, 2-propanediol
Figure BDA0002898256410000113
Step 1, 5-bromo-3-iodo-1H-7-azaindole (1.00g,3.1mmol), dichloromethane (20.00mL), triethylamine (0.930g,9.2mmol) and DMAP (0.040g,0.31mmol) are respectively added into a 50mL dry round-bottom flask, benzenesulfonyl chloride (0.66g,3.72mmol) is dropwise added under the condition of ice-water bath, stirring is carried out for 1 hour at room temperature after dropwise addition is finished, the reaction solution is washed for 3 times, saturated common salt is washed for 1 time, an organic phase is dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, and the crude product is pulped by n-hexane to obtain a white solid, namely 5-bromo-3-iodo-1- (benzenesulfonyl) -1H-7-azaindole (Yield, 86%).
Step 2. to a 50mL round bottom flask, under nitrogen, were added the compound 5-bromo-3-iodo-1- (benzenesulfonyl) -1H-7-azaindole (1.000g,2.16mmol), phenylboronic acid (0.268g,2.20mmol), anhydrous potassium carbonate (0.900g,6.60mmol), water (5.00mL), 1, 4-dioxane (25.00mL) and catalyst PdCl, respectively2(dppf) (0.06g,8.8 × 10-2mmol), followed by reaction at 40 ℃ for 24 hours, cooling to room temperature, diluting with water, neutralizing with 6M hydrochloric acid to pH 5-6, extracting with dichloromethane (25mL × 2), washing the organic phase with water, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the target product 5-bromo-3-phenyl-1- (phenylsulfonyl) -1H-7-azaindole (Yield, 70%).
Step 3.N2Under protection, a 25mL three-necked flask is respectively added with a compound 5-bromo-3-phenyl-1- (bensulfonyl) -1H-7-azaindole (0.50g, 1.21mmol), TMEDA (0.147g, 1.27mmol) and anhydrous THF10mL, fully cooled to-40 ℃, dropwise added with a THF solution of LDA (2M, 1.20mL, 2.40mmol), kept at the temperature and stirred for 30min, added with I2(0.60g, 2.37mmol), continuously reacted for 3H, followed by a liquid phase, stopped reacting after the raw materials disappear, and added with water for destruction. Adding 15mLCH2Cl2 into the reaction system, washing with Na2S2O4 solution, diluted hydrochloric acid, water and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the target product 5-bromo-2-iodo-3-phenyl-1- (benzenesulfonyl) -1H-7-azaindole (Yield: 74%).
Step 4. under the protection of nitrogen, respectively adding a compound 5-bromo-2-iodo-3-phenyl-1- (benzenesulfonyl) -1H-7-azaindole (0.40g,0.74mmol), a vinyl boronic acid pinacol ester (0.135g,0.88mmol), potassium acetate (0.181g,1.85mmol), 1, 4-dioxane (10.00mL) and a catalyst PdCl2(dppf) (29.3mg,0.04mmol) into a 25mL round-bottomed flask, reacting at 50 ℃ for 12 hours, cooling to room temperature, diluting the reaction liquid with ethyl acetate, respectively washing with saturated saline, organically drying and concentrating, purifying by column chromatography to obtain a target product 5-bromo-2-vinyl-3-phenyl-1- (benzenesulfonyl) -1H-7-azaindole (Yield, 57%).
Step 5.10mL round-bottomed flask was charged with compound 5-bromo-2-vinyl-3-phenyl-1- (phenylsulfonyl) -1H-7-azaindole (0.120g, 0.27mmol), 2.0mL acetone, ice-water cooled to 0 deg.C and then K was slowly added dropwise2MnO4(28.4mg, 0.18mmol) and MgSO4(10.8mg, 0.09mmol) of a mixed aqueous solution (4.0mL), stirring for 30min, raising to room temperature, adding a trace amount of hydroquinone (2.0mg, 0.027mmol) to the reaction mixture, filtering, adding 0.5mL of 6M NaOH solution to the filtrate, concentrating to dryness at 60 deg.C, allowing a small amount of residual water to be taken up with ethanol, and purifying the residue directly by column Chromatography (CH)2Cl2MeOH) to obtain the target product 1- (5-bromo-3-phenyl-1H-7-azaindol-2-yl) -1, 2-propanediol (yield: 35%)
Preparation N4: 5-bromo-2-cyclopropane-3- (pyridin-4-yl) -1H-7-azaindole
Figure BDA0002898256410000121
Step 1. in an ice-water bath, dry DMAC (8mL) and 5-bromo-2-cyclopropyl-3-iodo-1H-7-azaindole (1.5g,3mmol) were sequentially added to a 25mL round-bottomed flask, then NaH (0.18g,6.18mmol, 60% mineral oil mixture) was added in portions, and after stirring for 10 minutes, 2- (trimethylsilyl) ethoxymethyl chloride (0.95mL,5.25mmol) was added dropwise, and after the addition was complete, stirring was carried out at room temperature for 1 hour. Water was added for trituration, ethyl acetate was extracted (3X 10mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the crude product was purified on a silica gel column to give the product 5-bromo-2-cyclopropyl-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-7-azaindole.
Step 2.N2Under protection, 1, 4-dioxane (5.0mL) and 5-bromo-2-cyclopropyl-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] ethanol were sequentially added into a 25mL three-necked flask]Methyl } -1H-7-azaindole (75.1mg,0.22mmol), pyridine boronic acid (27.3mg,0.22mmol), Pd (PPh)3)4 (10.6mg,0.008mmol)、K2CO3(90.3mg,0.66mmol), oil bath heating reflux reaction for 3H, cooling to room temperature, adding water (5mL) for dilution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filtering, vacuum concentration to remove solvent, purifying by a silica gel column after passing through to obtain a solid product, and removing a protecting group to obtain the 3-phenyl-5-bromine-2-cyclopropyl-1H-7-azaindole. If desired for subsequent reactions, the protecting group may not be removed.
Preparation N5: 5-bromo-3- (2-fluoropyridin-4-yl) -1H-7-azaindole
Figure BDA0002898256410000122
Step 1. in an ice-water bath, dry DMAC (8mL) and 5-bromo-3-iodo-1H-7-azaindole (1.1 g,3mmol) were sequentially added to a 25mL round-bottomed flask, followed by addition of NaH (0.18g,6.18mmol, 60% mineral oil mixture) in portions, stirring for 10 minutes, then 2- (trimethylsilyl) ethoxymethyl chloride (0.91mL,5.25mmol) was added dropwise, and after the addition was complete, stirring was carried out at room temperature for 1 hour. Water was added for trituration, extracted with ethyl acetate (3X 10mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the crude product purified on a silica gel column to give the product 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-7-azaindole.
Step 2.N2Under protection, 1, 4-dioxane (10mL) and 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] are sequentially added into a 50mL three-necked flask]Methyl } -1H-7-azaindole (70.2mg,0.22mmol), 2-fluoropyridine-4-boronic acid (27.5mg,0.22mmol), Pd (PPh)3)4 (10.1mg,0.008mmol)、K2CO3(90.5mg,0.66mmol), oil bath heating reflux reaction for 3h, cooling to room temperature, adding water (5mL) for dilution, dichloromethane extracting, organic phase anhydrous sodium sulfate drying, filtering, vacuum concentrating to remove solvent, passing through silica gel column for purification to obtain solidAnd removing the protecting group of the product to obtain the 3- (2-fluoropyridine-4-yl) -5-bromo-1H-7-azaindole. If necessary for the subsequent reaction, the protecting group may not be removed
Preparation N6: 5-bromo-3- (1-methyl-1H-pyrazol-4-yl) -1H-7-azaindole
Figure BDA0002898256410000131
Step 1. in an ice-water bath, dry DMF (8mL), 5-bromo-3-iodo-1H-7-azaindole (1.2g, 3mmol) were added sequentially to a 25mL round-bottomed flask, then NaH (0.12g,6.18mmol, 60% mineral oil mixture) was added in portions, stirring was carried out for 10 minutes, 2- (trimethylsilyl) ethoxymethyl chloride (0.92mL,5.25mmol) was added dropwise, and after completion of the addition, stirring was carried out at room temperature for 1 hour. Water was added for trituration, extracted with ethyl acetate (3X 10mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the crude product purified on a silica gel column to give the product 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-7-azaindole.
Step 2.100mL three-necked flask was charged with 1, 4-dioxane (20mL), 4-bromo-1-methyl-1H-pyrazole (0.33g,2mmol), pinacol ester bisboronic acid (0.78g,3mmol), anhydrous sodium acetate (0.58g,5.2mmol), Pt [ P (C) P6H5)3]4(0.036g,0.03mmol), refluxing under stirring, purifying by a silica gel column after passing through to obtain a solid product, and hydrolyzing and recrystallizing the product to obtain the 4-boric acid-1-methyl-1H-pyrazole.
Step 3.N2Under protection, 1, 4-dioxane (10mL) and 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] are sequentially added into a 50mL three-necked flask]Methyl } -1H-7-azaindole (70.1mg,0.22mmol), 4-boronic acid-1-methyl-1H-pyrazole (27.3mg,0.22mmol), Pd (PPh)3)4(10.1mg,0.008mmol)、K2CO3(90.5mg,0.66mmol), oil bath heating reflux reaction for 3H, cooling to room temperature, adding water (5mL) for dilution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filtering, vacuum concentration to remove solvent, purifying by a silica gel column after passing through to obtain a solid product, and then removing a protecting group to obtain 5-bromo-3- (1-methyl-1H-pyrazol-4-yl) -1H-7-azaindole. If the subsequent reaction is carried outIf desired, the protecting group may not be removed.
