CN113773273B - Benzisothiazole compound, preparation method and application thereof - Google Patents
Benzisothiazole compound, preparation method and application thereof Download PDFInfo
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- CN113773273B CN113773273B CN202111082474.1A CN202111082474A CN113773273B CN 113773273 B CN113773273 B CN 113773273B CN 202111082474 A CN202111082474 A CN 202111082474A CN 113773273 B CN113773273 B CN 113773273B
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- China
- Prior art keywords
- alkyl
- amino
- isothiazol
- reaction
- ethyl acetate
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- -1 Benzisothiazole compound Chemical class 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 230000004850 protein–protein interaction Effects 0.000 claims abstract description 17
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 239000003112 inhibitor Substances 0.000 claims abstract description 13
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 230000009385 viral infection Effects 0.000 claims abstract description 3
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract 5
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 176
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 208000035473 Communicable disease Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000019491 signal transduction Effects 0.000 claims description 5
- 208000018359 Systemic autoimmune disease Diseases 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
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- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000001204 Hashimoto Disease Diseases 0.000 claims description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 2
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 206010020850 Hyperthyroidism Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
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- 206010036105 Polyneuropathy Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000004732 Systemic Vasculitis Diseases 0.000 claims description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 206010047115 Vasculitis Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
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- 102100040678 Programmed cell death protein 1 Human genes 0.000 abstract description 32
- 101710089372 Programmed cell death protein 1 Proteins 0.000 abstract description 32
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- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 abstract 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 abstract 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 300
- 238000006243 chemical reaction Methods 0.000 description 168
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- 125000001793 isothiazol-3-yl group Chemical group [H]C1=C([H])C(*)=NS1 0.000 description 118
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 106
- 239000002904 solvent Substances 0.000 description 99
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 86
- 125000005605 benzo group Chemical group 0.000 description 75
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 74
- 230000002829 reductive effect Effects 0.000 description 73
- 239000007787 solid Substances 0.000 description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 57
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 54
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 53
- 238000004821 distillation Methods 0.000 description 51
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 50
- 238000000967 suction filtration Methods 0.000 description 43
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 38
- 238000000746 purification Methods 0.000 description 37
- 239000010410 layer Substances 0.000 description 35
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 229910052757 nitrogen Inorganic materials 0.000 description 27
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
- 239000002994 raw material Substances 0.000 description 25
- 238000000605 extraction Methods 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000000926 separation method Methods 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
- 239000012065 filter cake Substances 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- IYCKMNAVTMOAKD-UHFFFAOYSA-N 1,2-thiazol-3-amine Chemical class NC=1C=CSN=1 IYCKMNAVTMOAKD-UHFFFAOYSA-N 0.000 description 16
- WIJQCPIRWXSWQG-UHFFFAOYSA-N 1,2-benzothiazol-3-amine Chemical compound C1=CC=C2C(N)=NSC2=C1 WIJQCPIRWXSWQG-UHFFFAOYSA-N 0.000 description 14
- 238000010009 beating Methods 0.000 description 14
- 238000012746 preparative thin layer chromatography Methods 0.000 description 14
- 239000011734 sodium Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 150000003384 small molecules Chemical class 0.000 description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000005489 Bromoxynil Substances 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical class C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
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- LDYVDYZLCRUOTM-UHFFFAOYSA-N 4-bromo-3-chlorobenzaldehyde Chemical compound ClC1=CC(C=O)=CC=C1Br LDYVDYZLCRUOTM-UHFFFAOYSA-N 0.000 description 6
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a benzisothiazole compound with a structure shown in a general formula I and a three-dimensional structure thereofIsomers, tautomers, racemates, metabolites, metabolic precursors, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof, and preparation methods and uses thereof in preparing PD-1/PD-L1 protein-protein interaction inhibitors. In vitro activity test results show that the compound has an obvious inhibition effect on the interaction of PD-1/PD-L1 protein-protein, and can be used as an immune checkpoint inhibitor for immunotherapy of cancers and treatment of various diseases such as autoimmune diseases, virus infection and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a benzisothiazole compound, a stereoisomer, a tautomer, a racemate, a metabolite, a metabolic precursor, a prodrug, a hydrate, a solvate or a pharmaceutically acceptable salt thereof, a preparation method thereof and application thereof in preparing a PD-1/PD-L1 protein-protein interaction inhibitor.
Background
In recent years, the incidence of cancer and the mortality rate have rapidly increased worldwide, which are one of the leading causes of human death. With the progress of research, immune checkpoint blockade therapy has been considered as a promising cancer treatment strategy, where inhibition of the PD-1/PD-L1 signaling pathway has become one of the major advances in cancer immunotherapy.
Programmed cell death protein1 (PD-1) and a ligand PD-L1 (Programmed cell death-ligand 1) thereof are transmembrane immune checkpoint proteins and are mainly expressed on various immune cells; wherein PD-1 is expressed on activated T cells, B cells, natural killer cells and the like, and PD-L1 is expressed on T cells, B cells, macrophages, dendritic cells, tumor cells and the like. PD-1 is a type I transmembrane protein consisting of 288 amino acid residues and encoded by a gene PDCD1, and the structure of the protein comprises four parts: extracellular immunoglobulin variable domains (igvs), hydrophobic transmembrane domains, intracellular Immunoreceptor Tyrosine Inhibition Motifs (ITIMs) and Immunoreceptor Tyrosine Switch Motifs (ITSMs). PD-L1 is a type I transmembrane protein consisting of 290 amino acid residues and encoded by the CD274 gene, and its extracellular structure consists of an immunoglobulin variable region (IgV) and an immunoglobulin stable region (IgC).
The PD-1/PD-L1 immune checkpoint pathway plays an important role in maintaining self tolerance, controlling excessive immune response, preventing autoimmune diseases and the like. Tumor cells can evade immune surveillance and destroy the cytotoxic capacity of immune cells by increasing the expression of PD-L1, and nearly 30% of solid and hematological tumors, including melanoma, non-small cell lung cancer and renal cancer, are now found with up-regulated PD-L1 expression. PD-L1 on the tumor cell is combined with PD-1 on the T cell, thus weakening the proliferation and the function of the T cell and improving the survival capability of the tumor cell in a host body. Blocking the PD-1/PD-L1 protein-protein interaction restores the antitumor activity of tumor specific T lymphocytes, reverses immunosuppression, leads to tumor shrinkage and prolongs the survival time of tumor patients. Therefore, the development of monoclonal antibodies and/or small molecule inhibitors directed against the PD-1/PD-L1 protein-protein interaction is an attractive cancer immunotherapy strategy.
To date, six monoclonal antibodies have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of PD-1/PD-L1-associated cancers, with nivolumab (nivolumab), pembrolizumab (pembrolizumab) and cimiciprizumab (cemipimab) targeting PD-1, and avilumab (avelumab), atelizumab (atezolizumab) and Durvalizumab (durvalumab) targeting PD-L1. In addition, monoclonal antibodies targeting PD-1, which were developed by Henry medicine, xinda, baiji Shenzhou, etc., have been marketed domestically and used for the treatment of non-small cell lung cancer.
Despite the great success of these antibody drugs in cancer therapy, there are still some disadvantages including poor bioavailability, severe toxic side effects due to immunogenicity, and high treatment costs. To overcome the above disadvantages, some researchers have been devoted to research and development of small molecule inhibitors against the PD-1/PD-L1 protein-protein interaction. Compared with antibody drugs, the small molecule inhibitor has the advantages of better bioavailability, more controllable adverse reaction, low treatment cost and the like. Therefore, it is a feasible approach to develop small molecule inhibitors against the PD-1/PD-L1 protein-protein interaction for immunotherapy of cancer.
At present, the development of the PD-1/PD-L1 protein-protein interaction small-molecule inhibitor is in AN early stage, no small-molecule inhibitor medicament is on the market, most of the small-molecule inhibitors are still in preclinical research, and only a few small-molecule inhibitors enter clinical research, such as CA-170 of Curis corporation, AN4005 of Ano medicine and MAX-10181 of Re-polar medicine. Therefore, the development of a novel PD-1/PD-L1 protein-protein interaction small molecule inhibitor with good anti-tumor activity has great significance.
Disclosure of Invention
The inventor designs and synthesizes a series of novel benzisothiazole compounds on the basis of the prior literature report. The activity research result shows that the compound can obviously inhibit the PD-1/PD-L1 protein-protein interaction.
The invention relates to benzisothiazole compounds shown as a general formula I, and stereoisomers, tautomers, racemates, metabolites, metabolic precursors, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof,
wherein,
ring A is selected from unsubstituted or substituted by 1-3R 1 A substituted phenyl group, which is substituted,
R 1 independently selected from halogen, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, cyano, hydroxy, carboxy or amino;
ring B is selected from:
wherein Y is 1 、Y 2 、Y 3 And Y 4 Independently CH or N;
R 2 and R 3 Each independently selected from hydrogen, (C) 1 -C 4 ) Alkyl, methoxy (C) 1 -C 4 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, hydroxy (C) 1 -C 4 ) Alkyl, amino (C) 1 -C 4 ) Alkyl, carbamoyl (C) 1 -C 4 ) Alkyl, carboxyl (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxycarbonyl (C) 1 -C 4 ) Alkyl, tetrahydropyran-4-yl, oxetan-3-yl, morpholin-4- (C) 1 -C 4 ) Alkyl or N-methylpiperazine-4- (C) 1 -C 4 ) An alkyl group;
said (C) 1 -C 4 ) Alkyl, methoxy (C) 1 -C 4 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, hydroxy (C) 1 -C 4 ) Alkyl, amino (C) 1 -C 4 ) Alkyl, carbamoyl (C) 1 -C 4 ) Alkyl, carboxyl (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxycarbonyl (C) 1 -C 4 ) Alkyl, tetrahydropyran-4-yl, oxetan-3-yl, morpholin-4- (C) 1 -C 4 ) Alkyl, N-methylpiperazine-4- (C) 1 -C 4 ) Alkyl is optionally substituted with 1-3R 8 Substitution;
or R 2 、R 3 And together with the nitrogen atom to which they are attached form a 3-7 membered nitrogen containing heterocyclic ring;
said nitrogen-containing heterocycle being optionally substituted with 1-3R 9 Substitution;
R 4 、R 5 、R 6 and R 7 Each independently selected from hydrogen, halogen, hydroxyl and (C) 1 -C 4 ) Alkyl or (C) 1 -C 4 ) An alkoxy group;
R 8 independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C) 1 -C 4 ) Alkyl, hydroxy (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy (C) 1 -C 4 ) Alkyl, carboxyl (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxycarbonyl (C) 1 -C 4 ) Alkyl or (C) 1 -C 4 ) An acyl group;
R 9 independently selected from hydrogen, hydroxyl, carboxyl, amino and (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy group, (C) 1 -C 4 ) Alcoxyl formyl group and hydroxyl group (C) 1 -C 4 ) Alkyl or amino (C) 1 -C 4 ) An alkyl group.
The invention preferably relates to benzisothiazole compounds shown in the general formula I, stereoisomers, tautomers, racemates, metabolites, metabolic precursors, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof,
wherein,
ring A is selected from phenyl which is unsubstituted or substituted by 1-3 halogen, methyl and methoxy,
ring B is selected from
Wherein,
Y 1 、Y 2 、Y 3 and Y 4 Each independently selected from CH or N;
R 4 、R 5 、R 6 and R 7 Each independently selected from hydrogen, halogen, hydroxy, methyl or methoxy;
preferably, the benzisothiazole compounds represented by the general formula I of the present invention, stereoisomers, tautomers, racemates, metabolites, metabolic precursors, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof are selected from the following compounds, but these compounds are not meant to limit the present invention in any way:
in addition, the present invention also includes prodrugs of the compounds of the present invention. Prodrugs of the compounds of the invention are derivatives of formula i, which themselves may have a weak or even no activity, but which, after administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) into the corresponding biologically active form.
As used herein, the "pharmaceutically acceptable salts" include salts with inorganic acids, organic acids, alkali metal ions; the inorganic acid is selected from: hydrochloric, hydrobromic, hydrofluoric, sulfuric or phosphoric acids; the organic acid is selected from: succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, or p-toluenesulfonic acid; the alkali metal ions are selected from lithium ions, sodium ions or potassium ions.
"halogen" in the present invention means fluorine, chlorine, bromine or iodine; "alkyl" refers to straight or branched chain alkyl; "Nitrogen-containing heterocycle" refers to a monocyclic or polycyclic ring system containing a nitrogen atom, the ring system being non-aromatic or aromatic.
