CN110156785B - Indazole compound and preparation method and application thereof - Google Patents
Indazole compound and preparation method and application thereof Download PDFInfo
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- CN110156785B CN110156785B CN201910299910.7A CN201910299910A CN110156785B CN 110156785 B CN110156785 B CN 110156785B CN 201910299910 A CN201910299910 A CN 201910299910A CN 110156785 B CN110156785 B CN 110156785B
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- Prior art keywords
- indazol
- ethyl
- pyridin
- fluoro
- amino
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- 238000002360 preparation method Methods 0.000 title claims abstract description 96
- -1 Indazole compound Chemical class 0.000 title claims abstract description 28
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- 108091007960 PI3Ks Proteins 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 11
- 230000000694 effects Effects 0.000 claims abstract description 11
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 24
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 7
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 6
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 6
- 201000003444 follicular lymphoma Diseases 0.000 claims description 6
- 150000002473 indoazoles Chemical class 0.000 claims description 6
- SVHVVUZHQNXYGB-UHFFFAOYSA-N 6-[1-(6-fluoro-1-pyridin-3-ylindazol-3-yl)ethyl]purine-2,6-diamine Chemical compound FC1=CC=C2C(=NN(C2=C1)C=1C=NC=CC1)C(C)C1(C2=NC=NC2=NC(=N1)N)N SVHVVUZHQNXYGB-UHFFFAOYSA-N 0.000 claims description 5
- NLDYNXNBPYQEDM-NSHDSACASA-N FC1=CC=C2C(=NN(C2=C1)C=1C=NC=CC1)[C@H](C)N1C=NC2=NC=NC2=C1N Chemical compound FC1=CC=C2C(=NN(C2=C1)C=1C=NC=CC1)[C@H](C)N1C=NC2=NC=NC2=C1N NLDYNXNBPYQEDM-NSHDSACASA-N 0.000 claims description 5
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- NIJSHLJWHLHONN-ZDUSSCGKSA-N 2-[[(1S)-1-(6-fluoro-1-pyridin-3-ylindazol-3-yl)ethyl]amino]pyridine-3-carbonitrile Chemical compound FC1=CC=C2C(=NN(C2=C1)C=1C=NC=CC1)[C@H](C)NC1=C(C#N)C=CC=N1 NIJSHLJWHLHONN-ZDUSSCGKSA-N 0.000 claims description 4
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- VGSSLTPCGYPSOR-JTQLQIEISA-N 2,4-diamino-6-[[(1S)-1-(6-chloro-1-pyridin-3-ylindazol-3-yl)ethyl]amino]pyrimidine-5-carbonitrile Chemical compound NC1=NC(=C(C(=N1)N)C#N)N[C@@H](C)C1=NN(C2=CC(=CC=C12)Cl)C=1C=NC=CC1 VGSSLTPCGYPSOR-JTQLQIEISA-N 0.000 claims description 3
- HFIKWTYEHANIRQ-JTQLQIEISA-N 2,4-diamino-6-[[(1S)-1-(6-fluoro-1-pyridin-3-ylindazol-3-yl)ethyl]amino]pyrimidine-5-carbonitrile Chemical compound NC1=NC(=C(C(=N1)N)C#N)N[C@@H](C)C1=NN(C2=CC(=CC=C12)F)C=1C=NC=CC1 HFIKWTYEHANIRQ-JTQLQIEISA-N 0.000 claims description 3
- IIKYNGNMJPJEFN-JTQLQIEISA-N 2,4-diamino-6-[[(1S)-1-(6-fluoro-1-pyridin-4-ylindazol-3-yl)ethyl]amino]pyrimidine-5-carbonitrile Chemical compound NC1=NC(=C(C(=N1)N)C#N)N[C@@H](C)C1=NN(C2=CC(=CC=C12)F)C1=CC=NC=C1 IIKYNGNMJPJEFN-JTQLQIEISA-N 0.000 claims description 3
- PQBYGMJCPPEJIO-JTQLQIEISA-N 2,4-diamino-6-[[(1S)-1-[1-pyridin-3-yl-6-(trifluoromethyl)indazol-3-yl]ethyl]amino]pyrimidine-5-carbonitrile Chemical compound NC1=NC(=C(C(=N1)N)C#N)N[C@@H](C)C1=NN(C2=CC(=CC=C12)C(F)(F)F)C=1C=NC=CC1 PQBYGMJCPPEJIO-JTQLQIEISA-N 0.000 claims description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—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
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an indazole compound, and a preparation method and application thereof. The indazole compound provided by the invention has better kinase subtype selectivity and better in vitro proliferation inhibition activity on tumor cell strains. Can be applied to the preparation of antitumor drugs and the preparation of active drugs for inhibiting PI3K kinase, and provides a new approach for the research of antitumor drugs. The invention has the advantages of cheap and easily obtained raw materials, simple preparation method and suitability for large-scale production. The general structural formula is as follows:
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an indazole compound, a preparation method and application thereof in preparation of antitumor drugs.
