CN102675286B - Indazole compounds, preparation method, application and pharmaceutical composition thereof - Google Patents

Abstract

The present invention provides indazole compounds of general formula (I), their stereoisomers, tautomers, solvates, prodrug forms, N-oxides and pharmaceutically acceptable salts, and their preparation Methods and pharmaceutical compositions comprising such compounds. This type of compound can inhibit PI3K activity, so it can be used to treat diseases caused by abnormal cell survival, proliferation, differentiation, apoptosis and other functions related to PI3K, such as cancer, immune disease, cardiovascular disease, inflammation, metabolism, etc. / Endocrine dysfunction and neurological diseases.

Description

A class of indazole compounds and their preparation method, use and pharmaceutical composition

technical field

The present invention relates to a class of indazole compounds represented by the following general formula (I) and its preparation method and application. Such compounds are useful as PI3K inhibitors and thus useful in the treatment of diseases and conditions resulting from abnormal cellular functions and behaviors associated with PI3K. The present invention also relates to pharmaceutically acceptable compositions containing these compounds as active ingredients.

Background technique

Phosphoinositide 3-kinases (Phosphoinositide 3-kinases, PI3K) is a class of lipid kinases, as the main downstream effector of receptor tyrosine kinases and G protein-coupled receptors, PI3K phosphorylates 4, Phosphatidylinositol 5-diphosphate (PIP2) converts it into phosphatidylinositol 3,4,5-triphosphate (PIP3), and transmits the signals of various growth factors and cytokines into the cell. As a second messenger in cells, PIP3 can activate Akt (PKB) and other downstream effectors such as mTOR to cause a series of biological effects (Vivanco I, Sawyers CL.Nat.Rev.Cancer 2002; 2:489-501 ).

According to the structural characteristics and substrate specificity of PI3K, it can be divided into three types: I, II, and III, among which type I is the most studied. Class I PI3Ks are heterodimers, composed of a catalytic subunit (molecular weight 110kDa, expressed as p110) and a regulatory subunit, including four homologous isomers of PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ. They are p110α, p110β, p110γ and p110δ respectively. Class I PI3Ks can be further divided into two subclasses, IA and IB. IA subclasses, including PI3Kα, PI3Kβ and PI3Kδ, the catalytic subunit p100 (p110α, p110β and p110δ) binds to the regulatory subunit p85. PI3Kγ belongs to subclass IB, and its catalytic subunit p100γ binds to regulatory subunits p101, p84 or p87. IA subclass can be activated by receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs) and some oncogene proteins such as RAS protein, while IB subclass can only be activated by GPCRs (Kong DX, Yamori T. Curr. Med. Chem. 2009;16:2839-2854).

PI3K-mediated signal transduction pathways regulate many cell biological processes such as cell survival, proliferation, differentiation, apoptosis, angiogenesis, etc., and these biological processes play a vital role in the occurrence and development of tumors. The tumor suppressor gene protein PTEN (Phosphatase and tensin homolog), as a phospholipase, catalyzes the dephosphorylation of PIP3 to PIP2, thereby antagonizing the effect of PI3K and negatively regulating the PI3K signaling pathway. In recent years, human tumor genomics studies have shown that in a variety of human tumors, the PI3K signaling pathway is overactivated due to mutations in many of the protein-coding genes. For example, the genes encoding PI3K have different degrees of functional gain in various tumors. Sexual mutation, amplification or overexpression, while PTEN is generally missing, which makes the inhibition of PI3K activity an important strategy for tumor therapy (Liu PX, Cheng HL, Roberts TM, Zhao JJ.Nat.Rev.Drug Discovery 2009;8:627- 644). At present, several PI3K inhibitors have entered the clinical research stage, which indicates that PI3K inhibitors are likely to become a new generation of anti-tumor drugs and enter clinical use. The present invention precisely targets PI3K as a target for diseases, especially tumors.

Contents of the invention

One object of the present invention is to provide a class of indazole compounds, including their stereoisomers, tautomers, solvates, prodrug forms, N-oxides and pharmaceutically acceptable salts.

Another object of the present invention is to provide a preparation method of such compounds.

Another object of the present invention is to provide the use of this compound in the preparation of medicines.

Still another object of the present invention is to provide pharmaceutical compositions comprising such compounds as active ingredients.

According to the purpose of the present invention, there are provided indazole compounds represented by general formula (I) as follows, including stereoisomers, tautomers, solvates, prodrug forms, N-oxides and pharmaceutical Acceptable salts on:

in:

R ¹ is bonded to the 1-position nitrogen atom on the ring or to the 2-position nitrogen atom on the ring; and is hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl or contains 1-4 A five-membered or six-membered heteroaryl group selected from heteroatoms in N, O and S (such as furyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, etc.);

R ² is hydrogen, C6-C10 aryl, heterocyclic group (such as piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydropyranyl, dihydropyryl pyryl, tetrahydropyridyl, etc.), or a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S (such as furyl, thienyl, Thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, Quinolinyl, isoquinolyl, quinoxalinyl, quinazolinyl, etc.); said aryl, heterocyclyl and heteroaryl are optionally substituted by 1-3 groups selected from the following groups: Oxygen, halogen, amino, C1-C6 alkylamino, C1-C6 alkylcarbonylamino, hydroxyl, trifluoromethyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkylaminocarbonyl, hydroxyl C1-C6 alkylaminocarbonyl, (C1-C6 alkyl)-SO ₂ -NH-, (C1-C6 alkyl)-SO ₂ -, (C1-C6 alkyl) -CO-NH-(C1-C6 alkyl)-, tert-butoxycarbonyl, heterocyclylcarbonyl, C1-C6 alkyl substituted heterocyclylcarbonyl, hydroxyC1-C6 alkyl substituted heterocyclylcarbonyl, heterocyclylcarbonyl Cyclic C1-C6 alkyl, unsubstituted or C1-C6 alkyl substituted heterocyclic group, NH ₂ -SO ₂ -, C1-C6 alkylaminosulfonyl or hydroxy C1-C6 alkylaminosulfonyl; the The heterocyclic group is 5-7-membered and contains 1-2 heteroatoms selected from N, O and S;

