CN114195771A - Multi-kinase inhibitors and uses thereof - Google Patents

Multi-kinase inhibitors and uses thereof Download PDF

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CN114195771A
CN114195771A CN202210018194.2A CN202210018194A CN114195771A CN 114195771 A CN114195771 A CN 114195771A CN 202210018194 A CN202210018194 A CN 202210018194A CN 114195771 A CN114195771 A CN 114195771A
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王景炳
谢玲芝
乔丹丹
D.达斯
洪健
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Suzhou Anrui Pharmaceutical Co ltd
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • 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
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Abstract

The present invention relates to a multi-kinase inhibitor and uses thereof, compounds of formula I, isotopic forms, stereoisomeric forms, tautomeric forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs thereof. The invention relates to a process for the preparation of a compound of formula I, wherein A, B, R1、R2、W1、W2、W3、W4、W5、W6、W7、W8And Y is as described in the description. The compounds and pharmaceutical compositions thereof are multi-kinase inhibitors and are useful for the treatment of cancer and immune related diseases.

Description

Multi-kinase inhibitors and uses thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a multi-kinase inhibitor and application thereof.
Background
Protein phosphorylation regulates various aspects of cellular function such as cell division, metabolism, motility, survival and apoptosis. Disruption of any phosphorylation alters cellular function and may lead to a number of diseases including cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases and metabolic diseases. Phosphorylation is catalyzed by kinases. Protein kinases transfer a gamma-phosphate group from ATP to various amino acid residues. Upon activation, the kinase phosphorylates either the tyrosine hydroxyl group (tyrosine kinase) or the serine or threonine hydroxyl group (serine/threonine kinase). Protein kinases play a vital role in signal transduction, cell differentiation, cell proliferation, cell cycle progression, and the like. Protein Tyrosine Kinases (PTKs) act primarily as growth factor receptors. PTKs with receptor activity are also known as Receptor Tyrosine Kinases (RTKs). RTKs are cell surface receptors that have an extracellular domain that selectively bind to and are activated by a variety of growth factors, such as Epidermal Growth Factor (EGF), Vascular Endothelial Growth Factor (VEGF), insulin-like growth factor (IGF).
Angiogenesis is a key process for the growth of solid cancers. Cancer cells absorb necessary oxygen and nutrients from the surrounding environment. Due to the growth of solid tumors, low oxygen pressure, malnutrition, low pH, called hypoxia, occurs in regions 1-2 mm or more from the nearest blood vessel. Cancer cells respond to this stress by producing various angiogenic factors to stimulate angiogenesis and solid tumor growth of nearby vascular endothelial cells. Angiogenesis includes: (a) rupture of the basement membrane of the vessel wall; (b) migration and proliferation of vascular endothelial cell membranes; (c) and (4) forming blood vessels. Growth factors such as Fibroblast Growth Factor (FGF), platelet-derived growth factor (PDGF), Vascular Endothelial Growth Factor (VEGF) and the like have been observed as their mechanism of action. VEGF enhances microvascular permeability, sometimes referred to as vascular permeability factor. VEGF and VEGFR play a role in angiogenesis, the process of angiogenesis, and metastasis in solid tumors. VEGF is known to bind to three receptor tyrosine kinases, VEGFR1(FLT-1), VEGFR2(KDR), VEGFR3(FLT 4). VEGFR kinases have been used as targets for solid tumors, such as highly vascular renal, glioblastoma and liver cancers. Recently, angiogenesis inhibitors such as VEGFR2 or KDR directed against VEGF or inhibiting VEGFR kinase activity have become molecular targets for drug development (expeperotion Investigational Drugs 2003,12, 51-64).
FGFR, PDGFR, c-Met have been reported to be involved directly or indirectly in angiogenesis. Kinase inhibitors directed against these receptors are being investigated as therapeutic agents for cancer. FMS-like tyrosine kinase 3(FLT3), a RTK of the same family as PDGFR, is expressed in undifferentiated hematopoietic cells and signals hematopoietic cell proliferation and survival by binding to ligand FL expressed in bone marrow and other organs. Mutations in FLT3 are observed in about 30% of Acute Myeloid Leukemia (AML) and about 5% of myeloid language disorder syndrome (MDS). This variation leads to ligand-independent activation to signal aberrant proliferation and anti-apoptosis and is thought to be closely related to the progression of Acute Myeloid Leukemia (AML).
Multi-kinase inhibitors or broad-spectrum specific inhibitors are expected to exhibit high therapeutic effects by jointly inhibiting a few specific targets. Multi-kinase inhibitors are not able to selectively inhibit one kinase as a molecular target, and many multi-kinase inhibitors have been developed in recent years. In pharmaceutical chemistry methodologies, there are still many problems how to determine a specific set of kinases that can be targeted by a multi-kinase inhibitor to obtain good therapeutic effect and to suppress side effects. However, when considering heterogeneity and drug resistance of cancer cells, multi-kinase inhibitors are expected to be effective means for overcoming the above problems.
The multi-kinase inhibitor crizotinib has been shown to be effective in non-small cell lung Cancer (NSCLC) with altered MET exon 14 (Cancer discovmatch 1,2020,10(3), 337); multikinase inhibitors are used in the treatment of thyroid cancer (anker et el. int.j. mol. sci.2019,21(1), 10).
Sorafenib (Bay 43-9006) is a potent, oral multi-kinase inhibitor, being an inhibitor of VEGFR2, VEGFR3, PDGFRb, FLT3, c-Kit (IC50 ═ 90, 15, 20, 57, 58nM) and Raf-1 and B-Raf kinases (Wilhelm SM Cancer res.2004, 64, 7099-. Sorafenib is used to treat hepatocellular carcinoma (HCC), renal cancer and some type of thyroid cancer that have spread to other parts of the body. However, sorafenib has problems of high lipophilicity and low water solubility due to high hydrophobicity and high lattice of the phenylurea skeleton. The low solubility in water is a serious problem, especially in the clinical development of oral drugs, which is likely to cause problems of decreased absorption, unstable action and tendency to accumulate due to inter-patient pharmacokinetic variations (Pharma Zeutische Indret trie 2002, 64(9), 985-.
Levatinib is an inhibitor of VEGFR receptors 1-3, FGFR1-4, PDGFRa and KIT. Recently, a randomized phase 3 clinical trial was completed on lenvatinib and sorafenib in patients with hepatocellular carcinoma who could not be resected by first line therapy, and Kudo et al reported a randomized phase 3 non-adverse efficacy trial. (Kudo et al, the Lancet,2018,391, 1163-1173). Lenvatinib is also an effective drug for the treatment of certain thyroid cancers.
In addition, patented multikinase inhibitors such as: WO-2019036367 (multikinase inhibitors and their use in reproductive and digestive tract fibrosis), WO2019133022 (multikinase inhibitors and their use in prostate hyperplasia and urinary tract diseases), WO-2019125798 (carbamate and urea compounds as multikinase inhibitors, WO-2018022437 (multikinase inhibitors and their use in ocular fibrosis), WO-2018148653 (multigene inhibitors of VEGF and TGF-beta and their use), WO-2015128698 (substituted heterocyclic amine derivatives as multikinase inhibitors for the treatment of cancer), WO2009015368 (multikinase inhibitors for the treatment of cancer), JP-2013189458-A (multikinase inhibitors for the treatment of cancer) discloses compounds as multikinase inhibitors, and for the treatment of a number of kinase-mediated diseases it is therefore necessary to develop more novel multi-kinase inhibitors for the treatment of cancer.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a multi-kinase inhibitor which can effectively inhibit kinase activities such as FLT1, FLT3, FLT4, FGFR1-4, VEGFR2/KDR, PDGFRa, PDGFRb and cKit.
The first purpose of the invention is to disclose a multi-kinase inhibitor, the structural formula of which is shown in formula (I):
Figure BDA0003460951360000031
wherein:
a is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and the substituent on the substituted aryl or substituted heteroaryl is selected from substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C1-10One or more of alkoxy, halogen and nitrile group;
b is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a group of formula (II), substituted or unsubstituted saturated or unsaturated C3-10Cycloalkyl or a heteroatom substituted or unsubstituted 4-7 membered cyclic amine; wherein the content of the first and second substances,
the substituents on the substituted aryl or substituted heteroaryl are selected from C1-10Alkyl radical, C1-10One or more of alkoxy, carboxyl, ester group, sulfone group and sulfonamide group; wherein the hydrogen in the alkyl group may be substituted with one or more deuterium atoms and the hydrogen in the alkyl group may be substituted with one or more fluorine atoms.
The group of formula (II) is as follows:
Figure BDA0003460951360000032
wherein R is3And R4Each independently selected from hydrogen and C1-10Alkyl radical, C1-10Alkoxy radical, C1-10Alkylamino radical or C1-6A hydroxyalkyl group;
or R3And R4Linked to form a ring to form a substituted C3-10Cycloalkyl radicals, substituted C3-10Cycloalkyl radicals including hetero atomsA substituted cycloalkyl or spirocyclic carbocyclic ring containing NH and/or oxygen atoms;
4-7 membered cyclic amine substituted or unsubstituted by hetero atom is chiral molecule or achiral molecule;
R1selected from hydrogen, substituted or unsubstituted C1-10An alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; the substituents on the substituted aryl or substituted heteroaryl groups are selected from substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C1-10One or more of alkoxy, halogen and halogen;
R2selected from hydrogen, C1-3Alkyl, cyano, C1-3Fluoroalkyl or halogen;
W1、W2、W3、W4、W5、W6and W7Is C, CH or N satisfying the valence state, and at least W1、W2、W3、W4、W5、W6And W7One of them is N;
W8o, S, NH or NMe;
y is selected from a group of the following structural formula:
Figure BDA0003460951360000041
in the present invention, unless otherwise specified,
Figure BDA0003460951360000042
represents the site of attachment of the group.
Further, in the group A or B, the aryl group therein is C6-C9Aryl, heteroaryl including C with nitrogen and/or sulfur as hetero atoms4-C6A heteroaryl group.