The invention can include benzisothiazole compounds shown in the general formula I, stereoisomers, tautomers, racemates, metabolites, metabolic precursors, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof as active ingredients, and the active ingredients are mixed with pharmaceutically acceptable auxiliary materials to prepare the composition. The pharmaceutically acceptable excipients include diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like which are well known in the art. Diluents include, but are not limited to, starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, dibasic calcium phosphate, and the like; the humectant includes water, ethanol, isopropanol, etc.; binders include, but are not limited to, starch syrup, dextrin, syrup, honey, dextrose solution, acacia syrup, gelatin syrup, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyethylene glycol, and the like; disintegrants include, but are not limited to, dry starch, microcrystalline cellulose, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, sodium lauryl sulfate, and the like; lubricants and glidants include, but are not limited to, talc, silicon dioxide, polyethylene glycol, and the like.
The pharmaceutical composition of the present invention can be formulated into several dosage forms including, but not limited to, injections, tablets, capsules, and the like.
The benzisothiazole compound shown in the general formula I, and the stereoisomer, the tautomer, the racemate, the metabolite, the metabolic precursor, the prodrug, the hydrate, the solvate or the pharmaceutically acceptable salt thereof can be combined with other active ingredients for use, so that a better treatment effect is achieved.
The invention also provides an application of the benzisothiazole compound shown in the general formula I, and a stereoisomer, a tautomer, a racemate, a metabolite, a metabolic precursor, a prodrug, a hydrate, a solvate or pharmaceutically acceptable salt thereof in preparing a PD-1/PD-L1 protein-protein interaction inhibitor.
The invention also provides application of the benzisothiazole compound shown in the general formula I, and a stereoisomer, a tautomer, a racemate, a metabolite, a metabolic precursor, a prodrug, a hydrate, a solvate or pharmaceutically acceptable salt thereof in preparing medicines for treating diseases related to the PD-1/PD-L1 signal channel.
The disease related to the PD-1/PD-L1 signal pathway is selected from cancer, autoimmune disease or disease infectious disease. The cancer is selected from lung cancer, skin cancer, hematological tumor, glioma, digestive system tumor, breast cancer, lymphoma, nervous system tumor, melanoma; the autoimmune disease is selected from organ-specific autoimmune disease or systemic autoimmune disease; the infectious disease is selected from bacterial infection or viral infection. Wherein the organ-specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, ulcerative colitis, or acute idiopathic polyneuritis, and the systemic autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, or autoimmune hemolytic anemia.
The following synthetic schemes outline and describe the preparation of the benzisothiazole compounds of formula i of the present invention, all starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All final derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry.
The synthesis route is as follows:
(a) 2-fluoro-3-bromoxynil (R-1) is taken as an initial raw material and undergoes Suzuki coupling reaction with benzene, substituted benzene or heteroaromatic boric acid or boric acid ester to obtain an intermediate R-2.
(b) Taking an intermediate R-2 as a raw material, and sequentially reacting with Na 2 S·9H 2 O, naOH solution, NH 3 ·H 2 O and NaClO solution, through intramolecularCyclization gives the intermediate R-3.
(c) Taking the intermediate R-3 as a raw material, and carrying out Buchwald-Hartwig coupling reaction with benzene, substituted benzene or heteroaromatic ring formaldehyde to obtain intermediates R-4 and R-5.
(d) Taking the intermediates R-4 and R-5 as raw materials, carrying out condensation reaction with amine compounds, and then reducing by sodium borohydride or cyano sodium borohydride to obtain target products R-6 and R-7.
(e) Taking the intermediates R-4 and R-5 as raw materials, carrying out condensation reaction with amine compounds, reducing by sodium borohydride or sodium cyanoborohydride to obtain an esterified intermediate, and then carrying out hydrolysis reaction with lithium hydroxide to finally obtain target products R-6 and R-7.
In the above route, the ring A, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、Y 1 、Y 2 、Y 3 And Y 4 Is as defined in the claims. The benzisothiazole compound with the general formula I can be prepared according to the reaction route.
Compared with the prior art, the invention has the following beneficial effects:
the benzisothiazole compound has a novel chemical structure, has high inhibitory activity on PD-1/PD-L1 protein-protein interaction in-vitro research, and can be used for treating various diseases such as cancer, autoimmune diseases or infectious diseases.
Detailed Description
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.
In the following examples, methods of preparing some of the compounds are depicted. It is to be understood that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described herein. The examples are intended to illustrate, but not to limit, the scope of the invention.
The examples do not specify particular techniques or conditions, and are to be construed in accordance with the description of the art in the literature or with the specification of the product. The reagents or instruments used are conventional products which are not indicated by manufacturers and are available from normal sources.
The experimental procedures in the following examples are all conventional ones unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.
Example 1:2- ((4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 2-fluoro- [1,1' -biphenyl ] -3-carbonitrile
2-fluoro-3-bromoxynil (10.00g, 49.99mmol), phenylboronic acid (7.31g, 59.99mmol) and Pd (PPh) 3 ) 4 (1.44g, 1.25mmol) and K 2 CO 3 (13.82g, 99.98mmol) was placed in a reaction flask, and a suitable amount of Dioxane/H was added 2 O (3/1) as a solvent. And reacting for 5 hours at 95 ℃ under the protection of nitrogen. After completion of the reaction, the reaction mixture was poured into 300ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, column chromatography (petroleum ether: ethyl acetate volume ratio of 50: 1) separation and purification to obtain white solid 8.49g, yield 86.1%.
And 2, step: 7-phenylbenzo [ d ] isothiazol-3-amines
Reacting 2-fluoro- [1,1' -biphenyl]-3-carbonitrile (10.00g, 50.71mmol) was dissolved in DMSO in appropriate amount, na was added 2 S·9H 2 O (12.79g, 53.25mmol) was reacted at 70 ℃ for 24h. The reaction mixture was cooled to room temperature, and 4Mol/l of an LNaOH solution (38 ml), an aqueous ammonia solution (25 Wt.%,152 ml), and a sodium hypochlorite solution (not less than 7.0% available chlorine, 76 ml) were added thereto in this order with stirring, and the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 300ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Vacuum filtering, vacuum distilling to remove solvent, and passing through ethyl acetateThe ester was purified by slurrying to give 6.71g of a white solid in 58.5% yield.
And step 3:4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (1.00g, 4.42mmol), 4-bromobenzaldehyde (0.90g, 4.86mmol), pd (OAc) 2 (50mg, 0.22mmol), xant-phos (256mg, 0.44mmol) and Cs 2 CO 3 (2.88g, 8.84mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction was diluted with THF, filtered off with suction, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by slurrying with ethyl acetate to obtain 0.88g of a yellow solid at a yield of 60.3%.
And 4, step 4:2- ((4- ((7-Phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 1)
A mixture of 4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (125mg, 0.38mmol) was dissolved in THF/MeOH (1/1) and ethanolamine (228ul, 3.78mmol) was added and the reaction stirred at 50 ℃ for 1h. Cooling the reaction solution to room temperature, and adding NaBH 4 (72mg, 1.89mmol), the reaction was stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration and reduced pressure distillation were performed to remove the solvent, and separation and purification were performed by preparative thin layer chromatography (volume ratio of dichloromethane to methanol: 10: 1) to obtain 64mg of a white solid in a yield of 45.1%. HRMS (ESI) for C 22 H 21 N 3 OS[M+Na] + :calcd,398.1303；found,398.1312； 1 HNMR(600MHz,DMSO-d6)δ9.65–9.62(s,1H),8.54–8.50(dd,J＝0.9,8.1Hz,1H),7.93–7.88(d,J＝8.6Hz,2H),7.77–7.72(m,3H),7.69–7.64(t,J＝7.6Hz,1H),7.61–7.56(t,J＝7.7Hz,2H),7.52–7.46(t,J＝7.4Hz,1H),7.33–7.28(d,J＝8.5Hz,2H),4.78–4.19(s,1H),3.71–3.68(s,2H),3.52–3.47(t,J＝5.8Hz,2H),2.63–2.58(t,J＝5.8Hz,2H).
Example 2: n- (2- ((4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethyl) acetamide
With reference to the synthesis of example 1, with 4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and ethanolamine is replaced by N-acetyl ethylenediamine. Finally, 52mg of a white solid was obtained in a yield of 41.3%. HRMS (ESI) for C 24 H 24 N 4 OS[M+Na] + :calcd,439.1569；found,439.1573； 1 HNMR(600MHz,DMSO-d6)δ9.69–9.66(s,1H),8.56–8.51(d,J＝8.0Hz,1H),7.94–7.90(d,J＝8.1Hz,2H),7.87–7.82(t,J＝5.6Hz,1H),7.77–7.73(m,3H),7.69–7.64(t,J＝7.6Hz,1H),7.62–7.56(t,J＝7.6Hz,2H),7.52–7.46(t,J＝7.4Hz,1H),7.34–7.30(d,J＝8.1Hz,2H),3.72–3.69(s,2H),3.20–3.14(q,J＝6.2Hz,2H),2.62–2.57(t,J＝6.5Hz,2H),1.82–1.79(s,3H).
Example 3:2- (((6- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) pyridin-3-yl) methyl) amino) ethan-1-ol
Step 1:6- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) pyridine-3-carbaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 2-bromo-5-formylpyridine (452mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) is placed in a reaction flask, and a proper amount of anhydrous dioxane is added as a solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction was diluted with THF, filtered off with suction, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by beating with ethyl acetate to obtain 0.58g of a yellow solid with a yield of 79.2%.
Step 2:2- (((6- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) pyridin-3-yl) methyl) amino) ethan-1-ol (example 2)
Reacting 6- ((7-phenylbenzo [ d ]]Isothiazoles-3-yl) amino) pyridine-3-carbaldehyde (100mg, 0.30mmol) was dissolved in THF/MeOH (1/1), ethanolamine (182ul, 3.02mmol) was added, and the reaction stirred at 50 deg.C for 3h. Cooling the reaction solution to room temperature, and adding NaBH 4 (57mg, 1.51mmol), the reaction was stirred at room temperature for 2h. After the reaction, the solvent was distilled off under reduced pressure, and 30ml of water was added to conduct extraction with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration and reduced pressure distillation were performed to remove the solvent, and separation and purification were performed by preparative thin layer chromatography (dichloromethane: methanol volume ratio 7.5. HRMS (ESI) for C 21 H 20 N 4 OS[M+H] + :calcd,377.1431；found,377.1441； 1 HNMR(600MHz,DMSO-d6)δ10.46–10.43(s,1H),8.69–8.65(d,J＝8.1Hz,1H),8.42–8.37(d,J＝8.5Hz,1H),8.32–8.28(d,J＝2.3Hz,1H),7.81–7.76(dd,J＝2.4,8.6Hz,1H),7.76–7.73(m,3H),7.66–7.61(t,J＝7.6Hz,1H),7.61–7.56(t,J＝7.7Hz,2H),7.52–7.46(t,J＝7.4Hz,1H),4.73–4.38(s,1H),3.74–3.71(s,2H),3.52–3.48(t,J＝5.8Hz,2H),2.64–2.59(t,J＝5.8Hz,2H).
Example 4:2- (((5- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) pyridin-2-yl) methyl) amino) ethan-1-ol
Step 1:5- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) pyridine-2-carbaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 5-bromo-2-formylpyridine (452mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction was diluted with THF, filtered off with suction, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and the mixture was purified by beating with ethyl acetate to obtain 0.45g of a yellow solid with a yield of 61.5%.
Step 2:2- (((5- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) pyridin-2-yl) methyl) amino) ethan-1-ol (example 4)
A reaction product of 5- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) pyridine-2-carbaldehyde (100mg, 0.30mmol) was dissolved in THF/MeOH (1/1), followed by the addition of ethanolamine (182ul, 3.02mmol) and the reaction stirred at 50 deg.C for 2h. Cooling the reaction solution to room temperature, and adding NaBH 4 (57mg, 1.51mmol), the reaction was stirred at room temperature for 2h. After the reaction, the solvent was distilled off under reduced pressure, and 30ml of water was added to conduct extraction with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove solvent, preparation of thin layer chromatography separation and purification (dichloromethane: methanol volume ratio of 7:1), obtained light yellow solid 35mg, yield 30.1%. HRMS (ESI) for C 21 H 20 N 4 OS[M+H] + :calcd,377.1431；found,377.1439； 1 HNMR(600MHz,DMSO-d6)δ10.01–9.98(s,1H),9.07–9.04(d,J＝2.7Hz,1H),8.60–8.55(d,J＝8.0Hz,1H),8.48–8.43(dd,J＝2.7,8.4Hz,1H),7.79–7.73(m,3H),7.71–7.66(t,J＝7.6Hz,1H),7.62–7.56(t,J＝7.5Hz,2H),7.52–7.47(t,J＝7.4Hz,1H),7.45–7.40(d,J＝8.5Hz,1H),4.77–4.50(s,1H),3.90–3.83(s,2H),3.56–3.51(t,J＝5.6Hz,2H),2.72–2.67(t,J＝5.6Hz,2H).