Background
Malignant tumors have long severely threatened human health, particularly B-cell malignancies, including chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin's lymphoma, follicular lymphoma, and the like. Early therapeutic approaches, mainly the alleviation of patient symptoms by traditional cytotoxic drugs, were gradually recognized by biologists as a result of their intensive studies on the mechanism of tumor formation, and various physiological processes in tumor cells, such as signal pathway transduction, cell cycle regulation, apoptosis, angiogenesis, etc. Among them, the PI3K/Akt signaling pathway is an important signaling pathway in mammals, and abnormal activation of its signaling is considered to be closely related to the occurrence and development of tumors.
In the PI3K/Akt signaling pathway, PI3Ks is an important nodal protein, a class of lipid kinases with serine/threonine (ser/Thr) kinase activity and phosphatidylinositol kinase activity, whose function is primarily to phosphorylate the 3' hydroxyl group of phosphatidylinositol. PI3Ks is mainly activated by two means, one is by RTKs or GPCRs and the other is by binding of the catalytic subunit p110 to Ras, leading to PI3K activation. Activated PI3Ks phosphorylates PIP2 to form PIP3, PIP3 serves as a second messenger to recruit and activate protein kinases PDK1 and Akt, thereby activating downstream effectors and regulating cell proliferation, differentiation, survival and migration.
PI3K, an important member of PI3Ks family, exists specifically in hematopoietic cells and immune cells, plays an important role in B cell surface receptor signaling, and regulates the proliferation, differentiation, and survival of B cells. PI3K is considered to be an important target for the treatment of B cell malignancies and immune diseases. Three PI3K inhibitors are currently approved by the FDA for marketing, namely Idelalisib marketed by Gliade in 2014 for the treatment of B-cell non-hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia in combination with rituximab, Copanlisib, a Follicular Lymphoma (FL) adult patient marketed by Bayer in 2017 for the treatment of relapses after at least 2 systemic therapies, and Duvelisib, an oral drug for the first monotherapy marketed by Intellikine in 2018 for the treatment of relapses, refractory chronic lymphocytic leukemia, small lymphocytic lymphoma patients, and dual drug resistant follicular lymphoma patients. Although marketed drugs have significant therapeutic effects for the treatment of B cell malignancies, they also have some serious clinical side effects and drug interactions. Therefore, the development of a novel and safer selective inhibitor of PI3K is urgently needed.
Disclosure of Invention
The invention aims to provide an indazole compound, which has the following structural general formula (I):
and optical isomers thereof or pharmaceutically acceptable salts or solvates thereof,
wherein: r1、R2、R3、R4Same or different and selected from hydrogen, halogen atoms, C1-6Alkyl, halogenated C1-6Alkyl or C1-6An alkoxy group;
R5is selected from C1-6Alkyl radical, C1-6An alkyl cycloalkyl group;
R6selected from mono-or poly-substitutionAn aromatic ring or an aromatic heterocycle; the substituents on the ring are selected from hydrogen, halogen atoms, C1-6Alkyl radical, C1-6Alkoxy, sulfone, cyano, amide;
R7selected from mono-or poly-substituted aromatic rings or aromatic heterocycles; the substituents on the ring are selected from hydrogen, halogen atoms, C1-6Alkyl radical, C1-6Alkoxy, sulfone, cyano, amide.
More specifically, preferred compounds of the structure of formula (I) according to the invention are selected from:
(S) -N- (1- (1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine (11)
N- (1- (1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine (12)
(S) -N- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine (13)
(S) -N- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) propyl) -6-aminopurine (14)
(S) -N- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) -2-methylpropyl) -6-aminopurine (15)
(S) -N- (1- (6-chloro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine (16)
(S) -N- (1- (5-methyl-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine (17)
(S) -N- (1- (5-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine (18)
(S) -N- (1- (6-fluoro-1- (3-fluorophenyl) -1H-indazol-3-yl) ethyl) -6-aminopurine (19)
(S) -N- (1- (1- (3, 5-difluorophenyl) -6-fluoro-3-yl) ethyl) -6-aminopurine (20)
(S) -N- (1- (6-fluoro-1- (pyridin-4-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine (21)
(S) -N- (1- (6-fluoro-1- (pyridin-2-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine (22)
(S) -4- (3- (1- ((7H-purin-6-yl) amino) ethyl) -6-fluoro-1-indazolyl) benzonitrile (23)
(S) -N- (1- (6-fluoro-1- (3- (methylsulfonyl) phenyl) -1H-indazol-3-yl) ethyl) -6-aminopurine (24)
(S)-N6- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -2, 6-diaminopurine (25)
(S) -4-amino-6- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine (26)
(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine (27)
(S) -2- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) nicotinonitrile (28)
(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) propyl) amino) -5-cyanopyrimidine (29)
(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (4-pyridinyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine (30)
(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (3- (methylsulfonyl) phenyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine (31)
(S) -2, 4-diamino-6- (((6-chloro-1- (3- (methylsulfonyl) phenyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine (32)
(S) -2, 4-diamino-6- ((1- (6-chloro-1- (pyridin-3-yl) -1H-indazol-3-yl) propyl) amino) -5-cyanopyrimidine (33)
(S) -2, 4-diamino-6- ((1- (6-chloro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine (34)
(S) -2, 4-diamino-6- ((1- (1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine (35)
(S) -2, 4-diamino-6- ((1- (1- (pyridin-3-yl) -6- (trifluoromethyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine (36)
And optical isomers of these compounds or pharmaceutically acceptable salts or solvates thereof.
