CN114605329B - Substituted indazole carboxamides or substituted azaindazole carboxamides FLT3 inhibitors and uses thereof - Google Patents

Substituted indazole carboxamides or substituted azaindazole carboxamides FLT3 inhibitors and uses thereof Download PDF

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CN114605329B
CN114605329B CN202210312097.4A CN202210312097A CN114605329B CN 114605329 B CN114605329 B CN 114605329B CN 202210312097 A CN202210312097 A CN 202210312097A CN 114605329 B CN114605329 B CN 114605329B
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substituted
carboxamide
unsubstituted
indazole
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CN114605329A (en
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支燕乐
杜锟
贾会亚
薛贵民
吴亚
弓建红
李晓坤
杨波
陈辉
冯卫生
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Henan University of Traditional Chinese Medicine HUTCM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention relates to a substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor and application thereof, which can effectively solve the application problem in medicines for inhibiting FLT3 activity and preventing or treating clinical symptoms related to FLT3 and other kinases, and the compound has strong inhibition activity on FLT3, shows a certain selectivity on other kinases, can be used for preventing or treating clinical diseases related to FLT3, and has strong anti-tumor activity.

Description

Substituted indazole carboxamides or substituted azaindazole carboxamides FLT3 inhibitors and uses thereof
Technical Field
The invention relates to medicine, in particular to a substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor and application thereof.
Background
Protein kinases are important messengers of cellular vital activity, and catalyze the transfer of gamma-phosphate groups at the ATP terminus to substrates, affecting the structure and activity of the substrates, and delivering various intracellular and extracellular signals to respond appropriately to environmental stimuli. In most cases, this phosphorylation occurs at serine (ser), threonine (thr), or tyrosine (tyr) residues of protein kinases. Phosphorylation regulates vital activities evolutionarily very old, and can be traced back to single cell prokaryotes 10 hundred million years ago. At least 538 protein kinases are found in humans, whereas more than 900 genes encoding proteins with kinase activity account for about 2.5% of the human genome. Protein kinases are involved in a number of physiological regulatory processes including cell survival, proliferation, differentiation, apoptosis, metabolism, and the like. Pathology and pharmacology studies have shown that protein kinase dysfunction is closely associated with a number of diseases including tumors, autoimmune, inflammatory responses, central nervous system diseases, cardiovascular diseases, and diabetes, among others.
FLT3 has been found to be an important marker for various hematological malignancies including leukemia, lymphoma (non-hodgkin's lymphoma), hodgkin's disease (also known as hodgkin's lymphoma) and myeloma such as Acute Lymphoblastic Leukemia (ALL), acute myelogenous leukemia or Acute Myelogenous Leukemia (AML), acute Promyelocytic Leukemia (APL), chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic Neutrophilic Leukemia (CNL), acute Undifferentiated Leukemia (AUL), dysplastic large cell lymphoma (ALCL), adult T-cell ALL, AML with blue-line (trilineage) myelodysplasia (AML/TMDS), mixed-line leukemia (MLL), myelodysplastic syndrome (mds), myelodysplastic (MPD), multiple Myeloma (MM), and spinal sarcoma, among others. Psoriasis is a chronic, recurrent inflammatory skin disease, and studies have shown that FLT3 inhibitors can also be used in the treatment of immune system disorders such as psoriasis.
Among the many applications of FLT3, FLT3 inhibitors are most rapidly developing for the treatment of AML, with FLT3 being overexpressed in about 70% of AML patients. Clinical studies indicate that FLT3 overexpression is associated with poor prognosis. Reversible FLT3 inhibitors are classified into first generation non-selective FLT3 inhibitors and second generation selective FLT3 inhibitors according to the degree of kinase selectivity. First generation nonselective inhibitors are Sorafenib, sunitinib, ponatinib, cabozantinib, midostourin, etc. Taken together, the first generation of FLT3 inhibitors are multi-target kinase inhibitors, lack of specificity for FLT3, and these drugs also inhibit PDGFR, KIT and VEGFR, leading to more off-target activity, toxicity and adverse side effects, in addition to inhibiting FLT 3. It is due to off-target toxic side effects that the effective FLT3 inhibitory concentration cannot be achieved in vivo by limiting the dosing dose. Subsequently, people turn their eyes to a new generation of highly potent, highly selective FLT3 inhibitors, mainly Quizartinib, crenolanib, gilteritinib, etc. Currently Quizartinib, crenolanib, gilteritinib is marketed for the treatment of AML, but is still resistant to drugs in clinical use, leading to disease recurrence.
Disclosure of Invention
In view of the above, the present invention aims to overcome the defects of the prior art, and provides a substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor and use thereof, which can effectively solve the application problems in medicines for inhibiting FLT3 activity and preventing or treating clinical conditions related to kinases such as FLT 3.
1. The technical scheme is that the substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor is a compound with the following structural formula (I) or pharmaceutically acceptable salt thereof:
wherein:
R 1 is-L-R a L represents bond, O, NH, C (O), NHC (O) NH, substituted or unsubstituted C 1-6 Straight-chain or branched alkylene, substituted or unsubstituted C 3-6 Cyclic saturated alkyl, wherein C 1-6 Any carbon atom in the alkylene group may be substituted with 1 to 3 NH, N, O or S; r is R a Selected from hydrogen, halogen atoms, -NH 2 -OH, substituted or unsubstituted C 1-6 Straight-chain or branched alkyl, substituted or unsubstituted C 1-6 Straight-chain or branched haloalkyl, substituted or unsubstituted C 3-8 Cyclic saturated alkyl, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkenyl, substituted or unsubstituted C 1-6 Alkylamino, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C 6-14 Aryl or substituted or unsubstituted aromatic heterocycle;
g is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkenyl, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aromatic heterocycle;
a is N or CR 2 B is N or CR 3 D and E are each independently N, CR 4 Or CR (CR) 5 One and only one of D and E is CR 5 ，R 2 、R 3 、R 4 Each independently selected from hydrogen, halogen, hydroxy, cyano, methoxy, substituted or unsubstituted C 1-6 Alkyl, R 5 Selected from-NR b -SO 2 -R c or-NR b -CO-R c ，R c is-CR d ＝CHR e 、-C≡C-CH 3 or-C.ident.CH, R b 、R d 、R e Each independently selected from H, -CN, substituted or unsubstituted C 1-6 An alkyl group;
the heterocycloalkyl is selected from monocyclic saturated hydrocarbon groups with 3-6 carbon atoms and bicyclic saturated hydrocarbon groups with 6-12 carbon atoms, wherein the carbon atoms on the ring are independently substituted by 1-4O, S, N or NH;
the C is 6-14 The aryl is selected from one of phenyl, naphthyl, acenaphthylenyl or tetrahydronaphthyl;
the aromatic heterocycle is selected from a monocyclic heterocycle of pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1,4] dioxanyl or benzo [1,3] dioxolyl;
The substituents are selected from halogen, C 1-6 Haloalkyl, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 1-6 One or more of alkylthio groups; halogen is selected from fluorine, chlorine, bromine or iodine.
2. The invention has the preferable scheme that:
g is selected from substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aromatic heterocycle.
3. Another preferred embodiment of the present invention is as follows:
a is N or CR 2 B is CR 3 D and E are each independently CR 4 Or CR (CR) 5 。
4. Another preferred embodiment of the present invention is as follows:
R 1 is-L-R a L is selected from bond, O, NH, C (O), NHC (O) NH or methylene; r is R a Selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, C 3-8 Cyclic saturated alkyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, aziridinyl, azetidinyl, -OH, -NH 2 、C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 1-6 One of the alkylamino groups; wherein phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, C 3 -C 8 Cyclic saturated alkyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, aziridinyl, azetidinyl, each independently, optionally substituted with one or more R f Substituted, R f Selected from hydrogen, cyano, halogen, hydroxy, mercapto or amino;
g is selected from one of the following aromatic rings or aromatic heterocyclic rings: phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl or pyrimidinyl, wherein the above aromatic ring or aromatic heterocycle may be optionally substituted with 1 or 3 substituents each independently selected from halogen, methyl, ethyl, isopropyl, methoxy or trifluoromethyl;
a is N or CR 2 B is CR 3 D and E are each independently CR 4 Or CR (CR) 5 One and only one of D and E is CR 5 ，R 2 、R 3 、R 4 Each independently selected from hydrogen, halogen, hydroxy, cyano, methoxy, substituted or unsubstituted C 1-6 Alkyl, R 5 Selected from-NR b -SO 2 -R c or-NR b -CO-R c ，R c is-CR d ＝CHR e 、-C≡C-CH 3 or-C.ident.CH, R b 、R d 、R e Each independently selected from H, -CN, C 1-6 An alkyl group.