Example 5:2- ((2-methoxy-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 2-methoxy-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 4-bromo-2-methoxybenzaldehyde (523mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by slurrying with ethyl acetate to obtain 0.46g of a yellow solid at a yield of 57.8%.
And 2, step: 2- ((2-methoxy-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 5)
Reacting 2-methoxy-4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.28mmol) was dissolved in THF/MeOH (1/1), ethanolamine (167ul, 2.77mmol) was added and the reaction stirred at 50 ℃ for 2h. Cooling the reaction solution to room temperature, and adding NaBH 4 (52mg, 1.39mmol), the reaction was stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration and reduced pressure distillation were performed to remove the solvent, and separation and purification by preparative thin layer chromatography (dichloromethane: methanol volume ratio 7.5. HRMS (ESI) for C 23 H 23 N 3 O 2 S[M+H] + :calcd,406.1584；found,406.1591； 1 HNMR(600MHz,DMSO-d6)δ9.87–9.76(s,1H),8.61–8.57(d,J＝7.7Hz,1H),7.79–7.73(m,3H),7.71–7.65(m,3H),7.62–7.56(t,J＝7.7Hz,2H),7.52–7.46(t,J＝7.4Hz,1H),7.33–7.29(d,J＝8.2Hz,1H),5.25–4.46(s,1H),3.86–3.85(s,2H),3.85–3.84(s,3H),3.60–3.55(t,J＝5.6Hz,2H),2.78–2.73(t,J＝5.6Hz,2H).
Example 6:2- ((2-methyl-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 2-methyl-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 4-bromo-2-methylbenzaldehyde (325ul, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by beating with ethyl acetate to obtain 0.38g of a yellow solid with a yield of 49.9%.
Step 2:2- ((2-methyl-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 6)
Reacting 2-methyl-4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.29mmol) was dissolved in THF/MeOH (1/1), then ethanolamine (175ul, 2.90mmol) was added and the reaction stirred at 50 ℃ for 2h. Cooling the reaction solution to room temperature, and adding NaBH 4 (55mg, 1.45mmol) and the reaction stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. After suction filtration and removal of the solvent by distillation under the reduced pressure, the residue was separated and purified by preparative thin layer chromatography (volume ratio of dichloromethane to methanol: 7.5: 1) to obtain 57mg of a white solid in a yield of 50.4%. HRMS (ESI) for C 23 H 23 N 3 OS[M－H] － :calcd,388.1489；found,388.1509； 1 HNMR(600MHz,DMSO-d6)δ9.66–9.63(s,1H),8.58–8.53(d,J＝8.0Hz,1H),7.84–7.80(dd,J＝2.4,8.3Hz,1H),7.78–7.76(d,J＝2.3Hz,1H),7.76–7.72(m,3H),7.68–7.63(t,J＝7.6Hz,1H),7.61–7.56(t,J＝7.7Hz,2H),7.52–7.46(t,J＝7.4Hz,1H),7.32–7.28(d,J＝8.3Hz,1H),4.75–4.62(s,1H),3.79–3.76(s,2H),3.58–3.53(t,J＝5.7Hz,2H),2.76–2.71(t,J＝5.7Hz,2H),2.37–2.34(s,3H).
Example 7:2- ((2-chloro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 2-chloro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 2-chloro-4-bromobenzaldehyde (533mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction was diluted with THF, filtered off with suction, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by slurrying with ethyl acetate to obtain 0.61g of a yellow solid at a yield of 75.7%.
Step 2:2- ((2-chloro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 7)
Reacting 2-chloro-4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.27mmol) was dissolved in THF/MeOH (1/1), then ethanolamine (165ul, 2.74mmol) was added and the reaction stirred at 50 ℃ for 1h. Cooling the reaction solution to room temperature, and adding NaBH 4 (52mg, 1.37mmol), the reaction was stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. After suction filtration and removal of the solvent by distillation under the reduced pressure, the residue was separated and purified by preparative thin layer chromatography (volume ratio of dichloromethane to methanol: 7.5: 1) to obtain 22mg of a white solid in a yield of 19.6%. HRMS (ESI) for C 22 H 20 ClN 3 OS[M+H] + :calcd,410.1088；found,410.1098； 1 HNMR(600MHz,DMSO-d6)δ10.00–9.97(s,1H),8.59–8.54(d,J＝8.2Hz,1H),8.26–8.23(s,1H),7.92–7.87(d,J＝8.5Hz,1H),7.79–7.73(m,3H),7.71–7.66(t,J＝7.7Hz,1H),7.62–7.57(t,J＝7.6Hz,2H),7.56–7.52(d,J＝8.4Hz,1H),7.52–7.47(t,J＝7.5Hz,1H),4.88–4.69(s,1H),3.95–3.92(s,2H),3.60–3.55(t,J＝5.6Hz,2H),2.79–2.74(t,J＝5.6Hz,2H).
Example 8:2- ((3-chloro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 3-chloro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 4-bromo-3-chloro-benzaldehyde (533mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction was diluted with THF, filtered off with suction, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by beating with ethyl acetate to obtain 0.59g of a yellow solid with a yield of 73.2%.
Step 2:2- ((3-chloro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 8)
Reacting 3-chloro-4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.27mmol) was dissolved in THF/MeOH (1/1) and ethanolamine (165ul, 2.74mmol) was added and the reaction stirred at 50 ℃ for 1.5h. Cooling the reaction solution to room temperature, and adding NaBH 4 (52mg, 1.37mmol), the reaction was stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration and reduced pressure distillation were performed to remove the solvent, and separation and purification were performed by preparative thin layer chromatography (dichloromethane: methanol volume ratio 10: 1) to obtain 61mg of a white solid in a yield of 54.3%. HRMS (ESI) for C 22 H 20 ClN 3 OS[M+H] + :calcd,410.1088；found,410.1089； 1 HNMR(600MHz,DMSO-d6)δ9.08–9.05(s,1H),8.40–8.36(d,J＝8.0Hz,1H),7.94–7.89(d,J＝8.2Hz,1H),7.78–7.71(m,3H),7.68–7.63(t,J＝7.6Hz,1H),7.61–7.55(t,J＝7.6Hz,2H),7.55–7.52(d,J＝2.0Hz,1H),7.51–7.46(t,J＝7.4Hz,1H),7.36–7.31(dd,J＝2.0,8.2Hz,1H),4.68–4.43(s,1H),3.77–3.74(s,2H),3.53–3.48(t,J＝5.8Hz,2H),2.64–2.59(t,J＝5.8Hz,2H).
Example 9:2- ((3-methyl-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 3-methyl-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 4-bromo-3-methylbenzaldehyde (484mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and the mixture was purified by beating with ethyl acetate to obtain 0.46g of a yellow solid with a yield of 60.4%.
Step 2:2- ((3-methyl-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 9)
Reacting 3-methyl-4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.29mmol) was dissolved in THF/MeOH (1/1), ethanolamine (175ul, 2.90mmol) was added, and the reaction stirred at 50 ℃ for 2h. Cooling the reaction solution to room temperature, and adding NaBH 4 (55mg, 1.45mmol) and the reaction stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration and reduced pressure distillation were performed to remove the solvent, and separation and purification by preparative thin layer chromatography (dichloromethane: methanol volume ratio 10. HRMS (ESI) for C 23 H 23 N 3 OS[M－H] － :calcd,388.1489；found,388.1508； 1 HNMR(600MHz,DMSO-d6)δ8.92–8.89(s,1H),8.41–8.36(dd,J＝1.0,8.1Hz,1H),7.76–7.70(m,3H),7.67–7.62(t,J＝7.6Hz,1H),7.60–7.56(m,3H),7.50–7.45(t,J＝7.4Hz,1H),7.28–7.24(d,J＝2.1Hz,1H),7.23–7.18(dd,J＝2.1,8.0Hz,1H),4.73–4.52(s,1H),3.78–3.75(s,2H),3.55–3.50(t,J＝5.7Hz,2H),2.69–2.64(t,J＝5.8Hz,2H),2.30–2.27(s,3H).
Example 10:2- ((2,6-dimethoxy-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1:2,6-dimethoxy-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 4-bromo-2,6-dimethoxybenzaldehyde (596mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) is placed in a reaction flask, and a proper amount of anhydrous dioxane is added as a solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction was diluted with THF, filtered off with suction, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by beating with ethyl acetate to obtain 0.28g of a yellow solid with a yield of 32.4%.
And 2, step: 2- ((2,6-dimethoxy-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 10)
2,6-dimethoxy-4- ((7-phenylbenzo [ d)]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.26mmol) was dissolved in THF/MeOH (1/1), ethanolamine (155ul, 2.56mmol) was added and the reaction stirred at 50 ℃ for 2h. Cooling the reaction solution to room temperature, and adding NaBH 4 (48mg, 1.28mmol), the reaction was stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration and reduced pressure distillation were performed to remove the solvent, and separation and purification by preparative thin layer chromatography (dichloromethane: methanol volume ratio 7.5. HRMS (ESI) for C 24 H 25 N 3 O 3 S[M+H] + :calcd,436.1689；found,436.1697； 1 HNMR(600MHz,DMSO-d6)δ10.11–10.08(s,1H),8.73–8.69(dd,J＝0.9,8.2Hz,1H),7.79–7.73(m,3H),7.71–7.65(t,J＝7.6Hz,1H),7.61–7.58(t,J＝7.2Hz,2H),7.58–7.57(s,2H),7.52–7.47(t,J＝7.4Hz,1H),5.33–5.15(s,1H),4.07–4.04(s,2H),3.88–3.85(s,6H),3.69–3.64(t,J＝5.5Hz,2H),2.91–2.86(t,J＝5.5Hz,2H).
Example 11:2- ((3-fluoro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 3-fluoro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 3-fluoro-4-bromobenzaldehyde (494mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction was diluted with THF, filtered off with suction, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and the mixture was purified by beating with ethyl acetate to obtain 0.71g of a yellow solid in a yield of 92.2%.
And 2, step: 2- ((3-fluoro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 11)
Reacting 3-fluoro-4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.29mmol) was dissolved in THF/MeOH (1/1), ethanolamine (173ul, 2.87mmol) was added, and the reaction was stirred at 50 ℃ for 1h. Cooling the reaction solution to room temperature, and adding NaBH 4 (54mg, 1.44mmol), the reaction was stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration and reduced pressure distillation were performed to remove the solvent, and separation and purification were performed by preparative thin layer chromatography (dichloromethane: methanol volume ratio 7.5. HRMS (ESI) for C 22 H 20 FN 3 OS[M+H] + :calcd,394.1384；found,394.1396； 1 HNMR(600MHz,DMSO-d6)δ9.27–9.24(s,1H),8.47–8.42(d,J＝8.0Hz,1H),7.95–7.90(t,J＝8.3Hz,1H),7.77–7.71(m,3H),7.67–7.62(t,J＝7.6Hz,1H),7.61–7.55(t,J＝7.7Hz,2H),7.51–7.45(t,J＝7.4Hz,1H),7.29–7.24(dd,J＝1.9,12.0Hz,1H),7.18–7.14(dd,J＝1.8,8.3Hz,1H),4.57–4.46(s,1H),3.75–3.72(s,2H),3.52–3.47(t,J＝5.8Hz,2H),2.62–2.57(t,J＝5.8Hz,2H).
Example 12:2- ((3-methoxy-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 3-methoxy-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 4-bromo-3-methoxybenzaldehyde (523mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and the mixture was purified by beating with ethyl acetate to obtain 0.69g of a yellow solid with a yield of 86.7%.
