CN116217551A - Substituted indazole or azaindazole compounds and application thereof - Google Patents
Substituted indazole or azaindazole compounds and application thereof Download PDFInfo
- Publication number
- CN116217551A CN116217551A CN202310142117.2A CN202310142117A CN116217551A CN 116217551 A CN116217551 A CN 116217551A CN 202310142117 A CN202310142117 A CN 202310142117A CN 116217551 A CN116217551 A CN 116217551A
- Authority
- CN
- China
- Prior art keywords
- indazol
- benzimidazol
- substituted
- unsubstituted
- benzoimidazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 title abstract 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical class C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 title description 2
- -1 azaindazole compound Chemical class 0.000 claims abstract description 163
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims abstract description 39
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- JOXWSDNHLSQKCC-UHFFFAOYSA-N ethenesulfonamide Chemical compound NS(=O)(=O)C=C JOXWSDNHLSQKCC-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 7
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
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- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
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- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
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- 229910052740 iodine Inorganic materials 0.000 claims description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
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- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
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- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims 1
- FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-UHFFFAOYSA-N 0.000 claims 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 1
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Abstract
The invention relates to a substituted indazole or azaindazole compound and application thereof, which have excellent FLT3 inhibitory activity and stronger anti-tumor activity, wherein the compound comprises pharmaceutically acceptable salts, solvates, isomers, esters, acids, metabolites or prodrugs thereof, pharmacological test results show that the compound has stronger inhibitory activity on FLT3 and has certain selectivity on other kinases, can be used for preventing or treating clinical diseases related to FLT3, and has remarkable economic and social benefits.
Description
Technical Field
The present invention relates to the field of medicine, in particular to novel FLT3 kinase inhibitor compounds, pharmaceutical compositions comprising the compounds, and substituted indazole or azaindazole-type compounds that use these compounds and compositions to reduce or inhibit FLT3 kinase and/or mutant FLT3 kinase activity in cells or subjects, and to prevent or treat cell proliferative disorders and/or FLT3 related disorders in subjects, and uses thereof.
Background
Protein Kinases (PKs) are key mediators of cellular function, and about 500 or more PKs have been found in humans, and a homologous catalytic domain consisting of 250 to 300 amino acid residues exists in the molecule. PK is widely found in systems such as cell signaling, cell cycle regulation and the like. Such enzymes catalyze the transfer of phosphate from ATP and covalently bind to the hydroxyl groups of certain serine, threonine or tyrosine residues in a particular protein molecule, thereby altering the conformation and activity of the protein, enzyme. Pathology and pharmacology studies have shown that PK dysfunction is closely associated with a number of diseases including central nervous system diseases, tumors, cardiovascular diseases and autoimmunity, among others.
It has been found that FLT3 has become an important marker for different hematological malignancies, such as Acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), lymphoma, hodgkin's disease, etc. 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.
AML is one of the most common leukemias in adults, and it is statistically that more than 25 tens of thousands of adults worldwide are diagnosed as AML each year, with less than 50% of AML patients having a total 5-year survival. In the clinical application of FLT3, FLT3 inhibitors are widely used in the treatment of AML. FLT3 is 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 selectivity of the compound for FLT 3. First generation nonselective inhibitors are Cabozantinib, sunitinib, midostourin, etc. According to research, the first generation of FLT3 inhibitors are multi-target kinase inhibitors, lack of specificity for FLT3, and besides inhibiting FLT3, the drugs also inhibit PDGFR, KIT and VEGFR, and often cause toxicity and adverse reaction due to off-target, thus limiting clinical treatment effects. Subsequently, a new generation of highly potent, highly selective FLT3 inhibitors, mainly Quizartinib, crenolanib, gilteritinib, etc., have been further developed. 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
The invention aims at: in order to solve the problems, the invention provides a compound which has excellent FLT3 inhibitory activity and shows strong anti-tumor activity. Comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, ester, acid, metabolite or prodrug thereof:
the technical scheme of the invention is as follows:
1. a compound having the following structural formula (I):
wherein:
R 1 is-L-R a L represents a bond, O, NH, S, C (O) NH, C (O), NHC (O) NH, substituted or unsubstituted C 1-3 An alkylene group; r is R a Is selected from hydrogen, halogen atom, -NH 2 -OH, hydroxy, nitro, carboxy, nitrile, substituted or unsubstitutedC 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 4-8 Cycloalkenyl, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkylamino, substituted or unsubstituted C 3-8 A heterocycloalkyl group;
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 Are 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 、
R b 、R d 、R e Each independently selected from H, -CN, substituted or unsubstituted C 1-6 An alkyl group;
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 Alkylthio, C 3-8 One or more of heterocycloalkyl;
halogen is selected from fluorine, chlorine, bromine or iodine;
C 1-6 haloalkyl is a straight or branched saturated hydrocarbon radical substituted with halogen and having 1 to 6 carbon atoms;
C 2-6 alkenyl is a straight or branched chain alkenyl group having 2 to 6 carbon atoms;
C 1-6 alkyl is a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms;
C 3-8 cycloalkyl radicals are cyclic radicals formed from 3 to 8 carbon atomsAn alkane group;
C 4-8 cycloalkenyl is a partially unsaturated cyclic olefin formed from 4 to 8 carbon atoms;
C 3-8 heterocycloalkyl is a saturated or partially unsaturated heterocycloalkyl having 3 to 8 carbon atoms containing one or more (e.g. 2 or 3) heteroatoms selected from O, N and S.
The invention has the preferable scheme that:
R 1 is-L-R a L each independently represents a bond, O, NH, C (O), NHC (O) NH, substituted or unsubstituted C 1-3 An alkylene group; r is R a Is selected from hydrogen, halogen atom, -NH 2 -OH, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkylamino, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 4-8 Cycloalkenyl, substituted or unsubstituted C 3-8 A heterocycloalkyl group;
the substituents are selected from halogen, C 1-6 Haloalkyl, hydroxy, C 1-6 One or more of alkyl groups;
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 Are each independently selected from hydrogen, halogen, hydroxy, cyano, methoxy, substituted or unsubstituted C 1-6 Alkyl, R 5 Selected from the group consisting of-NH-SO 2 -R c or-NH-CO-R c ，R c For-ch=chr e 、
R e Selected from H, -CN, C 1-6 An alkyl group. />
Another preferred embodiment of the present invention is as follows:
R 1 is-L 1 -R a ,L 1 Each independently represents a bond, S, O, NH, C (O) NH, C (O), NHC (O) NH, substituted or unsubstituted C 1-3 An alkylene group; r is R a Is selected from hydrogen, halogen atom, -NH 2 -OH, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkylamino, substituted or unsubstituted C 3-8 Heterocycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 4-8 Cycloalkenyl of (a);
the substituents are selected from halogen, C 1-6 Haloalkyl, hydroxy, C 1-6 One or more of alkyl groups;
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 Are each independently selected from hydrogen, halogen, hydroxy, cyano, methoxy, substituted or unsubstituted C 1-6 Alkyl, R 5 Selected from the group consisting of-NH-SO 2 -R c or-NH-CO-R c ，R c For-ch=chr e 、
R e Each selected from H, substituted or unsubstituted C 1-4 An alkyl group.
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, methylene, ethylene; r is R a Is selected from substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 4-8 Cycloalkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 A heterocycloalkyl group;
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 Are each independently selected from hydrogen, halogen, hydroxy, cyano, methoxy, substituted or unsubstituted C 1-6 Alkyl, R 5 Selected from the group consisting of-NH-SO 2 -R c or-NH-CO-R c ，R c For-ch=chr e 、
R e Each selected from H, substituted or unsubstituted C 1-4 An alkyl group.
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 tetrahydropyrrolyl, piperidinyl, N-methylpiperidin-4-yl, morpholinyl, N-methylpiperazinyl, 3-methylpiperidin-1-yl, piperazinyl, or a substituted amino, substituted oxy selected from the group consisting of: n, N-dipropylamino, N-diethylamino, N-dimethylamino, N-butylamino, 2- (cyclohexen-1-yl) ethylamino, 2-methoxyethoxy, 2-hydroxyethylamino, N-di (2-methoxyethyl) amino;
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 、
R e Selected from H, -CN, methyl, ethyl, isopropyl or propyl.
