CN110156785A - Indazole compounds and its preparation method and application - Google Patents
Indazole compounds and its preparation method and application Download PDFInfo
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- CN110156785A CN110156785A CN201910299910.7A CN201910299910A CN110156785A CN 110156785 A CN110156785 A CN 110156785A CN 201910299910 A CN201910299910 A CN 201910299910A CN 110156785 A CN110156785 A CN 110156785A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Abstract
The present invention provides a kind of indazole compounds and preparation method and application.The present invention is using indazole as structure parent nucleus, a series of completely new small molecule PI3K δ inhibitor are designed and synthesized, and the test of PI3K δ kinase inhibiting activity and the test of MV-4-11 cell activity are carried out to such compound, indazole compounds provided by the invention show better kinase sub-families selectivity, and show better in-vitro multiplication inhibitory activity to tumor cell line.Anti-tumor drug and the application in the active medicine that preparation inhibits PI3K δ kinases can be being prepared, provide new approach for anti-tumor drug research.Raw material of the present invention is cheap and easy to get, preparation method is simple, is suitble to large-scale production.General structure is as follows:
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of indazole compounds and preparation method and anti-swollen in preparation
Application in tumor medicine.
Background technique
All the time, malignant tumour seriously threatens human health, especially B cell malignant tumour, including chronic lymphatic
Chronic myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, follicular lymphoma etc..The treatment means master of early stage
If by traditional cell toxicity medicament come the symptom of reduction of patient with biologists deeply grinding to tumour Forming Mechanism
Study carefully, the transduction, the regulation of cell cycle of various physiology courses such as signal path, natural death of cerebral cells, angiogenesis etc. in tumour cell
Gradually recognized by people.Wherein PI3K/Akt signal transduction pathway is signal path important in mammal, and signal passes
The occurrence and development that the abnormal activation led is considered with tumour are closely related.
In PI3K/Akt signal path, PI3Ks is important node albumen, it is a lipoid kinases, with serine/
The activity of threonine (ser/Thr) kinase activity and phosphatidyl inositol kinase, function are mainly phosphorylation phosphatidylinositols
3 ' hydroxyls.PI3Ks is mainly activated by two ways, and one is being activated by RTKs or GPCRs, another way is by urging
Change subunit p110 promotes PI3K to activate in conjunction with Ras.The PI3Ks phosphorylation PIP2 being activated forms PIP3, and PIP3 is as second
Courier, recruitment and activated protein kinase PDK1 and Akt, so that downstream effector is activated, the proliferation of regulating cell, differentiation, survival
And migration.
PI3K δ is present in hematopoietic cell and immunocyte as important a member in PI3Ks family, specificity, thin in B
It is played an important role in cellular surface receptors signal transduction, regulates and controls proliferation, differentiation and the survival of B cell.PI3K δ is considered as controlling
Treat the important target spot of B cell malignant tumour and immunity disease.There are three PI3K δ inhibitor at present is ratified to list by FDA, point
Be not Gliade in 2014 list a company for treat B cell non-Hodgkin lymphoma (NHL) and with Rituximab join
It is used to treat at least two kinds of systems with what Idelalisib, the Bayer in 2017 for the treatment of chronic lymphocytic leukemia listed a company
Sex therapy treatment after disease relapse follicular lymphoma (FL) adult patient intravenous injection class drug Copanlisib and
First single medication the treatment recurrent, intractable chronic lymphocytic leukemia, primary lymphedema that Intellikine in 2018 lists a company
The oral drugs Duvelisib of cell lymphoma patient and dual drug resistant follicular lymphoma patient.Although marketed drug pair
Treatment B cell malignant tumour has significant ground therapeutic effect, but also has some serious clinical side effects and drug interaction.
Therefore it is badly in need of developing a kind of novel safer PI3K δ selective depressant.
Summary of the invention
The object of the present invention is to provide a kind of indazole compounds, general structure (I) is as follows:
And its optical isomer or its pharmaceutically acceptable salt or solvate,
Wherein: R1、R2、R3、R4It is identical or different, it is selected from hydrogen, halogen atom, C1-6Alkyl, halogenated C1-6Alkyl or C1-6Alkoxy；
R5Selected from C1-6Alkyl, C1-6Alkyl-cycloalkyl；
R6Selected from monosubstituted or polysubstituted aromatic ring or heteroaromatic；The ring substituents are selected from hydrogen, halogen atom, C1-6Alkyl, C1-6
Alkoxy, sulfuryl, cyano, amide；
R7Selected from monosubstituted or polysubstituted aromatic ring or heteroaromatic；The ring substituents are selected from hydrogen, halogen atom, C1-6Alkyl, C1-6
Alkoxy, sulfuryl, cyano, amide.
More specifically, the preferred compound of general formula (I) structure of the present invention is selected from:
(S)-N- (1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine (11)
N- (1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine (12)
(S)-N- (1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine (13)
(S)-N- (1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) propyl)-adenine (14)
(S)-N- (1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) -2- methyl-propyl) -6- amino is fast (15)
(S)-N- (1- (6- chloro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine (16)
(S)-N- (1- (5- methyl-1-(pyridin-3-yl)-1H- indazole-3- base) ethyl)-adenine (17)
(S)-N- (1- (5- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine (18)
(S)-N- (1- (the fluoro- 1- of 6- (3- fluorophenyl) -1H- indazole -3- base) ethyl)-adenine (19)
(S)-N- (1- (the fluoro- 3- yl of 1- (3,5- difluorophenyl) -6-) ethyl)-adenine (20)
(S)-N- (1- (6- fluoro- 1- (pyridin-4-yl) -1H- indazole -3- base) ethyl)-adenine (21)
(S)-N- (1- (the fluoro- 1- of 6- (pyridine -2- base) -1H- indazole -3- base) ethyl)-adenine (22)
(S) -4- (3- (1- ((7H- purine -6- base) amino) ethyl) the fluoro- 1- indazolyl of -6-) benzonitrile (23)
(S)-N- (1- (the fluoro- 1- of 6- (3- (mesyl) phenyl) -1H- indazole -3- base) ethyl)-adenine (24)
(S)-N6(1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) -2,6- diaminopurine (25)
(S) -4- amino -6- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) -5- cyanopyrimidine
(26)
(S) -2,4- diamino -6- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) -5- cyano is phonetic
Pyridine (27)
(S) -2- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) nicotinic acid nitrile (28)
(S) -2,4- diamino -6- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) propyl) amino) -5- cyano is phonetic
Pyridine (29)
(S) -2,4- diamino -6- ((1- (the fluoro- 1- of 6- (4- pyridyl group) -1H- indazole -3- base) ethyl) amino) -5- cyano is phonetic
Pyridine (30)
(S) -2,4- diamino -6- ((1- (the fluoro- 1- of 6- (3- (mesyl) phenyl) -1H- indazole -3- base) ethyl) amino) -
5- cyanopyrimidine (31)
(S) -2,4- diamino -6- ((- (the chloro- 1- of 6- (3- (mesyl) phenyl) -1H- indazole -3- base) ethyl) amino) -5-
Cyanopyrimidine (32)
(S) -2,4- diamino -6- ((1- (6- chloro- 1- (pyridin-3-yl) -1H- indazole -3- base) propyl) amino) -5- cyano is phonetic
Pyridine (33)
(S) -2,4- diamino -6- ((1- (6- chloro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) -5- cyano is phonetic
Pyridine (34)
(S) -2,4- diamino -6- ((1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) -5- cyanopyrimidine
(35)
(S) -2,4- diamino -6- ((1- (1- (pyridin-3-yl) -6- (trifluoromethyl) -1H- indazole -3- base) ethyl) amino) -
5- cyanopyrimidine (36)
And its optical isomer or its pharmaceutically acceptable salt or solvate of these compounds.