And 2, step: 2- ((3-methoxy-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 12)
Reacting 3-methoxy-4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.28mmol) was dissolved in THF/MeOH (1/1), ethanolamine (167ul, 2.77mmol) was added, and the reaction stirred at 50 ℃ for 1h. Cooling the reaction solution to room temperature, and adding NaBH 4 (52mg, 1.39mmol), the reaction was stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. Mixing ethyl acetate layers, washing with saturated saline solution for 3 times, and collecting filtrateAnd (5) drying. After suction filtration and removal of the solvent by distillation under the reduced pressure, the residue was separated and purified by preparative thin layer chromatography (volume ratio of dichloromethane to methanol: 7.5: 1) to obtain 54mg of a white solid in a yield of 48.0%. HRMS (ESI) for C 23 H 23 N 3 O 2 S[M－H] － :calcd,404.1438；found,404.1456； 1 HNMR(600MHz,DMSO-d6)δ8.62–8.59(s,1H),8.38–8.33(dd,J＝0.9,8.2Hz,1H),8.21–8.16(d,J＝8.1Hz,1H),7.77–7.71(m,3H),7.67–7.61(t,J＝7.6Hz,1H),7.61–7.56(t,J＝7.7Hz,2H),7.51–7.46(t,J＝7.4Hz,1H),7.15–7.12(d,J＝1.8Hz,1H),6.98–6.93(dd,J＝1.8,8.1Hz,1H),4.75–4.44(s,1H),3.93–3.90(s,3H),3.79–3.76(s,2H),3.55–3.50(t,J＝5.7Hz,2H),2.69–2.64(t,J＝5.7Hz,2H).
Example 13:2- ((3-bromo-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 3-bromo-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 3,4-dibromobenzaldehyde (641mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) is placed in a reaction flask, and a proper amount of anhydrous dioxane is added as a solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by beating with ethyl acetate to obtain 0.58g of a yellow solid at a yield of 64.2%.
Step 2:2- ((3-bromo-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 13)
Reacting 3-bromo-4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.24mmol) was dissolved in THF/MeOH (1/1), ethanolamine (147ul, 2.44mmol) was added and the reaction stirred at 50 ℃ for 1h. Cooling the reaction solution to room temperature, and adding NaBH 4 (46mg,1.22mmol), stirring the mixture at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove solvent, preparation of thin layer chromatography separation and purification (dichloromethane: methanol volume ratio of 7:1), white solid 56mg, yield 50.5%. HRMS (ESI) for C 22 H 20 BrN 3 OS[M+Na] + :calcd,478.0388；found,478.0397； 1 HNMR(600MHz,DMSO-d6)δ9.04–9.01(s,1H),8.37–8.33(d,J＝8.0Hz,1H),7.87–7.83(d,J＝8.1Hz,1H),7.78–7.71(m,3H),7.71–7.68(d,J＝1.9Hz,1H),7.68–7.63(t,J＝7.6Hz,1H),7.61–7.55(t,J＝7.7Hz,2H),7.51–7.45(t,J＝7.4Hz,1H),7.40–7.36(dd,J＝2.0,8.2Hz,1H),4.65–4.46(s,1H),3.77–3.74(s,2H),3.53–3.48(t,J＝5.8Hz,2H),2.64–2.59(t,J＝5.8Hz,2H).
Example 14:2- ((2-fluoro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 2-fluoro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzaldehyde
By reacting 7-phenylbenzo [ d ]]Isothiazol-3-amine (500mg, 2.21mmol), 4-bromo-2-fluorobenzaldehyde (494mg, 2.43mmol), pd (OAc) 2 (25mg, 0.11mmol), xant-phos (128mg, 0.22mmol) and Cs 2 CO 3 (1.44g, 4.42mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and the mixture was purified by slurrying with ethyl acetate to obtain 0.49g of a yellow solid in a yield of 63.6%.
Step 2:2- ((2-fluoro-4- ((7-phenylbenzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 14)
Reacting 2-fluoro-4- ((7-phenylbenzo [ d ]]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.29mmol) Dissolved in THF/MeOH (1/1) and ethanolamine (173ul, 2.87mmol) was added and the reaction stirred at 50 ℃ for 1h. The reaction was cooled to room temperature and NaBH was added 4 (54mg, 1.44mmol), the reaction was stirred at room temperature for 2h. After the reaction, the solvent was distilled off under reduced pressure, and 30ml of water was added to conduct extraction with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove solvent, preparation of thin layer chromatography separation and purification (dichloromethane: methanol volume ratio of 7:1), white solid 43mg, yield 38.1%. HRMS (ESI) for C 22 H 20 FN 3 OS[M+Na] + :calcd,416.1209；found,416.1216； 1 HNMR(600MHz,DMSO-d6)δ9.94–9.91(s,1H),8.57–8.52(d,J＝8.0Hz,1H),8.00–7.94(dd,J＝2.1,13.1Hz,1H),7.79–7.73(m,3H),7.71–7.64(m,2H),7.62–7.56(t,J＝7.7Hz,2H),7.52–7.46(t,J＝7.4Hz,1H),7.44–7.38(t,J＝8.6Hz,1H),4.66–4.47(s,1H),3.77–3.74(s,2H),3.52–3.48(t,J＝5.7Hz,2H),2.66–2.61(t,J＝5.7Hz,2H).
Example 15:2- ((3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1:3- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-fluorobenzonitrile
2-fluoro-3-bromoxynil (3.00g, 15.00mmol), benzo-1,4-dioxane-6-boronic acid (2.96g, 16.45mmol), pd (PPh) 3 ) 4 (520mg, 0.45mmol) and K 2 CO 3 (4.56g, 32.99mmol) was placed in a reaction flask and appropriate amount of Dioxane/H was added 2 O (3/1) is used as a solvent. And reacting for 5 hours at 95 ℃ under the protection of nitrogen. After completion of the reaction, the reaction mixture was poured into 200ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, column chromatography (petroleum ether: ethyl acetate volume ratio of 20: 1) separation and purification to obtain white solid 3.40g, yield 88.8%.
Step 2:7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-amine
Reacting 3- (2,3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) -2-fluorobenzonitrile (1.50g, 5.88mmol) was dissolved in an appropriate amount of DMSO and Na was added 2 S·9H 2 O (1.55g, 6.45mmol) was reacted at 70 ℃ for 24h. The reaction solution was cooled to room temperature, and 4Mol/l of an LNaOH solution (4.35 ml), an aqueous ammonia solution (25 Wt.%,17.66 ml), and a sodium hypochlorite solution (effective chlorine ≧ 7.0%,8.82 ml) were sequentially added under stirring, and the reaction was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 100ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, and pulping and purification by ethyl acetate to obtain 0.75g of white solid with yield of 44.9%.
And 3, step 3: 3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzaldehyde
Reacting 7- (2,3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-amine (500mg, 1.76mmol), 4-bromo-3-chlorobenzaldehyde (425mg, 1.94mmol), pd (OAc) 2 (20mg, 0.089mmol), xant-phos (102mg, 0.18mmol) and Cs 2 CO 3 (1147 mg, 3.52mmol) in a reaction flask, and adding appropriate amount of anhydrous dioxane as solvent. And reacting for 12 hours at 80 ℃ under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and the mixture was purified by beating with ethyl acetate to obtain 0.71g of a yellow solid in a yield of 95.4%.
And 4, step 4:2- ((3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 15)
Reacting 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.24mmol) was dissolved in THF/MeOH (1/1) and ethanolamine (143ul, 2.37mmol) was added and the reaction stirred at 50 ℃ for 1h. Cooling the reaction solution to room temperature, and adding NaBH 4 (45mg, 1.19mmol) and the reaction stirred at room temperature for 2h. After the reaction, the solvent was distilled off under reduced pressure30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove solvent, preparation of thin layer chromatography separation and purification (dichloromethane: methanol volume ratio of 7:1), white solid 45mg, yield 40.5%. HRMS (ESI) for C 24 H 22 ClN 3 O 3 S[M+Na] + :calcd,490.0968；found,490.0971； 1 HNMR(600MHz,DMSO-d6)δ9.03–9.00(s,1H),8.34–8.30(dd,J＝1.0,8.1Hz,1H),7.92–7.88(d,J＝8.2Hz,1H),7.71–7.66(dd,J＝1.0,7.2Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.54–7.50(d,J＝1.9Hz,1H),7.35–7.30(dd,J＝1.9,8.3Hz,1H),7.23–7.18(m,2H),7.07–7.02(d,J＝8.0Hz,1H),4.66–4.43(s,1H),4.33–4.30(s,4H),3.76–3.73(s,2H),3.52–3.47(t,J＝5.8Hz,2H),2.63–2.58(t,J＝5.8Hz,2H).
Example 16:2- ((4- ((7- (benzo [ d ] [1,3] dioxolan-5-yl) benzo [ d ] isothiazol-3-yl) amino) -3-chlorobenzyl) amino) ethan-1-ol
Step 1:3- (benzo [ d ] [1,3] dioxolan-5-yl) -2-fluorobenzonitrile
2-fluoro-3-bromoxynil (2.50g, 12.50mmol), 3,4- (methylenedioxy) phenylboronic acid (2.49g, 15.00mmol), pd (PPh) 3 ) 4 (430mg, 0.37mmol) and K 2 CO 3 (3.46g, 25.03mmol) is placed in a reaction flask, and a proper amount of Dioxane/H is added 2 O (3/1) is used as a solvent. And reacting for 5 hours at 95 ℃ under the protection of nitrogen. After completion of the reaction, the reaction mixture was poured into 150ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, column chromatography (petroleum ether: ethyl acetate volume ratio of 20: 1) separation and purification to obtain 2.82g of white solid, yield 93.4%.
Step 2:7- (benzo [ d ] [1,3] dioxolan-5-yl) benzo [ d ] isothiazol-3-amine
Reacting 3- (benzo [ d ]][1,3]Dioxolane-5-yl) -2-fluorobenzonitrile (1.10g, 4.56mmol) was dissolved in an appropriate amount of DMSO, and Na was added 2 S·9H 2 O (1.20g, 5.00mmol) was reacted at 70 ℃ for 24 hours. The reaction mixture was cooled to room temperature, and 4Mol/l of an LNaOH solution (3.37 ml), an aqueous ammonia solution (25 Wt.%,14.00 ml), and a sodium hypochlorite solution (effective chlorine ≧ 7.0%,6.80 ml) were sequentially added thereto with stirring, and the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 100ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, and pulping and purification by ethyl acetate to obtain 0.48g of white solid with the yield of 39.0%.
And 3, step 3:4- ((7- (benzo [ d ] [1,3] dioxolan-5-yl) benzo [ d ] isothiazol-3-yl) amino) -3-chlorobenzaldehyde
Reacting 7- (benzo [ d ]][1,3]Dioxolan-5-yl) benzo [ d]Isothiazol-3-amine (400mg, 1.48mmol), 4-bromo-3-chlorobenzaldehyde (357mg, 1.63mmol), pd (OAc) 2 (17mg, 0.076 mmol), xant-phos (86mg, 0.15mmol) and Cs 2 CO 3 (964 mg, 2.96mmol) was placed in a reaction flask, and an appropriate amount of anhydrous dioxane was added as a solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by beating with ethyl acetate to obtain 0.58g of a yellow solid at a yield of 95.9%.
And 4, step 4:2- ((4- ((7- (benzo [ d ] [1,3] dioxolan-5-yl) benzo [ d ] isothiazol-3-yl) amino) -3-chlorobenzyl) amino) ethan-1-ol (example 16)
A mixture of 4- ((7- (benzo [ d ]) and][1,3]dioxolan-5-yl) benzo [ d]Isothiazol-3-yl) amino) -3-chlorobenzaldehyde (100mg, 0.24mmol) was dissolved in THF/MeOH (1/1), ethanolamine (148ul, 2.45mmol) was added and the reaction stirred at 50 deg.C for 1h. The reaction was cooled to room temperature and NaBH was added 4 (46mg, 1.22mmol) and the reaction stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Vacuum filtering, distilling under reduced pressure to remove solvent, and separating and purifying by preparative thin layer chromatography (dichloromethane: A)The volume ratio of alcohol was 7:1) to give 52mg of white solid in 46.8% yield. HRMS (ESI) for C 23 H 20 ClN 3 O 3 S[M+Na] + :calcd,476.0812；found,476.0820； 1 HNMR(600MHz,DMSO-d6)δ9.05–9.02(s,1H),8.35–8.31(dd,J＝1.0,8.1Hz,1H),7.93–7.88(d,J＝8.2Hz,1H),7.71–7.67(dd,J＝1.0,7.3Hz,1H),7.64–7.58(t,J＝7.4,7.9Hz,1H),7.54–7.51(d,J＝1.9Hz,1H),7.36–7.31(dd,J＝1.9,8.3Hz,1H),7.29–7.26(d,J＝1.9Hz,1H),7.24–7.19(dd,J＝1.9,8.0Hz,1H),7.13–7.08(d,J＝8.0Hz,1H),6.14–6.11(s,2H),4.69–4.42(s,1H),3.77–3.74(s,2H),3.53–3.48(t,J＝5.8Hz,2H),2.64–2.59(t,J＝5.8Hz,2H).