Another object of the present invention is to provide a method for producing the indazole compound, which comprises the steps of:
mono-substituted or multi-substituted aniline (compound 1), chloral hydrate and hydroxylamine hydrochloride react in a sodium sulfate aqueous solution to generate a compound 2, the compound 2 generates a compound 3 under the action of concentrated sulfuric acid, the compound 3 generates ring opening, diazotization, reduction and cyclization to form substituted indazole-3-formic acid 4, and then the substituted indazole-3-formic acid 4 is condensed with dimethylhydroxylamine hydrochloride to form a compound 5. Forming ketone (compound 6) by the compound 5 under the action of a Grignard reagent, then carrying out Ullman coupling on the compound 6 and a bromide to generate a compound 7, condensing the compound 7 and R- (+) -tert-butyl sulfinamide to generate a compound 8, reducing the compound 8 under the action of lithium tri-sec-butyl borohydride or sodium borohydride to generate a compound 9, then removing tert-butyl sulfinyl under an acidic condition to form a compound 10, and finally carrying out nucleophilic substitution reaction with a chloride to generate a target compound; the reaction formula is as follows:
R1，R2，R3，R4，R5，R6，R7are as described in claim 1, respectively.
The invention further aims to provide the application of the indazole compound in preparing anti-tumor drugs, wherein the tumors are chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, follicular lymphoma or liver cancer and breast cancer. One or more of immune diseases.
The invention also provides application of the indazole compound in preparing medicaments for inhibiting the activity of PI3K kinase.
The invention provides a compound with novel structure, which has cheap and easily obtained raw materials, simple preparation method and is suitable for large-scale production. Compared with a positive control, the indazole compound has better kinase subtype selectivity and better in-vitro proliferation inhibition activity on tumor cell strains.
Detailed Description
The present invention will be further described with reference to examples. The following examples are illustrative of the invention and are not intended to limit the invention in any way.
Preparation example Synthesis of 12- (hydroxyethylamine) -N-phenylacetamide 2
Chloral hydrate (19.8g, 0.12mol) was dissolved in 150mL of water, sodium sulfate (99.4g, 0.7mol) was added portionwise at 50 ℃ and stirred until all was dissolved for use. 3-fluoroaniline (9.3g, 0.1mol) is dissolved in 6M hydrochloric acid aqueous solution (20mL), slowly dropwise added into the mixed solution, hydroxylamine hydrochloride (20.9g, 0.3mol) is dissolved in a small amount of water and dropwise added into the reaction solution, the temperature is increased to 80-90 ℃ for reaction for 2 hours, the reaction solution is slowly cooled to 60 ℃, suction filtration is carried out, the solid is washed by a large amount of warm water, and the crude product 2 is obtained after drying.
Preparative example 2 Synthesis of isatin 3
Adding 50mL of concentrated sulfuric acid into a two-mouth bottle, heating to 60 ℃, adding the raw material 2 into the concentrated sulfuric acid in batches, keeping the internal temperature not more than 65 ℃, reacting for 30min, heating to about 85 ℃ of the internal temperature, reacting for 15min, slowly cooling to room temperature, slowly pouring the reaction liquid into ice water, keeping the temperature not more than 25 ℃, stirring for a period of time, separating out a large amount of solid, performing suction filtration, extracting the filtrate with ethyl acetate, drying with sodium sulfate, and combining with the filter cake in a rotary drying manner. Dissolving the crude product in 50 ℃ sodium hydroxide solution, stirring for 1h, then removing insoluble substances by suction filtration, cooling the filtrate to 0 ℃, dropwise adding hydrochloric acid until the pH value is 1, stirring for 2h, then performing suction filtration, washing with ice water, collecting solids, and drying to obtain isatin 3(11.76g, the combined yield of the two steps is 80%).