Further preferred embodiments of the present application are the following compounds:
n- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl) acrylamide (I-1)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-yl) acrylamide (I-2)
N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl acrylamide (I-3)
N- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl) ethenesulfonamide (I-4)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-yl) ethenesulfonamide (I-5)
N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl ethylene sulfonamide (I-6)
3-chloro-N- (3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-indazol-5-yl-propionamide (I-7)
3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-yl-propionamide (I-8)
3-chloro-N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl) propanamide (I-9)
3-chloro-N- (3- (6-morpholinomethyl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl-propionamide (I-10)
3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl) -1H-indazol-4-ylpropionamide (I-11)
3-chloro-N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzoimidazol-2-yl) -1H-indazol-4-yl-propionamide (I-12)
N- (3- (6-morpholinomethyl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl acrylamide (I-13)
N- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl-1H-indazol-4-ylacrylamide (I-14)
N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzoimidazol-2-yl) -1H-indazol-4-ylacrylamide (I-15)
N- (3- (6-morpholinomethyl) -1H-benzimidazol-2-yl-1H-indazol-4-yl) ethenesulfonamide (I-16)
N- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl-1H-indazol-4-yl ethylenesulphonamide (I-17)
N- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl-1H-indazol-4-yl ethylenesulphonamide (I-18)
3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl-propionamide (I-19)
3-chloro-N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-yl) propanamide (I-20)
3-chloro-N- (3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-indazol-4-yl) propanamide (I-21)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl) ethylenesulphonamide (I-22)
N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-yl) ethenesulfonamide (I-23)
N- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-4-yl) ethenesulfonamide (I-24)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl) acrylamide (I-25)
N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-yl acrylamide (I-26)
N- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-4-yl acrylamide (I-27)
3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propionamide (I-28) 3-chloro-N- (3- (6-fluoro-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propionamide (I-29)
3-chloro-N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propionamide (I-30) 3-chloro-N- (3- (6-morpholin-4-carbonyl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propionamide (I-31)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) vinylsulfonamide (I-32) N- (3- (6-morpholino-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) vinylsulfonamide (I-33)
N- (3- (6-fluoro-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) ethenesulfonamide (I-34)
N- (3- (6- (4-methylpiperazin-1-carbonyl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) vinylsulfonamide (I-35) N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-36) N- (3- (6-fluoro-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-37)
N- (3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-38)
N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-39) N- (3- (6- (diethylamino) -1H-benzimidazol-2-yl) -1H-indazol-5-yl) acrylamide (I-40)
N- (3- (6- (diethylamino) -1H-benzimidazol-2-yl) -1H-indazol-4-yl) acrylamide (I-41)
The molecular structural formula is as follows:
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:
and a third method:
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.
Drawings
FIG. 1 is a diagram showing the general molecular structure of the compound of the present invention.
Detailed Description
The following describes specific embodiments of the present invention in detail with reference to examples and specific cases.
The invention may be embodied by the following examples.
Example 1: 5-morpholinyl-2-nitroaniline (1 a)
In a 150mL single-necked flask was added 5-fluoro-2-nitroaniline (6.0 g,0.0384 mol), dissolved with 80mL N-methylpyrrolidone, followed by DIPEA (16.76 mL,0.0960 mol) and morpholine (13.4397 mL,0.1536 mol), and the addition was heated to reflux at 100℃for 8h, and TLC detected the disappearance of starting material (methanol: dichloromethane=1:60). The reaction solution was added to 400mL of saturated sodium bicarbonate solution, a yellow solid was precipitated, suction filtration and drying under reduced pressure to give yellow solid 1a (7.5 g), yield 92.6%, MS [ M+H ]] + :224.19. the product was directly subjected to the next reaction without further purification.
Example 2: 4-Morpholinylbenzene-1, 2-diamine (1 b)
In a 250mL single-necked flask was added 1a crude (7.5 g,0.0336 mol), dissolved in 150mL methanol, followed by 10% palladium on carbon (375 mg), and after the addition, hydrogen was introduced and air was purged three times, and reacted at room temperature for 2 hours, and TLC detected the disappearance of starting material (ethyl acetate: petroleum ether=1:1). The reaction solution was suction-filtered, and the filtrate was concentrated in vacuo to give 1b (6.49 g) as a dark purple solid in 100% yield, MS [ M+H ] ] + :194.31. The product was directly subjected to the next reaction without further purification.
Example 3:5- (4-methylpiperazin-1-yl) -2-nitroaniline (1 c)
Using 5-fluoro-2-nitroaniline (6.0 g,0.0384 mol) and methylpiperazine (17.052 mL,0.1536 mol) as starting materials, the same preparation method as 1a gave 1c (8.6 g) as a yellow solid with a yield of 95.6%, MS [ M+H ]] + :237.25. The product was directly subjected to the next reaction without further purification.
Example 4:4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (1 d)
1c (8.6 g,0.0364 mol) is used as raw material, the preparation method is the same as 1b, black purple solid 1d (7.5 g) is obtained, the yield is 100%, MS [ M+H ]] + :207.17. The product was directly subjected to the next reaction without further purification.
Example 5: 4-fluorobenzene-1, 2-diamine (1 e)
Using 5-fluoro-2-nitroaniline (6.0 g,0.0384 mol) as raw material, the same preparation method as 1b, black purple solid 1e (4.845 g) was obtained, yield 100%, MS [ M+H ]] + :127.22. The product was directly subjected to the next reaction without further purification.
Example 6: (3, 4-dinitrophenyl) -morpholin-4-yl-methanone (1 f)
In a 100mL single-necked flask, 3, 4-dinitrobenzoic acid (10.0 g,0.0471 mol) and 30mL thionyl chloride were added, and the mixture was heated under reflux at 85℃for 2 hours. After the reaction solution was cooled to room temperature, a small amount of toluene was added, and the excess thionyl chloride was removed by vacuum concentration. The residue was then dissolved with 100mL of tetrahydrofuran, morpholine (4.1 mL,0.0472 mol) and triethylamine (7.2 mL,0.0977 mol) were added to the mixture at 0deg.C, and the mixture was stirred at room temperature for 3h after the addition, and TLC checked for disappearance of starting material (methanol: chloroform=1:10). To the reaction solution was added 100mL of water, followed by extraction with ethyl acetate, and the organic layer was washed three times with a saturated sodium chloride solution, followed by drying over anhydrous sodium sulfate. The dried solution was filtered, the filtrate was concentrated in vacuo, and the residue was recrystallized from methanol to give yellow solid 1f (8.23 g), yield 62.1%, MS [ M+H ] ] + :282.13。
Example 7:4- (3, 4-dinitrobenzyl) morpholine (1 g)
1f (2.84 g,0.0101 mol) was added to a 150mL single-necked flask, and then 50mL of anhydrous tetrahydrofuran was added to dissolve the mixture, followed by NaBH 4 (954 mg) and 3.2mL of boron trifluoride etherate were added dropwise, and the mixture was stirred at room temperature for 3 hours, and the disappearance of starting material was detected by TLC (methanol: dichloromethane=1:30). A little methanol was added to quench, concentrated in vacuo, then 100mL of water was added to the residue, extracted with ethyl acetate, and the organic layer was washed three times with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Vacuum filtering the dried liquid, vacuum concentrating the filtrate, making sand, purifying by column chromatography to obtain 1g (1.08 g), yield 40.1%, MS [ M+H ]] + :268.11。
Example 8:4- (morpholinomethyl) benzene-1, 2-diamine (1 h)
1g (1.08 g,0.0040 mol) of a black-violet solid (0.8376 g) is obtained in the same manner as 1b, with a yield of 100%, MS [ M+H ]] + :208.14. The product was directly subjected to the next reaction without further purification.
Example 9: (3, 4-diaminophenyl) (morpholinyl) methanone (1 i)
1f (1.08 g,0.0040 mol) was used as the starting material, the same procedure as 1b was followed to give 1i (0.9648 g) as a dark purple solid with a yield of 100%, MS [ M+H ]] + :252.12. The product was directly subjected to the next reaction without further purification.
Example 10: (3, 4-dinitrophenyl) (4-methylpiperazin-1-yl) methanone (1 j)
Using 3, 4-dinitrobenzoic acid (10.0 g,0.0472 mol) and methylpiperazine (8.2140 mL,0.0742 mol) as raw materials, the same method as 1f gave 1j (9.04 g) as a yellow solid with a yield of 65.2%, MS [ M+H ]] + :295.15。
Example 11:1- (3, 4-dinitrobenzyl) -4-methylpiperazine (1 k)
1k (1.14 g) was obtained in the same manner as 1g using 1i (2.84 g,0.0097 mol) as a starting material, with a yield of 42.1%, MS [ M+H ]] + :281.21。
Example 12:4- ((4-methylpiperazin-1-yl) methyl) benzene-1, 2-diamine (1 l)
1l (0.896 g) of black-violet solid is obtained by using 1j (1.14 g,0.0041 mol) as a raw material and the preparation method is the same as 1b, wherein the yield is 100%, and MS [ M+H ]] + :221.23. The product was directly subjected to the next reaction without further purification.