R ³ is a C6-C10 aryl group or a 5-membered or 6-membered heteroaryl group (such as pyridyl, pyrimidinyl, etc.) containing 1-2 N heteroatoms; the aryl and heteroaryl groups are optionally replaced by halogen , amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, hydroxyl substituted C1-C6 alkyl, -SO ₂ NHR ⁷ or -NHSO ₂ R ⁷ substituted; where R ⁷ is selected from: unsubstituted or hydroxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, or 5-membered ～ containing 1-4 heteroatoms selected from N, O and S 10-membered heteroaryl, the aryl and heteroaryl are optionally substituted by 1-5 groups selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, halogen, amino, trifluoromethane group, cyano group, hydroxyl group, C1-C6 alkoxy group or -(CH ₂ ) _p COOH, wherein p is an integer of 0-2;

R is selected from C1-C6 alkyl, C3-C7 cycloalkyl, C1- ^C4 alkoxy, C1-C4 alkanoyl, halogen, amino, cyano, hydroxyl and nitro;

n is 0, 1 or 2; it represents the number of R ⁴ ;

X is C or N;

Y is absent or is a trans double or triple bond;

Z is absent or is a triple bond or methylene.

According to the compound of the present invention, when R is bonded to the ¹ -position nitrogen atom on the ring, it has the structure shown in the following structural formula (Ia):

wherein R ¹ , R ² , R ³ , R ⁴ , n, X, Y and Z are as defined above.

Particularly, in the above structural formula (Ia):

R ¹ is preferably hydrogen or methyl;

^R3 is preferably pyridyl; said pyridyl is optionally substituted by halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, hydroxyl substituted C1-C6 alkane Substituted by -SO ₂ NHR ⁷ or -NHSO ₂ R ⁷ ; where R ⁷ is selected from: unsubstituted or hydroxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl or containing 1-4 A 5-10-membered heteroaryl group of heteroatoms selected from N, O and S, the aryl and heteroaryl groups are optionally substituted by 1-5 groups selected from the following groups: C1-C6 alkane Base, C3-C6 cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, C1-C6 alkoxy or -(CH ₂ ) _p COOH, wherein p is an integer of 0-2;

Y and Z are preferably absent.

According to the compound of the present invention, when R is bonded to the ² -position nitrogen atom on the ring, it has a structure shown in the following structural formula (Ib):

wherein R ¹ , R ² , R ³ , R ⁴ , n, X, Y and Z are as defined above.

Particularly, in the above structural formula (Ib):

R ¹ is preferably methyl;

^R3 is preferably pyridyl; said pyridyl is optionally substituted by halogen, amino, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, hydroxyl substituted C1-C6 alkane Substituted by -SO ₂ NHR ⁷ or -NHSO ₂ R ⁷ ; where R ⁷ is selected from: unsubstituted or hydroxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl or containing 1-4 A 5-10-membered heteroaryl group of heteroatoms selected from N, O and S, the aryl and heteroaryl groups are optionally substituted by 1-5 groups selected from the following groups: C1-C6 alkane Base, C3-C6 cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, C1-C6 alkoxy or -(CH ₂ ) _p COOH, wherein p is an integer of 0-2;

Y and Z are preferably absent.

According to the compound of the present invention, when Y and Z do not exist, ^R is a substituted pyridyl group, which has the structure shown in the following structural formulas (Ic) and (Id):

in:

R ¹ , R ² , R ⁴ , n and X are as defined in structural formula (I);

^In particular, in the above structural formulas (Ic) and (Id), R is preferably hydrogen or methyl;

R ⁵ is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, halogen, amino, cyano or hydroxyl;

m is 0 or 1; it represents the number of R ⁵ ;

R ⁶ is -SO ₂ NHR ⁷ or -NHSO ₂ R ⁷ , wherein R ⁷ is selected from: unsubstituted or hydroxy-substituted C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl or containing 1-4 A 5-10-membered heteroaryl group of heteroatoms selected from N, O and S, the aryl and heteroaryl groups are optionally substituted by 1-5 groups selected from the following groups: C1-C6 alkane radical, C3-C6 cycloalkyl, halogen, amino, trifluoromethyl, cyano, hydroxyl, C1-C6 alkoxy or -(CH ₂ ) _p COOH, wherein p is an integer of 0-2.

Compounds of the invention are preferably:

Compounds of formula (I) may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof (eg racemic mixtures) form part of the invention.

The compounds of formula (I) may also exist in different tautomeric forms, all of which are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that interconvert via a low energy barrier.

The compound of structural formula (I) can exist in unsolvated form and solvated form containing pharmaceutically acceptable solvents (such as water, ethanol, etc.), and the present invention includes solvated and unsolvated forms.

The compound of formula (I) has a basic group and can therefore form "pharmaceutically acceptable salts" with inorganic or organic acids, including pharmaceutically acceptable acid addition salts, when such salts are possible, by using inorganic acids Or the free base of organic acid treatment structural formula (I) compound, can obtain pharmaceutically acceptable salt, and described inorganic acid is as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and described organic acid is as ascorbic acid, nicotinic acid, lemon acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, oxalic acid, malic acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene Sulfonic acid etc.

The compounds of the present invention having general structural formula (I) can be synthesized by methods including those well known in the field of chemistry, especially according to the description of the present invention. Starting materials are generally available from commercial sources such as Sigma-Aldrich, or are readily prepared using methods well known to those skilled in the art.