Preparation N7: 5-bromo-3- (pyrazin-4-yl) -1H-7-azaindole
Figure BDA0002898256410000132
Step 1. in an ice-water bath, dry DMAC (10mL) and 5-bromo-3-iodo-1H-7-azaindole (1.1 g,3mmol) were sequentially added to a 50mL round-bottomed flask, followed by addition of NaH (0.15g,6.18mmol, 60% mineral oil mixture) in portions, stirring for 10 minutes, then 2- (trimethylsilyl) ethoxymethyl chloride (0.95mL,5.25mmol) was added dropwise, and after the addition was complete, stirring was carried out at room temperature for 1 hour. Water was added for trituration, extracted with ethyl acetate (3X 10mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the crude product purified on a silica gel column to give the product 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-7-azaindole.
Step 2.N2Under protection, 1, 4-dioxane (10mL) and 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] are sequentially added into a 50mL three-necked flask]Methyl } -1H-7-azaindole (70.5mg,0.22mmol), 4-boronic acid pyrazine (28.5mg,0.22mmol), Pd (PPh)3)4(10.1mg, 0.008mmol)、K2CO3(90.8mg,0.66mmol), oil bath heating reflux reaction for 3H, cooling to room temperature, adding water (5mL) for dilution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filtering, vacuum concentration to remove solvent, purifying by a silica gel column after passing through to obtain a solid product, and then removing a protecting group to obtain 5-bromo-3- (pyrazine-4-yl) -1H-7-azaindole. If desired for subsequent reactions, the protecting group may not be removed.
Preparation N8: 4- (5- (5-bromo-1H-7-azaindol-3-yl) pyridin-2-yl) morpholine
Figure BDA0002898256410000141
Step 1.50mL round-bottom flask was sequentially charged with dry acetonitrile (10mL), 2-amino-3-bromopyridine (0.34g,2mmol), 1-bromo-2- (2-bromoethoxy) ethane (0.58g,2.5mmol), potassium carbonate (1.01g,6.6mmol), heated under nitrogen at reflux, followed by thin layer chromatography until the starting material point disappeared, rotary evaporation, and purification by column chromatography to give 4- (5-bromopyridin-2-yl) morpholine.
Step 2.100mL three-necked flask was charged with 1, 4-dioxane (20mL), 4- (5-bromopyridin-2-yl) morpholine (0.36g,1.5mmol), pinacol bisboronic acid (0.78g,3mmol), anhydrous sodium acetate (0.61g,5.3mmol), Pt [ P (C. sub.P)6H5)3]4(0.038g,0.03mmol), refluxing under stirring, purifying by silica gel column to obtain solid product, and hydrolyzing and recrystallizing to obtain (6-morpholine-pyridine-3-yl) boric acid.
Step 3. in an ice-water bath, dry DMF (10mL), 5-bromo-3-iodo-1H-pyrrolo [2,3-b ] pyridine (0.92g,3mmol) were added sequentially to a 50mL round-bottomed flask, then NaH (0.15g,6.18mmol, 60% mineral oil mixture) was added in portions, stirring was carried out for 10 minutes, 2- (trimethylsilyl) ethoxymethyl chloride (0.95mL,5.25mmol) was added dropwise, and after completion of the addition, stirring was carried out at room temperature for 1 hour. Water was added for trituration, extracted with ethyl acetate (3X 10mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the crude product purified on a silica gel column to give the product 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-7-azaindole.
Step 4.N2Under protection, 1, 4-dioxane (10mL) and 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] are sequentially added into a 50mL three-necked flask]Methyl } -1H-7-azaindole (70.5mg,0.22mmol), (6-morpholin-pyridin-3-yl) boronic acid (35.6mg,0.22mmol), Pd (PPh)3)4(10.8mg,0.008mmol)、K2CO3(90.8mg,0.66mmol), oil bath heating reflux reaction for 3H, cooling to room temperature, adding water (5mL) for dilution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filtering, vacuum concentration to remove solvent, purifying by a silica gel column after passing through to obtain a solid product, and then removing a protecting group to obtain 4- (5- (5-bromo-1H-7-azaindol-3-yl) pyridine-2-yl) morpholine. If desired for subsequent reactions, the protecting group may not be removed.
Preparation N9: 4- (5-bromo-1H-7-azaindol-3-yl) morpholine
Figure BDA0002898256410000142
Step 1. in a 50mL round-bottom flask, dry DMF (10mL), 5-bromo-3-iodo-1H-7-azaindole (0.95g,3mmol) were added sequentially, NaH (0.16g,6.18mmol, 60% mineral oil mixture) was added in portions, stirring was carried out for 10 minutes, 2- (trimethylsilyl) ethoxymethyl chloride (0.95mL,5.25mmol) was added dropwise, and stirring was carried out at room temperature for 1 hour after completion of the addition. Water was added for trituration, extracted with ethyl acetate (3X 10mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the crude product purified on a silica gel column to give the product 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-7-azaindole.
Step 2. tetrahydrofuran (10mL), 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-7-azaindole (70.1mg,0.22mmol), morpholine (20.1mg,0.22mmol), and potassium carbonate (0.21g,1.5 mmol) were sequentially added in a 50mL three-necked flask under nitrogen protection, heated, stirred under reflux, followed by thin layer chromatography to track the disappearance of the reactant spots, rotary evaporation, column chromatography to isolate the purified solid product, and deprotection to give the title product 4- (5-bromo-1H-7-azaindol-3-yl) morpholine. If desired for subsequent reactions, the protecting group may not be removed.
Preparation N10: (E) -5-bromo-3- (2-cyclopropylvinyl) -1H-7-azaindole
Figure BDA0002898256410000151
Step 1. in a 50mL round-bottom flask, dry DMF (10mL), 5-bromo-3-iodo-1H-7-azaindole (0.95g,3mmol) were added sequentially, NaH (0.16g,6.18mmol, 60% mineral oil mixture) was added in portions, stirring was carried out for 10 minutes, 2- (trimethylsilyl) ethoxymethyl chloride (0.95mL,5.25mmol) was added dropwise, and stirring was carried out at room temperature for 1 hour after completion of the addition. Water was added for trituration, extracted with ethyl acetate (3X 10mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and the crude product purified on a silica gel column to give the product 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] methyl } -1H-7-azaindole.
Step 2. in a 50mL three-necked flask under the protection of N21, 4-dioxane (10mL), 5-bromo-3-iodo-1- { [2- (trimethylsilyl) ethoxy ] was added sequentially]Methyl } -1H-7-azaindole (70.5mg,0.22mmol), (E) - (2-Cyclopropylethenyl) boronic acid (25.2mg,0.22mmol), Pd (PPh)3)4(10.1mg,0.008mmol)、K2CO3(90.2mg,0.66mmol), oil bath heating reflux reaction for 3H, cooling to room temperature, adding water (5mL) for dilution, dichloromethane extraction, organic phase anhydrous sodium sulfate drying, filtering, vacuum concentration to remove solvent, purifying by a silica gel column after passing through to obtain a solid product, and then removing a protecting group to obtain (E) -5-bromine-3- (2-cyclopropyl vinyl) -1H-7-azaindole. If desired for subsequent reactions, the protecting group may not be removed.
EXAMPLE 1N- { 2-chloro-5- [3- (6-morpholin-pyridin-3-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000152
To a 10.0mL round bottom flask, under nitrogen, was added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.253mmol), 4- (5- (5-bromo-1H-7-azaindol-3-yl) pyridin-2-yl) morpholine (i.e., N8) (0.10g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL), and PdCl, respectively2(dppf) (0.0055g，7.59×10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, spin-drying the solvent under reduced pressure, and purification by column chromatography to give 1 as a pale brown solid (yield: 39%).1H NMR(400MHz,DMSO-d6)δ3.51 (t,J＝4.4Hz,4H),3.75(t,J＝4.4Hz,4H),6.98(d,J＝8.8Hz,1H),7.61(t,J＝7.2Hz,2H),7.69(t,J＝7.2 Hz,1H),7.79(d,J＝7.6Hz,2H),7.90(d,J＝2.0Hz,1H),7.94(d,J＝1.6Hz,1H),7.99(dd,J1＝2.0Hz,J2＝6.4Hz,1H),8.34(s,1H),8.50(s,1H),8.61(d,J＝2.4Hz,1H),8.70(d,J＝1.6Hz,1H),10.42(s,1H), 12.08(s,1H).
EXAMPLE 2N- { 2-methoxy-5- [3- (1-methyl-1H-pyrazol-4-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000153
To a 10.0mL round bottom flask, under nitrogen, were added N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.256mmol), 5-bromo-3- (1-methyl-1H-pyrazol-4-yl) -1H-7-azaindole (0.077g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088 g，7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 2 as a brown solid (yield: 46%).1H NMR(400MHz,DMSO-d6)δ3.83 (s,3H),3.91(s,3H),7.59(t,J＝7.2Hz,2H),7.68(t,J＝7.2Hz,1H),7.77(d,J＝7.2Hz,3H),7.91(s,1H), 8.01(s,1H),8.25(s,1H),8.40(s,1H),8.45(s,1H),8.70(s,1H),10.45(s,1H),11.89(s,1H).