Preferably, a is selected from the group of the following structural formulae:
Figure BDA0003460951360000043
further, B is selected from the group represented by formula (II):
Figure BDA0003460951360000044
wherein R is3And R4Each independently selected from hydrogen and C1-10Alkyl radical, C1-10Alkoxy radical, C1-6Alkylamino radical or C1-6A hydroxyalkyl group; the alkylamino group is a primary amino group or a secondary amino group; a 3-7 membered carbocyclic ring; 4-7 membered cyclic amines; 4-7 membered heteroatom substituted cyclic amine; chiral 5-7 membered amines; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; substituted or unsubstituted piperazine, substituted or unsubstituted morpholine; a carbocyclic ring containing no heteroatoms, a carbocyclic ring containing heteroatoms, an unsaturated carbocyclic ring, a spirocyclic carbocyclic ring containing NH and oxygen atoms.
Preferably, B is selected from a group of the following formulae:
Figure BDA0003460951360000045
Figure BDA0003460951360000051
further, R1Selected from biphenyl or a group of the formula:
Figure BDA0003460951360000052
preferably, R2Selected from hydrogen, methyl, cyano, trifluoromethyl or halogen.
In some embodiments, a represents a six-membered aromatic ring and the multi-kinase inhibitor has formulas Ia, Ib, Ic and pharmaceutically acceptable salts and solvates thereof:
Figure BDA0003460951360000053
wherein, B, R1And R2As described above, R3Selected from the group consisting of hydrogen, methyl, phenyl and 4-chlorophenyl.
In some embodiments, a represents a six-or five-membered heterocycle, and the multi-kinase inhibitor has the formula Id, Ie, If, Ig:
Figure BDA0003460951360000061
wherein, B, R1、R2And W6As described above.
Further, the structural formula of the multi-kinase inhibitor is shown in one of formulas I-1 to I-90:
Figure BDA0003460951360000062
Figure BDA0003460951360000071
Figure BDA0003460951360000081
Figure BDA0003460951360000091
Figure BDA0003460951360000101
the second purpose of the invention is to disclose a pharmaceutical preparation, which comprises the multi-kinase inhibitor shown in the formula (I), or pharmaceutically acceptable salt, stereoisomer, deuterium-substituted derivative, hydrate or solvate thereof, and other pharmaceutically acceptable carriers.
Further, the pharmaceutical formulation is administered alone or in combination with other therapeutic agents.
A third object of the present invention is to disclose the use of a multi-kinase inhibitor of formula (I), or a pharmaceutically acceptable salt, stereoisomer, deuterium substituted derivative, hydrate or solvate thereof, for the preparation of a medicament for the treatment of a condition which can be ameliorated or prevented by the inhibition of kinase activity or for the inhibition of cell or enzyme proliferation; the kinases comprise one or more of FLT1, FLT3, FLT4, FGFR1-4, VEGFR2/KDR, PDGFRa, PDGFRb, cKit and the like.
In the above application, the method comprises administering a therapeutically effective amount of the pharmaceutical preparation containing the multi-kinase inhibitor shown in the formula (I) to an individual.
Further, the disorder is selected from cancer and/or immune related diseases, preferably one or more of liver cancer, bone marrow cancer, gastrointestinal stromal tumor (GIST), colon cancer, kidney cancer, lung cancer, breast cancer, kidney cancer, glioblastoma and Irritable Bowel Syndrome (IBS).
Further, the drug is administered orally, parenterally, intravenously, or transdermally.
By the scheme, the invention at least has the following advantages:
the invention discloses a multi-kinase inhibitor shown in a formula (I), which can be used for preparing medicines for improving or preventing diseases or inhibiting cell or enzyme proliferation by inhibiting kinase activity and provides a new direction for treating cancers and immune related diseases.
The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a preferred embodiment of the present invention and is described in detail below.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
In the following examples of the present invention, Biotage SP4 was used for column chromatography. Solvent removal was performed using a Buchi rotary evaporator or a Genevac centrifugal evaporator. Preparation of LC/MS A C18 column under acidic mobile phase conditions was run using a Waters autosifier and a 19X 100mm XTerra 5 micron MS. Nuclear magnetic resonance spectroscopy was recorded using a warian 400MHz spectrometer. When the term "inert" is used to describe a reactor (e.g., reaction vessel, flask, glass reactor, etc.), it means that the air in the reactor has been replaced with an inert gas that is substantially free of water or dry (e.g., nitrogen, argon, etc.).
The following examples refer to the following abbreviations in english and the corresponding chinese names:
HATU: 2- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluramino hexafluorophosphate; DPCI: n, N' -diisopropylcarbodiimide; DIEA: n, N-diisopropylethylamine; TEA: triethylamine; DMAP: dimethylaminopyridine; DMF: n, N-dimethylformamide; NMP: n-methylpyrrolidine; THF: tetrahydrofuran; DCM: dichloromethane; TFA: trifluoroacetic acid; DMA: n, N-dimethylacetamide; TLC: thin layer chromatography; TMOF: trimethyl orthoformate; PTSA: p-toluenesulfonic acid; NIS: n-iodosuccinimide; eq: equivalent weight; mmol: millimole; mol: molar ratio; mL: ml; l: lifting; MHz: megahertz; δ: chemical shift; DMSO-d 6: deuterated dimethyl sulfoxide; hrs, hr, h: hours; ms: mass spectrometry; m/z: mass to charge ratio.
The following starting materials or intermediates are commercially available or can be prepared according to known literature procedures:
Figure BDA0003460951360000121
Figure BDA0003460951360000131
the synthetic route for compounds 6a-6j is as follows:
Figure BDA0003460951360000132
wherein, the structural formula of 2a-l is as follows:
Figure BDA0003460951360000133
wherein 2- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) acetic acid (6a) is prepared according to the above scheme as follows:
step 1: adding the compound 2a (6.1g, 34.3mmol) to a mixed solution of the compound 1(5.0g, 22.8mmol) and DMA (60ml) at room temperature, heating the mixture to 145-160 ℃, stirring for 8-10h until the TLC monitoring reaction is completed, cooling the reaction mixture to room temperature, washing the organic phase with water and brine respectively, drying over anhydrous sodium sulfate and evaporating to dryness to obtain a crude product, purifying by silica gel column chromatography to obtain the product 3a (6.51g, yield: 75.6%),
1H NMR(DMSO-d6,400MHz):δ＝9.42(s,1H),8.21(d,1H),7.61(dd,1H),7.30(dd,4H),7.09(d,1H),4.12-4.07(m,2H),3.68(s,2H),1.22-1.18(t,3H)。
step 2: to a solution of compound 3a (6.5g, 17.2mmol), Zn powder (11.2g, 171.2mmol) in ethanol (100mL) at 0 deg.C was added dropwise a mixed solution of AcOH (7.2g, 120.4mmol) in EtOH (8mL) over about 1 hour, the reaction mixture was stirred at 0 deg.C for 3-8 hours, the reaction was monitored by TLC until compound 3a was completely consumed, the reaction mixture was warmed to room temperature, ethyl acetate (10 mL. times.3) was extracted, the organic phase was washed with water and brine, respectively, anhydrous Na2SO4Dried and evaporated to dryness to give crude 4a (5.7g, yield: 95.2%, product 4a was sufficiently pure to be used in the next synthesis step without further purification).
1HNMR(DMSO-d6,400MHz):δ＝7.09(s,1H),7.04-7.02(m,2H),6.91-6.89(m,2H),6.70-6.68(m,2H),6.65-6.63(m,1H),5.04(s,2H),4.08-4.03(m,2H),3.49(s,2H),1.23-1.17(t,3H)。
And step 3: to a mixture of 4a (5.7g, 16.4mmol) and TMOF (13.0g, 122.8mmol) was added PTSA (280 mg, 1.64mmol) at room temperature and stirred at this temperature for 2-5h until TLC monitoring showed complete consumption of compound 4a, evaporated offExcess TMOF and other volatiles, extracted with ethyl acetate (10 ml. times.3), the organic phase washed with water and brine, respectively, anhydrous Na2SO4Dried and evaporated to dryness to give crude 5a (5.9g, yield: 100%, product 5a sufficiently pure to be used in the next synthesis step without further purification).
1H NMR(DMSO-d6,400MHz):δ＝8.01(s,1H),8.00(s,1H),7.51-7.49(m,2H),7.45-7.41(m,4H),4.23-4.17(m,2H),3.72(s,2H),1.29-1.27(t,3H)。
And 4, step 4: to compound 5a (3.0g, 8.38mmol) in MeOH (30ml) at room temperature was added NaOH (1.0g, 25.1mmol) in dropwise fashion in H2O (10ml) solution and stirred for 2-5h until TLC monitoring the reaction showed complete consumption of compound 5 a. The mixture was cooled to room temperature, the pH was adjusted to 1 with 2N Cl, and solid 6a (2.5g, yield: 91.1%) was collected by filtration.