For the purpose of illustrating the present invention, Schemes 1 and 2 below show general methods for preparing compounds of formula (I) and key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are described and discussed in the following schemes, other starting materials and reagents can be readily substituted to provide various derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

The indazole compound of structural formula (I) of the present invention can be prepared by the following scheme, in which R ¹ , R ² , R ³ , R ⁴ , n, X, Y and Z are as defined above;

Option One:

As shown in the reaction equation of Scheme 1, starting material A can be obtained from commercial sources or reference method (CheungM, Boloor A, Stafford JA.J.Org.Chem.2003; 68:4093-4095, the entire contents of which are disclosed by reference Incorporated into this application) made.

a: The 3-position iodide of raw material A is used to obtain compound B. The reaction reagents are iodine, pyridine and [bis(trifluoroacetoxy)iodo]benzene, the reaction solvent is dichloromethane or chloroform, and the reaction temperature is 20°C-100°C between;

b: When Z does not exist, Suzuki coupling reaction between compound B and boronic ^acid substituted by R2 group or its boronic acid ester in the presence of palladium catalyst, or when Z is a triple bond, ^compound B and acetylene substituted by R2 group A Sonogashira coupling reaction occurs in the presence of a palladium catalyst and cuprous iodide to obtain a 3-substituted compound C;

c: When Y does not exist, compound C performs Suzuki coupling reaction with ^R3 substituted boronic acid or its boronic acid ester, or when Y is a triple bond, compound C performs Sonogashira coupling reaction with ^R3 substituted acetylene, or Y is In case of trans double bond, compound C and R ³ substituted ethylene are subjected to Heck coupling reaction to obtain compound (I).

Option II:

As shown in the reaction equation of Scheme 2, raw material A can be obtained from commercial sources or prepared by referring to literature methods (CheungM, Boloor A, Stafford JA.J.Org.Chem.2003; 68:4093-4095).

a: When Y does not exist, raw material A undergoes Suzuki coupling reaction with ^R3 -substituted boronic acid or its boronic acid ester, or when Y is a triple bond, raw material A undergoes Sonogashira coupling reaction with ^R3 -substituted acetylene, or Y is In the case of a trans double bond, the raw material A and the ethylene substituted by ^R3 undergo a Heck coupling reaction to obtain compound E;

b: The 3-position iodide of compound E obtains compound F, the reaction reagents are iodine, pyridine and [bis(trifluoroacetoxy) iodine]benzene, the reaction solvent is dichloromethane or chloroform, and the reaction temperature is 20°C-100°C between;

c: When Z does not exist, Suzuki coupling reaction between compound F and boronic ^acid substituted by R2 group or its boronic acid ester in the presence of palladium catalyst, or when Z is a triple bond, ^compound F and acetylene substituted by R2 group Sonogashira coupling reaction occurs in the presence of palladium catalyst and cuprous iodide to obtain compound (I);

In particular, when R ² of compound (I) is defined as hydrogen, only step a in scheme two is carried out, and the subsequent two-step reaction of b and c is not carried out.

In the scheme one or scheme two of the above-mentioned preparation of the indazole compound of structural formula (I) of the present invention:

The palladium catalyst used in the Suzuki coupling reaction is selected from palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, or [1,1′-bis(diphenylphosphine)dicene Iron] palladium dichloride dichloromethane complex, the reaction solvent is 1,4-dioxane/water mixed solvent, the reaction temperature is between 80°C and 130°C, and conventional heating or microwave conditions can be used;

The palladium catalyst used in the Sonogashira coupling reaction is selected from four (triphenylphosphine) palladium, two (triphenylphosphine) palladium dichloride, two (cyanobenzene) palladium dichloride, and reaction solvent is 1,4- Dioxane or N,N-dimethylformamide, the reaction temperature is between 20°C and 100°C;

The palladium catalyst used in the Heck coupling reaction is palladium acetate, tetrakis (triphenylphosphine) palladium, two (triphenylphosphine) palladium dichloride, three (dibenzylidene indene acetone) dipalladium, and reaction solvent is 1 , 4-dioxane or N, N-dimethylformamide, the reaction temperature is between 20°C and 100°C.

Biological tests show that the compounds provided by the present invention are PI3K inhibitors, therefore, the compounds of the present invention can be used to treat diseases or conditions caused by abnormal cell growth, function or behavior related to P13K. These diseases and conditions include proliferative diseases (such as cancer), immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine disorders and neurological diseases. Examples of metabolic/endocrine disorders include diabetes and obesity. Examples of cancers that may be treated using the compounds of the present invention include leukemia, brain tumors, kidney cancer, gastric cancer, and cancers of the skin, bladder, breast, uterus, lung, colon, prostate, ovary, and pancreas.

The present invention also provides a pharmaceutical composition for treating diseases or conditions caused by abnormal cell growth, function or behavior related to PI3K, which comprises a therapeutically effective amount of one or more indazoles having the general structural formula (I) Class compounds, including their stereoisomers, tautomers, solvates, prodrug forms, N-oxides and pharmaceutically acceptable salts as active ingredients and pharmaceutically acceptable carriers, adjuvants or excipients .

Detailed ways

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the examples provided below are only to further illustrate the present invention and are not meant to limit the scope of the present invention in any way.

Starting materials are either commercially available or prepared by methods known in the art or as described herein.

The structures of the compounds were determined by nuclear magnetic resonance ( ¹ H-NMR) and/or mass spectroscopy (MS). The NMR measurement is carried out with a VarianAMX-300 nuclear magnetic resonance instrument, the measurement solvent is deuterated chloroform (CDCl ₃ ) or deuterated dimethyl sulfoxide (DMSO-D ₆ ), and TMS is used as an internal standard. MS was determined using a Thermo Finnigan LCQ-Deca XP (ESI) liquid chromatography-mass spectrometer. The product was separated and purified by column chromatography using ISCO Rf75 rapid preparative chromatograph, the carrier uses 200-300 mesh silica gel from Qingdao Ocean Chemical Factory. Microwave heating was performed using a Biotage Initiator microwave synthesizer.