Example 3(S) -5-chloro-N- {1- [ 2-methoxy-5- (3-morpholin-1H-7-azaindol-5-yl) pyridin-3-yl ] propyl } -2, 6-dimethylpyrimidin-4-amine
Figure BDA0002898256410000161
To a 10.0mL round bottom flask, under nitrogen, was added (S) -5-chloro-N- (1- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) propyl) -2, 6-dimethylpyrimidin-4-amine (0.10g,0.23mmol), 4- (5-bromo-1H-7-azaindol-3-yl) morpholine (0.079g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh), respectively3)4(0.0088g，7.59×10- 3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 3 as a brown solid (yield: 36%).1H NMR(400MHz, DMSO-d6)δ0.94(t,J＝8.0Hz,3H),1.79-1.93(m,2H),2.39(s,3H),2.42(s,3H),2.83(t,J＝4.4Hz,4H), 3.72(t,J＝4.4Hz,4H),3.81(t,J＝7.2Hz,1H),4.03(s,3H),6.79(s,1H),6.86(s,1H),8.03(s,1H),8.09 (s,1H),8.22(s,1H),9.24(s,1H),9.5(s,1H).
Example 4(S) -4- { [1- (2-chloro-5- (3- (pyridazin-4-yl) -1H-7-azaindol-5-yl) pyridin-3-yl) ethyl ] amino } -5-fluoro-2 (1H) pyrimidinone
Figure BDA0002898256410000162
To a 10.0mL round bottom flask, under nitrogen, was added (S) -4- ((1- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) propyl) -5-fluoropyrimidinone (0.10g,0.25mmol), 5-bromo-3- (pyridazin-4-yl) -1H-7-azaindole (0.077g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl, respectively2(dppf) (0.0055g, 7.59X 10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, spin-drying the solvent under reduced pressure, and concentrating by column chromatography to give 4 (yield: 40%) as a pale brown solid.1H NMR(400MHz,DMSO-d6) δ1.48(d,J＝8.0Hz,3H),4.0(q,J＝6.8Hz,1H),6.86(s,3H),7.89(t,J＝7.6Hz,1H),8.51(s,1H),9.13 (s,1H),9.24(s,1H),9.43(d,J＝7.2Hz,1H),9.58(s,1H),9.70(s,1H),10.09(s,1H),11.01(s,1H).
Example 5N- {1- [ 2-methoxy-5- (3- (pyridin-4-yl) -1H-7-azaindol-5-yl) pyridin-3-yl ] butyl } -9H-purin-6-amine
Figure BDA0002898256410000171
To a 10.0mL round bottom flask under nitrogen was added N- (1- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) butyl) -9H-purin-6-amine (0.10g,0.24mmol), 5-bromo-3- (pyridin-4-yl) -1H-7-azaindole (0.076g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088 g，7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give a brown solid 5 (yield: 30%).1H NMR(400MHz,DMSO-d6)δ0.89 (t,J＝8.0Hz,3H),1.28-1.34(m,2H),3.81(t,J＝7.2Hz,1H),4.03(s,3H),6.79(s,1H),6.86(s,1H),7.86 (s,1H),8.06(d,J＝7.6Hz,2H),8.21(d,J＝7.2Hz,2H),8.33(d,J＝7.6Hz,2H),8.69(d,J＝8.0Hz,2H), 9.24(s,1H),9.58(s,1H),13.65(s,1H).
Example 6N- {1- [ 2-methoxy-5- (3- (pyridazin-4-yl) -1H-7-azaindol-5-yl) pyridin-3-yl ] butyl } -9H-purin-6-amine
Figure BDA0002898256410000172
To a 10.0mL round bottom flask, under nitrogen, was added N- (1- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) butyl) -9H-purin-6-amine (0.10g,0.24mmol), 5-bromo-3- (pyridazin-4-yl) -1H-7-azaindole (0.076g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088 g，7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give brown solid 6 (yield: 35%).1H NMR(400MHz,DMSO-d6)δ0.89 (t,J＝8.0Hz,3H),1.28-1.34(m,2H),3.81(t,J＝7.2Hz,1H),4.03(s,3H),6.79(s,1H),6.86(s,1H),7.86 (s,1H),8.06(d,J＝7.6Hz,2H),8.21(d,J＝7.2Hz,2H),8.33(d,J＝7.6Hz,2H),9.24(s,1H),9.43(d,J＝ 7.2Hz,1H),9.56(s,1H),13.65(s,1H).
EXAMPLE 7N- [ 2-chloro-5- (2-phenyl-1H-7-azaindol-6-yl) pyridin-3-yl ] methanesulfonamide
Figure BDA0002898256410000173
Respectively to a 10.0mL round-bottom flask under nitrogen atmosphereTo this was added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) methanesulfonamide (0.10g,0.30mmol), 5-bromo-2-phenyl-1H-7-azaindole (0.076g,0.279mmol), anhydrous sodium carbonate (0.054g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl2(dppf) (0.0055g, 7.59X 10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, spin-drying the solvent under reduced pressure, and concentrating by column chromatography to give 7 (yield: 40%) as a brown solid.1H NMR(400MHz,DMSO-d6)δ2.95(s,3H),7.50(d,J＝ 7.2Hz,3H),7.89(s,1H),8.09(s,2H),8.19(d,J＝7.2Hz,2H),8.77(s,1H),9.24(s,1H),10.58(s,1H), 13.01(s,1H).
Example 82, 4-difluoro-N- [ 3-methoxy-6- (1H-7-azaindol-5-yl) pyridin-2-yl ] -N-propylbenzenesulfonamide
Figure BDA0002898256410000181
To a 10.0mL round bottom flask, under nitrogen, was added 2, 4-difluoro N- (3-methoxy-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) -N-propylbenzenesulfonamide (0.10g,0.21mmol), 5-bromo-1-BOC-7-azaindole (0.083g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088g， 7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give brown solid 8 (yield: 35%).1H NMR(400MHz,DMSO-d6)δ0.87(t,J＝ 8.0Hz,3H),1.28-1.34(m,2H),3.14(t,J＝7.2Hz,2H),3.83(s,3H),6.93(t,J＝7.2Hz,1H),7.17(d,J＝ 7.6Hz,2H),7.37(d,J＝8.0Hz,1H),7.76(d,J＝7.6Hz,2H),8.48(s,1H),9.63(s,1H),12.00(s,1H).
Example 9N- { 3-chloro-6- [3- (pyridin-4-yl) -1H-7-azaindol-5-yl ] pyridin-2-yl } -6-fluoropyridine-3-sulfonamide
Figure BDA0002898256410000182
To a 10.0mL round bottom flask was added N- (3-chloro-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) -6-fluoropyridine-3-sulfonamide (0.10g,0.24mmol), 5-bromo-3-pyridinyl-1-BOC-7-azaindole (0.1g,0.279 mmol), anhydrous sodium carbonate (0.054g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl, respectively, under a nitrogen atmosphere2(dppf) (0.0055g, 7.59X 10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, spin-drying the solvent under reduced pressure, and concentrating by column chromatography to give 9 (yield: 39%) as a brown solid.1H NMR(400MHz,DMSO-d6)δ7.41(d,J ＝7.6Hz,1H),7.53(t,J＝7.2Hz,1H),7.80(d,J＝8.0Hz,1H),7.99(d,J＝7.2Hz,2H),8.48(s,1H),8.62 (s,2H),8.75(d,J＝7.2Hz,2H),8.85(d,J＝6.4Hz,1H),9.63(s,1H),11.38(s,1H),13.23(s,1H).
EXAMPLE 10N- [ 3-chloro-6- (1H-7-azaindol-5-yl) pyridin-2-yl ] benzenesulfonamide
Figure BDA0002898256410000183
To a 10.0mL round bottom flask, under nitrogen, was added N- (3-chloro-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) benzenesulfonamide (0.10g,0.25mmol), 1-BOC-5-bromo-7 azaindole (0.083g,0.279mmol), anhydrous sodium carbonate (0.054g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl, respectively2(dppf) (0.0055g, 7.59X 10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, spin-drying the solvent under reduced pressure, and concentrating by column chromatography to give a light brown solid 10 (yield: 39%).1H NMR(400MHz,DMSO-d6)δ7.41(d,J＝7.6Hz, 2H),7.55-7.67(m,5H),7.80(d,J＝8.0Hz,1H),8.48(s,1H),9.63(s,1H),11.38(s,1H),13.23(s,1H).
EXAMPLE 114-fluoro-N- [ 3-methoxy-6- (3-morpholin-1H-7-azaindol-5-yl) pyridin-2-yl ] benzenesulfonamide
Figure BDA0002898256410000191
To a 10.0mL round bottom flask was added 4-fluoro-N- (3-methoxy-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) benzenesulfonamide (0.10g,0.24mmol), 4- (5-bromo-1-BOC-7-azaindol-3-yl) morpholine (0.11g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh) respectively under a nitrogen atmosphere3)4(0.0088g， 7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 11 as a brown solid (yield: 46%).1H NMR(400MHz,DMSO-d6)δ3.22(t,J ＝4.4Hz,4H),3.70(t,J＝4.4Hz,4H),3.83(s,3H),7.17(d,J＝8.8Hz,1H),7.38(t,J＝7.6Hz,3H),7.98 (d,J＝7.2Hz,2H),8.48(s,2H),9.63(s,1H),11.38(s,1H),12.20(s,1H).