5. Another preferred embodiment of the present invention is as follows:
R 1 is-L 1 -R a ，L 1 Selected from bond, O, NH, C (O), NHC (O) NH or methylene; r is R a Is selected from the group consisting of tetrahydropyrrolyl, piperidinyl, N-methylpiperidin-4-yl, morpholinyl, N-methylpiperazinyl, 3-methylpiperidin-1-yl, piperazinyl, N-dipropylamino, N-diethylamino, N-dimethylamino, N-butylamino, 2- (cyclohexen-1-yl) ethylamino, 2-methoxyethoxy, 2-hydroxyethylamino, N-di (2-methoxyethyl) amino;
G is selected from one of the following aromatic rings or aromatic heterocyclic rings: phenyl, naphthyl, pyridinyl, pyrazinyl or pyrimidinyl, wherein the aromatic ring or aromatic heterocycle optionally has 1 or 2 substituents, each independently selected from halogen, methyl, ethyl, isopropyl, methoxy or trifluoromethyl;
a is N or CR 2 B is CR 3 D and E are each independently CR 4 Or CR (CR) 5 One and only one of D and E is CR 5 ，R 2 、R 3 、R 4 Is independently selected from hydrogen, halogen, hydroxy, cyano, methoxy, methyl, ethyl, isopropyl or trifluoromethyl, R 5 Selected from the group consisting of-NH-SO 2 -R c or-NH-CO-R c ，R c For-ch=chr e 、 -C≡C-CH 3 or-C.ident.CH, R e Selected from H, -CN, methyl, ethyl, isopropyl or propyl.
Further preferred embodiments of the present application are the following compounds:
5-acrylamido-N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (I-1)
5-acrylamido-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (I-2)
5-acrylamido-N- (4-fluorophenyl) -1H-indazole-3-carboxamide (I-3)
N- (4-morpholinophenyl) -5- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-4)
N- (4- (4-methylpiperazin-1-yl) phenyl) -5- (vinylsulphonamide) -1H-indazole-3-carboxamide (I-5)
N- (4-fluorophenyl) -5- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-6)
5- (3-Chloropropionamide) -N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (I-7)
5- (3-Chloropropionamide) -N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (I-8)
5- (3-Chloropropionamide) -N- (4-fluorophenyl) -1H-indazole-3-carboxamide (I-9)
5- (3-Chloropropionamide) -N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazole-3-carboxamide (I-10)
5- (3-Chloropropionamido) -N- (4- (morpholinomethyl) phenyl) -1H-indazole-3-carboxamide (I-11)
5- (3-Chloropropionamido) -N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-indazole-3-carboxamide (I-12)
5-acrylamide-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazole-3-carboxamide (I-13)
5-acrylamide-N- (4- (morpholinomethyl) phenyl) -1H-indazole-3-carboxamide (I-14)
5-acrylamido-N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-indazole-3-carboxamide (I-15)
N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -5- (vinylsulphonamide) -1H-indazole-3-carboxamide (I-16)
N- (4- (morpholinomethyl) phenyl) -5- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-17)
N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -5- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-18)
N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -5-propanamido-1H-indazole-3-carboxamide (I-19)
N- (4- (morpholinomethyl) phenyl) -5-propionamido-1H-indazole-3-carboxamide (I-20)
4- (3-Chloropropionamide) -N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (I-21)
4- (3-Chloropropionamido) -N- (4-fluorophenyl) -1H-indazole-3-carboxamide (I-22)
4- (3-Chloropropionamido) -N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (I-23)
N- (4- (4-methylpiperazin-1-yl) phenyl) -4- (vinylsulphonamide) -1H-indazole-3-carboxamide (I-24)
N- (4-fluorophenyl) -4- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-25)
N- (4-morpholinophenyl) -4- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-26)
4-acrylamide-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (I-27)
4-acrylamide-N- (4-fluorophenyl) -1H-indazole-3-carboxamide (I-28)
4-acrylamido-N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (I-29)
5- (3-Chloropropionamido) -N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-30)
5- (3-Chloropropionamide) -N- (4-fluorophenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-31)
5- (3-Chloropropionamide) -N- (1-methylpiperidin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-32)
5- (3-Chloropropionamido) -N- (4- (morpholine-4-carbonyl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-33)
5- (3-Chloropropionamido) -N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-34)
N- (4- (4-methylpiperazin-1-yl) phenyl) -5- (vinylsulphonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-35)
N- (4-fluorophenyl) -5- (vinylsulfonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-36)
N- (1-methylpiperidin-4-yl) -5- (vinylsulfonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-37)
N- (4-morpholinophenyl) -5- (vinylsulfonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-38)
N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -5- (vinylsulfonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-39)
5-acrylamido-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-40)
5-acrylamido-N- (4-fluorophenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-41)
5-acrylamide-N- (1-methylpiperidin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-42)
5-acrylamido-N- (4-morpholinophenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-43)
5-acrylamido-N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-44)
The preparation method of part of the compounds of the invention comprises the following steps:
The method comprises the following steps:
the second method is as follows:
method 3:
the compound of the invention can be prepared by the preparation method or the preparation method similar to the preparation method, and corresponding raw materials are selected according to different substituents and different substituent positions.
Pharmacological test results show that the compound has stronger inhibition activity on FLT3 and certain selectivity on other kinases, and can be used for preventing or treating clinical diseases related to FLT3, wherein the diseases can be: leukemia, lymphoma (non-hodgkin's lymphoma), hodgkin's disease (also known as hodgkin's lymphoma), and myeloma such as, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), acute Promyelocytic Leukemia (APL), chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic Neutrophilic Leukemia (CNL), acute Undifferentiated Leukemia (AUL), dysplastic large cell lymphoma (ALCL), adult T-cell ALL, AML (AML/TMDS) with blue-line (trilineage) myelodysplasia, mixed-lineage leukemia (MLL), myelodysplastic syndrome (MDSs), myelodysplastic (MPD), multiple Myeloma (MM) and spinal sarcoma, lung cancer, melanoma, liver cancer, kidney cancer, leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gall bladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, thyroid follicular cancer, gastrointestinal cancer, tumors of the central or peripheral nervous system (e.g., astrocytoma, neuroblastoma, autoimmune disease, diabetes mellitus, or other type II, insulin-dependent or non-peripheral nervous system tumor, or the like.
Detailed Description
The melting point is measured by a b-shaped melting point tube, the medium is methyl silicone oil, and the thermometer is uncorrected; 1 HNMR is JEOL FX90Q type Fourier transform nuclear magnetic resonance apparatus, BRUKER ACF-300 type nuclear magnetic resonance apparatus (TMS internal standard); MS was determined using a Nicolet model 2000 Fourier transform mass spectrometer and a MAT-212 mass spectrometer.
Example 1
1-methyl-4- (4-nitrobenzyl) piperazine (1 a)
In a 500mL single-necked flask, p-nitrobenzyl bromide (10.0 g,46.3 mmol) and 100mL of methylene chloride were added, and a mixture of N-methylpiperazine (4.7 g,47.0 mmol) and triethylamine (7.1 g,70.3 mmol) in methylene chloride was slowly added dropwise under ice-water bath (0-5 ℃ C.) and heated under reflux for 1h after the addition, and TLC detection of disappearance of starting material (ethyl acetate: petroleum ether=1:2, volume ratio). 150mL of chloroform and 100mL of saturated sodium bicarbonate solution were added to the reaction solution, the mixture was vigorously stirred at room temperature for 30min, the reaction solution was extracted with chloroform (100 mL. Times.3), the organic layers were combined, washed once with water and saturated sodium chloride respectively (100 mL. Times.1), dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to give 8.5g of pale yellow solid, yield 78.1%, and the product was directly put into the next reaction without further purification.
Example 2
4- ((4-methylpiperazin-1-yl) methyl) aniline (1 b)
A500 mL single-necked flask was charged with crude I-a (8.5 g,36.2 mmol), feO (OH)/C catalyst (2.0 g) and 100mL of 95% ethanol, and the mixture was heated under reflux, and hydrazine hydrate (25 mL) and 95% ethanol (20 mL) were slowly added dropwise, followed by TLC detection of the disappearance of starting material (methanol: chloroform=1:15, volume ratio). The mixture is filtered while hot, the filter cake is washed twice with hot ethanol (30 mL multiplied by 2), the solvent is distilled off under reduced pressure to obtain white solid, and the white solid is dried in vacuum to obtain 1b (6.7 g), the yield is 90.3%, and the product is directly put into the next reaction without further purification.
Example 3
1-methyl-4- (4-nitrophenyl) piperazine (1 c)
In a 500mL single-necked flask, p-fluoronitrobenzene (5 g,35.5 mmol) and potassium carbonate (7.3 g,106.4 mmol) were added, dissolved in 100mL of LDMSO, a solution of N-methylpiperazine (5.3 g,53.3 mmol) in DMSO was slowly added dropwise under an ice-water bath (0-5 ℃ C.), the reaction was heated at 80℃for 8 hours, TLC was used to detect the disappearance of starting material (ethyl acetate: petroleum ether=1:2, volume ratio), 1000mL of water was added to precipitate a yellow solid, the yellow solid was obtained by filtration and drying under reduced pressure as 7a (6.8 g), yield 86.2% MS [ M+H ]] + 222.14. The product was directly subjected to the next reaction without further purification.
Example 4
4- (4-methylpiperazin-1-yl) aniline (1 d)
1c (5.0 g,22.6 mmol) is used as raw material, the preparation method is the same as 1b, white solid is obtained, 1d (3.4 g) is obtained by ethanol recrystallization, yield 78%, MS [ M+H ] ] + 192.13。
Example 5
4- (4-nitrophenyl) morpholine (1 e)
Using p-fluoronitrobenzene (5.0 g,35.5 mmol) and morpholine (4.6 g,53.3 mmol) as starting material, the same preparation as 1c gave 1e (5.8 g) as a yellow solid in 78.3% yield, MS [ M+H ]] + 209.23; the product is directly carried out on the next step without further purificationAnd (3) performing a step reaction.