1H NMR(DMSO-d6,400MHz):δ＝8.61(s,1H),7.99(d,J＝2.0Hz,1H),7.63-7.61(m,2H),7.59-7.57(m,1H),7.53-7.48(m,2H),7.47-7.45(m,1H),3.71(s,2H)。
The intermediate 6b-l was prepared according to the same procedure and has the following structural formula:
Figure BDA0003460951360000141
the intermediate 6b-l names and characterization results are shown in table 1:
TABLE 1 intermediates 6b-l
Figure BDA0003460951360000142
Figure BDA0003460951360000151
The synthetic route for compound 8 is as follows:
Figure BDA0003460951360000152
following the above scheme, the specific steps for compounds 8a-8ii are as follows:
mixing compound 6(0.5mmol) with compound 7(0.6mmol, 1.2eq), HATU (0.55mmol, 1.1eq), Et3A mixed solution of N (1.5mmol, 3eq) in THF (10ml) will be stirred at room temperature for 2-5 hours until TLC monitoring of the reaction shows complete consumption of compound 6. The residue obtained by distilling off THF was diluted with ethyl acetate and washed with water and brine, respectively, and the organic phase was washed with anhydrous Na2SO4Drying and evaporating to dryness to obtain crude product, and purifying with silica gel column chromatography (eluting with dichloromethane and methanol) to obtain compound 8 with moderate to good yield (45-85%). The structural formula of the intermediate 8a-8ee is as follows in sequence:
Figure BDA0003460951360000161
Figure BDA0003460951360000171
the names and characterization results for intermediates 8a-8ii are shown in table 2:
TABLE 2 intermediates 8a-8ii
Figure BDA0003460951360000172
Figure BDA0003460951360000181
Figure BDA0003460951360000191
Figure BDA0003460951360000201
The title compounds of examples 1-19 were prepared according to the following suzuki reaction scheme:
Figure BDA0003460951360000202
wherein compounds 9, 10 comprise the following structural formulae:
Figure BDA0003460951360000203
the specific steps of the suzuki reaction are as follows:
under nitrogen protection, compound 8(0.77mmol), boric acid derivative 9 or borate derivative 10(0.93mmol), Pd (dppf) Cl2(28mg，0.039mmol)、Na2CO3(1.2mL, 2.32mmol, 2N aq.) and dioxane (3mL) were stirred at 65-90 deg.C for 6-10 hours until TLC monitoring of the reaction indicated complete consumption of Compound 8, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (15 mL. times.3), the organic phase was washed with water and brine, respectively, anhydrous Na2SO4Drying and evaporating to dryness to obtain crude product, and purifying by preparative thin layer chromatography to obtain medium to good yield. Specifically, the characterization results of each example and the target product are as follows:
EXAMPLE 1 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (isoxazol-5-yl) acetamide (I-1)
The intermediate 8a was used to react with the N-Boc pyrazole borate derivative (10c) to give the desired product. And (3) product characterization results:
MS:m/z:385.1(M+H)+。
EXAMPLE 2 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3-methylisoxazol-5-yl) acetamide (I-2)
The intermediate 8b and the N-Boc pyrazole borate derivative (10c) were used to give the desired product.
MS:m/z:399.2(M+H)+。
EXAMPLE 3 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-3)
The target product was prepared using intermediate 8c and N-methylpyrazole boronic acid (9 b).
MS:m/z:455.2(M+H)+；1H NMR(DMSO-d6,400MHz):δ＝11.87(s,1H),8.53(s,1H),8.17(s,1H),7.97(s,1H),7.92(s,1H),7.68-7.65(m,2H),7.59-7.56(m,4H),6.23(s,1H),3.88(s,3H),3.83(s,2H),1.25(s,9H)；13C NMR(DMSO,100MHz):δ＝172.9,167.9,161.4,145.0,144.0,136.5,135.2,134.9,132.1,131.3,128.1,127.9,123.8,122.8,121.8,116.3,111.4,86.4,42.1,32.4,29.4。
EXAMPLE 4 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (tert-butyl) isoxazol-5-yl) acetamide (I-4)
The intermediate 8c and N-Boc pyrazole borate derivative (10c) were used to prepare the target product.
MS:m/z:441.2(M+H)+；1H NMR(DMSO,400MHz):δ＝12.90(s,1H),11.86(s,1H),8.52(s,1H),8.25(s,1H),8.03(s,1H),7.99(s,1H),7.68-7.65(m,2H),7.59-7.55(m,4H),6.23(s,1H),3.83(s,2H),1.25(s,9H)；13C NMR(DMSO,100MHz):δ＝172.9,167.9,161.4,145.1,144.0,136.7,135.3,134.9,132.0,131.3,128.3,125.7,123.9,122.1,121.9,116.4,111.4,86.4,49.1,42.1,32.4,29.5。
EXAMPLE 5 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3-isopropylisoxazol-5-yl) acetamide (I-5)
The desired product was prepared using intermediate 8d and N-methylpyrazole boronic acid (9 b).
1HNMR(DMSO-d6,400MHz):δ＝11.87(s,1H),8.53(s,1H),8.17(s,1H),7.97(s,1H),7.92(s,1H),7.67-7.65(m,2H),7.58-7.55(m,4H),6.18(s,1H),3.87(s,3H),3.83(s,2H),2.94-2.90(m,1H),1.19(d,6H)；13C NMR(DMSO-d6,100MHz):δ＝170.3,168.0,161.4,144.9,144.0,136.4,135.2,134.9,132.0,131.3,128.0,127.9,127.5,123.8,122.8,121.8,116.6,116.2,111.4,86.6,42.1,26.7,21.7.MS:m/z:441.2(M+H)+。
EXAMPLE 6 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (trifluoromethyl) isoxazol-5-yl) acetamide (I-6)
The intermediate 8e and the N-Boc pyrazole borate derivative (10c) were used to prepare the desired product.
MS:m/z:453.1(M+H)+。
EXAMPLE 7 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3-propylisoxazol-5-yl) acetamide (I-7)
The target product was prepared using intermediate 8f and N-methylpyrazole boronic acid (9 b).
1H NMR(DMSO-d6,400MHz):δ＝11.85(s,1H),8.53(s,1H),8.16(s,1H),7.98(s,1H),7.91(s,1H),7.67-7.65(m,2H),7.59-7.55(m,4H),6.15(s,1H),3.88(s,3H),3.84(s,2H),2.53-2.51(m,2H),1.62-1.59(m,2H),0.91-0.87(t,3H)；13C NMR(DMSO-d6,100MHz):δ＝167.9,165.0,161.4,144.8,144.1,136.5,135.2,134.9,132.0,131.3,128.1,128.0,123.9,122.8,121.8,116.2,111.5,88.1,42.1,28.0,21.3,13.9；MS:m/z:441.2(M+H)+。
EXAMPLE 8 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3-cyclopropylisoxazol-5-yl) acetamide (I-8)
The target product was obtained using intermediate 8g and N-Boc pyrazole borate derivative (10 c).
MS:m/z:425.2(M+H)+。
EXAMPLE 9 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3, 4-dimethylisoxazol-5-yl) acetamide (I-9)
The intermediate 8h and the N-Boc pyrazole borate derivative (10c) were used to prepare the desired product.
MS:m/z:413.2(M+H)+。
EXAMPLE 10 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (4-cyano-3-methylisoxazol-5-yl) acetamide (I-10)
The intermediate 8i and the N-Boc pyrazole borate derivative (10c) were used to give the desired product.
MS:m/z:424.1(M+H)+。
EXAMPLE 11 Synthesis of 2- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3-phenylisoxazol-5-yl) acetamide (I-11)
The intermediate 8j and N-methylpyrazole boronic acid (9b) were used to obtain the desired product.
MS:m/z:475.2(M+H)+；1H NMR(DMSO-d6,400MHz):δ＝12.09(s,1H),8.54(s,1H),8.18(s,1H),7.97(s,1H),7.92(s,1H),7.85-7.84(m,2H),7.69-7.67(m,2H),7.61-7.59(m,3H),7.56-7.54(m,1H),7.51-7.49(m,3H),6.74(s,1H),3.90(s,2H),3.87(s,3H)；13C NMR(DMSO-d6,100MHz):δ＝168.1,163.1,162.5,145.0,144.1,136.5,135.2,134.8,132.0,131.4,130.7,129.5,129.2,128.0,127.9,126.9,123.9,122.8,121.8,116.2,111.5,86.5,42.1。
EXAMPLE 12 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (2-chlorophenyl) isoxazol-5-yl) acetamide (I-12)
The intermediate 8k and N-Boc pyrazole borate derivative (10c) were used to give the desired product.
MS:m/z:495.1(M+H)+。
EXAMPLE 13 Synthesis of N- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (4- (5- (1-methyl-1H-pyrazol) -4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-13)
The desired product was obtained using intermediate 8l and N-methylpyrazole boronic acid (9 b).
EXAMPLE 14 Synthesis of N- (3- (4-fluorophenyl) isoxazol-5-yl) -2- (4- (5- (1-methyl-1H-pyrazol-ol) -4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-14)
This compound was prepared according to general scheme 3 using intermediate 8m and N-methylpyrazole boronic acid (9b) to afford the desired product.
MS:m/z:493.2(M+H)+。
EXAMPLE 15 Synthesis of 2- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (m-tolyl) isoxazol-5-yl) acetamide (I-15)
The intermediate 8N and N-methylpyrazole boronic acid (9b) were used to give the desired product.
MS:m/z:489.2(M+H)+。
EXAMPLE 16 Synthesis of N- (3- (3-methoxyphenyl) isoxazol-5-yl) -2- (4- (5- (1-methyl-1H) -pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-16)
The intermediate 8o and N-methylpyrazole boronic acid (9b) were used to give the desired product.
MS:m/z:505.2(M+H)+。
EXAMPLE 17 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (3- (trifluoromethyl) phenyl) isoxazol-5-yl) acetamide (I-17)
The intermediate 8p and the N-Boc pyrazole borate derivative (10c) were used to give the desired product.
MS:m/z:529.2(M+H)+。
EXAMPLE 18 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (3-bromophenyl) isoxazol-5-yl) acetamide (I-18)
The intermediate 8q and N-Boc pyrazole borate derivative (10c) were used to give the desired product.
MS:m/z:539.1(M+H)+。
EXAMPLE 19 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (pyridin-3-yl) isoxazol-5-yl) acetamide (I-19)
The intermediate 8r and N-Boc pyrazole borate derivative (10c) were used to give the desired product.
MS:m/z:462.2(M+H)+。
EXAMPLE 20 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] [1,2,3] triazol-1-yl) phenyl) acetamide (I-20)
Figure BDA0003460951360000241
Step 1: to a mixture of compound 4a (3.0g, 8.59mmol), HCl (5N, 10ml) and AcOH (10ml) NaNO was slowly added dropwise at-5 ℃ to 0 ℃2(0.89g, 12.9mmol) of H2O (8ml) solution, after the addition was complete, stirring at room temperature was continued for 1-3h until TLC monitoring of the reaction showed complete consumption of compound 4a, the reaction mixture was poured into an ice bath, the system pH was adjusted to 7 with 2N NaOH, and ethyl acetate (2)0 ml. times.3). The organic phase was washed with water and brine, respectively, anhydrous Na2SO4Drying and evaporation to dryness gave compound 11(2.6g, yield: 84%).