Preparation Examples:

Example 1: 5-(6-methoxypyridin-3-yl)-2-methyl-3-(4-pyridyl)-2H-indazole

Carry out according to the reaction scheme of scheme one, concrete route is:

Reagents and conditions: a) iodine, pyridine, [bis(trifluoroacetoxy)iodo]benzene, dichloromethane, room temperature; b) pyridine-4-boronic acid, potassium carbonate, [1,1′-bis(diphenyl Phosphine) ferrocene] dichloropalladium dichloromethane complex, 1,4-dioxane-water (4:1), 100 ° C; c) 6-methoxypyridine-3-boronic acid, Potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 1,4-dioxane-water (4:1), 100°C.

a) 2-methyl-5-bromo-3-iodo-2H-indazole

Iodine (5.08g, 20mmol) was dissolved in 40mL of dichloromethane, followed by adding pyridine (3.2mL, 40mmol) and [bis(trifluoroacetoxy)iodo]benzene (8.6g, 20mmol), stirring at room temperature for 15 minutes before adding 2-Methyl-5-bromo-2H-indazole (3.8g, 18mmol), continued to stir at room temperature overnight, and the precipitated solid was collected by suction filtration to obtain 4.8g of the title compound as an off-white solid, with a yield of 79.1%. MS(ES): m/z 337.0[M+H] ⁺ ; ¹ H NMR(300MHz, DMSO-d ₆ ): δ4.18(s, 3H), 7.36(d, J=8.4Hz, 1H), 7.58 (s, 1H), 7.59 (d, J=8.4Hz, 1H).

b) 2-methyl-5-bromo-3-(4-pyridyl)-2H-indazole

2-Methyl-5-bromo-3-iodo-2H-indazole (1.02g, 3.0mmol) and pyridine-4-boronic acid (0.37g, 3.0mmol) were dissolved in 24mL of dioxane, added 6mL of distilled water and Potassium carbonate (1.25g, 9.0mmol), after argon gas bubbling for several minutes, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (123mg, 0.15 mmol), and then reacted in an oil bath at 100°C for 1 hour. The reaction solution was cooled to room temperature, the dioxane layer was separated, concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography, eluting with petroleum ether/ethyl acetate (V/V=2:1) to obtain the title compound 0.73 g, an off-white solid with a yield of 84.5%. MS (ES): m/z 288.2 [M+H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ : δ4.23 (s, 3H), 7.39 (d, J = 9.0 Hz, 1H), 7.44-7.46 ( m, 2H), 7.62 (d, J=9.0 Hz, 1H), 7.77 (s, 1H), 8.83 (d, J=6.0 Hz, 2H).

c) 5-(6-methoxypyridin-3-yl)-2-methyl-3-(4-pyridyl)-2H-indazole

2-Methyl-5-bromo-3-(4-pyridyl)-2H-indazole (115mg, 0.4mmol) and 6-methoxypyridine-3-boronic acid (74mg, 0.48mmol) were dissolved in 4mL dioxygen Add 1mL of distilled water and potassium carbonate (166mg, 1.2mmol) to the six rings, and then add [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloride after bubbling with argon for several minutes Methane complex (16mg, 0.02mmol) was then reacted in an oil bath at 100°C for 2 hours. The reaction solution was cooled to room temperature, the dioxane layer was separated, concentrated under reduced pressure, and the dark brown residue was purified by flash silica gel column chromatography, eluting with petroleum ether/ethyl acetate (V/V=1:1) to obtain the title 95 mg of the compound is a yellow-brown solid, and the yield is 75.2%. MS(ES): m/z 317.3[M+H] ⁺ ; ¹ H NMR(300MHz, CDCl ₃ ): δ3.98(s, 3H), 4.27(s, 3H), 6.82(d, J=8.7Hz , 1H), 7.15-7.56(m, 3H), 7.70(s, 1H), 7.81(dd, J=8.7, 2.4Hz, 2H), 8.40(d, J=2.4Hz, 1H), 8.83(d, J=5.4Hz, 2H).

The following compounds were or could be prepared by the general methods used to prepare the compound of Example 1:

Example 10: (E)-2,4-difluoro-N-{5-[(2-methyl-3-(4-pyridyl)-2H-5-indazolyl)ethenyl]-3- Pyridyl}benzenesulfonamide

The title compound was prepared by the method for preparing the compound of Example 1. Steps a and b were the same, except that step c was changed to Heck coupling reaction: add 2-methyl-5-bromo-3-(4- Pyridyl)-2H-indazole (70mg, 0.24mmol), 2,4-difluoro-N-(5-vinyl-pyridin-4-yl)benzenesulfonamide (80mg, 0.27mmol), tris(diethylene benzyl indene acetone) dipalladium (2.2mg, 0.0024mmol), tri-tert-butylphosphine (10% n-pentane solution, 15μL, 0.0049mmol), N-methyldicyclohexylamine (52mg, 0.26mmol) and Anhydrous 1,4-dioxane (1 mL), and then the reactant was reacted overnight in an oil bath at 100° C. under the protection of argon. The reaction solution was directly evaporated to dryness under reduced pressure, and the residue was purified by flash silica gel column chromatography, eluting with petroleum ether/ethyl acetate (V/V=1:1), to obtain 68 mg of the title compound as a bright yellow powder, with a yield of 56.3% . MS(ES): m/z 504.2[M+H] ⁺ ; ¹ H NMR(300MHz, CDCl ₃ ): δ4.25(s, 3H), 6.88-6.94(m, 2H), 7.01(d, J= 16.5Hz, 1H), 7.19(d, J=16.5Hz, 1H), 7.52(d, J=5.1Hz, 2H), 7.60-7.74(m, 3H), 7.85-7.92(m, 2H), 8.24( s, 1H), 8.51 (s, 1H), 8.87 (d, J=4.2Hz, 2H).

Example 11: 2-Methyl-3-(4-pyridyl)-5-(3-pyridylethynyl)-2H-indazole

The title compound was prepared by the method for preparing the compound of Example 1. Steps a and b were the same, except that step c was changed to Sonogashira coupling reaction: add 2-methyl-5-bromo-3-(4- Pyridyl)-2H-indazole (120mg, 0.42mmol), 3-ethynylpyridine (48mg, 0.47mmol), cuprous iodide (6.5mg, 0.034mmol), bis(cyanophenyl)palladium dichloride ( 6.5mg, 0.017mmol), tri-tert-butylphosphine (10% n-pentane solution, 100μL, 0.033mmol), diisopropylamine (90μL, 0.64mmol) and anhydrous 1,4-dioxane ( 3 mL), and then the reaction mixture was reacted overnight at room temperature under the protection of argon. The reaction solution was diluted with ethyl acetate, filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography, eluting with petroleum ether/ethyl acetate (V/V=1:2) to obtain the title compound 98 mg, as a yellow-brown solid, yield 75.3%. MS(ES): m/z 311.3[M+H] ⁺ ; ¹ H NMR(300MHz, CDCl ₃ ): δ4.26(s, 3H), 7.26-7.30(m, 1H), 7.44-7.51(m, 3H), 7.71-7.82(m, 2H), 7.88(s, 1H), 8.53(d, J=3.9Hz, 1H), 8.77(s, 1H), 8.85(d, J=4.2Hz, 2H).