Example 6
4-morpholinoaniline (1 f)
1e (5.0 g,24.0 mmol) is used as raw material, the preparation method is the same as 1b, white solid is obtained, 1f (3.9 g) is obtained by ethanol recrystallization, the yield is 90.4%, MS [ M+H ]] + 179.13。
Example 7
Morpholinyl-4-nitrophenyl methanone (1 g)
Into a 100mL round bottom flask was charged p-nitrobenzoic acid (5.0 g,29.9 mmol), morpholine (2.9 g,32.9 mmol), EDC.HCl (8.6 g,44.9 mmol), HOBt (6.1 g,44.9 mmol) and anhydrous DMF (30 mL) and stirred at room temperature for 24h. TLC detected disappearance of starting material (methanol: chloroform=1:10, volume ratio). Pouring the reaction solution into 200mL of ice water, precipitating a large amount of solid, standing, filtering to obtain white solid, and drying to obtain 11a (6.7 g), yield 95.3%, MS [ M+H ]] + 236.15。
Example 8
4-aminophenylmorpholinomethionone (1 h)
1g (5.0 g,21.1 mmol) of the raw material is taken as a raw material, the preparation method is the same as 1b, white solid is obtained, 1H (3.4 g) is obtained by ethanol recrystallization, the yield is 77.2%, MS [ M+H ]] + 207.21。
Example 9
4-methylpiperazin-1-yl-4-nitrophenyl methanone (1 i)
Using p-nitrobenzoic acid (5.0 g,29.9 mmol) and N-methylpiperazine (3.3 g,32.9 mmol) as raw materials, the same method as 1g gave a white solid, which was dried to give 1i (7.2 g), yield 97.1%, MS [ M+H ]] + 250.22。
Example 10
4-aminophenyl-4-methylpiperazin-1-yl ketone (1 j)
1i (5.0 g,20.1 mmol) is used as raw material, the preparation method is the same as 1b, white solid is obtained, 1j (3.1 g) is obtained by ethanol recrystallization, the yield is 71%, MS [ M+H ]] + ：219.15。
Example 11
N- (4- (4-methylpiperazin-1-yl) phenyl) -5-nitro-1H-indazole-3-carboxamide (2 a)
5-nitro-1H-indazole-3-carboxylic acid @ is added into a single-necked flask1.91g,10.0 mmol) and 1d (2.10 g,11.0 mmol) were dissolved in anhydrous DMF (10 mL), EDCI (2.87 g,15.0 mmol), hoBt (2.01 g,15 mmol) and DIPEA (1.94 g,15 mmol) were added at 0deg.C, reaction was carried out at normal temperature for 12H, TLC detected the disappearance of starting material, water (100 mL) was added to the reaction solution to precipitate a solid, which was suction filtered to give brown solid 2a (1.98 g), yield 52.0%, MS [ M+H] + :381.19 the product was directly subjected to the next reaction without further purification.
Example 12
N- (4-fluorophenyl) -5-nitro-1H-indazole-3-carboxamide (2 b)
Using 5-nitro-1H-indazole-3-carboxylic acid (1.91 g,10.0 mmol) and 4-fluoroaniline (1.22 g,11.0 mmol) as raw materials, the same process as 2a was followed by suction filtration to give 2b (1.90 g) as a brown solid, yield 63.0%, MS [ M+H ] ] + :301.05 the product was directly subjected to the next reaction without further purification.
Example 13
N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -5-nitro-1H-indazole-3-carboxamide (2 c)
Using 5-nitro-1H-indazole-3-carboxylic acid (1.91 g,10.0 mmol) and 1b (2.26 g,11.0 mmol) as starting materials, the same procedure was followed as for 2a, suction filtration to give 2c (2.18 g) as a brown solid with a yield of 55.3%, MS [ M+H ]] + :395.16 the product was directly subjected to the next reaction without further purification.
Example 14
N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -5-nitro-1H-indazole-3-carboxamide (2 d)
Using 5-nitro-1H-indazole-3-carboxylic acid (1.91 g,10.0 mmol) and 1i (2.40 g,11.0 mmol) as starting materials, the same procedure was followed as for 2a, suction filtration to give 2d (2.06 g) as a brown solid with a yield of 50.6%, MS [ M+H ]] + :408.17 the product was directly subjected to the next reaction without further purification.
Example 15
N- (4- (morpholine-4-carbonyl) phenyl) -5-nitro-1H-indazole-3-carboxamide (2 e)
Using 5-nitro-1H-indazole-3-carboxylic acid (1.91 g,10.0 mmol) and 1H (2.27 g,11.0 mmol) as starting materials, the same procedure was followed as for 2a, suction filtration to give brown solid 2e (2.37 g), yield 60.1%, MS [ M+H ]] + :395.11, productThe next reaction was carried out directly without further purification.
Example 16
N- (4- (4-methylpiperazin-1-yl) phenyl) -5-nitro-1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (2 f)
In a 250mL single-necked flask, 5-nitro-1H-pyrazine [3,4-B was added]Pyridine-3-carboxylic acid (1.00 g,4.8 mmol), dissolved in 30mL anhydrous THF, was added dropwise oxalyl chloride (0.8 g,6.2 mmol) under ice-water bath, and reacted at room temperature for 0.5h; 1d (1.10 g,5.7 mmol) was dissolved in anhydrous THF and added to the above solution, triethylamine (0.63 g,6.2 mmol) was added, reacted at room temperature for 1H, TLC was used to detect the disappearance of starting material, THF was evaporated under reduced pressure, water was added, solids were precipitated, and suction filtration was performed to give brown solid 2f (1.55 g), yield 84.3%, MS [ M+H ]] + ：382.19。
Example 17
N- (4-fluorophenyl) -5-nitro-1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (2 g)
With 5-nitro-1H-pyrazine [3,4-B]Pyridine-3-carboxylic acid (1.00 g,4.8 mmol) and 4-fluoronitrobenzene (0.81 g,5.7 mmol) were used as starting materials, the same procedure was followed as for 2f, and 2g (1.12 g) of brown solid was obtained by suction filtration in 77.2% yield, MS [ M+H ]] + :302.09 the product was directly subjected to the next reaction without further purification.
Example 18
N- (4- (morpholine-4-carbonyl) phenyl) -5-nitro-1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (2H)
With 5-nitro-1H-pyrazine [3,4-B]Pyridine-3-carboxylic acid (1.00 g,4.8 mmol) and 1H (1.17 g,5.7 mmol) were used as starting materials, the same as 2f, and a brown solid was obtained by suction filtration for 2H (1.51 g), yield 79.3%, MS [ M+H ] ] + :396.13 the product was directly subjected to the next reaction without further purification.
Example 19
N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -5-nitro-1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (2 i)
With 5-nitro-1H-pyrazine [3,4-B]Pyridine-3-carboxylic acid (1.00 g,4.8 mmol) and 1j (1.25 g,5.7 mmol) were used as starting materials, the same as 2f, and a brown solid 2i (1.58 g) was obtained by suction filtration in 80.6% yield, MS [ M+H ]] + :409.15, the product does not need to be further purified,the next reaction was directly carried out.
Example 20
N- (4-fluorophenyl) -5-nitro-1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (2 g)
With 5-nitro-1H-pyrazine [3,4-B]Pyridine-3-carboxylic acid (1.00 g,4.8 mmol) and 4-fluoronitrobenzene (0.80 g,5.7 mmol) were used as starting materials, the same procedure was followed as for 2f, and 2g (1.12 g) of brown solid was obtained by suction filtration in 77.2% yield, MS [ M+H ]] + :302.09 the product was directly subjected to the next reaction without further purification.
Example 21
N- (4- (morpholine-4-carbonyl) phenyl) -5-nitro-1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (2H)
With 5-nitro-1H-pyrazine [3,4-B]Pyridine-3-carboxylic acid (1.00 g,4.8 mmol) and 1H (1.17 g,5.7 mmol) were used as starting materials, the same as 2f, and a brown solid was obtained by suction filtration for 2H (1.33 g), yield 70.1%, MS [ M+H ]] + :396.13 the product was directly subjected to the next reaction without further purification.
Example 22
N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -5-nitro-1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (2 i)
With 5-nitro-1H-pyrazine [3,4-B]Pyridine-3-carboxylic acid (1.00 g,4.8 mmol) and 1j (1.24 g,5.7 mmol) were used as starting materials, the same as 2f, and 2i (1.44 g) was obtained as a brown solid by suction filtration in 73.3% yield, MS [ M+H ]] + :409.16 the product was directly subjected to the next reaction without further purification.
Example 23
N- (4- (4-methylpiperazin-1-yl) phenyl) -4-nitro-1H-indazole-3-carboxamide (2 j)
With 5-nitro-1H-pyrazine [3,4-B]Pyridine-3-carboxylic acid (1.00 g,4.8 mmol) and 1d (1.09 g,5.7 mmol) were used as starting materials, prepared as in 2a, and suction filtered to give 2j (1.36 g) as a brown solid with a yield of 74.2%, MS [ M+H ]] + :381.16, the product was directly subjected to the next reaction without further purification.
Example 24
N- (4-morpholinophenyl) -4-nitro-1H-indazole-3-carboxamide (2 k)
With 5-nitro-1H-pyrazine [3,4-B]Pyridine-3Carboxylic acid (1.00 g,4.8 mmol) and 1f (1.02 g,5.7 mmol) as starting materials, prepared in the same manner as 2a, and suction filtered to give brown solid 2k (1.23 g), yield 69.4%, MS [ M+H ]] + :368.12, the product was directly subjected to the next reaction without further purification.