Example 13: (3, 4-diaminophenyl) (4-methylpiperazin-1-yl) methanone (1 m)
1i (3.0 g,0.0102 mol) is used as raw material, the preparation method is the same as 1b, black-purple solid 1M (2.388 g) is obtained, the yield is 100%, MS [ M+H ]] + :235.10. The product was directly subjected to the next reaction without further purification.
Example 14: n (N) 1 ,N 1 -diethyl-4-nitrobenzene-1, 3-diamine (1 n)
Using 5-fluoro-2-nitroaniline (6.0 g,0.0384 mol) and diethylamine (15.89 ml,0.1536 mol) as starting materials, the same procedure was followed as for 1a to give 1n (7.346 g) as a yellow solid with a yield of 91.4%, MS [ M+H ] ] + :210.17。
Example 15: n (N) 4 ,N 4 -diethylbenzene-1, 2, 4-triamine (1 o)
1M (3.0 g,0.0143 mol) was used as the starting material, the same procedure as 1b was followed to give 1o (2.57 g) as a dark purple solid with 100% yield, MS [ M+H ]] + :180.20. The product has noFurther purification is needed, and the next reaction is directly carried out.
Example 16:4- (2- (5-nitro-1H-indazol-3-yl) -1H-benzoimidazol-6-yl-morpholine (2 a)
5-nitroindazole formaldehyde (2.0 g,0.0105 mol) was added to a 50ml round bottom flask and dissolved in 15ml anhydrous DMF. Subsequently, 4A molecular sieves (3.0 g), 1b (3.07 g,0.0159 mol) were added and the reaction was heated at 80℃for 3.5h. TLC detects the disappearance of starting material (methanol: dichloromethane=1:15). The reaction solution was filtered by suction, an excess saturated NaCl solution was added to the filtrate, followed by extraction with DCM, and the organic layer, anhydrous NaSO, was collected 4 Drying, vacuum concentrating, sand making, purifying by column chromatography to obtain solid 2a (1.11 g), yield 29.1%, MS [ M+H ]] + :365.19。
Example 17:3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -5-nitro-1H-indazole (2 b)
Using 5-nitroindazole-carbaldehyde (2.0 g,0.0105 mol) and 1d (3.278 g,0.0159 mol) as starting materials, the same procedure was followed as for 2a to give 2b (1.243 g) as a solid, 31.5% yield, MS [ M+H ]] + :378.21。
Example 18:3- (6-fluoro-1H-benzoimidazol-2-yl) -5-nitro-1H-indazole (2 c)
Using 5-nitroindazole-carbaldehyde (2.0 g,0.0105 mol) and 1e (2.0 g,0.0159 mol) as raw materials, the same procedure was followed as for preparation of 2a to give 2c (1.42 g) as a solid with a yield of 45.7%, MS [ M+H ]] + :298.05。
Example 19: n, N-diethyl-2- (5-nitro-1H-indazol-3-yl) -1H-benzimidazol-6-amine (2 d)
Using 5-nitroindazole-carbaldehyde (2.0 g,0.0105 mol) and 1o (2.84 g,0.0159 mol) as starting materials, the same procedure was followed as for 2a to give 2d (1.46 g) as a solid in 39.8% yield, MS [ M+H ]] + :351.12。
Example 20:4- (2- (5-nitropyrazolo [3,4-b ] pyridin-3-yl) -1H-benzimidazol-6-yl) morpholine (2 e)
With 5-nitro-1H-pyrazolo [3,4-b]Pyridine-3-carbaldehyde (4.0 g,0.0105 mol) and 1b (6.03 g,0.0159 mol) were used as starting materials, and 2a was prepared in the same manner as described above to give 2e (1.79 g) as a solid, yield 23.6%, MS [ M+H ]] + :366.17。
Example 21:3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -5-nitropyrazolo [3,4-b ] pyridine (2 f)
With 5-nitro-1H-pyrazolo [3,4-b]Pyridine-3-carbaldehyde (4.0 g,0.0105 mol) and 1d (6.44 g,0.0159 mol) were used as starting materials, and 2a was prepared in the same manner as above to give 2f (2.13 g) as a solid, yield 27.1%, MS [ M+H ]] + :379.19。
Example 22:3- (6-fluoro-1H-benzimidazol-2-yl) -5-nitropyrazolo [3,4-b ] pyridine (2 g)
With 5-nitro-1H-pyrazolo [3,4-b]Pyridine-3-carbaldehyde (4.0 g,0.0105 mol) and 1e (3.94 g,0.0159 mol) were used as starting materials, and 2a was prepared in the same manner as above to give 2g (2.0 g) of a solid, yield 32.3%, MS [ M+H ] ] + :299.11。
Example 23: (4-methylpiperazin-1-yl) (2- (5-nitropyrazolo [3,4-b ] pyridin-3-yl) -1H-benzimidazol-6-yl) methanone (2H)
With 5-nitro-1H-pyrazolo [3,4-b]Pyridine-3-carbaldehyde (4.0 g,0.0105 mol) and 1M (7.35 g,0.0159 mol) were used as starting materials, and the same procedure as for 2a was used to give 2H (2.44 g) as a solid, yield 28.7%, MS [ M+H ]] + :407.23。
Example 24: morpholinyl (2- (5-nitro-1H-pyrazolo [3,4-b ] pyridin-3-yl) -1H-benzimidazol-6-yl) methanone (2 i)
With 5-nitro-1H-pyrazolo [3,4-b]Pyridine-3-carbaldehyde (4.0 g,0.0105 mol) and 1i (7.89 g,0.0159 mol) were used as starting materials, and 2a was prepared in the same manner to give 2i (2.40 g) as a solid, yield 29.1%, MS [ M+H ]] + :394.15。
Example 25:4- ((2- (4-nitro-1H-indazol-3-yl) -1H-benzimidazol-6-yl) methyl) morpholine (2 j)
Starting with 4-nitro-1H-indazole-3-carbaldehyde (2.0 g,0.0105 mol) and 1H (3.255 g,0.0159 mol), the same procedure was followed as for 2a to give solid 2j (1.33 g), 33.6% yield, MS [ M+H ]] + :379.16。
Example 26:3- (6- ((4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl) -4-nitro-1H-indazole (2 k)
Starting with 4-nitro-1H-indazole-3-carbaldehyde (2.0 g,0.0105 mol) and 1l (3.458 g,0.0159 mol), the same procedure was followed as for 2a to give 2k (1.72 g) as a solid, yield 42.1%, MS [ M+H ]] + :392.25。
Example 27: (4-methylpiperazin-1-yl) (2- (4-nitro-1H-indazol-3-yl) -1H-benzimidazol-6-yl) methanone (2 l)
Starting with 4-nitro-1H-indazole-3-carbaldehyde (2.0 g,0.0105 mol) and 1M (3.677 g,0.0159 mol), the same procedure was followed as for 2a to give 2l (1.06 g) of solid, yield 25%, MS [ M+H ]] + :406.19。
Example 28:3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -4-nitro-1H-indazole (2 m)
Starting with 4-nitro-1H-indazole-3-carbaldehyde (2.0 g,0.0105 mol) and 1d (3.278 g,0.0159 mol), the same procedure was followed as for 2a to give 2M (1.26 g) as a solid, yield 32%, MS [ M+H ]] + :378.20。
Example 29:3- (6-fluoro-1H-benzoimidazol-2-yl) -4-nitro-1H-indazole (2 n)
Starting with 4-nitro-1H-indazole-3-carbaldehyde (2.0 g,0.0105 mol) and 1e (2.0 g,0.0159 mol), the same procedure was followed as for 2a to give solid 2n (1.37 g), yield 44.1%, MS [ M+H ]] + :298.14。
Example 30:4- (2- (4-nitro-1H-indazol-3-yl) -1H-benzimidazol-6-yl) morpholine (2 o)
