CN112794851B - 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor and preparation method and application thereof - Google Patents

3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor and preparation method and application thereof Download PDF

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CN112794851B
CN112794851B CN202110104809.9A CN202110104809A CN112794851B CN 112794851 B CN112794851 B CN 112794851B CN 202110104809 A CN202110104809 A CN 202110104809A CN 112794851 B CN112794851 B CN 112794851B
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azaindole
pi3k
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周亚明
凌云
贾瑜
杨永泰
刘小锋
邓名莉
陈珍霞
杨成斌
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Abstract

The invention provides a 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor shown in formula I, wherein R is 1 ,R 2 ,R 3 ,R 4 All have the meanings defined in the description of the invention. The compound contained in the formula I or the salt thereof and the related medicine composition can obviously inhibit the activity of PI3K delta kinase, has potential therapeutic application on diseases, diseases and symptoms related to PI3K delta kinase overexpression, and has great clinical prospect.

Description

3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemical drugs, in particular to a 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor, a preparation method and application thereof in pharmacy for treating immune diseases and cell proliferation or malignant tumors related to PI3K delta kinase.
Background
PI3K delta is one of the four subunits of PI3K kinase and is also an important member of the PI3K-AKT-mTOR signaling pathway. This pathway is critical for the growth of tumors, and tumor cells rely on this pathway to maintain growth, metastasis, and spread. Research shows that PI3K delta has an important role in regulating immune cells (such as B cells and T cells) and innate immune systems (such as neutrophils, mast cells and macrophages) and is a potential effective therapeutic target for various immune diseases. At present, the research and development of new drugs aiming at the target point in the world are in an active stage, and China is no exception. Representative PI3K δ inhibitors include: parsaclibib (shown below), developed by Incyte corporation, for use in inhibiting the growth and survival of malignant B-cell lymphoma; HMPL-689 developed by Chi-Med company is applied to high-selectivity inhibition of PI3K delta but not the activity of another subtype PI3K gamma of the same family, so that the risk of serious infection caused by immunosuppression can be reduced to the maximum extent; duvelisib developed by Verastem (shown below) for simultaneous inhibition of PI3K δ and PI3K γ activities to inhibit the survival and growth of cancerous B cells was approved by FDA for three lymphomas including: chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), and Follicular Lymphoma (FL); idelalisib (shown below) developed by Gilead corporation is used to induce apoptosis and inhibit proliferation of cells from malignant B-cells and primary tumors, achieving the goal of treating symptoms including leukemia and lymphoma. There are many applications of the same-species (Idelalisib) pharmaceutical imitation clinical trial proposed by China local enterprises, and all the applications have already been approved clinically, including 3.1 types of registration applications from Jiangsu Haofen and Zhengda Ningqing. However, Idelalisib carries 4 black box warnings, with the risk of serious adverse events. In addition, there is the application of Copanlisib (shown below) developed by Bayer corporation to inhibit both PI3K α and PI3K δ kinase subtypes in malignant B cells, thereby inducing tumor cell death and inhibiting proliferation of primary malignant B cells; CDZ173(Ieniolisib, shown below) developed by Novartis was applied to the syndrome associated with PI3K δ kinase (APDS) and primary immunodeficiency caused by mutations in related genes.
Figure RE-GDA0003013486140000021
Because the indole compounds have good biological activity, the research and development of related derivatives are widely concerned in the field of medicine. Chinese patent CN200980131983.X discloses an indole 2-position derivative functionalized IAP kinase inhibitor; chinese patents CN201280007145.3 and CN201610048667.8 disclose a 7-azaindole derivative, which mainly has the inhibitory effect on PDK1 and cell proliferation/cell viability; chinese patent CN201580007276.5 discloses a JAK3 inhibitor with 7-azaindole 4-position functionalized modification; chinese patent CN201580058210.9 discloses a 4-azaindole derivative having AMPK activation; 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 No. CN201910107786.X discloses an agonist with high selectivity, high affinity and high activity on a cannabinoid 2 receptor (CB2), which is azaindole functionally modified by amantadine; chinese patent CN202010265070.5 discloses an azaindole compound capable of effectively inhibiting SMAD 3-phosphorylation.
Although the indole compounds disclosed in the above are partially structurally related to indole derivative inhibitors including 3-position functionalization, the application field is not PI3K delta kinase and treatment of related diseases. Chinese patent No. CN201380043657.X discloses a 4-azaindole derivative PI3K delta inhibitor, which mainly comprises a compound based on the 5-position functional diffraction of 4-azaindole, and the structure of the derivative is a drug fragment based on tinib.
The invention provides an indole 3-position substituted derivative PI3K delta inhibitor, which is a 3-position substituted diffractogram based on azaindole or indole structure, and is different from the compound inhibitor disclosed above, and the 3-position substituted indole derivative provided by the invention is applied to the treatment of PI3K delta kinase and related diseases, disorders or symptoms, and is different from the application field of the indole compound disclosed above. Moreover, the 3-position substituted indole derivative PI3K delta inhibitor provided by the invention is structurally different from the drugs which are already in clinical use or are approved to be on the market, and simultaneously reaches nanomolar level in the aspect of selectively inhibiting the activity of PI3K delta kinase, so that the inhibitor has obvious advantages and potential huge clinical research and development values.
Disclosure of Invention
The invention aims to provide a 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor and a pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide pharmaceutical combinations of said 3- (pyridin-3 yl) -7-azaindole derivatives PI3K δ inhibitors or pharmaceutically acceptable salts thereof and to provide their inhibitory effect on PI3K δ kinase and related cells.
Still another object of the present invention is to provide a process for producing the 3- (pyridin-3 yl) -7-azaindole derivative PI3K δ inhibitor.