Example 122, 4-difluoro-N- { 2-methoxy-5- [3- (pyridazin-4-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000192
To a 10.0mL round bottom flask, under nitrogen, were added 2, 4-difluoro N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.23mmol), 5-bromo-3- (pyridazin-4-yl) -1-BOC-7-azaindole (0.10g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088g， 7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 12 as a brown solid (yield: 46%).1H NMR(400MHz,DMSO-d6)δ3.83(s,3H), 6.93(t,J＝7.6Hz,1H),7.17(t,J＝7.2Hz,1H),7.60(s,1H),7.67(s,1H),7.76(d,J＝7.2Hz,1H),7.89(d, J＝7.2Hz,1H),8.09(s,1H),9.24(s,2H),9.43(d,J＝7.2Hz,1H),9.58(s,1H),10.01(s,1H),13.23(s,1H).
Example 135- (5-fluoro-6-methoxypyridin-3-yl) -3- (pyridazin-4-yl) -1H-7-azaindole
Figure BDA0002898256410000193
To a 10.0mL round bottom flask, under nitrogen, were added 3-fluoro-2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.10g,0.40mmol), 5-bromo-3- (pyridazin-4-yl) -1-BOC-7-azaindole (0.17g,0.44mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088g，7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 13 as a brown solid (yield: 51%).1H NMR(400MHz,DMSO-d6)δ4.06(s,3H),7.80(d,J＝7.6 Hz,2H),7.89(d,J＝7.2Hz,1H),8.09(s,1H),9.24(s,2H),9.43(d,J＝7.2Hz,1H),9.58(s,1H),13.23(s, 1H).
Example 144- [5- (5, 6-Dimethoxypyridin-3-yl) -1H-7-azaindol-3-yl) morpholine
Figure BDA0002898256410000201
To a 10.0mL round bottom flask, under nitrogen, were added 2, 3-dimethoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.10g,0.38mmol), 5-bromo-3- (pyridazin-4-yl) -1-BOC-7-azaindole (0.16g,0.42mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088g，7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 14 as a brown solid (yield: 46%).1H NMR(400MHz,DMSO-d6)δ3.22(t,J＝4.4Hz,4H),3.70 (t,J＝4.4Hz,4H),3.83(s,3H),4.06(s,3H),7.72(s,1H),7.79(s,1H),8.09(s,2H),9.24(s,1H),12.20(s, 1H).
EXAMPLE 15(E) -N- {5- [3- (2-Cyclopropylvinyl) -1H-7-azaindol-5-yl ] -2-methoxypyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000202
To a 10.0mL round bottom flask, under nitrogen, were added N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.26mmol), (E) -5-bromo-3- (2-cyclopropylvinyl) -1-BOC-7-azaindole (0.10g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088 g，7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 15 as a brown solid (yield: 43%).1H NMR(400MHz,DMSO-d6)δ 0.18-0.23(m,2H),0.43-0.47(m,2H),1.34-1.39(m,1H),3.83(s,3H),5.68(dd,J1＝6.2Hz,J2＝16.0Hz, 1H),6.42(d,J＝6.2Hz,1H),7.55-7.67(m,6H),8.09(s,2H),9.24(s,1H),10.01(s,1H),13.23(s,1H).
EXAMPLE 16N- { 2-chloro-5- [2- (1, 2-dihydroxyethyl) -3-phenyl-1H-7-azaindol-5-yl ] pyridin-3-yl } -4-fluorobenzenesulfonamide
Figure BDA0002898256410000211
To a 10.0mL round bottom flask was added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -4-fluorobenzenesulfonamide (0.10g,0.24mmol), 1- (5-bromo-3-phenyl-1H-7-azaindol-2-yl) -1, 2-dihydroxyethyl (0.093g,0.279mmol), anhydrous sodium carbonate (0.054g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL), and PdCl, respectively, under a nitrogen atmosphere2(dppf) (0.0055g, 7.59X 10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature,the reaction solution was diluted with ethyl acetate, the solvent was spin-dried under reduced pressure, and concentrated by column chromatography to give 16 as a brown solid (yield: 39%).1H NMR(400MHz, DMSO-d6)δ3.81-3.84(m,1H),4.08(m,1H),4.59(s,1H),4.88(t,J＝7.6Hz,1H),5.17(s,1H),7.41(t,J ＝7.6Hz,3H),7.57(d,J＝7.6Hz,4H),7.89(s,1H),7.98(d,J＝7.2Hz,2H),8.09(s,1H),8.77(s,1H),9.24 (s,1H),10.01(s,1H),11.94(s,1H).
EXAMPLE 17N- [ 2-chloro-5- (3-phenyl-1H-7-azaindol-5-yl) pyridin-3-yl ] benzenesulfonamide
Figure BDA0002898256410000212
To a 10.0mL round bottom flask, under nitrogen, were added N- (3-chloro-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) benzenesulfonamide (0.10g,0.25mmol), 5-bromo-3-phenyl-1H-7-azaindole (0.077g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl, respectively2(dppf) (0.0055g, 7.59X 10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, diluting the reaction mixture with ethyl acetate, spin-drying the solvent under reduced pressure, and concentrating by column chromatography to obtain beige solid 17 (yield: 32%).1H NMR(400MHz,DMSO-d6)δ7.30(s,1H),7.48(d,J＝ 4.8Hz,1H),7.58(q,J＝6.4Hz,4H),7.66-7.68(m,1H),7.77(d,J＝7.6Hz,2H),8.12-8.13(m,3H),8.77(d, J＝6.0Hz,2H),8.83(s,1H),10.45(s,1H),12.16(s,1H).
Example 18(S) -5-chloro-N- {1- [ 2-methoxy-5- (3- (pyridin-4-yl) -1H-7-azaindol-5-yl) pyridin-3-yl ] propyl } -2, 6-dimethylpyrimidin-4-amine
Figure BDA0002898256410000213
To a 10.0mL round bottom flask under nitrogen was added (S) -5-chloro-N- (1- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) propyl) -2, 6-dimethylpyrimidin-4-amine (0.10g,0.23mmol), 5-bromo-3-pyridine-1H-7-azaindole(0.077g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl2(dppf) (0.0055g, 7.59X 10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, spin-drying the solvent under reduced pressure, and concentrating by column chromatography to obtain a yellow solid 18 (yield: 30%).1H NMR(400MHz, DMSO-d6)δ0.94(t,J＝7.6Hz,3H),1.85(q,J＝7.6Hz,2H),2.41(d,J＝7.6Hz,3H),3.81(t,J＝7.2Hz, 1H),4.03(s,3H),6.79(d,J＝7.2Hz,1H),7.40(d,J＝8.0Hz,2H),8.03(s,1H),8.09(s,1H),8.22(s,2H), 8.42(d,J＝7.6Hz,2H),9.24(s,1H),1154(S,1H).
EXAMPLE 19N- { 2-chloro-5- [3- (2-morpholinopyrimidin-5-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000221
To a 10.0mL round bottom flask, under nitrogen, was added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.25mmol), 4- (5- (5-bromo-1H-7-azaindol-3-yl) pyrimidin-2-yl) morpholine (0.10g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl, respectively2(dppf) (0.0055g, 7.59X 10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, spin-drying the solvent under reduced pressure, and concentrating by column chromatography to give 19 (yield: 32%) as a brown solid.1H NMR(400MHz,DMSO-d6)δ3.71(t,J＝ 4.4Hz,4H),3.78(t,J＝4.4Hz,4H),4.03(s,3H),7.61(t,J＝7.6Hz,2H),7.69(t,J＝7.2Hz,1H),7.79(d, J＝7.6Hz,2H),7.95(d,J＝2.4Hz,1H),7.99(d,J＝2.0Hz,1H),8.39(s,1H),8.52(d,J＝1.2Hz,1H),8.72 (s,J＝2.0Hz,1H),8.85(s,2H),10.41(s,1H),12.15(s,1H).
EXAMPLE 20N- {5- [3- (2-Aminopyridin-4-yl) -1H-7-azaindol-5-yl ] -2-chloropyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000222
To a 10.0mL round bottom flask, N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.25mmol), 4- (5-bromo-1H-7-azaindol-3-yl) pyridin-2-amine (0.081g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh) were added under a nitrogen atmosphere, respectively3)4(0.0088g，7.59×10-3mmol), then reacted at 110 ℃ for 10 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 20 as a brown solid (yield: 41%).1H NMR(400MHz,DMSO-d6)δ6.61(s,2H),7.11 (d,J＝9.2Hz,2H),7.56(t,J＝10.0Hz,3H),7.78(d,J＝5.6Hz,2H),7.93(d,J＝6.8Hz,2H),8.26(s,1H), 8.46(s,3H),12.49(s,1H).
Example 21N- {5- [3- (4-amino-2-fluorophenyl) -1H-7-azaindol-5-yl ] -2-chloropyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000231
To a 10.0mL round-bottomed flask were added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.25mmol), 4- (5-bromo-1H-7-azaindol-3-yl) 3-fluoroaniline (0.085g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh) respectively under a nitrogen atmosphere3)4(0.0088g，7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with dichloromethane, dried under reduced pressure, purified by column chromatography, and concentrated to give 21 as a brown solid (yield: 45%).1H NMR(400MHz,DMSO-d6)δ6.54(t,J＝6.4Hz,2H),7.38 (t,J＝8.8Hz,1H),7.56-7.68(m,6H),7.79(d,J＝7.6Hz,2H),7.84(s,2H),8.06(s,1H),8.49(s,1H), 8.64(s,1H),12.02(s,1H).