1H NMR(DMSO-d6,400MHz):δ＝8.51-8.50(m,1H),7.93-7.91(m,1H),7.85-7.83(m,2H),7.80-7.77(m,1H),7.60-7.58(m,2H),4.15-4.10(m,2H),3.85(s,2H),1.24-1.20(t,3H).
Step 2: under nitrogen protection, compound 11(500mg, 1.39mmol) was reacted with N-methylpyrazole boronic acid (9b) (261mg, 2.09mmol), Pd (dppf) Cl2(51mg，0.069mmol)、Na2CO3(2.1mL, 4.18mmol, 2N aq.) in dioxane (5mL) was stirred at 70-80 deg.C for 2h until TLC monitoring the reaction showed complete consumption of Compound 11, the reaction mixture was cooled to room temperature, ethyl acetate (20 mL. times.3) was extracted, the organic layer was washed with water and brine, anhydrous Na2SO4Drying to dryness to obtain crude product, and purifying by column chromatography to obtain compound 12(451mg, yield: 90%).
1H NMR(DMSO-d6,400MHz):δ＝8.39-8.37(m,1H),8.33(s,1H),8.06(s,1H),7.92-7.90(m,2H),7.88-7.85(m,2H),7.60-7.58(m,2H),4.16-4.11(m,2H),3.90(s,3H),3.85(s,2H),1.24-1.21(t,3H).
And step 3: to compound 12(400mg, 1.11mmol) in MeOH (4ml) and H2NaOH (88mg, 2.22mmol) was added to a mixed solvent of O (1ml), warmed to 80 ℃ and stirred for 2-6h until TLC monitoring the reaction showed complete consumption of compound 6i, the reaction mixture was cooled to room temperature, adjusted to pH 1 with 2N HCl, filtered and collected solid compound 13(245mg, yield: 66%).
1H NMR(DMSO-d6,400MHz):δ＝8.36-8.33(m,2H),8.06(s,1H),7.93-7.90(m,2H),7.86-7.84(m,2H),7.60-7.57(m,2H),3.90(s,3H),3.76(s,2H).
And 4, step 4: compound 13(120mg, 0.36mmol) was reacted with compound 7c (61mg, 0.43mmol), HATU (205mg, 0.54mmol), Et at room temperature3A solution of N (109mg, 1.08mmol) in THF (5ml) was stirred for 1-3h until TLC monitoring showed complete consumption of starting material, THF was evaporated and extracted with ethyl acetate (20 ml. times.3), the organic phase was washed with water and brine, respectively, anhydrous Na2SO4Dried and evaporated to dryness to give crude product, purified by preparative TLC to give the desired product I-20(100 mg).
1H NMR(DMSO-d6,400MHz):δ＝11.31(s,1H),8.34(d,2H),8.05(s,1H),7.91-7.85(m,4H),7.63(d,2H),6.60(s,1H),3.90(s,3H),3.84(s,2H),1.28(s,9H)。
Example 21: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (6- (1-methyl-1H-pyrazol-4-yl) -3H-imidazo [4,5-c ] pyridin-3-yl) phenyl) acetamide (I-21)
Figure BDA0003460951360000251
Intermediate 19 was synthesized according to the method for synthesizing intermediates 6b to 6l, and then the target product was prepared using intermediate 19 and N-methylpyrazole boronic acid (9 b).
MS m/z:456.2(M+H)+。
EXAMPLE 22 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (2- (1-methyl-1H-pyrazol-4-yl) -7H-purin-7-yl) phenyl) acetamide (I-22)
Figure BDA0003460951360000261
Step 1: under nitrogen protection, compound 20(500mg, 2.53mmol), compound 21(750mg, 3.79mmol), Pd2(dba)3(116mg，0.13mmol)，XantPhos(295mg，0.51mmol)，Cs2CO3(2.5g, 7.58mmol) in toluene (5mL) was heated to 65-90 ℃ and stirred for 8-12h until TLC monitoring the reaction showed complete consumption of compound 20, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (30 mL. times.3), the organic phase was washed with water and brine, respectively, anhydrous Na2SO4Drying and evaporation to dryness gave crude product, which was purified on silica gel column to give product 22(415mg, yield: 46%).
Step 2: to compound 22(415mg, 1.15mmol) in MeOH (6ml) and H2To a mixed solution of O (2ml) was added NaOH (92mg, 2.30mmol) and the mixture was stirred at 80 ℃ for 2-6 hours until TLC monitoring of the reactionIndicating complete consumption of compound 22, the mixture was cooled to room temperature, adjusted to pH 1 with 2N HCl, filtered and the solid 23 was collected (320mg, yield: 83%).
And step 3: a mixture of compound 23(300mg, 0.90mmol), compound 7c (152mg, 1.08mmol), HATU (378mg, 0.99mmol), Et3A solution of N (274mg, 2.71mmol) in THF (8mL) was stirred at room temperature for 2-6h until TLC monitoring of the reaction indicated complete consumption of starting material. The THF was evaporated off, extracted with ethyl acetate (20 mL. times.3), the organic phase was washed with water and brine, respectively, anhydrous Na2SO4Dried and evaporated to dryness to give a crude product, which was purified by column chromatography to give 24(318mg, yield: 78%).
And 4, step 4: under nitrogen protection, compound 24(125mg, 0.28mmol), N-methylpyrazole boronic acid (9b) (52mg, 0.41mmol), Pd (dppf) Cl2(40mg，0.055mmol)，Na2CO3(0.3mL, 0.55mmol, 2N aq.) in dioxane (5mL) was stirred at 70-80 ℃ for 3h until TLC monitoring of the reaction indicated complete consumption of compound 24, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (20 mL. times.3), the organic phase was washed with water and brine, respectively, anhydrous Na2SO4Drying and evaporating to dryness to obtain crude product, and purifying by preparative TLC to obtain target product I-22(62mg, yield: 49%)
MS m/z:457.2(M+H)+。
EXAMPLE 23 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (6- (1-methyl-1H-pyrazol-4-yl) pyrazoline [1,5-a ] pyridin-3-yl) phenyl) acetamide (I-23)
Figure BDA0003460951360000271
Step 1: under nitrogen protection, compound 25(500mg, 2.55mmol), N-methylpyrazole boronic acid (9b) (482mg, 3.83mmol), Pd (dppf) Cl2(93mg，0.13mmol)，Na2CO3A solution of dioxane (8mL) (3.8mL, 7.65mmol, 2N aq.) was stirred at 70-80 deg.C for 2h until TLC monitoring of the reaction indicated complete consumption of compound 25, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (20 mL. times.3). The organic phase is respectively watered andwashed with brine and anhydrous Na2SO4Dried and evaporated to dryness to give a crude product, which was purified with silica gel column to give compound 26(320mg, yield: 63%).
Step 2: to a solution of compound 26(300mg, 1.51mmol) in DMF (5mL) was added NIS (375mg, 1.67mmol) and stirred at room temperature for 3-5h until TLC monitoring of the reaction showed complete consumption of compound 26 and extraction with ethyl acetate (20 mL. times.3). The organic phase was washed with water and brine, respectively, anhydrous Na2SO4Dried and evaporated to dryness to give a crude product, which was purified with silica gel column to give compound 27(410mg, yield: 82%).
And step 3: under nitrogen protection, compound 27(410mg, 1.27mmol), compound 28(551mg, 1.89mmol), Pd (dppf) Cl2(46mg，0.063mmol)、Na2CO3(1.9mL, 3.79mmol, 2N aq.) in dioxane (10mL) was stirred at 70-80 ℃ for 4h until TLC monitoring of the reaction showed complete consumption of compound 27, the reaction mixture was cooled to room temperature, ethyl acetate (20 mL. times.3) was extracted, the organic phase was washed with water and brine, respectively, anhydrous Na2SO4Dried and evaporated to dryness to give a crude product, which was purified with silica gel column to give compound 29(330mg, yield: 72%).
And 4, step 4: to mixture 29(330mg, 0.92mmol) in MeOH (4ml) and H2To a mixed solution of O (1ml) was added NaOH (73mg, 1.83mmol) and stirred at 80 ℃ for 2-6 hours until TLC monitoring the reaction showed complete consumption of compound 29, the reaction mixture was cooled to room temperature, adjusted to pH 1 with 2N HCl, filtered and the solid was collected to give compound 30(230mg, yield: 76%).
And 5: a mixture of 30(110mg, 0.33mmol), 7C (55mg, 0.40mmol), HATU (138mg, 0.36mmol) and Et3N (101mg, 0.99mmol) in THF (5mL) was stirred at room temperature for 1-3h until TLC monitoring showed complete consumption of starting material, the solvent THF was evaporated, ethyl acetate (20 mL. times.3) was extracted, the organic layer was washed with water and brine, respectively, anhydrous Na2SO4Drying and evaporating to dryness to obtain crude product, and purifying by preparative TLC to obtain product I-23(75 mg).
MS m/z:455.2(M+H)+。
EXAMPLE 24 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridin-2-yl) acetamide (I-24)
The desired product was obtained according to the method for the synthesis of I-1 using intermediate 8s and N-methylpyrazole boronic acid (9 b).
MS m/z:456.2(M+H)+。
EXAMPLE 25 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyrazin-2-yl) acetamide (I-25)
The desired product was obtained according to the method for synthesizing I-1 using intermediate 8t and N-methylpyrazole boronic acid (9 b).
MS m/z:457.2(M+H)+。
EXAMPLE 26 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (2- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) thiazol-5-yl) acetamide (I-26)
The desired product was obtained according to the method for synthesizing I-1 using intermediate 8u and N-methylpyrazole boronic acid (9 b).
MS m/z:462.2(M+H)+。
EXAMPLE 27 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (2- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) thiazol-4-yl) acetamide (I-27)
The desired product was prepared according to the procedure for the synthesis of I-1, using intermediate 8v and N-methylpyrazole boronic acid (9 b).