Preparation example 3 Synthesis of indazole-3-carboxylic acid 4
Dissolving isatin 3(7.35g,50mmol) in 5M sodium hydroxide (2g, 50mmol) solution, reacting for 30min, clarifying the solution, cooling to 0 ℃, slowly adding sodium nitrite (4.14g, 60mmol) aqueous solution, keeping the internal temperature below 4 ℃, reacting for 30min, slowly dropping the reaction solution into sulfuric acid solution (50mL, 2N), adding a small amount of diethyl ether to prevent foam generation, reacting for 30min at 0 ℃, dissolving stannous chloride dihydrate (28.2g, 125mmol) in 20mL concentrated hydrochloric acid under mechanical stirring, slowly dropping into the reaction solution, keeping the internal temperature below 0 ℃, and adding a small amount of diethyl ether to prevent a large amount of foam generation. Stirring for 2h, performing suction filtration, washing with a large amount of warm water, collecting a solid, dissolving the solid in a sodium hydroxide solution, extracting with ethyl acetate, collecting a water phase, adding hydrochloric acid at low temperature to adjust the pH to be about 3 to separate out a light yellow solid, performing suction filtration, washing with water, collecting the solid, and drying to obtain a crude indazole-3-formic acid 4 product.
Preparation example 4 Synthesis of N-methoxy-N-methyl-1H-indazole-3-carboxamide 5
Indazole-3-carboxylic acid, dimethylhydroxylamine hydrochloride (7.3g,75mmol) were added to a reaction flask, 50mL THF was added, cooled to 0 deg.C, pyridine (7.9g,0.1mol) was added dropwise, stirred for 1h, then moved to room temperature and stirred for 30min, EDCI (12.5g,65mmol), pyridine (8.7g,0.11mol) were added, and stirred at room temperature overnight. And detecting the reaction progress by TLC, after the reaction is finished, spin-drying the solvent, adding water for ultrasonic treatment, performing suction filtration, and washing by a large amount of water. Collecting solid, dissolving with dichloromethane, vacuum filtering to remove insoluble substances, extracting the filtrate with water, collecting organic layer, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and purifying by EA/PE (v/v,1: 5) eluent column chromatography to obtain light yellow solid 5(4.6g, two steps combined yield 45%)
Preparation example Synthesis of 53-acetylindazole 6
Adding raw material 5(4.1g,20mmol) into a two-mouth bottle, vacuumizing, introducing argon, replacing for three times, adding anhydrous THF, cooling the reaction liquid to-10 ℃, slowly dropwise adding methyl magnesium chloride (20mL,3.0M in THF), transferring to room temperature after dropwise adding, reacting at low temperature, quenching with saturated ammonium chloride solution, collecting an organic layer, washing with saturated salt water, drying with sodium sulfate, concentrating, and separating by using an eluent column chromatography of EA/PE (v/v,1:10) to obtain a light yellow solid 6(2.56g, 80%)
Preparation example Synthesis of 61- (3-pyridyl) -3-acetylindazole 7
6(2.4g,15mmol), cuprous iodide (572mg,3mmol), L-proline (690mg,6mmol), potassium carbonate (4.14g,30mmol) were weighed into a two-necked flask, 30mL of DMSO was added under argon protection, and 3-bromopyridine (3.56g,22.5mmol) was added at room temperature and warmed to 120 ℃ for reaction. After the reaction was complete, cooled to room temperature, 50mL ethyl acetate was added and stirred for 20min, the insoluble material was removed by suction filtration, water was added to the filtrate, the organic layer was collected, washed with saturated brine, dried over sodium sulfate, concentrated, the crude product was recrystallized from PE/EA, and suction filtration gave 7(2.92g, 82%) as a yellow solid.
Preparation example 7 Synthesis of (R) -2-methyl-N- (1- (1- (pyridin-3-yl) -3-indazolyl) ethylene) propane-2-sulfinamide 8
7(2.37g,10mmol), R- (+) -tert-butylsulfinamide (1.82g,15mmol) was charged into a two-necked flask under argon, 20mL of anhydrous THF was added, tetraethyltitanate (2.28g,10mmol) was added, and the reaction was heated under reflux overnight. And after the reaction is finished, adding water, stirring for 20min, repeatedly performing suction filtration until a large amount of solid is generated, washing with ethyl acetate, layering, collecting an organic layer, washing with saturated salt solution, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product 8.