EXAMPLE 22N- {6- [3- (5-chloro-2-fluoropyridin-4-yl) -1H-7-azaindol-5-yl ] -3-methoxypyridin-2-yl } pyridine-3-sulfonamide
Figure BDA0002898256410000232
To a 10.0mL round bottom flask was added N- (3-methoxy-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) pyridine-3-sulfonamide (0.10g,0.26mmol), 5-bromo-3- (5-chloro-2-fluoropyridin-4-yl) -1H-7-azaindole (0.091g, 0.279mmol), anhydrous sodium carbonate (0.054g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh) respectively under nitrogen atmosphere3)4(0.0088 g，7.59×10-3mmol), then reacted at 110 ℃ for 6 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 22 as a beige solid (yield: 32%).1H NMR(400MHz,DMSO-d6)δ3.83 (s,3H),6.86(s,1H),7.17(d,J＝7.2Hz,1H),7.37(d,J＝7.2Hz,1H),7.59(t,J＝7.6Hz,1H),7.81(d,J＝ 7.2Hz,1H),8.46(t,J＝7.2Hz,2H),8.66(s,1H),8.87(d,J＝7.2Hz,2H),9.50(s,1H),9.63(s,1H),11.38 (s,1H).
EXAMPLE 23N- [ 2-chloro-5- (3-methyl-1H-7-azaindol-5-yl) pyridin-3-yl ] benzenesulfonamide
Figure BDA0002898256410000233
To a 10.0mL round bottom flask, N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.25mmol), 5-bromo-3-methyl-1H-7-azaindole (0.059g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh) were added under a nitrogen atmosphere, respectively3)4(0.0088g，7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with dichloromethane, dried under reduced pressure, purified by column chromatography, and concentrated to give 23 as a yellow solid (yield: 45%).1H NMR(400MHz,DMSO-d6)δ2.09(s,3H),5.53(s,1H), 7.55-7.67(m,5H),7.89(s,1H),8.09(s,1H),8.77(s,1H),9.24(s,1H),10.01(s,1H),11.23(s,1H).
EXAMPLE 24N- { 2-chloro-5- [3- (2-methyl-1-allyl) -1H-7-azaindol-5-yl ] pyridin-3-yl } -4-fluorobenzenesulfonamide
Figure BDA0002898256410000241
To a 10.0mL round bottom flask, under nitrogen, were added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -4-fluorobenzenesulfonamide (0.10g,0.24mmol), 5-bromo-3- (2-methyl-1-allyl) -1H-7-azaindole (0.070g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd, respectively2(dba)3(0.0070g， 7.59×10-3mmol), then reacted at 110 ℃ for 6 hours, cooled to room temperature, spin-dried under reduced pressure, purified by column chromatography, and concentrated to give 24 as a yellow solid (yield: 49%).1H NMR(400MHz,DMSO-d6)δ1.79(d,J＝5.6Hz,2H),6.13(d,J＝ 5.6Hz,1H),6.86(s,1H),7.40(t,J＝7.2Hz,2H),7.89(s,1H),7.98(t,J＝7.2Hz,2H),8.09(s,1H),8.77 (s,1H),9.24(s,1H),9.5(s,1H),9.50(s,1H),10.01(s,1H).
Example 25N- { 2-chloro-5- [3- (2-methyl-1-allyl) -1H-7-azaindol-5-yl ] pyridin-3-yl } -2, 4-difluorobenzenesulfonamide
Figure BDA0002898256410000242
To a 10.0mL round bottom flask, under nitrogen, was added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide (0.10g,0.23mmol), 5-bromo-3- (2-methyl-1-allyl) -1H-7-azaindole (0.070g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd, respectively2(dba)3(0.0070g， 7.59×10-3mmol), then reacted at 110 ℃ for 6 hours, cooled to room temperature, spin-dried under reduced pressure, purified by column chromatography, and concentrated to give beige solid 25 (yield: 39%).1H NMR(400MHz,DMSO-d6)δ1.79(d,J＝5.6Hz,2H),6.13(d, J＝5.6Hz,1H),6.86(s,1H),7.40(t,J＝7.6Hz,2H),7.89(s,1H),7.98(t,J＝7.6Hz,1H),8.09(s,1H), 8.77(s,1H),9.24(s,1H),9.5(s,1H),9.50(s,1H),10.01(s,1H).
EXAMPLE 26N- { 2-methoxy-5- [3- (2-methyl-1-allyl) -1H-7-azaindol-5-yl ] pyridin-3-yl } -2, 4-difluorobenzenesulfonamide
Figure BDA0002898256410000243
To a 10.0mL round bottom flask, under nitrogen, was added N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2, 4-difluorobenzenesulfonamide (0.10g,0.23mmol), 5-bromo-3- (2-methyl-1-allyl) -1H-7-azaindole (0.070g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd, respectively2(dba)3(0.0070 g，7.59×10-3mmol), then reacted at 110 ℃ for 6 hours, cooled to room temperature, spin-dried under reduced pressure, purified by column chromatography, and concentrated to give beige solid 26 (yield: 41%).1H NMR(400MHz,DMSO-d6)δ1.79(d,J＝5.6Hz,2H),3.83(s, 3H),6.13(d,J＝5.6Hz,1H),6.86(s,1H),7.40(t,J＝7.6Hz,2H),7.89(s,1H),7.98(t,J＝7.6Hz,1H), 8.09(s,1H),8.77(s,1H),9.24(s,1H),9.5(s,1H),9.50(s,1H),10.01(s,1H).
Example 272, 4-difluoro-N- { 3-methoxy-6- [3- (2-methyl-1-allyl) -1H-7-azaindol-5-yl ] pyridin-2-yl } benzenesulfonamide
Figure BDA0002898256410000251
To a 10.0mL round bottom flask, under nitrogen, was added N- (3-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) -2, 4-difluorobenzenesulfonamide (0.10g,0.23mmol), 5-bromo-3- (2-methyl-1-allyl) -1H-7-azaindole (0.070g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd, respectively2(dba)3(0.0070 g，7.59×10-3mmol), followed by reaction at 110 ℃ for 6 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, purification by column chromatography, and concentration to give 27 as a brown solid (yield: 35%).1H NMR(400MHz,DMSO-d6)δ1.79(d,J＝5.6Hz,2H),3.83(s, 3H),6.13(d,J＝5.6Hz,1H),6.86(s,1H),6.93(t,J＝8.0Hz,1H),7.17(q,J＝8.0Hz,2H),7.37(d,J＝ 7.6Hz,1H),7.76(q,J＝7.6Hz,1H),8.48(s,1H),9.50(s,1H),9.63(s,1H),11.38(s,1H).
EXAMPLE 28N- { 2-chloro-5- [3- (2-fluoropyridin-4-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000252
To a 10.0mL round bottom flask, N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.25mmol), 5-bromo-3- (2-fluoropyridin-4-yl) -1-BOC-7-azaindole (0.11g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh) were added under a nitrogen atmosphere, respectively3)4(0.0088g，7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with dichloromethane, dried under reduced pressure, purified by column chromatography, and concentrated to give a brown solid 28 (yield: 36%).1H NMR(400MHz,DMSO-d6)δ7.61(q,J＝7.6Hz, 3H),7.68(t,J＝7.2Hz,1H),7.78(d,J＝7.2Hz,2H),7.85(d,J＝4.0Hz,1H),8.07(s,1H),8.25(d,J＝5.2 Hz,1H),8.44(s,1H),8.55(s,1H),8.66(s,1H),8.74(s,1H),10.45(s,1H),12.56(s,1H).
Example 29(S) -N- {1- [ 2-methoxy-5- (3- (pyridin-3-yl) -1H-7-azaindol-5-yl) pyridin-3-yl ] propyl } -9H-purin-6-amine
Figure BDA0002898256410000261
To a 10.0mL round bottom flask, under nitrogen, was added (S) -6-N- (1- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) propane, respectivelyYl) -9H-purine (0.10g,0.25mmol), 5-bromo-3- (pyridin-3-yl) -1-BOC-7-azaindole (0.10g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), Water (0.50mL), toluene (2.00mL) and Pd2(dba)3(0.0070 g，7.59×10-3mmol), then reacted at 110 ℃ for 6 hours, cooled to room temperature, spin-dried under reduced pressure, purified by column chromatography, and concentrated to give beige solid 29 (yield: 41%).1H NMR(400MHz,DMSO-d6)δ0.94(t,J＝8.0Hz,3H), 1.79-1.93(m,2H),3.81(t,J＝7.2Hz,1H),4.03(s,3H),6.79(s,1H),7.57(t,J＝6.0Hz,1H),7.86(s,1H), 8.03(s,1H),8.09(s,2H),8.22(s,2H),8.42(d,J＝7.2Hz,1H),8.70(d,J＝7.6Hz,1H),9.24(s,2H),13.23 (s,1H),13.65(s,1H).