Example 25
N- (4-fluorophenyl) -4-nitro-1H-indazole-3-carboxamide (2 l)
With 5-nitro-1H-pyrazine [3,4-B]Pyridine-3-carboxylic acid (1.00 g,4.8 mmol) and 4-fluoroaniline (0.80 g,5.7 mmol) were used as starting materials, the same as 2a, and 2l (1.01 g) of brown solid was obtained by suction filtration, the yield was 70.5%, MS [ M+H ]] + :300.08 the product was directly subjected to the next reaction without further purification.
Example 26
N- (4-morpholinophenyl) -5-nitro-1H-indazole-3-carboxamide (2 m)
Using 5-nitro-1H-indazole-3-carboxylic acid (1.91 g,10.0 mmol) and 1f (1.96 g,11.0 mmol) as starting materials, the same procedure was followed as for 2a, with suction to give a brown solid 2M (2.59 g), yield 70.3%, MS [ M+H ]] + :368.16 the product was directly subjected to the next reaction without further purification.
Example 27
5-amino-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (3 a)
2a (1.40 g,3.7 mmol) is taken as raw material, the preparation method is the same as 1b, light brown solid 2b (0.8 g) is obtained by column chromatography, the yield is 62.2%, 1 HNMR[500MHz,DMSO-d 6 ]:δ13.27(s,1H,-NH),9.83(s,1H，-NH),7.75–7.65(m,2H，ArH),7.33(d,J＝8.7Hz,1H，ArH),7.28(d,J＝2.0Hz,1H，ArH),6.91(d,J＝9.1Hz,2H,ArH),6.84(dd,J＝8.8,2.1Hz,1H，ArH)，5.07(s，2H，-NH 2 )，3.33(s,2H,-CH 2 -),3.11(t,J＝4.9Hz,4H，-CH 2 -×2),3.00(s,2H，-CH 2 -),2.27(s,3H，-CH 3 )，MS[M+H] + ：351.20。
example 28
5-amino-N- (4-fluorophenyl) -1H-indazole-3-carboxamide (3 b)
Using 2b (1.1 g,3.7 mmol) as raw material, the same method as 1b, light brown solid 3b (0.8 g) was obtained by column chromatography, yield62.4％， 1 HNMR(500MHz,MeOD-d 4 )δ7.15–7.09(m,2H),6.76(dd,J＝2.2,0.7Hz,1H),6.71(dd,J＝8.8,0.7Hz,1H),6.43(t,J＝8.8Hz,2H),6.27(dd,J＝8.8,2.1Hz,1H)，MS[M+H] + ：271.10。
Example 29
5-amino-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazole-3-carboxamide (3 c)
Using 2c (1.5 g,3.7 mmol) as raw material, the same method as 1b, light brown solid 3c (0.91 g) was obtained by column chromatography in 67.3% yield, MS [ M+H ] ] + ：365.21。
Example 30
5-amino-N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-indazole-3-carboxamide (3 d)
Using 2d (1.5 g,3.7 mmol) as raw material, the preparation method is the same as 1b, and light brown solid 3d (1.06 g) is obtained by column chromatography, yield 75.3%, MS [ M+H ]] + ：379.19。
Example 31
5-amino-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazole-3-carboxamide (3 e)
2e (1.46 g,3.7 mmol) is taken as raw material, the preparation method is the same as 1b, light brown solid 3d (1.07 g) is obtained through column chromatography, the yield is 79.4%, 1 HNMR(500MHz,DMSO)δ13.30(s,1H),10.01(s,1H),7.80(d,J＝8.5Hz,2H),7.34(d,J＝8.8Hz,1H),7.29(d,J＝1.8Hz,1H),7.23(d,J＝8.5Hz,2H),6.85(dd,J＝8.8,2.1Hz,1H),5.06(s,2H),3.41(s,2H),2.35–2.34(m,8H),2.16(s,3H)；MS[M+H] + ：365.21。
example 32
5-amino-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (3 f)
Using 2f (1.41 g,3.7 mmol) as raw material, the preparation method was the same as 1b, and light brown solid 3f (1.05 g) was obtained by column chromatography, the yield was 80.3%, 1 H NMR[500MHz,Methanol-d 4 )]:δ13.80(s,1H，-NH-),9.96(s,1H，-NH-),8.11(d,J＝2.6Hz,1H，ArH),7.69(d,J＝9.0Hz,2H，ArH),7.61(d,J＝2.6Hz,1H，ArH),6.91(d,J＝9.1Hz,2H，ArH),5.32(s,2H，-NH 2 ),3.09(m,4H，-CH 2 -×2),2.46(m,4H，-CH 2 -×2),2.23(s,3H)，MS[M+H] + ：352.18。
example 33
5-amino-N- (4-fluorophenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (3 g)
Using 2g (1.12 g,3.7 mmol) as raw material, the preparation method is the same as 1b, and 3g (0.77 g) of light brown solid is obtained through column chromatography, the yield is 76.5%, 1 HNMR(500MHz,MeOD-d 4 )δ8.48(d,J＝2.6Hz,1H),8.17(d,J＝2.6Hz,1H),8.03-7.95(m,2H),7.43-7.31(m,2H)；MS[M+H] + ：272.10。
example 34
5-amino-N- (4- (morpholine-4-carbonyl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (3H)
Using 2H (1.47 g,3.7 mmol) as raw material, the same preparation method as 1b, light brown solid was obtained by column chromatography for 3H (1.06 g), yield 77.9%, MS [ M+H ]] + ：367.16。
Example 35
5-amino-N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (3 i)
Using 2i (1.51 g,3.7 mmol) as raw material, the same method as 1b, light brown solid 3i (1.13 g) was obtained by column chromatography, yield 80.6%, MS [ M+H ]] + ：380.19。
Example 36
4-amino-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (3 j)
Using 2j (1.41 g,3.7 mmol) as raw material, the preparation method was the same as 1b, and light brown solid 3j (1.10 g) was obtained by column chromatography, yield 84.9%, 1 H NMR[500MHz,DMSO-d 6 ]:δ13.37(s,1H，-NH-),10.22(s,1H，-NH),7.67(d,J＝9.1Hz,2H，ArH),7.09(s,1H，ArH),6.92(d,J＝9.1Hz,2H，ArH),6.75(s,2H，-NH 2 ),6.67(s,1H，ArH),6.26(d,J＝7.5Hz,1H，ArH),3.10(m,4H，-CH 2 -×2),2.46(br,4H，-CH 2 -×2),2.22(s，3H)，MS[M+H] + ：351.20。
example 37
4-amino-N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (3 k)
Using 2k (1.36 g,3.7 mmol) as raw material, the preparation method is the same as 1b, throughColumn chromatography gave 3k (1.08 g) as a pale brown solid in 86.4% yield, MS [ M+H ]] + ：338.16。
Example 38
4-amino-N- (4-fluorophenyl) -1H-indazole-3-carboxamide (3 l)
Using 2l (1.11 g,3.7 mmol) as raw material, the preparation method was the same as 1b, and 3l (0.84 g) of pale brown solid was obtained by column chromatography, the yield was 84.2%, 1 H NMR(500MHz,MeOD-d 4 )δ7.28–6.96(m,1H),6.54(dd,J＝8.3,7.5Hz,1H),6.49(dd,J＝9.1,8.5Hz,1H),6.17(dd,J＝8.3,0.7Hz,1H),5.79(dd,J＝7.5,0.8Hz,1H)；MS[M+H] + ：271.10。
example 39
5-amino-N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (3 m)
Using 2m (1.36 g,3.7 mmol) as raw material, the preparation method is the same as 1b, light brown solid 3m (1.08 g) is obtained through column chromatography, the yield is 75.5%, 1 HNMR(500MHz,DMSO-d 6 )δ13.25(s,1H),9.85(s,1H),7.72(d,J＝9.0Hz,2H),7.34(d,J＝8.8Hz,1H),7.29(d,J＝2.0Hz,1H),6.92(d,J＝9.1Hz,2H),6.85(dd,J＝8.9,2.1Hz,1H),5.05(s,2H),3.74(m,4H),3.06(m,4H)；MS[M+H] + ：388.16。
example 40
5-amino-N- (1-methylpiperidin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (3N)
Using 1-methylpiperidin-4-amine (1.36 g,3.7 mmol) as a starting material, the same procedure was followed as 3f, giving 3n (0.57 g) as a pale brown solid by column chromatography in 55.7% yield, MS [ M+H ]] + ：275.15。
Example 41
5-amino-N- (4- (morpholinomethyl) phenyl) -1H-indazole-3-carboxamide (3 o)
By using morphine as an initial starting material (3.15 g,36.2 mmol) and adopting the preparation method as 3c, light brown solid 3o (0.57 g) and MS [ M+H ] are obtained through four-step reaction] + ：275.15。
Example 42
5-acrylamido-N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (I-1)
In a single-necked flask, 3m (199.4 mg,0.59 mmol) was added and THF (3 mL) was added to dissolveSubsequently, acryloyl chloride (58.8 mg,0.65 mmol) and TEA (65.7 mg,0.65 mmol) were added. The reaction was carried out at room temperature for 2h, and TLC showed the disappearance of starting material (methanol: dichloro=1:20, volume ratio). The solvent was evaporated to dryness under reduced pressure, and a pale yellow solid was obtained by column chromatography as I-1 (95.1 mg) in 41.1% yield. 1 H NMR(500MHz,DMSO-d 6 )δ13.68(s,1H),10.28(s,1H),8.74–8.53(m,2H),7.83–7.69(m,4H),7.62(d,J＝9.0Hz,1H),6.95(d,J＝9.0Hz,3H),6.46(d,J＝10.2Hz,1H),6.28(dd,J＝17.0,1.9Hz,1H),5.76(dd,J＝10.1,1.8Hz,1H),3.83–3.64(m,7H),3.37(s,9H),3.16–2.99(m,7H)；HRMS-EI m/z[M+H] + calcd for C 21 H 22 N 5 O 3 :392.1723,found:392.1735。