In order to achieve the above objects, the present invention provides a 3- (pyridin-3 yl) -7-azaindole derivative PI3K δ inhibitor, which is a compound having a structure represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or cis-trans isomer thereof:
Figure RE-GDA0003013486140000041
or a pharmaceutically acceptable salt thereof, wherein:
in the above formula I:
R 1 is H, F, Cl OR-OR a ；
R 2 Is H, F, Cl, (-OR) a )、(-NHR 21 ) Or (-CHR) a R 22 )；
R 3 Is prepared byR a Piperidinyl, pyrrolyl, morpholinyl, pyrimidinyl, pyridazinyl or 5- (R) 31 -yl) -oxazole;
R 4 is-R a Piperidinyl, pyrrolyl, morpholinyl, pyrimidinyl, pyridazinyl or 5- (R) 31 -yl) -oxazole;
R a is H, C 1-4 Alkyl, cyclopropyl or cyclohexyl;
R 21 is C 1-4 An alkylsulfonyl, substituted benzenesulfonamide, or substituted pyridinesulfonamide group;
R 22 is-NH-hetCycle;
R 31 is 1-ethyl-4-isopropyl piperazine, 4-ethyl-2, 6-dimethyl morpholine.
It is to be noted that formula I shall include stereoisomers, tautomers or cis-trans isomers.
The key of the substituent combination of the 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor with the structure of the general formula I is as follows: r is 1 、R 2 、R 3 、R 4 Not H at the same time.
The invention provides a 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor with a structure shown in a general formula I, wherein R is 2 is-NHR 21 The substituent is specifically any one of the following structural formulae.
Figure RE-GDA0003013486140000051
Wherein: when R is 2 In the case of alkylsulfonamides, n-0 is the most preferable inhibitory activity or pharmaceutical activity; when R is 2 The benzenesulfonamide or pyridinesulfonamide modified with a fluorine function is most preferable in the inhibitory activity or the pharmaceutical activity of the benzenesulfonamide or pyridinesulfonamide.
The present invention provides 3- (pyridin-3 yl) -7-azaindole derivatives of formula I, PI3K delta inhibitors, wherein R is 3 is-CHR a R 22 When the substituent is selected from any one of the following structural formulas:
Figure RE-GDA0003013486140000061
wherein, the compound has better PI3K delta inhibitory activity when being selected from the following structural formulas:
Figure RE-GDA0003013486140000062
it should be noted that the optically pure structure in the above structural formula has better PI3K δ inhibitory activity than the racemate.
The invention provides 3- (pyridin-3 yl) -7-azaindole derivatives PI3K delta inhibitors having the formula I wherein R 3 And R 4 And cannot be simultaneously non-hydrogen groups.
When R is 3 When H, R 4 Is any one of the structural formulas shown as follows:
Figure RE-GDA0003013486140000071
when R is 4 When H, R 3 Is any one of the structural formulas shown as follows:
Figure RE-GDA0003013486140000072
wherein R is 3 When R4 is H, the 3- (pyridin-3 yl) -7-azaindole derivative has a better PI3K δ inhibitory activity.
In addition, R is as defined above 3 Or R 4 The optically pure structure in the structural formula has better PI3K delta selective inhibition activity or better druggability than that of racemate, and the specific structural formula is one of the following structures.
Figure RE-GDA0003013486140000073
It should be noted that the 3- (pyridine-3-yl) -7-azaindole derivative PI3K δ inhibitor provided by the present invention is different from a canonical PI3K inhibitor with quinoline as a core in structural formula (shown in the following formula, Knight, s. etc., ACS med. chem. lett.2010,1(1), 39-43; Nishimura, n. etc., j.med. chem.2011,54(13), 4735-:
Figure RE-GDA0003013486140000074
wherein: r 1 ，R 2 The specific chemical meaning of the group is defined in the literature.
The 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor provided by the invention is different from any PI3K delta inhibitor clinically or on the market (described in the background).
It should be noted that the 3- (pyridin-3 yl) -7-azaindole derivative PI3K δ inhibitor provided by the present invention is neither different from the compound related to chinese patent 201380043657.
Figure RE-GDA0003013486140000081
In order to achieve the above object, the present invention provides a pilot plant production method for preparing the 3- (pyridin-3 yl) -7-azaindole derivative PI3K delta inhibitor.
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, heating and refluxing for 10-48 hours under the conditions of alkali or no alkali and organic solvent by using a catalyst and an organic ligand to perform a coupling reaction, directly separating and purifying to obtain formula I if the formula II and the formula III are free of protecting groups, removing the protecting groups under the corresponding deprotection conditions after the reaction if the formula II and the formula III are limited to have one or more protecting groups under the reaction conditions, and separating and purifying to obtain the formula I.
Flow (a)
Figure RE-GDA0003013486140000082
Incidentally, the preparation of formula I can also be obtained by using the reaction steps described in (a) for formula IV and formula V, which are defined as (b) accordingly.
Figure RE-GDA0003013486140000091
It should be noted that the noble metal catalyst and the organic ligand are catalyst equivalents of the reaction substrate, preferably 0.05 to 0.15 equivalent.
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, [1, 1' -bis (diphenylphosphino) ferrocene ] rhodium dichloride, rhodium chloride, rhodium acetate, palladium acetylacetonate, rhodium acetylacetonate, palladium carbon and rhodium carbon, and the organic ligand includes: 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 a chiral structure of formula I is prepared, a chiral organophosphine ligand is 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, and it is noted that when the substituents contain chiral structures, chiral catalysis, separation or resolution can be used in the raw material stage, or after the formula I is obtained by synthesis, a preparative chiral column can be used for resolution.
Another object of the present invention is to provide the 3- (pyridin-3 yl) -7-azaindole derivative PI3K delta inhibitor which is pharmaceutically acceptableA salt. 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 acids, hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids with a pKa under standard conditions 1 <4.5, it is preferable that the biological compatibility is good and the pharmacodynamic activity of the formula I is not seriously affected.
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 is reacted with the appropriate acid to obtain the desired salt, or the protecting group is removed from the protecting group precursor of the formula I under the corresponding acid condition to obtain the formula I which is directly salified.
It is noted that the formula I or the above pharmaceutically acceptable salts may exist in amorphous or crystalline form when used in pharmaceutical applications.
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 solvent molecules are contained, water molecules, ethanol molecules, DMSO molecules are used.
Another object of the present invention is to provide the inhibitory effect of the 3- (pyridin-3 yl) -7-azaindole derivative PI3K delta inhibitor or pharmaceutically acceptable salt on PI3K delta kinase and related cell proliferation.