MS m/z:462.2(M+H)+。
EXAMPLE 28 Synthesis of 2- (4- (5- (2-oxo-6-azaspiro [3.3] heptane 6-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (tert-butyl) isoxazol-5-yl) acetamide 1H-benzo [ d ] imidazol-1-yl) benzamide (I-28)
Figure BDA0003460951360000281
Under the protection of nitrogen, compound 8c (1.11mmol), amine 31(1.33mmol) and Pd2(dba)3(202mg，0.22mmol)、Xantphos(128mg，0.22mmol)、tBuona (212mg, 2.21mmol) in toluene(5ml) the combined solution was stirred at 65-90 ℃ for 8-12h until TLC monitoring of the reaction showed complete consumption of Compound 8c, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (30 ml. times.3), the organic phase was washed with water and brine, respectively, anhydrous Na2SO4Drying and evaporating to dryness to obtain a crude product, and purifying by preparative TLC to obtain a product. The structure of the compound is shown by1HNMR、13CNMR was performed for characterization.
Compound I-28 was prepared according to the above route, specifically from intermediate 8c and 2-oxa-6-aza-spiro [3, 3]]And (3) preparing heptane. The characterization result is as follows: MS M/z 472.2(M + H)+；1H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.39(s,1H),7.60(d,J＝8.4Hz,2H),7.53(d,2H),7.46(d,J＝8.7Hz,1H),6.75(d,J＝1.8Hz,1H),6.53(dd,1H),6.22(s,1H),4.74(s,4H),3.98(s,4H),3.84–3.75(m,2H),1.24(s,9H).
EXAMPLE 29 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -1- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) cyclopropane-1-carboxamide (I-29)
The desired product was prepared following a similar procedure to that for the synthesis of I-1, using intermediate 8x and N-methylpyrazole boronic acid (9 b).
MS:m/z:481.2(M+H)+。
EXAMPLE 30 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2, 2-difluoro-2- (4- (5- (1-methyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-30)
The desired product was prepared following a similar procedure to that for the synthesis of I-1, using intermediate 8y and N-methylpyrazole boronic acid (9 b).
MS:m/z:491.2(M+H)+。
EXAMPLE 31 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5-morpholin-1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-31)
Following a similar procedure to that for the synthesis of I-28, intermediate 8c and morpholine were used to give the desired product.
MS:m/z:460.2(M+H)+；1H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.45(s,1H),7.63(d,J＝8.3Hz,2H),7.54(d,J＝8.4Hz,2H),7.51(d,J＝9.0Hz,1H),7.25(s,1H),7.10(dd,J＝9.1,2.0Hz,1H),6.22(s,1H) 3.81(s,2H), 3.80-3.72 (m,4H), 3.15-3.07 (m,4H),1.24(s,9H). Example 32N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (piperazin-1-yl) -1H-benzo [ d]Synthesis of imidazol-1-yl) phenyl) acetamide (I-32)
The desired product was obtained in a similar manner to the synthesis of I-28, using intermediate 8c and 1-tert-butoxycarbonylpiperazine. MS M/z 459.2(M + H)+.
EXAMPLE 33 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- ((2-hydroxy-2-methylpropyl) amino) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-33)
The desired product was obtained in a similar manner to that for the synthesis of I-28, using intermediate 8c and 1-amino-2-methylpropan-2-ol.
MS:m/z:462.2(M+H)+。
EXAMPLE 34 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (4-hydroxypiperidin-1-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-34)
The desired product was obtained in analogy to the synthesis of I-28, using intermediate 8c and piperidin-4-ol.
MS:m/z:474.2(M+H)+。
EXAMPLE 35 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (piperidin-1-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-35)
The desired product was prepared following a procedure analogous to that for the synthesis of I-28, using intermediate 8c and piperidine.
MS:m/z:458.2(M+H)+。
EXAMPLE 36 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5-thiomorpholin-1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-36)
The desired product was obtained in a similar manner to that for the synthesis of I-28, using intermediate 8c and thiomorpholine.
MS:m/z:476.5(M+H)+。
EXAMPLE 37 Synthesis of 2- (4- (5- (1, 4-oxazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (tert-butyl) isoxazol-5-yl) acetamide (I-37)
The desired product was obtained following a similar procedure to that for the synthesis of I-28, using intermediate 8c and 1, 4-oxazolidine.
MS:m/z:474.5(M+H)+。
EXAMPLE 38 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (3-hydroxyazetidin-1-yl) -1H-benzo [ d ] -imidazol-1-yl) phenyl) acetamide (I-38)
The desired product was obtained following a similar procedure to that for the synthesis of I-28, using intermediate 8c and azetidin-3-ol. MS M/z 446.5(M + H)+。
EXAMPLE 39 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (3-hydroxypyrrolidin-1-yl) -1H-benzo [ d ] -imidazol-1-yl) phenyl) acetamide (I-39)
The desired product was obtained in a similar manner to that for the synthesis of I-28, using intermediate 8c and pyrrolidin-3-ol. MS M/z 460.2(M + H) +.
EXAMPLE 40 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (4-hydroxy-4-methylpiperidin-1-yl) -1H-benzo [ d ] -imidazol-1-yl) phenyl) acetamide (I-40)
The desired product was obtained in analogy to the synthesis of I-28, using intermediate 8c and 4-methylpiperidin-4-ol.
MS:m/z:488.2(M+H)+。
Example 41: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (N-Boc-3, 6-dihydropyridin-1 (2H) -) -4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-41)
The desired product was obtained by a similar procedure to that for the synthesis of I-1, using intermediate 8c and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (9 d).
MS:m/z:556.3(M+H)+；1H NMR(DMSO-d6,400MHz):δ＝11.86(s,1H),8.54(s,1H),7.80(s,1H),7.66-7.64(m,2H),7.59-7.55(m,4H),7.47-7.45(m,1H),6.22(s,1H),6.18(s,1H),4.04-4.02(m,2H),3.82(s,2H),3.60-3.58(m,2H),2.56-2.54(m,2H),1.44(s,9H),1.24(s,9H)。
EXAMPLE 42 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (1,2,3, 6-tetrahydropyridin) -4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-42)
Figure BDA0003460951360000301
The intermediate I-41 and trifluoroacetic acid were used according to the above route to give the desired product I-42.
MS m/z:456.2(M+H)+；1H NMR(DMSO-d6,400MHz):δ＝11.99(s,1H),9.42(s,1H),8.58(s,1H),7.86(s,1H),7.67-7.63(m,2H),7.61-7.57(m,3H),7.50-7.48(m,1H),6.23-6.22(m,1H),6.21(s,1H),3.85(s,2H),3.76-3.75(m,2H),3.33-3.32(m,2H),2.81-2.79(m,2H),1.24(s,9H).13C NMR(DMSO-d6,100MHz):δ＝172.9,168.0,161.4,144.5,135.2,135.0,134.3,133.2,131.4,123.9,121.3,116.6,111.2,86.4,45.8,42.0,41.9,32.4,29.4,24.0。
EXAMPLE 43 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (piperidin-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-43)
Figure BDA0003460951360000311
Step 1: the I-41 and Pd/C mixture was suspended in methanol and stirred overnight under hydrogen until TLC monitoring of the reaction showed complete consumption of compound I-41, the mixture was filtered through a pad of celite and the filtrate was concentrated to give compound I-41-2H.
MS m/z:558.3(M+H)+；1H NMR(DMSO-d6,400MHz):δ＝11.86(s,1H),8.50(s,1H),7.64-7.61(m,3H),7.57-7.53(m,3H),7.24-7.22(m,1H),6.22(s,1H),4.04-4.02(m,2H),3.82(s,2H),3.59-3.58(m,2H),2.56-2.54(m,2H),1.58-1.55(m,2H),1.44(s,9H),1.24(s,9H).
Step 2: to a solution of I-41-2H in methylene chloride was added CF3COOH, the reaction mixture was stirred at room temperature for 1H until TLC monitoring the reaction showed complete consumption of compound I-41-2H, and saturated NaHCO was used3Adjusting pH to 7, extracting with dichloromethane, washing the organic phase with water and brine, respectively, and extracting with anhydrous Na2SO4Drying and evaporating to obtain a crude product, and purifying by preparative TLC to obtain a compound I-43.
MS m/z:458.2(M+H)+；1H NMR(DMSO-d6,400MHz):δ＝8.52(s,1H),7.65-7.62(m,3H),7.59-7.57(m,4H),7.22-7.20(m,1H),6.06(s,1H),3.95(s,2H),3.39-3.36(m,2H),3.04-2.98(m,3H),2.00-1.89(m,4H),1.19(s,9H)。
Example 44: synthesis of ethyl 2- (4- (1- (4- (2- ((3- (tert-butyl) isoxazol-5-yl) amino) -2-oxoethyl) phenyl) -1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) acetate (I-44)
Figure BDA0003460951360000321
The compounds I-4 and ethyl 2-bromoacetate, K were used according to the above route2CO3Obtaining the target product.1H NMR(DMSO-d6,400MHz):δ＝11.92(s,1H),8.60(s,1H),8.28(s,1H),8.06-8.05(m,2H),7.74-7.72(m,2H),7.69-7.67(m,1H),7.64-7.61(m,3H),6.28(s,1H),5.15(s,2H),4.25-4.21(m,2H),3.88(s,2H),1.31(s,9H),1.30-1.27(t,3H)；13C NMR(100MHz,DMSO-d6)δ172.98,168.66,167.98,161.39,145.04,144.14,137.40,135.22,134.97,132.23,131.33,128.73,127.63,123.92,123.22,121.84,116.39,111.53,86.43,61.57,56.48,55.35,53.21,32.41,29.48,19.01,14.51.MS m/z:527.2(M+H)+。
Example 45: synthesis of tert-butyl 2- (4- (1- (4- (2- ((3- (tert-butyl) isoxazol-5-yl) amino) -2-oxoethyl) phenyl) -1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) acetate (I-45)
Figure BDA0003460951360000322
Using Compound I-4 and t-butyl acetate, K according to the above route2CO3Obtaining a target product I-45.