Preparation example 8 Synthesis of (R) -2-methyl-N- ((S) -1- (1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) propane-2-sulfinamide 9
Putting the crude product 8 into a two-neck bottle, adding anhydrous THF for dissolving under the protection of argon, cooling to-78 ℃, slowly adding lithium tri-sec-butyl borohydride (10mL,1M in THF), reacting for 3h, adding water for quenching reaction, adding ethyl acetate for layering, collecting an organic layer, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography with an eluent of EA/PE (v/v,2:1) to obtain a light yellow solid 9(1.73g, 50% over two steps).
Note that: preparation of the racemate sodium borohydride was used as a reducing agent in this step to reduce the imine.
Preparation example 9 Synthesis of (S) -1- (1- (pyridin-3-yl) -3-indazolyl) ethan-1-amine 10
Weighing 9(1.73g,5mmol), placing into a single-neck bottle, adding methanol for dissolving, adding 5mL of 6N HCl at room temperature, carrying out reaction for 2h, then carrying out spin-drying on the methanol, adding water/ethyl acetate for layering, collecting a water layer, adding sodium hydroxide for adjusting to be alkaline, adding ethyl acetate for extraction, collecting an organic layer, washing with saturated salt water, drying with anhydrous sodium sulfate, concentrating to obtain a crude product, and recrystallizing with PE/EA to obtain a light yellow solid 2-10c (952mg, 80%).
Preparation example 10(S) -N- (1- (1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine 11
Weighing 10(238mg, 1mmol) and 6-chloropurine (232mg, 1.5mmol), placing into a pressure resistant tube, adding n-butanol for dissolving, adding DIPEA (258mg,2mmol), heating to 140 ℃ for overnight reaction, adding water/ethyl acetate for layering after the reaction is finished, collecting an organic layer, washing with saturated common salt water, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography with an eluent of DCM/MeOH (v/v,50:1) to obtain a light yellow solid 11(107mg, 30%).
m.p.221-223℃；1H NMR(400MHz,CDCl3)9.08(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)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.
Preparation example 11N- (1- (1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine 12
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out to obtain yellow solid 12, and the yield is 37%
m.p.212-214℃；1H NMR(400MHz,CD3OD)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)155.6,153.9,153.1,150.9,148.8,141.3,139.7,129.1,127.8,124.8,123.5,122.3,121.3,121.0,116.5,1144,11.1,61.6,30.8；HRMS(ESI)m/z Calcd for C21H16N8(M+):356.1498；Found:356.1498.
Preparation example 12((S) -N- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine 13
The preparation method is the same as that of preparation examples 1-9, and the light yellow solid obtained by column chromatography is 13, and the yield is 52%.
m.p.218-220℃；1H NMR(400MHz,CD3OD)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)；13CNMR(150MHz,DMSO-d6)163.1,161.5,152.3,150.6,147.4,143.0,139.8and139.7,136.1,129.2,124.5,123.33and 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.
Preparation example 13(S) -N- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) propyl) -6-aminopurine 14
The preparation method is the same as that of preparation examples 1-9, and the column chromatography is carried out on 14 pale yellow solid with the yield of 65%.
m.p.180-182℃；1H NMR(400MHz,CDCl3)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)；13CNMR(100MHz,CDCl3)164.5,162.0,152.6,149.0,147.7,143.5,140.4and140.2,138.3,136.7,129.8,124.3,122.8,122.7,120.6,111.9and 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.
Preparation example 14(S) -N- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) -2-methylpropyl) -6-aminopurine 15
The preparation method is the same as that of preparation embodiment 1-9, column chromatography light yellow solid 15, yield 54%
m.p.72-74℃；1H NMR(400MHz,CDCl3)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)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.
Preparation example 15(S) -N- (1- (6-chloro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine 16
The preparation method is the same as that of preparation embodiment 1-9, column chromatography is carried out on light yellow solid 16, and the yield is 55 percent
m.p.86-88℃；1H NMR(400MHz,CD3OD)9.00(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)153.8,151.5,148.1,144.2,141.7,141.08,141.06,138.2,135.6,131.3,125.9,124.0,123.5,123.2,111.2,100.0,45.2,21.0；HRMS(ESI)m/z Calcd for C19H15ClN8(M+):390.1108；Found:390.1108.
Preparation example 16(S) -N- (1- (5-methyl-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine 17
The preparation method is the same as that of preparation embodiment 1-9, column chromatography light yellow solid 17, yield 72%
m.p.81-83℃；1H NMR(400MHz,CDCl3)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)154.1,152.5,149.0,147.1,143.2,138.6,138.4,137.2,131.7,130.1,129.5,124.2,123.6,120.3,110.0,100.1,60.6,29.8,21.5；HRMS(ESI)m/z Calcd for C20H18N8(M+):370.1654；Found:370.1654.