The invention also aims to provide the 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor or pharmaceutically acceptable salt or pharmaceutical combination thereof, which is applied to the treatment effect of the inoculated tumor of the mammals and the related basic pharmaceutical evaluation.
It is noted that formula I or a salt thereof or a corresponding pharmaceutical combination thereof as indicated above is applied for the treatment of said PI3K δ kinase overexpression and its associated cell proliferation or its associated clinical diseases, comprising: an immune system disease, a liquid tumor, a solid tumor, or a cancerous disease for which a beneficial therapeutic effect is obtained, comprising: lymphoma, hematological tumor, myeloid leukemia, multiple myeloma, brain tumor, lung cancer, non-small cell lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, human breast ductal tumor, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumor, prostate cancer, thyroid cancer, cancer of the female reproductive tract, carcinoma in situ, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, melanoma, glioma, or sarcoma.
The 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor provided by the invention has the beneficial effects or has the main advantages compared with the existing clinical test inhibitors:
(1) the invention provides a 3- (pyridine-3-yl) -7-azaindole derivative PI3K delta inhibitor, R 1 、R 2 、R 3 、R 4 Groups or elements of definite chemical significance and combinations thereof, the compounds of formula I resulting from the combination thereof being free of indole compounds which are also not encompassed by the relevant chinese patents which have been published prior to the present patent application.
(2) The 3- (pyridine-3-yl) -7-azaindole derivative provided by the invention is a PI3K delta kinase inhibitor or a salt thereof, is applied to PI3K delta kinase to inhibit IC50 of the PI3 3578 delta kinase to reach nanomole level, has the inhibition activity comparable to or superior to that of a PI3K delta inhibitor in clinical research or on the market, and has expected beneficial effects.
(3) The 3- (pyridine-3-yl) -7-azaindole derivative provided by the invention is a PI3K delta kinase inhibitor or a salt or a pharmaceutical composition thereof, shows good inhibition of cell level and therapeutic effect of model animals, has high bioavailability, meets basic biological safety, and has great clinical research value.
Drawings
FIG. 1 shows the general formula of the molecular structure of formula I.
FIG. 2 shows the cell proliferation inhibitory effect and cell morphology of MOLM-16 cells acted on by the molecule of formula I.
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.
In order to more clearly show the summary of the invention, the specific molecular structure of the compound of formula I was synthesized according to scheme (a) described in the present specification. It is to be noted that formula I presented below is only representative in the present description.
EXAMPLE 1N- (2-chloro-5- (1H-7-azaindol-3-yl) pyridin-3-yl) benzenesulfonamide
Figure RE-GDA0003013486140000111
To a 10.0mL round bottom flask, under a nitrogen atmosphere, 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), 1-BOC-3-bromo-7-azaindole (0.083g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl, respectively 2 (dppf)(0.0055g，7.59×10 -3 mmol), and then reacted at 100 deg.c for 12 hours, cooled to room temperature, dried the solvent under reduced pressure, and purified by column chromatography to give 1 as a brown solid (yield: 40%). 1 H NMR(400MHz,DMSO-d 6 )δ7.19 (s,1H),7.62(d,J＝5.6Hz,2H),7.70(d,J＝6.0Hz,1H),7.81(d,J＝6.0Hz,2H), 7.91(s,2H),8.06(s,1H),8.32(s,1H),8.61(s,1H),10.43(s,1H),12.19(s,1H)。
Example 2 Aza- (2-methoxy-5- (1H-7-azaindol-3-yl) pyridin-3-yl) benzenesulfonamide
Figure RE-GDA0003013486140000121
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) benzenesulfonamide (0.10g,0.26mmol), 1-BOC-3-bromo-7-azaindole (0.083g,0.279mmol), respectivelyPotassium carbonate hydrate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and Pd (PPh) 3 ) 4 (0.0088g，7.59×10 -3 mmol), then reacted at 100 ℃ for 12 hours, cooled to room temperature, spin-dried the solvent under reduced pressure, and purified by column chromatography to give brown solid 2 (yield: 43%). 1 H NMR(400MHz,DMSO-d 6 )δ3.83 (s,3H),7.19(s,1H),7.62(d,J＝5.6Hz,2H),7.70(d,J＝6.0Hz,1H),7.83(d,J＝ 6.0Hz,2H),7.93(s,2H),8.11(s,1H),8.32(s,1H),8.61(s,1H),10.31(s,1H), 11.93(s,1H)。
Example 34-fluoro-N- (2-methoxy-5- (1H-7-azaindol-3-yl) pyridin-3-yl) benzenesulfonamide
Figure RE-GDA0003013486140000122