Example 43
5-acrylamido-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (I-2)
Using 3a (207.1 mg,0.59 mmol) as a raw material, the same preparation method as I-1 was conducted to obtain pale yellow solid I-2 (82.0 mg) by column chromatography, the yield was 34.3%. 1 H NMR(500MHz,Methanol-d 4 )δ14.50(s,1H),11.12(s,1H),10.87(s,1H),9.44(s,1H),8.69–8.48(m,4H),8.43(d,J＝9.0Hz,1H),7.74(d,J＝9.0Hz,2H),7.31(dd,J＝16.9,10.1Hz,1H),7.10(dd,J＝17.0,1.7Hz,1H),6.57(dd,J＝10.2,1.7Hz,1H),3.97–3.85(m,7H),3.40–3.19(m,14H),3.07(s,3H)；HRMS-EI m/z[M+H] + calcd for C 22 H 25 N 6 O 2 :405.2039,found:405.2027。
Example 44
5-acrylamido-N- (4-fluorophenyl) -1H-indazole-3-carboxamide (I-3)
3b (160.0 mg,0.59 mmol) was used as a raw material, the same as I-1 was prepared, and a pale yellow solid I-3 (71.5 mg) was obtained by column chromatography in 37.4% yield; HRMS-EI M/z [ M+H ]] + calcd for C 17 H 14 FN 4 O 2 :325.1101，found:325.1112。
Example 45
N- (4-morpholinophenyl) -5- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-4)
In a single-necked flask, 3m (199.4 mg,0.59 mmol) was added and DMF (3 mL) was added to dissolve, followed byChloroethylsulfonyl chloride (96.2 mg,0.59 mmol) and DIPEA (228.3 mg,1.77 mmol) were added. The reaction was carried out at room temperature for 8h, and TLC showed the disappearance of starting material. The solvent was evaporated to dryness under reduced pressure, and a pale yellow solid was obtained by column chromatography as I-4 (40.1 mg) in 15.9% yield. 1 H NMR(500MHz,DMSO-d 6 )δ13.72(s,1H),10.10(s,1H),9.94(s,1H),8.03(d,J＝1.6Hz,1H),7.73(d,J＝9.0Hz,2H),7.61(d,J＝8.9Hz,1H),7.31(dd,J＝8.9,2.0Hz,1H),6.93(d,J＝9.1Hz,2H),6.76(dd,J＝16.5,10.0Hz,1H),6.01(m,2H),3.74(m,4H),3.07(m,4H)；HRMS-EI m/z[M+H] + calcd for C 20 H 22 N 5 O 4 S:428.1392,found:428.1399。
Example 46
N- (4- (4-methylpiperazin-1-yl) phenyl) -5- (vinylsulphonamide) -1H-indazole-3-carboxamide (I-5)
Using 3a (207.1 mg,0.59 mmol) as a raw material, the same preparation method as I-4 was followed by column chromatography to give pale yellow solid I-5 (42.2 mg), yield 16.2%. 1 H NMR(500MHz,DMSO-d 6 )δ13.71(s,1H),10.07(s,1H),9.94(s,1H),8.03(d,J＝2.1Hz,1H),7.77–7.67(m,2H),7.61(d,J＝9.0Hz,1H),7.31(dd,J＝8.9,2.1Hz,1H),7.00–6.83(m,2H),6.76(dd,J＝16.5,10.0Hz,1H),6.10–5.93(m,2H),3.10(dd,J＝6.2,3.7Hz,4H),2.47(t,J＝4.9Hz,4H),2.23(s,3H).HRMS-EI m/z[M+H] + calcd for C 21 H 25 N 6 O 3 S:441.1709,found:441.1710。
Example 47
N- (4-fluorophenyl) -5- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-6)
Using 3b (160.0 mg,0.59 mmol) as raw material, the same preparation method as I-4, pale yellow solid I-6 (29.2 mg) was obtained by column chromatography, the yield was 13.7%. 1 H NMR(500MHz,DMSO-d 6 )δ13.79(s,1H),10.40(s,1H),9.97(s,1H),8.03(d,J＝1.9Hz,1H),7.94–7.87(m,2H),7.63(d,J＝8.9Hz,1H),7.32(dd,J＝9.0,2.1Hz,1H),7.19(t,J＝8.9Hz,2H),6.77(dd,J＝16.4,10.0Hz,1H),6.17–5.93(m,2H)；HRMS-EI m/z[M+H] + calcd for C 16 H 14 FN 4 O 3 S:441.1709,found:361.0771。
Example 48
5- (3-Chloropropionamide) -N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (I-7)
In a single-necked flask was added 3m (199.4 mg,0.59 mmol), DMF (3 mL) was added to dissolve, followed by 3-chloropropionyl chloride (89.5 mg,0.71 mmol) and DIPEA (152.2 mg,1.18 mmol). The reaction was stopped by TLC at room temperature. The solvent was evaporated to dryness under reduced pressure, and a pale yellow solid was obtained by column chromatography as I-7 (40.1 mg) in 20.1% yield. HRMS-EIm/z [ M+H ] ] + calcd for C 21 H 23 ClN 5 O 3 :428.1489，found:428.1479。
Example 49
5- (3-Chloropropionamide) -N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (I-8)
3a (207.1 mg,0.59 mmol) was used as a raw material, the same preparation method as I-7 was used, and a pale yellow solid I-8 (60.0 mg) was obtained by column chromatography, with a yield of 23.1%; HRMS-EI M/z [ M+H ]] + calcd for C 22 H 26 ClN 6 O 2 :441.1806，found:441.1811。
Example 50
5- (3-Chloropropionamide) -N- (4-fluorophenyl) -1H-indazole-3-carboxamide (I-9)
3b (160.0 mg,0.59 mmol) was used as a raw material, the same as I-7 was prepared, and a pale yellow solid I-9 (48.5 mg) was obtained by column chromatography, with a yield of 18.7%; HRMS-EI M/z [ M+H ]] + calcd for C 17 H 15 ClFN 4 O 2 :361.0868，found:361.0866。
Example 51
5- (3-Chloropropionamide) -N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazole-3-carboxamide (I-10)
3c (215.5 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-7, and light yellow solid I-10 (44.0 mg) is obtained through column chromatography, and the yield is 16.4%; 1 H NMR(500MHz,DMSO)δ13.85(s,1H),10.33(s,1H),10.26(s,1H),8.60(s,1H),7.86(d,J＝5.4Hz,2H),7.62(d,J＝5.0Hz,2H),7.27(s,2H),3.91(s,2H),3.50(s,2H),2.87(s,2H),2.63(s,8H),2.36(s,3H).HRMS-EI m/z[M+H] + calcd for C 23 H 28 ClN6O 2 :455.1962,found:455.1955。
example 52
5- (3-Chloropropionamido) -N- (4- (morpholinomethyl) phenyl) -1H-indazole-3-carboxamide (I-11)
Using 3o (207.7 mg,0.59 mmol) as raw material, the preparation method was the same as I-7, and pale yellow solid I-11 (50.0 mg) was obtained by column chromatography, yield 19.2%; HRMS-EI M/z [ M+H ]] + calcd for C 22 H 25 ClN 5 O 3 :442.1646，found:442.1637。
Example 53
5- (3-Chloropropionamido) -N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-indazole-3-carboxamide (I-12)
3d (223.6 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-7, and light yellow solid I-11 (55.5 mg) is obtained through column chromatography, and the yield is 20.1%; HRMS-EI M/z [ M+H ] ] + calcd for C 23 H 26 ClN 6 O 3 :469.1755，found:469.1749。
Example 54
5-acrylamide-N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazole-3-carboxamide (I-13)
3c (215.5 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-1, and light yellow solid I-13 (75.5 mg) is obtained through column chromatography, and the yield is 30.6%; 1 H NMR(500MHz,MeOD)δ8.59(s,1H),7.80(d,J＝8.2Hz,2H),7.75(dd,J＝9.0,1.8Hz,1H),7.62(d,J＝9.0Hz,1H),7.40(d,J＝8.2Hz,2H),6.51(dd,J＝17.0,10.0Hz,1H),6.41(dd,J＝17.0,1.7Hz,1H),5.81(dd,J＝10.1,1.7Hz,1H),3.72(s,2H),3.21(s,8H),2.82(s,3H).HRMS-EI m/z[M+H] + calcd for C 23 H 27 N 6 O 2 :419.2195,found:419.2201。
example 55
5-acrylamide-N- (4- (morpholinomethyl) phenyl) -1H-indazole-3-carboxamide (I-14)
Using 3o (207.7 mg,0.59 mmol) as raw material, the preparation method was the same as I-1, and pale yellow solid I-14 (70.7 mg) was obtained by column chromatography, yield 29.6%; HRMS-EI M/z [ M+H ]] + calcd for C 22 H 24 N 5 O 3 :406.1879，found:406.1871。
Example 56
5-acrylamido-N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-indazole-3-carboxamide (I-15)
3d (223.6 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-1, and light yellow solid I-15 (65.5 mg) is obtained through column chromatography, and the yield is 25.7%; HRMS-EI M/z [ M+H ]] + calcd for C 23 H 25 N 6 O 3 :433.1988，found:433.1976。
Example 57
N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -5- (vinylsulphonamide) -1H-indazole-3-carboxamide (I-16)
3c (215.4 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-4, and light yellow solid I-16 (39.1 mg) is obtained through column chromatography, and the yield is 14.6%; HRMS-EI M/z [ M+H ]] + calcd for C 22 H 27 N 6 O 3 S:455.1865，found:455.1857。
Example 58