Starting with 4-nitro-1H-indazole-3-carbaldehyde (2.0 g,0.0105 mol) and 1b (3.07 g,0.0159 mol), the same procedure was followed as for 2a to give 2o (1.14 g) as a solid with a yield of 30% MS [ M+H ]] + :365.14。
Example 31: n, N-diethyl-2- (4-nitro-1H-indazol-3-yl) -1H-benzimidazol-6-amine (2 p)
Starting with 4-nitro-1H-indazole-3-carbaldehyde (2.0 g,0.0105 mol) and 1o (2.84 g,0.0159 mol), the same procedure was followed as for 2a to give 2p (1.36 g) as a solid, yield 37.2%, MS [ M+H ] ] + :351.17。
Example 32:3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-5-amine (3 a)
In a 150ml single-necked flask, 2a (1.11 g, 0.003mol) was added, dissolved in 50ml of methanol, followed by 10% palladium on carbon (0.111 g), and after the addition, the reaction was carried out three times by introducing hydrogen and evacuating air, and the disappearance of the starting material was detected by TLC (methanol: dichloromethane=1:10) at room temperature. Filtering the reaction solution, concentrating the filtrate in vacuum, preparing sand, and purifying by column chromatography to obtain solidBody 3a (0.73 g), yield 72.3%, MS [ M+H ]] + :335.19。
Example 33:3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-amine (3 b)
Using 2b (1.243 g, 0.003mol) as a raw material, the same method as 3a was used to obtain 3b (0.916 g) as a reddish brown solid, with a yield of 80%. 1 H NMR(500MHz,Methanol-d 4 )δ7.66(dd,J＝2.1,0.7Hz,1H,ArH),7.55(d,J＝8.8Hz,1H,ArH),7.40(dd,J＝8.9,0.7Hz,1H,ArH),7.21–7.18(m,1H,ArH),7.04(ddd,J＝16.2,8.8,2.2Hz,2H,ArH),3.25(t,J＝5.1Hz,4H,-CH 2 -×2),2.74(t,J＝5.0Hz,4H,-CH 2 -×2),2.42(s,3H,-CH 3 )；MS[M+H] + :348.21。
Example 34:3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-amine (3 c)
Using 2c (1.42 g,0.0048 mol) as a starting material, the same procedure as 3a gave 3c (1.05 g) as a solid with a yield of 82.3%, MS [ M+H ]] + :268.13。
Example 35:3- (6- (diethylamino) -1H-benzimidazol-2-yl) -1H-indazol-5-amine (3 d)
Using 2d (1.46 g,0.0042 mol) as a starting material, the same procedure was followed as for 3a to give 3d (1.06 g) as a pale yellow solid in 79.2% yield. 1 H NMR(500MHz,Methanol-d 4 )δ7.67(d,J＝2.0Hz,1H,ArH),7.52(d,J＝8.8Hz,1H,ArH),7.39(d,J＝8.8Hz,1H,ArH),7.08–6.97(m,2H,ArH),6.88(dd,J＝8.9,2.3Hz,1H,ArH),3.37(q,J＝7.0Hz,4H,-CH 2 -×2),1.15(t,J＝7.1Hz,6H,-CH 3 ×2)；MS[M+H] + :321.23。
Example 36:3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-amine (3 e)
Using 2e (1.79 g,0.0049 mol) as a starting material, the same procedure was followed as for 3a to give 3e (1.26 g) as a solid in 76.5% yield, MS [ M+H ]] + :336.25。
Example 37:3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-amine (3 f)
Using 2f (2.13 g,0.0056 mol) as raw material, the same procedure was followed as for 3a to give 3f (1.57 g) as a solid in 80.1% yield, MS [ M+H ]] + :349.27。
Example 38:3- (6-fluoro-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-amine (3 g)
Using 2g (2.0 g,0.0067 mol) as raw material, the same method as 3a, 3g (1.43 g) of solid was obtained, yield 79.7%, MS [ M+H ]] + :269.14。
Example 39: (2- (5-amino-1H-pyrazolo [3,4-b ] pyridin-3-yl) -1H-benzimidazol-6-yl) (4-methylpiperazin-1-yl) methanone (3H)
Using 2H (2.44 g,0.0060 mol) as a starting material, the same procedure as 3a gave a solid 3H (1.82 g), 80.5% yield, MS [ M+H ]] + :377.25。
Example 40: (2- (5-amino-1H-pyrazolo [3,4-b ] pyridin-3-yl) -1H-benzimidazol-6-yl) (morpholinyl) methanone (3 i)
Using 2i (2.40 g,0.0061 mol) as a starting material, the same procedure as 3a gave 3i (1.64 g) as a solid with a yield of 73.9%, MS [ M+H ]] + :364.17。
Example 41:3- (6-morpholinomethyl) -1H-benzimidazol-2-yl-1H-indazol-4-amine (3 j)
Using 2j (1.33 g,0.0035 mol) as a starting material, the same procedure was followed as for 3a to give 3j (1.03 g) as a solid in 84.1% yield, MS [ M+H ] ] + :349.23。
Example 42:3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl) -1H-indazol-4-amine (3 k)
Using 2k (1.72 g,0.0044 mol) as a starting material, the same procedure as 3a gave 3k (1.29 g) as a solid in 81.1% yield, MS [ M+H ]] + :362.18。
Example 43:2- (4-amino-1H-indazol-3-yl) -1H-benzimidazol-6-yl) (4-methylpiperazin-1-yl) methanone (3 l)
Using 2l (1.06 g,0.0026 mol) as raw material, the same preparation method as 3a, 3l (0.729 g) of solid was obtained, yield 74.3%, MS [ M+H ]] + :376.26。
Example 44:3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-amine (3 m)
Using 2m (1.26 g,0.0033 mol) as a starting material, the same procedure was followed as for 3a, giving 3m (0.973 g) as a gray solid with a yield of 83.9%. 1 H NMR(500MHz,DMSO-d 6 )δ13.19(d,J＝19.5Hz,1H,-NH-),12.66(s,1H,-NH-),7.50(d,J＝8.8Hz,2H,ArH),7.09–7.03(m,1H.ArH),6.97–6.90(m,1H,ArH),6.61(dd,J＝8.1,2.9Hz,1H,ArH),6.23(t,J＝7.8Hz,1H,ArH),3.23–3.04(m,8H,-CH 2 -×4),2.24(s,3H,-CH 3 )；MS[M+H] + :348.24。
Example 45:3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-amine (3 n)
Using 2n (1.37 g,0.0046 mol) as a starting material, the same procedure as 3a gave 3n (1.0 g) as an off-white solid in 81.5% yield. 1 H NMR(500MHz,Methanol-d 4 )δ7.46(dd,J＝8.8,4.7Hz,1H,ArH),7.19(dd,J＝9.2,2.4Hz,1H,ArH),7.04(dt,J＝7.8,3.8Hz,1H,ArH),6.91(td,J＝9.3,2.5Hz,1H,ArH),6.66(d,J＝8.2Hz,1H,ArH),6.29(d,J＝7.5Hz,1H,ArH)；MS[M+H] + :268.19。
Example 46:3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-4-amine (3 o)
Using 2o (1.14 g,0.0031 mol) as a starting material, the same procedure was followed as for 3a, giving 3o (0.88 g) as a gray solid in 84.1% yield. 1 H NMR(500MHz,DMSO-d 6 )δ13.19(d,J＝18.5Hz,1H,-NH-),12.71(d,J＝18.7Hz,1H,-NH-),7.58–7.45(m,2H,ArH),7.06(td,J＝7.8,2.1Hz,1H,ArH),6.98–6.86(m,1H,ArH),6.60(dd,J＝8.1,2.3Hz,1H,ArH),6.32–6.19(m,1H,ArH),3.76(dd,J＝6.0,3.3Hz,4H,-CH 2 -×2),3.09(dq,J＝4.9,2.6Hz,4H,-CH 2 -×2)；MS[M+H] + :335.17。
Example 47:3- (6- (diethylamino) -1H-benzimidazol-2-yl) -1H-indazol-4-amine (3 p)
Using 2p (1.36 g,0.0039 mol) as a starting material, the same procedure was followed as for 3a, giving 3p (0.997 g) as a brown solid in 80.2% yield. 1 H NMR(500MHz,Methanol-d 4 )δ7.47(d,J＝8.8Hz,1H,ArH),7.13(t,J＝7.9Hz,1H,ArH),6.97(s,1H,ArH),6.87(dd,J＝8.8,2.3Hz,1H,ArH),6.75(d,J＝8.2Hz,1H,ArH),6.37(d,J＝7.4Hz,1H,ArH),3.36(q,J＝7.1Hz,4H,-CH 2 -×2),1.14(t,J＝7.1Hz,6H,-CH 3 ×2)；MS[M+H] + :321.23。