1H NMR(DMSO-d6,400MHz):δ＝11.28(s,2H),8.53(s,1H),8.21(s,1H),7.99(s,1H),7.67-7.65(m,2H),7.6-7.56(m,4H),6.59(s,1H),4.96(s,2H),3.79(s,2H),1.45(s,9H),1.29(s,9H)；13C NMR(100MHz,DMSO-d6)δ181.00,169.65,167.73,158.40,145.04,144.12,137.26,135.35,135.15,132.22,131.26,128.73,127.70,123.89,123.13,121.82,116.36,111.50,93.59,82.19,56.51,55.34,53.82,42.43,32.97,29.44,28.80,28.17,19.01，MS m/z:555.2(M+H)+。
EXAMPLE 46 Synthesis of 2- (4- (1- (4- (2- ((3- (tert-butyl) isoxazol-5-yl) amino) -2-oxoethyl) phenyl) -1H-benzo [ d ] imidazol-5-yl) -1H-pyrazol-1-yl) acetic acid (I-46)
Compound I-46 is prepared using product I-45 and HCl/EA, or compound I-46 is prepared using product I-44 and LiOH hydrolysis conditions.
1HNMR(DMSO-d6,400MHz):δ＝11.28(s,1H),9.47(s,1H),8.28(s,1H),7.99(s,2H),7.71-7.69(m,4H),7.60-7.58(m,2H),6.52(s,1H),4.94(s,2H),3.78(s,2H),1.21(s,9H)；MS m/z:499.2(M+H)+。
EXAMPLE 47 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (pyrimidin-5-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-47)
Following a similar procedure to that for the synthesis of I-1, intermediate 8c and pyrimidin-5-ylboronic acid (9k) were used to afford the desired product.
MS m/z:453.2(M+H)+。
EXAMPLE 48 Synthesis of N- (3- (tert-butyl) isothiazol-5-yl) -2- (4- (5- (pyrimidin-5-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-48)
Following a similar procedure to that for the synthesis of I-1, intermediate 8z and pyrimidin-5-ylboronic acid (9k) were used to afford the desired product.
MS m/z:469.2(M+H)+。
EXAMPLE 49 Synthesis of N- (3- (tert-butyl) isothiazol-5-yl) -2- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-49)
The desired product was prepared following a similar procedure to that for the synthesis of I-1, using intermediate 8z and (1-methyl-1H-pyrazol-4-yl) boronic acid (9 b).
MS m/z:471.2(M+H)+。
EXAMPLE 50 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (tert-butyl) isothiazol-5-yl) acetamide (I-50)
According to a similar synthesis of I-1Process for the preparation of (5, 3, 2-tetramethyl- [1,3, 5-tetramethyl ] -8 z intermediate]Dioxolan-2-yl) -pyrazole-1-carboxylic acid tert-butyl ester (10c) preparation of the expected product. MS M/z 457.2(M + H)+。
EXAMPLE 51 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3-methylisothiazol-5-yl) acetamide (I-51)
The title product was prepared in analogy to the synthesis of I-1, using intermediate 8aa and tert-butyl (3-4,4,5, 5-tetramethyl- [1,3,2] dioxolan-2-yl) -pyrazole-1-carboxylate (10 c).
MS m/z:415.1(M+H)+,1H NMR(DMSO-d6,400MHz):δ＝12.90(s,1H),12.19(s,1H),8.53(s,1H),8.13(s,1H),8.04(s,1H),7.68-7.66(m,2H),7.60-7.56(m,4H),6.77(s,1H),3.92(s,2H),2.32(s,3H)。
EXAMPLE 52 Synthesis of 2- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3-methylisothiazol-5-yl) acetamide (I-52)
The desired product was prepared following a similar procedure to that for synthesis of I-1, using intermediate 8aa and (1-methyl-1H-pyrazol-4-yl) boronic acid (9 b).
MS m/z:429.1(M+H)+。
EXAMPLE 53 Synthesis of N- (3- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yl) -2- (4- (5- (1-methyl-1H) -pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-53)
The desired product was prepared following a similar procedure to that for the synthesis of I-1, using intermediate 8bb and (1-methyl-1H-pyrazol-4-yl) boronic acid (9 b).
MS m/z:522.2(M+H)+。
EXAMPLE 54 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (4) -chlorophenyl) -1-methyl-1H-pyrazol-5-yl) acetamide (I-54)
The desired product was obtained in analogy to the synthesis of I-1, using intermediate 8bb and tert-butyl (3-4,4,5, 5-tetramethyl- [1,3,2] dioxolan-2-yl) -pyrazole-1-carboxylate (10 c).
MS m/z:508.2(M+H)+。
EXAMPLE 55 Synthesis of 2- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3-methyl-1H-pyrazol-5-yl) acetamide (I-55)
The desired product was prepared following a similar procedure to that for the synthesis of I-1, using intermediate 8cc and (1-methyl-1H-pyrazol-4-yl) boronic acid (9 b).
MS m/z:412.2(M+H)+。
EXAMPLE 56 Synthesis of N- (3- (tert-butyl) -1H-pyrazol-5-yl) -2- (4- (5- (pyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-56)
Following a similar procedure to that for the synthesis of I-1, using intermediate 8dd preparation and pyridin-3-ylboronic acid (9g) gave the desired product.
MS m/z:451.2(M+H)+。
EXAMPLE 57 Synthesis of N- (3- (tert-butyl) -1H-pyrazol-5-yl) -2- (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-57)
Following an analogous procedure to that for the synthesis of I-1, intermediate 8dd was used to prepare and the (1-methyl-1H-pyrazol-4-yl) boronic acid (9b) gave the desired product.
MS m/z:454.2(M+H)+,1H NMR(DMSO-d6,400MHz):δ＝8.54(s,1H),8.20(s,1H),7.98(s,1H),7.92(s,3H),7.67-7.56(m,6H),6.56(s,2H),5.32(s,1H),4.43(s,2H),3.88(s,3H),1.25(s,9H)。
EXAMPLE 58 Synthesis of 2- (4- (5- (1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (tert-butyl) -1-methyl-1H-pyrazol-5-yl) acetamide (I-58)
The desired product is obtained analogously to the synthesis of I-1, using intermediate 8ee and tert-butyl (3-4,4,5, 5-tetramethyl- [1,3,2] dioxolan-2-yl) -pyrazole-1-carboxylate (10 c).
MS m/z:454.2(M+H)+。
EXAMPLE 59 Synthesis of N- (3- (tert-butyl) -1-methyl-1H-pyrazol-5-yl) -2- (4- (5- (1-methyl-1H-pyrazol) -4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-59)
The title product was prepared in analogy to the synthesis of I-1, using intermediate 8ee and (1-methyl-1H-pyrazol-4-yl) boronic acid (9 b).
MS m/z:468.2(M+H)+。
EXAMPLE 60 Synthesis of N- (3- (tert-butyl) -1-methyl-1H-pyrazol-5-yl) -2- (4- (5- (pyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-60)
The desired product was obtained in analogy to the synthesis of I-1, using intermediate 8ee and pyridin-3-ylboronic acid (9 g).
MS m/z:465.2(M+H)+。
Example 61: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (pyridin-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-61)
The desired product was obtained in analogy to the synthesis of I-1, using intermediate 8c and pyridin-4-ylboronic acid (9 e).
MS m/z:452.5(M+H)+。
EXAMPLE 62 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (pyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-62)
Following a similar procedure to that for the synthesis of I-1, intermediate 8c and pyridin-3-ylboronic acid (9g) were used to afford the desired product.
MS m/z:452.5(M+H)+；1H NMR(DMSO-d6,400MHz):δ＝8.97(s,1H),8.63(s,1H),8.57-8.56(m,1H),8.16-8.14(m,2H),7.75-7.68(m,4H),7.60-7.58(m,2H),7.51-7.48(m,1H),6.23(s,1H),3.84(s,2H),1.24(s,9H).13C NMR(DMSO-d6,100MHz):δ＝172.9,167.9,161.3,148.4,148.3,145.0,144.7,136.5,135.1,135.0,134.7,133.5,132.3,131.3,124.3,124.0,123.2,118.7,111.8,86.4,42.1,32.4,29.4。
EXAMPLE 63 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (pyridin-2-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-63)
The desired product was obtained in analogy to the synthesis of I-1, using intermediate 8c and pyridin-2-ylboronic acid (9 f).
MS m/z:452.5(M+H)+。
EXAMPLE 64 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (6-methylpyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-64)
Following a similar procedure to that for the synthesis of I-1, intermediate 8c and (6-methylpyridin-3-yl) boronic acid (9h) were used to give the desired product.
MS m/z:466.2(M+H)+。
EXAMPLE 65 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (6-methoxypyridin-3-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-65)
The desired product was obtained in analogy to the synthesis of I-1, using intermediate 8c and (6-methoxypyridin-3-yl) boronic acid (9I).
MS m/z:482.2(M+H)+。
Example 66: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) thiophen-2-yl) acetamide (I-66)
The desired product was prepared according to a similar procedure to that for the synthesis of I-1, using intermediate 8gg and N-methylpyrazole boronic acid (9 b).
MS m/z:461.2(M+H)+。
Example 67: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (7- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2a ] pyridin-3-yl) phenyl) acetamide (I-67)
Figure BDA0003460951360000361
Compound 33 was synthesized using commercially available 2-amino-4-bromopyridine with ethyl 2- (3- (1-bromo-2-oxoethyl) phenylacetate under the conditions referred to CN104650076 and WO2012007345, and the first and second steps used intermediate 35 prepared by a method analogous to that for synthesizing compound 6 or 8, and then the target product was prepared using intermediate 35 and N-methylpyrazole boronic acid (9b) according to a method analogous to that for synthesizing I-1.