N- (4- (morpholinomethyl) phenyl) -5- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-17)
Using 3o (207.1 mg,0.59 mmol) as raw material, the preparation method was the same as I-4, and pale yellow solid I-17 (33.6 mg) was obtained by column chromatography, yield 12.9%; HRMS-EI M/z [ M+H ] ] + calcd for C 21 H 24 N 5 O 4 S:442.1549，found:442.1542。
Example 59
N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -5- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-18)
Using 3d (223.0 mg,0.59 mmol) as raw material, the preparation method was the same as I-4, and pale yellow solid I-18 (43.1 mg) was obtained by column chromatography, yield 15.6%; HRMS-EIm/z [ M+H ]] + calcd for C 22 H 25 N 6 O 4 S:469.1658，found:469.1649。
Example 60
N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -5-propanamido-1H-indazole-3-carboxamide (I-19)
Using 3c (215.5 mg,0.59 mmol) and propionyl chloride (65.7 mg,0.71 mmol) as raw materials, the preparation method was the same as I-1, and pale yellow solid I-19 (113.6 mg) was obtained by column chromatography in 45.7 yield％； 1 H NMR(500MHz，DMSO)δ13.85(d,J＝15.7Hz,1H),10.24(s,1H),10.10(d,J＝12.2Hz,1H),8.58(s,1H),7.86(d,J＝7.8Hz,2H),7.64(d,J＝9.1Hz,1H),7.59(d,J＝9.0Hz,1H),7.28(s,2H),3.51(s,2H),3.25–2.57(m,8H),2.55(s,3H),2.36(q,J＝7.6Hz,2H),1.11(t,J＝7.5Hz,3H)；HRMS-EI m/z[M+H] + calcd for C 23 H 29 N 6 O 2 :421.2352,found:421.2344。
Example 61
N- (4- (morpholinomethyl) phenyl) -5-propionamido-1H-indazole-3-carboxamide (I-20)
Using 3o (207.1 mg,0.59 mmol) and propionyl chloride (65.7 mg,0.71 mmol) as raw materials, the same preparation method as I-1 was followed by column chromatography to give pale yellow solid I-20 (98.2 mg), yield 40.9%; HRMS-EIm/z [ M+H ]] + calcdfor C 22 H 26 N 5 O 3 :408.2036，found:408.2021。
Example 62
4- (3-Chloropropionamide) -N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (I-21)
Using 3j (207.1 mg,0.59 mmol) as raw material, the same preparation method as I-7, pale yellow solid I-21 (96.0 mg) was obtained by column chromatography, with a yield of 36.9%. 1 H NMR(500MHz，DMSO-d 6 )δ14.11(s,1H),12.65(s,1H),10.60(s,1H),8.29(d,J＝7.7Hz,1H),7.72–7.64(m,2H),7.42(t,J＝8.0Hz,1H),7.35(d,J＝8.3Hz,1H),7.01–6.94(m,2H),3.95(d,J＝6.2Hz,2H),3.19(s,4H),2.93(t,J＝6.2Hz,2H),2.62(s,4H),2.34(s,3H)；HRMS-EI m/z[M+H] + calcd for C 22 H 26 ClN 6 O 2 :441.1806,found:441.1811。
Example 63
4- (3-Chloropropionamido) -N- (4-fluorophenyl) -1H-indazole-3-carboxamide (I-22)
3l (159.9 mg,0.59 mmol) of the extract was used as a raw material, the same as I-7, and a pale yellow solid I-22 (53.7 mg) was obtained by column chromatography, with a yield of 25.3%; HRMS-EI M/z [ M+H ] ] + calcd for C 17 H 15 ClFN 4 O 2 :361.0868，found:361.0871。
Example 64
4- (3-Chloropropionamido) -N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (I-23)
Using 3k (199.4 mg,0.59 mmol) as raw material, the preparation method was the same as I-7, and pale yellow solid I-23 (74.6 mg) was obtained by column chromatography, yield 29.6%; HRMS-EI M/z [ M+H ]] + calcd for C 21 H 23 ClN 5 O 3 :428.1489，found:428.1480。
Example 65
N- (4- (4-methylpiperazin-1-yl) phenyl) -4- (vinylsulphonamide) -1H-indazole-3-carboxamide (I-24)
Using 3j (207.1 mg,0.59 mmol) as raw material, the preparation method was the same as I-4, and pale yellow solid I-24 (71.1 mg) was obtained by column chromatography, yield 27.4%; HRMS-EIm/z [ M+H ]] + calcd for C 21 H 25 N 6 O 3 S:441.1709，found:441.1711。
Example 66
N- (4-fluorophenyl) -4- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-25)
3l (159.9 mg,0.59 mmol) of the extract was used as a raw material, the same as that of I-4, and a pale yellow solid I-25 (41.4 mg) was obtained by column chromatography, with a yield of 19.5%; HRMS-EI M/z [ M+H ]] + calcd for C 16 H 14 FN 4 O 3 S:361.0771，found:361.0766。
Example 67
N- (4-morpholinophenyl) -4- (vinylsulfonamide) -1H-indazole-3-carboxamide (I-26)
Using 3k (198.8 mg,0.59 mmol) as raw material, the preparation method is the same as I-4, and pale yellow solid I-26 (46.9 mg) is obtained through column chromatography, the yield is 18.6%; HRMS-EIm/z [ M+H ]] + calcd for C 20 H 22 N 5 O 4 S:428.1392，found:428.1399。
Example 68
4-acrylamide-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-indazole-3-carboxamide (I-27)
Using 3j (207.1 mg,0.59 mmol) as raw material, the preparation method was the same as I-1, and pale yellow solid I-27 (63.2 mg) was obtained by column chromatography, yield 26.6%; HRMS-EIm/z [ M+H ] ] + calcd for C 22 H 24 N 6 O 2 :404.1961，found:404.1956。
Example 69
4-acrylamide-N- (4-fluorophenyl) -1H-indazole-3-carboxamide (I-28)
Using 3l (160.0 mg,0.59 mmol) as raw material, the same preparation method as I-1, pale yellow solid I-28 (65.2 mg) was obtained by column chromatography, with a yield of 34.1%. 1 H NMR(500MHz,DMSO-d 6 )δ14.10(s,1H),12.64(s,1H),10.89(s,1H),8.53–8.36(m,1H),7.98–7.81(m,2H),7.49–7.42(m,1H),7.38(d,J＝8.3Hz,1H),7.30–7.22(m,2H),6.50–6.31(m,2H),5.94–5.82(m,1H)；HRMS-EI m/z[M+H] + calcd for C 17 H 13 FN 4 O 2 :324.1023,found:324.1029。
Example 70
4-acrylamido-N- (4-morpholinophenyl) -1H-indazole-3-carboxamide (I-29)
Using 3k (199.4 mg,0.59 mmol) as raw material, the preparation method was the same as I-1, and pale yellow solid I-29 (62.7 mg) was obtained by column chromatography, yield 27.2%; HRMS-EI M/z [ M+H ]] + calcd for C 21 H 22 N 5 O 3 :392.1723，found:392.1734。
Example 71
5- (3-Chloropropionamido) -N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-30)
3f (207.7 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-7, and light yellow solid I-30 (63.2 mg) is obtained through column chromatography, and the yield is 24.3%; HRMS-EI M/z [ M+H ]] + calcd for C 21 H 25 ClN 7 O 2 :442.1758，found:442.1749。
Example 72
5- (3-Chloropropionamide) -N- (4-fluorophenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-31)
3g (160.5 mg,0.59 mmol) of the extract was used as a raw material, the preparation method was the same as that of I-7, and a pale yellow solid I-31 (64.5 mg) was obtained by column chromatography, with a yield of 30.2%; HRMS-EI M/z [ M+H ]] + calcd for C 16 H 14 ClFN 5 O 2 :362.0820，found:362.0818。
Example 73
5- (3-Chloropropionamide) -N- (1-methylpiperidin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-32)
3n (162.3 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-7, and light yellow solid I-32 (98.1 mg) is obtained through column chromatography, and the yield is 45.7%; HRMS-EI M/z [ M+H ] ] + calcd for C 16 H 22 ClN 6 O 2 :365.1493，found:365.1488。
Example 74
5- (3-Chloropropionamido) -N- (4- (morpholine-4-carbonyl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-33)
Using 3h (215.9 mg,0.59 mmol) as raw material, the preparation method was the same as I-7, and pale yellow solid I-33 (42.0 mg) was obtained by column chromatography, yield 15.6%; HRMS-EI M/z [ M+H ]] + calcd for C 21 H 22 ClN 6 O 4 :457.1391，found:457.1387。
Example 75
5- (3-Chloropropionamido) -N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-34)
3I (223.6 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-7, and light yellow solid I-34 (40.7 mg) is obtained through column chromatography, and the yield is 14.7%; HRMS-EI M/z [ M+H ]] + calcd for C 22 H 25 ClN 7 O 3 :470.1707，found:470.1701。
Example 76
N- (4- (4-methylpiperazin-1-yl) phenyl) -5- (vinylsulphonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-35)