Example 48: n- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl) acrylamide (I-1)
3a (150 mg) was added to a 25ml single necked flask0.449 mmol) was dissolved by adding 10ml of anhydrous tetrahydrofuran followed by the addition of acryloyl chloride (44.69 mg,0.494 mmol). The reaction was carried out at room temperature for 30min, and TLC detected the disappearance of starting material (methanol: dichloromethane=1:10). The solvent was evaporated to dryness under reduced pressure, and column chromatography was performed to give solid I-1 (38.33 mg), yield 22%, MS [ M+H ]] + :389.18。
Example 49: n- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-yl) acrylamide (I-2)
3b (150 mg, 0.433 mmol) was used as the raw material, the same preparation method as I-1, and a white solid I-2 (40.04 mg) was obtained by column chromatography in 23.1% yield, 1 H NMR(500MHz,Methanol-d4)δ8.56(d,J＝1.9Hz,1H,ArH),7.81(dd,J＝8.9,2.0Hz,1H,ArH),7.58(dd,J＝8.9,5.5Hz,2H,ArH),7.19(d,J＝2.3Hz,1H,ArH),7.07(dd,J＝8.8,2.3Hz,1H,ArH),6.50(dd,J＝17.0,10.1Hz,1H,＝CH),6.40(dd,J＝17.0,1.8Hz,1H,＝CH),5.80(dd,J＝10.0,1.8Hz,1H,＝CH-),3.28(dd,J＝6.5,3.5Hz,4H,-CH 2 -×2),2.82(t,J＝5.0Hz,4H,-CH 2 -×2),2.48(s,3H,-CH 3 )；MS[M+H] + :402.28。
example 50: n- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl acrylamide (I-3)
Using 3c (150 mg,0.562 mmol) as raw material, the preparation method is the same as I-1, and solid I-3 (45.62 mg) is obtained by column chromatography, yield 25.3%, MS [ M+H ]] + :322.17。
Example 51: n- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl) ethenesulfonamide (I-4)
In a 25ml single neck flask was added 3a (150 mg,0.449 mmol), dissolved in 10ml anhydrous DMF, followed by chloroethylsulfonyl chloride (73.18 mg,0.449 mmol) and DIPEA (174.1 mg,1.35 mmol). The reaction was carried out at room temperature for 1h, and TLC detection of the disappearance of starting material (methanol: ethyl acetate=1:20). Filtering the reaction liquid to obtain filter cake, making sand from the filter cake, column chromatography to obtain solid I-4 (36.75 mg), yield 19.3%, MS [ M+H ] ] + :425.15。
Example 52: n- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-yl) ethenesulfonamide (I-5)
Preparation method using 3b (150 mg,0.432 mmol) as raw materialWith I-4, solid I-5 (28.33 mg) was obtained by column chromatography in 15.0% yield, MS [ M+H ]] + :438.23。
Example 53: n- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl ethylene sulfonamide (I-6)
Using 3c (150 mg,0.562 mmol) as raw material, the preparation method is the same as I-4, and solid I-6 (56.75 mg) is obtained by column chromatography, yield 28.3%, MS [ M+H ]] + :358.16。
Example 54: 3-chloro-N- (3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-indazol-5-yl-propionamide (I-7)
In a 25ml single-necked flask was charged 3a (150 mg,0.449 mmol), 10ml of anhydrous tetrahydrofuran was added to dissolve, followed by 3-chloropropionyl chloride (91.19 mg, 0.719 mmol). The reaction was carried out at room temperature for 30min, and TLC detected the disappearance of starting material (methanol: dichloromethane=1:20). The solvent was evaporated to dryness under reduced pressure, and the solid I-7 (32.56 mg) was obtained by column chromatography in 17.1% yield, MS [ M+H ]] + :425.18。
Example 55: 3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-yl-propionamide (I-8)
Using 3b (150 mg, 0.433 mmol) as a starting material, the same procedure as I-7 was followed by column chromatography to give I-8 (36.83 mg) as a white solid in 19.5% yield. 1 H NMR(500MHz,Methanol-d 4 )δ8.52(d,J＝1.8Hz,1H,ArH),7.70(dd,J＝9.0,2.0Hz,1H,ArH),7.57(dt,J＝8.9,3.6Hz,2H,ArH),7.20(d,J＝2.2Hz,1H,ArH),7.06(dd,J＝8.8,2.3Hz,1H,ArH),3.92(t,J＝6.4Hz,2H,-CH 2 -),3.32(s,4H,-CH 2 -×2),2.99(t,J＝4.9Hz,4H,-CH 2 -×2),2.90(t,J＝6.3Hz,2H,-CH 2 -),2.61(s,3H,-CH 3 )； 13 C NMR(126MHz,Methanol-d 4 )δ169.49,147.95,139.12,135.84,132.82,132.71,131.11,126.29,122.07,120.77,115.14,112.31,110.19,54.48,49.92,44.10,39.67,39.30；MS[M+H] + :438.27。
Example 56: 3-chloro-N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl) propanamide (I-9)
Using 3c (150 mg,0.562 mmol) as raw material, the preparation method is the same as I-7, and solid I-9 (45.52 mg) is obtained by column chromatography, yield 22.7%, MS [ M+H ]] + :358.16。
Example 57: 3-chloro-N- (3- (6-morpholinomethyl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl-propionamide (I-10)
Using 3j (150 mg,0.431 mmol) as raw material, the preparation method is the same as I-7, and solid I-10 (30.4 mg) is obtained by column chromatography, the yield is 16.1%, MS [ M+H ]] + :439.14。
Example 58: 3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl) -1H-indazol-4-ylpropionamide (I-11)
Using 3k (150 mg,0.415 mmol) as raw material, the same preparation method as I-7, solid I-11 (34.9 mg) was obtained by column chromatography, yield 18.6%, MS [ M+H ]] + :452.24。
Example 59: 3-chloro-N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzoimidazol-2-yl) -1H-indazol-4-yl-propionamide (I-12)
Using 3l (150 mg,0.400 mmol) as raw material, the same method as I-7, solid I-12 (25.10 mg) was obtained by column chromatography, yield 13.5%, MS [ M+H ]] + :466.19。
Example 60: n- (3- (6-morpholinomethyl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl acrylamide (I-13)
Using 3j (150 mg,0.431 mmol) as raw material, the preparation method is the same as I-1, and solid I-13 (32.75 mg) is obtained by column chromatography, yield 18.9%, MS [ M+H ] ] + :403.16。
Example 61: n- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl-1H-indazol-4-ylacrylamide (I-14)
Using 3k (150 mg,0.415 mmol) as raw material, the same preparation method as I-1, solid I-14 (31.21 mg) was obtained by column chromatography, yield 18.1%, MS [ M+H ]] + :416.27。
Example 62: n- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzoimidazol-2-yl) -1H-indazol-4-ylacrylamide (I-15)
Using 3l (150 mg,0.400 mmol) as raw material, the same method as I-1, solid I-15 (28.64 mg) was obtained by column chromatography, yield 15.4%, MS [ M+H ]] + :430.21。