Example 12: 2-Methyl-3-(4-pyridyl)-5-phenylethynyl-2H-indazole

The title compound was prepared by the method for preparing the compound of Example 11, except that 3-ethynylpyridine was replaced by phenylacetylene. The title compound was a tan solid with a yield of 64.2%. MS(ES): m/z 310.3[M+H] ⁺ ; ¹ H NMR(300MHz, CDCl ₃ ): δ4.25(s, 3H), 7.32-7.34(m, 3H), 7.44-7.54(m, 5H), 7.70 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 8.83 (d, J = 5.4 Hz, 2H).

Example 13: 2,4-difluoro-N-[2-methoxy-5-(2-methyl-2H-5-indazolyl]-3-pyridyl]benzenesulfonamide

Carry out according to the reaction route of scheme two, just only carry out a step reaction in the scheme and not carry out follow-up b, c two steps, specific route is:

Reagents and conditions: a) 2,4-difluoro-N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3-pyridyl]benzenesulfonamide, potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 1,4 - Dioxane-water (4:1), 100°C.

a) 2,4-Difluoro-N-[2-methoxy-5-(2-methyl-2H-5-indazolyl]-3-pyridyl]benzenesulfonamide

2-Methyl-5-bromo-2H-indazole (253mg, 1.2mmol) and 2,4-difluoro-N-[2-methoxy-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-3-pyridyl]benzenesulfonamide (426 mg, 1.0 mmol) was dissolved in 8 mL of dioxane, and 2 mL of distilled water and potassium carbonate were added (415mg, 3.0mmol), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (41mg, 0.05mmol) after argon gas bubbling for several minutes , and then reacted in an oil bath at 100°C for 1 hour. The reaction solution was cooled to room temperature, the dioxane layer was separated, concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography, eluting with petroleum ether/ethyl acetate (V/V=1:1) to obtain 328 mg of the title compound , as an off-white solid with a yield of 76.3%. MS(ES): m/z 431.1[M+H] ⁺ ; ¹ H NMR(300MHz, CDCl ₃ ): δ3.94(s, 3H), 4.25(s, 3H), 6.90-6.97(m, 2H) , 7.40(dd, J=9.0, 4.2Hz, 1H), 7.72-7.78(m, 2H), 7.87(m, 1H), 7.96(s, 1H), 8.00(d, J=2.4Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H).

The following compounds were or could be prepared by the general methods used to prepare the compound of Example 13:

Example 22: 2,4-Difluoro-N-{2-methoxy-5-[2-methyl-3-(1-methyl-1H-4-pyrazolyl)-2H-5-ind Azolyl]-3-pyridyl}benzenesulfonamide

Carry out according to the reaction scheme in scheme two, concrete route is:

Reagents and conditions: a) 2,4-difluoro-N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)-3-pyridyl]benzenesulfonamide, potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 1,4 -Dioxane-water (4:1), 100°C; b) iodine, pyridine, [bis(trifluoroacetoxy) iodo]benzene, dichloromethane, room temperature; c) 1-methyl-4- Pyrazole borate pinacol ester, potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 1,4-dioxane-water ( 4:1), microwave at 120°C for 30 minutes.

a) 2,4-Difluoro-N-[2-methoxy-5-(2-methyl-2H-5-indazolyl]-3-pyridyl]benzenesulfonamide

The synthesis of the title compound was the same as in Example 13.

b) 2,4-difluoro-N-[2-methoxy-5-(2-methyl-3-iodo-2H-5-indazolyl]-3-pyridyl]benzenesulfonamide

Iodine (508mg, 2.0mmol) was dissolved in 5mL of dichloromethane, pyridine (0.32mL, 4.0mmol) and [bis(trifluoroacetoxy)iodo]benzene (860mg, 2.0mmol) were added successively, stirred at room temperature for 15 minutes and then Add 2,4-difluoro-N-[2-methoxy-5-(2-methyl-2H-5-indazolyl]-3-pyridyl]benzenesulfonamide (810 mg, 1.9 mmol) and continue Stirring overnight at room temperature, the precipitated solid was collected by suction filtration to obtain 756 mg of the title compound as an off-white solid with a yield of 71.6%. MS (ES): m/z 557.0 [M+H] ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ3.66(s, 3H), 4.22(3H), 7.23(t, J=8.4Hz, 1H), 7.51-7.62(m, 3H), 7.70-7.82(m, 2H), 7.90 (s, 1H), 8.37 (s, 1H), 10.31 (s, 1H).

c) 2,4-difluoro-N-{2-methoxy-5-[2-methyl-3-(1-methyl-1H-4-pyrazolyl)-2H-5-indazolyl ]-3-pyridyl}benzenesulfonamide

2,4-Difluoro-N-[2-methoxy-5-(2-methyl-3-iodo-2H-5-indazolyl]-3-pyridyl]benzenesulfonamide (112mg, 0.20mmol ) and 1-methyl-4-pyrazole boronic acid pinacol ester (58mg, 0.28mmol) were dissolved in 4mL of dioxane, 1mL of distilled water and potassium carbonate (104mg, 0.75mmol) were added, and argon was bubbled for several Minutes later, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (10mg, 0.012mmol) was added, and reacted under microwave at 120°C for 30 minutes. The reaction solution After cooling to room temperature, the dioxane layer was separated and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography and eluted with petroleum ether/ethyl acetate (V/V=1:2) to obtain 68 mg of the title compound as Off-white solid, yield 66.6%. MS (ES): m/z 511.1[M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ3.93(s, 3H), 4.08(s, 3H) , 4.22(s, 3H), 6.93(m, 2H), 7.42(d, J=9.3Hz, 1H), 7.61(s, 1H), 7.72-7.86(m, 4H), 7.96(s, 1H), 8.10(s, 1H).