It is a further object to provide the preparation methods of above-mentioned indazole compounds, which is characterized in that by with
Lower step is realized:
Monosubstituted or polysubstituted aniline (compound 1) is reacted in aqueous sodium persulfate solution with chloraldurate, hydroxylamine hydrochloride
Compound 2 is generated, compound 2 generates compound 3 after the concentrated sulfuric acid acts on, and open loop, diazotising, reduction, cyclisation occur for compound 3
Substituted indazole -3- formic acid 4 is formed, then is condensed to form compound 5 with dimethyl azanol hydrochloride.Compound 5 is acted in grignard reagent
Lower formation ketone (compound 6), subsequent 6, which occur Ullman coupling with bromo-derivative, generates compound 7, compound 7 and R- (+)-tertiary fourth
The condensation of base sulfenamide generates compound 8, and compound 8 restores generationization under 3-sec-butyl lithium borohydride or sodium borohydride effect
Object 9 is closed, terf-butylsulfinyl is then sloughed in acid condition and forms compound 10, nucleophilic finally occurs with chloro thing again and takes
Generation reaction generates target compound；Reaction equation is as follows:
R1, R2, R3, R4, R5, R6, R7Respectively with described in claim 1.
It is described it is also another object of the present invention to provide the indazole compounds application in preparation of anti-tumor drugs
Tumour is chronic lymphocytic leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, follicular lymphoma or liver
Cancer, breast cancer.One of immunity disease is a variety of.
A further object of the present invention is to provide the active medicine that the indazole compounds inhibit PI3K δ kinases in preparation
In application.
The present invention is to provide the compound of a kind of structure novel, raw material is cheap and easy to get, preparation method is simple, is suitble to big rule
Mould production.Compared with positive control, which shows better kinase sub-families selectivity, and to tumour cell
Strain shows better in-vitro multiplication inhibitory activity.
Specific embodiment
The present invention is further described in conjunction with the embodiments.Embodiment below is to illustrate the present invention, rather than with any
Mode limits the present invention.
Prepare the synthesis of 1 2- of embodiment (oxyethylamine)-N- phenyl acetamide 2
Chloraldurate (19.8g, 0.12mol) is dissolved in 150mL water, be added portionwise at 50 DEG C sodium sulphate (99.4g,
0.7mol), stirring is spare to all dissolutions.3- fluoroaniline (9.3g, 0.1mol) is dissolved in 6M aqueous hydrochloric acid solution (20mL), slowly
It is added drop-wise to mixed solution, then hydroxylamine hydrochloride (20.9g, 0.3mol) is dissolved in a small amount of water and is added drop-wise in reaction solution, is warming up to 80-
90 DEG C of reaction 2h slowly cool to 60 DEG C, filter, and solid is washed with a large amount of warm water, obtain crude product 2 after drying.
Prepare the synthesis of 2 isatin 3 of embodiment
The 50mL concentrated sulfuric acid is added in two-mouth bottle, is warming up to 60 DEG C, raw material 2 is added portionwise in the concentrated sulfuric acid, in holding
Temperature is no more than 65 DEG C, after reacting 30min, is warming up to 85 DEG C or so reaction 15min of interior temperature, is slowly cooled to room temperature, by reaction solution
Being poured slowly into ice water keeps temperature to be no more than 25 DEG C, has a large amount of solids to be precipitated after stirring a period of time, filters, filtrate acetic acid
Ethyl ester extraction, sodium sulphate is dry, is spin-dried for merging with filter cake.Crude product is dissolved in 50 DEG C of sodium hydroxide solutions, it will after stirring 1h
Insoluble matter, which filters, to be removed, and filtrate is cooled to 0 DEG C, and hydrochloric acid is added dropwise to PH=1, filters after stirring 2h, ice water washing is collected solid and dried
Do to obtain isatin 3 (11.76g, two steps merge yield 80%).
Prepare the synthesis of 3 indazole -3- formic acid 4 of embodiment
Isatin 3 (7.35g, 50mmol) is dissolved in sodium hydroxide (2g, 50mmol) solution of 5M, after reacting 30min
Solution clarification, is cooled to 0 DEG C, is slowly added to sodium nitrite (4.14g, 60mmol) aqueous solution, keeps interior temperature to be lower than 4 DEG C, reaction
After 30min, (50mL, 2N) is slowly added dropwise into sulfuric acid solution in reaction solution, is added the generation that a small amount of ether prevents foam, 0 DEG C
Two hydrated stannous chlorides (28.2g, 125mmol) are dissolved in 20mL concentrated hydrochloric acid under mechanical stirring by lower reaction 30min, are slowly dripped
It is added in reaction solution, keeps interior temperature to be lower than 0 DEG C, the generation that a small amount of ether prevents a large amount of foams is added.After stirring 2h, filter, greatly
Amount warm water is washed, and is collected solid and is dissolved in sodium hydroxide solution, ethyl acetate extraction, collects water phase, hydrochloric acid is added under low temperature and adjusts
PH=3 or so has faint yellow solid precipitation, filters, washing, collects solid and dries to obtain 4 crude product of indazole -3- formic acid.