Preparation example 17(S) -N- (1- (5-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine 18
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out on light yellow solid 18, and the yield is 75 percent
m.p.212-241℃；1H NMR(400MHz,CDCl3)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)157.1,152.7,149.4,147.9,143.5,13.3,137.0,136.8,129.9,124.3,123.7,123.6,117.7,117.54,111.5,105.9,6.1,29.8；HRMS(ESI)m/z Calcd for C19H15FN8(M+):374.1404；Found:374.1404.
Preparation example 18(S) -N- (1- (6-fluoro-1- (3-fluorophenyl) -1H-indazol-3-yl) ethyl) -6-aminopurine 19
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out on the light yellow solid 19, and the yield is 50 percent
m.p.209-211℃；1H NMR(400M,CD3OD)8.30(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)163.4,163.1,161.7and161.5,152.3,150.2,140.9and 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 108.9,97.2and97.0,43.4；20.3；HRMS(ESI)m/z Calcd for C20H15F2N7(M+):391.1357；Found:391.1359.
Preparation example 19(S) -N- (1- (1- (3, 5-difluorophenyl) -6-fluoro-3-yl) ethyl) -6-aminopurine 20
The preparation method is the same as that of preparation embodiment 1-9, column chromatography is carried out on the light yellow solid 20 percent, and the yield is 48 percent
m.p.158-160℃；1H NMR(400MHz,CDCl3)8.50(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)163.7and163.6,163.2,162.1and 162.0,161.6,152.2,150.7,141.64and 141.55,140.0,139.5and 139.4,123.3and 123.2,120.5and 120.2,111.5and111.3,108.1,105(dd,J1＝7.5Hz,J2＝22.5Hz,1C),101.6(t,J＝25.5Hz,1C),97.6and97.4,43.5,20.1；HRMS(ESI)m/z Calcd for C20H14F3N7(M+):409.1263；Found:409.1263.
Preparation example 20(S) -N- (1- (6-fluoro-1- (pyridin-4-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine 21
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out on the light yellow solid 21, and the yield is 43 percent
m.p.224-226℃；1H NMR(400MHz,CDCl3)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)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.
Preparation example 21(S) -N- (1- (6-fluoro-1- (pyridin-2-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine 22
The preparation method is the same as that of preparation embodiment 1-9, column chromatography is carried out on the light yellow solid 22, and the yield is 32 percent
m.p.114-116℃；1H NMR(400MHz,CD3OD)8.53-8.43(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)164.3,161.9,154.0,152.5,149.5,147.7,140.5and 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.
Preparation example 22(S) -4- (3- (1- ((7H-purin-6-yl) amino) ethyl) -6-fluoro-1-indazolyl) benzonitrile 23
The preparation method is the same as that of preparation embodiment 1-9, column chromatography is carried out on the light yellow solid 23, and the yield is 56 percent
m.p.228-230℃；1H NMR(400MHz,CDCl3)8.51(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)163.2and 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 forC21H15FN8(M+):398.1404；Found:398.1410.
Preparation example 23(S) -N- (1- (6-fluoro-1- (3- (methylsulfonyl) phenyl) -1H-indazol-3-yl) ethyl) -6-aminopurine 24
The preparation method is the same as that of preparation embodiment 1-9, column chromatography is carried out on the light yellow solid 24, and the yield is 65 percent
m.p.93-95℃；1H NMR(400MHz,CDCl3)8.49(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)162.6,162.1,152.6,150.0,142.4,142.3,141.0,138.4,131.0,130.9,126.8,125.1,122.9and 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.
Preparation of example 24(S) -N6- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -2, 6-diaminopurine 25
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out on light yellow solid 25, and the yield is 31 percent
m.p.89-91℃；1H NMR(400MHz,CD3OD)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)165.7,163.3,161.9,155.2,151.8,147.8,143.9,141.6and 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 Calcdfor C19H16FN9(M+):389.1513；Found:389.1520.
Preparation example 25(S) -4-amino-6- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine 26
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out on the light yellow solid 26, and the yield is 54 percent
m.p.204-206℃；1H NMR(400MHz,CD3OD)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)164.6,161.9,161.6,159.9,149.9,147.4,142.9,139.8and 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.
Preparation example 26(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine 27
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out on the light yellow solid 27, and the yield is 52 percent
m.p.96-98℃；1H NMR(400MHz,CDCl3)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)165.2,164.4,163.03and 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.
Preparation example 27(S) -2- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) nicotinonitrile 28
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out on light yellow solid 28, and the yield is 25%
m.p.108-110℃；1H NMR(400MHz,CD3OD)8.99(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)163.1,161.5,157.3,152.8,150.3,147.4,143.0and 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.