The following compounds were or could be prepared by the general methods used to prepare the compound of Example 22:

Example 67: 2,4-Difluoro-N-{2-methoxy-5-[2-methyl-3-(3-pyridylethynyl)-2H-5-indazolyl]-3-pyridine phenylsulfonamide

The title compound was prepared by the method for preparing the compound of Example 21. Steps a and b were the same, except that step c was changed to Sonogashira coupling reaction: add 2,4-difluoro-N-[2-methoxy to a 10mL reaction tube yl-5-(2-methyl-3-iodo-2H-5-indazolyl]-3-pyridyl]benzenesulfonamide (112 mg, 0.20 mmol), bis(triphenylphosphine)palladium dichloride ( 7mg, 0.01mmol) and cuprous iodide (1.9mg, 0.01mmol), vacuumize, and then argon, repeat this three times, then add N,N-dimethylformamide (2mL), diisopropyl Ethylamine (175 μL, 1.0 mmol) and 3-ethynylpyridine (25 mg, 0.24 mmol). The reaction mixture was reacted overnight in an oil bath at 60° C. under the protection of argon. The reactant was cooled to room temperature, diluted with dichloromethane, and then Washed successively with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography, eluting with petroleum ether/ethyl acetate (V/V=1:2) 57 mg of the title compound was obtained as an off-white solid with a yield of 53.6%. MS (ES): m/z 532.1[M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ3.94 (s, 3H) , 4.34(s, 3H), 6.89-6.97(m, 2H), 7.31(s, 1H), 7.36-7.40(m, 1H), 7.46(d, J=8.7Hz, 1H), 7.79-7.95(m , 4H), 8.03 (s, 1H), 8.16 (s, 1H), 8.64 (d, J=4.5Hz, 1H), 8.88 (s, 1H).

Example 68: 2,4-Difluoro-N-{2-methoxy-5-[2-methyl-3-(4-pyridylethynyl)-2H-5-indazolyl]-3-pyridine phenylsulfonamide

The title compound was prepared by the method for preparing the compound of Example 67, except that 3-ethynylpyridine was replaced by 4-ethynylpyridine hydrochloride. It was a tan solid with a yield of 61.3%. MS (ES): m/z 532.1 [M+H] ⁺ .

Example 69: 2,4-Difluoro-N-{2-methoxy-5-[2-methyl-3-((4-thiasulfonylpiperazin-1-yl)methyl)-2H- 5-indazolyl]-3-pyridyl}benzenesulfonamide

The synthetic route of the title compound is as follows:

Reagents and conditions: a) lithium diisopropylamide, N,N-dimethylformamide, tetrahydrofuran, -78°C; b) sodium borohydride, methanol, 0°C; c) thionyl chloride, dichloromethane, room temperature ; d) 1-thiamphenicol-piperazine, potassium carbonate, sodium iodide, N,N-dimethylformamide, 60°C; e) 2,4-difluoro-N-[2-methoxy-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]benzenesulfonamide, [1,1′-bis (Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex, potassium carbonate, 1,4-dioxane-water (4:1), 100°C.

a) 2-methyl-5-bromo-2H-indazole-3-carbaldehyde

2-Methyl-5-bromo-2H-indazole (6.0g, 28.4mmol) was dissolved in anhydrous tetrahydrofuran (120mL), then cooled to -78°C (dry ice-acetone bath), and lithium diisopropylamide ( 2mol/L, 24mL, 48.0mmol), the dropwise addition was completed in about 30 minutes, the dry ice-acetone bath was removed, the reaction solution was stirred at room temperature for 40 minutes and then cooled to -78°C again, and anhydrous N,N-dimethyl Dimethylformamide (6.0 mL, 77.5 mmol) was added dropwise in about 60 minutes. The reaction solution was stirred overnight at room temperature, quenched by adding saturated ammonium chloride (80 mL) dropwise, the reaction solution was extracted twice with ethyl acetate (120 mL×2), the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate , filtered, concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography, eluting with petroleum ether/ethyl acetate (V/V=10:1), to obtain 6.0 g of the title compound as a tan solid, with a yield of 88.5% . MS(ES): m/z 239[M+H] ⁺ ; ¹ H NMR(300MHz, DMSO-d ₆ ): δ4.48(s, 3H), 7.53(dd, J=2.1, 9.3Hz, 1H) , 7.82 (d, J=8.7Hz, 1H), 8.35 (s, 1H), 10.31 (s, 1H).

b) (2-methyl-5-bromo-2H-indazol-3-yl)methanol

2-Methyl-5-bromo-2H-indazole-3-carbaldehyde (1.0g, 4.1mmol) was dissolved in methanol (20mL), and sodium borohydride (0.19g, 5.0mmol) was added under cooling in an ice-water bath, and the Stir in a water bath for 30 minutes, drop into saturated ammonium chloride (10mL) to quench the reaction, add 50mL of water to the reaction solution, extract twice with ethyl acetate (80mL×2), and wash the organic phase with saturated brine, anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure. The solid residue is dispersed in a mixed solvent of petroleum ether/ethyl acetate (V/V=2:1), sonicated for several minutes, and then filtered with suction to obtain 0.68 g of the title compound in a yellowish brown color. Powder, yield 68.8%. MS(ES): m/z 241[M+H] ⁺ ; ¹ H NMR(300MHz, DMSO-d ₆ ): δ4.12(s, 3H), 4.87(d, J=5.7Hz, 2H), 5.45 (t, J=5.4Hz, 1H), 7.29 (dd, J=1.8, 9.0Hz, 1H), 7.53 (d, J=9.0Hz, 1H), 8.02 (d, J=1.2Hz, 1H).