To a 10.0mL round bottom flask under nitrogen was added 4-fluoro-N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.24mmol), 1-BOC-3-bromo-7-azaindole (0.083g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and Pd (PPh) 3 ) 4 (0.0088g，7.59×10 -3 mmol), and then reacted at 100 c for 12 hours, cooled to room temperature, dried the solvent under reduced pressure, and purified by column chromatography to give 3 (yield: 36%) as a brown yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ 3.83(s,3H),7.21(s,1H),7.62(d,J＝5.6Hz,2H),7.81(d,J＝6.0Hz,2H),7.91 (s,2H),8.06(s,1H),8.13(s,1H),8.66(s,1H),10.45(s,1H),12.07(s,1H)。
Example 42, 4-difluoro-N- (2-chloro-5- (1H-7-azaindol-3-yl) pyridin-3-yl) benzenesulfonamide
Figure RE-GDA0003013486140000131
To a 10.0mL round bottom flask under nitrogen was added 2, 4-difluoro-nitrogen- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.23mmol), 1-BOC-3-bromo-7-azaindole (0.083g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and PdCl 2 (dppf)(0.0055g， 7.59×10 -3 mmol), and then reacted at 100 deg.c for 12 hours, cooled to room temperature, dried the solvent under reduced pressure, and purified by column chromatography to give 4 (yield: 39%) as a brown solid. 1 H NMR(400MHz, DMSO-d 6 )δ7.16(s,1H),7.62(d,J＝5.6Hz,1H),7.70(d,J＝6.0Hz,1H),7.85 (d,J＝6.0Hz,1H),7.86(s,2H),8.06(s,1H),8.29(s,1H),8.63(s,1H),10.01(s, 1H),12.25(s,1H)。
Example 52, 4-difluoro-N- (2-methoxy-5- (1H-7-azaindol-3-yl) pyridin-3-yl) benzenesulfonamide
Figure RE-GDA0003013486140000141
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) benzenesulfonamide (0.10g,0.23mmol), 1-BOC-3-bromo-7-azaindole (0.083g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and Pd (PPh) 3 ) 4 (0.0088g， 7.59×10 -3 mmol), then reacted at 100 ℃ for 12 hours, cooled to room temperature, spin-dried the solvent under reduced pressure, and purified by column chromatography to give a tan solid 5 (yield: 36%). 1 H NMR(400MHz, DMSO-d 6 )δ3.83(s,3H),7.21(s,1H),7.62(d,J＝5.6Hz,1H),7.81(d,J＝6.0 Hz,2H),7.88(s,2H),8.06(s,1H),8.19(s,1H),8.56(s,1H),10.31(s,1H),12.07 (s,1H)。
Example 6 Nitrogen- (2-chloro-5- (1H-7-azaindol-3-yl) pyridin-3-yl) methanesulfonamide
Figure RE-GDA0003013486140000142
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) methanesulfonamide (0.10g,0, respectively30mmol), 1-BOC-3-bromo-7-azaindole (0.083g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (1.50mL) and PdCl 2 (dppf)(0.0055g，7.59×10 -3 mmol), followed by reaction at 110 ℃ for 6 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, and purification by column chromatography to give brown solid 6 (yield: 40%). 1 H NMR(400MHz,DMSO-d 6 )δ2.95(s,3H),7.10 (s,1H),7.26(d,J＝6.0Hz,1H),7.70(s,1H),7.81(d,J＝6.0Hz,2H),8.63(s, 1H),10.43(s,1H),12.19(s,1H)。
EXAMPLE 7 Aza- { 2-methoxy-5- [5- (piperidin-1-yl) -1H-7-azaindol-3-yl ] pyridin-3-yl } methanesulfonamide
Figure RE-GDA0003013486140000151
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) methanesulfonamide (0.10g,0.30mmol), 1-BOC-3-bromo-5-piperidine-7-azaindole (0.106g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (1.50mL) and Pd (PPh) 3 ) 4 (0.0088g，7.59×10 -3 mmol), followed by reaction at 110 ℃ for 6 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, and purification by column chromatography to give 7 as a brown solid (yield: 41%). 1 H NMR(400MHz,DMSO-d 6 )δ 1.60-1.66(m,6H),2.95(s,3H),3.08(d,J＝7.2Hz,4H),3.83(s,3H),7.10(s,1H), 7.26(s,1H),7.70(d,J＝6.0Hz,2H),8.04(s,1H),10.13(s,1H),11.79(s,1H)。
EXAMPLE 8 Aza- { 2-chloro-5- [5- (piperidin-1-yl) -1H-7-azaindol-3-yl ] pyridin-3-yl } pyridine-4-sulfonamide
Figure RE-GDA0003013486140000152
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) pyridine-4-sulfonamide (0.10g,0.25mmol), respectively) 1-BOC-3-bromo-5-piperidine-7-azaindole (0.106g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (1.50mL) and Pd (PPh) 3 ) 4 (0.0088g，7.59×10 -3 mmol), followed by reaction at 110 ℃ for 6 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, and purification by column chromatography to give brown solid 8 (yield: 35%). 1 H NMR(400MHz,DMSO-d 6 )δ 1.60-1.66(m,6H),3.06(d,J＝7.2Hz,4H),6.83(s,1H),7.10(s,1H),7.86(s,1H), 8.36(d,J＝6.0Hz,3H),8.79(t,J＝7.6Hz,3H),10.23(s,1H),11.59(s,1H)。
Example 9 Aza- { 2-chloro-5- [5- (morpholin-1-yl) -1H-7-azaindol-3-yl ] pyridin-3-yl } pyridine-4-sulfonamide
Figure RE-GDA0003013486140000161
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) pyridine-4-sulfonamide (0.10g,0.25mmol), 1-BOC-3-bromo-5-morpholine-7-azaindole (0.106g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (1.50mL), and Pd (PPh) 3 ) 4 (0.0088g，7.59×10 -3 mmol), followed by reaction at 110 ℃ for 6 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, and purification by column chromatography to give brown solid 9 (yield: 35%). 1 H NMR(400MHz,DMSO-d 6 )δ3.18 (t,J＝7.2Hz,4H),3.72(t,J＝7.2Hz,4H),6.86(s,1H),7.10(s,1H),7.80(s,1H), 8.39(d,J＝6.0Hz,3H),8.79(t,J＝7.6Hz,3H),10.13(s,1H),12.09(s,1H)。
EXAMPLE 10 Aza- { 2-chloro-5- [5- (tetrahydropyrrol-1-yl) -1H-7-azaindol-3-yl ] pyridin-3-yl } pyridine-4-sulfonamide
Figure RE-GDA0003013486140000162