Prepare the synthesis of embodiment 4N- methoxy-. N-methyl -1H- indazole -3- formamide 5
Indazole -3- formic acid, dimethyl azanol hydrochloride (7.3g, 75mmol) are added in reaction flask, 50mL THF is added,
Be cooled to 0 DEG C, be added dropwise pyridine (7.9g, 0.1mol), stirring 1h is moved back to 30min is stirred at room temperature, be added EDCI (12.5g,
65mmol), pyridine (8.7g, 0.11mol), is stirred overnight at room temperature.TLC detects extent of reaction, is after the reaction was completed spin-dried for solvent,
Water ultrasound is added, filters, massive laundering.Solid to be collected, is dissolved with methylene chloride, filters and removes insoluble matter, filtrate adds water to extract,
Collected organic layer, saturated common salt washing, anhydrous sodium sulfate is dry, is chromatographed after concentration by the eluent column of EA/PE (v/v, 1:5)
Isolate and purify to obtain faint yellow solid 5 (4.6g, two steps merge yield 45%)
Prepare the synthesis of 5 3- acetyl indazole 6 of embodiment
Raw material 5 (4.1g, 20mmol) is added in two-mouth bottle, logical argon gas is vacuumized, three times, anhydrous THF is added in displacement,
Reaction solution is cooled to -10 DEG C, methyl-magnesium-chloride (20mL, 3.0M in THF) is slowly added dropwise, be added dropwise to complete move back it is anti-to room temperature
It answers, saturated ammonium chloride solution quenching reaction, collected organic layer, saturated common salt washing, sulfuric acid is added at low temperature after the reaction was completed
Sodium is dry, and concentration obtains faint yellow solid 6 (2.56g, 80%) with the eluent column chromatography for separation of EA/PE (v/v, 1:10)
Prepare the synthesis of 6 1- of embodiment (3- pyridyl group) -3- acetyl indazole 7
Weigh 6 (2.4g, 15mmol), cuprous iodide (572mg, 3mmol), L-PROLINE (690mg, 6mmol), potassium carbonate
(4.14g, 30mmol) is added in two-mouth bottle, argon gas protection be added 30mL DMSO, at room temperature be added 3- bromopyridine (3.56g,
22.5mmol) it is warming up to 120 DEG C of reactions.After the reaction was completed, it is cooled to room temperature, 50mL ethyl acetate is added and stirs 20min, filters
Insoluble matter is removed, water is added in filtrate, and collected organic layer, saturated common salt washing, sodium sulphate is dry, and concentration, crude product is tied again with PE/EA
Crystalline substance filters to obtain yellow solid 7 (2.92g, 82%).
Prepare embodiment 7 (R) -2- methyl-N- (1- (1- (the pyridin-3-yl) -3- indazolyl) ethylidene) Asia propane -2- sulphur
The synthesis of amide 8
7 (2.37g, 10mmol), R- (+)-t-butyl sulfonamide (1.82g, 15mmol) are added in two-mouth bottle,
Argon gas protection, is added the anhydrous THF of 20mL, is added tetraethyl titanate (2.28g, 10mmol), heating reflux reaction is overnight.It has reacted
20min is stirred at rear addition water, there are a large amount of solids to generate, is filtered repeatedly until filtrate is clarified, ethyl acetate is washed, and is layered, and is collected
Organic layer, saturated common salt washing, anhydrous sodium sulfate is dry, is concentrated to give crude product 8.
Prepare embodiment 8 (R) -2- methyl-N- ((S) -1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) propane -
The synthesis of 2- sulfenamide 9
Crude product 8 is put into two-mouth bottle, argon gas protection, anhydrous THF dissolution is added, is cooled to -78 DEG C, it is secondary to be slowly added to three
Butyl lithium borohydride (10mL, 1M in THF) reacts 3h, and water quenching reaction is added, and ethyl acetate layering is added, collects organic
Layer, saturated common salt washing, anhydrous sodium sulfate is dry, concentration, is obtained with the eluent of EA/PE (v/v, 2:1) through column chromatography for separation light
Yellow solid 9 (1.73g, 50%over two steps).
Note: the preparation of raceme walks herein does reducing agent reduction imines using sodium borohydride.
Prepare the synthesis of embodiment 9 (S) -1- (1- (pyridin-3-yl) -3- indazolyl) second -1- amine 10
It weighs 9 (1.73g, 5mmol) to be put into single port bottle, methanol dissolution is added, 5mL 6N HCl, reaction are added at room temperature
It is spin-dried for methanol after 2h, water/ethyl acetate layering is added, collects water layer addition sodium hydroxide and is adjusted to alkalinity, ethyl acetate extraction is added
It takes, collected organic layer, saturated common salt washing, anhydrous sodium sulfate is dry, and crude product is obtained after concentration, recrystallizes faint yellow with PE/EA
Solid 2-10c (952mg, 80%).
Prepare embodiment 10 (S)-N- (1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine 11
It weighs 10 (238mg, 1mmol) and 6-chloropurine (232mg, 1.5mmol) is put into pressure pipe, it is molten that n-butanol is added
Solution is added DIPEA (258mg, 2mmol), is warming up to 140 DEG C of reactions overnight, and water/ethyl acetate layering is added after the reaction was completed,
Collected organic layer, saturated common salt washing, anhydrous sodium sulfate is dry, concentration, with the eluent of DCM/MeOH (v/v, 50:1) through column
Chromatography obtains faint yellow solid 11 (107mg, 30%).
m.p.221-223℃；1H NMR(400MHz,CDCl3)δ9.08(s,1H),8.57-8.55(m,1H),8.49(s,
1H), 8.07 (d, J=6.8Hz, 1H), 7.97 (s, 1H), 7.92-7.89 (m, 1H), 7.72-7.68 (m, 1H), 7.47-7.40
(m, 2H), 7.29-7.17 (m, 2H), 6.23 (s, 1H), 1.89 (d, J=5.6Hz, 3H)；13C NMR(100MHz,CDCl3)δ
154.1,152.5,149.6,147.2,143.3,139.9,138.5,137.0,129.7,128.0,124.2,123.3,
122.0,121.2,119.4,110.2,103.7,60.5,29.8；HRMS(ESI)m/z Calcd for C19H16N8(M+):
356.1498；Found:356.1498.
Prepare embodiment 11N- (1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine 12
Preparation method chromatographs to obtain yellow solid 12, yield 37% with preparation embodiment 1-9, column
m.p.212-214℃；1H NMR(400MHz,CD3OD) δ 8.76 (d, J=8.4Hz, 1H), 8.50-8.48 (m,
1H),8.32(s,1H),8.12(s,1H),8.09-8.07(m,1H),7.91-7.85(m.3H),7.49-7.45(m,1H),
7.25-7.18 (m, 2H), 6.13 (s, 1H) 1.87 (d, J=7.2Hz, 3H)；13C NMR(100MHz,CD3OD)δ155.6,
153.9,153.1,150.9,148.8,141.3,139.7,129.1,127.8,124.8,123.5,122.3,121.3,
121.0,116.5,1144,11.1,61.6,30.8；HRMS(ESI)m/z Calcd for C21H16N8(M+):356.1498；
Found:356.1498.
Preparing embodiment 12, ((S)-N- (1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) -6- amino is fast
Purine 13
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 13 of column chromatography, yield 52%.
m.p.218-220℃；1H NMR(400MHz,CD3OD) δ 9.01 (d, J=2.4Hz, 1H), 8.55 (d, J=
4.8Hz,1H),8.30(s,1H),8.26(dd,J1=1.2Hz, J2=8.0Hz, 1H), 8.11 (s, 1H), 7.97 (dd, J1=
4.8Hz,J2=8.8Hz, 1H), 7.64 (dd, J1=4.8Hz, J2=8.0Hz, 1H), 7.55 (dd, J1=2.0Hz, J2=
9.2Hz,1H),7.06(td,J1=2.0Hz, J2=9.2Hz, 1H), 6.13 (s, 1H), 1.86 (d, J=7.2Hz, 3H)；13C
NMR(150MHz,DMSO-d6)δ163.1,161.5,152.3,150.6,147.4,143.0,139.8and139.7,136.1,
129.2,124.5,123.33and 123.26,120.0,111.3and 111.0,97.0and 96.8,43.5,20.3；HRMS
(ESI)m/z Calcd for C19H15FN8(M+):374.1404；Found:374.1404.