Example 63: n- (3- (6-morpholinomethyl) -1H-benzimidazol-2-yl-1H-indazol-4-yl) ethenesulfonamide (I-16)
Using 3j (150 mg,0.431 mmol) as raw material, the same preparation method as I-4, solid I-16 (36.24 mg) was obtained by column chromatography, yield 19.2%, MS [ M+H ]] + :439.16。
Example 64: n- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl-1H-indazol-4-yl ethylenesulphonamide (I-17)
Using 3k (150 mg,0.415 mmol) as raw material, the same preparation method as I-4, solid I-17 (30.92 mg) was obtained by column chromatography, yield 16.5%, MS [ M+H ]] + :452.15。
Example 65: n- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl-1H-indazol-4-yl ethylenesulphonamide (I-18)
Using 3l (150 mg,0.400 mmol) as raw material, the same method as I-4, solid I-18 (26.97 mg) was obtained by column chromatography, yield 14.5%, MS [ M+H ] ] + :466.20。
Example 66: 3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl-propionamide (I-19)
Using 3M (150 mg, 0.433 mmol) as raw material, the preparation method is the same as I-7, and solid I-19 (36.07 mg) is obtained by column chromatography, yield 19.1%, MS [ M+H ]] + :438.19。
Example 67: 3-chloro-N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-yl) propanamide (I-20)
Using 3n (150 mg,0.562 mmol) as the raw material, the same preparation method as I-7, off-white solid I-20 (40.31 mg) was obtained by column chromatography, yield 20.1%. 1 H NMR(600MHz,DMSO-d 6 )δ14.00(d,J＝7.4Hz,1H,-NH-),13.93(d,J＝14.9Hz,1H,-NH-),13.47(d,J＝5.7Hz,1H,-NH-),8.34(dd,J＝7.6,3.4Hz,1H,ArH),7.77(dd,J＝8.8,4.8Hz,1H,ArH),7.58(ddd,J＝19.0,9.1,3.6Hz,1H,ArH),7.46–7.40(m,1H,ArH),7.32(td,J＝8.7,2.5Hz,1H,ArH),7.23–7.12(m,1H,ArH),4.06(q,J＝5.9Hz,2H,-CH 2 -),3.19(td,J＝6.1,4.8Hz,2H,-CH 2 -)； 13 C NMR(151MHz,DMSO-d 6 )δ167.72,161.70,148.59,142.23,137.70,133.66,131.91,130.22,127.68,118.48,112.10,111.50,110.94,109.91,109.18,104.81,97.76,40.38,39.71；MS[M+H] + :358.13。
Example 68: 3-chloro-N- (3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-indazol-4-yl) propanamide (I-21)
Using 3o (150 mg,0.562 mmol) as raw material, the preparation method is the same as I-7, and solid I-21 (34.65 mg) is obtained by column chromatography, yield 18.2%, MS [ M+H ]] + :425.18。
Example 69: n- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl) ethylenesulphonamide (I-22)
Using 3m (150 mg, 0.433 mmol) as the raw material, the same method as I-4, grey solid I-22 (29.09 mg) was obtained by column chromatography, yield 15.4%. 1 H NMR(500MHz,Methanol-d 4 )δ7.54(s,1H,ArH),7.35(t,J＝8.0Hz,1H,ArH),7.24(dd,J＝8.0,2.1Hz,2H,ArH),7.06(d,J＝9.0Hz,2H,ArH),6.63(dd,J＝16.5,9.9Hz,1H,＝CH),6.24(d,J＝16.5Hz,1H,＝CH),5.90(d,J＝9.9Hz,1H,＝CH-),3.23(t,J＝5.0Hz,4H,-CH 2 -×2),2.68(t,J＝5.0Hz,4H,-CH 2 -×2),2.37(s,3H,-CH 3 )； 13 C NMR(126MHz,Methanol-d 4 )δ143.30,135.88,131.94,127.81,126.74,113.16,108.56,104.74,54.72,50.21,44.64；MS[M+H] + :438.19。
Example 70: n- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-yl) ethenesulfonamide (I-23)
Using 3n (150 mg,0.562 mmol) as the raw material, the same procedure as I-4 was followed by column chromatography to give off-white solid I-23 (53.34 mg) in 26.6% yield. 1 H NMR(600MHz,DMSO-d 6 )δ14.41(d,J＝3.2Hz,1H,-NH-),13.95(d,J＝18.8Hz,1H,-NH-),13.54(d,J＝13.4Hz,1H,-NH-),7.58(ddd,J＝29.6,8.8,4.8Hz,1H,ArH),7.41(td,J＝8.1,2.2Hz,1H,ArH),7.31(dd,J＝8.4,4.2Hz,2H,ArH),7.23–7.15(m,1H,ArH),7.13(dd,J＝7.6,3.9Hz,1H,ArH),6.84(dd,J＝16.4,9.9Hz,1H,＝CH),6.25(dd,J＝16.3,1.8Hz,1H,＝CH),6.04(d,J＝9.9Hz,1H,＝CH-)； 13 C NMR(151MHz,DMSO-d 6 )δ148.23,147.67,142.41,137.19,135.54,133.63,131.08,130.11,127.83,118.47,112.03,110.10,107.27,104.58,102.92,97.63；MS[M+H] + :358.13。
Example 71: n- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-4-yl) ethenesulfonamide (I-24)
Using 3o (150 mg,0.449 mmol) as raw material, the same method as I-4, and column chromatography gave I-24 (35.80 mg) as pale yellow solid, yield 18.8%. 1 H NMR(600MHz,DMSO-d 6 )δ14.87(d,J＝51.2Hz,1H,-NH-),13.82(d,J＝27.6Hz,1H,-NH-),13.17(d,J＝39.4Hz,1H,-NH-),7.49–7.35(m,2H,ArH),7.28(dd,J＝8.4,3.2Hz,1H,ArH),7.16–7.02(m,2H,ArH),6.95(d,J＝2.3Hz,1H,ArH),6.82(ddd,J＝16.3,9.9,3.6Hz,1H,＝CH),6.24(dd,J＝16.4,4.7Hz,1H,＝CH),6.03(dd,J＝9.9,2.7Hz,1H,＝CH-),3.79(t,J＝4.6Hz,4H,-CH 2 -×2),3.12(dt,J＝16.4,4.7Hz,4H,-CH 2 -×2)； 13 C NMR(151MHz,DMSO-d 6 )δ161.70,148.30,145.45,135.64,134.55,134.34,134.20,131.28,127.62,117.59,113.27,111.97,106.94,104.36,96.53,65.64(d,J＝9.4Hz),49.51(d,J＝81.7Hz)；MS
[M+H] + :425.16。
Example 72: n- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl) acrylamide (I-25)
Using 3m (150 mg, 0.433 mmol) as the raw material, the same method as I-1 was followed by column chromatography to give I-25 (33.45 mg) as a white solid with a yield of 19.3%. 1 H NMR(500MHz,DMSO-d 6 )δ14.28(d,J＝20.7Hz,1H,-NH-),14.06–13.94(m,1H,-NH-),13.15(d,J＝26.8Hz,1H,-NH-),8.41(d,J＝7.6Hz,1H,ArH),7.65(d,J＝8.8Hz,1H,ArH),7.50–7.38(m,1H,ArH),7.34(dd,J＝8.3,4.6Hz,1H,ArH),7.09(ddd,J＝20.6,8.9,2.2Hz,1H,ArH),6.99(d,J＝2.3Hz,1H,ArH),6.80(ddd,J＝16.9,10.2,3.1Hz,1H,＝CH),6.44(dt,J＝17.1,2.5Hz,1H,＝CH),6.11–5.96(m,1H,＝CH-),3.31–3.23(m,4H,-CH 2 -×2),2.77(s,4H,-CH 2 -×2),2.42(s,3H,-CH 3 )； 13 C NMR(126MHz,DMSO-d 6 )δ164.14,146.99,143.26,136.19,135.51,135.12,133.11,132.59,128.55,127.77,118.62,116.13,114.68,112.52,110.42,106.07,98.16,54.46,49.20,21.59；MS[M+H] + :402.18。
Example 73: n- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-yl acrylamide (I-26)
Using 3n (150 mg,0.562 mmol) as raw material, the preparation method is the same as I-1, and white solid I is obtained by column chromatography26 (36.60 mg), yield 20.3%, 1 H NMR(600MHz,DMSO-d 6 )δ14.01(d,J＝23.4Hz,1H,-NH-),13.95(d,J＝14.7Hz,1H,-NH-),13.47(d,J＝3.7Hz,1H,-NH-),8.44(dd,J＝7.6,4.4Hz,1H,ArH),7.83(dd,J＝8.8,4.7Hz,1H,ArH),7.61(ddd,J＝57.6,9.1,3.6Hz,1H,ArH),7.55–7.40(m,1H,ArH),7.35(dd,J＝8.2,2.5Hz,1H,ArH),7.18(dtd,J＝18.9,9.4,2.6Hz,1H,ArH),6.80(ddd,J＝16.9,10.3,1.5Hz,1H,ArH),6.44(ddd,J＝16.8,4.6,1.8Hz,1H,ArH),6.02(ddd,J＝18.1,10.2,1.9Hz,1H,ArH)； 13 C NMR(151MHz,DMSO-d 6 )δ163.18,148.60,142.25,137.72,133.68,131.94,131.64,130.23,127.67,126.96,112.00,111.64,109.74,105.07,103.35,97.73；MS[M+H] + :322.16。