Example 17:2- ((3-chloro-4- ((7- (3,4-dimethoxyphenyl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 2-fluoro-3 ',4' -dimethoxy- [1,1' -biphenyl ] -3-carbonitrile
2-fluoro-3-bromoxynil (2.50g, 12.50mmol), 3,4-dimethoxyphenylboronic acid (2.73g, 15.00mmol), pd (PPh) 3 ) 4 (430mg, 0.37mmol) and K 2 CO 3 (3.46g, 25.03mmol) in a reaction flask, adding a proper amount of Dioxane/H 2 O (3/1) as a solvent. And reacting at 95 ℃ for 5 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was poured into 150ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, column chromatography (volume ratio of petroleum ether to ethyl acetate is 10.
Step 2:7- (3,4-dimethoxyphenyl) benzo [ d ] isothiazol-3-amine
2-fluoro-3 ',4' -dimethoxy- [1,1' -biphenyl group]-3-carbonitrile (1.20g, 4.66mmol) was dissolved in an appropriate amount of DMSO, and Na was added 2 S·9H 2 O (1.23g, 5.12mmol), reacted at 70 ℃ for 24h. Cooling the reaction solution to room temperature, adding the reaction solution in turn under stirring4Mol/LNaOH solution (3.45 ml), ammonia solution (25 Wt.%,14.00 ml), sodium hypochlorite solution (available chlorine ≧ 7.0%,7.00 ml), and stirred at room temperature for reaction for 6h. After completion of the reaction, the reaction mixture was poured into 100ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, and purification by ethyl acetate pulping to obtain 1.23g of white solid with a yield of 91.8%.
And step 3: 3-chloro-4- ((7- (3,4-dimethoxyphenyl) benzo [ d ] isothiazol-3-yl) amino) benzaldehyde
Reacting 7- (3,4-dimethoxyphenyl) benzo [ d]Isothiazol-3-amine (500mg, 1.75mmol), 4-bromo-3-chlorobenzaldehyde (422mg, 1.92mmol), pd (OAc) 2 (20mg, 0.089mmol), xant-phos (101mg, 0.17mmol) and Cs 2 CO 3 (1138mg, 3.49mmol) was placed in a reaction flask, and an appropriate amount of anhydrous dioxane was added as a solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by slurrying with ethyl acetate to obtain 0.43g of a yellow solid at a yield of 57.9%. And 4, step 4:2- ((3-chloro-4- ((7- (3,4-dimethoxyphenyl) benzo [ d]Isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 17)
Reacting 3-chloro-4- ((7- (3,4-dimethoxyphenyl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.24mmol) was dissolved in THF/MeOH (1/1), then ethanolamine (142ul, 2.35mmol) was added and the reaction stirred at 50 ℃ for 1h. Cooling the reaction solution to room temperature, and adding NaBH 4 (45mg, 1.19mmol) and the reaction stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove solvent, preparation of thin layer chromatography separation and purification (dichloromethane: methanol volume ratio of 8:1), white solid 49mg, yield 44.1%. HRMS (ESI) for C 24 H 24 ClN 3 O 3 S[M－H] － :calcd,468.1154；found,468.1181； 1 HNMR(600MHz,DMSO-d6)δ9.03–9.00(s,1H),8.34–8.30(dd,J＝0.9,8.1Hz,1H),7.94–7.89(d,J＝8.2Hz,1H),7.78–7.74(dd,J＝0.9,7.3Hz,1H),7.65–7.59(t,J＝7.6Hz,1H),7.53–7.50(d,J＝1.9Hz,1H),7.35–7.31(dd,J＝1.9,8.3Hz,1H),7.31–7.26(m,2H),7.17–7.12(d,J＝9.0Hz,1H),4.60–4.45(s,1H),3.87–3.85(s,3H),3.85–3.82(s,3H),3.75–3.72(s,2H),3.52–3.47(t,J＝5.8Hz,2H),2.62–2.57(t,J＝5.8Hz,2H).
Example 18:2- ((3-chloro-4- ((7- (naphthalen-2-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 2-fluoro-3- (naphthalen-2-yl) benzonitrile
2-fluoro-3-bromoxynil (2.50g, 12.50mmol), 2-naphthoic acid (2.58g, 15.00mmol) and Pd (PPh) 3 ) 4 (430mg, 0.37mmol) and K 2 CO 3 (3.46g, 25.03mmol) in a reaction flask, adding a proper amount of Dioxane/H 2 O (3/1) as a solvent. And reacting at 95 ℃ for 5 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was poured into 150ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, column chromatography (petroleum ether: ethyl acetate volume ratio of 20: 1) separation and purification, white solid 2.80g, yield 90.6%.
Step 2:7- (naphthalen-2-yl) benzo [ d ] isothiazol-3-amines
2-fluoro-3- (naphthalen-2-yl) benzonitrile (1.10g, 4.45mmol) was dissolved in an appropriate amount of DMSO, and Na was added 2 S·9H 2 O (1.18g, 4.91mmol) was reacted at 70 ℃ for 24 hours. The reaction mixture was cooled to room temperature, and 4Mol/l of an LNaOH solution (3.30 ml), an aqueous ammonia solution (25 Wt.%,13.35 ml), and a sodium hypochlorite solution (effective chlorine ≧ 7.0%,6.67 ml) were sequentially added under stirring, and the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 100ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Vacuum filtering, distilling under reduced pressure to remove solvent, pulping with ethyl acetate, and purifying to obtain white solid0.64g of the product was obtained, representing a yield of 52.0%.
And step 3: 3-chloro-4- ((7- (naphthalen-2-yl) benzo [ d ] isothiazol-3-yl) amino) benzaldehyde
Reacting 7- (naphthalen-2-yl) benzo [ d]Isothiazol-3-amine (500mg, 1.81mmol), 4-bromo-3-chlorobenzaldehyde (437mg, 1.99mmol), pd (OAc) 2 (21mg, 0.094mmol), xant-phos (105mg, 0.18mmol) and Cs 2 CO 3 (1179mg, 3.62mmol) in a reaction bottle, and adding a proper amount of anhydrous dioxane as a solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by beating with ethyl acetate to obtain 0.62g of a yellow solid at a yield of 82.6%.
And 4, step 4:2- ((3-chloro-4- ((7- (naphthalen-2-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 18)
Reacting 3-chloro-4- ((7- (naphthalen-2-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.24mmol) was dissolved in THF/MeOH (1/1), ethanolamine (145ul, 2.41mmol) was added and the reaction stirred at 50 deg.C for 1h. Cooling the reaction solution to room temperature, and adding NaBH 4 (46mg, 1.22mmol) and the reaction stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove solvent, preparation of thin layer chromatography separation and purification (dichloromethane: methanol volume ratio of 8:1), white solid 50mg, yield 45.5%. HRMS (ESI) for C 26 H 22 ClN 3 OS[M－H] － :calcd,458.1099；found,458.1123； 1 HNMR(600MHz,DMSO-d6)δ9.11–9.08(s,1H),8.44–8.39(dd,J＝1.0,8.1Hz,1H),8.30–8.26(d,J＝1.9Hz,1H),8.14–8.10(d,J＝8.5Hz,1H),8.08–8.03(m,1H),8.03–7.98(m,1H),7.94–7.91(d,J＝8.2Hz,1H),7.91–7.86(m,2H),7.72–7.68(t,J＝7.6Hz,1H),7.64–7.57(m,2H),7.55–7.51(d,J＝1.9Hz,1H),7.36–7.31(dd,J＝2.0,8.3Hz,1H),4.67–4.40(s,1H),3.76–3.73(s,2H),3.53–3.48(t,J＝5.8Hz,2H),2.63–2.58(t,J＝5.8Hz,2H).
Example 19:2- ((3-chloro-4- ((7- (pyridin-3-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 2-fluoro-3- (pyridin-3-yl) benzonitrile
2-fluoro-3-bromoxynil (2.50g, 12.50mmol), 3-pyridineboronic acid (1.69g, 13.75mmol), pd (PPh) 3 ) 4 (430mg, 0.37mmol) and K 2 CO 3 (3.46g, 25.03mmol) in a reaction flask, adding a proper amount of Dioxane/H 2 O (3/1) as a solvent. And reacting at 95 ℃ for 5 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was poured into 150ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove solvent, column chromatography (volume ratio of petroleum ether to ethyl acetate 3:1) separation and purification to obtain white solid 1.99g, yield 80.2%.
And 2, step: 7- (pyridin-3-yl) benzo [ d ] isothiazol-3-amines
2-fluoro-3- (pyridin-3-yl) benzonitrile (1.00g, 5.05mmol) was dissolved in an appropriate amount of DMSO, na was added 2 S·9H 2 O (1.33g, 5.54mmol) was reacted at 70 ℃ for 24h. The reaction solution was cooled to room temperature, and 4Mol/l of an LNaOH solution (3.73 ml), an aqueous ammonia solution (25 Wt.%,15.13 ml) and a sodium hypochlorite solution (effective chlorine ≧ 7.0%,7.57 ml) were sequentially added under stirring, and the reaction was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 100ml of water and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, and purification by ethyl acetate pulping to obtain white solid 0.79g, yield 68.7%.
And step 3: 3-chloro-4- ((7- (pyridin-3-yl) benzo [ d ] isothiazol-3-yl) amino) benzaldehyde
Reacting 7- (pyridin-3-yl) benzo [ d]Isothiazol-3-amine (400mg, 1.76mmol), 4-bromo-3-chlorobenzaldehyde (425mg, 1.94mmol), pd (OAc) 2 (20mg, 0.089mmol), xant-phos (102mg, 0.18mmol) and Cs 2 CO 3 (1147mg, 3.52mmol) in a reaction flask, and adding appropriate amount of anhydrous dioxane as solvent. And reacting for 12 hours at 80 ℃ under the protection of nitrogen. After the reaction was completed, THF was added to dilute the reaction solution, followed by suction filtration, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and purification was carried out by beating with ethyl acetate to obtain 0.57g of a yellow solid with a yield of 88.5%.
And 4, step 4:2- ((3-chloro-4- ((7- (pyridin-3-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 19)
Reacting 3-chloro-4- ((7- (pyridin-3-yl) benzo [ d)]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.27mmol) was dissolved in THF/MeOH (1/1), ethanolamine (165ul, 2.74mmol) was added, and the reaction was stirred at 50 ℃ for 1h. Cooling the reaction solution to room temperature, and adding NaBH 4 (52mg, 1.37mmol), the reaction was stirred at room temperature for 2h. After completion of the reaction, the solvent was distilled off under reduced pressure, 30ml of water was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove solvent, preparation of thin layer chromatography separation and purification (dichloromethane: methanol volume ratio of 7:1), white solid 39mg, yield 34.8%. HRMS (ESI) for C 21 H 19 ClN 4 OS[M+Na] + :calcd,433.0866；found,433.0882； 1 HNMR(600MHz,DMSO-d6)δ9.15–9.12(s,1H),8.96–8.92(d,J＝2.4Hz,1H),8.71–8.67(dd,J＝1.6,4.8Hz,1H),8.46–8.42(d,J＝8.1Hz,1H),8.17–8.12(dt,J＝2.0,7.9Hz,1H),7.90–7.87(d,J＝8.2Hz,1H),7.86–7.82(d,J＝7.2Hz,1H),7.71–7.67(t,J＝7.7Hz,1H),7.63–7.59(dd,J＝4.8,7.9Hz,1H),7.54–7.52(d,J＝1.9Hz,1H),7.36–7.31(dd,J＝2.0,8.2Hz,1H),4.64–4.45(s,1H),3.77–3.74(s,2H),3.51–3.49(t,J＝5.8Hz,2H),2.62–2.60(t,J＝5.8Hz,2H).