To a 10.0mL round bottom flask, under nitrogen, was added nitrogen- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)) Pyridin-3-yl) pyridine-4-sulfonamide (0.10g,0.25mmol), 1-BOC-3-bromo-5-tetrahydropyrrole-7-azaindole (0.102g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), dioxane (1.50mL) and Pd (PPh) 3 ) 4 (0.0088g， 7.59×10 -3 mmol), then reacted at 100 ℃ for 12 hours, cooled to room temperature, spin-dried the solvent under reduced pressure, and purified by column chromatography to give 10 as a yellow solid (yield: 45%). 1 H NMR(400MHz, DMSO-d 6 )δ1.93(t,J＝7.6Hz,4H),3.52(t,J＝7.6Hz,4H),6.91(s,1H),7.16(s, 1H),7.81(s,1H),8.39(d,J＝6.0Hz,3H),8.79(t,J＝7.6Hz,3H),10.21(s,1H), 11.35(s,1H)。
EXAMPLE 11 Aza- { 2-chloro-5- [6- (pyrimidin-5-yl) -1H-7-azaindol-3-yl ] pyridin-3-yl } -2-fluoropyridine-4-sulfonamide
Figure RE-GDA0003013486140000171
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-fluoropyridine-4-sulfonamide (0.10g,0.24mmol), 1-BOC-3-bromo-6-pyrimidine-7-azaindole (0.105g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (1.50mL) and PdCl, respectively 2 (dppf)(0.0055g，7.59×10 -3 mmol), followed by reaction at 110 ℃ for 5 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, and purification by column chromatography to give 11 as a yellow solid (yield: 45%). 1 H NMR(400MHz,DMSO-d 6 )δ 6.86(s,1H),7.89-8.00(m,4H),8.21(d,J＝7.6Hz,1H),8.51(d,J＝7.6Hz,1H), 8.69(s,1H),9.36(s,1H),9.67(s,1H),10.21(s,1H),11.35(s,1H)。
EXAMPLE 12 Aza- { 2-chloro-5- [6- (pyridazin-5-yl) -1H-7-azaindol-3-yl ] pyridin-3-yl } -2-fluoropyridine-4-sulfonamide
Figure RE-GDA0003013486140000172
Separately, under nitrogen atmosphere, nitrogen was added to a 10.0mL round-bottomed flask- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) -2-fluoropyridine-4-sulfonamide (0.10g,0.17mmol), 1-BOC-3-bromo-6-pyridazine-7-azaindole (0.105g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (1.50mL) and PdCl 2 (dppf)(0.0055g，7.59×10 -3 mmol), followed by reaction at 110 ℃ for 5 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, and purification by column chromatography to give 12 as a brown solid (yield: 43%). 1 H NMR(400MHz,DMSO-d 6 )δ 6.93(s,1H),7.86-8.01(m,4H),8.23(d,J＝7.6Hz,1H),8.49(d,J＝7.6Hz,1H), 8.69(s,1H),9.36(s,1H),9.73(s,1H),10.61(s,1H),12.15(s,1H)。
Example 134-fluoro-N- {5- [5- (5- ((4-isopropylpiperazin-1-yl) methyl) oxazol-2-yl ] -1H-7-azaindol-3-yl-2-methoxypyridin-3-yl } benzenesulfonamide
Figure RE-GDA0003013486140000181
To a 10.0mL round bottom flask under nitrogen was added 4-fluoro-N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.24mmol), 1-BOC-3-bromo-5- (5- ((4-isopropylpiperazin-1-yl) methyl) oxazol-2-yl) -1H-7-azaindole (0.141g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and Pd (PPh), respectively 3 ) 4 (0.0088g，7.59×10 -3 mmol), followed by reaction at 100 ℃ for 12 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, and purification by column chromatography to give brown solid 13 (yield: 36%). 1 H NMR(400MHz,DMSO-d 6 )δ1.12(d,J＝7.6Hz,6H),2.32 (t,J＝7.2Hz,4H),2.49(t,J＝7.2Hz,4H),2.73(m,1H),3.83(s,3H),3.93(s, 2H),7.21(s,1H),7.68(s,1H),7.62(d,J＝5.6Hz,2H),7.81(d,J＝6.0Hz,2H), 7.98(d,J＝5.6Hz,2H),8.13(s,1H),9.06(s,1H),10.61(s,1H),11.96(s,1H)。
EXAMPLE 14 Aza- {5- [5- (5- (((2S,6R) -2, 6-dimethylmorpholine) methyl) oxazol-2-yl ] -1H-7-azaindol-3-yl-2-methoxypyridin-3-yl } 4-fluorobenzenesulfonamide
Figure RE-GDA0003013486140000191
To a 10.0mL round bottom flask was added under nitrogen, respectively, 4-fluoro-N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.24mmol), 1-BOC-3-bromo-5- (5- (((2S,6R) -2, 6-dimethylmorpholine) methyl) oxazol-2-yl) -1H-7-azaindole (0.137g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and Pd (PPh) 3 ) 4 (0.0088g，7.59×10 -3 mmol), then reacted at 100 ℃ for 12 hours, cooled to room temperature, spin-dried the solvent under reduced pressure, and purified by column chromatography to give 14 as a beige solid (yield: 40%). 1 H NMR(400MHz,DMSO-d 6 )δ1.12(d,J＝7.6Hz,6H), 2.36(t,J＝7.2Hz,4H),3.47-3.69(m,2H),3.83(s,3H),6.96(s,1H),7.68(s,1H), 7.62(d,J＝5.6Hz,2H),7.83(d,J＝7.2Hz,2H),7.98(d,J＝5.6Hz,2H),9.31(s, 1H),10.61(s,1H),11.96(s,1H)。
EXAMPLE 15N- [5- (5-cyclobutyl-1H-7-azaindol-3-yl) -2-methoxypyridin-3-yl ] -4-fluorobenzenesulfonamide
Figure RE-GDA0003013486140000192
To a 10.0mL round bottom flask was added 4-fluoro-N- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.10g,0.24mmol), 1-BOC-3-bromo-5-cyclobutyl-7-azaindole (0.098g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), 1, 4-dioxane (1.50mL) and Pd (PPh) respectively under a nitrogen atmosphere 3 ) 4 (0.0088 g，7.59×10 -3 mmol), and then reacted at 100 deg.c for 12 hours, cooled to room temperature, dried the solvent under reduced pressure, and purified by column chromatography to obtain 15 (yield: 36%) as a yellow solid. 1 H NMR(400MHz, DMSO-d 6 )δ1.61-1.70(m,2H),1.81-2.06(m,4H),3.11-3.21(m,1H),3.86(s,3H), 7.16(s,1H),7.49(d,J＝6.0Hz,2H),7.81(d,J＝6.0Hz,3H),7.98(d,J＝7.2Hz, 2H),8.47(s,1H),11.15(s,1H),12.07(s,1H)。