c) 2-methyl-3-chloromethyl-5-bromo-2H-indazole

(2-Methyl-5-bromo-2H-indazol-3-yl)methanol (241 mg, 1.0 mmol) and thionyl chloride (90 μL, 12 mmol) were stirred overnight at room temperature in anhydrous dichloromethane (6 mL). The precipitated solid was collected by suction filtration to obtain 237 mg of the title compound as beige powder with a yield of 91.5%. ¹ H NMR (300MHz, DMSO-d ₆ ): δ4.18(s, 3H), 5.41(s, 2H), 7.34(dd, J=1.8, 9.0Hz, 1H), 7.58(d, J=9.0Hz , 1H), 8.16(s, 1H).

d) 2-methyl-5-bromo-3-[(4-thiamphenicol-piperazin-1-yl)methyl]-2H-indazole

2-methyl-3-chloromethyl-5-bromo-2H-indazole (150mg, 0.58mmol), 1-thiamphenicol-piperazine (114mg, 0.69mmol), potassium carbonate (97mg, 0.70mmol) and iodine Sodium chloride (10mg, 0.067mmol) was dissolved in anhydrous N,N-dimethylformamide (2mL), and the reaction solution was placed in an oil bath at 60°C for 2 hours. After the reaction solution was cooled to room temperature, 40 mL of ethyl acetate was added, and then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography, using petroleum ether/ethyl acetate (V/V=2:1) was eluted to obtain 196 mg of the title compound as a pale yellow-brown solid with a yield of 87.5%. MS(ES): m/z 387[M+H] ⁺ ; ¹ H NMR(300MHz, DMSO-d ₆ ): δ2.50(m, 4H), 2.87(s, 3H), 3.09(m, 4H) , 3.98(s, 2H), 4.15(s, 3H), 7.30(d, J=9.0Hz, 1H), 7.50(d, J=9.0Hz, 1H), 8.02(s, 1H).

e) 2,4-difluoro-N-{2-methoxy-5-[2-methyl-3-((4-thiamphenicol-piperazin-1-yl)methyl)-2H-5- Indazolyl]-3-pyridyl}benzenesulfonamide

2-Methyl-5-bromo-3-[(4-thiamphenicol-piperazin-1-yl)methyl]-2H-indazole (70mg, 0.18mmol) and 2,4-difluoro-N-[ 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]benzenesulfonamide ( 100mg, 0.23mmol) and dissolved in 4mL dioxane, add 1mL distilled water and potassium carbonate (70mg, 0.50mmol), and add [1,1′-bis(diphenylphosphine ) ferrocene]palladium dichloride dichloromethane complex (7.4mg, 0.009mmol), and then reacted in microwave at 100°C for 30 minutes. The reaction solution was cooled to room temperature, the dioxane layer was separated, concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography, eluting with petroleum ether/ethyl acetate (V/V=1:1) to obtain 78 mg of the title compound , as an off-white solid with a yield of 71.6%. MS (ES): m/z 606.9 [M+H] ⁺ .

Example 70: 2,4-Difluoro-N-{2-methoxy-5-[2-methyl-3-((4-methylpiperazin-1-yl)methyl)-2H-5 -Indazolyl]-3-pyridyl}benzenesulfonamide

The title compound was prepared by the method for preparing the compound of Example 69, except that the 1-thiamphenicol-piperazine in step d was replaced with 1-methylpiperazine, and it was a tan solid. MS (ES): m/z 543.2 [M+H] ⁺ .

Example 71: 2,4-Difluoro-N-[2-methoxy-5-(2-methyl-3-morpholinomethyl-2H-5-indazolyl)-3-pyridyl]benzene Sulfonamide

The title compound was prepared by the method for preparing the compound of Example 69, except that the 1-thiamphenicol-piperazine in step d was replaced by morpholine, and it was an off-white solid. MS (ES): m/z 530.1 [M+H] ⁺ .

Examples of pharmacological experiments

ELISA to detect the effect of compounds on the phosphorylation of Akt1S473 in Rh30 cells (pAkt-S473ELISA Assay)

Akt is one of the important effector proteins downstream of PI3K, and the phosphorylation level of Akt directly reflects the activity of PI3K in cells. In order to study the pharmacological activity of the compounds of the present invention, a method for screening PI3K inhibitors at the cellular level has been established, that is, to determine whether the compounds inhibit PI3K activity by detecting the changes in intracellular Akt phosphorylation after the compounds act.

Experimental procedure: cells were seeded in 24-well plates at 1×10 ⁵ cells/well/500 μL culture medium, and cultured overnight. The next day, cells were washed twice with D-PBS and then cultured in serum-free RPMI 1640 for 24 hours. Then add the compound to be tested and DMSO control, and act for 1 hour, and add IGF1 with a final concentration of 100 ng/mL in the last 10 minutes of the effect. Discard the liquid in the wells, add pre-cooled lysate to lyse the cells, immediately transfer the cell lysate to the wells of the microplate plate coated with Akt antibody and blocked with BSA, add 50 μL/well of diluted Akt pS473 antibody, 4 °C Leave overnight. Aspirate the AktpS473 antibody in the wells of the enzyme labeling plate, wash the wells of the plate three times with D-PBST, add 50 μL/well of diluted HRP-labeled anti-rabbit antibody, and incubate for 2 hours at room temperature in a wet box on a shaker. Wash the wells of the plate three times with D-PBST, add TMB chromogenic solution, 100 μL/well, and fix it on a shaker to develop color until the blue color is obvious. Finally, stop the color development with 2M H ₂ SO ₄ 50 μL/well, and read the OD450 value.

Inhibition rate (%)=100×(OD450 of DMSO control wells stimulated by IGF1-OD450 of compound wells stimulated by IGF1)/(OD450 of DMSO control wells stimulated by IGF1-OD450 of wells without IGF1 stimulation).