Example 20: n- (2- ((3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethyl) acetamide
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and replacing ethanolamine with N-acetyl ethylenediamine. Finally, 55mg of a white solid was obtained in a yield of 45.7%. HRMS (ESI) for C 26 H 25 ClN 4 O 3 S[M+H] + :calcd,509.1409；found,509.1430； 1 HNMR(600MHz,DMSO-d6)δ9.04–9.01(s,1H),8.34–8.30(d,J＝8.0Hz,1H),7.92–7.88(d,J＝8.2Hz,1H),7.86–7.81(t,J＝5.7Hz,1H),7.71–7.67(d,J＝7.2Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.54–7.51(d,J＝2.0Hz,1H),7.35–7.30(dd,J＝1.9,8.2Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.34–4.31(s,4H),3.74–3.71(s,2H),3.19–3.13(q,J＝6.3Hz,2H),2.60–2.55(t,J＝6.5Hz,2H),1.82–1.79(s,3H).
Example 21: n- (2-chloro-4- (((2-methoxyethyl) amino) methyl) phenyl) -7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-amine
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and ethanolamine is replaced by 2-methoxyethylamine. Finally 51mg of white gummy substance are obtained, yield 44.7%. HRMS (ESI) for C 25 H 24 ClN 3 O 3 S[M+H] + :calcd,482.1300；found,482.1311； 1 HNMR(600MHz,DMSO-d6)δ9.03–9.00(s,1H),8.34–8.30(d,J＝7.9Hz,1H),7.93–7.88(d,J＝8.2Hz,1H),7.71–7.66(d,J＝7.1Hz,1H),7.63–7.57(t,J＝7.6Hz,1H),7.52–7.49(d,J＝2.0Hz,1H),7.34–7.29(dd,J＝1.9,8.3Hz,1H),7.23–7.17(m,2H),7.07–7.02(d,J＝8.1Hz,1H),4.33–4.30(s,4H),3.75–3.72(s,2H),3.44–3.39(t,J＝5.7Hz,2H),3.27–3.24(s,3H),2.70–2.65(t,J＝5.7Hz,2H).
Example 22: n is a radical of hydrogen 1 - (3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) Benzyl) -N 2 ,N 2 -dimethylethane-1,2-diamine
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and ethanolamine is replaced by N, N-dimethylethylenediamine. 34mg of white gummy substance is finally obtained, yield 29.1%. HRMS (ESI) for C 26 H 27 ClN 4 O 2 S[M+H] + :calcd,495.1616；found,495.1690； 1 HNMR(600MHz,DMSO-d6)δ9.05–9.02(s,1H),8.34–8.30(d,J＝8.0Hz,1H),7.96–7.91(d,J＝8.2Hz,1H),7.71–7.67(d,J＝7.2Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.56–7.53(d,J＝2.0Hz,1H),7.37–7.32(dd,J＝1.9,8.3Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.35–4.29(s,4H),3.80–3.77(s,2H),2.69–2.64(t,J＝6.3Hz,2H),2.48–2.45(t,J＝6.3Hz,2H),2.25–2.18(s,6H).
Example 23: n is a radical of hydrogen 1 - (3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzyl) -N 3 ,N 3 -dimethylpropane-1,3 diamine
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and ethanolamine is replaced by N, N-dimethyl-1,3-diaminopropane. 37mg of a white solid was obtained finally, with a yield of 30.7%. HRMS (ESI) for C 27 H 29 ClN 4 O 2 S[M+H] + :calcd,509.1773；found,509.1838； 1 HNMR(600MHz,DMSO-d6)δ9.07–9.04(s,1H),8.34–8.30(d,J＝8.1Hz,1H),7.98–7.94(d,J＝8.2Hz,1H),7.71–7.67(d,J＝7.3Hz,1H),7.62–7.59(t,J＝7.8Hz,1H),7.59–7.57(s,1H),7.40–7.36(d,J＝8.3Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.33–4.31(s,4H),3.86–3.83(s,2H),2.70–2.65(t,J＝7.1Hz,2H),2.44–2.39(t,J＝7.1Hz,2H),2.25–2.22(s,6H),1.72–1.64(p,J＝7.0Hz,2H).
Example 24:3- ((3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) propan-1-ol
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and ethanolamine is replaced by 3-amino-1-propanol. 53mg of a white solid is obtained in 46.5% yield. HRMS (ESI) for C 25 H 24 ClN 3 O 3 S[M+H] + :calcd,482.1300；found,482.1314； 1 HNMR(600MHz,DMSO-d6)δ9.04–9.01(s,1H),8.34–8.30(d,J＝7.8Hz,1H),7.94–7.88(d,J＝8.2Hz,1H),7.71–7.66(d,J＝7.1Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.54–7.50(d,J＝2.0Hz,1H),7.35–7.30(dd,J＝2.0,8.3Hz,1H),7.23–7.17(m,2H),7.07–7.02(d,J＝8.1Hz,1H),4.35–4.29(s,4H),3.74–3.71(s,2H),3.52–3.45(t,J＝6.3Hz,2H),2.63–2.57(t,J＝7.0Hz,2H),1.65–1.58(p,J＝6.6Hz,2H).
Example 25: (1r, 4r) -4- ((3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) cyclohexan-1-ol
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and ethanolamine is replaced by trans-p-aminocyclohexanol. Finally, 55mg of a white solid was obtained in 44.5% yield. HRMS (ESI) for C 28 H 28 ClN 3 O 3 S[M－H] － :calcd,520.1467；found,520.1457； 1 HNMR(600MHz,DMSO-d6)δ9.03–9.00(s,1H),8.35–8.29(d,J＝7.8Hz,1H),7.91–7.87(d,J＝8.2Hz,1H),7.71–7.66(d,J＝7.1Hz,1H),7.63–7.57(t,J＝7.6Hz,1H),7.53–7.50(d,J＝2.0Hz,1H),7.34–7.30(dd,J＝1.9,8.3Hz,1H),7.23–7.18(m,2H),7.07–7.02(d,J＝8.1Hz,1H),4.51–4.44(s,1H),4.35–4.28(s,4H),3.75–3.72(s,2H),3.39–3.36(m,1H),2.41–2.33(t,J＝10.0Hz,1H),1.91–1.86(d,J＝10.8Hz,2H),1.83–1.77(d,J＝10.8Hz,2H),1.15–1.06(m,4H).
Example 26: n- (2-chloro-4- (((tetrahydro-2H-pyran-4-yl) amino) methyl) phenyl) -7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-amine
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and ethanolamine is replaced by 4-aminotetrahydropyran. Finally, 55mg of a white solid was obtained in a yield of 45.8%. HRMS (ESI) for C 27 H 26 ClN 3 O 3 S[M－H] － :calcd,506.1311；found,506.1301； 1 HNMR(600MHz,DMSO-d6)δ9.02–8.99(s,1H),8.34–8.29(d,J＝8.0Hz,1H),7.91–7.87(d,J＝8.2Hz,1H),7.71–7.66(d,J＝7.2Hz,1H),7.63–7.57(t,J＝7.6Hz,1H),7.55–7.51(d,J＝2.0Hz,1H),7.36–7.31(dd,J＝1.9,8.3Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.34–4.29(s,4H),3.86–3.80(dt,J＝3.7,11.6Hz,2H),3.77–3.74(s,2H),3.29–3.24(t,J＝11.0Hz,2H),2.65–2.59(p,1H),1.82–1.76(d,J＝12.1Hz,2H),1.33–1.25(qd,J＝4.2,11.1Hz,2H).
Example 27:2- ((3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) (methyl) amino) ethan-1-ol
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde is used as a raw material, and ethanolamine is replaced by 2-methylamino ethanol. 23mg of a white solid was finally obtained in a yield of 20.2%. HRMS (ESI) for C 25 H 24 ClN 3 O 3 S[M+H] + :calcd,482.1300；found,482.1324； 1 HNMR(600MHz,DMSO-d6)δ9.02–8.99(s,1H),8.34–8.30(d,J＝8.0Hz,1H),7.95–7.91(d,J＝8.2Hz,1H),7.71–7.67(d,J＝7.2Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.50–7.47(d,J＝1.9Hz,1H),7.33–7.28(dd,J＝1.9,8.2Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.48–4.43(s,1H),4.34–4.30(s,4H),3.56–3.50(m,4H),2.49–2.44(t,J＝6.4Hz,2H),2.21–2.18(s,3H).
Example 28:1- (3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) piperidin-4-ol
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and ethanolamine is replaced by 4-hydroxypiperidine. 25mg of a pale yellow solid was finally obtained in a yield of 20.8%. HRMS (ESI) for C 27 H 26 ClN 3 O 3 S[M+H] + :calcd,508.1456；found,508.1475； 1 HNMR(600MHz,DMSO-d6)δ9.03–9.00(s,1H),8.34–8.30(d,J＝8.0Hz,1H),7.94–7.90(d,J＝8.2Hz,1H),7.71–7.67(d,J＝7.2Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.45–7.42(d,J＝1.9Hz,1H),7.31–7.26(dd,J＝1.9,8.2Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.60–4.52(s,1H),4.34–4.31(s,4H),3.50–3.42(m,3H),2.71–2.66(t,J＝5.3,6.0Hz,2H),2.12–2.04(t,J＝11.0Hz,2H),1.75–1.68(dd,J＝6.9,16.3Hz,2H),1.44–1.38(dd,J＝7.6,17.5Hz,2H).
Example 29: (R) -3- ((3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) propane-1,2-diol
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde is used as a raw material, and ethanolamine is replaced by (R) -3-amino-1,2-propylene glycol. Finally, 52mg of a white solid was obtained in 44.1% yield. HRMS (ESI) for C 25 H 24 ClN 3 O 4 S[M－H] － :calcd,496.1103；found,496.1105； 1 HNMR(600MHz,DMSO-d6)δ9.03–9.00(s,1H),8.34–8.30(d,J＝8.0Hz,1H),7.92–7.88(d,J＝8.2Hz,1H),7.71–7.66(d,J＝7.2Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.53–7.50(d,J＝1.6Hz,1H),7.35–7.30(dd,J＝1.7,8.4Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.71–4.51(s,1H),4.33–4.30(s,4H),3.75–3.71(s,2H),3.61–3.55(p,J＝5.5Hz,1H),3.36–3.33(m,2H),2.64–2.59(dd,J＝4.5,11.7Hz,1H),2.48–2.44(dd,J＝7.2,11.8Hz,1H).
Example 30: (S) -3- ((3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) propane-1,2-diol
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde is used as a raw material, and ethanolamine is replaced by (S) -3-amino-1,2-propylene glycol. Finally, 55mg of a white solid was obtained in a yield of 46.7%. HRMS (ESI) for C 25 H 24 ClN 3 O 4 S[M+H] + :calcd,498.1249；found,498.1273； 1 HNMR(600MHz,DMSO-d6)δ9.04–9.01(s,1H),8.34–8.30(d,J＝8.0Hz,1H),7.95–7.89(d,J＝8.2Hz,1H),7.71–7.66(d,J＝7.2Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.53–7.50(d,J＝1.8Hz,1H),7.35–7.30(dd,J＝1.8,8.3Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.73–4.55(s,1H),4.34–4.31(s,4H),3.76–3.73(s,2H),3.61–3.56(p,J＝5.4Hz,1H),3.37–3.33(m,2H),2.65–2.60(dd,J＝4.4,11.8Hz,1H),2.49–2.44(dd,J＝7.2,11.7Hz,1H).
Example 31: n- (2-chloro-4- ((oxetan-3-ylamino) methyl) phenyl) -7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-amine
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and ethanolamine is replaced by 3-oxetane. 53mg of a white solid is obtained in 46.7% yield. HRMS (ESI) for C 25 H 22 ClN 3 O 3 S[M+H] + :calcd,480.1143；found,480.1164； 1 HNMR(600MHz,DMSO-d6)δ9.03–9.00(s,1H),8.34–8.29(d,J＝8.0Hz,1H),7.92–7.88(d,J＝8.2Hz,1H),7.71–7.66(d,J＝7.2Hz,1H),7.63–7.56(t,J＝7.7Hz,1H),7.51–7.47(d,J＝2.0Hz,1H),7.32–7.28(dd,J＝2.0,8.3Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.60–4.55(t,J＝6.5Hz,2H),4.34–4.29(m,6H),3.92–3.85(p,J＝6.7Hz,1H),3.66–3.60(s,2H).