Example 30N- { 2-chloro-5- [3- (5-fluoro-2-methylpyridin-4-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000262
To a 10.0mL round bottom flask, under nitrogen, were added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.25mmol), 5-bromo-3- (2-methyl-5-fluoropyridin-4-yl) -1-BOC-7-azaindole (0.11g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088g， 7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with dichloromethane, dried under reduced pressure, purified by column chromatography, and concentrated to give 30 as a brown solid (yield: 43%).1H NMR(400MHz,DMSO-d6)δ2.69(s,3H), 7.55-7.67(m,4H),7.81(d,J＝7.6Hz,1H),7.89(s,1H),8.09(s,2H),8.57(d,J＝7.6Hz,1H),8.77(s,1H), 9.24(s,1H),10.01(s,1H),13.23(s,1H).
EXAMPLE 31N- { 2-chloro-5- [3- (6-fluoro-4-methylpyridin-3-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000263
To a 10.0mL round bottom flask, under nitrogen, were added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.25mmol), 5-bromo-3- (4-methyl-2-fluoropyridin-3-yl) -1-BOC-7-azaindole (0.11g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088 g，7.59×10-3mmol), followed by reaction at 110 ℃ for 8 hours, cooling to room temperature, dilution of the reaction solution with dichloromethane, spin-drying of the solvent under reduced pressure, purification by column chromatography, and concentration to give 31 as a brown solid (yield: 43%).1H NMR(400MHz,DMSO-d6) δ 7.26 (s,1H),7.57(t, J ═ 7.6Hz,2H),7.63(t, J ═ 7.6Hz,1H),7.77(d, J ═ 7.2Hz,2H),7.81(d, J ═ 2.4Hz,1H), 7.89(d, J ═ 2.0Hz,1H),8.02(s,1H),8.26(s,1H),8.56(d, J ═ 1.6Hz,1H),8.66(d, J ═ 2.0Hz,1H),10.41(s, 1H),12.26(s,1H). example 322-fluoro-N- { 2-methoxy-5- [3- (pyridin-4-yl) -1H-7-azaindol-5-yl]Pyridin-3-yl-benzenesulfonamides
Figure BDA0002898256410000271
To a 10.0mL round bottom flask, under nitrogen, were added N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2-fluorobenzenesulfonamide (0.10g,0.24mmol), 5-bromo-3- (pyridin-4-yl) -1H-7-azaindole (0.076g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (2.00mL) and Pd, respectively2(dba)3(0.0070 g，7.59×10-3mmol), then reacted at 100 ℃ for 8 hours, cooled to room temperature, spin-dried under reduced pressure, purified by column chromatography, and concentrated to give 32 as a brown solid (yield: 36%).1H NMR(400MHz,DMSO-d6)δ3.62(s,3H),7.32(t,J＝7.6Hz, 1H),7.47(d,J＝6.4Hz,1H),7.71(q,J＝5.6Hz,2H),7.86(d,J＝5.6Hz,2H),7.98(d,J＝2.4Hz,1H), 8.29(d,J＝2.4Hz,1H),8.42(d,J＝2.0Hz,1H),8.51-8.58(m,4H),10.25(s,1H),12.37(s,1H).
EXAMPLE 334-fluoro-N- { 3-methoxy-6- [3- (4-methoxyphenyl) -1H-7-azaindol-5-yl ] pyridin-2-yl } -N-propylbenzenesulfonamide
Figure BDA0002898256410000272
To a 10.0mL round bottom flask under nitrogen was added 4-fluoro-N- (3-methoxy-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) -N-propylbenzenesulfonamide (0.10g,0.22mmol), 5-bromo-3- (4-methoxyphenyl) -1H-7-azaindole (0.076g,0.279mmol), anhydrous potassium carbonate (0.073g,0.24mmol), water (0.50mL), 1, 4-dioxane (2.00mL) and Pd, respectively2(dba)3 (0.0070g，7.59×10-3mmol), followed by reaction at 100 ℃ for 9 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, purification by column chromatography, and concentration to give 33 as a brown solid (yield: 33%).1H NMR(400MHz,DMSO-d6)δ0.87(t,J＝8.0Hz,3H), 1.54-1.60(m,2H),3.14(t,J＝7.2Hz,2H),3.83(s,6H),6.87(s,1H),7.02(d,J＝7.6Hz,2H),7.17(d,J＝ 8.0Hz,1H),7.37-7.40(m,3H),7.71(d,J＝7.6Hz,2H),7.98(q,J＝7.6Hz,2H),8.48(s,1H),9.60(s,1H), 9.63(s,1H).
Example 342, 4-difluoro-N- { 2-methoxy-5- [3- (pyridin-4-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } -N-methylbenzenesulfonamide
Figure BDA0002898256410000281
To a 10.0mL round bottom flask under nitrogen was added 2, 4-difluoro-N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -N-methylbenzenesulfonamide (0.10g,0.23mmol), 5-bromo-3- (pyridin-4-yl) -1-BOC-7-azaindole (0.10g,0.279 mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088 g，7.59×10-3mmol), reacting at 110 deg.C for 8 hr, cooling to room temperature, diluting the reaction solution with dichloromethane, spin-drying the solvent under reduced pressure, purifying by column chromatography, and concentrating to obtain brown solid 34 (product)Rate: 31%).1H NMR(400MHz,DMSO-d6)δ3.28 (s,3H),3.83(s,3H),6.93(t,J＝8.0Hz,1H),7.17(t,J＝7.6Hz,1H),7.60(s,1H),7.67(s,1H),7.76(d,J＝ 7.2Hz,1H),7.99(d,J＝7.2Hz,2H),8.09(s,2H),8.75(d,J＝7.2Hz,2H),9.24(s,1H),13.23(s,1H).
Example 35N- { 2-chloro-5- [3- (2-fluoropyridin-4-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } ethylsulfonamide
Figure BDA0002898256410000282
To a 10.0mL round bottom flask, under nitrogen, were added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) propyl-1-sulfonamide (0.10g,0.28mmol), 5-bromo-3- (2-fluoropyridin-4-yl) -1-BOC-7-azaindole (0.11g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088g， 7.59×10-3mmol), then reacted at 110 ℃ for 8 hours, cooled to room temperature, diluted with dichloromethane, dried under reduced pressure, purified by column chromatography, and concentrated to give 35 as a brown solid (yield: 31%).1H NMR(400MHz,DMSO-d6)δ1.22(t,J ＝7.6Hz,3H),3.45(q,J＝7.6Hz,2H),7.62(d,J＝8.0Hz,1H),7.89(s,1H),8.09(s,1H),8.46-8.52(m,2H), 8.77(s,2H),9.24(s,1H),10.58(s,1H),13.23(s,1H).
EXAMPLE 36N-Ethyl-2-fluoro-N- [ 3-methoxy-6- (3-phenyl-1H-7-azaindol-5-yl) pyridin-2-yl ] pyridine-4-sulfonamide
Figure BDA0002898256410000283
To a 10.0mL round bottom flask under nitrogen was added N-ethyl-2-fluoro-N- (3-methoxy-6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-2-yl) pyridine-4-sulfonamide (0.10g,0.23mmol), 5-bromo-3-phenyl-1H-7-azaindole (0.076g,0.279mmol), anhydrous potassium carbonate (0.073g,0.24mmol), water (0.50mL), 1, 4-dioxane (2.00mL) and Pd, respectively2(dba)3(0.0070 g，7.59×10-3mmol), then reacted at 100 ℃ for 8 hours, cooled to room temperature, spin-dried under reduced pressure, purified by column chromatography, and concentrated to give 36 as a brown solid (yield: 37%).1H NMR(400MHz,DMSO-d6)δ1.12(t,J＝8.0Hz,3H),3.10(q, J＝8.0Hz,2H),3.83(s,3H),7.17(d,J＝7.6Hz,1H),7.37-7.51(m,5H),7.96(d,J＝8.0Hz,1H),8.18(d, J＝7.6Hz,1H),8.52(d,J＝7.6Hz,1H),9.63(s,2H).
EXAMPLE 37N- [ 2-chloro-5- (3-vinyl-1H-7-azaindol-5-yl) pyridin-3-yl ] benzenesulfonamide
Figure BDA0002898256410000291
To a 10.0mL round bottom flask under nitrogen was added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.25mmol), 5-bromo-3-vinyl-1H-7-azaindole (0.062g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd, respectively2(dba)3(0.0070g，7.59×10-3mmol), then reacted at 110 ℃ for 6 hours, cooled to room temperature, spin-dried under reduced pressure of the solvent, purified by column chromatography, and concentrated to give 37 as a brown solid (yield: 40%).1H NMR(400MHz,DMSO-d6)δ5.18(d,J＝11.6Hz,1H),5.79(d,J＝17.6Hz,1H),6.89 (q,J＝6.4Hz,1H),7.61(t,J＝7.6Hz,2H),7.68-7.74(m,2H),7.79(d,J＝7.2Hz,2H),7.97(d,J＝2.4Hz, 1H),8.46(dd,J1＝2.0Hz,J2＝20.0Hz,2H),8.67(d,J＝2.4Hz,1H),10.43(s,1H),11.98(s,1H).