It is fast to prepare embodiment 13 (S)-N- (1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) propyl) -6- amino
Purine 14
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 14 of column chromatography, yield 65%.
m.p.180-182℃；1H NMR(400MHz,CDCl3) δ 9.03 (d, J=2.4Hz, 1H), 8.62 (dd, J1=
1.6Hz,J2=4.8Hz, 1H), 8.49 (s, 1H), 8.06-8.03 (m, 1H), 7.98 (s, 1H), 7.90 (dd, J1=5.2Hz, J2
=8.8Hz, 1H), 7.49 (dd, J1=4.8Hz, J2=8.0Hz, 1H), 7.37 (dd, J1=2.0Hz, J2=9.6Hz, 1H),
7.03-6.98 (m, 1H), 6.63 (s, 1H), 6.07 (s, 1H), 2.41-2.18 (m, 2H), 1.07 (t, J=7.2Hz, 3H)；13C
NMR(100MHz,CDCl3)δ164.5,162.0,152.6,149.0,147.7,143.5,140.4and140.2,138.3,
136.7,129.8,124.3,122.8,122.7,120.6,111.9and 111.6,95.6and 96.3,60.5,29.8,
10.4；HRMS(ESI)m/z Calcd for C20H17FN8(M+):388.1560；Found:388.1560.
Prepare embodiment 14 (S)-N- (1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) -2- methyl-propyl) -6-
Adenine phosphate 15
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 15 of column chromatography, yield 54%
m.p.72-74℃；1H NMR(400MHz,CDCl3) δ 9.04-9.02 (m, 1H), 8.59 (d, J=2.8Hz, 1H),
8.45(s,1H),8.04-7.94(m,3H),7.48-7.36(m,2H),7.06-6.97(m,2H),5.99(s,1H),2.64-
2.61 (m, 1H), 1.15 (d, J=6.0Hz, 3H), 1.09 (d, J=6.4Hz, 3H)；13C NMR(100MHz,CDCl3)δ
164.3,161.9,154.7,152.4,149.8,148.7,147.5,143.3,140.0and 139.9,138.5,136.7,
129.7,124.2,122.9,121.1,119.4,111.8and 111.6,96.5and 96.2,60.5,29.8,19.7,
19.1；HRMS(ESI)m/z Calcd for C21H19FN8(M+):402.1717；Found:402.1707.
Prepare embodiment 15 (S)-N- (1- (6- chloro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) -6 adenine phosphates
16
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 16 of column chromatography, yield 55%
m.p.86-88℃；1H NMR(400MHz,CD3OD)δ9.00(s,1H),8.56(s,1H),8.30(s,1H),8.24
(d, J=8.0Hz, 1H), 8.11 (s, 1H), 7.92 (d, J=8.4Hz, 1H), 7.82 (s, 1H), 7.66-7.63 (m, 1H),
7.23-7.20 (m, 1H), 6.14 (s, 1H), 1.86 (d, J=5.6Hz, 1H)；13C NMR(100MHz,CD3OD)δ153.8,
151.5,148.1,144.2,141.7,141.08,141.06,138.2,135.6,131.3,125.9,124.0,123.5,
123.2,111.2,100.0,45.2,21.0；HRMS(ESI)m/z Calcd for C19H15ClN8(M+):390.1108；
Found:390.1108.
Prepare embodiment 16 (S)-N- (1- (5- methyl-1-(pyridin-3-yl)-1H- indazole-3- base) ethyl)-6- amino
Purine 17
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 17 of column chromatography, yield 72%
m.p.81-83℃；1H NMR(400MHz,CDCl3) δ 9.08 (d, J=2.4Hz, 1H), 8.56 (dd, J1=
2.4Hz,J2=4.8Hz, 1H), 8.50 (s, 1H), 8.10-8.07 (m, 1H), 7.99 (s, 1H), 7.67 (s, 1H), 7.63 (d, J
=8.8Hz, 1H), 7.46 (dd, J1=4.8Hz, J2=8.4Hz, 1H), 7.29 (dd, J1=6.0Hz, J2=9.2Hz, 1H),
7.02 (d, J=8.0Hz, 1H), 6.16 (s, 1H), 2.45 (s, 3H), 1.88 (d, J=6.8Hz, 3H)；13C NMR(100MHz,
CDCl3)δ154.1,152.5,149.0,147.1,143.2,138.6,138.4,137.2,131.7,130.1,129.5,
124.2,123.6,120.3,110.0,100.1,60.6,29.8,21.5；HRMS(ESI)m/z Calcd for C20H18N8(M+):370.1654；Found:370.1654.
It is fast to prepare embodiment 17 (S)-N- (1- (5- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) -6- amino
Purine 18
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 18 of column chromatography, yield 75%
m.p.212-241℃；1H NMR(400MHz,CDCl3) δ 9.05 (d, J=2.4Hz, 1H), 8.62 (dd, J1=
0.8Hz,J2=4.4Hz, 1H) 8.52 (s, 1H), 8.07 (d, J=8.4Hz, 1H), 8.00 (s, 1H), 7.66 (dd, J1=
4.0Hz,J2=9.2Hz, 1H), 7.56 (dd, J1=2.0Hz, J2=8.8Hz, 1H), 7.49 (dd, J1=4.8Hz, J2=
8.4Hz, 1H), 7.23 (m, 1H), 6.71-6.69 (m, 1H), 6.19 (s, 1H), 1.90 (d, J=6.8Hz, 3H)；13C NMR
(100MHz,CDCl3)δ157.1,152.7,149.4,147.9,143.5,13.3,137.0,136.8,129.9,124.3,
123.7,123.6,117.7,117.54,111.5,105.9,6.1,29.8；HRMS(ESI)m/z Calcd for C19H15FN8
(M+):374.1404；Found:374.1404.
Prepare embodiment 18 (S)-N- (1- (the fluoro- 1- of 6- (3- fluorophenyl) -1H- indazole -3- base) ethyl)-adenine
19
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 19 of column chromatography, yield 50%
m.p.209-211℃；1H NMR(400M,CD3OD)δ8.30(s,1H),8.10(s,1H),7.95-7.91(m,
1H),7.58-7.49(m,4H),7.15-7.09(m,1H),7.02(td,J1=2.0Hz, J2=8.8Hz, 1H), 6.13 (s,
1H), 1.85 (d, J=6.8Hz, 3H)；13C NMR(150MHz,DMSO-d6)δ163.4,163.1,161.7and161.5,
152.3,150.2,140.9and 140.8,139.5and 139.4,131.56and 131.50,123.3and 123.2,
120.0,117.60and 117.59,113.3and 113.1,111.2and 111.0,109.1and 108.9,97.2and
97.0,43.4；20.3；HRMS(ESI)m/z Calcd for C20H15F2N7(M+):391.1357；Found:391.1359.