Example 32:2- ((3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) propane-1,3-diol
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde is used as a raw material, and ethanolamine is replaced by 2-amino-1,3-propylene glycol. The final yield was 61mg of white solid, 51.8%. HRMS (ESI) for C 25 H 24 ClN 3 O 4 S[M－H] － :calcd,496.1103；found,496.1123； 1 HNMR(600MHz,DMSO-d6)δ9.03–9.00(s,1H),8.34–8.30(d,J＝8.0Hz,1H),7.92–7.88(d,J＝8.2Hz,1H),7.71–7.66(d,J＝7.2Hz,1H),7.63–7.57(t,J＝7.6Hz,1H),7.56–7.52(d,J＝2.0Hz,1H),7.37–7.32(dd,J＝2.0,8.3Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.55–4.40(s,2H),4.36–4.28(s,4H),3.81–3.78(s,2H),3.49–3.42(dd,J＝5.6,10.9Hz,2H),3.42–3.36(dd,J＝5.4,10.8Hz,2H),2.61–2.55(p,J＝5.6Hz,1H).
Example 33: n- (2-chloro-4- (((2- (4-methylpiperazin-1-yl) ethyl) amino) methyl) phenyl) -7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-amine
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde is used as a raw material, and ethanolamine is replaced by 4-methyl-1-piperazineethanolamine. Finally 57mg of a white solid are obtained, yield 43.8%. HRMS (ESI) for C 29 H 32 ClN 5 O 2 S[M+H] + :calcd,550.2038；found,550.2051； 1 HNMR(600MHz,DMSO-d6)δ9.04–9.01(s,1H),8.34–8.30(dd,J＝1.0,8.1Hz,1H),7.92–7.88(d,J＝8.2Hz,1H),7.71–7.66(dd,J＝1.0,7.3Hz,1H),7.63–7.57(t,J＝7.6Hz,1H),7.51–7.48(d,J＝1.9Hz,1H),7.33–7.28(dd,J＝1.9,8.2Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.33–4.30(s,4H),3.75–3.69(s,2H),2.61–2.56(t,J＝6.5Hz,2H),2.40–2.38(t,J＝6.5Hz,2H),2.42–2.22(s,8H),2.15–2.12(s,3H).
Example 34: n- (2-chloro-4- (((2-morpholinoethyl) amino) methyl) phenyl) -7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-amine
With reference to the synthesis of example 15, 3-chloro-4- ((7- (2,3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde is used as a raw material, and ethanolamine is replaced by 4- (2-aminoethyl) morpholine. 44mg of a pale yellow oily substance was finally obtained in a yield of 34.6%. HRMS (ESI) for C 28 H 29 ClN 4 O 3 S[M+H] + :calcd,537.1722；found,537.1706； 1 HNMR(600MHz,DMSO-d6)δ9.03–9.00(s,1H),8.34–8.29(dd,J＝1.0,8.1Hz,1H),7.92–7.88(d,J＝8.2Hz,1H),7.71–7.66(dd,J＝1.0,7.3Hz,1H),7.63–7.57(t,J＝7.2,7.8Hz,1H),7.52–7.48(d,J＝1.9Hz,1H),7.33–7.28(dd,J＝1.9,8.3Hz,1H),7.23–7.17(m,2H),7.07–7.02(d,J＝8.1Hz,1H),4.33–4.30(s,4H),3.73–3.70(s,2H),3.58–3.54(t,J＝4.6Hz,4H),2.63–2.57(t,J＝6.5Hz,2H),2.42–2.38(t,J＝6.5Hz,2H),2.37–2.30(t,J＝4.4Hz,4H).
Example 35: (3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ D ] isothiazol-3-yl) amino) benzyl) -D-serine ethyl ester
Reacting 3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde (150mg, 0.35mmol) was dissolved in THF, and D-serine ethyl ester hydrochloride (301mg, 1.77mmol) and triethylamine (247ul, 1.77mmol) were added and the reaction stirred at 50 ℃ for 5h. An appropriate amount of saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, dissolution of the residue in THF, addition of NaBH 3 CN (111mg, 1.77mmol) and a drop of glacial acetic acid were stirred for 6h at RT. After completion of the reaction, a saturated sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, separation and purification by preparative thin layer chromatography (volume ratio of dichloromethane to methanol 35:1) 89mg of a white solid was obtained in a yield of 46.5%. HRMS (ESI) for C 27 H 26 ClN 3 O 5 S[M+H] + :calcd,540.1354；found,540.1346； 1 HNMR(600MHz,DMSO-d6)δ9.04–9.01(s,1H),8.34–8.30(d,J＝8.0Hz,1H),7.93–7.88(d,J＝8.2Hz,1H),7.71–7.66(d,J＝7.2Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.52–7.48(d,J＝2.0Hz,1H),7.33–7.28(dd,J＝2.0,8.2Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.88–4.83(t,J＝5.8Hz,1H),4.33–4.31(s,4H),4.14–4.08(qd,J＝2.2,7.1Hz,2H),3.82–3.77(d,J＝13.7Hz,1H),3.66–3.62(d,J＝13.8Hz,1H),3.62–3.58(t,J＝5.5Hz,2H),3.29–3.24(t,J＝5.2Hz,1H),1.23–1.20(t,J＝7.1Hz,3H).
Example 36: (3-chloro-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ D ] isothiazol-3-yl) amino) benzyl) -D-serine
Mixing (3-chloro-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzyl) -D-serine ethyl ester (60mg, 0.11mmol) was dissolved in THF/MeOH/H 2 To O (2/1/1), liOH (27mg, 1.11mmol) was added, and the reaction was stirred at room temperature for 5 hours. After the reaction was complete, the solvent was distilled off under reduced pressure, and the residue was dissolved in THF/H 2 O (2/1). The pH of the solution was adjusted to 7 with 1Mol/LHCl solution, filtered to give a white gummy material, which was infrared dried to give 47mg of a pale yellow solid in 82.6% yield. HRMS (ESI) for C 25 H 22 ClN 3 O 5 S[M+H] + :calcd,512.1041；found,512.1056； 1 HNMR(600MHz,DMSO-d6)δ9.07–9.04(s,1H),8.34–8.29(dd,J＝1.0,8.2Hz,1H),8.01–7.96(d,J＝8.3Hz,1H),7.71–7.67(dd,J＝0.9,7.3Hz,1H),7.64–7.58(m,2H),7.43–7.38(dd,J＝2.0,8.3Hz,1H),7.22–7.18(m,2H),7.08–7.01(d,J＝8.1Hz,1H),4.33–4.31(s,4H),4.01–3.96(d,J＝13.5Hz,1H),3.93–3.88(d,J＝13.5Hz,1H),3.72–3.68(dd,J＝4.7,11.1Hz,1H),3.67–3.63(dd,J＝6.1,11.1Hz,1H),3.22–3.17(t,J＝5.4Hz,1H).
Example 37:2- ((3-bromo-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol
Step 1: 3-bromo-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzaldehyde
Reacting 7- (2,3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-amine (2.00g, 7.03mmol), 3,4-dibromobenzaldehyde (1.95g, 7.39mmol), pd (OAc) 2 (79mg, 0.35mmol), xant-phos (407mg, 0.70mmol) and Cs 2 CO 3 (4.60g, 14.07mmol) was placed in a reaction flask and an appropriate amount of anhydrous dioxane was added as solvent. And reacting at 80 ℃ for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction was diluted with THF, filtered off with suction, and the filter cake was washed with THF. The THF organic layers were combined, the solvent was removed by distillation under the reduced pressure, and the mixture was purified by beating with ethyl acetate to obtain 3.03g of a yellow solid in a yield of 92.2%.
Step 2:2- ((3-bromo-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) ethan-1-ol (example 37)
Reacting 3-bromo-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde (100mg, 0.21mmol) was dissolved in THF, then ethanolamine (65ul, 1.07mmol) was added and the reaction stirred at 50 ℃ for 2h. Cooling the reaction solution to room temperature, and adding NaBH 3 CN (67mg, 1.07mmol) and a drop of glacial acetic acid were stirred at RT for 6h. After the reaction was completed, a saturated sodium hydrogencarbonate solution was added thereto, and extraction was performed with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. After suction filtration and removal of the solvent by distillation under the reduced pressure, the residue was separated and purified by preparative thin layer chromatography (volume ratio of dichloromethane to methanol: 7.5: 1) to obtain 62mg of a white solid in a yield of 56.6%. HRMS (ESI) for C 24 H 22 BrN 3 O 3 S[M+H] + :calcd,512.0638；found,512.0634； 1 HNMR(600MHz,DMSO-d6)δ9.00–8.97(s,1H),8.31–8.27(dd,J＝1.0,8.1Hz,1H),7.87–7.82(d,J＝8.1Hz,1H),7.71–7.66(m,2H),7.63–7.58(t,J＝7.6Hz,1H),7.39–7.35(dd,J＝1.9,8.2Hz,1H),7.23–7.17(m,2H),7.07–7.02(d,J＝8.1Hz,1H),4.60–4.48(s,1H),4.33–4.30(s,4H),3.76–3.73(s,2H),3.52–3.47(t,J＝5.8Hz,2H),2.63–2.58(t,J＝5.8Hz,2H).
Example 38:2- ((3-bromo-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) propane-1,3-diol
Referring to the synthesis of example 37, 3-bromo-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde is used as a raw material, and ethanolamine is replaced by 2-amino-1,3-propylene glycol. 56mg of a white solid are finally obtained in a yield of 48.2%. HRMS (ESI) for C 25 H 24 BrN 3 O 4 S[M+H] + :calcd,542.0744；found,542.0720； 1 HNMR(600MHz,DMSO-d6)δ8.99–8.96(s,1H),8.31–8.27(dd,J＝1.0,8.1Hz,1H),7.86–7.82(d,J＝8.2Hz,1H),7.72–7.69(d,J＝1.9Hz,1H),7.69–7.66(dd,J＝1.0,7.3Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.41–7.36(dd,J＝1.9,8.3Hz,1H),7.23–7.17(m,2H),7.07–7.02(d,J＝8.1Hz,1H),4.51–4.42(s,2H),4.33–4.31(s,4H),3.81–3.78(s,2H),3.47–3.36(m,4H),2.61–2.54(p,J＝5.6Hz,1H).
Example 39: (R) -3- ((3-bromo-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) amino) propane-1,2-diol
With reference to the synthesis of example 37, 3-bromo-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde is used as a raw material, and ethanolamine is replaced by (R) -3-amino-1,2-propylene glycol.53mg of a white solid was obtained in a yield of 45.7%. HRMS (ESI) for C 25 H 24 BrN 3 O 4 S[M+H] + :calcd,542.0744；found,542.0723； 1 HNMR(600MHz,DMSO-d6)δ8.99–8.96(s,1H),8.31–8.26(dd,J＝0.9,8.1Hz,1H),7.87–7.82(d,J＝8.2Hz,1H),7.71–7.66(m,2H),7.63–7.58(t,J＝7.6Hz,1H),7.39–7.34(dd,J＝1.9,8.2Hz,1H),7.23–7.17(m,2H),7.07–7.02(d,J＝8.1Hz,1H),4.67–4.55(s,1H),4.33–4.31(s,4H),3.75–3.72(s,2H),3.60–3.55(p,J＝5.8Hz,1H),3.36–3.33(m,2H),2.63–2.59(dd,J＝4.5,11.8Hz,1H),2.48–2.44(dd,J＝7.2,11.8Hz,1H).
Example 40: (3-bromo-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ D ] isothiazol-3-yl) amino) benzyl) -D-serine ethyl ester
Reacting 3-bromo-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde (150mg, 0.32mmol) was dissolved in THF, then D-serine ethyl ester hydrochloride (273mg, 1.61mmol) and triethylamine (224ul, 1.61mmol) were added and the reaction stirred at 50 ℃ for 5h. An appropriate amount of saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure distillation to remove the solvent, dissolution of the residue in THF, addition of NaBH 3 CN (101mg, 1.61mmol) and a drop of glacial acetic acid were stirred at room temperature for 6h. After completion of the reaction, a saturated sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate. Suction filtration and reduced pressure distillation were performed to remove the solvent, and separation and purification were performed by preparative thin layer chromatography (dichloromethane: methanol volume ratio 20. HRMS (ESI) for C 27 H 26 BrN 3 O 5 S[M+H] + :calcd,584.0849；found,584.0823； 1 HNMR(600MHz,DMSO-d6)δ8.99–8.96(s,1H),8.31–8.27(dd,J＝1.0,8.1Hz,1H),7.86–7.82(d,J＝8.2Hz,1H),7.70–7.67(dd,J＝0.9,7.3Hz,1H),7.67–7.65(d,J＝1.9Hz,1H),7.63–7.58(t,J＝7.6Hz,1H),7.37–7.33(dd,J＝1.9,8.3Hz,1H),7.23–7.18(m,2H),7.07–7.02(d,J＝8.1Hz,1H),4.88–4.83(t,J＝5.8Hz,1H),4.33–4.30(s,4H),4.14–4.08(qd,J＝2.5,7.1Hz,2H),3.82–3.77(d,J＝13.8Hz,1H),3.66–3.62(d,J＝13.8Hz,1H),3.62–3.58(t,J＝5.6Hz,2H),3.29–3.24(t,J＝5.2Hz,1H),1.23–1.20(t,J＝7.1Hz,3H).