example 74: n- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-4-yl acrylamide (I-27)
Using 3o (150 mg,0.449 mmol) as the raw material, the same method as I-1 was followed by column chromatography to give I-27 (32.41 mg) as a white solid in 18.6% yield. 1 H NMR(600MHz,DMSO-d 6 )δ14.28(d,J＝22.9Hz,1H,-NH-),13.83(d,J＝26.2Hz,1H,-NH-),13.11(d,J＝30.3Hz,1H,-NH-),8.42(d,J＝7.6Hz,1H,ArH),7.65(d,J＝8.8Hz,1H,ArH),7.43(td,J＝8.4,4.5Hz,1H,ArH),7.33(dd,J＝8.3,5.1Hz,1H,ArH),7.08(ddd,J＝23.5,8.8,2.3Hz,1H,ArH),6.97(d,J＝2.3Hz,1H,ArH),6.80(dd,J＝17.0,10.2Hz,1H,＝CH),6.44(dt,J＝17.0,1.9Hz,1H,＝CH),6.02(ddd,J＝20.0,10.2,1.7Hz,1H,＝CH-),3.80(dd,J＝6.0,3.7Hz,4H,-CH 2 -×2),3.18–3.08(m,4H,-CH 2 -×2)； 13 C NMR(151MHz,DMSO-d 6 )δ163.10,148.25,145.87,142.22,135.14,134.49,134.20,132.11,131.55,127.57,126.68,117.59,113.12,109.41,104.92,103.05,96.59,65.68(d,J＝17.3Hz),49.50(d,J＝68.5Hz)；MS[M+H] + :389.24。
Example 75: 3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propanamide (I-28)
Using 3f (150 mg,0.431 mmol) as raw material, the same preparation method as I-7, solid I-28 (28.50 mg) was obtained by column chromatography, yield 15.1%, MS [ M+H ] ] + :439.21。
Example 76: 3-chloro-N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propanamide (I-29)
Using 3g (150 mg,0.560 mmol) as raw material, the preparation method was the same as I-7, and solid I-29 (32.66 mg) was obtained by column chromatography, yield 16.3%, MS [ M+H ]] + :359.15。
Example 77: 3-chloro-N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzoimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propanamide (I-30)
Using 3H (150 mg,0.399 mmol) as raw material, the preparation method was the same as I-7, and solid I-30 (21.38 mg) was obtained by column chromatography, yield 11.5%, MS [ M+H ]] + :467.18。
Example 78: 3-chloro-N- (3- (6-morpholine-4-carbonyl) -1H-benzoimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propanamide (I-31)
Using 3i (150 mg,0.413 mmol) as raw material, the same method as I-7, solid I-31 (23.40 mg) was obtained by column chromatography, yield 12.5%, MS [ M+H ]] + :454.10。
Example 79: n- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) ethenesulfonamide (I-32)
Using 3f (150 mg,0.431 mmol) as raw material, the preparation method is the same as I-4, and solid I-32 (24.54 mg) is obtained by column chromatography, yield 13.0%, MS [ M+H ]] + :439.20。
Example 80: n- (3- (6-morpholino-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) ethenesulfonamide (I-33)
Using 3e (150 mg, 0.447 mmol) as raw material, the same method as I-4, solid I-33 (28.16 mg) was obtained by column chromatography in 14.8% yield, MS [ M+H ]] + :426.17。
Example 81: n- (3- (6-fluoro-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) ethenesulfonamide (I-34)
Using 3g (150 mg,0.560 mmol) as raw material, the preparation method was the same as I-4, and solid I-34 (34.46 mg) was obtained by column chromatography, yield 17.2%, MS [ M+H ]] + :359.11。
Example 82: n- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) ethenesulfonamide (I-35)
Using 3H (150 mg,0.399 mmol) as raw material, the preparation method was the same as I-4, and solid I-35 (24.72 mg) was obtained by column chromatography, yield 13.3%, MS [ M+H ]] + :467.09。
Example 83: n- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-36)
Using 3f (150 mg,0.431 mmol) as raw material, the same preparation method as I-1, solid I-36 (27.03 mg) was obtained by column chromatography, yield 15.6%, MS [ M+H ]] + :403.16。
Example 84: n- (3- (6-fluoro-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-37)
Using 3g (150 mg,0.560 mmol) as raw material, the preparation method was the same as I-1, and solid I-37 (30.82 mg) was obtained by column chromatography, yield 17.1%, MS [ M+H ] ] + :323.17。
Example 85: n- (3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-38)
Using 3e (150 mg, 0.447 mmol) as raw material, the same method as I-1, solid I-38 (27.17 mg) was obtained by column chromatography in 15.6% yield, MS [ M+H ]] + :390.20。
Example 86: n- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-39)
Using 3H (150 mg,0.399 mmol) as raw material, the preparation method was the same as I-1, and solid I-39 (25.90 mg) was obtained by column chromatography, yield 15.1%, MS [ M+H ]] + :431.14。
Example 87: n- (3- (6- (diethylamino) -1H-benzimidazol-2-yl) -1H-indazol-5-yl) acrylamide (I-40)
Using 3d (150 mg,0.469 mmol) as raw material, the same preparation method as I-1, yellow solid I-40 (44.18 mg) was obtained by column chromatography in 25.2% yield. 1 H NMR(500MHz,Methanol-d 4 )δ8.53(d,J＝1.9Hz,1H,ArH),7.83(dd,J＝9.0,2.0Hz,1H,ArH),7.55(dd,J＝20.3,8.9Hz,2H,ArH),6.99(d,J＝2.4Hz,1H,ArH),6.90(dd,J＝8.9,2.3Hz,1H,ArH),6.49(dd,J＝17.0,10.0Hz,1H,＝CH),6.40(dd,J＝17.1,1.8Hz,1H,
＝CH),5.80(dd,J＝10.0,1.8Hz,1H,＝CH-),3.38(t,J＝7.1Hz,4H,-CH 2 -×2),1.16(t,J＝7.0Hz,6H,-CH 3 ×2)； 13 C NMR(126MHz,Methanol-d 4 )δ164.83,145.15,139.11,136.06,132.73,131.12,126.24,121.90,120.76,112.32,110.13,45.70,11.35；MS[M+H] + :375.15。
Example 88: n- (3- (6- (diethylamino) -1H-benzimidazol-2-yl) -1H-indazol-4-yl) acrylamide (I-41)
Using 3p (150 mg,0.469 mmol) as a raw material, the same preparation method as I-1 was conducted to obtain brown solid I-41 (44.70 mg) in 25.5% yield. 1 H NMR(500MHz,Methanol-d 4 )δ8.38(d,J＝7.6Hz,1H,ArH),7.53(d,J＝9.2Hz,1H,ArH),7.38(t,J＝8.0Hz,1H,ArH),7.27(d,J＝8.3Hz,1H,ArH),δ6.89(d,J＝10.3Hz,1H,＝CH),6.88–6.82(m,2H,ArH),6.50(dd,J＝17.1,1.4Hz,1H,＝CH),5.94(d,J＝10.3Hz,1H,＝CH-),3.40(q,J＝7.8,7.4Hz,4H,-CH 2 -×2),1.18(t,J＝6.9Hz,6H,-CH 3 ×2)； 13 C NMR(126MHz,Methanol-d 4 )δ165.21,145.83,143.03,132.39,131.89,127.71,125.99,118.01,111.40,110.66,105.32,94.74,45.20,11.44；MS[M+H] + :375.23。
The structure of the above example was measured, the melting point was measured using a b-shaped melting point tube, the medium was methyl silicone oil, and the thermometer was uncorrected; 1 HNMR is JEOL FX90Q type Fourier transform nuclear magnetic resonance apparatus, BRUKER 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.