Prepare embodiment 19 (S)-N- (1- (the fluoro- 3- yl of 1- (3,5- difluorophenyl) -6-) ethyl)-adenine 20
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 20 of column chromatography, yield 48%
m.p.158-160℃；1H NMR(400MHz,CDCl3)δ8.50(s,1H),7.98(s,1H),7.86(dd,J1=
5.2Hz,J2=8.8Hz, 1H), 7.41 (dd, J1=2.0Hz, J2=9.6Hz, 1H), 7.30 (dd, J1=2.0Hz, J2=
9.6Hz,1H),7.00(td,J1=2.0Hz, J2=8.8Hz, 1H), 6.83-6.78 (m, 1H), 1.88 (d, J=6.8Hz, 3H)
；13C NMR(150MHz,DMSO-d6)δ163.7and163.6,163.2,162.1and 162.0,161.6,152.2,150.7,
141.64and 141.55,140.0,139.5and 139.4,123.3and 123.2,120.5and 120.2,111.5and
111.3,108.1,105(dd,J1=7.5Hz, J2=22.5Hz, 1C), 101.6 (t, J=25.5Hz, 1C), 97.6and
97.4,43.5,20.1；HRMS(ESI)m/z Calcd for C20H14F3N7(M+):409.1263；Found:409.1263.
It is fast to prepare embodiment 20 (S)-N- (1- (6- fluoro- 1- (pyridin-4-yl) -1H- indazole -3- base) ethyl) -6- amino
Purine 21
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 21 of column chromatography, yield 43%
m.p.224-226℃；1H NMR(400MHz,CDCl3) δ 8.74 (d, J=6.0Hz, 2H), 8.50 (s, 1H), 8.00
(s, 1H), 7.90-7.87 (m, 1H), 7.74 (d, J=6.0Hz, 2H), 7.54 (d, J=9.2Hz, 1H), 7.06-7.02 (m,
1H), 6.76-6.75 (m, 1H), 6.20 (s, 1H), 1.89 (d, J=6.8Hz, 3H)；13C NMR(150MHz,DMSO-d6)δ
163.3,161.7,152.3,151.5,151.2,145.8,139.5and 139.4,123.5and 123.4,120.8,
114.5,111.8and 111.6,98.3and 98.1,43.4,20.1；
HRMS(ESI)m/z Calcd for C19H15FN8(M+):374.1404；Found:374.1404.
It is fast to prepare embodiment 21 (S)-N- (1- (the fluoro- 1- of 6- (pyridine -2- base) -1H- indazole -3- base) ethyl) -6- amino
Purine 22
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 22 of column chromatography, yield 32%
m.p.114-116℃；1H NMR(400MHz,CD3OD)δ8.53-8.43(m,3H),8.05-7.96(m,2H),
7.80-7.74(m,2H),7.22-7.20(m,3H),7.10-7.07(m,1H),6.99-6.93(m,1H),6.17(s,1H),
1.88 (d, J=6.0Hz, 3H)；13C NMR(100MHz,CDCl3)δ164.3,161.9,154.0,152.5,149.5,147.7,
140.5and 140.3,138.5,138.4,121.5and 121.4,120.4,120.0,113.3 112.1and11.8,
102.1and 101.8,60.6,29.8；HRMS(ESI)m/z Calcd for C19H15FN8(M+):374.1404；Found:
374.1404.
Prepare embodiment 22 (S) -4- (3- (1- ((7H- purine -6- base) amino) ethyl) the fluoro- 1- indazolyl of -6-) benzonitrile
23
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 23 of column chromatography, yield 56%
m.p.228-230℃；1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.0(s,1H),7.90-7.82(m,
5H),7.44(dd,J1=2.0Hz, J2=9.2Hz, 1H), 7.03 (td, J1=2.0Hz, J2=8.8Hz, 1H), 6.65 (s,
1H), 6.20 (s, 1H), 1.88 (d, J=6.8Hz, 3H)；13C NMR(150MHz,DMSO-d6)δ163.2and 161.6,
152.4,151.2,142.9,139.5and 139.4,139.1,123.4and 123.3,121.5,120.5,118.6,
111.6and 111.4,108.0,106.1,97.7and 97.5,57.3,29.0；HRMS(ESI)m/z Calcd for
C21H15FN8(M+):398.1404；Found:398.1410.
Prepare embodiment 23 (S)-N- (1- (the fluoro- 1- of 6- (3- (mesyl) phenyl) -1H- indazole -3- base) ethyl) -6-
Adenine phosphate 24
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 24 of column chromatography, yield 65%
m.p.93-95℃；1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.34-8.30(m,1H),8.03-8.00
(m,4H),7.92-7.86(m,2H),7.77-7.73(m,1H),7.38(dd,J1=2.0Hz, J2=9.2Hz, 1H), 7.00
(td,J1=2.0Hz, J2=8.8Hz, 1H), 6.91 (s, 1H), 6.20 (s, 1H), 1.89 (d, J=6.8Hz, 3H)；13C NMR
(100MHz,CDCl3)δ162.6,162.1,152.6,150.0,142.4,142.3,141.0,138.4,131.0,130.9,
126.8,125.1,122.9and 122.8,121.0,120.3,112.1and 111.8,100.1,96.5,66.7,44.5,
29.6；HRMS(ESI)m/z Calcd for C21H18FN7O2S(M+):451.1227；Found:451.1227.
Prepare embodiment 24 (S)-N6(1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) -2,6- diamino
Base purine 25
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 25 of column chromatography, yield 31%
m.p.89-91℃；1H NMR(400MHz,CD3OD) δ 9.00 (s, 1H), 8.53-8.51 (m, 1H), 8.20 (d, J=
8.4Hz, 1H), 7.96-7.92 (m, 1H), 7.73 (s, 1H), 7.62-7.58 (m, 1H), 7.48 (d, J=9.6Hz, 1H), 7.00
(t, J=9.2Hz, 1H), 6.05 (s, 1H), 1.80 (d, J=6.8Hz, 3H)；13C NMR(100MHz,CD3OD)δ165.7,
163.3,161.9,155.2,151.8,147.8,143.9,141.6and 141.5,138.3,137.7,131.0,125.8,
124.3and 124.1 121.4,112.6,112.3,97.5and 97.3,66.5,20.9；HRMS(ESI)m/z Calcd
for C19H16FN9(M+):389.1513；Found:389.1520.
Prepare embodiment 25 (S) -4- amino -6- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) ammonia
Base) -5- cyanopyrimidine 26
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 26 of column chromatography, yield 54%
m.p.204-206℃；1H NMR(400MHz,CD3OD) δ 9.00 (s, 1H), 8.55 (s, 1H), 8.24 (d, J=
8.0Hz, 1H), 8.08 (d, J=2.4Hz, 1H), 7.91-7.87 (m, 1H), 7.66-7.62 (m, 1H), 7.56-7.53 (m,
1H), 7.12-7.07 (m, 1H), 6.04-5.99 (m, 1H), 4.61 (s, 1H), 1.78 (d, J=6.4Hz, 3H)；13C NMR
(150MHz,DMSO-d6)δ164.6,161.9,161.6,159.9,149.9,147.4,142.9,139.8and 139.7,
136.1,129.2,124.6,123.1and 123.0,115.5,111.4and 111.3,97.1and 96.9,67.8,44.1,
19.8；HRMS(ESI)m/z Calcd for C19H15FN8(M+):374.1404；Found:374.1404.