MS m/z:455.2(M+H)+。
Example 68: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5a ] pyrimidin-3-yl) phenyl) acetamide (I-68)
Figure BDA0003460951360000362
Compound 36 was prepared according to the procedure of CN108484608 using commercially available 6-bromo-3-iodo-pyrazolo [1,5-a ] pyrimidine and linalool (4-ethoxycarbonyltolyl) borate as starting materials, then intermediate 38 prepared according to the procedure analogous to the synthesis of compound 6 or 8 was used with compound 36, and then the desired product was prepared according to the procedure analogous to the synthesis of I-1 using intermediate 38 and N-methylpyrazole boronic acid (9 b).
MS m/z:456.2(M+H)+。
Example 69: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (6- (1-methyl-1H-pyrazol-4-yl) pyrazolo [1,5a ] pyrazin-3-yl) phenyl) acetamide (I-69)
Figure BDA0003460951360000371
Compound 39 was prepared using commercially available 2-bromo-5-iodopyrazine and pinacol (4-ethoxycarbonyltolyl) borate as starting materials with reference to the method of WO2008078091, intermediate 41 prepared in the first and second steps using a method similar to that for the synthesis of compound 6 or 8, and then the target product was prepared using intermediate 41 and N-methylpyrazole boronic acid (9b) with reference to a method similar to that for the synthesis of I-1.
MS m/z:456.2(M+H)+。
Example 70: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (7- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2b ] pyridazin-3-yl) phenyl) acetamide (I-70)
The objective product was prepared by a similar method to that of example 68 using commercially available 7-chloro-3-iodoimidazo (1,2-B) pyrazine as a starting material.
MS m/z:456.2(M+H)+。
Example 71: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- ((2- (2-methoxyethoxy) ethyl) (methyl) amino) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-71)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8c and 2- (2-methoxyethoxy) -N-methylethyl-1-amine to give the desired product.
MS m/z:506.3(M+H)+。
Example 72: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- ((3- (dimethylamino) propyl) (methyl) amino) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-72)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8c and N, N, N' -trimethylethylenediamine to give the desired product.
MS m/z:489.3(M+H)+。
Example 73: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- ((3-methoxypropyl) (methyl) amino) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-73)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8c and 3-methoxy-N-methyl-1-propylamine to give the desired product.
MS m/z:476.3(M+H)+。
Example 74: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- ((2-methoxyethyl) (methyl) amino) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-74)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8c and 2-methoxy-N-methylethan-1-amine to give the desired product.
MS m/z:462.2(M+H)+。
Example 75: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- ((2-hydroxyethyl) (methyl) amino) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-75)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8c and 2- (methylamino) ethan-1-ol to give the desired product.
MS m/z:448.2(M+H)+。
Example 76: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) 2- (4- (5- (piperidine-4-acylamino) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-76)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8c and piperidin-4-amine to give the desired product.
MS m/z:473.3(M+H)+。
Example 77: synthesis of 2- (4- (5- (2-azaspiro [3.3] heptan-2-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (tert-butyl) -isoxazol-5-yl) acetamide (I-77)
This compound was prepared in a similar manner to the synthesis of compound I-31 using intermediate 8c and 2-azaspiro [3.3] heptane hydrochloride to afford the desired product.
MS m/z:470.3(M+H)+。
Example 78: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (6-hydroxy-6-methyl-2-azaspiro [3.3] heptan-2-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-78)
This compound was prepared according to a similar method to that for the synthesis of compound I-31, using intermediate 8c and 6-methyl-2-azaspiro [3.3] heptane-6-ol hydrochloride to give the desired product.
MS m/z:500.3(M+H)+。
Example 79: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (2- (3-methoxypropoxy) -ethoxy) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-79)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8c and 2- (3-methoxypropoxy) ethan-1-ol to give the desired product.
MS m/z:507.3(M+H)+。
Example 80: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2-methyl-2 (4- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) propanamide (I-80)
This compound was prepared in a similar manner to the synthesis of compound I-1, using intermediate 8ff and N-methylpyrazole boronic acid (9b) to prepare the desired product.
MS m/z:483.2(M+H)+。
Example 81: (E) synthesis of (E) -N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (3-hydroxypropyl-1-en-1-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-81)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8c and trans-3-hydroxypropylboronic acid pinacol ester to give the desired product.
MS m/z:431.2(M+H)+。
Example 82: synthesis of N- (3 (tert-butyl) isoxazol-5-yl) -2- (4- (5- (3-hydroxypropyl-1-yn-1-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-82)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8c and propynyloxytrimethylsilane to give the desired product.
MS m/z:429.2(M+H)+。
Example 83: synthesis of 2- (4- (5- (2,6 diazaspiro [3.3] heptan-2-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -N- (3- (tert-butyl) isoxazol-5-yl) acetamide (I-83)
This compound was prepared in a similar manner to the synthesis of compound I-31 using intermediate 8c and tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate to afford the desired product.
MS m/z:471.2(M+H)+，1H NMR(DMSO-d6,400MHz):δ＝11.94(s,1H),10.15(s,1H),
8.44(s,1H),7.61-7.59(m,3H),7.55-7.53(m,2H),7.47(d,1H),6.71(s,1H),6.21(s,1H),4.19-4.16(s,4H),4.00-3.98(s,4H),3.82(s,2H),1.24(s,9H)。
Example 84: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (6- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyridazin-3-yl) acetamide (I-84)
This compound was prepared in a similar manner to the synthesis of compound I-1, using intermediate 8hh and N-methylpyrazole boronic acid (9b) to prepare the desired product.
MS m/z:457.2(M+H)+。
Example 85: synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (5- (5- (1-methyl-1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) pyrimidin-2-yl) acetamide (I-85)
This compound was prepared in a similar manner to the synthesis of compound I-1, using intermediate 8ii and N-methylpyrazole boronic acid (9b) to prepare the desired product.
MS m/z:457.2(M+H)+。
Example 86: synthesis of N- (3-isopropylisoxazol-5-yl) -2- (4- (5-morpholinyl-1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-86)
This compound was prepared in a similar manner to the synthesis of compound I-31, using intermediate 8d and morpholine to give the desired product.
1H NMR(400MHz,CDCl3)δ8.37(s,1H),7.99(s,1H),7.45(m,4H),7.39(d,1H),7.31(s,1H),7.01(d,1H),6.23(s,1H),3.88–3.82(m,4H),3.80(s,2H),3.16–3.08(m,4H),2.93(m,1H),1.20(d,6H)。MS m/z:446.4(M+H)+。
Example 87N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (1- (methyl-d)3) -1H-pyrazol-4-yl) -1H-benzo [ d]Synthesis of imidazol-1-yl) phenyl) acetamide (I-87)
Using intermediates 8c and N- (methyl-d)3) Pyrazole boronic acid (9l) prepared the desired product.
MS:m/z:458.2(M+H)+。
EXAMPLE 88 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (1- (fluoromethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-88)
The target product was prepared using intermediate 8c and N- (fluoromethyl) pyrazole boronic acid (9 m).
MS:m/z:473.2(M+H)+。
EXAMPLE 89 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (1- (difluoromethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-89)
The target product was prepared using intermediate 8c and N- (difluoromethyl) pyrazole boronic acid (9N).
MS:m/z:491.2(M+H)+。
EXAMPLE 90 Synthesis of N- (3- (tert-butyl) isoxazol-5-yl) -2- (4- (5- (1- (trifluoromethyl) -1H-pyrazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) phenyl) acetamide (I-90)
The target product was prepared using intermediate 8c and N- (trifluoromethyl) pyrazole boronic acid (9 o).
MS:m/z:509.2(M+H)+。
Example 91: study of biological Activity
The in vitro inhibitory activity of some compounds of the invention against 4 enzymes was determined using the mobility transfer method, as follows:
kinase buffer was prepared at 1-fold concentration. Compounds were serially diluted in 3-fold gradients with dimethyl sulfoxide for a total of 10 concentrations. The final concentrations tested for compounds were 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.45, 0.15, 0.05nM, respectively.
The control was serially diluted with a 3-fold gradient of 10 concentrations of dimethyl maple. The final concentrations tested for compounds were 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.45, 0.15, 0.05nM, respectively.
Using a dispenser Echo550 to 384 microporous transfer 250nL100 times the final concentration of the test compounds. A kinase solution with a final concentration of 2.5 times was prepared by diluting with a kinase buffer solution with a concentration of 1 time. Mu.l of a 2.5 fold final concentration kinase solution was added to 384 microwell plates. mu.L of 1-fold concentration kinase buffer was added to the negative control wells. The enzyme and test compound were pre-incubated for 10 minutes at room temperature. A mixed solution of ATP and substrate at a final concentration of 5/3 times was prepared using 1-fold kinase buffer. mu.L of a mixed solution of ATP and substrate at 5/3-fold final concentration was added to a 384-well plate and reacted at room temperature. The reaction was stopped by adding 30. mu.L of stop buffer.
The conversion was read using Caliper EZReader II. The data analysis method is as follows:
(1) % Inh ═ 100 (max signal-composite signal)/(max signal-min signal).
(2) In the absence of compound, the maximum signal was obtained.
(3) Minimal signal was obtained in the absence of enzyme.
Table 3 lists the IC's of several test compounds against several kinases50The value is obtained.
TABLE 3 results of in vitro kinase inhibition assay (unit: nM) with different compounds
Figure BDA0003460951360000411
The protocol for the in vitro inhibitory activity test of some compounds of the invention on 5 cells is as follows:
(1) day 0: bed plate
Cells were digested with 0.25% trypsin and resuspended cells were counted in an automatic cell counter. The cell suspension was diluted to the desired density according to seeding density. Add 100. mu.L of cells to each well at 37 ℃ with 5% CO2The culture was carried out overnight.
(2) Preparation of Day 1 Compound
The compound is prepared into 200 times final solution by dimethyl sulfoxide, and the compound is subjected to 3 times gradient serial dilution by dimethyl sulfoxide to total 10 concentrations. Final assay final concentrations of compound were 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.45, 0.15, 0.05nM, respectively. mu.L of 200-fold final solution was added to 197. mu.L of the medium to prepare a 3-fold final solution. 50 μ L of 3 fold final solution was added to the well plate, incubated at 37 ℃ with 5% CO2 for 72 hours.