EXAMPLE 38N- [ 2-methoxy-5- (3-morpholin-1H-7-azaindol-5-yl) pyridin-3-yl ] pyridine-3-sulfonamide
Figure BDA0002898256410000292
To a 10.0mL round bottom flask, under nitrogen, was added N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) pyridine, respectively-3-sulfonamide (0.10g,0.26mmol), 5-bromo-3-morpholine-1-BOC-7-azaindole (0.11g,0.279mmol), anhydrous sodium carbonate (0.054g,0.633mmol), water (0.50mL), toluene (2.00mL) and Pd (PPh)3)4(0.0088g，7.59×10-3mmol), then reacted at 110 ℃ for 6 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give 38 as a beige solid (yield: 32%).1H NMR(400MHz,DMSO-d6)δ3.22(t,J＝8.0Hz, 4H),3.70(t,J＝8.0Hz,4H),3.83(s,3H),7.59(t,J＝7.6Hz,2H),7.67(s,1H),8.09(s,1H),8.43(d,J＝ 7.6Hz,1H),8.85(d,J＝7.6Hz,1H),8.91(s,2H),9.24(s,1H),10.01(s,1H),12.20(s,1H).
EXAMPLE 39N- { 2-chloro-5- [3- (2-morpholinopyrimidin-5-yl) -1H-7-azaindol-5-yl ] pyridin-3-yl } benzenesulfonamide
Figure BDA0002898256410000293
To a 10.0mL round bottom flask, under nitrogen, were added N- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.25mmol), 5-bromo-3- (2-morpholinopyrimidin-5-yl) -1-BOC-7-azaindole (0.13g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl, respectively2(dppf) (0.0055g, 7.59X 10-3mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, spin-drying the solvent under reduced pressure, and concentrating by column chromatography to give 39 (yield: 35%) as a brown solid.1H NMR(400MHz,DMSO-d6)δ3.71(d,J＝4.8 Hz,4H),3.76(d,J＝5.2Hz,4H),7.61(t,J＝7.6Hz,2H),7.69(t,J＝7.2Hz,1H),7.79(d,J＝7.6Hz,1H), 7.95(d,J＝2.4Hz,1H),7.99(d,J＝2.0Hz,1H),8.39(s,1H),8.52(d,J＝1.2Hz,1H),8.71(d,J＝2.0Hz, 1H),8.85(s,2H),10.41(s,1H),12.15(s,1H).
Example 40 hydrochloride salt.
To 10mL of a mixed solvent of ethanol and water, n- (2-chloro-5- (1H-7-azaindol-5-yl) pyridin-3-yl) benzenesulfonamide (0.385g,1mmol) was weighed (V: V ═ 1: 1). While stirring, a molar equivalent of aqueous hydrochloric acid solution was added. After the completion of the addition, the mixture was stirred at room temperature for 30min, followed by filtration, and the filtrate was allowed to stand for one week to give N- (2-chloro-5- (1H-7-azaindol-5-yl) pyridin-3-yl) benzenesulfonamide hydrochloride (yield: 15%). By adjusting the ratio of hydrochloric acid to formula I, different molar ratios of hydrochloride salts can be obtained.
Example 41 citrate salt
N- (2-chloro-5- (3- (pyridin-4-yl) -1H-7-azaindol-5-yl) pyridin-3-yl) -4-fluorobenzenesulfonamide (0.481g,1mmol) was weighed, added to 15mL of an ethanol solution, a molar equivalent of citric acid was added with stirring, stirred at room temperature for 30min, then transferred to a 20mL reaction vessel, heated with a solvent at 60 ℃ for 12 hours, then naturally cooled to room temperature, and filtered to give N- (2-chloro-5- (3- (pyridin-4-yl) -1H-7-azaindol-5-yl) pyridin-3-yl) -4-fluorobenzenesulfonamide monocitrate (yield: 78%). By adjusting the ratio of citric acid to formula I, different molar ratios of citrate can be obtained.
EXAMPLE 42 Benzenesulfonate salt
Weighing (S) -nitrogen- (1- (2-chloro-5- (3- (pyrazine-4-yl) -1H-7-azaindol-5-yl) pyridine-3-yl) propyl) -9H-purine-6-amine (0.482g,1mmol), adding a small amount of DMSO, heating to 50 ℃, dropwise adding DMSO to completely dissolve, dropwise adding benzenesulfonic acid with molar equivalent, continuously stirring for reaction for 10 minutes, filtering, cooling to 4 ℃, standing the filtrate until solid is separated out to obtain benzenesulfonic acid (S) -nitrogen- (1- (2-chloro-5- (3- (pyrazine-4-yl) -1H-7-azaindol-5-yl) pyridine-3-yl) propyl) -9H-purine-6-amine salt (product) Rate: 23%). By adjusting the ratio of benzenesulfonic acid to formula I, different molar ratios of benzenesulfonate can be obtained.
EXAMPLE 43 methanesulfonic acid salt
Weighing (S) -N- (1- (2-methoxy-5- (3- (pyrazine-4-yl) -1H-7-azaindol-5-yl) pyridine-3-yl) propyl) -9H-purine-6-amine (0.482g,1mmol), adding a small amount of DMSO, heating to 50 ℃, dropwise adding DMSO until the DMSO is completely dissolved, dropwise adding methanesulfonic acid with molar equivalent, continuing stirring for reaction for 10 minutes, filtering, cooling to 4 ℃, standing the filtrate until solid is separated out, and obtaining methanesulfonic acid (S) -N- (1- (2-methoxy-5- (3- (pyrazine-4-yl) -1H-7-azaindol-5-yl) pyridine-3-yl) propyl) -9H-purine-6- Amine salt (yield: 19%). By adjusting the ratio of methanesulfonic acid to formula I, salts with different molar ratios can be obtained.
EXAMPLE 44 maleate salt
Weighing and adding nitrogen- (2-chloro-5- (3- (2-fluoropyridin-4-yl) -1H-7-azaindol-5-yl) pyridin-3-yl) benzenesulfonamide (0.497g,1mmol) into a mixed solution of ethanol and water (20mL,1:1), heating to 60 ℃ under stirring, adding equivalent maleic acid, continuing stirring for reaction for 30min, then filtering and cooling to 4 ℃, and standing the filtrate until solid is separated out to obtain the maleic acid nitrogen- (2-chloro-5- (3- (2-fluoropyridin-4-yl) -1H-7-azaindol-5-yl) pyridin-3-yl) benzenesulfonamide (yield: 18%). By adjusting the ratio of maleic acid to formula I, salts of different molar ratios can be obtained.
EXAMPLE 45 lactate salt
Nitrogen- (2-chloro-5- (3- (6-morpholinopyridin-3-yl) -1H-7-azaindol-5-yl) pyridin-3-yl) benzenesulfonamide (0.546g,1mmol) was weighed and added to a 10mL DMSO solution, heated and stirred for 10min, then lactic acid was added dropwise in a molar equivalent amount, the reaction was continued for 30min, then filtered and cooled to 4 ℃, and the filtrate was allowed to stand until a solid was precipitated, to obtain nitrogen-mono-lactate- (2-chloro-5- (3- (6-morpholinopyridin-3-yl) -1H-7-azaindol-5-yl) pyridin-3-yl) benzenesulfonamide (yield: 27%). By adjusting the ratio of lactic acid to formula I, salts of different molar ratios can be obtained.
EXAMPLE 46 preparation of a tablet of formula I or a salt thereof
Raw and auxiliary materials Mass percent/tablet
A salt of formula I 5 to 10% (based on formula I)
Microcrystalline cellulose 61～56％
Calcium hydrogen phosphate 31～26％
Sodium starch glycolate 2％
Magnesium stearate
1％
Total of 100
The preparation method comprises the following steps: the freshly prepared granules of formula I or salts thereof are dried overnight at 40 ℃ under vacuum, then ultrasonically crushed, sieved through a 100 mesh sieve, and then all the auxiliary materials are added. Mixing completely with a mixer, and making into tablet.
Example 47 lists the relevant PI3K delta enzyme inhibitory effects of most of the formula I or salts described in the examples. "+" represents the intensity of inhibition. The more "+" the stronger the inhibition, and 6 "+" represent 5nM and below. (selected, including salts one + represents 200Nm, two 100nM, three 50, four 20, 5 10, 65 Nm or less)
TABLE 1 associated PI3K delta enzyme inhibitory Effect of the majority of formula I or salts described in the examples
Example numbering IC50 Example numbering IC50
1 ++++++ 2 ++++++
3 +++ 4 +++
5 +++ 6 ++
7 ++++ 8 +++
9 ++++++ 10 ++++++
11 ++++++ 12 ++++++
13 ++ 14 ++
15 +++++ 16 ++++
17 ++++++ 18 ++++
19 ++++++ 20 ++++++
21 ++++++ 22 +++++
23 ++++ 24 ++++++
25 ++++++ 26 ++++++
27 ++++++ 28 ++++++
29 ++++ 30 ++++++
31 ++++++ 32 ++++++
33 ++++++ 34 +++++
35 ++++++ 36 +++++
37 ++++++ 38 ++++++
39 +++++ 40 +++++
41 ++++ 42 ++++
43 ++++++ 44 ++++++
45 ++++ / /
Example 48 in vitro inhibition of cell proliferation and morphological Observation experiments
Subjecting the marrow cells in logarithmic growth phase to 2 × 104One cell/100. mu.L/well was inoculated into a 96-well plate and incubated at 37 ℃ with 5% CO2The incubator stands still and grows stably for 2 hours. Test sample compounds were diluted 3-fold at 10 μ M initial concentration to 8 different treatment concentrations, with 200 μ L per well of treatment system, with three more wells per concentration. The reference compound CAL-101 was used as a positive control, with 0.1% DMSO solvent as a negative control. Cells were treated for 48h under standard culture conditions. Relative cell viability, the cell proliferation inhibition IC50 (shown in figure 2) is calculated by analyzing through GraphPad Prism software and fitting a four-parameter inhibition viability curve, and the activity of the candidate drug molecule provided by the invention on a cell level is obviously better than that of the marketed drug CAL-101.