3f (207.7 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-4, and light yellow solid I-35 (31.6 mg) is obtained through column chromatography, and the yield is 12.1%; 1 H NMR(500MHz,DMSO-d 6 )δ14.37(s,1H),10.25(s,1H),8.46(d,J＝2.5Hz,1H),8.35(d,J＝2.4Hz,1H),7.72(d,J＝9.0Hz,2H),7.02–6.89(m,2H),6.85(dd,J＝16.4,9.9Hz,1H),6.05(s,1H),6.03(d,J＝5.4Hz,1H),3.15(t,J＝4.9Hz,4H),2.59(t,J＝4.9Hz,4H),2.32(s,3H).HRMS-EI m/z[M+H] + calcd for C 20 H 24 N 7 O 3 S:442.1661,found:442.1667。
example 77
N- (4-fluorophenyl) -5- (vinylsulfonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-36)
3g (160.5 mg,0.59 mmol) of I-4 was used as a raw material, and a pale yellow solid I-36 (29.2 mg) was obtained by column chromatography in a yield of 13.7%; HRMS-EI M/z [ M+H ]] + calcd for C 15 H 13 FN 5 O 3 S:362.0723，found:362.0716。
Example 78
N- (1-methylpiperidin-4-yl) -5- (vinylsulfonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-37)
3n (161.7 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-4, and light yellow solid I-37 (48.1 mg) is obtained through column chromatography, and the yield is 22.4%; 1 H NMR(500MHz，DMSO-d 6 )δ13.79(s,1H),10.40(s,1H),9.97(s,1H),8.03(d,J＝1.9Hz,1H),7.94–7.87(m,2H),7.63(d,J＝8.9Hz,1H),7.32(dd,J＝9.0,2.1Hz,1H),7.19(t,J＝8.9Hz,2H),6.77(dd,J＝16.4,10.0Hz,1H),6.17–5.93(m,2H)；HRMS-EI m/z[M+H] + calcd for C 15 H 21 N 6 O 3 S:365.1396,found:365.1399。
example 79
N- (4-morpholinophenyl) -5- (vinylsulfonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-38)
Using 3k (198.8 mg,0.59 mmol) as raw material, the preparation method is the same as I-4, and pale yellow solid I-38 (34.5 mg) is obtained through column chromatography, the yield is 13.7%; 1 H NMR(500MHz,DMSO-d 6 )δ14.54(s,1H),11.99(s,1H),10.31(s,1H),8.85(d,2H),8.71(s,1H),7.75(d,J＝8.6Hz,2H),7.33(m,1H),6.94(d,J＝8.7Hz,2H),3.74(t,J＝4.7Hz,4H),3.07(t,J＝4.7Hz,4H).HRMS-EI m/z[M+H] + calcd for C 19 H 21 N 6 O 4 S:429.1345,found:429.1338。
example 80
N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -5- (vinylsulfonamide) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-39)
Using 3I (224.2 mg,0.59 mmol) as raw material, the preparation method is the same as I-4, column chromatography to give pale yellow solid I-39 (43.2 mg), yield 15.6%; HRMS-EI M/z [ M+H ]] + calcd for C 21 H 24 N 7 O 4 S:470.1610，found:470.1621。
Example 81
5-acrylamido-N- (4- (4-methylpiperazin-1-yl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-40)
Using 3f (207.7 mg,0.59 mmol) as raw material, the same preparation method as I-1, pale yellow solid I-40 (70.7 mg) was obtained by column chromatography, the yield was 29.5%. 1 H NMR(500MHz,DMSO-d 6 )δ14.32(s,1H),10.76(s,1H),10.22(s,1H),9.03(d,J＝2.3Hz,1H),8.83(d,J＝2.4Hz,1H),7.74(d,J＝9.1Hz,2H),6.96(d,J＝9.1Hz,2H),6.55(dd,J＝17.0,10.2Hz,1H),6.32(dd,J＝17.1,1.9Hz,1H),5.82(dd,J＝10.2,1.9Hz,1H),5.82(dd,J＝10.2,1.9Hz,1H)，3.11(m,4H),2.45(m,4H),2.21(s,3H)；HRMS-EI m/z[M+H] + calcd for C 21 H 24 N 7 O 2 :406.1991,found:406.1988。
Example 82
5-acrylamido-N- (4-fluorophenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-41)
Using 3g (160.5 mg,0.59 mmol) as raw material, the same preparation method as I-1, pale yellow solid I-41 (40.8 mg) was obtained by column chromatography, the yield was 21.2%. 1 H NMR(500MHz,DMSO-d 6 )δ14.35(s,1H),10.54(s,1H),10.52(s,1H),9.01(s,1H),8.81(s,1H),7.92(dd,J＝8.7,4.9Hz,2H),7.21(t,J＝8.7Hz,2H),6.49(dd,J＝17.0,10.1Hz,1H),6.34(d,J＝16.9Hz,1H),5.83(d,J＝10.2Hz,1H)；HRMS-EI m/z[M+H] + calcd for C 16 H 13 FN 5 O 2 :326.1053,found:326.1047。
Example 83
5-acrylamide-N- (1-methylpiperidin-4-yl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-42)
3n (162.3 mg,0.59 mmol) is taken as a raw material, the preparation method is the same as that of I-1, and light yellow solid I-42 (86.9 mg) is obtained through column chromatography, and the yield is 44.9%; HRMS-EI M/z [ M+H ]] + calcd for C 16 H 21 N 6 O 2 :329.1726，found:329.1733。
Example 84
5-acrylamido-N- (4-morpholinophenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-43)
Using 3k (198.8 mg,0.59 mmol) as raw material, the preparation method is the same as I-1, and pale yellow solid I-43 (47.6 mg) is obtained through column chromatography, and the yield is 20.6%; 1 H NMR(500MHz,DMSO-d 6 )δ14.27(s,1H),10.54(s,1H),10.21(s,1H),9.00(d,J＝2.4Hz,1H),8.79(d,J＝2.4Hz,1H),7.94–7.55(m,2H),7.07–6.80(m,2H),6.49(dd,J＝16.9,10.1Hz,1H),6.33(dd,J＝17.0,1.9Hz,1H),5.83(dd,J＝10.1,1.9Hz,1H),3.83–3.69(m,4H),3.17–3.03(m,4H).HRMS-EI m/z[M+H] + calcd for C 20 H 21 N 6 O 3 :393.1675,found:393.1669。
example 85
5-acrylamido-N- (4- (4-methylpiperazine-1-carbonyl) phenyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboxamide (I-44)
Using 3I (224.2 mg,0.59 mmol) as raw material, the same preparation method as I-1, pale yellow solid I-44 (64.1 mg) was obtained by column chromatography, yield 25.1%. HRMS-EI M/z [ M+H ]] + calcd for C 22 H 24 N 7 O 3 :434.1941，found:434.1937。
Example 86
N- (1-methylpiperidin-4-yl) -1H-indazole-3-carboxamide (I-45)
Indazole-3-carboxylic acid (1.62 g,10.0 mmol) and 1-methylpiperidin-4-amine (1.25 g,11 mmol) were used as starting materials, the preparation method was the same as 2a, and pale yellow solid I-45 (1.97 g) was obtained by column chromatography in 76.3% yield; 1 H NMR(500MHz,DMSO-d 6 )δ13.54(s,1H),8.15(dd,J＝14.5,8.2Hz,1H),7.60(d,J＝8.4Hz,0H),7.42(s,0H),7.24(d,J＝7.5Hz,0H),2.76(dt,J＝12.1,3.5Hz,1H),2.17(s,1H),2.06–1.92(m,1H),1.71(ddd,J＝36.1,12.3,3.7Hz,2H)；HRMS-EI m/z[M+H] + calcd for C 14 H 19 N 4 O:259.1559,found:259.1546。
example 87
N- (4- ((4-methylpiperazin-1-yl) methyl) phenyl) -1H-indazole-3-carboxamide (I-46)
Indazole-3-carboxylic acid (1.62 g,10.0 mmol) and 1b (2.26 g,11.0 mmol) were used as raw materials, the same method as 2a was used, and a pale yellow solid I-45 (2.67 g) was obtained by column chromatography, yield 76.3%; 1 H NMR(500MHz,DMSO-d 6 )δ14.00(s,1H),10.33(s,1H),8.22(d,J＝8.0Hz,1H),7.87(d,J＝7.0Hz,1H),7.68(d,J＝8.4Hz,1H),7.45(m,1H),7.29(m,2H),3.51(s,2H),3.04(m,8H),2.68(s,3H)；HRMS-EI m/z[M+H] + calcd for C 20 H 24 N 5 O:350.1981,found:350.1979。
Pharmacological Activity test
(1) Inhibition activity test of target compound on FLT3
The synthesized compounds were tested for their inhibitory activity against FLT3 by Fluorescence Resonance Energy Transfer (FRET) method, and compared with a positive control, compounds having a better activity were selected. The above-mentioned kinase is obtained by purification or direct purchase of the kit. Taking the inhibition activity test of FLT3 as an example, the specific method is as follows:
FLT3 was used after dilution to the appropriate concentration with kinase diluent. The kinase reaction mixture contained FLT3, peptidesubstrate, HEPES (pH 7.5), BRIJ-35, mgCl2 and EDTA. CDK2phospho-peptide substrate was used as 100% phosphorylation control and no ATP was added as 0% phosphorylation control. After 1h of reaction at room temperature, development ReagentA was added to the reaction system in moderate dilution. The reaction was continued at room temperature for 1 hour, and Stop Reagent was added to Stop the reaction. Excitation wavelength was 400nm, and fluorescence intensities at 445nm (coumarin) and 520nm (fluorescein) were detected simultaneously. The inhibition rate of the tested compound is calculated according to the formula.