Prepare embodiment 26 (S) -2,4- diamino -6- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) second
Base) amino) -5- cyanopyrimidine 27
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 27 of column chromatography, yield 52%
m.p.96-98℃；1H NMR(400MHz,CDCl3) δ 9.02 (d, J=2.4Hz, 1H), 8.62 (d, J=4.4Hz,
1H), 8.04 (d, J=8.0Hz, 1H), 7.77 (dd, J1=4.8Hz, J2=8.8Hz, 1H), 7.50 (dd, J1=4.4Hz, J2=
8.0Hz,1H),7.38-7.36(m,1H),7.02(td,J1=2.4Hz, J2=8.8Hz, 1H), 5.93-5.86 (m, 2H), 5.32
(s, 2H), 5.17 (s, 2H), 1.72 (d, J=6.0Hz, 3H)；13C NMR(100MHz,CDCl3)δ165.2,164.4,
163.03and 163.00,162.0,149.5,147.8,143.4,140.5and 140.4,136.6,129.8,124.3,
122.5and 122.4,120.0,116.9,112.0and 111.7,96.7and 96.4,62.6,44.0,29.8；HRMS
(ESI)m/z Calcd for C19H10FN9(M+):389.1513；Found:389.1515.
Prepare embodiment 27 (S) -2- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) nicotinic acid nitrile
28
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 28 of column chromatography, yield 25%
m.p.108-110℃；1H NMR(400MHz,CD3OD)δ8.99(s,1H),8.54(s,1H),8.28-8.22(m,
2H), 7.96-7.93 (m, 1H), 7.84-7.87 (m, 1H), 7.66-7.62 (m, 1H), 7.54 (d, J=8.8Hz, 1H), 6.71-
6.67 (m, 1H), 5.96-5.93 (m, 1H), 1.80 (d, J=6.8Hz, 3H)；13C NMR(150MHz,DMSO-d6)δ163.1,
161.5,157.3,152.8,150.3,147.4,143.0and 142.9,139.8and 139.7,136.0,129.1,
124.5,123.2and 123.1,119.9,116.8,112.3,111.3and 111.1,97.1and 96.9,90.9,44.5,
20.0；HRMS(ESI)m/z Calcd for C20H15FN6(M+):358.1342；Found:358.1343.
Prepare embodiment 28 (S) -2,4- diamino -6- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) third
Base) amino) -5- cyanopyrimidine 29
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 29 of column chromatography, yield 65%
m.p.97-99℃；1H NMR(400MHz,CD3OD) δ 8.99 (s, 1H), 8.54 (d, J=3.2Hz, 1H), 8.22
(d, J=8.8Hz, 1H), 7.97 (dd, J1=5.2Hz, J2=8.8Hz 1H), 7.63 (dd, J1=4.8Hz, J2=8.0Hz,
1H),7.52(dd,J1=2.4Hz, J2=9.6Hz 1H), 7.07 (td, J1=1.6Hz, J2=8.8Hz 1H), 5.82 (t, J=
6.8Hz, 1H), 2.30-2.10 (m, 2H), 1.03 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CD3OD)δ167.0,
165.8,165.0,164.8and 163.4,151.0,148.0,144.0,141.6and 141.5,138.3,131.1,
125.9,124.3and 124.2,121.8,118.1,112.7and 112.4,97.6and 97.3,61.7,50.5,28.4,
10.9；HRMS(ESI)m/z Calcd for C20H18FN9(M+):403.1669；Found:403.1669.
Prepare embodiment 29 (S) -2,4- diamino -6- ((1- (the fluoro- 1- of 6- (4- pyridyl group) -1H- indazole -3- base) second
Base) amino) -5- cyanopyrimidine 30
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 30 of column chromatography, yield 56%.
m.p.97-99℃；13H NMR(600MHz,DMSO-d6) δ 8.69 (d, J=6.0Hz, 1H), 7.96-7.91 (m,
2H), 7.89-7.86 (m, 2H), 7.26 (d, J=8.4Hz, 1H), 7.23 (td, J1=1.8Hz, J2=9.0Hz, 1H), 6.66
(s, 2H), 6.53 (s, 2H), 6.00-5.95 (m, 1H), 1.69 (d, J=7.8Hz, 3H)；13C NMR(150MHz,DMSO-d6)δ
165.5,163.4,163.1and 162.9,161.8,151.2,145.9,139.5and 139.4,123.53and 123.45,
121.0,117.7,114.5,111.8and 111.7,98.2and 98.1,59.9,43.1,19.6；HRMS(ESI)m/z
Calcd for C19H16FN9(M+):389.1513；Found:389.1513.
Prepare embodiment 30 (S) -2,4- diamino -6- ((1- (the fluoro- 1- of 6- (3- (mesyl) phenyl) -1H- indazole -
3- yl) ethyl) amino) -5- cyanopyrimidine 31
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 31 of column chromatography, yield 68%.
m.p.112-114℃；1H NMR(400MHz,CD3OD) δ 8.31 (s, 1H), 8.12 (d, J=8.4Hz, 1H),
7.96-7.93 (m, 2H), 7.84 (t, J=8.0Hz, 1H), 7.55 (dd, J1=9.6Hz, J2=2.4Hz, 1H), 7.09 (t, J=
8.8Hz, 1H), 6.02-5.97 (m, 1H), 3.23 (s, 1H), 1.76 (d, J=6.8Hz, 3H)；13C NMR(150MHz,DMSO-
d6)δ165.5,163.1,162.9,161.6,150.4,142.3,140.0,139.6and 139.5,131.3,126.3,
124.7,123.5,120.3,117.6,111.5and 111.3,97.0and 96.8,60.0,43.5,43.1,19.9；HRMS
(ESI)m/z Calcd for C21H19FN8O2S(M+):466.1336；Found:466.1338.
Prepare embodiment 31 (S) -2,4- diamino -6- ((- (the chloro- 1- of 6- (3- (mesyl) phenyl) -1H- indazole -3-
Base) ethyl) amino) -5- cyanopyrimidine 32
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 32 of column chromatography, yield 56%.
m.p.108-110℃；1H NMR(400MHz,CD3OD)δ8.29(s,1H),8.10-8.08(m,1H),7.95-
7.79 (m, 4H), 7.24 (d, J=9.2Hz, 1H), 6.01-5.95 (m, 1H), 3.22 (s, 3H), 1.75 (d, J=6.8Hz,
3H)；13C NMR(100MHz,CD3OD)δ167.0,164.8,164.6,151.6,143.7,141.8,141.5,135.6,
132.1,127.9,126.2,124.0,123.7,123.3,122.0,118.1,111.2,61.8,45.1,44.3,20.6；
HRMS(ESI)m/z Calcd for C21H19ClN8O2S(M+):482.1040；Found:482.1040.