(3) Day 4 detection
The test well plate was equilibrated to room temperature. Add 40. mu.L of CellTiter-Glo reagent to each well, shake for 2 minutes, and incubate at room temperature for 60 minutes. Detection was by Envision.
Data analysis
(1) IC calculation Using GraphPad Prism 550。
(2) % Inh ═ (max-compound number)/(max-min) × 100.
(3) Maximum is no compound added but DMSO alone.
(4) The minimum is to add medium only to the entire well plate.
TABLE 4 in vitro inhibition test results (unit: nM) of different compounds on hepatoma cell lines
Figure BDA0003460951360000421
TABLE 5 in vitro inhibition test results (unit: nM) of different compounds on colorectal cancer cell lines
Compound (I) HT-29 HCT116
I-3 3533 2625
I-4 4400 3222
Sorafenib 5352 4433
Cabozantinib 5835 7262
Pz-1 5725 6067
TABLE 6 in vitro inhibition test results (unit: nM) of different compounds on lung cancer cell lines
Compound (I) NCIH1581
I-3 144.8
I-4 174.4
I-87 114.2
I-89 232.8
Sorafenib 1910.4
Lenvatinib 752.1
Pz-1 380.3
TABLE 7 results of in vitro inhibition assay for gastric cancer cell lines with different compounds (unit: nM)
Compound (I) KATOШ SNU16
I-3 11.6 14.4
I-4 18.3 23.9
I-87 10.2 18.0
I-89 19.5 29.6
Sorafenib 704.6 883.1
Lenvatinib 124.8 174.9
Pz-1 38.8 70.9
Rat in vivo DMPK study
The purpose of the test is as follows: male SD rats were used as test animals, and the compound blood concentration was measured and pharmacokinetic behavior was evaluated after a single administration.
And (3) test operation: selecting 3 healthy adult male SD rats as an intravenous injection group, wherein the solvent of the intravenous injection group is 5% DMSO + 5% solutol + 90% saline; . Weighing a proper amount of compound, adding 5% DMSO with a corresponding volume to dissolve the compound, then adding 5% solutol and 90% saline with a corresponding volume to mix uniformly, and dissolving the mixture by vortex shaking to prepare a clear solution of 0.1 mg/mL. After 1mg/kg of rat is administrated by intravenous injection, whole blood is collected for a certain time to prepare plasma, the concentration of the original drug in the plasma is detected by an LC-MS/MS method, relevant pharmacokinetic parameters are calculated by WinNonlin software, and test results are shown in the following table.
TABLE 8 pharmacokinetic parameters given to rats at 1mg/kg by intravenous injection
Figure BDA0003460951360000431
Figure BDA0003460951360000441
Description of the drawings: pz-1 data was derived from Bredan Frett, France sca Carlogno, Angew. chem. int. Ed.2015,54, 8717-.
Healthy adult male SD rats 3 are selected as oral groups, and the solvents of the oral groups are 5% DMSO + 5% solutol + 90% saline; . Weighing a proper amount of compound, adding 5% DMSO with a corresponding volume to dissolve the compound, then adding 5% solutol and 90% saline with a corresponding volume to mix uniformly, and dissolving the mixture by vortex shaking to prepare a 1mg/mL clear solution. After 10mg/kg of oral administration of rats, whole blood is collected for a certain period of time to prepare plasma, the concentration of the original drug in the plasma is detected by an LC-MS/MS method, relevant pharmacokinetic parameters are calculated by WinNonlin software, and test results are shown in the following table.
TABLE 9 pharmacokinetic parameters for gavage in SD rats (n ═ 3, male)
Figure BDA0003460951360000442
Description of the drawings: pz-1 data was derived from Bredan Frett, France sca Carlogno, Angew. chem. int. Ed.2015,54, 8717-.
Compared with the compound Pz-1, the exposure of the compound I-87 and the compound I-89 in intravenous injection and oral administration is greatly improved, wherein the half-life period of the compound I-89 is obviously prolonged, and the compound I-89 has better pharmacokinetic property.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A multi-kinase inhibitor having a structural formula as shown in formula I:
Figure FDA0003460951350000011
wherein:
a is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and the substituent on the substituted aryl or substituted heteroaryl is selected from substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C1-10One or more of alkoxy, halogen and nitrile group;
b is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a group of formula (II), substituted or unsubstituted saturated or unsaturated C3-10Cycloalkyl or a heteroatom substituted or unsubstituted 4-7 membered cyclic amine; wherein the content of the first and second substances,
the substituents on the substituted aryl or substituted heteroaryl are selected from C1-10Alkyl radical, C1-10One or more of alkoxy, carboxyl, ester group, sulfone group and sulfonamide group; wherein the hydrogen in the alkyl group may be substituted with one or more deuterium atoms and the hydrogen in the alkyl group may be substituted with one or more fluorine atoms;
the group of formula (II) is as follows:
Figure FDA0003460951350000012
wherein R is3And R4Each independently selected from hydrogen and C1-10Alkyl radical, C1-10Alkoxy radical, C1-10Alkylamino radical or C1-6A hydroxyalkyl group;
or R3And R4Linked to form a ring to form a substituted C3-10Cycloalkyl, said substituted C3-10Cycloalkyl includes heteroatom-substituted cycloalkyl or a spiro carbocyclic ring containing NH and/or oxygen atoms;
4-7 membered cyclic amine substituted or unsubstituted by hetero atom is chiral molecule or achiral molecule;
R1selected from hydrogen, substituted or unsubstituted C1-10An alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; the substituents on the substituted aryl or substituted heteroaryl groups are selected from substituted or unsubstituted C1-10Alkyl, substituted or unsubstituted C1-10One or more of alkoxy, halogen and halogen;
R2selected from hydrogen, C1-3Alkyl, cyano, C1-3Fluoroalkyl or halogen;
W1、W2、W3、W4、W5、W6and W7Is C, CH or N satisfying the valence state, and at least W1、W2、W3、W4、W5、W6And W7One of them is N;
W8o, S, NH or NMe;
y is selected from a group of the following structural formula:
Figure FDA0003460951350000021
2. the multi-kinase inhibitor of claim 1, wherein: in the A or B group, the aryl group is C6-C9Aryl, heteroaryl including C with nitrogen and/or sulfur as hetero atoms4-C6A heteroaryl group.
3. The multi-kinase inhibitor of claim 1, wherein: a is selected from a group of the following structural formula:
Figure FDA0003460951350000022
4. the multi-kinase inhibitor of claim 1, wherein B is selected from a group of formulae:
Figure FDA0003460951350000023
Figure FDA0003460951350000031
5. the multi-kinase inhibitor of claim 1, wherein R is1Selected from a group of the following structural formulae:
Figure FDA0003460951350000032
6. the multi-kinase inhibitor of claim 1, having a formula as shown in one of formulas I-1 to I-90:
Figure FDA0003460951350000041
Figure FDA0003460951350000051
Figure FDA0003460951350000061
Figure FDA0003460951350000071
Figure FDA0003460951350000081
7. a pharmaceutical formulation characterized by: comprising the multi-kinase inhibitor of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, deuterium-substituted derivative, hydrate or solvate thereof.
8. Use of a multi-kinase inhibitor of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, deuterium-substituted derivative, hydrate or solvate thereof, in the manufacture of a medicament for treating a condition that can be ameliorated or prevented by inhibition of kinase activity or inhibiting proliferation of a cell or enzyme; the kinases include one or more of FLT1, FLT3, FLT4, FGFR1-4, VEGFR2/KDR, PDGFRa, PDGFRb and cKit kinases.
9. Use according to claim 8, wherein the condition is selected from cancer and/or immune-related diseases.
10. The use according to claim 8, wherein the medicament is administered orally, parenterally, intravenously or transdermally.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101128461A (en) * 2005-02-24 2008-02-20 伊莱利利公司 Imidazo (1, 2-a) pyridine compounds as VEGF-R2 inhibitors
CN107074778A (en) * 2014-06-03 2017-08-18 代表亚利桑那大学的亚利桑那校董会 Benzimidazole analogues and correlation technique
CN112552302A (en) * 2019-09-26 2021-03-26 深圳市塔吉瑞生物医药有限公司 Substituted aromatic fused ring derivatives, compositions and uses thereof
CN112778294A (en) * 2021-01-07 2021-05-11 苏州安睿药业有限公司 5-aminoisoxazole derivative and application thereof in preparation of multi-kinase inhibitor

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0507575D0 (en) * 2005-04-14 2005-05-18 Novartis Ag Organic compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101128461A (en) * 2005-02-24 2008-02-20 伊莱利利公司 Imidazo (1, 2-a) pyridine compounds as VEGF-R2 inhibitors
CN107074778A (en) * 2014-06-03 2017-08-18 代表亚利桑那大学的亚利桑那校董会 Benzimidazole analogues and correlation technique
CN112552302A (en) * 2019-09-26 2021-03-26 深圳市塔吉瑞生物医药有限公司 Substituted aromatic fused ring derivatives, compositions and uses thereof
CN112778294A (en) * 2021-01-07 2021-05-11 苏州安睿药业有限公司 5-aminoisoxazole derivative and application thereof in preparation of multi-kinase inhibitor
CN113321645A (en) * 2021-01-07 2021-08-31 苏州安睿药业有限公司 5-aminoisoxazole derivative and application thereof in preparation of multi-kinase inhibitor

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRENDAN FRETT ET AL.: "Fragment-Based Discovery of aDual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology", 《ANGEW.CHEM. INT.ED.》, vol. 54, pages 8717 - 8721, XP055949700, DOI: 10.1002/anie.201501104 *
MARIALUISA MOCCIA ET AL.: "Bioisosteric Discovery of NPA101.3, a Second-Generation RET/VEGFR2 Inhibitor Optimized for Single-Agent Polypharmacology", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 63, pages 4506 - 4516, XP055949695, DOI: 10.1021/acs.jmedchem.9b01336 *

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