TABLE 1 inhibition activity of compounds on partial kinases (inhibition ratio, 1X 10) -6 mol/L) (color removal in tables)
TABLE 2 partial Compounds to FLT3IC 50 Value (nM)
(2) In vitro antitumor Activity assay of Compounds of interest
The inhibition effect on tumor cell lines such as gastric cancer cell line MGC803, leukemia cell line K562, breast cancer cell line MCF7, leukemia cell line MV4-11, lung cancer cell line A549 and the like is measured by an MTT method.
The MTT method utilizes the presence of NADP-related dehydrogenase in the mitochondria of living cells to reduce exogenous MTT to insoluble blue-violet crystals (formalzan) and deposit in cells, whereas dead cells do not. Purple crystals in the cells are dissolved by dimethyl sulfoxide (DMSO) or triple solution (10% SDS-5% isobutanol-0.01 mol/L HCL), and OD value is measured at 570nm wavelength by an ELISA detector to indirectly reflect the living cell quantity.
The specific method comprises the following steps: inoculating tumor cells in logarithmic cell growth phase into 96-well culture plate, culturing for 24 hr, adding sieved sample (directly adding suspension cell after plating), and culturing at 37deg.C under 5% CO 2 After culturing for 48 hours, MTT was added for 4 hours, and the crystals were dissolved in DMSO and detected under an ELISA reader.
The in vitro anti-tumor activity of the target compound at a concentration of 10. Mu.M against the tumor cell lines resulted in the following (inhibition%) as follows:
TABLE 3 antiproliferative activity of targeted conjugates on tumor cells
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And (3) injection: a: inhibition >80%, B:79% > inhibition >60%, C:59% > inhibition >30%, D:29% > -inhibition ratio
It was found by activity test that R 5 The introduction of the group is beneficial to the improvement of the inhibition activity of the compound on the FLT3, and compared with the corresponding compound without the structure, the compound has obvious inhibition activity on the FLT 3. Wherein when allyl tradeamide and chloroethyl propionamide are introduced, the obtained compound has more remarkable inhibitory activity on FLT3, and IC of the obtained compound 50 The values were comparable to AC220 (marketed FLT3 inhibitor) and FN-1501. According to preliminary studies, compounds incorporating such groups were shown to bind irreversibly to kinases easily, and according to molecular binding pattern studies, were irreversible inhibitors of FLT 3. The FLT3 inhibitors on the market at present are reversible, and the discovery of the irreversible FLT3 inhibitors lays a foundation for the research and development of novel anti-tumor drugs targeting FLT 3.

Claims (9)

1. A substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor, characterized in that it is a compound having the following structural formula (I):
wherein:
R 1 is-L-R a L represents bond, O, NH, C (O), NHC (O) NH, substituted or unsubstituted C 1-6 Straight-chain or branched alkylene, substituted or unsubstituted C 3-6 Cyclic saturated alkyl, wherein C 1-6 Any carbon atom in the alkylene group is substituted with 1 to 3 NH, N, O or S; r is R a Selected from hydrogen, halogen atoms, -NH 2 -OH, substituted or unsubstituted C 1-6 Straight-chain or branched alkyl, substituted or unsubstituted C 1-6 Straight or branched haloalkyl, substituted or unsubstitutedSubstituted C 3-8 Cyclic saturated alkyl, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkenyl, substituted or unsubstituted C 3-6 Cycloalkenyl, substituted or unsubstituted C 1-6 Alkylamino, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C 6-14 Aryl or substituted or unsubstituted aromatic heterocycle;
g is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkenyl, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aromatic heterocycle;
a is N or CR 2 B is N or CR 3 D and E are each independently N, CR 4 Or CR (CR) 5 One and only one of D and E is CR 5 ，R 2 、R 3 、R 4 Each independently selected from hydrogen, halogen, hydroxy, cyano, methoxy, substituted or unsubstituted C 1-6 Alkyl, R 5 Selected from-NR b -SO 2 -R c or-NR b -CO-R c ，R c is-CR d ＝CHR e 、C≡C-CH 3 Or C.ident.CH, R b 、R d 、R e Each independently selected from H, -CN, substituted or unsubstituted C 1-6 An alkyl group;
the heterocycloalkyl is selected from monocyclic saturated hydrocarbon groups with 3-6 carbon atoms and bicyclic saturated hydrocarbon groups with 6-12 carbon atoms, wherein the carbon atoms on the ring are independently substituted by 1-4O, S, N or NH;
the C is 6-14 The aryl is selected from one of phenyl, naphthyl, acenaphthylenyl or tetrahydronaphthyl;
the aromatic heterocycle is selected from a monocyclic heterocycle of pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1,4] dioxanyl or benzo [1,3] dioxolyl;
the substituents are selected from halogen, C 1-6 Haloalkyl, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 1-6 One or more of alkylthio groups; halogen is selected from fluorine, chlorine, bromine or iodine.
2. A substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor according to claim 1, wherein said G is selected from substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aromatic heterocycle.
3. The substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor according to claim 1, wherein a is N or CR 2 B is CR 3 D and E are each independently CR 4 Or CR (CR) 5 。
4. The substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor according to claim 1, wherein said R 1 is-L-R a L is selected from bond, O, NH, C (O), NHC (O) NH or methylene; r is R a Selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, C 3-8 Cyclic saturated alkyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, aziridinyl, azetidinyl, -OH, -NH 2 、C 1-6 Alkylthio, C 1-6 Alkoxy, C 1-6 One of the alkylamino groups; wherein phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, C 3 -C 8 Cyclic saturated alkyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, piperazinyl, aziridinyl,Azetidinyl groups are each independently optionally substituted with one or more R f Substituted, R f Selected from halogen or hydroxy;
G is selected from one of the following aromatic rings or aromatic heterocyclic rings: phenyl, naphthyl, pyrrolyl, furyl, thienyl, pyridyl, pyrazinyl or pyrimidinyl, wherein the above aromatic ring or aromatic heterocycle is optionally substituted with 1 or 3 substituents each independently selected from halogen, methyl, ethyl, isopropyl, methoxy or trifluoromethyl;
a is N or CR 2 B is CR 3 D and E are each independently CR 4 Or CR (CR) 5 One and only one of D and E is CR 5 ，R 2 、R 3 、R 4 Each independently selected from hydrogen, halogen, hydroxy, cyano, methoxy, substituted or unsubstituted C 1-6 Alkyl, R 5 Selected from-NR b -SO 2 -R c or-NR b -CO-R c ，R c is-CR d ＝CHR e 、C≡C-CH 3 Or C.ident.CH, R b 、R d 、R e Each independently selected from H, -CN, C 1-6 An alkyl group.
5. The substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor according to claim 1, wherein said R 1 is-L 1 -R a ,L 1 Selected from bond, O, NH, C (O), NHC (O) NH or methylene; r is R a Is selected from the group consisting of tetrahydropyrrolyl, piperidinyl, N-methylpiperidin-4-yl, morpholinyl, N-methylpiperazinyl, 3-methylpiperidin-1-yl, piperazinyl, N-dipropylamino, N-diethylamino, N-dimethylamino, N-butylamino, 2-methoxyethoxy, 2-hydroxyethylamino, N-bis (2-methoxyethyl) amino;
G is selected from one of the following aromatic rings or aromatic heterocyclic rings: phenyl, naphthyl, pyridinyl, pyrazinyl or pyrimidinyl, wherein the aromatic ring or aromatic heterocycle optionally has 1 or 2 substituents, each independently selected from halogen, methyl, ethyl, isopropyl, methoxy or trifluoromethyl;
a is N or CR 2 B is CR 3 D and E are each independently CR 4 Or CR (CR) 5 One and only one of D and E is CR 5 ，R 2 、R 3 、R 4 Is independently selected from hydrogen, halogen, hydroxy, cyano, methoxy, methyl, ethyl, isopropyl or trifluoromethyl, R 5 Selected from the group consisting of-NH-SO 2 -R c or-NH-CO-R c ，R c For-ch=chr e 、 C≡C-CH 3 Or C.ident.CH, R e Selected from H, -CN, methyl, ethyl, isopropyl or propyl.
6. The substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor according to claim 1, wherein said compound or a pharmaceutically acceptable salt thereof has the structural formula:
7. a substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor according to any of claims 1 to 6, characterized in that said pharmaceutically acceptable salt is an acid addition salt of a compound of general formula (I) with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid.
8. A pharmaceutical composition comprising a substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor compound according to any of claims 1 to 7, and a pharmaceutically acceptable carrier.
9. Use of a substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitor according to any one of claims 1 to 7 for the manufacture of a medicament for the prevention or treatment of a clinical condition related to the kinase of FLT 3.
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