Prepare embodiment 32 (S) -2,4- diamino -6- ((1- (6- chloro- 1- (pyridin-3-yl) -1H- indazole -3- base) third
Base) amino) -5- cyanopyrimidine 33
Preparation method is same to prepare case study on implementation 1-9, the faint yellow solid 33 of column chromatography, yield 72%.
m.p.83-85℃；1H NMR(400MHz,CD3OD) δ 8.99 (s, 1H), 8.56 (s, 1H), 8.23 (d, J=
8.4Hz, 1H), 7.94 (d, J=7.2Hz, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 7.26 (d, J=8.8Hz, 1H), 5.82
(s,1H),2.26-2.13(m,2H),1.03(m,3H)；13C NMR(100MHz,CD3OD)δ167.0,165.0,164.8,
151.0,148.2,144.2,141.6,138.2,135.7,131.4,125.9,124.0,123.7,118.1,111.1,
100.0,83.4,50.5,28.4,10.9；HRMS(ESI)m/z Calcd for C20H18ClN9(M+):419.1374；Found:
419.1370.
Prepare embodiment 33 (S) -2,4- diamino -6- ((1- (6- chloro- 1- (pyridin-3-yl) -1H- indazole -3- base) second
Base) amino) -5- cyanopyrimidine 34
For preparation method with case study on implementation 1-9 is prepared, column chromatographs to obtain faint yellow solid 34, yield 62%.
m.p.100-102℃；1H NMR(400MHz,CD3OD) δ 8.98 (s, 1H), 8.55 (d, J=4.4Hz, 1H), 8.23
(d, J=8.4Hz, 1H), 7.89 (d, J=8.4Hz, 1H), 7.80 (s, 1H), 7.66-7.62 (m, 1H), 7.25 (d, J=
8.8Hz, 1H), 6.02-5.96 (m, 1H), 1.75 (d, J=6.8Hz, 3H)；13C NMR(100MHz,CD3OD)δ167.0,
164.8,164.6,151.7,148.1,144.2,141.7,138.2,135.6,131.3,125.9,123.7,123.3,
118.1,117.5,111.1,61.8,45.1,20.6；HRMS(ESI)m/z Calcd for C19H16ClN9(M+):
405.1217；Found:405.1215.
Prepare embodiment 34 (S) -2,4- diamino -6- ((1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) ammonia
Base) -5- cyanopyrimidine 35
For preparation method with case study on implementation 1-9 is prepared, column chromatographs to obtain faint yellow solid 35, yield 45%.
m.p.90-91℃；1H NMR(400MHz,CD3OD) δ 9.06 (s, 1H), 8.53 (d, J=3.6Hz 1H), 8.25
(d, J=8.0Hz, 1H), 7.95-7.90 (m, 1H), 7.81-7.77 (m, 1H), 7.65-7.62 (m, 1H), 7.51 (t, J=
7.6Hz, 1H), 7.27 (t, J=7.6Hz, 1H), 6.03-5.97 (m, 1H), 1.76 (d, J=6.8Hz, 3H)；13C NMR
(100MHz,CD3OD)δ167.0,164.8,164.6,151.6,147.6,143.9,138.7,131.3,129.3,125.9,
124.5,123.1,122.6,122.4,118.1,111.3,61.7,45.3,20.8；HRMS(ESI)m/z Calcd for
C19H17N9(M+):371.1607；Found:371.1607.
Prepare embodiment 35 (S) -2,4- diamino -6- ((1- (1- (pyridin-3-yl) -6- (trifluoromethyl) -1H- indazole -
3- yl) ethyl) amino) -5- cyanopyrimidine 36
For preparation method with case study on implementation 1-9 is prepared, column chromatographs to obtain faint yellow solid 36, yield 58%
m.p.128-130℃；1H NMR(400MHz,CD3OD) δ 9.01 (s, 1H), 8.59 (d, J=4.8Hz, 1H), 8.26
(d, J=8.0Hz, 1H), 8.13 (d, J=8.4Hz, 1H), 8.04 (s, 1H), 7.68-7.65 (m, 1H), 7.52 (d, J=
8.4Hz, 1H), 6.09-6.04 (m, 1H), 1.79 (d, J=6.8Hz, 3H)；13C NMR(100MHz,CD3OD)δ167.1,
164.8,164.6,151.8,148.5,144.5,140.4,138.0,131.8,131.1and 130.8,127.1and126.5,
126.6,124.4,123.9,119.4and 119.3,118.0,108.91and 108.86,61.8,45.1,20.5；HRMS
(ESI)m/z Calcd for C20H18FN9(M+):439.1481；Found:439.1481.
Bioexperiment embodiment 1: indazole analog derivative tests the inhibitory activity of PI3K δ
Using ADP-GloTMKinase tests to measure.A series of concentration needed for test-compound is diluted to test, respectively take
50nL is transferred on 384 orifice plates, adds the DMSO of 50nl in negative control hole and Positive control wells respectively, will with kinase buffer solution
By PI3K α, beta, gamma and δ are diluted to 1.25nM, 1.25nM, 10nM, 1.25nM respectively, are then added to 384 orifice plates with every 2 μ L of hole
On, 2.5 μ L are added in negative and Positive control wells, are centrifuged 30 seconds, oscillation is incubated at room temperature 10 minutes after mixing, and 2.5 μ L are added
The mixed solution of ATP and PIP2 is centrifuged 30 seconds, and oscillation is incubated at room temperature 2 hours after mixing, and 5 μ L ADP-Glo Reagent are added
10 μ L Kinase Detection Reagent are added in room temperature after being incubated for 3 hours after oscillation mixes, and oscillation is incubated at room temperature after mixing
1 hour, sample read RLU value after the processing such as centrifugation, with Enspire microplate reader, and calculates inhibiting rate according to formula.
Using the log value of concentration as X-axis, percent inhibition is Y-axis, using analysis software GraphPad Prism's 5
Log (inhibitor) vs.response-Variable slope is fitted amount effect curve, to obtain each compound to enzyme activity
The IC of property50Value.
The PI3K δ inhibitory activity of 1 indazole analog derivative of table
As shown in Table 1, using general I type PI3K kinase inhibitor PI-103 as positive control, the chemical combination of such brand new
Majority of compounds shows preferable PI3K δ inhibitory activity in object, provides newly to prepare the research of cancer treatment drugs
Foundation.
The subtype-selective of 2 compound of table is evaluated
As shown in Table 2, compound 16,27,32,33 and 34 is shown outstanding relative to positive control medicine PI-103
Subtype-selective.
The anti tumor activity in vitro of 2 indazole analog derivative of Bioexperiment embodiment
Using MTS method measurement part indazole compounds to the In-vitro Inhibitory Effect of acute leukemia cells MV-4-11, and calculate
Half-inhibitory concentration.The result shows that synthesized indazole compounds all show good tumors inhibition activity in cell,
And majority of compounds is shown and the better inhibitory activity of positive drug Idelalisib.