Example 16(S) -Nitrogen- (1- (2-methoxy-5- (1H-7-azaindol-3-yl) pyridin-3-yl) propyl) -9H-purin-6-amine
Figure RE-GDA0003013486140000201
To a 10.0mL round bottom flask under nitrogen was added N- (1- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-3-yl) propyl) -9H-purin-6-amine (0.10g,0.24mmol), 1-BOC-3-bromo-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 -3 mmol), 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 16 as a brown solid (yield: 30%). 1 H NMR(400MHz,DMSO-d 6 )δ0.89(t,J＝8.0Hz,3H),1.28-1.34(m,2H), 3.81(t,J＝8.0Hz,1H),4.03(s,3H),6.81(s,1H),6.89(s,1H),7.17(t,J＝7.2Hz, 1H),7.86(s,1H),8.03(s,1H),8.20(s,2H),8.39(d,J＝7.2Hz,1H),8.51(d,J＝ 7.2Hz,1H),10.18(s,1H),12.65(s,1H)。
Example 17(S) -Nitrogen- (1- (2-chloro-5- (1H-7-azaindol-3-yl) pyridin-3-yl) propyl) -9H-purin-6-amine
Figure RE-GDA0003013486140000202
To a 10.0mL round bottom flask, under nitrogen, was added N- (1- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) propyl) -9H-purin-6-amine (0.10g,0.24mmol), 1-BOC-3-bromo-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 -3 mmol), reacting at 110 deg.C for 6 hr, cooling to room temperature, diluting the reaction solution with ethyl acetate, and reducing pressureThe solvent was dried by spinning, purified by column chromatography, and concentrated to give 17 (yield: 33%) as a brown solid. 1 H NMR (400MHz,DMSO-d 6 )δ0.89(t,J＝8.0Hz,3H),1.28-1.34(m,2H),3.81(t,J＝ 8.0Hz,1H),6.83(s,1H),7.16(s,1H),7.37(t,J＝7.2Hz,1H),7.86(s,1H),8.13 (s,1H),8.23(s,2H),8.39(d,J＝7.2Hz,1H),8.51(d,J＝7.2Hz,1H),10.08(s, 1H),12.35(s,1H)。
Example 18(S) -Nitrogen- (1- (2-chloro-5- (5- (piperidin-1-yl) -1H-7-azaindol-3-yl) pyridin-3-yl) propyl) -9H-purin-6-amine
Figure RE-GDA0003013486140000211
To a 10.0mL round bottom flask, under nitrogen, was added N- (1- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) propyl) -9H-purin-6-amine (0.10g,0.24mmol), 1-BOC-3-bromo-5-piperidine-7-azaindole (0.106g,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 -3 mmol), 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 18 as a brown solid (yield: 35%). 1 H NMR(400MHz,DMSO-d 6 )δ0.89(t,J＝8.0Hz,3H),1.28-1.34(m,2H), 1.60-1.76(m,6H),3.06(t,J＝4.0Hz,4H),3.81(t,J＝8.0Hz,1H),6.83(s,1H), 7.16(s,1H),7.26(s,1H),7.86(s,1H),8.13(s,1H),8.23(s,1H),8.51(s,1H), 9.13(s,1H),11.18(s,1H),12.35(s,1H)。
Example 19(S) -Nitrogen- (1- (2-chloro-5- (5- (morpholin-1-yl) -1H-7-azaindol-3-yl) pyridin-3-yl) propyl) -9H-purin-6-amine
Figure RE-GDA0003013486140000221
To a 10.0mL round bottom flask, under nitrogen, was added N- (1- (2-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) propyl) -9H-purin-6-amine (0.10g,0, respectively24mmol), 1-BOC-3-bromo-5-morpholine-7-azaindole (0.107g,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 -3 mmol), 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 19 as a brown solid (yield: 40%). 1 H NMR(400MHz,DMSO-d 6 )δ0.94(t,J＝8.0Hz,3H),1.28-1.34(m,2H), 3.18(t,J＝5.6Hz,4H),3.36-3.72(m,4H),3.81(t,J＝8.0Hz,1H),6.83(s,1H), 7.16(s,1H),7.26(s,1H),7.86(s,1H),8.13(s,1H),8.23(s,1H),8.51(s,1H), 9.13(s,1H),11.18(s,1H),12.35(s,1H)。
Example 20(S) -4- (1- (2-chloro-5- (6- (5- ((4-isopropylpiperazin-1-yl) methyl) oxazol-2-yl) -1H-7-azaindol-3-yl) pyridin-3-yl) ethyl) amino) -5-fluoropyrimidin-2 (1H) -one
Figure RE-GDA0003013486140000222
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-dioxapentaborane-2-yl) pyridin-3-yl) ethyl) amino) -5-fluoropyrimidin-2 (1H) -one (0.10g,0.25mmol), 1-BOC-3-bromo-6- (5- ((4-isopropylpiperazin-1-yl) methyl) oxazol-2-yl) -1H-7-azaindole (0.141g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and PdCl, respectively 2 (dppf)(0.0055g，7.59×10 -3 mmol), 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 20 as a brown solid (yield: 41%). 1 H NMR(400MHz, DMSO-d 6 )δ1.02(d,J＝7.2Hz,6H),1.51(d,J＝7.6Hz,3H),2.33(t,J＝7.2Hz, 4H),2.53(t,J＝7.2Hz,4H),2.60-2.72(m,1H),3.81(s,1H),3.96(q,J＝7.6Hz, 1H),6.83(s,1H),7.16(s,1H),7.96-8.13(m,3H),8.86(s,1H),9.13(s,1H),9.61 (s,1H),11.18(s,1H),12.35(s,1H)。
Example 215-chloro-N- ((S) -1- (5- (5- (((2S,6R) -2, 6-dimethylmorpholine) methyl) oxazol-2-yl) -1H-7-azaindol-3-yl) -2-methoxypyridin-3-yl) ethyl) -2, 6-dimethylpyrimidin-4-amine
Figure RE-GDA0003013486140000231
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-dioxapentaborane-2-yl) pyridin-3-yl) ethyl) -2, 6-dimethylpyrimidin-4-amine (0.10g,0.24mmol), 1-BOC-3-bromo-5- (5- (((2S,6R) -2, 6-dimethylmorpholine) methyl) oxazol-2-yl) -1H-7-azaindole (0.137g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and PdCl, respectively 2 (dppf)(0.0055g，7.59×10 -3 mmol), then reacted at 110 ℃ for 6 hours, cooled to room temperature, diluted with ethyl acetate, dried under reduced pressure of the solvent, purified by column chromatography, and concentrated to give 21 as a yellow solid (yield: 39%). 1 H NMR(400MHz,DMSO-d 6 )δ1.12(d,J＝7.2Hz,6H),1.38(d,J＝7.6Hz, 3H),2.33(d,J＝7.2Hz,2H),2.37(d,J＝7.2Hz,2H),2.46(s,6H),3.59-3.63(m, 4H),4.02(m,4H),7.01(s,1H),7.26(s,1H),7.83(s,1H),8.13(d,J＝7.2Hz,2H), 8.36(s,1H),9.13(s,1H),11.18(s,1H)。