Preparation example 28(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) propyl) amino) -5-cyanopyrimidine 29
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out on the light yellow solid 29, and the yield is 65 percent
m.p.97-99℃；1H NMR(400MHz,CD3OD)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)167.0,165.8,165.0,164.8and 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.
Preparation example 29(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (4-pyridinyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine 30
The preparation method is the same as that of preparation examples 1-9, column chromatography is carried out on the light yellow solid of 30 percent, and the yield is 56 percent.
m.p.97-99℃；13H NMR(600MHz,DMSO-d6)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)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/zCalcd for C19H16FN9(M+):389.1513；Found:389.1513.
Preparation example 30(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (3- (methylsulfonyl) phenyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine 31
The preparation method is the same as that of preparation examples 1-9, and the light yellow solid of column chromatography is 31, and the yield is 68%.
m.p.112-114℃；1H NMR(400MHz,CD3OD)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)165.5,163.1,162.9,161.6,150.4,142.3,140.0,139.6and 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。
Preparation example 31(S) -2, 4-diamino-6- ((((6-chloro-1- (3- (methylsulfonyl) phenyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine 32
The preparation method is the same as that of preparation examples 1-9, and the light yellow solid obtained by column chromatography is 32 percent, and the yield is 56 percent.
m.p.108-110℃；1H NMR(400MHz,CD3OD)8.29(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)167.0,164.8,164.6,151.6,143.7,141.8,141.5,135.6,132.1,127.9,126.2,124.0,123.7,123.3,122.0,118.1,111.2,61.8,45.1,44.3,20.6；HRMS(ESI)m/z Calcd for C21H19ClN8O2S(M+):482.1040；Found:482.1040.
Preparation example 32(S) -2, 4-diamino-6- ((1- (6-chloro-1- (pyridin-3-yl) -1H-indazol-3-yl) propyl) amino) -5-cyanopyrimidine 33
The preparation method is the same as that of preparation examples 1-9, and the column chromatography is carried out on 33 percent of light yellow solid with the yield of 72 percent.
m.p.83-85℃；1H NMR(400MHz,CD3OD)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)167.0,165.0,164.8,151.0,148.2,144.2,141.6,138.2,135.7,131.4,125.9,124.0,123.7,118.1,111.1,100.0,83.4,50.5,28.4,10.9；HRMS(ESI)m/z Calcd for C20H18ClN9(M+):419.1374；Found:419.1370.
Preparation example 33(S) -2, 4-diamino-6- ((1- (6-chloro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine 34
The preparation method is the same as the preparation embodiment 1-9, and column chromatography is carried out to obtain 34 percent of light yellow solid with the yield of 62 percent.
m.p.100-102℃；1H NMR(400MHz,CD3OD)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)167.0,164.8,164.6,151.7,148.1,144.2,141.7,138.2,135.6,131.3,125.9,123.7,123.3,118.1,117.5,111.1,61.8,45.1,20.6；HRMS(ESI)m/z Calcd for C19H16ClN9(M+):405.1217；Found:405.1215.
Preparation example 34(S) -2, 4-diamino-6- ((1- (1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine 35
The preparation method is the same as the preparation embodiment 1-9, column chromatography is carried out to obtain 35 percent of light yellow solid, and the yield is 45 percent.
m.p.90-91℃；1H NMR(400MHz,CD3OD)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)167.0,164.8,164.6,151.6,147.6,143.9,138.7,131.3,129.3,125.9,124.5,123.1,122.6,122.4,118.1,111.3,61.7,45.3,20.8；HRMS(ESI)m/z Calcd forC19H17N9(M+):371.1607；Found:371.1607。
Preparation example 35(S) -2, 4-diamino-6- ((1- (1- (pyridin-3-yl) -6- (trifluoromethyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine 36
The preparation method is the same as that of preparation embodiment 1-9, column chromatography is carried out to obtain light yellow solid 36, and the yield is 58 percent
m.p.128-130℃；1H NMR(400MHz,CD3OD)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)167.1,164.8,164.6,151.8,148.5,144.5,140.4,138.0,131.8,131.1and 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.
Biological experiment example 1: indazole derivative inhibitory activity test on PI3K
With ADP-GloTMDiluting the test compound to a series of concentrations required for the assay, transferring 50nL each to a 384 well plate, adding 50nL DMSO to each of a negative control well and a positive control well, diluting PI3K α, γ to 1.25nM, 1.25nM, 10nM, 1.25nM using a Kinase buffer solution, adding 2 μ L of DMSO to each well, adding 2.5 μ L to each of the negative and positive control wells, centrifuging for 30 seconds, incubating for 10 minutes at room temperature after shaking, adding a mixed solution of 2.5 μ L ATP and PIP2, centrifuging for 30 seconds, incubating for 2 hours at room temperature after shaking, adding 5 μ L ADP-GloReagen, incubating for 3 hours at room temperature after shaking, adding 10 μ L of Kinase Detection Reagent, and incubating for 1 hour at room temperature after shakingAfter the sample is treated by centrifugation and the like, the RLU value is read by an Enspire microplate reader, and the inhibition rate is calculated according to a formula.