External inhibitory activity of 3 part of compounds of table to MV-4-11
| Compound | MV-4-11IC50(μM) |
| 11 | 7.02±1.65 |
| 13 | 6.54±2.45 |
| 16 | 8.57±1.58 |
| 22 | 3.01±0.75 |
| 24 | 2.91±0.47 |
| 25 | 5.70±1.41 |
| 27 | 3.51±0.41 |
| 29 | 4.02±0.98 |
| 30 | 3.24±0.53 |
| 31 | 3.54±0.67 |
| 32 | 0.46±0.07 |
| 33 | 1.61±0.26 |
| 34 | 0.69±0.16 |
| 35 | 11.77±2.11 |
| Idelalisib | 7.08±2.58 |
As shown in Table 3, using the PI3K δ Kinase Selectivity inhibitor Idelalisib that has listed at present as positive right
According to there is part of compounds to show preferable inhibitory activity, the work of majority of compounds in the compound of such brand new
Property be more than positive control Idelalisib, for prepare cancer treatment drugs research provide new foundation.
Claims (5)
1. a kind of indazole analog derivative, which is characterized in that general structure is as follows:
And its optical isomer or its pharmaceutically acceptable salt or solvate,
Wherein: R1、R2、R3、R4It is identical or different, it is selected from hydrogen, halogen atom, C1-6Alkyl, halogenated C1-6Alkyl or C1-6Alkoxy；
R5Selected from C1-6Alkyl, C1-6Alkyl-cycloalkyl；
R6Selected from monosubstituted or polysubstituted aromatic ring or heteroaromatic；The ring substituents are selected from hydrogen, halogen atom, C1-6Alkyl, C1-6Alkane
Oxygroup, sulfuryl, cyano, amide；
R7Selected from monosubstituted or polysubstituted aromatic ring or heteroaromatic；The ring substituents are selected from hydrogen, halogen atom, C1-6Alkyl, C1-6Alkane
Oxygroup, sulfuryl, cyano, amide.
2. a kind of indazole analog derivative according to claim 1, which is characterized in that be selected from following compound:
(S)-N- (1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine
N- (1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine
(S)-N- (1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine
(S)-N- (1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) propyl)-adenine
(S)-N- (1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) -2- methyl-propyl)-adenine (S)-N-
(1- (6- chloro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine
(S)-N- (1- (5- methyl-1-(pyridin-3-yl)-1H- indazole-3- base) ethyl)-adenine
(S)-N- (1- (5- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl)-adenine
(S)-N- (1- (the fluoro- 1- of 6- (3- fluorophenyl) -1H- indazole -3- base) ethyl)-adenine
(S)-N- (1- (the fluoro- 3- yl of 1- (3,5- difluorophenyl) -6-) ethyl)-adenine
(S)-N- (1- (6- fluoro- 1- (pyridin-4-yl) -1H- indazole -3- base) ethyl)-adenine
(S)-N- (1- (the fluoro- 1- of 6- (pyridine -2- base) -1H- indazole -3- base) ethyl)-adenine
(S) -4- (3- (1- ((7H- purine -6- base) amino) ethyl) the fluoro- 1- indazolyl of -6-) benzonitrile
(S)-N- (1- (the fluoro- 1- of 6- (3- (mesyl) phenyl) -1H- indazole -3- base) ethyl)-adenine (S)-N6-
(1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) -2,6- diaminopurine
(S) -4- amino -6- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) -5- cyanopyrimidine
(S) -2,4- diamino -6- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) -5- cyano is phonetic
Pyridine
(S) -2- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) nicotinic acid nitrile
(S) -2,4- diamino -6- ((1- (6- fluoro- 1- (pyridin-3-yl) -1H- indazole -3- base) propyl) amino) -5- cyano is phonetic
Pyridine
(S) -2,4- diamino -6- ((1- (the fluoro- 1- of 6- (4- pyridyl group) -1H- indazole -3- base) ethyl) amino) -5- cyano is phonetic
Pyridine
(S) -2,4- diamino -6- ((1- (the fluoro- 1- of 6- (3- (mesyl) phenyl) -1H- indazole -3- base) ethyl) amino) -
5- cyanopyrimidine
(S) -2,4- diamino -6- ((- (the chloro- 1- of 6- (3- (mesyl) phenyl) -1H- indazole -3- base) ethyl) amino) -5-
Cyanopyrimidine
(S) -2,4- diamino -6- ((1- (6- chloro- 1- (pyridin-3-yl) -1H- indazole -3- base) propyl) amino) -5- cyano is phonetic
Pyridine
(S) -2,4- diamino -6- ((1- (6- chloro- 1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) -5- cyano is phonetic
Pyridine
(S) -2,4- diamino -6- ((1- (1- (pyridin-3-yl) -1H- indazole -3- base) ethyl) amino) -5- cyanopyrimidine
(S) -2,4- diamino -6- ((1- (1- (pyridin-3-yl) -6- (trifluoromethyl) -1H- indazole -3- base) ethyl) amino) -
The optical isomer or its pharmaceutically acceptable salt or solvate of 5- cyanopyrimidine and its these compounds.
3. a kind of preparation method of indazole analog derivative according to claim 1, which is characterized in that pass through following steps reality
Existing: compound 1 reacts in aqueous sodium persulfate solution with chloraldurate, hydroxylamine hydrochloride generates compound 2, and compound 2 is through the concentrated sulfuric acid
Generate compound 3 after effect, open loop occurs for compound 3, diazotising, reduction, cyclisation form substituted indazole -3- formic acid 4, then with two
First hydroxylamine hydrochloride is condensed to form compound 5.Compound 5 forms compound 6 under grignard reagent effect, and subsequent 6 and bromo-derivative
Ullman coupling occurs and generates compound 7, compound 7 and the condensation of R- (+)-t-butyl sulfonamide generate compound 8, compound
8 restore generation compound 9 under 3-sec-butyl lithium borohydride or sodium borohydride effect, then slough tert-butyl in acid condition
Sulfinyl forms compound 10, and nucleophilic substitution finally occurs with chloro thing again and generates target compound, reaction equation is as follows:
Wherein R1、R2、R3、R4、R5、R6、R7Definition with described in claim 1.
4. a kind of indazole analog derivative application in preparation of anti-tumor drugs according to claim 1, which is characterized in that
The tumour be chronic lymphocytic leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, follicular lymphoma or
Person's liver cancer, breast cancer.One of immunity disease is a variety of.
5. application of a kind of indazole analog derivative in the active medicine that preparation inhibits PI3K δ kinases according to claim 4.
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| WO2024051720A1 (en) * | 2022-09-07 | 2024-03-14 | 中国药科大学 | 5-pyridine-1h-indazole compound for targeted inhibition of clk2 and use of compound |
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| WO2024051720A1 (en) * | 2022-09-07 | 2024-03-14 | 中国药科大学 | 5-pyridine-1h-indazole compound for targeted inhibition of clk2 and use of compound |
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