Example 22(S) -5-chloro-N- (1- (2-methoxy-5- (5- (tetrahydropyrrol-1-yl) -1H-7-azaindol-3-yl) -pyridin-3-yl) ethyl) -2, 6-dimethylpyrimidin-4-amine
Figure RE-GDA0003013486140000241
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) ethyl) -2, 6-dimethylpyrimidin-4-amine (0.10g,0.24mmol), 1-BOC-3-bromo-5-tetrahydropyrrole-7-azaindole (0.102g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and PdCl, respectively 2 (dppf)(0.0055g，7.59×10 - 3 mmol) and then reacted at 110 deg.CAfter 6 hours, it was cooled to room temperature, the reaction was diluted with ethyl acetate, the solvent was dried by spinning under reduced pressure, purified by column chromatography, and concentrated to give 22 (yield: 35%) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ1.38(d,J ＝7.6Hz,3H),2.33(t,J＝7.2Hz,4H),2.37(s,6H),2.46(t,J＝7.2Hz,4H), 3.59-3.63(m,4H),7.01(s,1H),7.23(s,1H),7.68(s,1H),8.13(d,J＝7.2Hz,2H), 8.56(s,1H),10.18(s,1H)。
Example 23(S) -5-chloro-N- (1- (2-methoxy-5- (5- (piperidin-1-yl) -1H-7-azaindol-3-yl) -pyridin-3-yl) propyl) -2, 6-dimethylpyrimidin-4-amine
Figure RE-GDA0003013486140000242
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,0.21mmol), 1-BOC-3-bromo-5-piperidine-7-azaindole (0.106g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (2.00mL) and PdCl, respectively 2 (dppf)(0.0055g，7.59×10 - 3 mmol), followed by reaction at 110 ℃ for 6 hours, cooling to room temperature, dilution of the reaction solution with ethyl acetate, spin-drying of the solvent under reduced pressure, purification by column chromatography, and concentration to give 23 as a brown solid (yield: 39%). 1 H NMR(400MHz,DMSO-d 6 )δ1.02(t,J ＝7.6Hz,3H),1.45-1.49(m,2H),2.13(t,J＝7.6Hz,6H),2.27(s,6H),2.49(t,J ＝7.6Hz,4H),3.57-3.61(m,4H),7.13(s,1H),7.21(s,1H),7.58(s,1H),8.03(d, J＝7.2Hz,2H),8.36(s,1H),10.07(s,1H)。
Example 24(S) -5-chloro-N- (1- (2-methoxy-5- (6- (pyrimidin-5-yl) -1H-7-azaindol-3-yl) -pyridin-3-yl) propyl) -2, 6-dimethylpyrimidin-4-amine
Figure RE-GDA0003013486140000251
To a 10.0mL round bottom flask, under nitrogen, was added (S) -5-chloro-N- (1- (2-methyl) separatelyOxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) propyl) -2, 6-dimethylpyrimidin-4-amine (0.10g,0.21mmol), 1-BOC-3-bromo-6-pyrimidine-7-azaindole (0.105g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (1.50mL) and PdCl 2 (dppf)(0.0055g，7.59×10 - 3 mmol), then reacted at 110 ℃ for 5 hours, cooled to room temperature, diluted with ethyl acetate, spin-dried the solvent under reduced pressure, purified by column chromatography, and concentrated to give off-white solid 24 (yield: 39%). 1 H NMR(400MHz,DMSO-d 6 )δ1.02(t, J＝7.6Hz,3H),1.45-1.49(m,2H),2.13(t,J＝7.6Hz,6H),3.81(t,J＝7.6Hz, 1H),4.03(s,3H),7.13(s,1H),7.23(s,1H),7.94-8.05(m,3H),8.23(s,1H),9.36 (s,1H),10.07(s,2H),11.01(s,1H)。
Example 255-chloro-N- (1- (5- (6-cyclobutyl-1H-7-azaindol-3-yl) -2-methoxypyridin-3-yl) ethyl) -2, 6-dimethylpyrimidin-4-amine
Figure RE-GDA0003013486140000261
To a 10.0mL round bottom flask under nitrogen was added 5-chloro-N- (1- (2-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) pyridin-3-yl) ethyl) -2, 6-dimethylpyrimidin-4-amine (0.10g,0.24mmol), 1-BOC-3-bromo-6-cyclobutyl-7-azaindole (0.098g,0.279mmol), anhydrous potassium carbonate (0.087g,0.633mmol), water (0.50mL), toluene (1.50mL) and PdCl, respectively 2 (dppf)(0.0055g，7.59×10 - 3 mmol), then reacted at 110 ℃ for 5 hours, cooled to room temperature, diluted with ethyl acetate, dried under reduced pressure of the solvent, purified by column chromatography, and concentrated to give a tan solid 25 (yield: 39%). 1 H NMR(400MHz,DMSO-d 6 )δ1.38(d, J＝7.6Hz,3H),1.61-1.71(m,2H),1.81-2.09(m,4H),2.13(s,6H),3.01-3.19(m, 1H),3.97-4.03(m,4H),5.13(s,1H),7.02(s,1H),7.23(d,J＝7.2Hz,1H),7.43(d, J＝7.2Hz,1H),8.05(s,1H),8.23(s,1H),10.01(s,1H)。
Example 26(S) -Nitrogen- (1- (5- (5- (5- ((4-isopropylpiperazin-1-yl) methyl) oxazol-2-yl) -1H-7-azaindol-3-yl) -2-methoxypyridin-3-yl) propyl) -9H-purin-6-amine
Figure RE-GDA0003013486140000262
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) propyl) -9H-purin-6-amine (0.10g,0.24mmol), 1-BOC-3-bromo-5- (5- ((4-isopropylpiperazin-1-yl) methyl) oxazol-2-yl) -1H-7-azaindole (0.141g,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 -3 mmol), 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 26 as a brown solid (yield: 36%). 1 H NMR(400MHz, DMSO-d 6 )δ1.01(t,J＝8.0Hz,9H),1.28-1.34(m,2H),2.36(t,J＝8.0Hz,4H), 2.48(t,J＝8.0Hz,4H),2.65-2.71(m,1H),3.81(t,J＝7.6Hz,1H),3.93(s,2H), 4.03(s,3H),6.81(s,1H),6.89(s,1H),7.17(s,1H),7.86(s,1H),8.06(s,2H), 8.21(s,2H),9.26(s,1H),10.03(s,1H),12.65(s,1H)。
Example 27 hydrochloride salt.