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, peptide substrate, HEPES (pH 7.5), BRIJ-35, mgCl2 and EDTA. FLT3 phospho-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 Reagent A 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 FLT3 (inhibition ratio, 1X 10) -6 mol/L)
TABLE 2 IC of partial Compounds to FLT3 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 growth phase of cells to be tested according to a certain cell quantityCulturing in 96-well culture plate for 24 hr, adding the sieved sample (directly adding suspension cell after plating), and culturing at 37deg.C with 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
Note that: 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 improving the inhibition activity of the compound on FLT3, and compared with the corresponding compound without the structure, the compound has obvious inhibition activity on FLT 3. Wherein, when acrylamide and chloropropionamide are introduced into the molecule, the obtained compound has more remarkable inhibitory activity on FLT3, and the obtained compound has IC on FLT3 50 Values were comparable to AC220 (marketed FLT3 inhibitor) and FN-1501; also shows stronger antiproliferative activity in acute myelogenous leukemia cell strain MV4-11, IC 50 The values reach the single digit nanomolar scale. Preliminary structure-activity relationship analysis shows that covalent structures in the molecules can form irreversible binding with FLT3, and the binding molecules are in butt joint, so that the compound is inferred to be an irreversible inhibitor of FLT 3. The FLT3 inhibitors on the market at present are reversible inhibitors, 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 (10)
1. A compound having the following structural formula (I):
wherein:
R 1 is-L-R a L represents a bond, O, NH, S, C (O) NH, C (O), NHC (O) NH, substituted or unsubstituted C 1-3 An alkylene group; r is R a Is selected from hydrogen, halogen atom, -NH 2 -OH, hydroxy, nitro, carboxy, nitrile, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 4-8 Cycloalkenyl, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 1-6 Alkylamino, substituted or unsubstituted C 3-8 A heterocycloalkyl group;
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 Are 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 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 Alkylthio, C 3-8 One or more of the heterocycloalkyl groupsA kind of module is assembled in the module and the module is assembled in the module.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:
halogen is fluorine, chlorine, bromine or iodine;
C 1-6 haloalkyl is a straight or branched saturated hydrocarbon radical substituted with halogen and having 1 to 6 carbon atoms;
C 2-6 Alkenyl is a straight or branched chain alkenyl group having 2 to 6 carbon atoms;
C 1-6 alkyl is a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms;
C 3-8 cycloalkyl is a cyclic alkanyl radical formed from 3 to 8 carbon atoms;
C 4-8 cycloalkenyl is a partially unsaturated cyclic olefin formed from 4 to 8 carbon atoms;
C 3-8 heterocycloalkyl is a saturated or partially unsaturated heterocycloalkyl having 3 to 8 carbon atoms containing one or more heteroatoms selected from O, N and S.
3. The compound of claim 1, wherein said:
R 1 is-L 1 -R a ,L 1 Each independently represents a bond, S, O, NH, C (O) NH, C (O), NHC (O) NH, substituted or unsubstituted C 1-3 An alkylene group; r is R a Is selected from hydrogen, halogen atom, -NH 2 -OH, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkylamino, substituted or unsubstituted C 3-8 Heterocycloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 4-8 Cycloalkenyl of (a);
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 Each selected from H, substituted or unsubstituted C 1-4 An alkyl group.
4. A compound according to claim 1, characterized in that:
R 1 is-L 1 -R a ,L 1 Selected from bond, O, NH, C (O), NHC (O) NH, methylene, ethylene; r is R a Is selected from substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 4-8 Cycloalkenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 A heterocycloalkyl group;
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 Each selected from H, substituted or unsubstituted C 1-4 An alkyl group.
5. A compound according to any one of claims 1, wherein:
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 tetrahydropyrrolyl, piperidinyl, N-methylpiperidin-4-yl, morpholinyl, N-methylpiperazinyl, 3-methylpiperidin-1-yl, piperazinyl, or a substituted amino, substituted oxy selected from the group consisting of: n, N-dipropylamino, N-diethylamino, N-dimethylamino, N-butylamino, 2- (cyclohexen-1-yl) ethylamino, 2-methoxyethoxy, 2-hydroxyethylethylA alkylamino group, an N, N-bis (2-methoxyethyl) amino group;
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 compound of claim 1 having a structure selected from the group consisting of:
n- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl) acrylamide (I-1)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-yl) acrylamide (I-2)
N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl acrylamide (I-3)
N- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-5-yl) ethenesulfonamide (I-4)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-yl) ethenesulfonamide (I-5)
N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl ethylene sulfonamide (I-6)
3-chloro-N- (3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-indazol-5-yl-propionamide (I-7)
3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-5-yl-propionamide (I-8)
3-chloro-N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-5-yl) propanamide (I-9)
3-chloro-N- (3- (6-morpholinomethyl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl-propionamide (I-10)
3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl) -1H-indazol-4-ylpropionamide (I-11)
3-chloro-N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzoimidazol-2-yl) -1H-indazol-4-yl-propionamide (I-12)
N- (3- (6-morpholinomethyl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl acrylamide (I-13)
N- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl-1H-indazol-4-ylacrylamide (I-14)
N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzoimidazol-2-yl) -1H-indazol-4-ylacrylamide (I-15)
N- (3- (6-morpholinomethyl) -1H-benzimidazol-2-yl-1H-indazol-4-yl) ethenesulfonamide (I-16)
N- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl-1H-indazol-4-yl ethylenesulphonamide (I-17)
N- (3- (6- (4-methylpiperazin-1-yl) methyl) -1H-benzimidazol-2-yl-1H-indazol-4-yl ethylenesulphonamide (I-18)
3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl-propionamide (I-19)
3-chloro-N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-yl) propanamide (I-20)
3-chloro-N- (3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-indazol-4-yl) propanamide (I-21)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl) ethylenesulphonamide (I-22)
N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-yl) ethenesulfonamide (I-23)
N- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-4-yl) ethenesulfonamide (I-24)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-indazol-4-yl) acrylamide (I-25)
N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-indazol-4-yl acrylamide (I-26)
N- (3- (6-morpholinyl-1H-benzoimidazol-2-yl) -1H-indazol-4-yl acrylamide (I-27)
3-chloro-N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propanamide (I-28)
3-chloro-N- (3- (6-fluoro-1H-benzoimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propanamide (I-29)
3-chloro-N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzoimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propanamide (I-30)
3-chloro-N- (3- (6-morpholine-4-carbonyl) -1H-benzoimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) propanamide (I-31)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) ethenesulfonamide (I-32)
N- (3- (6-morpholino-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) ethenesulfonamide (I-33)
N- (3- (6-fluoro-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) ethenesulfonamide (I-34)
N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) ethenesulfonamide (I-35)
N- (3- (6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-36) N- (3- (6-fluoro-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-37)
N- (3- (6-morpholinyl-1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-38)
N- (3- (6- (4-methylpiperazine-1-carbonyl) -1H-benzimidazol-2-yl) -1H-pyrazolo [3,4-b ] pyridin-5-yl) acrylamide (I-39)
N- (3- (6- (diethylamino) -1H-benzimidazol-2-yl) -1H-indazol-5-yl) acrylamide (I-40)
N- (3- (6- (diethylamino) -1H-benzimidazol-2-yl) -1H-indazol-4-yl) acrylamide (I-41).
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an acid addition salt of a compound of 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 or mandelic acid.
8. A pharmaceutical composition comprising a compound according to any one of claims 1-7 and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1-6 in the manufacture of a medicament for the prevention or treatment of a clinical condition associated with FLT3 kinase.
10. The use of claim 9, wherein the FLT-3 related disorder is selected from lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, ovarian cancer, testicular cancer, breast cancer, bladder cancer, gall bladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin dependent diabetes mellitus, autoimmune disease, or psoriasis.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102573846A (en) * | 2009-08-17 | 2012-07-11 | 因特利凯公司 | Heterocyclic compounds and uses thereof |
| CN109970717A (en) * | 2017-12-28 | 2019-07-05 | 中国药科大学 | 4- (cycloaliphatic ring and pyrimidine/pyridine replaces) amino -1H-3- pyrazole carboxamides FLT3 inhibitor and application thereof |
| CN114605329A (en) * | 2022-03-28 | 2022-06-10 | 河南中医药大学 | Substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitors and uses thereof |
| WO2023287128A1 (en) * | 2021-07-12 | 2023-01-19 | 한양대학교 에리카산학협력단 | Indazole yl benzimidazole derivative or pharmaceutically acceptable salt thereof, and use thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102573846A (en) * | 2009-08-17 | 2012-07-11 | 因特利凯公司 | Heterocyclic compounds and uses thereof |
| CN109970717A (en) * | 2017-12-28 | 2019-07-05 | 中国药科大学 | 4- (cycloaliphatic ring and pyrimidine/pyridine replaces) amino -1H-3- pyrazole carboxamides FLT3 inhibitor and application thereof |
| WO2023287128A1 (en) * | 2021-07-12 | 2023-01-19 | 한양대학교 에리카산학협력단 | Indazole yl benzimidazole derivative or pharmaceutically acceptable salt thereof, and use thereof |
| CN114605329A (en) * | 2022-03-28 | 2022-06-10 | 河南中医药大学 | Substituted indazole carboxamide or substituted azaindazole carboxamide FLT3 inhibitors and uses thereof |
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