Cellular level PI3K/Akt pathway pharmacological experiment data

The following table 1 shows the biological activity results of some compounds in the preparation examples of the present invention obtained in the pharmacological experiment examples, and the concentration of the tested compounds is 10 μM:

Table 1

compound Inhibition rate(%) compound Inhibition rate(%) Example 1 62.5 Example 29 114.7 Example 2 107.3 Example 50 99.5

Example 7 111.0 Example 51 105.5 Example 8 107.2 Example 52 103.1 Example 9 110.5 Example 53 113.3 Example 10 61.6 Example 54 106.4 Example 13 99.6 Example 55 113.4 Example 16 98.6 Example 56 112.7 Example 17 69.6 Example 58 103.7 Example 19 104.7 Example 60 111.1 Example 20 118.7 Example 61 108.5 Example 22 112.9 Example 67 96.1 Example 28 110.7 LY294002 58.3 Example 43 100.4 PI-103 103.3 Example 46 76.2

Among them: LY294002 (Vlahos CJ, Matter WF, Hui KY, et al. J. Biol. Chem. 1994; 269: 5241-5248) and PI-103 (Raynaud FI, Eccles S, Clarke PA, et al. Cancer Res. 2007;67:5840-5850) is a PI3K inhibitor reported in the literature.

All compounds listed in Table 1 have an inhibitory rate to Akt phosphorylation that is greater than that of the PI3K inhibitor LY294002, and most compounds have an inhibitory rate to Akt phosphorylation that is comparable to that of the PI3K inhibitor PI-103, indicating that the compounds of the present invention have an inhibitory effect on PI3K at the cellular level. Significantly inhibiting the activity, the compounds of the present invention are therefore useful in the treatment of diseases caused by abnormal cellular functions related to PI3K, especially cancer.

Claims (8)

1. A class of indazole compounds or pharmaceutically acceptable salts thereof, wherein the indazole compounds are specifically: 2. A preparation method of an indazole compound represented by general structural formula (I) or a pharmaceutically acceptable salt thereof, which adopts any one of the following two schemes; in, R ¹ is bonded to the 1-position nitrogen atom on the ring or is bonded to the 2-position nitrogen atom on the ring; and is methyl; R ² is hydrogen, C6-C10 aryl or a 5-10-membered monocyclic or bicyclic heteroaryl containing 1-4 N heteroatoms; the aryl and heteroaryl are optionally replaced by 1-3 Substituted by a group selected from the following groups: amino, hydroxyl, trifluoromethyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylaminocarbonyl, hydroxyl C1-C6 alkylamino Carbonyl, (C1-C6 alkyl)-SO ₂ -NH- or (C1-C6 alkyl)-SO ₂ -; R ³ is pyridyl; the pyridyl is substituted by halogen, C1-C6 alkoxy or -NHSO ₂ R ⁷ ; wherein R ⁷ is C6-C10 aryl, and the aryl is optionally replaced by 1-5 halogen replace; R is selected from C1-C6 alkyl, C1- ^C4 alkoxy, halogen, amino, cyano, hydroxyl and nitro; n is 0; X is C; Y does not exist; Z does not exist or is a triple bond; Option One: a: The 3-position iodide of raw material A is used to obtain compound B. The reaction reagents are iodine, pyridine and [bis(trifluoroacetoxy)iodo]benzene, the reaction solvent is dichloromethane or chloroform, and the reaction temperature is 20°C-100°C ; b: When Z does not exist, Suzuki coupling reaction between compound B and boronic ^acid substituted by R2 group or its boronic acid ester in the presence of palladium catalyst, or when Z is a triple bond, ^compound B and acetylene substituted by R2 group A Sonogashira coupling reaction occurs in the presence of a palladium catalyst and cuprous iodide to obtain a 3-substituted compound C; c: when Y does not exist, the compound C is subjected to a Suzuki coupling reaction with a boronic acid substituted by ^R or its boronic acid ester, thereby obtaining compound (I); Option II: a: In the absence of Y, Suzuki coupling reaction of raw material A with ^R3 -substituted boronic acid or its boronic acid ester; b: The 3-position iodide of compound E obtains compound F, the reaction reagents are iodine, pyridine and [bis(trifluoroacetoxy) iodine]benzene, the reaction solvent is dichloromethane or chloroform, and the reaction temperature is 20°C-100°C ; c: When Z does not exist, Suzuki coupling reaction between compound F and boronic ^acid substituted by R2 group or its boronic acid ester in the presence of palladium catalyst, or when Z is a triple bond, ^compound F and acetylene substituted by R2 group Sonogashira coupling reaction occurs in the presence of palladium catalyst and cuprous iodide to obtain compound (I); When the R2 of ^compound (I) is defined as hydrogen, only step a in scheme two is carried out, and the subsequent two-step reaction of b and c is not carried out. 3. the preparation method of indazole compound or its pharmaceutically acceptable salt according to claim 2, is characterized in that, The palladium catalyst used in the Suzuki coupling reaction is selected from palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or [1,1'-bis(diphenylphosphine) Ferrocene]palladium dichloride dichloromethane complex, the reaction solvent is a 1,4-dioxane/water mixed solvent, and the reaction temperature is 80°C-130°C; The palladium catalyst used in the Sonogashira coupling reaction is selected from tetrakis (triphenylphosphine) palladium, two (triphenylphosphine) palladium dichloride, two (cyanobenzene) palladium dichloride, and the reaction solvent is 1,4- Dioxane or N,N-dimethylformamide, the reaction temperature is 20°C-100°C. 4. The use of the indazole compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of medicines for treating PI3K inhibitors. 5. Use of the indazole compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicine for treating diseases or diseases caused by abnormal cell growth, function or behavior related to P13K. 6. The use according to claim 5, characterized in that the diseases and diseases are proliferative diseases, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine disorders or neurological diseases. 7. The use according to claim 6, wherein the proliferative disease is cancer, and the metabolic/endocrine disorder is diabetes and obesity. 8. A pharmaceutical composition for the treatment of diseases or conditions caused by abnormal cell growth, function or behavior associated with PI3K, which comprises a therapeutically effective amount of one or more indazole compounds as claimed in claim 1 or its Pharmaceutically acceptable salts are used as active ingredients and pharmaceutically acceptable auxiliary materials.