A fresh amount of the compound of example 1 (about 0.45 g) was weighed and added to 10mL of a mixed solvent of ethanol and water (V: V ═ 1: 1). While stirring, a molar equivalent of aqueous hydrochloric acid solution was added. After the addition was completed, the mixture was stirred at room temperature for 30min, and then filtered, and the filtrate was allowed to stand for one week to give (S) -N- (1- (2-chloro-5- (2- (trifluoromethyl) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) pyridin-3-yl) propyl) -9H-purin-6-amine monohydrochloride (yield: 25%). By adjusting the ratio of hydrochloric acid to formula I, different molar ratios of hydrochloride salts can be obtained.
Example 28 citrate salt
Fresh compound of example 5 (0.39g) was weighed, added to 15mL of ethanol solution, and added with a molar equivalent of citric acid with stirring, stirred at room temperature for 30min, then transferred to a 20mL reaction vessel, solvothermal at 60 ℃ for 12 h, then cooled naturally to room temperature, and filtered to give the monocitrates of example 20 (yield: 58%). By adjusting the ratio of citric acid to formula I, different molar ratios of citrate can be obtained.
Example 29 fumarate salt
The newly prepared compound (0.51g) of example 15 was weighed, a small amount of DMSO was added, the mixture was heated to 50 ℃ and DMSO was added dropwise until the DMSO was completely dissolved, then, a molar equivalent of fumaric acid was added dropwise, the reaction was continued for 10 minutes with stirring, then, the mixture was filtered, cooled to 4 ℃ and the filtrate was allowed to stand until a solid precipitated, to obtain the fumarate salt of example 15 (yield: 32%). By adjusting the ratio of fumaric acid to formula I, different molar ratios of fumaric acid can be obtained.
EXAMPLE 30 maleate salt
The freshly prepared compound of example 22 (0.32g) was weighed into a mixed solution of ethanol and water (20 mL,1:1), heated to 60 ℃ with stirring, equivalent maleic acid was added, the reaction was continued with stirring for 30min, then filtered and cooled to 4 ℃, and the filtrate was allowed to stand until a solid precipitated, giving the mono-maleate salt of example 3 (yield: 38%). By adjusting the ratio of maleic acid to formula I, salts of different molar ratios can be obtained.
Example 31 lists the PI3K delta inhibitory effect of the part of formula I or salt described in the examples.
TABLE 1. PI3K delta inhibition of the partial salts of formula I or described in the examples (IC50 of less than 5nM for + + + + + + + +; 5-10 nM for + + + + +; 10-50 nM for + + + +; greater than 50nM for + + +)
Example numbering IC50 Activity Example numbering IC50 Activity
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 +++++
Example 32
MOLM-16 cells in logarithmic growth phase at 1X 10 5 One/4 mL/well was inoculated in 6-well plates and incubated at 37 ℃ with 5% CO 2 The incubator stands still and grows stably for 2 hours. The test sample compound was treated with formula I or its salt at a concentration of 0.125, 0.5, 1 μ M for 24h, DMSO as a negative control, DAPI stained, and the morphology of the cells was recorded and observed by confocal microscopy (FIG. 2).
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 (3)

1. A 3- (pyridin-3 yl) -7-azaindole derivative PI3K δ inhibitor, wherein the inhibitor is one of the compounds of the structure shown below, or a pharmaceutically acceptable salt of said compound:
Figure FDA0003632130090000011
Figure FDA0003632130090000021
Figure FDA0003632130090000031
2. a process for the preparation of the 3- (pyridin-3 yl) -7-azaindole derivative PI3K δ inhibitor according to claim 1, which is prepared by:
(a) reacting a compound of formula II
Figure FDA0003632130090000032
With compounds of the formula III
Figure FDA0003632130090000033
Heating and refluxing the catalyst and the organic ligand for 10 to 48 hours under the condition of alkali or no alkali and organic solvent to perform coupling reaction, and directly separating and purifying to obtain a compound shown in the formula I;
or:
(b) by using formula IV in place of formula II,
Figure FDA0003632130090000034
the formula V is substituted for the formula III,
Figure FDA0003632130090000041
obtaining formula I through the reaction steps of (a);
in the formula, R 1 、R 2 、R 3 、R 4 Is a group corresponding to a compound of the structure shown in claim 1;
the catalyst is any one of palladium chloride, palladium acetate, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride, zero-valent palladium, [1, 1' -bis (diphenylphosphino) ferrocene ] rhodium dichloride, rhodium chloride, rhodium acetate, palladium acetylacetonate, rhodium acetylacetonate, palladium carbon and rhodium carbon;
the organic ligand comprises: any one or a combination of two of triphenylphosphine, triphenylphosphine oxide, (S) - (-) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, (R) - (+) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl;
the catalyst and the organophosphorus ligand are 0.05-0.15 equivalent of a reaction substrate;
the alkali is inorganic alkali or organic alkali, including potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, ammonia water or triethylamine; the organic solvent is any one of 1, 4-dioxane, glycol dimethyl ether and tetrahydrofuran.
3. Use of the 3- (pyridin-3 yl) -7-azaindole derivative PI3K δ inhibitor according to claim 1 for the preparation of an inhibitor medicament for the treatment of immune diseases, liquid tumors, solid tumors caused by PI3K δ kinase overexpression.
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