Example 41: (3-bromo-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ D ] isothiazol-3-yl) amino) benzyl) -D-serine
Mixing (3-bromo-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzyl) -D-serine ethyl ester (60mg, 0.10mmol) was dissolved in THF/MeOH/H 2 To O (2/1/1), liOH (25mg, 1.04mmol) was added, and the reaction was stirred at room temperature for 5 hours. After the reaction was complete, the solvent was distilled off under reduced pressure, and the residue was dissolved in THF/H 2 O (2/1). The pH of the solution was adjusted to 7 with 1Mol/LHCl solution, filtered to give a white gummy material, which was infrared dried to give 45mg of a pale yellow solid in 78.8% yield. HRMS (ESI) for C 25 H 22 BrN 3 O 5 S[M+H] + :calcd,556.0536；found,556.0518； 1 HNMR(600MHz,DMSO-d6)δ9.02–8.99(s,1H),8.31–8.26(dd,J＝1.0,8.2Hz,1H),7.95–7.91(d,J＝8.2Hz,1H),7.82–7.78(d,J＝1.9Hz,1H),7.71–7.67(dd,J＝1.0,7.3Hz,1H),7.64–7.58(t,J＝7.6Hz,1H),7.47–7.42(dd,J＝1.9,8.3Hz,1H),7.23–7.18(m,2H),7.07–7.03(d,J＝8.0Hz,1H),4.33–4.30(s,4H),4.03–3.97(d,J＝13.4Hz,1H),3.94–3.89(d,J＝13.4Hz,1H),3.75–3.69(dd,J＝4.6,11.2Hz,1H),3.69–3.63(dd,J＝6.0,11.1Hz,1H),3.25–3.20(t,J＝5.3Hz,1H).
Example 42: (3-bromo-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) -L-serine ethyl ester
With reference to the synthesis of example 40, 3-bromo-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzaldehyde as a raw material, and replacing D-serine ethyl ester hydrochloride with L-serine ethyl ester hydrochloride. The final product was 87mg of a white solid in 46.4% yield. HRMS (ESI) for C 27 H 26 BrN 3 O 5 S[M+H] + :calcd,584.0849；found,584.0831； 1 HNMR(600MHz,DMSO-d6)δ8.99–8.96(s,1H),8.31–8.26(dd,J＝1.0,8.1Hz,1H),7.87–7.82(d,J＝8.2Hz,1H),7.70–7.68(dd,J＝1.0,7.3Hz,1H),7.68–7.65(d,J＝1.9Hz,1H),7.62–7.58(t,J＝7.6Hz,1H),7.37–7.33(dd,J＝1.9,8.2Hz,1H),7.23–7.18(m,2H),7.07–7.02(d,J＝8.2Hz,1H),4.87–4.83(t,J＝5.9Hz,1H),4.34–4.30(s,4H),4.13–4.08(qd,J＝2.4,7.1Hz,2H),3.82–3.77(d,J＝13.8Hz,1H),3.66–3.62(d,J＝13.8Hz,1H),3.62–3.59(t,J＝5.6Hz,2H),3.29–3.24(t,J＝5.2Hz,1H),1.23–1.20(t,J＝7.1Hz,3H).
Example 43: (3-bromo-4- ((7- (2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzo [ d ] isothiazol-3-yl) amino) benzyl) -L-serine
With reference to the synthesis of example 41, to (3-bromo-4- ((7- (2,3-dihydrobenzo [ b)][1,4]Dioxin-6-yl) benzo [ d]Isothiazol-3-yl) amino) benzyl) -L-serine ethyl ester raw material is subjected to hydrolysis reaction with lithium hydroxide to finally obtain 47mg of light yellow solid, wherein the yield is 82.3%. HRMS (ESI) for C 25 H 22 BrN 3 O 5 S[M+H] + :calcd,556.0536；found,556.0524； 1 HNMR(600MHz,DMSO-d6)δ9.02–8.99(s,1H),8.31–8.26(d,J＝8.0Hz,1H),7.95–7.90(d,J＝8.2Hz,1H),7.80–7.77(s,1H),7.71–7.67(d,J＝7.3Hz,1H),7.64–7.58(t,J＝7.7Hz,1H),7.47–7.42(d,J＝8.3Hz,1H),7.22–7.18(m,2H),7.07–7.03(d,J＝8.1Hz,1H),4.34–4.29(s,4H),4.02–3.96(d,J＝13.3Hz,1H),3.93–3.87(d,J＝13.4Hz,1H),3.73–3.68(dd,J＝4.7,11.1Hz,1H),3.68–3.62(dd,J＝6.0,11.3Hz,1H),3.22–3.18(t,J＝5.4Hz,1H).
Evaluation of biological Activity of the Compounds of the present invention:
the ability of the compounds of the invention to inhibit the PD-1/PD-L1 protein-protein interaction was determined by the homogeneous time-resolved fluorescence (HTRF) technique.
The detection kit is purchased from Cisbio company (CAT #64ICP01 PEG), and comprises Tag1-PD-L1, tag2-PD-1 and anti-Tag 1-Eu 3+ anti-Tag 2-XL665, diluent and detection buffer.
The experimental principle is as follows: anti-Tag 1-Eu 3+ As HTRF donor, anti-Tag 2-XL665 as HTRF acceptor, which causes anti-Tag 1-Eu when Tag1-PD-L1 and Tag2-PD-1 interact with each other 3+ And anti-Tag 2-XL 665. When the donor is excited by energy, part of the energy is transferred to the acceptor, thereby generating 665nm emission light. When the compound is added to block the PD-1/PD-L1 interaction, only 620nm of emitted light is generated. By comparing the magnitude of the ratio of 665nm signal/620 nm signal, the magnitude of the ability of a compound to inhibit the PD-1/PD-L1 interaction can be ultimately determined.
The experimental steps are as follows: the compound to be tested was diluted in a 3X gradient with diluent starting from the initial concentration and ending in 8 concentration gradients. Tag1-PD-L1 and Tag2-PD-1 were diluted with a diluent to working concentrations of 25nM and 250nM, respectively. anti-Tag 1-Eu 3+ The sample was diluted with a detection buffer of 1. Mu.l of the compound was added to a white 384-well plate, and 4. Mu.l of Tag1-PD-L1 and 4. Mu.l of Tag2-PD-1 were added, respectively, and incubated at room temperature for 15 minutes. Add 10. Mu.l of pre-mixed assay reagent and incubate for 2 hours at room temperature. By using
Detecting fluorescent signals at 665nm and 620nm by using a 500 multifunctional microplate reader to obtain HTRF rate = (signal)665 nm/signal 620 nm). Times.10 4 And calculating the inhibition rate of the compound on the protein combination according to the ratio of the fluorescence signals. Fitting of IC with PrismGraphd7.0 50 Curve line.
Activity Range or IC of Compounds for inhibiting PD-1/PD-L1 protein-protein interaction 50 As shown in table 1.
Wherein, A: IC (integrated circuit) 50 ≦100nM；B：100nM<IC 50 ≦1000nM；C：1000nM<IC 50 ≦10000nM。
Table 1: inhibitory Activity of the Compound of the present invention against PD-1/PD-L1 protein-protein interaction
HTRF test results indicate that the compounds of the invention (particularly, the compounds of the above examples) significantly inhibit PD-1/PD-L1 protein-protein interactions at the molecular level. Thus, the compounds of the present invention (in particular, the compounds of the above examples) have the potential to treat diseases associated with the PD-1/PD-L1 signaling pathway by inhibiting the PD-1/PD-L1 protein-protein interaction.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (10)
1. The benzisothiazole compound shown in the general formula I or pharmaceutically acceptable salt thereof is characterized in that:
wherein,
ring A is selected from unsubstituted or substituted by 1-3R 1 A substituted phenyl group, which is substituted,
R 1 independently selected from halogen, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, cyano, hydroxy, carboxy or amino;
ring B is selected from:
wherein, Y 1 、Y 2 、Y 3 And Y 4 Independently CH or N;
R 2 and R 3 Each independently selected from hydrogen, (C) 1 -C 4 ) Alkyl, methoxy (C) 1 -C 4 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, hydroxy (C) 1 -C 4 ) Alkyl, amino (C) 1 -C 4 ) Alkyl, carbamoyl (C) 1 -C 4 ) Alkyl, carboxyl (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxycarbonyl (C) 1 -C 4 ) Alkyl, tetrahydropyran-4-yl, oxetan-3-yl, morpholin-4- (C) 1 -C 4 ) Alkyl or N-methylpiperazine-4- (C) 1 -C 4 ) An alkyl group;
said (C) 1 -C 4 ) Alkyl, methoxy (C) 1 -C 4 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, hydroxy (C) 1 -C 4 ) Alkyl, amino (C) 1 -C 4 ) Alkyl, carbamoyl (C) 1 -C 4 ) Alkyl, carboxyl (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxycarbonyl (C) 1 -C 4 ) Alkyl, tetrahydropyran-4-yl, oxetan-3-yl, morpholin-4- (C) 1 -C 4 ) Alkyl, N-methylpiperazine-4- (C) 1 -C 4 ) Alkyl is optionally substituted with 1-3R 8 Substitution;
R 4 、R 5 、R 6 and R 7 Each independently selected from hydrogen, halogen, hydroxyl and (C) 1 -C 4 ) Alkyl or (C) 1 -C 4 ) An alkoxy group;
R 8 independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C) 1 -C 4 ) Alkyl, hydroxy (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy (C) 1 -C 4 ) Alkyl, carboxyl (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxycarbonyl (C) 1 -C 4 ) Alkyl or (C) 1 -C 4 ) An acyl group.
2. The benzisothiazole compound shown in the general formula i or the pharmaceutically acceptable salt thereof according to claim 1, wherein:
wherein,
ring A is selected from phenyl which is unsubstituted or substituted by 1 to 3 halogen, methyl or methoxy groups,
3. the benzisothiazole compound represented by the general formula i or the pharmaceutically acceptable salt thereof according to claim 1 or claim 2, wherein:
wherein,
ring B is selected from
Y 1 、Y 2 、Y 3 And Y 4 Each independently selected from CH or N;
R 4 、R 5 、R 6 and R 7 Each independently selected from hydrogen, halogen, hydroxy, methyl or methoxy.
4. The benzisothiazole compound of the general formula i according to claim 1, wherein the pharmaceutically acceptable salt thereof is:
wherein,
selected from:
5. the benzisothiazole compound shown in the general formula i or the pharmaceutically acceptable salt thereof according to claim 1, wherein: the benzisothiazole compound shown in the general formula I is selected from the following compounds:
6. a pharmaceutical composition characterized by: the pharmaceutical composition comprises a therapeutically effective amount of an active component and pharmaceutically acceptable excipients; the active component comprises the benzisothiazole compound shown in the general formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.
7. The use of the benzisothiazole compound represented by the general formula i or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 6 for the preparation of a PD-1/PD-L1 protein-protein interaction inhibitor.
8. Use of the benzisothiazole compound of the general formula i according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 6 for the preparation of a medicament for the treatment of a disease associated with the PD-1/PD-L1 signaling pathway.
9. Use according to claim 8, characterized in that: the disease related to the PD-1/PD-L1 signal pathway is selected from cancer, autoimmune disease or infectious disease.
10. Use according to claim 9, characterized in that: the cancer is selected from lung cancer, skin cancer, hematological tumor, glioma, digestive system tumor, breast cancer, lymphoma, nervous system tumor, melanoma; the autoimmune disease is selected from organ-specific or autoimmune disease or systemic autoimmune disease; the infectious disease is selected from bacterial infection or virus infection, wherein the organ-specific autoimmune disease is selected from chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, ulcerative colitis or acute idiopathic polyneuritis, and the systemic autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis or autoimmune hemolytic anemia.
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