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a dose-effect curve is fitted by adopting the log (inhibitor) vs. response-Variable slope of the GraphPad Prism 5 analysis software, so as to obtain the IC of each compound on the enzyme activity50The value is obtained.
Table 1 PI3K inhibitory activity of indazole derivatives
As can be seen from Table 1, by using pan-I PI3K kinase inhibitor PI-103 as a positive control, most compounds in the compounds with the brand-new structure show better PI3K inhibitory activity, and a new basis is provided for the research of preparing cancer treatment drugs.
TABLE 2 subtype Selective evaluation of Compounds
As can be seen from table 2, compounds 16, 27, 32, 33 and 34 all showed excellent subtype selectivity relative to the positive control drug PI-103.
Biological Experimental example 2 in vitro antitumor Activity of indazole derivatives
The in-vitro inhibition effect of a part of indazole compounds on acute leukemia cell MV-4-11 is determined by adopting an MTS method, and the median inhibition concentration is calculated. The result shows that the synthesized indazole compounds show good tumor inhibition activity in cells, and most compounds show better inhibition activity with the positive drug Idelalisib.
In vitro inhibitory Activity of some Compounds of Table 3 on MV-4-11
| Compound (I) | 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 can be seen from Table 3, by using the PI3K kinase selective inhibitor Idelalisib which is currently on the market as a positive control, some compounds in the compounds with the brand-new structure show better inhibitory activity, and the activity of most compounds exceeds that of the positive control Idelalisib, so that a new basis is provided for the research of preparing cancer treatment drugs.
Claims (3)
1. An indazole derivative, which is characterized by the following structural general formula:
a compound selected from the following or a pharmaceutically acceptable salt thereof:
(S)-N- (1- (1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine,
(S)-N- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine,
(S)-N- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) propyl) -6-aminopurine,
(S)-N- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) -2-methylpropyl) -6-aminopurine ((S)-N- (1- (6-chloro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine,
(S)-N- (1- (5-methyl-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminoA group of a purine base,
(S)-N- (1- (5-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine,
(S)-N- (1- (6-fluoro-1- (3-fluorophenyl) -1H-indazol-3-yl) ethyl) -6-aminopurine,
(S)-N- (1- (1- (3, 5-difluorophenyl) -6-fluoro-3-yl) ethyl) -6-aminopurine,
(S)-N- (1- (6-fluoro-1- (pyridin-4-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine,
(S)-N- (1- (6-fluoro-1- (pyridin-2-yl) -1H-indazol-3-yl) ethyl) -6-aminopurine,
(S) -4- (3- (1- ((7H-purin-6-yl) amino) ethyl) -6-fluoro-1-indazolyl) benzonitrile,
(S)-N- (1- (6-fluoro-1- (3- (methylsulfonyl) phenyl) -1H-indazol-3-yl) ethyl) -6-aminopurine (6-fluoro-1-phenyl)S)-N 6- (1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) -2, 6-diaminopurine,
(S) -4-amino-6- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine,
(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine,
(S) -2- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) nicotinonitrile,
(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (pyridin-3-yl) -1H-indazol-3-yl) propyl) amino) -5-cyanopyrimidine,
(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (4-pyridinyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine,
(S) -2, 4-diamino-6- ((1- (6-fluoro-1- (3- (methylsulfonyl) phenyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine,
(S) -2, 4-diamino-6- (((6-chloro-1- (3- (methylsulfonyl) phenyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine,
(S) -2, 4-diamino-6- ((1- (6-chloro-1- (pyridin-3-yl) -1H-indazol-3-yl) propyl) ammonia-a group) -5-cyanopyrimidine,
(S) -2, 4-diamino-6- ((1- (6-chloro-1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine,
(S) -2, 4-diamino-6- ((1- (1- (pyridin-3-yl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine,
(S) -2, 4-diamino-6- ((1- (1- (pyridin-3-yl) -6- (trifluoromethyl) -1H-indazol-3-yl) ethyl) amino) -5-cyanopyrimidine.
2. The use of an indazole derivative according to claim 1, for the preparation of an anti-tumor medicament, wherein said tumor is one or more of chronic lymphocytic leukemia, acute lymphocytic leukemia, non-hodgkin lymphoma, follicular lymphoma, liver cancer, breast cancer, and immune diseases.
3. The use of an indazole derivative according to claim 1, for the preparation of a medicament for inhibiting the activity of PI3K kinase.
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