Cells in logarithmic growth phase were grown at 1X 105One/4 mL/well was inoculated in 6-well plates and incubated at 37 ℃ with 5% CO2The incubator stands still and grows stably for 2 hours. The test sample compound is respectively treated with different concentrations of formula I or salt thereof for 24h, DMSO is used as a negative control, the cell morphology is observed and recorded by taking pictures by using a confocal microscope, and the cell nuclear plasma membrane morphology is observed (shown in figure 3).
Example 49 cellular protein level expression assay (shown in FIG. 4)
Cells in logarithmic growth phase at 4X 105And inoculating the cells in a cell culture bottle, setting different concentrations of the azaindole derivative myeloid cell proliferation inhibitor to treat the cells for 24 hours, collecting all the cells, and performing cracking on ice by using RIPA (Ribose nucleic acid) cracking liquid containing a protease inhibitor to extract the total protein of the cells. SDS-PAGE electrophoresis separation protein, wet transfer membrane method transfers the separation protein to PVDF membrane, the membrane transferred with protein is sealed in 5% skimmed milk for 1.5h, the sealing tableA non-specific antigen of the face. Adding the primary antibody of the detection target protein, and incubating overnight in a shaking table at 4 ℃. Then adding corresponding enzyme-linked labeled secondary antibody, and co-incubating for 1-2h in a shaking table at room temperature. And (3) the marked protein blotting membrane is used for developing and marking a target protein strip by using an ECL chemiluminescence method, and a multifunctional imager is used for collecting the information of the photo strip. And analyzing the gray value of the band by adopting ImageJ software, wherein the relative expression quantity of the target protein takes the expression quantity of the beta-actin reference protein as a reference.
EXAMPLE 50 in vivo experiment in mammalian nude mice (shown in FIG. 5)
Selecting 4-5 weeks male nude mice, inoculating the tumor cells under the skin of the nude mice with the inoculation amount of 1 × 10 per mouse7The cells are all nodulated for 7-10 days (subcutaneous tumor size reaches 50-150 mm)3) They were then randomly averaged into 4 groups of 5, each labeled as control, positive (CAL-101, i.e.: idelalisib) and experimental groups. The inhibitor is orally administrated, suspended in 0.1% PEG-400/0.5% cmcNA solution, the administration dose is 20mg/kg for positive group, the administration dose is 20mg/kg and 40mg/kg for experimental group, the administration is carried out once a day, the administration is continuously carried out for 14 days, the weight of the mouse and the size of subcutaneous tumor are recorded once 2-3 days, the state of the mouse is observed and recorded, the mouse is euthanized after 14 days, and the tumor is taken out. The in vivo treatment effect shows that the candidate drug molecule provided by the invention can be compared with a positive control group CAL-101.
EXAMPLE 51 in vivo tissue slice test experiment (shown in FIG. 6)
Feeding the food (90mg) of the azaindole derivative myeloproliferation inhibitor for one week, killing a nude mouse, taking tissue and viscera, washing the tissue and viscera with physiological saline or PBS, fixing the tissue and viscera in 4 percent paraformaldehyde, dehydrating and soaking the tissue and the viscera in wax, embedding, trimming blocks, slicing, sticking, fishing out slices, baking the slices, dewaxing, dyeing, dehydrating, sealing and taking pictures to obtain the azaindole derivative myeloproliferation inhibitor. The results of the tissue sections of the experimental groups show that the candidate drug molecules provided by the invention have no obvious damage to the tissues and organs.
It will be appreciated by persons skilled in the art that the embodiments of the invention described above and shown in the drawings are given by way of example only and are not limiting of the invention. The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (10)

1. An azaindole derivative myeloproliferative inhibitor, characterized in that the inhibitor has a compound having a structure represented by general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or cis-trans isomer thereof:
Figure FDA0002898256400000011
in the above formula I:
R1is H, -CH (OH) CH2OH、C1-4Alkyl, (C)1-4Alkyl) OH, isopropyl, cyclopropyl, phenyl or pyridyl;
R2is H, C1-6Alkyl radical, C1-6Branched alkyl, -CH2＝CRaRb、R21-phenyl, R22-pyridyl, methylpyrazole, piperidine, pyrrole, morpholine, pyrimidine or pyridazine;
R33in particular to one of the structures shown in the following formula:
Figure FDA0002898256400000012
R3is H, F, Cl, ORa、NRaRcOr CHRaR31；
R4Is H, Cl OR ORa；
RaIs H or C1-4An alkyl group;
Rbis H, C1-4Alkyl, cyclopropyl or cyclohexyl;
Rcis H, C1-4Alkyl radical, C1-4Alkylsulfonyl radical, R21-phenylsulfonyl or R22-a pyridine sulfonyl group;
R21is H, F, Cl, 2, 4-difluoro, 3, 5-difluoro, 3-fluoro-4-amine, -CONH2Morpholine or piperidine;
R22h, F, Cl, 2-fluoro-5-chloro, 2-fluoro-4-amine, morpholine or piperidine;
R31is H, C1-4Alkyl or-NH-hetCycle.
2. The azaindole derivative myelocyte proliferation inhibitor of claim 1, wherein R is1Is H, -CH (OH) CH2OH, cyclopropyl or pyridyl;
R2is H, -CH2＝CRaRb、R21-phenyl, R22-pyridyl, methylpyrazole, pyrrole, morpholine or pyrimidine;
R3is H, F, NRaRcOr CHRaR31；
R4Is H, Cl, OCH3Or OCH2CH3。
3. The azaindole derivative myelocyte proliferation inhibitor of claim 1, wherein R is31the-NH-hetCycle of (1), having any one of the following structural formulas:
Figure FDA0002898256400000013
4. an azaindole derivative myeloid cell proliferation inhibitor according to any of claims 1-3, wherein R is33The structural formula shown satisfies R3≠R4；
If R is33In R4Either Cl or-OCH3When R is3＝NRaRcOr CHRaR31；
If R is3＝NRaRcThen R is2Is R21-phenyl, R22-pyridyl, methylpyrazole, pyrrole or morpholine;
if R is3＝NRaRcAnd R iscIs R21-benzenesulfonyl, then R22Is F, 2-fluoro-5-chloro, 2-fluoro-4-amine, morpholine or piperidine;
if R is3＝CHRaR31Then R is2is-CH2＝CRaRb、R21-phenyl, methylpyrazole, piperidine, pyrrole, morpholine, pyrimidine or pyridazine.
5. The method for preparing an azaindole derivative myeloproliferative inhibitor according to claim 1, comprising the steps of:
(a) reacting a compound of formula II
Figure FDA0002898256400000021
With compounds of the formula III
Figure FDA0002898256400000022
Heating and refluxing the mixture for 8 to 10 hours by using a catalyst and an organic ligand under the conditions of alkali and an organic solvent to perform a coupling reaction;
if the formula II or the formula III has no protecting group, obtaining a corresponding formula I which is a final product;
if the formula II or the formula III carries a protecting group, the obtained formula I with the protecting group reacts with trifluoroacetic acid and dichloromethane or hydrochloric acid methanol solution at room temperature for 1-16 hours by stirring, and then the formula I is obtained by separation and purification;
or
(b) Reacting a compound of formula IV
Figure FDA0002898256400000023
With compounds of the formula V
Figure FDA0002898256400000024
Heating and refluxing the mixture for 8 to 10 hours by using a catalyst and an organic ligand under the conditions of alkali and an organic solvent to perform a coupling reaction;
if the formula II or the formula III has no protecting group, obtaining a corresponding formula I which is a final product;
if formula II or formula III has a protecting group, the obtained formula I with the protecting group is further reacted with trifluoroacetic acid and dichloromethane or hydrochloric acid methanol solution at room temperature for 1-16 hours under stirring, and then separated and purified to obtain the formula I.
6. The method for preparing the azaindole derivative myelocyte proliferation inhibitor according to claim 5, characterized in that the catalyst is any one of palladium chloride, palladium acetate, [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, zero-valent palladium, rhodium chloride, rhodium acetate, palladium acetylacetonate, rhodium acetylacetonate, palladium carbon and rhodium carbon.
7. The method of claim 5, wherein the organic ligand is selected from the group consisting of triphenylphosphine, triphenylphosphine oxide, (S) - (-) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, and (R) - (+) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, and combinations thereof.
8. The method for preparing an azaindole derivative myelocyte proliferation inhibitor according to claim 5, wherein the amount of the catalyst and the organic ligand is 0.02-0.1 equivalent of the reaction substrate, and the ratio of the catalyst to the organic ligand is 1: 0-1: 2.
9. The method for preparing an azaindole derivative myelocyte proliferation inhibitor according to claim 5, characterized in that the base is an inorganic base or an organic base selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, ammonia water or triethylamine; the organic solvent is selected from one of 1, 4-dioxane, glycol dimethyl ether or tetrahydrofuran.
10. The use of the azaindole derivative myelocyte proliferation inhibitor according to claim 1, which is used for preparing an inhibitor drug for myelocyte proliferation represented by MOLM-16, HL-60 and MV-4-11 or related autoimmune diseases, liquid tumors and solid tumors.
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Citations (4)

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